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New Study in JCFS



New Study on Adrenal Dysfunction in Journal of Chronic Fatigue Syndrome
A review just published in the Journal of Chronic Fatigue Syndrome, a major journal for the specialty treatment of CFS and FM

Diagnosis and Treatment of Hypothalamic-Pituitary-Adrenal (HPA) Axis Dysfunction in Patients with Chronic Fatigue Syndrome (CFS) and Fibromyalgia (FM). Journal of Chronic Fatigue Syndrome. 2008, 14(3):1-14.

Kent Holtorf, MD

KEY POINTS

  • 500 patient study demonstrated that a multi-system treatment protocol that addresses the known physiologic abnormalities in CFS and fibromyalgia resulted in:
    • 94 percent of patients had overall improvement by the 4th visit.
    • 75 percent noted significant overall improvement.
    • 62 percent reported substantial overall improvement.
    • The average energy level and sense of well-being for patients doubled by the fourth visit.
  • The effectiveness of this multi-system treatment was further confirmed through the analysis of the cumulative findings of over 40 independent physicians and over 5,000 patients.
  • Prior to treatment at the Holtorf Medical Group, Inc, the patients had seen an average of 7.2 different physicians for the treatment of CFS and/or FM without significant improvement.
  • There is controversy regarding the incidence and significance of adrenal dysfunction in chronic fatigue syndrome (CFS) and fibromyalgia (FM) as well as the effectiveness and appropriateness of such treatment.
  • Analysis of the data in over 50 studies that assessed adrenal function in CFS and FM patients demonstrates that the majority of CFS and FM patients have abnormal adrenal function due to hypothalamic-pituitary dysfunction.
  • It was also shown that the majority of patients should be treated for this adrenal dysfunction since many of the standard tests do not pick up this particular type of adrenal dysfunction. The data shows that such treatment is safer and more effective than commonly used treatments such as antidepressants.
  • While these conditions are similar, the abnormality in CFS is in the pituitary while the FM patients have abnormalities of the hypothalamus.
  • This review provides a new understanding that treating the known causes of illness in CFS and FM can improve the symptoms and quality-of-life of patients who suffer from these conditions.
  • Download the Complete Study (.PDF)



The Doctors



The doctors at Holtorf Medical Group, Inc. are sought after experts and pioneers in the field of chronic fatigue syndrome and fibromyalgia. their extensive experience and knowledge is evidenced by the over 3000 fibromyalgia and chronic fatigue patients they has successfully treated with unprecedented results. The medical practice focuses on these conditions as well as hypothyroidism, complex endocrine disorders and chronic infectious diseases, including Lyme disease. Dr. Holtorf has trained physicians across the country on effective and innovative treatments of CFS/FM and was the founding medical director and developed the protocols for the Fibromyalgia and Fatigue Centers.

“Mainstream” medicine is doing a very poor job at treating these diseases because standard laboratory test are usually normal, there is no simple treatment that works for all patients and they cannot be cured in the eight minute standard visit. Consequentially, millions of patients with chronic fatigue syndrome and fibromyalgia have gone without comprehensive treatments and have had to suffer for years with a poor quality of life. Even though these are complex diseases, the physiological causes underlying these conditions can usually be uncovered with specialty testing and then multi-faceted treatment protocols that address the numerous physiologic dysfunctions are successful. The doctors are committed to reversing these devastating illnesses.

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Call Now to Enroll in a Fibromyalgia Study

The study product is free of charge. You don’t have to be a patient to enroll (product is shipped), and there is no obligation other than accurately reporting your response

Study Name: THE ROLE OF D-RIBOSE IN PATIENTS DIAGNOSED WITH FIBROMYALGIA

ENROLLMENT CRITERIA

INCLUSION:

  • Adults between 18-78 years of age
  • Previous diagnosis of fibromyalgia by a physician, (ACR guidelines)
  • Completion a questionnaire for major and minor diagnostic criteria for CFS/Fibromyalgia symptoms and whether a diagnosis of CFS exists
  • Signed informed consent form

INTRODUCTION
Fibromyalgia is a chronic pain syndrome, which has been described in the literature for over 200 years. It is believed that fibromyalgia may affect millions of individuals in the United States alone. Fibromyalgia, as defined by the American College of Rheumatology, includes: diffused widespread pain, presence of multiple tender points, sleep disturbances, fatigue, reduced exercise tolerance, and irritable bowel syndrome.

Previous research involving muscle biopsies of tender points/sites, analyzed for high-energy phosphate levels, mainly adenosine triphosphate (ATP), revealed decreased energy compounds, suggesting a metabolic abnormality². Therefore, some have argued that by replenishing these decreased energy levels, symptoms may be lessened or alleviated. D-ribose, a naturally occurring pentose sugar, aids in the formation of adenine nucleotides, via an intermediate compound called phosphoribosyl-1-pyrophosphate (PRPP), which is essential for de novo synthesis and salvage of nucleotides 5.

Since the majority of fibromyalgia patients complain of chronic fatigue and with the possibility that reduced ATP levels are present at points of tenderness, supplementation of D-ribose may offer a clinical benefit in lessening or relieving symptoms to improve ones quality of life.

OBJECTIVES
The goal of this study is to determine the potential benefit of D-ribose versus placebo in patients afflicted with the diagnosis of fibromyalgia. Endpoints of this study will assess levels of relief in symptoms of fatigue and pain, as well as potential benefits in their quality of life, assessed by questionnaires.

Summary of Objectives:

  • Demonstrate a significant reduction in the symptoms of pain and fatigue
  • Demonstrate an improvement in ones quality of life

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Definition of Chronic Fatigue Syndrome

1.Clinically evaluated, unexplained, persistent, or relapsing chronic fatigue that is of new or definite onset (has not been lifelong): is not the result of ongoing exertion; is not substantially alleviated by rest; and results in substantial reduction in previous levels of occupational, educational, social, or personal activities.

2. Concurrent occurrence of four or more of the following symptoms, all of which must have persisted or recurred during six or more consecutive months of illness and must not have predated the fatigue:

A. Self-reported impairment in short term memory
B. Sore throat
C. Tender cervical or axillary lymph nodes
D. Muscle pain
E. Multijoint pain without joint swelling or redness
F. Headaches of a new type, pattern, or severity
G. Non refreshing sleep
H. Postexertional malaise lasting more that twenty-four hours

Problem with the definition is that it is a research definition and excludes many people with the syndrome.

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Fibromyalgia Definition

A history of widespread pain. The patient must be experiencing pain or achiness, steady or intermittent, for at least 3 months. At times, the pain must have been present:

A. On both sides of the body
B. Both above and below the waist
C. In the Mid-body-for example, in the neck, midchest, midback, or headache.
D. Pain on at least eleven of the eighteen tender points

Problem with the definition is that it is a research definition and excludes many people with the syndrome. 

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Basic dysfunctions



Basic dysfunctions can be generalized to be characterized by:
  1. Disordered sleep
  2. Hormonal deficiencies (not picked up on standard blood tests)
  3. Nutritional deficiencies
  4. Infections
  5. Mitochondrial dysfunction

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Associated Conditions

  • Chronic Sinusitis
  • Multiple Chemical Sensitivity (MCS)
  • Sensitive to medications
  • Allergies
  • Sensitivity to temperature or barometric changes
  • Intolerant to alcohol
  • Hypoglycemia
  • Dizziness
  • Low blood pressure
  • Low grade fevers
  • Heart palpitations
  • Frequent infections
  • Irritable Bowel Syndrome
  • Vulvadynia
  • Headaches (migraine and tension)
  • Depression
  • Autoimmune diseases (lupus, RA)
  • Restless Leg Syndrome
  • Weight Gain
  • Increased thirst
  • Low body temp
  • Insulin resistance
  • Yeast overgrowth
  • Carpal tunnel syndrome
  • Painful or irregular menstrual periods
  • Extreme exhaustion
  • Sleep disturbances
  • Brian fog
  • Shortness of breath
  • Confusion with numbers, names, words etc.
  • Mood swings
  • Numbness or tingling

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Integrative Treatment of the COD



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Cycle of Dysfunction



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New Standard for the Treatment of Chronic Fatigue Syndrome and Fibromyalgia

Chronic fatigue syndrome and fibromyalgia are complex diseases that involve multi-system disturbances and abnormalities. Because of this complexity, these conditions have been poorly treated by the current medical system in this country.

These conditions do not lend themselves to be successfully treated with the eight to fifteen minute visits that address only a portion of the wide spectrum of underlying dysfunctions. Through a more detailed evaluation and specialized testing, all identifiable etiologies contributing to the symptomotology may be appropriately addressed, and when multifaceted treatment is instituted that addresses the entire spectrum of these diseases, truly remarkable success and total cures can be obtained.

In general, successful treatment can be viewed in components. Treatment needs to be individualized, components may occur in different order and multiple components are often addressed simultaneously, but these can be broken down as follows:

Component One:
Stabilize the Patient This is a component in which pain and sleep disturbances are addressed. This may include the use of sleep medications, pain medications and antidepressants. This is in general a temporary "stop gap" phase because as the treatment progresses and the underlying problems are addressed, the medications that "mask the symptoms" are no longer needed. Unfortunately, the overwhelming majority of patients are never brought past this stage by their doctors. This is because this component is the limit of training for most doctors, but it really should only be the first step.

Component Two:
Mitochondrial Enhancement This component is actually integrated throughout the treatment program and tapered as the patient returns to normal functioning. The mitochondria are the energy producers of the cells and are critical for normal functioning. But they are shown to be poisoned in these conditions, leaving the cells starving for energy. Many things can poison the mitochondria including hormonal deficiencies, toxins and infections. Mitochondria dysfunction may be the common denominator and underlying mechanism that explains the symptoms of CFIDS/FM. In addition to the treatments above to rid the body of the offending agents, specific nutrients can be given to jump start the mitochondria and get the body functioning again. These can also be administered orally or via an intravenous route.

Component Three:
Balance the Hormones There are a number of hormonal deficiencies with these conditions that must be addressed to assure successful treatment. Unfortunately, these hormonal deficiencies are often missed or poorly treated because doctors have come to rely on standard blood tests that require an intact pituitary and hypothalamus for diagnosis and dosing of hormone levels. There is, however, severe hypothalamic and pituitary dysfunction with these conditions, making the standard blood tests inadequate. Some typical hormones functions, not just levels, that need to be evaluated include thyroid function, growth hormone, testosterone, aldosterone, cortisol, DHEA, pregnenolone, estradiol, progesterone, among others. When they are properly treated and balanced, tremendous results can be achieved.

Component Four:
Treat the lnfectious Component There are multiple infections that either may be the cause of CFIDS/FM or contribute to the dysfunction. Because of the immune dysfunctions, there is often more than one infection that must be addressed. Potential pathogens include a variety of viruses such as Epstein Barr (EBV), Cytomegalovirus( CMV), Human Herpes Virus 6 (HHV6), Enteroviruses, such as Coxsackie, Echo, and Stealth virus. Bacterial infections include intracellular organisms such as mycoplasma, Chlamydia pneumonia, Borrelia burgdorferi (Lyme disease) and ehrlichia. A number of yeasts such as Candida and parasites must also be evaluated. Infections with many of the above organisms will also further suppress the immunity, often resulting in further infections with other organisms.

Thus, many organisms must be evaluated and treated along with an assessment and treatment of the immune system. If a poor immune system is not addressed, successful eradication of the organisms is not likely, even with the most potent treatments. Treatment may be administered with oral medications or via an intravenous route.

Component Five:
Address Unique Etiologies There are a number of problems that must be addressed in select patients. For instance, some individuals have a coagulation defect that is set off by a chronic infection. This results in the laying down of a fibrin coating on the lumen of the vessel causing impaired oxygen and nutrient transfer. This can result in fatigue, muscle aches and "brain fog". If suspected, diagnosis requires specialized testing. If not treated, not only are the cells starved for oxygen and nutrients, but it is very difficult to eradicate any infection because they will "hide" in the fibrin coating. Also, if the organism is one that produces neurotoxins, this must also be addressed. These substances can remain in the body and continue to cause symptoms long after the organism that produced them are gone. Special testing and protocols must be done to rid the body of these tiny toxins.

Component Six:
Maintenance Here is where the patient is weaned to just a few core medications and supplements to remain symptom free and maintain their health. Significant recovery or complete resolution of symptoms is the rule rather than the exception when a multifaceted treatment plan is instituted.

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Multi-faceted Treatment Approach is Best

Chronic fatigue syndrome (CFS) and fibromyalgia (FM) are illnesses that often coexists and affect millions of Americans. Symptoms vary amongst individuals and commonly include severe fatigue, sleep disturbances, cognitive problems, commonly called brain fog, muscle pain and multiple infections. Unfortunately, many individuals and physicians continue to deny that these syndromes are legitimate diseases. The medical literature is, however, very clear that these are legitimate diseases and individuals with these syndromes have measurable hypothalamic, pituitary, immune and coagulation dysfunction. These abnormalities then result in a cascade of further abnormalities, in which stress plays a role by suppressing immunity and hypothalamic-pituitary function. The pituitary and hypothalamic dysfunction results in multiple hormonal deficiencies that are often not detected with standard blood tests, as well as autonomic dysfunction, including neutrally mediated hypotension. The immune dysfunction, which includes natural killer cell dysfunction, results in opportunistic infections and yeast overgrowth, making the symptoms worse. Recent studies have shown that the coagulation dysfunction is usually initiated by a viral infection and has genetic predisposition. This abnormal coagulation results in increased blood viscosity (slugging) and a deposition of soluble fibrin monomers along the capillary wall. This results in tissue and cellular hypoxia, resulting in fatigue and decreased cognition (brain fog). Neurotransmitter abnormalities and macro and micro nutrient deficiencies have also been shown to occur with these disorders.

Current research suggests that many triggers can initiate a cascade of events, causing the hypothalamic, pituitary, immune and coagulation dysfunction. The most common initiating cause is a viral or bacterial infection, which is very commonly Epstein Bar Virus (EBV), Cytomegalovirus (CMV), HHV6, mycoplasma, Chlamydia pneumonia or Lyme’s disease. When specialized testing is utilized, these infections are found in 30-80% of CFS and FM patients. Many people with these syndromes can pinpoint the start of their disease to a viral infection that never got better usually during significant life stressors.

Effective treatment, with 70 to 90 percent of individuals achieving significant clinical benefits, can be achieved by simultaneously treating the above problems that an individual is found to have. The mix of treatments needed varies from patient to patients, but there is consistent abnormal pathophysiology. For instance, a high percentage of individuals with these syndromes have low thyroid. This is, however, usually not picked up on the standard blood tests because the TSH is not elevated in these individuals because of the pituitary dysfunction. Many of these individuals will also have high levels of the anti-thyroid reverse T3, which is usually not measured on standard blood tests. In addition, the majority of individuals can also have a thyroid receptor resistance that is not detected on the blood tests. Consequently, thyroid treatment, especially with timed release T3 is effective for many patients. T4 preparations (inactive thyroid) such as Synthroid and Levoxyl do not work well for these conditions. In addition, adrenal insufficiency and growth hormone deficiency are also very common with these disorders, and supplementation with these hormones can often have profound effects. As with thyroid testing, these deficiencies are, unfortunately, usually not detected with the standard screen blood tests and require more specific testing.

When an individual is found to have one of the viruses discussed above, these can be treated with resulting improvement in symptoms. It can require a combination of medications, supplements and sometimes intravenous treatments to eradicate some of the persistent infections.

Although a concept that is sometimes uncomfortable and foreign to traditional medical styles of thinking, the need for multiple interventions is required for effective treatment of an illness that affects a critical control center (such as the hypothalamus), which impacts the multiple systems noted above. Unfortunately, there is not a single treatment that reverses hypothalamic dysfunction directly. Thus, this situation is different from illnesses that affect a single target organ and which can be treated with a single intervention. For example, pituitary dysfunction itself often requires treatment with several hormones. This effect is multiplied in hypothalamic dysfunction, which affects several critical systems in addition to the pituitary gland. An integrated treatment approach based on simultaneously treating the above problems is significantly beneficial in CFS and FMS. Individuals with these devastating syndromes can “get their lives back” despite the fact that they were previously told, “There is nothing that can be done,” or “It is all in your head.”

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Fibromyalgia: The Diet Connection
Find out what experts say really matters about the foods you eat -- and why staying away from certain foods might help your fibromyalgia symptoms.
By Colette Bouchez
WebMD Feature
Reviewed by Matthew Hoffman, MD

The condition is called fibromyalgia. It consists of a complex array of symptoms that include widespread muscle and joint pain along with overwhelming fatigue. And none of it goes away, no matter how much rest you get.

Fibromyalgia affects up to 4% of the population -- mostly women. And there is still no known cause or recognized treatment that works for everyone. That's one reason, say experts, that so many people have turned to diet as a way to relieve some of the symptoms.

The fact is there's little scientific evidence to support any single eating plan as a way to deal with fibromyalgia. Nevertheless, a trip around the Internet will show that dietary approaches to fibromyalgia abound. The variety is so diverse it's hard to imagine they are all aimed at treating the same disease.

Eat more whole grains. Don't eat any whole grains. All fruit is good. Some fruit is bad. Tomatoes are healthy. Tomatoes are harmful. Sugar is bad. Sugar has no impact. Avoid meat. Eat. . . .

Confused? Don't be. Experts say diversity is another hallmark of fibromyalgia.

"This is because fibromyalgia is not a specific illness," says Michael McNett, MD. McNett directs the Fibromyalgia Treatment Centers of America, headquartered in Chicago. "Fibromyalgia is more like a symptom complex, and different people appear to have different reasons why they get this symptom complex," he says. "So what works for one person very frequently does not work for another."

And this, say experts, includes dietary measures.

Kent Holtorf, MD, is the medical director of the Holtorf Medical Group Center for Endocrine, Neurological and Infection Related Illness in Torrance, California. He says, "We're at the point now where we know diet plays a role in this disease -- it's just not the same diet for everybody. And not everybody is helped in the same way."

Fibromyalgia and diet: Can what you eat help you?

Rheumatology experts like Alex Shikhman, MD, believe the diversity of dietary approaches may have less to do with the impact on fibromyalgia, and more to do with treating a secondary, possibly undiagnosed illness. "When patients are helped by a specific dietary measure," says Shikhman, who is director and founder of the Institute for Specialized Medicine in San Diego, "it is often because of the presence of a secondary condition that does have a recognized response to diet. And when you take care of that, you do get some relief from all the symptoms. You feel better overall."

There are a number of co-existing health conditions that have a tendency to occur in people with fibromyalgia. Many of these have overlapping symptoms. These include gluten intolerance, gout (a form of arthritis), and restless legs syndrome. Some doctors believe food sensitivity itself could sometimes be responsible for some of the pain and fatigue of fibromyalgia.

Moreover, Holtorf points out that because each of these secondary conditions responds to a different dietary approach, it's not hard to understand why "different dietary recommendations are reported to work."

Shikhman believes that sometimes fibromyalgia may even be the wrong diagnosis. That's another reason, he says, we can sometimes see such dramatic and immediate response to so many different dietary measures.

"Sometimes, if you carefully note which foods a patient responds to," Shikhman says, "you can actually get a significant clue as to the true nature of their underlying health problems. And it might not always be fibromyalgia."

Fibromyalgia: Seven foods to avoid

While there may not be a single set of dietary guidelines that are right for all fibromyalgia patients, there are certain foods, or food groups, that appear to make a difference for a significant number of people. But remember, avoiding these foods is not a guarantee that your symptoms will change. Also, avoiding one group may offer benefit while another may make no difference at all. Nevertheless, the experts WebMD talked to agree that eliminating at least some of these foods is worth a try.

1. Aspartame (NutraSweet). All the experts WebMD talked to agree that for a large majority of people with fibromyalgia, foods sweetened with aspartame could exacerbate fibromyalgia symptoms.

"There is a pain receptor in the nervous system known as NMDA," says McNett. "When pain turns from acute to chronic, it involves opening the NMDA pain receptor. Aspartame, which is classified as an excitotoxin, helps to stimulate this event." He also says people with fibromyalgia appear to already have overly active NMDA pain receptors, making them more susceptible to the stimulation.

In one study published in the Journal of Rheumatology in 2006, experts found patients with fibromyalgia did have an increased expression of NMDA receptors in their skin. This indicated a general increase in activity of peripheral nerves.

Fibromyalgia: Seven foods to avoid continued...

Holtorf says aspartame may play a role in stimulating those nerve pathways. Then he adds that for some people, "cutting it out of their diet can have a dramatic impact on pain."

That appeared to be the case for patients in one small study published in the Annals of Pharmacotherapy in 2001. Researchers found that, when patients with fibromyalgia avoided aspartame as well as the flavor enhancer MSG, they felt better overall.

Other artificial sweeteners such as Splenda, saccharin, and stevia do not appear to have the same effect as aspartame.

2. Food additives including MSG (monosodium glutamine) and nitrates. MSG is an additive or flavor enhancer that's found in many processed and frozen foods and in some Asian cuisines. Experts say it can intensify pain symptoms in many individuals. Like aspartame, MSG is classified as an excitotoxin and has the same potential for affecting NMDA receptors.

The same is true, says McNett, for foods containing preservatives such as nitrates, commonly found in lunchmeats like ham or bologna or in bacon.

"A lot of people who don't have fibromyalgia can't tolerate nitrates or MSG very well. But one of the hallmarks of this condition is that it amplifies unpleasant reactions," McNett says. "So a stimulus that some people would find mildly unpleasant becomes very unpleasant in those who have fibromyalgia." Cutting these ingredients out of the diet, he adds, usually helps.

3. Sugar, fructose, and simple carbohydrates. There is no clear evidence that cutting out simple carbohydrates -- like sugar, cake, or white bread -- will have an impact on fibromyalgia. What it can do, though, is reduce symptoms of chronic yeast infection -- a fungus that thrives on sugars and may be a secondary condition contributing to the pain of fibromyalgia. This theory, however, is still being debated by experts.

"Cutting out sugary foods, particularly high fructose corn syrup, can make a difference in these patients," says Holtorf. "And that's independent of any weight loss that might occur when they stop eating these foods."

Shikhman adds that cutting out carbonated beverages sweetened with fructose may yield even more noticeable results. That's because the carbonation, he says, causes a metabolic reaction. This reaction results in much more sugar pouring into the blood much more quickly.

"It's this quick rise in blood sugar," Shikhman says, "followed by the subsequent fall that exacerbates the fatigue element of fibromyalgia. That, in turn, creates more cravings for sugar, followed by still more fatigue -- allowing a vicious cycle to develop." Cutting out the sugar, he says, particularly soda, can result in better, more even control of blood sugar. Better control will help reduce fatigue and at least some of the related pain.

4. Caffeine -- including coffee, tea, colas, and chocolate. Because it is considered a stimulant, many fibromyalgia patients turn to caffeine-rich beverages as a source of energy. But McNett says the boost you get is false -- and can quickly exacerbate fatigue.

Fibromyalgia: Seven foods to avoid continued...

"The problem with caffeine is that the 'up' is relatively brief and transient," he says. "And it's followed by substantially longer and deeper sedative effect."

Because people with fibromyalgia are already tired, McNett cautions, those sedative effects can be much more powerful. "They are starting off from a point of fatigue, so the sedative qualities are amplified -- leading to a much deeper and long lasting sense of fatigue."

The good news is that cutting out caffeine can make a difference within less than a week. "Most patients begin to see a difference in their fatigue level almost right away," he says.

5. Yeast and gluten. Although these are two separate food substances, they frequently appear together -- particularly in baked goods like cake, donuts, and bread. For this reason, cutting out one, usually means you are cutting out both. That can actually yield two separate benefits for people with fibromyalgia.

In the case of yeast, some doctors say it fosters the overgrowth of the yeast fungus in the body. This overgrowth may cause or exacerbate much of the joint and muscle pain experienced by people with fibromyalgia. Research, though, has yet to confirm this link.

Gluten can exacerbate a condition known as gluten intolerance. Gluten intolerance, Shikhman says, frequently results in a variety of stomach ailments and other digestive problems. It also is associated with fatigue in patients with fibromyalgia.

"I have seen people with and without fibromyalgia experience enormous positive changes in their health by simply cutting out gluten products," Shikhman says.

6. Dairy. Be they low fat or high fat, some experts say, dairy products -- particularly, milk -- have been known to drive the symptoms of fibromyalgia. Avoiding these products may help some people turn their health around.

On the other hand, if you feel as if milk is doing your body some good, keep chugging a glass or two of skim milk a day. It's got calcium to build bones and protein to build muscle, and it's fat free.

7. Nightshade Plants: Tomatoes, chili and bell peppers, potatoes, and eggplant. There are over 2,000 species of plants that that can be listed under the category of "nightshade." Those which are edible comprise a group that some say can trigger flares of various types of arthritis, including fibromyalgia.

"I have seen patients who do much better when they cut these foods out of their diet," says Holtorf. We're not sure why, but it seems to work in a significant percentage of fibromyalgia patients." At the same time, these vegetables are among the most nutritious. So if they don't trigger your fibro pain, don't ban them from your fridge.

A final word - Nutrients and the power of a healthy diet

Avoiding certain foods may help individual patients better cope with their disease. Nutritionist Samantha Heller, MS, RD, says, however, that most can also benefit from an overall heart-healthy approach to good eating.

A final word - Nutrients and the power of a healthy diet continued...

"When you are eating a heart-healthy diet - one low in saturated fat, lean meats, and poultry and high in the fresh fruits and vegetables that don't cause you problems, your body is going to work in a more healthful way, " Heller says.

And while, she says, this won't necessarily reduce your fibromyalgia symptoms, it can help to reduce the risk of other ailments that can only compound your health issues.

"When your body is healthier overall," says Heller, "you may be better able to cope with any disease, and better able to respond to even small changes you make."

One small study published in the journal Complementary and Alternative Medicine in 2001 found that patients who ate a vegetarian diet consisting of mostly raw whole foods did see a reduction in their fibromyalgia symptoms.

Holtorf also believes that sticking to a heart-healthy diet may yield some specific helpful effects. "Patients with fibromyalgia have documented mitochondria dysfunction," he says. "This is the area of the cell where energy is made. Consequently, it's necessary to have high levels of nutrients to get the mitochondria to work and for energy to be produced." So, Holtorf adds, the higher your level of dietary nutrients, at least theoretically, the better off you might be.

What can also help, he says, is a high potency vitamin supplement as well as supplements containing omega 3 fatty acids. Omega 3 fatty acids -- which are also found in foods such as fish oil, flax seed, walnuts, some fortified cereals, and eggs -- are the "good fats" that have been shown to have an impact on inflammation.

"For some fibromyalgia patients," Holtorf says, "they work extremely well." Then he adds, "It is definitely worth a try."

Reviewed on May 16, 2008
© 2008 WebMD, LLC. All rights reserved.








Are All Chronic Fatigue Syndrome/Fibromyalgia Patients Low Thyroid?

There is mounting evidence that there is low thyroid activity present in the majority of chronic fatigue syndrome and fibromyalgia patients. Studies demonstrate that in addition to an increased incidence of primary hypothyroidism in chronic fatigue syndrome and fibromyalgia, there is a combination of secondary, tertiary and thyroid resistance in the overwhelming majority of CFS and FM patients, despite having normal thyroid tests because these latter forms of tissue hypothyroidism are not detected by standard thyroid function tests. Thus, many chronic fatigue syndrome and fibromyalgia patients are erroneously told over and over that their thyroid levels are fine.

TSH is secreted by the pituitary in the brain and stimulates the thyroid to secrete T4, which is not the active thyroid hormone. T4 must then be converted in the body to the active thyroid hormone T3. When T4 and T3 levels drop, the TSH should increase indicating hypothyroidism. This is the standard way to diagnose hypothyroidism and is the only way that the majority of physicians (endocrinologists, internists, family practitioners, ect.) know how to test for low thyroid levels. There are, however, multiple abnormalities in CFS and FM that result in tissue hypothyroidism that are not detected using the standard TSH, T4 and T3 testing. In fact, standard thyroid tests fail to detect tissue hypothyroidism 80-90% of the time in patients with chronic fatigue syndrome and fibromyalgia.

There is clearly hypothalamic and pituitary dysfunction in these conditions (can potentially be caused by viruses, bacteria, stress, yeast, inflammation, toxins, pesticides, plastics and mitochondria dysfunction). The hypothalamic dysfunction results in the production of TSH that has diminished biological activity so there are lower T4 and T3 levels for any given level of TSH. In addition, the pituitary dysfunction results in a diminished secretion of TSH, masking low tissue thyroid levels as the TSH is usually in the normal range. Very few doctors understand the significance of this and incorrectly state that the thyroid is fine based on a normal TSH level.

Furthermore, many chronic fatigue syndrome and fibromyalgia patients have relatively diminished T4 to T3 conversion and a relatively increased T4 to reverse T3 conversion, also resulting in low tissue levels of active thyroid hormone levels despite having a normal TSH. (See the handout Fatigued, Depressed, Difficulty Losing Weight). The type II deiodinase that converts T4 to T3 is down regulated in chronic fatigue syndrome and fibromyalgia while the type III deiodinase enzyme that increases T4 to reverse T3 (rT3) is unregulated in these conditions. This maladaptive response decreases the T3/rT3 ratio, further diminishing tissue thyroid levels but are also not detected by standard testing. The T3 and rT3 levels can be measured and the ratio calculated, but merely finding normal T3 and reverse T3 levels is not adequate to detect this abnormality.

Another significant cause of low tissue thyroid levels in chronic fatigue syndrome and fibromyalgia that is not detected by standard testing is the fact that there has been shown to be a peripheral thyroid hormone resistance found in these patients, meaning that there is a diminished thyroid effect for a given amount of thyroid hormone in the blood. This has been discounted in the past, but more and more evidence is surfacing proving that this is indeed a significant problem with these conditions.

The combination of factors present in chronic fatigue syndrome and fibromyalgia, including hypothalamic and pituitary dysfunction, diminished T3/rT3 production ratios and thyroid resistance, results in most, if not all, chronic fatigue syndrome and fibromyalgia patients having inadequate tissue thyroid effect. T4 preparations such as Synthroid and Levoxyl rarely work and Armour thyroid, a pig glandular product, is somewhat better, but definitely not adequate for most patients. The treating physician must know when to use a T4/T3 combination or straight T3. T3 works the best for many of these patients, but Cytomel, a very short acting T3 available at normal pharmacies, is also a poor choice because the varying blood levels can cause significant side effects. Compounded timed release T3 is usually the best treatment. However, to achieve significant improvement, the treating physician must be very knowledgeable about T3 and must realize that when on T3, standard bloods blood test will lead one to dose incorrectly and not obtain significant benefits. This includes doctors who previously felt that they were thyroid experts and had been using thyroid with in chronic fatigue syndrome and fibromyalgia for a long time. Ultimately, it is the expertise and dosing of the T3 or T4/T3 combinations and the makeup of the medications that determines the optimal treatment regimen and is one major component in the treatment of in chronic fatigue syndrome and fibromyalgia.

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Adrenal dysfunction in CFS/FM



Treatment of Hypothalamic-Pituitary-Adrenal Axis Dysfunction in Patients with Chronic Fatigue Syndrome (CFS) and Fibromyalgia (FM)

Points addressed:

  • A review of the literature regarding evidence of significant hypothalamic-pituitary-adrenal axis (HPA) dysfunction in CFS and FM.
  • Indications and efficacy of treatment with physiological doses of cortisol
  • Expected risks and benefits of such treatment

Abstract:

There is clear evidence that adrenal axis dysfunction is present in patients with chronic fatigue syndrome (CFS) and fibromyalgia (FM) 1-21,23-28 and that treatment with low physiologic doses of cortisol have been shown to be safe, appropriate and effective.8,9,10,23,30 It should be considered the standard of care to treat patients with CFS and FM who have baseline cortisol levels under 12 ug/ml.8,9,10,31,32,33

Evidence for significant HPA axis dysfunction with resultant adrenocortical dysfunction:

A study published in the Annals New York Academy of Sciences entitled Evidence for and Pathophysiologic Implications of Hypothalamic-Pituitary-Adrenal Axis Dysregulation in Fibromyalgia and Chronic Fatigue Syndrome discussed the evidence for HPA axis insufficiency in CFS and FM. They conclude, “Our group has established the impaired activation of the hypothalamic-pituitary-adrenal axis is an essential neuroendocrine feature of this condition.” 27

Cleare et al published a study in the American Journal of Psychiatry that obtained 24-hour urine collections from 121 consecutive patients with CFS. They found low 24 hour cortisol levels in all of the CFS patients. The authors conclude, “Urinary free cortisol was significantly lower in the subjects with chronic fatigue syndrome regardless of the presence or absence of current or past comorbid psychiatric illness…From whatever cause, low circulating cortisol is associated with fatigue; furthermore, raising cortisol levels can reduce fatigue in chronic fatigue syndrome. Thus, this study provides further evidence that adrenocortical dysfunction in chronic fatigue syndrome, whatever the etiology and whether primary or secondary, may be one piece of the multifactorial jigsaw underlying the production of symptoms in chronic fatigue syndrome.” 7 The authors agree that treating this adrenocortical dysfunction with cortisol replacement is a fundamentally necessary part of the appropriate multi-system treatment of this condition.

Another study published in the Journal of Endocrinological Investigation performed a combination of stimulation tests on FM patients. They found over 95% of these patients had HPA axis dysfunction.3 They state, “The etiology and pathophysiology of this disease is not fully understood but the current data suggests that the PFS [Primary Fibromyalgia Syndrome] is not a primary disease of muscle. In contrast, an increasing amount of evidence suggests that the central stress axis, the HPA axis, seems to play an important role in the development of PFS…This study clearly shows that the HPA axis is underactivated in PFS...” 3

Trophy et al. administered interleukin-6 (IL-6), which is a potent stimulator of the HPA axis, and measured plasma ACTH and cortisol levels. They found a delayed ACTH response in these patients, which is consistent with a defect in the hypothalamic CRH neuronal function as an etiology of symptoms in these patients.2

Cortisol levels normally increase with pain, but it has been shown that patients with CFS and FM either cannot appropriately increase cortisol production with pain or the inability to increase cortisol causes the increased pain. A study published in the November 2005 Journal Arthritis and Rheumatism demonstrated this strong relationship between cortisol levels and pain in individuals with CFS and FM and that low cortisol levels alone explained 38% of the variation in pain upon waking. The authors conclude, “The results of this study indicate that pain symptoms in women with FM are associated with cortisol concentrations during the early part of the day…These data support the hypothesis that HPA axis function is associated with symptoms in FM and accounts for the substantial percentage of pain symptom variance during the early part of the day.” 28

A study published in the Brazilian Journal of Infectious Disease (figure 2) demonstrates that in this type of patient population a baseline cortisol level of less than 12 has a specificity of greater than 90% for adrenocortical dysfunction and a level less than 10 ug/dl has a specificity of 98% for adrenocortical dysfunction.33 The most appropriate cutoff that optimizes specificity and sensitivity as found in this study, as well as by others, is 12 ug/dl.31,33 In addition, a normal ACTH does not rule-out secondary hypoadrenalism, but an abnormally low or low normal ACTH level can be considered confirmatory.

A study published in the Brazilian Journal of Infectious Disease (figure 2) demonstrates that in this type of patient population a baseline cortisol level of less than 12 has a specificity of greater than 90% for adrenocortical dysfunction and a level less than 10 ug/dl has a specificity of 98% for adrenocortical dysfunction.33 The most appropriate cutoff that optimizes specificity and sensitivity as found in this study as well as by others is 12 ug/dl.31,33 In addition, a normal ACTH does not rule-out secondary hypoadrenalism, but an abnormally low or low normal ACTH level can be considered confirmatory.

adrena_figure2.jpg

Dynamic testing:

Dynamic testing is certainly useful in straight forward primary and secondary adrenal insufficiency, but in patients with CFS, there is a complex interaction of hypothalamic and pituitary dysfunction. This results in a complex response that is initially elevated and then blunted, resulting in what is thought to be conflicting results, depending on which stimulation test was used, how an abnormal is defined and whether or not ACTH/cortisol ratios were used. 1,3,8,9,19,34-39 Consequently, the standard criteria does not apply to these patients significantly reducing the usefulness of dynamic testing with CFS and FM.1,9,19,27,34-39

It has been shown that a single ACTH stimulation test misses the majority of FM/CFS patients that have adrenocortical deficiency, but when a combination of stimulation tests are used, such as metyrapone test, or more sophisticated analysis is used, close to 100% of these individuals have documented adrenocortical dysfunction.1,3,8,9,19,27,34-39

Numerous studies demonstrate that this lack of sensitivity likely explains the seemingly contradictory findings between studies using stimulation tests.1,3,8,9,19,27,34-40 For instance, Scott et al in Clinical Endocrinology did 1ug ACTH stimulation tests on subjects with CFS and found a significant decrease in the delta cortisol value of patients with CFS vs. normals, but found that the reliance on this test and the arbitrary cutoffs that apply significantly impacts the sensitivity of stimulation tests in the patient population. They conclude, “In conclusion, the amount of cortisol released following stimulation with 1ug ACTH, is lower in CFS patients than in healthy volunteers…We propose, as has been suggested from previous studies, that the abnormality of HPA regulation is more likely to be central in origin. The demonstration of low basal ACTH in our CFS cohort would have supported this view…There is considerable debate surrounding the optimal dose of ACTH to use, with concern that the 250 mcg dose is “superphysiologic’ and may produce cortisol responses in patients suspected of having pituitary adrenal insufficiency that are falsely reassuring...Disparities between our healthy volunteer data and those of other groups using the 1 microgram ACTH test suggest that the test may not be as reliable as previously indicated…replacement therapy may more appropriately involve not only glucocorticoid, but mineralcorticoid supplements also.” 19

Another study that clearly demonstrates this confusion and that standard stimulation tests are not a reasonable method of evaluation of adrenal-cortical dysfunction is published in the Journal of Clinical Endocrinology and Metabolism entitled Evidence for Impaired Activation of the Hypothalamic Pituitary-Adrenal Axis in Patients with Chronic Fatigue Syndrome. The study found that compared to normal individuals, CFS patients were shown to have significantly reduced basal glucocorticoid levels (average 89 vs 148 nmol/l) and a low 24 hour urinary free cortisol excretion (122.7 nmol/L vs 203 nmol/L). The level of cortisol binding globulin CBG was also significantly higher in CFS patients making the free cortisol index lower in the patients (2.9 vs 8.9). There was a significant attenuated net integrated ACTH response to CRH but there was an initial increased initial sensitivity to ACTH with a reduced maximal response.1

adrena_figure3.jpg

Although this cortisol response to ACTH is clearly abnormal for all of the patients with CFS, the dose response curve varies. There is an initial exaggerated response followed by an abnormally blunted response, which is not the case for patients with primary or secondary adrenocortical insufficiency without a dysfunctional hypothalamus. Consequently, standard dynamic testing is not medically useful in these patients and it is improper to use the defined normal cutoffs of response as is done with other conditions. This has been demonstrated in other studies as well.1,3,8,9,19,27,34-39

Kirnap et al in a study published in Clinical Endocrinology compared standard and low dose ACTH stimulation tests on patients with primary fibromyalgia syndrome (PFS). They found a significantly reduced peak cortisol response in the PFS verses controls. They also found that if the standard cutoff of 550 nmol/l was used with the standard ACTH stimulation, many of the patients would have misdiagnoses as normal.4

adrena_figure4.jpg

There are a number of theories that have been postulated to explain such a response. The author of this study postulates that this is due to a lack of CRH (corticotrophin releasing hormone) with a secondary hyperresponsivness from inadequate levels of ACTH. They alternatively state that this HPA axis defect could be secondary to a chronic viral infection.

Treatment:

Further supporting the use of low dose cortisol in these patients is the fact that such treatment has been shown to improve the HPA axis response in these patients. This is counterintuitive to what physicians are taught and have found with higher pharmacological doses of glucocorticoids. In a study published in the 2001 Journal of Clinical Endocrinology & Metabolism entitled Hypothalamo-Pituitary-Adrenal Axis Dysfunction in Chronic Fatigue Syndrome, and the Effects of Low-Dose Hydrocortisone Therapy, the authors utilized ACTH and cortisol responses to CRH, insulin stress test, D-fenfluramine and 24 hour urinary free cortisol in 37 patients with CFS and treated these patients with low dose cortisol. They found that the treatment resulted in significant improvement and not only was there no adrenal suppression, but rather there was an improvement in the HPA axis as documented with CRH testing. They concluded, “In this group, there was a significant increase in the cortisol re¬sponse to human CRH, which reversed the previously ob¬served blunted responses seen in these patients. We conclude that the improvement in fatigue seen in some patients with chronic fatigue syndrome during hydrocortisone (same as cortisol) treatment is accompanied by a reversal of the blunted cortisol responses to human CRH.” 8

In a randomized, double-blind, placebo controlled, crossover, intent to treat trial published in The Lancet, patients with chronic fatigue syndrome were treated with low dose hydrocortisone (5-10 mg/day) or placebo. The study found significant improvements in those treated with low dose hydrocortisone vs. placebo and 28% improved to normal levels. The authors concluded, “This study shows that low-dose hydrocortisone results in significant reduction in self-rated fatigue and disability in patients with chronic fatigue syndrome…The degree of disability was reduced with hydrocortisone treatment, but not with placebo. Insulin stress tests showed that endogenous adrenal function was not suppressed by hydrocortisone.” 9 This demonstrates the effectiveness and appropriateness of this treatment.

Another randomized control trial published in JAMA also found significant improvement in fatigue scores with hydrocortisone replacement, but they used excessive dosing of 25-35 mg of cortisol. It is recommended that dosing be limited to 5-15 mg/day, as these doses have been shown to not be associated with any untoward effects and carries little to no risk of adrenal suppression.10,23,30,31 This considerable safety and negligible risk is also confirmed in endocrinology texts.54

Bashetti has published a number of studies on cortisol and CFS. He writes in the Journal of Endocrinology and Metabolism, “Hydrocortisone, the glucocorticoid that is routinely prescribed to correct the chronic cortisol deficiency of patients with Addison’s disease, has recently been confirmed to be significantly effective also in the treatment of chronic fatigue syndrome (CFS). This comes as no surprise if we consider that CFS and Addison’s disease share 26 features.” 41

A randomized, double blind placebo-controlled, intent to treat study by Teitelbaum published in the Journal of Chronic Fatigue Syndrome documented the effectiveness of an integrative treatment approach to CFS and FM that includes low dose cortisol (7.5-20 mg/day). The authors conclude,” 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 .” 31

A subsequent editorial in the peer reviewed, Journal of the American Academy of Pain Management reviewed this study and agreed that an integrative approach that includes low dose cortisol is the standard of care for these conditions. The author states, “The study by Dr. Teitelbaum et al. and years of clinical experience makes this approach an excellent and powerfully effective part of the standard of practice for treatment of people who suffer from FMS and MPS [myofacial pain syndrome]— both of which are common and devastating syndrome.” 48 The consensus opinion among those who are experts in the treatment of CSF and FM is that a treatment approach that includes low-dose cortisol is the standard of care.

A subsequent commentary by Teitelbaum published in JAMA states, “Our previously published pilot study and the work of Jefferies suggests that using low-dose hydrocortisone in CFS as dosages of 7.5 mg to 20 mg/day is safe and effective. These low dosages have not caused adrenal suppression…We recently completed a randomized, double-blind study that tested the effectiveness of treating patients with fibromyalgia and CFS for hypothalamic dysfunction in an integrated manner. This included treating suspected hormonal deficiencies (including low hydrocortisone) and the sleep disorder simultaneously. Using this protocol in 72 patients resulted in a significant improvement in active vs. placebo group.” 42 Cortisol replacement appears to be an essential part of a comprehensive treatment approach that can be used successfully in the treatment of CFS and FM.31,42

A study published in JAMA found that nearly half of the patients treated with mineralcorticoid reported complete or nearly complete resolution of CFS symptoms.43

The safety of low dose glucocorticoids was addressed in a 48 page review article published in last month’s Annals of Rheumatic Diseases entitled Low-dose glucocorticoid therapy in rheumatoid arthritis - A review on safety: published evidence and prospective trial data. This extensive review assessed the incidence and severity of adverse effects of long-term low-dose glucocorticoid therapy in rheumatoid arthritis. This review considered low dose as any dose below or equivalent to 40 mg hydrocortisone (this patient received a fraction of this dose 10mg/day).  They concluded, “Adverse-effects of glucocorticoids are abundantly referred to in literature. However, in the available literature on low-dose glucocorticoid therapy very little of the commonly held beliefs about their incidence, prevalence and impact of GC [glucocorticoid] proved to be supported by clear scientific evidence. Additional data from the randomized controlled clinical trials reviewed showed that the incidence, severity and impact of adverse effects of low dose glucocorticoid therapy in rheumatoid arthritis trials are modest, and often not statistically different to those of placebo.” 10

Low dose cortisol has been shown to improve immunity, as opposed to the well known immunosuppressive effect of pharmacological doses of glucocorticoids, 23,30,45,46 and has been shown to improve recovery from chronic infections such as EBV.47,22,29

In summary, it is becoming clear that the majority of patients with CFS and FM suffer from clinically significant adrenocortical dysfunction and that physiologic replacement of cortisol is an appropriate intervention in these patients. Cortisol doses of 5-15 mg/day have been shown to be safe, with little associated risk including adrenal suppression, and have the potential for significant clinical benefit. The current evidence supports the use of physiologic doses of cortisol in the treatment of CFS and FM, and a therapeutic trial of cortisol should be considered in these patients, especially those with basal cortisol levels less than 12 ug/dl.








References
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Adrenal Dysfunction (JCFS)



Key Study Points
  • There is controversy regarding the incidence and significance of adrenal dysfunction in chronic fatigue syndrome (CFS) and fibromyalgia (FM) as well as the effectiveness and appropriateness of such treatment. A review just published in the Journal of Chronic Fatigue Syndrome, a major journal for the specialty treatment of CFS and FM, addresses this controversy.
    .
  • Kent Holtorf MD, a CFS and FM specialist, analyzed the data in over 50 studies that assessed adrenal function in CFS and FM patients. Through his analysis he discovered that the majority of CFS and FM patients have abnormal adrenal function due to hypothalamic-pituitary dysfunction. It was also shown that the majority of patients should be treated for this adrenal dysfunction since many of the standard tests do not pick up this particular type of adrenal dysfunction. The data shows that such treatment is safer and more effective than commonly used treatments such as antidepressants.
    .
  • Dr. Holtorf demonstrates that while these conditions are similar, the abnormality in CFS is in the pituitary while the FM patients have abnormalities of the hypothalamus.
    .
  • Based on a study of 500 patients, Dr. Holtorf found that patients who were given the adrenal hormone cortisol as part of a multi-system treatment protocol that addresses the known physiologic abnormalities experienced significant overall and symptom improvement.
    • Prior to treatment the patients had seen an average of 7.2 different physicians for the treatment of CFS and/or FM without significant improvement.
    • 94 percent of patients had overall improvement by the 4th visit o 75 percent noted significant overall improvement
    • 62 percent reported substantial overall improvement
    • The average energy level and sense of well-being for patients doubled by the fourth visit
      .
      The effectiveness of this multi-system treatment was further confirmed through the analysis of the cumulative findings of over 40 independent physicians and over 5,000 patients
  • This review provides a new understanding that treating the known causes of illness in CFS and FM can improve the symptoms and quality-of-life of patients who suffer from these conditions.

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Infectious Causes of Chronic Fatigue Syndrome

Numerous studies have demonstrated a high incidence of chronic infections in chronic fatigue syndrome and fibromyalgia. These include viral infections of Epstein bar (EBV), cytomegalovirus (CMV), human herpes virus-6, (HHV-6), and bacterial infections such as mycoplasma, chlamydia pneumonia (CP) and Borrelia burgdorferi (Lyme disease). There is controversy regarding the presence of active infection in these conditions because physicians, including infectious disease specialists, do not understand that the standard way to diagnose acute infections, an elevation of IgG and IgM antibodies, is not a sensitive means of detecting chronic infections in these patients (1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21). With an acute infection, the body will start producing IgM antibodies against that infection and then start producing IgG antibodies after a few weeks so there is an elevation of both IgG and IgM antibodies. Chronic reactivating infection, such as those mentioned above, do not stimulate IgM antibodies as they are not new infections but rather intracellular reactivating infections, so most doctors, again including infectious disease specialists, will tell patients who have elevated IgG antibodies that they had an old infection or previous exposure and that there is no evidence of or they do not have an active infection because that is what they learned in medical school. This standard way of detecting active infections has clearly been shown to be inaccurate and miss the overwhelming majority of patients with active infections (1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16, 17,18, 19,20,21).

Polymerase chain reaction (PCR) testing is much more sensitive in a research setting than in the clinical setting because if the blood sits for more than a few hours, the infectious organism’s DNA degrades and often goes undetected. In a clinical setting, it is a specific test (if it is positive you know you have an active infection), but suffers from low sensitivity (often negative despite an active chronic infection). Additionally limiting sensitivity is the fact these infections are not concentrated in the blood or serum but rather in the tissues, especially nerves, brain and the white blood cells. Physicians must have a high incidence of suspicion and look for elevated IgG or early antigen (EA) antibodies along with other signs of chronic infections including low natural killer cell activity, high RNAse-L activity, high ACE (> 35), coagulation activation, high tumor necrosis factor (TNF), low melanocyte stimulation hormone (MSH), high interleukin-6 (IL-6), low WBC, increased 1-25 vitamin D/1-25 vitamin D ratio and elevated or decreased total IgA, IgM or IgG levels. Chronic infections are almost always present in those whose symptoms started very acutely, especially with an infection, those who’s symptoms were ever associated with swollen lymph nodes or sore throat and those with significant cognitive dysfunction or flu-like symptoms. It must be remembered that in order to have the highest probability of successful treatment, a multi-system approach should be initiated (see new standard of treatment).

Herpes Viruses (Epstein Bar, Cytomegalovirus and HHV-6)

EBV, CMV and HHV-6 cause or contribute to the symptoms of a large percentage of CFS and FM patients. As stated previously, the presence of active infections correlate with an elevated IgG antibody, despite the lack of IgM antibodies (10,11,12,13,14,15,16,17,18,19,20,21). These infections are generally not acute but rather intracellular reactivation of an old infection, an elevation of IgM antibodies is typically not seen with active infections of EBV, CMV, HHV-6, (10-21). Due to the immune dysfunction seen in CFS, in addition to a lack of IgM antibody formation, there may also be a lack of IgG antibodies present despite the presence of an active infection in CFS patients (22,17,23). This has also been demonstrated to be the case with AIDS patients, as demonstrated in the study published in the New England Journal of Medicine entitled Absence of detectable IgM antibodies during cytomegalovirus disease in patients with AIDS (22). It has also been shown that the presence of antithyroid antibodies in CFS patients has a significant correlation with active HHV-6 infection (24).

A study published in Acta Pathologica, Microbiologica et Immunologica Scandinavica entitled Multiple co-infections (Mycoplasma, Chlamydia, human herpes virus-6) in blood of Chronic Fatigue Syndrome Patients: Association with Signs and Symptoms found 52% of CFS patients had active mycoplamsa infection, 30.5% had active HHV-6 infection, and 7.5% had Chlamydia pneumonia infections vs. only 6%, 9% and 1% of controls, respectively. They conclude, “The results indicate that a large subset of CFS patients show evidence of bacterial and/or viral infection(s), and these infections may contribute to the severity of signs and symptoms found in these patients (25).”

A study entitled A Chronic Illness Characterized by Fatigue, Neurological and Immunological Disorders, and Active Human Herpes virus Type 6 Infection published in the Annals of Internal Medicine found 70% of patients with CFS had active HHV-6 infection through the use of primary cell cultures and confirmation using assays of monoclonal antibodies specific for HHV-6 proteins and by PCR. Again, an elevation of IgM antibodies is generally not seen (26).

infectious_photo1.jpgAs summarized below, when specialized testing is used to detect active vs. past infection of HHV-6, the overwhelming number of studies demonstrate a high incidence of active herpes virus infections. These reactivation infections often do not illicit an IgG and especially not an IgM response, so standard serologic testing is specific but not sensitive for such infections. As mentioned before, PCR testing in a research setting is much more reliable, sensitive and useful than in the clinical setting when the blood is usually not processed for 12-48 hours.

Wagner et al, found that 61% of CFS patients with elevated IgG antibodies and 81% with immune deficiency, had confirmed active HHV-6 infection vs only 19% of those patients who did not (15). This is regardless of whether or not IgM antibodies were elevated.

Below is a summary of studies that have looked at the incidence of active HHV-6 infection in CFS/FM patients vs. controls, with 83% of the studies demonstrating a large portion of CFS/FM patients have and active HHV-6 infection.

infectious_photo2.jpg

A study by Lerner found that treating patients with 6 months of Valtrex resulted in a significant improvement in symptoms (46). In a separate study, Lerner et al found that in CFS patients with elevated IgG antibody against CMV, treatment with the intravenous antiviral ganciclovir, which has a more broad spectrum coverage than Valtrex and anti-CMV activity, resulted in 72% of patients returning to their premorbid health states (total resolution of symptoms)(47). A randomized, placebo controlled study published in Clinical Infectious Diseases, demonstrated that in CFS patients with an elevated IgG antibodies against CMV, a combination of oral Valtrex and intravenous ganciclovir resulted in dramatic improvements with almost complete resolution of symptoms (27).

Montoya et al at Stanford University treated chronic fatigue syndrome patients with 6 months of valganciclovir (Valcyte) if they had elevated IgG tests for HHV-6 and EBV and had at least 4 of the following symptoms: impaired cognitive functioning, slowed processing speed, sleep disturbance, short-term memory deficit, fatigue and symptoms consistent with depression. Nine of the twelve treated patients (75%) “experienced near resolution of their symptoms, allowing them all to return to the workforce or full time activities.” In the nine patients with a symptomatic response to treatment, EBV VCA IgG and HHV-6 IgG titers significantly dropped. (21)

We have been using Valcyte in our center for the treatment of chronic fatigue syndrome for over 4 years and have found it to be effective, especially in patients with the flowing: flu-like symptoms or symptoms started with a flu-like illness; elevated IgG or EA against Epstein bar virus, cytomegalovirus and/or HHV-6; low natural killer cell activity; high RNAse-L activity; high ACE (> 35); coagulation activation; high tumor necrosis factor (TNF); low melanocyte stimulation hormone (MSH); high interleukin-6 (IL-6); low WBC; increased 1-25 vitamin D/25 vitamin D ratio and/or elevated or decreased total IgA, IgM or IgG levels.

This study contributes more confirmatory evidence that IgM antibodies are not typically elevated in chronic reactivating infections so most patients are incorrectly told they do not have an active infection based on such testing. This study also demonstrated the lack of sensitivity of standard PCR testing.

There is also evidence that CFS may be due to the above discussed infections with “stealth adaptation" (28,29,30,31,32,33,34,35,36,37,38). This is primarily due to the deletion of the genes coding for the major antigenic components normally targeted by the cellular immune system. “Stealth viral adaptation” results in replication that is less efficient than conventional viruses, but has a distinct advantage over conventional viruses in not having to confront the body's cellular immune defense mechanisms. They can, therefore, evade the immune system and create persistent ongoing infections in spite of an individual's intact immune system (28-38).

A number of studies have also shown dramatic improvement in patients with interferon treatments, especially those with low natural killer cell function, (39,40,41). While ganciclovir and interferon may be effective, their toxicity precludes their use and there are less toxic means of eradicating these infections.

Mycoplasma

Numerous studies have demonstrated a high incidence of active Mycoplasma infection in CFS and FM (1,44,45,46,47,48,49,50,51,52).Nijs et al published a study in the Journal Immunology and Medical Microbiology entitled High Prevalence of Mycoplasma infections among European Chronic Fatigue Syndrome Patients demonstrated that 68% of CFS patients had an active mycoplasma infection as diagnosed with specialized polymerase chain reaction (PCR) testing where the red and white cells were immediately lysed and centrifuged to concentrate and collect the DNA (1). Being predominantly intracellular, there is typically not a significant serologic antibody response or just an isolated IgG response with this number of other intracellular infections so IgG and especially IgM antibodies are almost always in the normal range despite the presence of an active infection (1,2,3,4,5,6,7,8,9).

This study and others discussed below demonstrated that IGM antibodies are not helpful in the diagnosis of an active infection in CFS and FM. Nijs et al stated, “Mycoplasma detection based on antibody testing is characterized by a very high specificity [if IGG and IGM positive], but extremely low sensitivity [active infection almost always present without elevated IgG and IgM antibodies] renders it useless as a diagnostic tool (1).” A study by Dylewski et al in the New England Journal of Medicine demonstrates that in immune compromised patients, such as this patient, active infections correlate with elevations in IgG antibodies without elevations of IgM antibody and that a lack of elevation of IgM is not useful in these patients as a way to rule-out active infection. A high clinical suspicion must be maintained and implementation of anti-infective treatment should be based on elevated IgG levels (9).

A study entitled Diagnosis and Treatment of Chronic Mycoplasmal Infections in Fibromyalgia and Chronic Fatigue Syndrome: Relationship to Gulf War Illness published in Biomedical Therapy investigated the presence of active mycoplasmal infection by forensic PCR in patients with CFS and/or FM vs. controls. They found that 63% of CFS/FM patients had active mycoplasmal species infection compared to 9% of normals and more specifically the incidence of active Mycoplasma fermentans infection was 50% in CFS/FM patients vs. 0% of controls (2).

A study published in the International Journal of Medicine Biology Environment tested the blood of 565 CFS and/or FM patients vs. 71 healthy controls. They found 53.1% of patients were positive for mycoplasmal infection vs. only 7 out of 71 controls and 24.6% of patients had an M. fermentans infection vs. 2.8% of normals (42).

In a study published in the International Journal of Occupational Medicine, Immunology and Toxicology found that through specialized testing over half of Gulf War Syndrome/CFS patients had active mycoplasma infections that would not have been detected by standard serological IgG and IgM testing and that 78% of the patients completely recovered with appropriate treatment. Additionally, all of recovered patients that were subsequently retested no longer had evidence of infection (7).

A study and review published in the Antimicrobics and Infectious Disease Newsletter discussed the high incidence of mycoplasma infections in CFS. They discuss the fact that the culturing procedures and serological testing are insensitive for detecting intracellular infections due to the fact that there is usually a lack of hormonal response with these infections resulting in “normal” antibody titers or an isolated elevation of IgG antibodies with a lack of IgM antibodies (8). Sophisticated PCR testing found multiple species of mycoplasma in the majority of CFS patients. They found of the 87 gulf war illness-chronic fatigue syndrome patients treated with antibiotics, most relapsed after the first 6 week trial and most felt worse, but after up to 6 cycles of 6 weeks of therapy approximately 80% of these patients recovered and were able to return to their normal functional capacity. This was not a placebo controlled trial, but they discuss the fact that it is unlikely a placebo effect that most patients felt worse during treatment. They conclude stating that in order to be successful in the treatment of gulf war illness-chronic fatigue syndrome, a comprehensive treatment approach must be used that addresses the numerous physiological abnormalities, including chronic infections (8).”

A study by Nasralla et al published in the European Journal of Clinical Microbiology & Infectious Disease entitled Multiple Mycoplasmal Infections Detected in Blood of Chronic Fatigue Syndrome and Fibromyalgia Syndrome Patients investigated the presence of different mycoplasmal species in blood samples from mycoplasma positive patients with chronic fatigue syndrome and/or Fibromyalgia. They found that the majority of patients had multiple species of mycoplasmal infections, with 59% of patients having active M. Pneumonia infections, 48% having active M fermentans infection, 31% having an active M. hominis and 20% having M pentrans (43).




References



1. Jo Nijs J et al. High prevalence of Mycoplasma infections among European chronic fatigue syndrome patients. Examination of four Mycoplasma species in blood of chronic fatigue syndrome patients. . Volume 34, Issue 3 , 15 November 2002, Pages 209-214.

2. Garth L. Nicolson, Marwan Nasralla, Joerg Haier and Nancy L. Nicolson

Diagnosis and Treatment of Chronic Mycoplasmal Infections in Fibromyalgia and Chronic Fatigue Syndromes: Relationship to Gulf War Illness. Biomed. Therapy 1998; 16: 266-271

3. Baseman JB, Tully JG. Mycoplasmas: Sophisticated, reemerging, and burdened by their Notoriety. Emerg Infect Dis 1997 (3): 21-32.

4. Lo S-C, Dawson MS, Newton PB III. Association of the virus-like infectious agent originally reported in patients with AIDS with acute fatal disease in previously healthy non-AIDS patients. Am J Trop Med Hyg 1989 (40): 399-409.

5. Lo SC, Wear DJ, Shih WK, Wang RYH, Newton PB, Rodriguez JF. Fatal systemic infections of non-human primates by Mycoplasma fermentans (incognitus strain). Clin Infect Dis 1993 (17) (Suppl 1): S283-288.

6. Lo SC, Buchholz CL, Wear DJ, Hohm RC, Marty AM. Histopathology and doxycycline treatment in a previously healthy non-AIDS patient systemically infected by Mycoplasma fermentans (incognitus strain). Mod Pathol 1991 (6): 750-754.

7. Nicolson G, Nicolson N. diagnosis and treatment of Mycoplamal Infections in Persian Gulf War Illness-CFIDS Patients. International Journal of Occupational Medicine, Immunology and Toxicology 1996;5:69-78.

8. Nasrala M et al. The Pathogenesis and Treatment of Mycoplasmal Infections. Antimicrobics and Infectious Disease Newsletter 1999;17(!!);81-88

9. Dylewski J et al. Absence of detectable IgM antibody during cytomegalovirus disease in patients with AIDS. New England Journal of Medicine 1985:309:493.

10. Carruthers et al. Myalgic Encepalomyelitis/Chronic Fatigue Syndrome: Clinical Working Case Definition, Diagnostic and Treatment Protocols. Journal of Chronic Fatigue Syndrome.Vol 11(1) 2003.

11. Ablashi DV, Zompetta C, Lease C, Josephs SF, Balachandran N, Komaroff AL, Krueger GRF, Henry B, Luka J and Salahuddin SZ. Human herpesvirus-6 (HHV-6) and chronic fatigue syndrome (CFS). Canada Disease Weekly Report 1991; 175E:33-40.

12. Zorenzenon M, Rukh G Botta GA et al. Active HHV-6 infection in chronic fatigue syndrome patients from Italy: New data. J Chron Fatigue Syndr 1996;2(4):3-12.

13. Knox KK, Brewer JH, and Carrigan DR. Persistent active human herpesvirus six (HHV-6) infections in patients with chronic fatigue syndrome. J Chron Fatigue Syndr 1999;5:245-246.

14. Brewer JH, Know KK and Carrigan DR. Longitudinal study of chronic active human herpesvirus 6 (HHV-6) viremia in patients with chronic fatigue syndrome. Abstract. IDSA. 37th Annual Meeting. Nov. 18-21, 1999. Philadelphia, Pennsylvania.

15. Wagner et al. Chronic Fatigue Syndrome: A critical Evaluation of Testing for Active Human Herpesvirus-6 Infection. Review of Data of 107 cases. Journal of Chronic Fatigue Syndorme;2(4) 1996.

16. 15 Krueger GRF, Ablashi DV and Gallo RC: Persistent herpesvirus infections . Current techniques in diagnosis. J Virol Methods 21 : 1- 326,1988.

17. Gerhard Rf et al. Clinical Correlates of Infection with Human Herpesvirus-6. In vivo 1994;8:457-86.

18. Ablashi DV et al. Human Herpes virus and chronic fatigue syndrome. Canad Dis Weekly Rep 1991;17S1:33-40.

19. Albashi DV et al. human B lymphotropic virus (human herpesvirus-6). J Virol Methods 1988;21:29-48.

20. Josephs SF et al HHV-6 reactivation in chronic fatigue syndrome. Lancet 1991;1346-7

21. Montoya et al. Use of valganciclovir (Valcyte) in patients with elevated antibody titers against Human Herpesvirus-6 (HHV-6) and Epstein-Barr Virus (EBV) who were experiencing central nervous system dysfunction including long-standing fatigue. Journal of Clinical Virology 2006;37:S33-38

22. Dylewski J, Chou S, Merigan TC. Absence of detectable 1gM antibody during cytomegalovirus disease in patients with AIDS. N Engl J Med 1985; 309: 493.

23. Krueger GRF et al. Overview of immunopathology of chronic active herpesvirus infection. J Virol Methods 1988;21:11-18

24. Krueger GRF, Klueppelberg U, Hoffmann A, Ablashi DV. Clinical corre­lates of infection with human herpesvirus-6. In Vivo 1994; 8:457-86.

25. Nicolson GL, Gan R, Haier J. Multiple co-infections (Mycoplasma, Chlamydia, human herpes virus-6) in blood of chronic fatigue syndrome patients: association with signs and symptoms. APMIS. 2003 May; 111(5): 557-66.

26. Buchwald D. et al. A Chronic Illness Characterized by Fatigue, Neurological and Immunological Disorders, and Active Human Herpesvirus Type 6 Infection published in the Annals of Internal Medicine 1992;116:103-113.

27. Lerner AM, Zervos M and Chang CH et al. A small, randomized, placebo-controlled trial of the use of antiviral therapy for patients with chronic fatigue syndrome. Clinical Infectious Diseases. 2001;32:1657-58.

28. Martin W.J. Viral infection in CFS patients. in "The Clinical and Scientific Basis of Myalgic Encephalomyelitis Chronic Fatigue Syndrome." Byron M. Hyde Editor. Nightingdale Research Foundation Press. Ottawa Canada pp 325-327, 1992.

29. Martin W.J. Detection of viral related sequences in CFS patients using the polymerase chain reaction.in "The Clinical and Scientific Basis of Myalgic Encephalomyelitis Chronic Fatigue Syndrome." Byron M. Hyde Editor. Nightingdale Research Foundation Press. Ottawa Canada pp 278-283, 1992.

30. Martin WJ, Zeng LC, Ahmed K, Roy M. Cytomegalovirus-related sequences in an atypical cytopathic virus repeatedly isolated from a patient with the chronic fatigue syndrome. Am. J. Path. 145: 441-452, 1994.

31. Martin W.J. Stealth viruses as neuropathogens. College of American Pathologist's publication "CAP Today" 8 67-70, 1994

32. Martin WJ. Stealth virus isolated from an autistic child. J. Aut. Dev. Dis. 25:223-224,1995

33. Martin WJ, Ahmed KN, Zeng LC, Olsen J-C, Seward JG, Seehrai JS. African green monkey origin of the atypical cytopathic 'stealth virus' isolated from a patient with chronic fatigue syndrome. Clin. Diag. Virol. 4: 93-103, 1995.

34. Martin WJ. Severe stealth virus encephalopathy following chronic fatigue syndrome-like illness: Clinical and histopathological features. Pathobiology 64:1-8, 1996.

35. Martin WJ. Stealth viral encephalopathy: Report of a fatal case complicated by cerebral vasculitis. Pathobiology 64:59-63, 1996.

36. Martin WJ. Simian cytomegalovirus-related stealth virus isolated from the cerebrospinal fluid of a patient with bipolar psychosis and acute encephalopathy. Pathobiology 64:64-66, 1996. 10. Gollard RP, Mayr A, Rice DA, Martin WJ. Herpesvirus-related sequences in salivary gland tumors. J. Exp. Clin. Can. Res. 15: 1-4, 1996.

37. Martin WJ. Genetic instability and fragmentation of a stealth viral genome. Pathobiology 64:9-17, 1996. 12. Martin WJ, Glass RT. Acute encephalopathy induced in cats with a stealth virus isolated from a patient with chronic fatigue syndrome. Pathobiology 63: 115-118, 1995.

38. Martin WJ. Detection of RNA sequences in cultures of a stealth virus isolated from the cerebrospinal fluid of a health care worker with chronic fatigue syndrome. Pathobiology (in press)

39. See DM, Tilles JG.Immunol Invest. alpha-Interferon treatment of patients with chronic fatigue syndrome.1996 Jan-Mar;25(1-2):153-64.

40. Brook MG, Bannister BA, Weir WR. Interferon-alpha therapy for patients with chronic fatigue syndrome. J Infect Dis. 1993 Sep;168(3):791-2.

41. J K S Chia. The role of enterovirus in chronic fatigue syndrome. J. of clin Path 2005;March 14:1126-1132.

42. Marwan Y. Nasralla, Jörg Haier, Nancy L. Nicolson Garth L. Nicolson. Examination of Mycoplasmas in Blood of 565 Chronic Illness Patietns by Polymerase Chain Reaction.. International Journal Medicine Biology Environment 2000; 28(1):15-23.

43. Nasralla M, Haier J, Nicolson GL. Multiple mycoplasmal infections detected in blood of patients with chronic fatigue syndrome and/or fibromyalgia syndrome. Eur J Clin Microbiol Infect Dis 1999 Dec;18(12):859-65.

44. Gerhard K. M. Endresen. Mycoplasma blood infection in chronic fatigue and fibromyalgia syndromes. Rheumatology International Issue: Volume 23, Number 5 September 2003: 211 – 215

45. Marwan Nasralla, Ph.D., Joerg Haier, M.D., Ph.D. and Garth L. Nicolson, Ph.D. Mycoplasmal Infections in Blood from Patients with Chronic Fatigue Syndrome, International CFS Conference, Sydney, Australia, 1998.

46. Lerner AM, Beqaj SH, and Deeter RG et al. A six-month trial of valacyclovir in the Epstein-Barr virus subset of chronic fatigue syndrome: improvement in left ventricular function. Drugs of Today. 2002;38:549-561.

47. Lerner AM, Zervos M and Dworkin HJ et al. New cardiomyopathy: A pilot study of intravenous ganciclovir in a subset of the chronic fatigue syndrome. Infectious Diseases In Clinical Practice 1997;6:110-117.

48. Vojdani A, Choppa PC, Tagle C, Andrin R, Samimi B, Lapp CW. Detection of Mycoplasma genus and Mycoplasma fermentans by PCR in patients with Chronic Fatigue Syndrome. FEMS Immunol Med Microbiol 1998 Dec;22(4):355-65

49. Vojdani, Aristo, and Al Robert Franco. Multiplex PCRF for the Detection of Mycoplasma fermentans, M. hominis, and M. penetrans in Patients with Chronic Fatigue Syndrome, Fibromyalgia, Rheumatoid Arthritis, and Gulf War Syndrome. Journal of Chronic Fatigue Syndrome Vol. T, No. ¾, 1999, pp. 187-197;

50. Vojdani, A, Franco A. Chronic Fatigue Syndrome: Advance in Epidemiologic, Clinical, and Basic Science Research. 1999, pp. 187-197. The Haworth Press, Inc., 1999

51. Choppa PC, Vojdani A, Tagle C, Andrin R, Magtoto L. Multiplex PCR for the detection of Mycoplasma fermentans, M. hominis and M. penetrans in cell cultures and blood samples of patients with chronic fatigue syndrome. Mol Cell Probes 1998 Oct;12(5):301-8

52. Nicolson G, Nasralla M, Franco R, DeMeirleir K et al. Role of Mycoplamsal Infections in Fatigue Illness: Chronic Fatigue and Fibromyalgia Syndromes, Gulf War Illness and Rheumatoid Arthritis. Journal of Chronic Fatigue Syndrome 2000;6(3/4):23-39.

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Neurotoxins - A cause of Chronic Fatigue Syndrome/Fibromyalgia

There is evidence that a subset of CFIDS and FM patients are suffering from chronic neurotoxin exposure. Research by K. Hudnell and R. Shomaker has shown that different infections can produce neurotoxins, resulting in symptoms that can not be differentiated from CFIDS/FM or be the cause of these syndromes. Symptoms include poor memory, fatigue, headache, rash, burning skin, eye irritation cough, light sensitivity, muscle aches, diarrhea, poor concentration, shortness of breath, abdominal pain and/or dizziness.

Neurotoxin production has been clearly demonstrated to be the result of Estuary-Associated Syndrome as discussed in the reference below, but numerous bacteria, viruses and yeast can also produce neurotoxins. These include Epstein bar virus (EBV), cytomegalovirus (CMV), HHV6, Borrelia burgdorferi (lyme’s disease), mycoplasma, enteroviruses, Chlamydia pneumonia, Candida and other molds.

The body tries to rid itself of the neurotoxins by excreting them into the intestines via the bile. This however does not work because these small compounds are reabsorbed from the GI tract and continue to poison the system. This is termed entero-hepatic circulation. Neurotoxins can affect all parts of the body and are diagnoses with a special visual test. Once diagnosed, the neurotoxins can be eliminate with a special regimen consisting of Questran, mega dose vitamin C and an alkalinizing diet along with eradication of the toxin producing infection.

I have found that there are a percentage of patients that have documented CFIDS or FM actually do suffer form neurotoxin poisoning. These patients can be cured in a matter of weeks with eradication of the infection and elimination of the neurotoxins.

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Is Abnormal Mitochondria Function at the Heart of Chronic Fatigue Syndrome and Fibromyalgia?

A number of studies have demonstrated that there is mitochondrial dysfunction in chronic fatigue syndrome and fibromyalgia patients. The mitochondria are the energy factories for the cells where sugar is burned and energy is produced in the form of ATP (adenosine-tri-phosphate). When the mitochondria are not working properly, the cells and tissues of the body are starved for energy. This abnormality may be the common endpoint for all the dysfunctions present in CFIDS and fibromyalgia. No sugar is burned resulting in weight gain, and no energy is produced, resulting in fatigue, muscle pain, poor concentration, gastrointestinal dysfunction, headaches, etc. A Great Britain Study demonstrated that 70 percent of CFIDS patients have ultrascructurally abnormal mitochondria. Mitochondria can be poisoned by numerous substances, including environmental toxins, pesticides, chronic bacterial, viral and fungal infections, neurotoxins and nutritional and hormone deficiencies.

Mitochondrial function can be boosted by removing the offending agent when it can be identified, such as infection, toxin, or hormone deficiency and/or by supplementing with mitochondria nutritional support. There are a number of supplements that can be effective. These include L-Carnitine, NADH, alpha-lipoic acid, malic acid, coenzyme Q10, adenosine mono-phosphate, riboflavin, selenium, vitamin k3 and magnesium. For instance a study published in the journal of Neuropsychobiology demonstrated that supplementation with L-carnitine for 2 months resulted in a significant improvement in symptoms. A study in the Annals of Allergy, Asthma and Immunology demonstrated that supplementation with NADH for one month resulted in significant improvement and numerous studies have shown improvement with magnesium, although minimal. In order to achieve optimal results one must both remove the offending agent and concurrently boost with mitochondria with nutritional support. This can result in drastic improvements in CFIDS and fibromyalgia symptoms.

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Molecular Dysfunction in CFIDS/Fibromyalgia being Revealed

While chronic fatigue syndrome and fibromyalgia have been recognized for many years, their underlying cause has been poorly understood. One important and interesting aspect of these conditions is the unusual susceptibility of individuals to a variety of chronic infections. These infections include viruses such as Epstein-Barr (EBV), HHV-6, enteroviruses and Cytomegolvirus (CMV), bacteria such as Mycoplasma and Chlamydia Pneumonia and yeast such as Candida. This unusual susceptibility to infections is suggestive of impaired immunity, but no single, consistent immune defect is observed although a number of deficiencies have been reported.

Recent advances in the study of intracellular communication are providing key insights into the immunological defect that may be underlying chronic fatigue syndrome and fibromyalgia. A number of research groups have reported an abnormality of an enzyme called human leukocyte elastase (HLE). This abnormal elastase enzyme degrades two important proteins required for normal immune function. One protein is called STAT1 and the other one called RNase-L, which are required for the white cells to utilize interferon and respond to the types of infections seen with these conditions. Consequentially, CFIDS and FM patients are not able to eradicate chronic infections like those without these conditions. For instance, it is not uncommon for patients to be able to point to a viral infection that they never fully recovered from. In normal individuals, the virus “runs its course” and is cleared in days to weeks. With chronic fatigue syndrome and fibromyalgia, the body is not able to completely rid the body of the virus. This results in a chronic low grade infection, causing fatigue, muscle pain and the other symptoms commonly seen in these conditions. The viruses often have intermittent replication, resulting in the varying nature and periodic worsening of symptoms often seen with these conditions.

A number of methods have already been developed to suppress this abnormal elastase enzyme. We currently use a number of them in the Centers, which include both natural and prescription medications.

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Hypercoagulable State and Chronic Fatigue Syndrome and Fibromyalgia

New research is indicating that many chronic fatigue syndrome (CFS) and fibromyalgia (FMS) patients are in a state of low level activation of the coagulation system and treatment of this coagulation activation can result in a complete or partial resolution of symptoms. Studies have found that approximately 80% of CFS and FM patients have this low level activation of the clotting system. This low level activation does not produce a blood clot, but rather an intermediate substance called a soluble fibrin monomer (SFM). This coats the inside of the blood vessel and limits oxygen and nutrient flow into the cells, resulting in the symptoms of CFS and FMS including fatigue, muscle pain, brain fog and sleep disturbances. It has been found that 40% of CFS/FMS patients have a genetic predisposition for the production of too much SFM, while 50% have a genetic predisposition that limits the breakdown of the SFM. Both conditions result in excessive SFM coating of the blood vessels.

This genetic predisposition can be set into action by a number of factors, including trauma, exposure to heavy metals, toxins pesticides and molds and viral, yeast and bacterial infections, including, Epstein Bar Virus (EBV), Cytomegalovirus (CMV), HHV6, Parvovirus, Enterovirus, Mycoplasma, Chlamydia Pneumonia and Lyme’s disease. The SFM coating not only limits the oxygen and nutrient flow, but it also provides a place for the virus, yeast and bacterial to “hide” and escape destruction by the immune system. Thus, it is very difficult for CFS/FMS patients to rid the body of these infections when compared to healthy individuals.

Diagnosis is made by the use of a specialized test called an ISAC (Immune System Activation of Clotting) panel, which measures platelet activation, soluble fibrin monomer, fibrinogen, prothrombin fragment 1 +2 and thrombin/antithrombin complexes. Treatment includes low dose heparin and substances to break up the fibrin as well as elimination of the initiating agent, whether it is a virus, bacteria, yeast or toxin. Intervention can be from several weeks to a number of months. We utilize this treatment at the Fibromyalgia and Fatigue Centers and have seen some dramatic improvements and sometimes complete resolution of symptoms.

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Growth Hormone Treatment of Fibromyalgia and Chronic Fatigue Syndrome

It has been shown that chronic fatigue syndrome and fibromyalgia patients have abnormal sleep patterns with a deficiency in stage 4 sleep (1). Stage 4 sleep is closely related to the pulsatile secretion of growth hormone and 80% of the total daily secretion of growth hormone is during this stage. It has also been shown that chronic fatigue syndrome/fibromyalgia patients are unable to mount a normal growth hormone response to exercise as compared to healthy individuals (2). Thus, it is not a surprise that growth hormone secretion is shown to be deficient in chronic fatigue syndrome/fibromyalgia patients (2-5), with lower than average IGF-1 levels (a marker for growth hormone secretion) (4,6,7). Supplementation of this deficiency with growth hormone is shown to result in significant symptomatic improvement in these conditions (6). As is the case with thyroid and cortisol production in these patients, where there are significant deficiencies in these hormones despite seemingly normal standard testing (8,9), it has also been shown that these patients have a relative growth hormone deficiency despite typically “normal” or low-normal serum markers of IGF-1 (2-4,7).

 

Bennett et al found that 92% of patients with fibromyalgia have pituitary dysfunction that results in low growth hormone secretion and that fibromyalgia patients have significantly lower IGF-1 levels that averaged 138 +/- 56 versus 215 +/- 86 (p = 0.00000000001) in non-fibromyalgia patients, demonstrating significant growth hormone deficiency despite IGF-1 levels in the “normal” range (4). This is consistent with another study that also found that fibromyalgia patients had deficient growth hormone as demonstrated by IGF-1 levels that averaged 124 +/- 47 ng/ml versus 175 +/- 60 ng/ml (p = 0.000001) in normal healthy individuals. The authors conclude, “These findings indicate that there is a distinctive disruption of the growth hormone-somatomedin C (IGF-1) neuroendocrine axis in a majority of fibromyalgia patients (7).”

 

In a subsequent double-blind, placebo-controlled study, the effectiveness of growth hormone supplementation in fifty women with fibromyalgia and low normal IGF-1 levels (< 160 ng/ml) was studied. Patients were treated with growth hormone to maintain an IGF-1 of 250 ng/ml for 9 months. It was found that fibromyalgia patients treated with growth hormone had significant improvement in symptoms as measured by the Fibromyalgia Impact Questionnaire and a significant reduction in muscle pain as measured by the tender point score compared to placebo. The treatment group also noted an increased sense of well-being and an increased ability to sustain increased levels of activity without the usual increase in muscle pain. The authors conclude, “Women with fibromyalgia and low IGF-1 levels experienced an improvement in their overall symptomatology and number of tender points after 9 months of daily growth hormone therapy. This suggests that a secondary growth hormone deficiency may be responsible for some of the symptoms of fibromyalgia (6).” There was a lag of about 6 months before patients noted improvements, but other studies, as well as our own experience, demonstrate that beneficial effects typically occur approximately 2-3 months after starting replacement.

 

Diagnosis of growth hormone deficiency

 

The diagnosis of growth hormone deficiency is a clinical diagnosis based on symptoms and is often supported by laboratory (IGF-1) testing. As shown in the study by Bennett et al, a relatively low IGF-1 level in the normal range demonstrates a relative growth hormone deficiency and it is reasonable to give a trial of growth hormone replacement in these patients if the IGF-1 level is below 200 ng/ml and there is a clinical diagnosis of growth hormone deficiency.

 

While many endocrinologists feel the diagnosis of growth hormone deficiency requires the use of growth hormone stimulation testing (dynamic testing), growth hormone and other stimulation tests are shown to be inaccurate, highly variable, nonphysiologic, lack adequate sensitivity to detect relative growth hormone deficiencies, do not correlate with the presence of deficiency and do not predict who will respond to therapy (3,5,9-20). Requiring stimulation testing to confirm growth hormone deficiency is unnecessary, expensive and carries significant risk to the patient. Thus, they neither are appropriate to perform nor required for the diagnosis of growth hormone deficiency.

 

Allaine et al found significantly attenuated IGF-1 levels in CFS patients (214 +/- 17 ug/l versus 263 +/- 13 ug/l) as well as reduced IGF-II, IGFBP-1 and peak growth hormone response to insulin tolerance testing (ITT), demonstrating abnormal production of growth hormone in this patient population. If, however, standard cutoffs were used with the ITT to define a normal response, the CFS patients would have been labeled as having normal growth hormone production, although this clearly was not the case (5).  

 

Hoeck et al evaluated the accuracy of the ITT, which is considered to be the most reliable (and risky) of the dynamic tests. They found that there was no correlation between results of repeated ITT’s, and the results were no better than flipping a coin. The authors conclude, “The results of this study illustrate the complexity of the regulation of GH secretion and indicate that the ITT is less useful for diagnosing growth hormone deficiency in adults than previously anticipated. The diagnosis of growth hormone deficiency in adults and especially in adult females should not be based on the results of a single ITT alone (14).”

 

Similarly, Hoeck and Jakobsen, et al evaluated the accuracy and reliability of commonly used stimulation tests. On each subject, 2 ITT, 2 GHRH, 2 clonidine + GHRH were done and then a pyridostigmine + GHRH stimulation tests were done on an extended group of subjects. It was found that there was no correlation in the results of the different tests and the results were not reproducible. The authors conclude, “In the individual subject, there was no systematic correlation between the peak growth hormone responses in the different stimulation tests. In conclusion, we found that the stimulated growth hormone responses were highly variable in all tests, and that the peak GH responses differed (15).” The authors expressed caution in the use and interpretation of stimulation tests in the diagnosis of growth hormone deficiency.  

 

This use of growth hormone stimulation testing in the diagnosis of growth hormone deficiency was reviewed by Rosenfeld et al in the Journal of Endocrinology and Metabolism. The authors state, “[stimulation testing] is often limited and relies on testing procedures that are, generally, nonphysiolgical, arbitrary, invasive, risky, and subject to considerable interassay variability (10).”

 

Moorkens et al evaluated the growth hormone secretion in chronic fatigue syndrome patients as compared to normal controls. This study compared physiologic nocturnal secretion, IGF-1 levels and response to various commonly used stimulation tests. This study found that CFS patients have an abnormally low production of growth hormone, as demonstrated by reduced nocturnal secretion of growth hormone and a significantly decreased GH response to ITT (both peak and AUC). The commonly used stimulation tests were shown, however, to have no correlation with ITT testing results (which again has significant risk), and that these stimulation tests were shown to lack the sensitivity to detect significant growth hormone deficiency in these patients (3).

 

In a prospective, randomized placebo controlled study, Rahim et al assessed the accuracy and reliability of commonly used stimulation tests by performing four different stimulation tests on each individual (ITT, glucagon, arginine and clonidine). As with other studies, this study also found that there was no correlation between the response to different agents in the same individual. Subjects who failed to achieve a growth hormone peak greater than 20mU/l in one test were not the same individuals who responded poorly to other tests. Again, the results of the stimulation tests were no better than flipping a coin. This study also demonstrated the risk and side-effects of performing such testing; all patients suffered from significant hypotension; over half of the patients could not carry out normal daily activities for the rest of the day after the tests; venous thrombosis occurred in over a third of patients and over 10% had significant nausea and vomiting (17). There have also been reported deaths and neurological damage associated with growth hormone stimulation testing (21).

 

Cacciari et al investigated the sensitivity of utilizing growth hormone stimulation tests in 98 children with clear evidence of impaired growth hormone production compared to 274 healthy controls. They found that growth hormone deficiency correlated with IGF-1 levels, but that standard arbitrary cutoffs of what is considered to be a normal IGF-1 level and the use of growth hormone stimulation tests with standard cutoffs lacked sufficient sensitivity. The majority of patients with clear evidence for growth hormone deficiency would have been inappropriately labeled as normal and children who would likely have benefited from treatment would have been left untreated. The authors conclude, “Our data adds weight to the opinion that present criteria for defining growth hormone deficit may be too restrictive. Consequent implications regarding therapy are evident (16).”  

 

Wilson et al reviewed the use of growth hormone stimulation tests in determining a person’s growth hormone secretory status in a 2005 edition of Growth Hormone & IGF Research. They state, “Historically, growth hormone stimulation testing has played a prominent role in diagnosing growth hormone deficiency. There are growing concerns, however, that growth hormone stimulation testing, particularly as currently conducted in the USA, is neither precise nor accurate in quantifying a patients growth hormone secretory status (18).”

 

Tassoni et al tested the variability of growth hormone stimulation tests in the Journal of Endocrinology and Metabolism. They performed several commonly used stimulation tests in duplicate as well as 12-hour overnight physiologic growth hormone secretion testing. They found that there was little or no correlation between repeated testing in the same individuals (coefficient of variance being 89% in one group and 66% in another) as well as little correlation with physiologic night-time growth hormone secretion. When the same stimulation test was repeated on the same individual, over half had disparate results (showing deficient on one test and normal on the other). Again, the results were almost no better than flipping a coin. They state that growth hormone stimulation tests cannot be used with any confidence to diagnose or rule-out growth hormone deficiency and recommend that repeated 12-hour overnight physiologic growth hormone secretion testing be utilized. This requires, however, that multiple venous samples be obtained throughout the night via an indwelling catheter, which is not practical outside of a research setting. The authors state, “In conclusion, the usual approach for evaluation growth hormone secretion does not take into account the variability of the response to the various tests. This may be misleading, especially for patients that have hormone secretion at the lower limit of normalcy (19).”

 

Gandrud et al reviewed the use of growth hormone stimulation testing in the 2004 Growth Hormone & IGF Research. This extensive review clearly demonstrates that growth hormone stimulation tests lack precision and accuracy, are not concordant with the proper diagnosis of growth hormone deficiency and do not predict response to therapy. They recommend that the diagnosis of growth hormone deficiency should be based on clinical parameters as well as IGF-1 and state, “…the insulin tolerance test using the current cutoff for failure should not be considered the gold standard for the diagnosis of growth hormone deficiency…We examined the pitfalls associated with growth hormone stimulation tests, specifically, the lack of reliability and accuracy of these tests, and their inability to predict who will benefit from growth hormone therapy. We recommend that growth hormone stimulation tests no longer routinely be used for the diagnosis of growth hormone deficiency…(20).”

 

Conclusion: Chronic fatigue syndrome and fibromyalgia patients are shown to have a relative deficiency of growth hormone and supplementation with growth hormone can be of significant benefit. A clinical diagnosis of growth hormone deficiency, often with support of low or low-normal IGF-1 levels, are the most appropriate means of making the diagnosis of relative growth hormone deficiency. Growth hormone stimulation tests are shown to be inaccurate, unreliable, highly variable, risky, nonphysiologic and lack adequate sensitivity to detect relative growth hormone deficiencies. Thus, the growth hormone stimulation tests generally do not add significant useful information in the clinical management of these patients and are not recommended in this patient population.

References

1. Moldofsky H, Scarisbrick P, England R, Smythe H. Musculosketal symptoms and non-REM sleep disturbance in patients with "fibrositis syndrome" and healthy subjects Psychosomatic Medicine 1975;37(4):341-51.

2. Paiva ES, Deodhar A, Jones KD, Bennett, RM. Impaired growth hormone secretion in fibromyalgia patients: evidence for augmented hypothalamic somatostatin tone. Arthritis Rheum 2002;46(5):1344-50.

3. Moorkens G, Berwaerts J, Wynants H, Abs R. Characterization of pituitary function with emphasis on GH secretion in chronic fatigue syndrome. Clin Endo 2000;53:99-106.

4. Bennett RM, Cook DM, Clark SR, Burckhardt CS, Campbell SM. Hypothalamic-pituitary-insulin-like growth factor-I axis dysfunction in patients with fibromyalgia. J Rheumatol 199l;24(7):1384–1389

5. Allain TJ, Bearn JA, Coskeran P, Jones J, Checkley, et al. Changes in growth hormone, insulin, insulin like growth factors (IGFs), and IGF-binding-1 in chronic fatigue syndrome. Biol Psychiatry 1997;41:567-73. 

6. Bennett RM, Clark SC, Walczyk J. A randomized, double-blind, placebo-controlled study of growth hormone in the treatment of fibromyalgia. Am J Med 1998;104(3):227-31.

7. Bennett RM, Clark SR, Campbell SM, Burckhardt CS. Low levels of Somatomedin C in patients with fibromyalgia syndrome. Arthritis & Rheumatism 1992; 35(10):1113-6.

8. Neeck G, Riedel W. Thyroid Function in Patients with Fibromyalgia Syndrome. J Rheumatology 1992:19-7:1120-1122.

9. Holtorf K. Diagnosis and treatment of hypothalamic-pituitary-adrenal (HPA) axis dysfunction in patients with chronic fatigue syndrome (CFS) and fibromyalgia (FM). J Chronic Fatiue Syndrome 2008;14(3).

10. Rosenfeld et al. Diagnostic Controversy: The diagnosis of childhood growth Hormone deficiency revisited. Journal of Endocrinology and Metabolism 1995;80(5):1532-40.

11. Cacciari E, Cicognani A, Pirazzoli P, Tassoni P, Salardi S, Capelli M, Zucchini S, Natali G, Righetti F, Ballardini D.Differences in somatomedin-C between short-normal subjects and those of normal height. J Pediatr. 1985 Jun;106(6):891-4.

12. Bennett R. Growth Hormone in Musculoskeletal Pain States. Current Pain and Headache Reports 2005, 9:331-338

13. Maghnie M et al. Diagnosis of GH deficiency in the transition period: accuracy of insulin tolerance test and insulin-like growth factor-I measurement. European Journal of Endocrinology 2005;152(4):589-96.

14. Hoeck HC, Vestergaard P, Jakobsen PE, Laurberg P. Test of growth hormone secretion in adults: poor reproducibility of the insulin tolerance test. Eur J Endo 1995;133:305-12.

15. Hoeck HC, Jakobsen PR, Vestergaard P, Falhof JF, Laurberg P. Differences in reproducibility and peak growth hormne responses to repeated testing with various stimulators I health adults. Growth Hormone & IGF Research 1999;9:18-24.

16. Cacciari E, Cicognani A, Pirazzoli P, Tassoni P, Salardi S, et al. Differences in somatomedin-C between short-normal subjects and those of nomal height. J Pediatrics 1985;106:891-4.

17. Rahim A, Toogood AA, Shalet SM. The assessment of growth hormone status in normal young adult males using a variety of provocative agents. Clin Endo 1996;45:557-62.

18. Wilson DM, Frane J. A brief review of the use and utility of growth hormone stimulation testing in the NCGS: Do we need to do provocative GH testing? Growth Hormone & IGF-1 Research 2005;15:S21-5.

19. Tassoni P, Cacciari E, Cau M, Colli C, et al. Variability of growth hormone response to pharmacological and sleep tests performed twice in short children. J Endo Met 1990;71(1):230-4.

20. Gandrud LM, Wilson DM. Is growth hormone stimulation testing in children still appropriate? Growth Hormone & IGF-1 Research 2004;14:185-94.

21. Shah A, Stanhope R, Matthew D. Hazards of pharmacological tests of growth hormone secretion in childhood. BMJ 1992;304:173-4.








Irritable Bowel Syndrome and CFIDS/Fibromyalgia

Recent studies demonstrate the majority of chronic fatigue syndrome and fibromyalgia patients suffer from bowel dysfunction, with the majority being irritable bowel syndrome (IBS). IBS can be significantly debilitating problem in its own right with chronic fatigue syndrome and fibromyalgia. It is a gastrointestinal disorder characterized by bloating, abdominal pain, diarrhea and/or constipation and the absence of any identifiable physical, laboratory or radiological abnormalities indicative of organic disease.

The newest criteria (Rome II) for IBS include at least 12 weeks (need not be consecutive) in the preceding 12 months of abdominal discomfort that is accompanied by at least two of the following three symptoms: the abdominal discomfort or pain is (a) relieved with defection, (b) associated with a change in frequency of defecation and/or (c) associated with a change in the form or appearance of the stool. There are a number of medications that can decrease the symptoms of IBS, but there also are a number of factors that are associated with IBS and when these are identified and treated, the results can be significant. These include food allergies, gluten, wheat sensitivity and small intestine bacterial and yeast overgrowth (SIBO).

A number of studies have documented a connection between SIBO and IBS. This especially appears to be the case with chronic fatigue syndrome and fibromyalgia patients, occurring in 70-90 percent of these patients. The small bowel should be free of bacteria and yeast, but when it is not, the food stuffs are utilized by these bacteria resulting in gas, inflammation, poor absorption, diarrhea and/or constipation. The dysfunctional immunity and frequent diminished stomach acid and digestive enzymes that is often present (including the use of medications designed to decrease stomach acid) in chronic fatigue syndrome and fibromyalgia make these patients more prone to SIBO and subsequently IBS.

There are tests to determine if SIBO is present, including the hydrogen breath test. This involves giving the carbohydrate lactulose and measuring the amount of hydrogen expired by the breath. If certain carbohydrates, such as lactulose, are digested by intestinal bacteria instead of the small intestine or stomach, hydrogen gas is produced and can be measured from the expired breath. Samples are taken every 15 minutes for 2 hours. Due to the fact that SIBO is so common with CFIDS and fibromyalgia, that it can be safety eradicated and that significant improvement or elimination of IBS symptoms can be achieved with treatment, the time and expense of the test is not generally necessary. Eradication of the yeast and bacterial overgrowth can be instituted without undergoing the test, but in addition to eradicating the yeast and bacterial overgrowth, one must also address the other dysfunctions present in order to obtain long term improvement. If the predisposing factors are not addressed, the bacteria and yeast will again populate the small bowel and symptoms will return.




Immune Support Interview



Kent Holtorf, M.D., on Treating Chronic Fatigue Syndrome & Fibromyalgia
ImmuneSupport.com

ImmuneSupport: In your article on the effective treatment of chronic fatigue syndrome and fibromyalgia*, you state that “individuals with these syndromes have measurable hypothalamic, pituitary, immune and coagulation dysfunction. These abnormalities then result in a cascade of further abnormalities, in which stress plays a role.” Could you discuss in as much detail as possible how you approach treating the following problems in CFS and FM patients?

Dr. Holtorf: There is a mixture of underlying causes of chronic fatigue syndrome (CFS) and fibromyalgia (FM), and each underlying abnormality can trigger further problems. This results in a cascade of multiple physiologic abnormalities and a perpetuating viscous cycle. Successful treatment requires that this viscous cycle be addressed on multiple levels. This cascade of abnormalities [beginning with the "Genetic Predisposition" and then "Triggering Event of Physiologic Stress"] is graphically depicted below and a few of the abnormalities are also discussed.

cycle_dysfunction_b.jpg

Immune dysfunction: If a complete immune panel is done on CFS and FM patients, almost all have immune dysfunction, which often includes poor natural killer cell function and/or high RNAse-L activity.

Natural killer cells: These cells are very important in killing viruses and bacteria. It is very difficult to eradicate chronic infections when these cells are not functioning well. Antibiotics and antivirals do not work well and are often infective if the immune system is not stimulated as well. You are never able to kill all the infectious agents unless the body is able to clean up the residual left by the antibiotic or antiviral.

There are a number of methods to do this. What we use depends on the infection present, but includes both natural and pharmaceutical antivirals, antibiotics, immune boosters and immune modulators. Growth hormone, thyroid and cortisol (adrenal hormone) are also very good immune enhancers. Yes, I said cortisol - low doses of cortisol for people who have adrenal insufficiency act as an immune enhancer. Large doses are immune suppressors. Your body normally increases cortisol in times of infection. Oxidative therapies, discussed below, can be very powerful. We customize the specific treatment for the patient.

RNase-L activity: In response to infection, the body can produce an enzyme called RNase-L that breaks down the viral RNA to rid the body of the infection. When the infection is gone this enzyme is then turned off. In CFS, however, the presence of chronic infections can result in the stimulation of an abnormal “super” RNase-L enzyme that also breaks down the cell’s own RNA that is used to code for proteins and required for normal functioning. The result is poorly functioning cells and an increase in cellular apoptosis (programmed cell death). Treatment consists of eradication of the chronic infection and immune modulators. The RNase-L activity can be done by Redlabs USA (www.RedlabsUSA.com). (No affiliation).

Coagulation problems: This is diagnosed with a specialized laboratory test that includes soluble fibrin monomer, prothrombin fragment 1 +2, fibrinogen and thrombin/antithrombin complex. Defects are typically treated with heparin and vascular enzymes such as lumbrokinase and serapeptidase to stop the excessive production of soluble fibrin monomers and to help clean up the fibrin already laid down. Eradication of chronic infections is also important, as there is often a chronic infection as the underlying stimulus of the abnormal activation of coagulation.

Low thyroid: CFS and FM patients almost always have low tissue levels of thryoid hormones due to hypothalamic and pituitary dysfunction and thyroid resistance, which has been documented in a number of studies. Unfortunately, this hypothryiodism is missed 80-90% of the time because standard thyroid tests and TSH levels are usually normal, and this is what 90% of doctors are accustomed to using to diagnose low thyroid. Currently, the best method to diagnose low thyroid in these conditions is to look at the T3/reverseT3 ratio.

When CFS and FM patients are treated with thyroid, they are almost always under-dosed because their pituitary dysfunction results in their TSH becoming quickly suppressed, which normally indicates too much thyroid. Because these patients have pituitary dysfunction, one must not rely on the TSH and not treat based on this parameter. In addition, due to the thyroid resistance, T4 preparations such as Synthroid and Levoxyl cannot provide adequate tissue levels of the active hormone. T4/T3 combinations such as Armour thyroid can be of benefit, but many patients also find that these preparations also do not provide adequate relief. Straight timed released T3 is often the best preparation to obtain adequate tissue levels.

Adrenal insufficiency: Standard blood testing will almost always miss this deficiency. Studies show that with sophisticated testing, close to 100% of CFS and FM have adrenal dysfunction and treatment can be very beneficial. To diagnose, we typically use symptoms and a combination of blood sugar, free cortisol, and HgA1C%. Again, one must have a high clinical suspicion and not just think in terms of normal and abnormal. These normal levels are determined for healthy individuals, not the chronically ill, so the cortisol levels should be higher with this illness. 24-hour urine and saliva tests can be done, but these can also result in false positive and false negative results.

Growth hormone deficiency: Many CFS and FM patients are low in growth hormone. This hormone is produced in the pituitary, and with the documented pituitary dysfunction in CFS and FM, it is not unexpected that there is such a deficiency in these illnesses. Treatment can sometimes make a tremendous impact and because the cost has come down significantly in recent years, it is a viable treatment for more patients. IGF-1 is the best indication for growth hormone levels, but again, one cannot use the standard laboratory normal ranges to diagnose.

ImmuneSupport: Once you’ve determined which problems a CFS or FM patient has, do you prescribe both traditional and alternative treatments, or do you focus on a single method at a time?

Dr. Holtorf: In order to treat these diseases adequately, one must simultaneously use both traditional and so-called alternative treatments. If one treatment were used at a time it would take many years before the patient feels better. Many treatments can be withdrawn as the patient improves.

ImmuneSupport: Please tell us a little bit about the Holtorf Medical Group, Inc: The Center for Hormone Imbalance, Hypothyroidism and Fatigue (www.HoltorfMed.com)where you practice.

Dr. Holtorf: I started the Holtorf Medical Group to concentrate on the treatment of complex endocrine dysfunction, hypothyroidism, fatigue, CFS and fibromyalgia. Eighty percent of our practice is for patients complaining of fatigue, with CFS and FM probably being the biggest part of the practice.

ImmuneSupport: What are the biggest challenges you face with treating CFS and FM patients?

Dr. Holtorf: Although we have good success with CFS and FM, these are challenging cases that require doctors to spend significant time with the patient. It cannot be accomplished with seven-minute office visits.

ImmuneSupport: What are the biggest successes you’ve experienced with treating CFS and FM?

Dr. Holtorf: Many of these patients are very sick and have given up. It is so gratifying to get these patients back to having a life. They are just so grateful. Many have been unable to work and/or have been on disability and now, following treatment, are happy, functional and productive.

ImmuneSupport: Are you working on any promising new treatments at this time – either through research or through a trial and error process with your patients?

Dr. Holtorf: We are continually working on and implementing new treatments every day in practice. We have been using and refining many of the so-called new treatments for many years. For instance, Valcyte is considered a new novel treatment for CFS, but we have been using it for 4 years since is was first approved.

ImmuneSupport: What are the most exciting developments you’ve seen recently in treatment options for CFS and FM?

Dr. Holtorf: Recent developments are taking place in a stepwise manner, but I do not believe it will be through the so-called mainstream medicine one-drug cures. I think these are very treatable conditions and advances will only continue to improve treatment. I do believe, however, that the incidences of CFS and FM will significantly increase and at some point will be considered an epidemic because they are very poorly treated through the standard health care delivery system.

------------------

*“Kent Holtorf, M.D., on Effective Treatment of Chronic Fatigue Syndrome and Fibromyalgia” on ImmuneSupport.com, at http://www.immunesupport.com/library/showarticle.cfm/id/4320

Holtorf Medical Group, Inc:
The Center for Hormone Imbalance, Hypothyroidism and Fatigue (www.HoltorfMed.com) (310) 375-2705

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Immune Support Interview #2



The Fibromyalgia & Fatigue Centers: Bringing Patients Effective Treatment Across the US
ImmuneSupport.com

06-25-2004

An interview with Mr. Robert S. Baurys, CEO and Dr. Kent Holtorf, Chief Medical Officer of the Fibromyalgia & Fatigue Centers, Inc.

ImmuneSupport.com: Please talk about how and when the Fibromyalgia & Fatigue Center was conceived, who was involved in establishing it, and what makes it unique.

Baurys: I first came down with fibromyalgia five years ago, and like so many patients it took over a year and a half, many doctors, lots of tests and a lot of wrong guesses before I was properly diagnosed.

But even then I still didn’t have any answers as to how to get my life back to normal. Having a strong background in health care I knew I needed to educate myself on this condition if I was ever going to find the answer to how to control it. And I also knew at that point, that if I ever did find treatments that would allow me to live a normal life again, I would do everything in my power to make it accessible to the millions of people all over the country who have FM and CFIDS.

After a lot of research and time spent talking to doctors who thought they knew what to do to make it bearable, I realized that frequently I knew more than the doctors did and no one really had a good idea of what to do. Until I found Dr. Holtorf. Kent was practicing in Torrance, CA and he specialized in FM and CFIDS patients. He himself has been struggling with CFIDS for 20 years and has spent much of that time researching and understanding exactly all the things that happen to the body when these conditions are present. He has treated over 3,500 patients and has remarkable outcomes with the majority of his patients able to lead normal productive and active lives once again. His approach made sense and so I became a patient. That was about a year ago.

Within a few months I was feeling great and asked Kent if we could teach other physicians all the complexities of the conditions and train them how to treat them to achieve the same incredible outcomes he had been having in his own practice. His answer was yes, and so the Fibromyalgia & Fatigue Centers (FFC) were established.

I have about 20 years experience in business development and part of that time was spent creating and establishing wound care centers all over the country. So, with Kent and my long time business partner Sue Hrim, who is also a registered nurse, we began outlining the prototype for the Centers and assembling our management team. Sue and I have been fortunate to have worked with very talented people throughout our careers, and when we asked some of these people to come and work with us to establish centers all over the country, they said yes. That was in November 2003.

Dr. Holtorf: What makes us unique are a couple of things. First, we really do understand the conditions we are treating. With both the CEO and the Chief Medical Officer living with these conditions every day, we have a first hand understanding of what it is like for our patients to do normal every day tasks most people take for granted. We also have a unique integrated approach to treating the patient which involves looking in-depth at everything that is going on with that person and treating the causes of the symptoms, not just the symptoms that are presenting during their appointments. We only use medications to ease symptoms, not mask them. And we really take our time with each patient.

Since the Center physician’s job is exclusively treating patients. He or she can take the time needed to really get to know the whole patient and create an individualized care plan for them. And finally, while there are a few physicians in the country that have pretty good outcomes in this field, they do not have the know how to replicate what they are doing in their practice to be able to reach out to patients nationwide and still maintain the quality of the outcomes. This combination of a unique clinical algorithm and the business savvy to expand nationwide is what really set us apart.

ImmuneSupport.com: Do you have a standard approach or program for treating CFS and FM patients? There is some information on your website http://www.fibroandfatigue.com regarding the "proven 6 step approach" that is used at your centers. Please describe the 6 steps.

Dr. Holtorf: As you may know, FM and CFIDS present differently in each patient. And even in each patient, the symptoms may vary in degree of severity from day to day, so there is no “one size fits all” treatment for these conditions. The treatment protocol is individualized for each patient, but we always follow our unique “six step approach” to determine what is wrong with each patient and then customize their treatment.

This integrated program addresses the underlying etiologies that cause those symptoms with the long term goal being elimination and/or significant reduction leading to a long term maintenance plan. Since treatment needs to be individualized, phases may occur in different orders and multiple phases are often done simultaneously, but simply put these phases can be broken down as follows:

  • stabilize the patient by addressing pain and sleep disturbances;
  • promote energy by enhancing the powerhouse of each cell, the mitochondria;
  • balance hormones by evaluating hypothalamus and pituitary function;
  • enhance immunity and treat underlying viral infections;
  • address unique etiologies such as neurotoxins and coagulation defects;
  • provide each patient with an individual maintenance program with the minimally necessary medications and supplements to assure absence of symptoms.

With over 3,550 patients treated using this method, and the majority of them having a significant increase in energy and decrease in pain we know that when implementing the full six-step approach, significant recovery or complete resolution of symptoms is the rule rather than the exception.

ImmuneSupport.com: Are your treatments expensive compared to traditional doctor's office visits? Do you accept insurance?

Baurys: When you think about the fact that the standard office visit gives you 8-10 minutes at most with the physician, and the patient usually pays a $20 co-payment per visit and the insurance company pays the physician another $45-50 per visit that makes the payment rate of $65-70 per 10 minute visit or $390- $420 per hour visit, if you were allowed to have such a thing in today’s reimbursement driven society.

At the FFC the patient spends between 60-90 minutes with the physician on their first two visits and the rate for those visits is $325. And then there is the additional time spent with the nurse and/or physician should treatments be given during those initial visits. After that each follow-up visit is $165 and usually lasts about 30 minutes with the doctor. So comparatively we are a bargain when you look at the time spent with the physician and the total cost and more importantly the outcome.

One of the reasons we can do what we do the way we do it and achieve the outcomes we do is the fact that we don’t accept insurance. If we took insurance payments we would be relegated to fall into the insurance model of the 10 minute office visit, since that is all the companies are willing to pay for. There is no way a physician can adequately get to know a patient and their condition in 10 minutes or less, and work out an individualized treatment protocol to get them on the road to wellness. It is just impossible.

We do however provide our patients with the necessary documentation should they choose to submit their claim for potential reimbursement. Most PPO insurance plans will reimburse the patient for out-of-network visits and that reimbursement rate usually ranges anywhere from 30% - 80% of the cost of the visit. So when you think about getting reimbursed for even 50% of the visit that means the out of pocket cost to the patient is only $160 for a 60-90 minute visit.

When you realize the average patient is probably seeing multiple doctors regularly for different symptoms caused by FM and CFIDS, then you know they probably spend that much every four to six weeks in co-pays alone and without improvement in their condition. To make it easier for our patients, we do have Quest Labs in each of our centers to do the blood draws and most of the lab work, and Quest will bill the patients’ insurance carrier directly.

ImmuneSupport.com: What do you believe are the biggest benefits of the Fibromyalgia & Fatigue Centers for patients seeking effective treatment?

Dr. Holtorf: The biggest benefits are the same things that make us different. Our patients are seen by health care providers who really understand their struggle and the challenges that living with FM and CFIDS brings to every day life. They ask questions and really get to the root of the problems and then aggressively work to get it under control. We are conveniently located and expanding all over the country so patients don’t have to travel great distances to get help. And we are affordable since treatment needs decrease as the condition improves and our goal is eventually for our patients to be able to live an active life with just minimal long term treatments to keep their FM AND CFIDS under control. But the most important benefit is our patients improve and regain quality to their lives, and after all, that is what it is all about.

ImmuneSupport.com: How many locations do you have so far, and what are your plans for adding additional locations in the future? How do you choose locations?

Baurys: We currently have Centers in Torrance, Dallas, Cleveland and Denver and we are opening in Atlanta, Houston, Long Island, Minneapolis, Detroit and Seattle by the end of 2004. Our ultimate goal is 30 Centers by the middle of 2006 and we are well on our way.

City selection is based on a variety of things. Our first FFC locations were selected to offer a reasonable option for patients in all regions of the country. We generally pick cities with high populations, major airports and easy access around the local area. Our first goal is to make sure we have FFCs covering all regions of the country and after that in 2005 we will fill in with additional Centers in each region. We also look at where there are hot spots for FM and CFIDS. Weather plays a big part in severity of symptoms and so we look at where weather conditions make it worse and we will have a heavier concentration of Centers in those areas.

ImmuneSupport.com: What can you offer patients with more recalcitrant cases of FM and/or CFS?

Dr. Holtorf: The majority of our patients are the tougher cases. We get referrals from other physicians who can’t or don’t know what to do to help their patients feel better. We get patients who have been struggling for 10-15 years, or even longer in some cases, and who have just about given up hope of ever feeling somewhat normal again.

When we review their medical history it sounds so familiar - years of struggle to figure out what is wrong, wrong diagnoses, at least 8-10 different physicians visited, hopes dashed and finally resignation that their life will be filled with pain and fatigue until the end. These patients are no different than those we see that have not yet been diagnosed or are newly diagnosed; the only difference is that the latter has not, in most likelihood, lost hope.

So to all our patients we offer hope, hope that you can realize optimal results if we work together to get your body back in balance and correct the problems that are causing your pain and fatigue. We also offer our proven method to help you regain control of this condition that has taken control of your life. We know that mild cases or more established and complex cases can all benefit from our approach and treatments.

ImmuneSupport.com: How many physicians are staffed at each location, and are patients able to choose a doctor - or several doctors if needed, to work with them on their treatment?

Baurys: Currently, each FFC is staffed with one physician who is the primary health care provider along with the RN Case Manager, who oversees the coordination of the patients care plan. Since getting to know the patient and their condition in such detail is the hallmark of our approach and critical to the success of developing the treatment plan for each patient, we felt it was important to have one highly trained physician responsible for the care of the patients in each location. The “partnership in healing” relationship that develops between the patient and the physician is one of the keys to positive outcomes.

We do however work with other healthcare providers outside our center in a cooperative collaboration for the care of the patient. If a patient is currently undergoing some adjunctive therapies that are proving to be beneficial to their condition, we will work with those health care providers to ensure a seamless integration of that therapy into the treatment plan. Occasionally, we will even recommend some therapies that require specialized treatment by other health care providers (i.e., sleep studies to pinpoint more complex sleep issues, etc.) and we will help coordinate that care. We also keep referring physicians abreast of patient progress if so requested.

ImmuneSupport.com: Do you think your centers work best for patients who take a more active role in their care and healing?

Baurys: Patients need to know they have a choice to live a full and productive life. It takes some significant level of commitment to get control of your life again but it can be done with the help of experienced and caring people. There are several steps to assuming a controlled pathway, all of which are critical to the outcome:

  1. You must decide that you truly want control of your life again. This is important as it becomes very easy to get inwardly focused on controlling the pain and minimizing the exposure instead of living your life. You need to decide if you really want control of your life again.
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  2. You must select your support team carefully. As you have undoubtedly already heard, some physicians still think this is a mental condition, not physically based. Thankfully, the overwhelming research has shown most intelligent practitioners that FM and CFIDS in fact have some distinct physical abnormalities associated with them.
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  3. You must commit to controlling your destiny. Each day, the battle must be fought. You must stay committed to owning control of your life, on your terms, to effectively manage your conditions.
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  4. You must enjoy your life again. The strongest medicine in the world is the ability to be happy. Attaining the state of contentment is a powerful elixir that puts everything else into a manageable context.

Patients who take this control and come to our centers are successful.

Dr. Holtorf: Bob is right. It is all about attitude in combination with the right medical approach. We think we offer patients who understand this, the best chance for leading a happy, productive and active life.

ImmuneSupport.com: Anything else our readers should know about the Fibromyalgia & Fatigue Centers?

Baurys: To our patients who are reading this, thank you for making our beginnings so successful and for encouraging us to grow and reach out to more people suffering as we have in the past. Thank you for trusting us with your wellness and for putting your faith in our proven medical protocols. Your smiles, hugs and shared stories of the active lives you are now leading are what motivate us to keep moving forward.

And to those readers who are not patients, please know there is hope and help out there so you too can begin to really live the life you deserve. Never give up hope and if in anyway we can help, please don’t hesitate to contact us at 1-866-443-4276.

Dr. Holtorf: I only have one more thing to add. When you are told that “it is all in your head”, or “you need a psychiatrist”, or “your lab tests all came back normal”, or “there is nothing that can be done for the pain or fatigue” - keep searching for answers! You are not crazy. You do not need a psychiatrist. Your body is telling you something is wrong and it is more accurate than some lab tests can be. And you can do something about the pain and fatigue. Both Bob and I and all our patients are living proof of that.

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Stordy Done on Patient Ellen K.

Tired of feeling tired and sick? Ellen was! After all, it was 24 years of going from doctor to doctor; vacillating between hopefulness and helplessness; and often times spending more than half of her annual income in search of the “cure” for a condition she was consistently told she can’t cure - only control. Now 47 years old, Ellen has spent almost half her life searching out and consulting with the fibromyalgia “gurus” and experimenting with new treatments. Occasionally, she would find temporary relief from the debilitating symptoms, but eventually she would return to the steady downward spiral that had become her “normal”.

The “experts” in the field were not able to help her significantly enough to warrant the costs and the emotional wear and tear associated with having, and then losing, hope. Shortly after graduating with her degree in music, Ellen, a talented young flutist, was suddenly afflicted with fibromyalgia. At first no one could properly diagnosis the condition. After all it was the early 1980’s and it really wasn’t even a recognized disease yet. Multiple specialists, most of whom were too intimidated by a condition they couldn’t correct to even tell her they had no idea what was wrong or how to fix it, ultimately told her it was all in her head - she was crazy. Depression overcame her. Suicide seemed like the best way to end the pain that wouldn’t even allow her to play her beloved instrument. For Ellen there was no light at the end of the tunnel for a long, long time.

Sound familiar? Most patients struggling with fibromyalgia and chronic fatigue syndrome have a similar story. Details may not be exactly the same. They may have to give up their love for a sport or their passion for dancing the night away, or even the hopes of one day having a family. But the basic elements are the same. Each patient has lost their life as they once knew it to be and they have lost the hopes for what that life might become. Goals have gone from becoming successful in their chosen profession to successfully getting out of bed each day and managing the simple life tasks of showering and dressing. Major decisions about relationships, career moves, and task prioritizations are replaced with daily major decisions about whether they should put in a load of laundry or wash the dishes left in the sink from dinner the night before. They know they will not have the strength or be pain-free long enough to do both, so the choice is tough.

For Ellen, her search and struggle ended a little over a year ago. Thanks to a strong Buddhist faith and determination she worked through the myriad of information available to patients. She followed her instincts about what was going on with her body and eventually came to find one doctor who did understand and who was willing to work with her so that she had choices and could control her fibromyalgia. Dr. Kent Holtorf, Chief Medical Officer of the Fibromyalgia and Fatigue Centers, Inc. has been working with Ellen to take control of the disease that forever changed the course of her life. Her energy levels over the past year have gone from 1-3 on a scale of 10 to solid and steady 6-8’s. Her pain has significantly decreased, going from 8 – 10 on a scale of 10 to now consistently rated between 0-2, a 90% improvement. Overall, her progress has been remarkable after such a long struggle to find the solutions. She credits Dr. Holtorf and the Center’s philosophy of a patient centric approach to identify and treat the underlying causes of her symptoms with helping her get back to a life she is happy to be living, not dreading. As Ellen continues to progress, she has the opportunity to potentially lead a symptom free life. Her hope is contagious, her smile genuine as she shares the joy of living life to it’s fullest, not having to settle for whatever her body would allow that minute or that hour or that day.

Ellen’s story is one of loss, but as she says it is also one of gain. She has gotten so much from having gone through the struggle that she can be okay with having had to go through it. A stronger faith, a caring husband and compassionate doctor who truly understands and supports her needs have all been benefits stemming from her struggle. She urges all patients to follow their hearts and never give up hope, there really is light at the end of the tunnel, no matter how long that tunnel may seem.

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Valcyte (valganciclovir) and CFS

Use of valganciclovir (Valcyte) in patients with elevated antibody titers against Human Herpesvirus-6 (HHV-6) and Epstein-Barr Virus (EBV) who were experiencing central nervous system dysfunction including long-standing fatigue. Journal of Clinical Virology 2006;37:S33-38

Montoya et al at Stanford University treated chronic fatigue syndrome patients with 6 months of valganciclovir (Valcyte) if they had elevated IgG tests for HHV-6 and EBV and had at least 4 of the following symptoms: impaired cognitive functioning, slowed processing speed, sleep disturbance, short-term memory deficit, fatigue and symptoms consistent with depression. Nine of the twelve treated patients (75%) “experienced near resolution of their symptoms, allowing them all to return to the workforce or full time activities.” In the nine patients with a symptomatic response to treatment, EBV VCA IgG and HHV-6 IgG titers significantly declined.

This is not a new finding, as previous studies as far back as 1997 have demonstrated significant improvement with similar antivirals.1,2,3 This study has, however, been much more publicized. We have been using Valcyte in our center for the treatment of chronic fatigue syndrome for over 4 years and have found it to be effective, especially in patients with the flowing: flu-like symptoms or having symptoms that started with a flu-like illness; elevated IgG or EA against Epstein bar virus, cytomegalovirus and/or HHV-6; low natural killer cell activity; high RNAse-L activity; high ACE (>35); coagulation activation; high tumor necrosis factor (TNF); low melanocyte stimulation hormone (MSH); high interleukin-6 (IL-6); low WBC; increased 1-25 vitamin D/25 vitamin D ratio and/or elevated or decreased total IgA, IgM or IgG levels.

This study contributes more confirmatory evidence that IgM antibodies are not typically elevated in chronic reactivating infections so most patients are incorrectly told they do not have an active infection based on such testing. High IgG levels are diagnostic for an active infection in these patients, which is not what is taught in medical school and contrary to the belief of most physicians, including infectious disease specialists. This study also demonstrated the lack of sensitivity of standard PCR testing.

1. Lerner AM, Zervos M and Dworkin HJ et al. New cardiomyopathy: A pilot study of intravenous ganciclovir in a subset of the chronic fatigue syndrome. Infectious Diseases In Clinical Practice 1997;6:110-117.

2. Lerner AM, Zervos M and Chang CH et al. A small, randomized, placebo-controlled trial of the use of antiviral therapy for patients with chronic fatigue syndrome. Clinical Infectious Diseases. 2001;32:1657-58.

3. Lerner AM, Beqaj SH, and Deeter RG et al. A six-month trial of valacyclovir in the Epstein-Barr virus subset of chronic fatigue syndrome: improvement in left ventricular function. Drugs of Today. 2002;38:549-561.

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Xyrem and Fibromyalgia

The Effects of Sodium Oxybate on Clinical Symptoms and Sleep Patterns in Patients with Fibromyalgia Journal of Rheumatology 2003;30(5):1070-1074.

Objective. Fibromyalgia (FM) is associated with the sleep phenomenon of alpha intrusion, and with low growth hormone secretion. Sodium oxybate (Xyrem) has been shown to increase both slow-wave sleep and growth hormone levels. This double blind, randomized, placebo controlled crossover trial was conducted to evaluate the effects of sodium oxybate on the subjective symptoms of pain, fatigue, and sleep quality and the objective polysomnographic (PSG) sleep variables of alpha intrusion, slowwave (stage 3/4) sleep, and sleep efficiency in patients with FM.

Methods. Patients received either 6.0 g/day sodium oxybate or placebo for 1 month, with an intervening 2 week washout period. Efficacy measures included PSG evaluations, tender point index (TPI), and subjective measurements from daily diary entries. Safety measures included clinical laboratory values, vital signs, and adverse events.

Results. Twenty-four female patients were included in the study; 18 completed the trial. TPI was decreased from baseline by 8.5, compared with an increase of 0.4 for placebo (p = 0.0079). Six of the 7 pain/fatigue scores (overall pain, pain at rest, pain during movement, end of day fatigue, overall fatigue, and morning fatigue) were relieved by 29% to 33% with sodium oxybate, compared with 6% to 10% relief with placebo (p < 0.005). Alpha intrusion, sleep latency, and rapid-eye-movement sleep were significantly decreased, while slow-wave (stage 3/4) sleep was significantly increased, compared with placebo (p < 0.005). Two of the 5 subjective sleep related variables were significantly different from placebo: morning alertness (improved by 18% with sodium oxybate, compared with 2% for placebo; p = 0.0033) and quality of sleep (improved by 33% and 10%, respectively; p = 0.0003).

Conclusion. Sodium oxybate effectively reduced the symptoms of pain and fatigue in patients with FM, and dramatically reduced the sleep abnormalities (alpha intrusion and decreased slow-wave sleep) associated with the nonrestorative sleep characteristic of this disorder.








Cardiac dysfunction resulting in CFS due to EBV and/or CMV infection

There are a number of studies indicating that an Epstein-Barr (EBV) and/or cytomegalovirus infection of the heart muscle can decreases the heart’s ability to pump and may be the cause of CFS in a number of patients. A rapid resting heart rate can be a sign that this is a problem. Studies also indicate that when the EBV and CMV infections are eradicated, there is significant or complete resolution of the symptoms of CFS. I have found many CFS/FM patients to be infected with active EBV and/or CMV infections, especially those with rapid heart rates. When these infections are eradicated, the patient can have tremendous improvement and his or her heart rate declines. Many patients are told that they do have these infections but that they are not treatable. These are, however, very treatable infections. It is important to note that just treating EBV, without treating the CMV co-infection, does not result in improvement. These were some of the first studies documenting abnormal heart function in patients with CFS.

Lerner AM, Lawrie C, Dworkin HJ. Repetitively negative changing T-waves at 24-h electrocardiographic monitors in patients with the chronic fatigue syndrome (left ventricular dysfunction in a cohort). Chest. 1993;104:1417-1421.

Dworkin HJ, Lawrie C, Bohdiewicz P and Lerner AM. Abnormal left ventricular myocardial dynamics in eleven patients with the chronic fatigue syndrome. Clinical Nuclear Medicine 1994;19:675-677.

Lerner AM, Goldstein J, Chang CH et al. Cardiac involvement in patients with chronic fatigue syndrome as documented with Holter and biopsy data in Birmingham, Michigan, 1991-1993. Infectious Diseases in Clinical Practice 1997;6:327-33.

These are some of the studies demonstrating that the abnormal heart function is due to EBV and/or CMV infection and has nothing to do coronary heart disease.

Lerner AM, Zervos M, Dworkin HJ, Chang, CH and O'Neill W. A unified theory of the cause of chronic fatigue syndrome. Infectious Diseases in Clinical Practice 1997;6:230-243.

Lerner AM. Editorial response: microbial persistence and idiopathic dilated cardiomyopathy. Clinical Infectious Diseases. 1999;29:526-7.

These are some of the studies demonstrating that eradication of the EBV and CMV infection results in significant improvement in heart function and resolution of the symptoms of CFS.

Lerner AM, Zervos M and Dworkin HJ et al. New cardiomyopathy: A pilot study of intravenous ganciclovir in a subset of the chronic fatigue syndrome. Infectious Diseases In Clinical Practice 1997;6:110-117.

Lerner AM, Zervos M and Chang CH et al. A small, randomized, placebo-controlled trial of the use of antiviral therapy for patients with chronic fatigue syndrome. Clinical Infectious Diseases. 2001;32:1657-58.

Lerner AM, Beqaj SH, and Deeter RG et al. A six-month trial of valacyclovir in the Epstein-Barr virus subset of chronic fatigue syndrome: improvement in left ventricular function. Drugs of Today. 2002;38:549-561.

Lerner AM, Beqaj SH, Deeter RG and Fitzgerald JT. IgM serum antibodies to human cytomegalovirus nonstructural gene products p52 and CM2 (UL44 and UL57) are uniquely present in a subset of patients with chronic fatigue syndrome. In Vivo. 2002;16:153-160.

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Multifaceted Treatment Approach
J Teitelbaum, B. Bird. Effective treatment of CFIDS and Fibromyalgia The Journal of Musculoskeletal Pain Volume 3, Issue 4 (1995).

This study was a ground breaking study that demonstrated that there are multiple physiologic abnormalities in CFS/FM and that effective treatment requires a multifaceted approach, which is foreign to traditional medical thinking. It was criticized by some, however, because there was no placebo group. Dr. Teitelbaum subsequently did a double-blind placebo controlled trial.

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Multifaceted Treatment Approach #2
Teitelbaum J, Bird B, Greenfield R, Weiss A., Muenz L, Gould L. Effective treatment of CFIDS and Fibromyalgia. The Journal of Chronic Fatigue Syndrome, Vol. 8(2) 2001.

This double blind placebo control study confirmed the previous study by demonstrating that there are varying physiologic abnormalities present in chronic fatigue syndrome and fibromyalgia, including disordered sleep, hormonal deficiencies, immunologic changes, nutritional deficiencies, autonomic dysfunction and chronic infections, and that these conditions are effectively treated with a comprehensive integrative multi-system approach. This is still difficult to grasp by many traditional physicians who are still looking for the “silver bullet” approach and continue to focus on only one area of abnormality that they are comfortable treating. These protocols served as a basis for this rapid growing field and allowed for more sophisticated and expanded treatment paradigms.

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Acetylchoinesterase Inhibitor

Trial of a selective acetylcholinesterase inhibitor, galanthamine hydrobromide, in the treatment of chronic fatigue syndrome. Journal of Chronic Fatigue Syndrome 1996; 2(2/3): 35-54.
Efficacy of a half dose of oral pyridostigmine in the treatment of chronic fatigue syndrome: three case reports.

These studies indicate that acetylcholinesterase inhibitors can improve the symptoms of chronic fatigue syndrome and fibromyalgia. These medications are used to treat Alzheimer’s disease and myasthenia gravis by increasing acetylcholine in the central nervous system. There is evidence that chronic EBV, CMV and HHV-6 infections can block the acetylcholine transmission, resulting in cognitive (memory) problems, muscle weakness, fatigue and depression. After 8 weeks of treatment with this medication, significant improvements were demonstrated in sleep, fatigue, muscle pain and dizziness. This is another medication that can be included in the arsenal of medications and can be used on an individualized basis with a comprehensive approach in the treatment of chronic fatigue syndrome and fibromyalgia.

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Pyridostigmine



Pyridostigmine

The case studies below demonstrated that pyridostigmine to be beneficial in chronic fatigue syndrome and fibromyalgia. While this was case reports of only 3 patients, I have also found pyridostigmine to be helpful in fatigue in weakness in some patients. It does seem to be more helpful in patients that are positive for EBV. This is an indication that this virus may somehow block or inhibit the acetylcholine function at the neuromuscular junction in some patients, resulting muscle weakness and fatigue.

Efficacy of a half dose of oral pyridostigmine in the treatment of chronic fatigue syndrome: three case reports.

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The Use Of Intravenous Lidocaine For The Treatment of Fibromyalgia
AJPM;6:15-18

This prospective, randomized, double-blind, placebo-controlled trial examined the efficacy of intravenous lidocaine in the treatment of fibromyalgia. Patients rated their pain scores prior to treatment or placebo infusion. The treatment (or placebo) was repeated 2 weeks later along with a report of pain scores after the second treatment and again 2 weeks and 6 weeks after the last treatment. Patients receiving the lidocaine infusion reported significantly improved pain scores 2 weeks after last infusion. The reduced pain scores lasted for approximately 4 weeks after last infusion and returned to baseline approximately 6 weeks after last infusion.






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