Chronic Fatigue Syndrome

Chronic fatigue syndrome (CFS) is a debilitating and complex disorder characterized by profound fatigue that is not improved by bed rest and that may be worsened by physical or mental activity. Persons with CFS most often function at a substantially lower level of activity than they were capable of before the onset of illness. CFS often occurs in conjunction with two other related illnesses: fibromyalgia syndrome (FMS) and myofascial pain syndrome (MPS), all of which are part of an overlapping spectrum of disabling syndromes. It is estimated that FMS alone affects 3 to 6 million Americans, causing more disability than rheumatoid arthritis. MPS affects many millions more. Although we still have much to learn, effective treatment is now available for the large majority of patients with these illnesses. CFS/FMS/MPS represents a syndrome, a spectrum of processes with a common end point. As CFS often coexists with FMS and MPS, the three are often referred to together.

Signs and Symptoms
Recent research has implicated mitochondrial and hypothalamic dysfunction as common denominators in these syndromes. These processes therefore reflect the human energy crisis. Dysfunction of hormonal, sleep and autonomic control (all centered in the hypothalamus) and energy production centers can explain the large number of symptoms and why most patients have a similar set of complaints.

To make it easier to explain to patients, physicians often use the model of a circuit breaker in a house.

“If the energy demands on your body are more than it can meet, your body 'blows a fuse.' The ensuing fatigue forces the person to use less energy, protecting them from harm. On the other hand, although a circuit breaker may protect the circuitry in the home, it does little good if you do not know how to turn it back on or that it even exists.”

This analogy reflects what actually occurs. As energy stores are depleted, hypothalamic dysfunction occurs, resulting in the disordered sleep, autonomic dysfunction, low body temperatures, and hormonal dysfunctions commonly seen in these syndromes. In addition, inadequate energy stores in a muscle results in muscle shortening (think of rigor mortis) and pain which is further accentuated by the loss of deep sleep. Therefore, restoring adequate energy production and eliminating the stresses that over-utilize energy (e.g., infections, situational stresses, etc.) restore function in the hypothalamic “circuit breaker” and also allows muscles to release, which allows pain to resolve. A published placebo-controlled study showed that when this was done, 91% of patients improved, with an average 90% improvement in quality of life, and the majority of patients no longer qualified as having CFS/FMS by the end of three months.

The CDC defines a case of CFS by the presence of the following symptoms:


 * 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.
 * 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:
 * Self-reported impairment in short-term memory or concentration severe enough to cause substantial reduction in previous levels of occupational, educational, social, or personal activities.
 * Sore throat.
 * Tender cervical (neck) or axillary (underarm) lymph nodes.
 * Muscle pain.
 * Multi-joint pain without joint swelling or redness.
 * Headaches of a new type, pattern, or severity.
 * Unrefreshing sleep.
 * Postexertional malaise lasting more than twenty-four hours.

In addition, the definition requires that other causes of fatigue be excluded.

Examination and lab tests


The preceding CDC definition was created to help create a “pure” group for CFS research, so it excludes most people who have CFS with an exclusion statement noting that if people have any other medical or psychological problems that could cause fatigue, they do not fit the CFS definition. Because of this, the number of people with CFS is generally underestimated.

Though the fibromyalgia definition was developed for research use, it is more inclusive than the CFS definition and is clinically useful. The criteria for a case of fibromyalgia (from the American College of Rheumatology) is applicable to CFS and are as follows:


 * Feeling pain both above and below the waist in both the left and right sides of the body.
 * Feeling pain somewhere down the middle of the body (e.g., headache, back, chest, or abdominal pain).
 * Being tender in 11 out of 18 arbitrarily chosen locations on the body points, called tender points. Tender points of fibromyalgia exist at these nine bilateral muscle locations:
 * Low cervical region (front neck area): at anterior aspect of the interspaces between the transverse processes of C5-C7.
 * Second rib (front chest area): at second costochondral junctions.
 * Occiput (back of the neck): at suboccipital muscle insertions.
 * Trapezius muscle (back shoulder area): at midpoint of the upper border.
 * Supraspinatus muscle (shoulder blade area): above the medial border of the scapular spine.
 * Lateral epicondyle (elbow area): two cm distal to the lateral epicondyle.
 * Gluteal (rear end): at upper outer quadrant of the buttocks.
 * Greater trochanter (rear hip): posterior to the greater trochanteric prominence.
 * Knee (knee area): at the medial fat pad proximal to the joint line.

Unfortunately, most doctors don’t know how to find and check the tender points, which are not necessarily the same as trigger points. And many of the major researchers in the field are recognizing that there is an intermediate form of fibromyalgia where people have fewer than 11 of the 18 tender points. The tender point exam will probably be eliminated when a good blood or urine test is defined for FMS (applicable to CFS).

As the definitions of both CFS and fibromyalgia were largely developed to serve the needs of researchers, it is helpful to apply a simpler approach to diagnosis that is also clinically effective. If patients experience the paradox of severe fatigue combined with insomnia (if exhausted, they should sleep all night), they don’t have severe primary depression, and these symptoms don’t go away with vacation, they likely have a CFS related process. If they also have widespread pain, fibromyalgia is probably also present.

Anything that results in inadequate energy production, or energy needs greater than the body’s production ability, can trigger hypothalamic dysfunction. This may include infections, disrupted sleep, pregnancy, hormonal deficiencies, toxin exposures, and other physical and/or situational stresses.

The “SHINE” protocol
Both CFS and FMS respond well to a proper treatment protocol that addresses five key health areas. These five areas can be summarized by the acronym “SHINE,” which stands for Sleep, Hormonal support, Infections, Nutritional support, and Exercise as able.

Two studies (including a well designed placebo-controlled study ) showed an average 90% improvement rate when using the SHINE protocol. When patients have fatigue and insomnia coupled with widespread pain, they essentially have a body-wide energy crisis. Treating with the SHINE approach has been shown to help 91% of patients. An editorial in the journal of AAPM notes:


 * “This study by Dr. Teitelbaum et al. confirms what years of clinical success have shown … that subclinical abnormalities are important, and that the comprehensive and aggressive metabolic approach to treatment in Teitelbaum's study is highly successful and … an excellent and powerfully effective part of the standard of practice for treatment of people who suffer from FMS (Fibromyalgia) and MPS (Myofascial Pain Syndrome—muscle pain).”

This section provides an introduction to the understanding of how to treat CFS/FMS/MPS using the SHINE protocol. For those seeking more information, a more thorough treatment protocol list based on SHINE is available from its author, Jacob Teitelbaum, M.D., at his website. This list is used by many physicians for treating CFS and fibromyalgia and includes over 270 useful natural and prescription therapies with resources and detailed instructions for use, organized by category.

Although nutritional support is the foundation of getting well in CFS/FMS, it is critical that the entire process be followed to achieve best results.

Disordered sleep
A foundation of recovering from CFS/FMS is treatment of the sleep disorder. Using medications that increase deep restorative sleep, so that the patient gets seven to nine hours of solid sleep without waking or hangover, is critical. Treatment may begin with natural therapies or with a low dose of sleep medications that do not decrease sleep stages three and four. Some patients will sleep well with natural therapies alone. If sleep medications are additionally needed (or alternatively preferred), doctors sometimes prescribe zolpidem (marketed in the U.S. as Ambien and other brand names) or trazodone (marketed in the U.S. as Desyrel and other brand names). Some patients require a surprisingly large amount of sleep support, because the malfunctioning hypothalamus controls sleep. Because of next-day sedation and the independent half-lives of each medication, doctors often advise CFS/FMS patients to combine low doses of several medications rather than a single high dose of one.

Although less common, three other sleep disturbances must be considered and treated if present. These are sleep apnea, UARS (Upper Airway Resistance Syndrome) and restless leg syndrome (RLS), which is also fairly common in fibromyalgia.

Natural remedies
Natural remedies that are helpful to improving sleep include the following:


 * Herbal preparations containing a mix of valerian root, wild lettuce, Jamaican Dogwood, passionflower, hops and theanine. These six herbs can help muscle pain and libido as well as improving sleep.
 * Melatonin.
 * 5-HTP (5-Hydroxytryptophan).
 * Calcium and magnesium.

Medication
Prescriptive medications that are helpful to improving sleep include the following:


 * Zolpidem.
 * Gabapentin (for example, Neurontin marketed in the U.S.).
 * Cyclobenzaprine (for example, Flexeril marketed in the U.S.).
 * Clonazepam (for example, Klonopin marketed in the U.S.).
 * Trazodone (for example, Desyrel marketed in the U.S.).

Evaluation and treatment of associated hormonal dysfunction
Hormonal imbalances are associated with CFS/fibromyalgia. Sources of imbalance include hypothalamic dysfunction, adrenal exhaustion from chronic stress, environmental toxins, and autoimmune processes such as Hashimoto’s thyroiditis. Most blood tests use two standard deviations to define blood test norms, with the lowest or highest 2.5% of the population defined as within the abnormal range. Other tests define an abnormal lab value by detecting late signs of deficiency such as anemia for iron or B12 levels. Unfortunately, some physicians confuse this statistically based normal range with what is healthy for the patient.

One way to convey the difference between the “normal” range based on two standard deviations and the optimal range which the patient would maintain if they did not have CFS/FMS is as follows:


 * “Pretend your lab test uses 2 standard deviations to diagnose a shoe problem, giving a normal range of sizes 4-13. If you accidentally put on someone else’s shoes and had on a size 5 when you wore a size 12, the normal range derived from the standard deviations would indicate you had absolutely no problem. You would insist the shoes did not fit although your shoe size would be in the normal range.  Similarly, if you lost your shoes, the doctor would pick any shoes out of the ‘normal range pile’ and expect them to fit you.”

The goal in CFS/FMS management is to restore optimal function while keeping lab test values within the normal range for safety.

Thyroid function
Suboptimal thyroid function is very common and it is important to treat all chronic muscle pain patients with thyroid hormone replacement if their Free T4 (a test that evaluates thyroid function) blood levels are below even the fiftieth percentile of normal. Many CFS/FMS patients also have difficulty in converting the main hormone the thyroid makes (called T4), which is fairly inactive, to T3, the active hormone. Additionally, T3 receptor resistance may be present and require higher levels of thyroid support.

TSH testing is not reliable in CFS and FMS because hypothalamic hypothyroidism is common and the patient’s TSH can be low, normal, or high despite having underactive thyroid function. The inadequacy of thyroid testing is further suggested by studies that have shown:


 * Most patients with suspected thyroid problems have normal blood studies.
 * When patients with symptoms of hypothyroidism and normal labs were treated with thyroid, a large majority improved sigificantly.

In addition, it is important to be aware that thyroid supplementation can increase a patient’s cortisol metabolism and unmask a case of subclinical adrenal insufficiency. If the patient feels worse on low-dose thyroid replacement, they may need adrenal support as well.

Adrenal insufficiency
Symptoms of an underactive adrenal include weakness, hypotension, dizziness, sugar craving, and recurrent infections—all of which are common in CFS/FMS. The hypothalamic-pituitary-adrenal (HPA) axis does not function well in CFS/FMS. Because early researchers were not aware of physiologic doses of cortisol, they treated with high doses and their patients developed severe complications. Doctors now avoid these side effects in patients by prescribing hydrocortisone (for example, marketed in the U.S. as Cortef) in lower, physiologic dosing.

Another option is to use a natural adrenal support which is safe and effective. These often contain licorice, adrenal glandulars, pantothenic acid, vitamin C, and other nutrients and herbs shown to support adrenal function. Excessive licorice can raise blood pressure, and high doses are best used under the guidance of a health practitioner trained in using natural remedies.

DHEA
Dehydroepiandrosterone (DHEA) is a major adrenal hormone that has recently received increased attention in the press for its role as a “fountain of youth” hormone.

Many CFS/FMS patients have suboptimal DHEA-S levels, and the benefit of treatment is sometimes dramatic. Doctors generally prescribe DHEA to patients at relatively low dosage levels, as too high of a dose can cause acne or darkening of facial hair.

Low estrogen and testosterone
Although physicians are trained to diagnose menopause by cessation of periods and hot flashes, these are late findings. Estrogen deficiency often begins many years before, and may coincide with the onset of CFS/FMS. To compound the problem, research has shown that the majority of women who have had a hysterectomy, even with the ovaries left in, begin menopause within six months to two years after.

The initial symptoms of estrogen deficiency are poor sleep, poor libido, brain fog, achiness, and especially worsening of CFS/FMS symptoms in the days to week before the period. Bioidentical estrogen and progesterone have been shown in numerous studies to be safer than synthetics, but this has become controversial because synthetic hormones can be patented, and are therefore more profitable.

Testosterone deficiency
Several physicians treating large numbers of CFS/FMS patients have found that approximately 70% of men and many women have free testosterone levels in the lowest quarter of the population while their total testosterone levels are normal.

In men, testosterone supplementation can also cause elevated thyroid hormone levels in men taking thyroid supplements. Despite the concerns about athletes using very high levels of synthetic testosterone, it is important to remember that research shows that raising a low testosterone level in men using natural testosterone actually results in lower cholesterol, decreased angina and depression, and improved diabetes.

Natural remedies
Natural remedies that are helpful to improving hormonal function include a number of prescription options, such as:
 * Naturally derived bioidentical alternatives to synthetic hormone replacement (for example, prescription Armour Thyroid for thyroid support or ultra low dose Cortef for adrenal support, both marketed in the U.S.). For estrogen and progesterone replacement, studies have shown that bioidentical hormones are far safer (and have less side effects) than synthetics.

Nutritional and herbal support that are also helpful include the following:


 * Iodine, selenium and tyrosine. Optimal thyroid function requires these in addition to other nutrients. (Iodine deficiency is increasingly problematic in the U.S. as it has become replaced by bromides in wheat products.)
 * Vitamin C, pantothenic acid, and licorice. These can support optimal adrenal function.
 * Black cohosh (for example, Remifemin marketed in the U.S.). This has been shown to be effective after 1-2 months of use.
 * Edamame (a preparation made from soybean pods, found in the frozen food section in most supermarkets) can effectively raise estrogen. Like peas, the inner beans are eaten and the outer pod discarded.

Medication
Prescription medications that are helpful to improving hormonal function include the following:


 * Hydrocortisone (for example, Cortef marketed in the U.S.).
 * Dessicated thyroid (for example, Armour Thyroid marketed in the U.S.).
 * Natural estrogen and progesterone (from compounding pharmacies)
 * Natural testosterone

Immune dysfunction and infections
Immune dysfunction is an integral part of the CFS/FMS process. Opportunistic infections present in CFS/FMS include chronic respiratory infections and sinusitis, bowel infections, and chronic, low-grade prostatitis. These need to be treated.

Chronic sinusitis responds poorly to antibiotics but responds well to antifungals. Bowel infections with alterations of normal bacterial flora, fungal overgrowth, and parasitic infections are also frequently present. This is reflected by the patient’s bowel symptoms. Because of the lack of a definitive test for yeast overgrowth, there is little research published in this area and treatment is controversial. Treatment is empiric, and based on the patient’s history. Yeast vaginitis, onchomycosis (nail fungal infections), sinusitis, a history of frequent antibiotic use (such as tetracycline for acne), gas, bloating, diarrhea or constipation warrants an empiric therapeutic antifungal trial in those with CFS/FMS because of the immune dysfunction. Many CFS/FMS patients who have failed other therapies for spastic colon or sinusitis respond well to anti-fungal treatments.

Numerous other opportunistic infections (i.e., infections that a healthy immune system would normally eliminate), such as parasitic infections, (e.g., chlamydia, mycoplasma incognitus), antibiotic sensitive infections, and viral infections (e.g., HHV-6, CMV, EBV) are also often active in CFS/FMS.

Natural remedies
Natural remedies that are helpful to improving immune function include the following:
 * Avoiding sugar.
 * Anti-fungal herbs, and supplementing with probiotics.

Medication
Prescription medications that are helpful for treating the fungal overgrowth require at least six weeks of therapy. The most frequently used antifungal for CFS is:


 * Fluconazole (for example, Diflucan marketed in the U.S.).

“N”—Nutritional support
CFS/FMS patients are often nutritionally deficient. B-vitamins, ribose, magnesium, iron, coenzyme Q10, malic acid and Acetyl-L-Carnitine are essential for mitochondrial function. These nutrients are also critical for many other processes. Although blood testing is not reliable or necessary for most nutrients, it is important to check B12, Fe, TIBC, and ferritin levels (three iron studies) in those with CFS/FMS.

Many doctors advise CFS/FMS patients to begin a nutritional regimen that includes:


 * A quality multivitamin suited for their needs. Using vitamin powders allow excellent nutritional support without the need for handfuls of pills.
 * Ribose. An excellent nutrient for enhancing energy production, ribose is recommended for all CFS/FMS patients as well as patients with heart disease. A recently published study showed that ribose increased energy an average of 45% in patients with CFS/FMS.
 * B12 injections (if levels are under 540 pg/ml). This can help not only the B12 deficiency (which can occur despite normal blood levels34), but can also help correct nitric oxide pathway (NO/ONOO) dysfunctions that may be present.
 * Coenzyme Q10.
 * Acetyl-L-carnitine.
 * Avoidance of sugar and caffeine.
 * Increased water intake.
 * Iron (if ferritin blood test is under 40).

Natural remedies
Natural remedies and supplements that are helpful to improving nutritional deficiency include the following:
 * A quality multivitamin suited for their needs. Vitamin powders that give overall nutritional support are recommended.
 * Ribose (for example, Corvalen marketed in the U.S.). An excellent nutrient for enhancing energy production, ribose is recommended for all CFS/FMS patients as well as patients with heart disease. A recently published study showed that ribose increased energy an average of 45% in patients with CFS/FMS. Ribose deficiency can be a critical rate limiting nutrient in the production of energy. The key energy molecules in our bodies are ATP, FADH and NADH. These molecules are made up predominantly of ribose plus B-vitamins and adenosine. It was helpful in 66% of CFS patients, and improvement is usually seen within one month.  Ribose may be a very powerful new addition to our therapeutic armamentarium for treating fatigue, pain, and cardiac dysfunction.
 * B-vitamins and, if levels are especially low, B12 injections. B12 injections can help not only the B12 deficiency (which can occur despite normal blood levels), but can also help correct nitric oxide pathway (NO/ONOO) dysfunctions that may be present.
 * Coenzyme Q10
 * Acetyl-L-carnitine
 * Avoidance of sugar and caffeine
 * Increased water intake
 * Iron (if ferritin blood test is under 40)
 * Magnesium
 * Malic acid

“E”—Exercise as able
Although conditioning is important, CFS patients can not make adequate energy, and therefore more easily tire during exercise, making conditioning difficult. In fact, post-exertional fatigue, which can leave people bedridden for one to two days after excess exertion, is a hallmark of CFS. Because of this, many doctors advise patients to simply walk as able (i.e., walk until they feel tired but good afterwards and better the next day). After 10 weeks on the SHINE protocol, people can then often increase walking by up to a minute a day, and then increase the intensity of their exercise when they are able to walk an hour a day as their body allows.

General pain relief
Pain is not a malfunction, but rather is the body’s way of saying that something desperately needs attention (like the oil light on your car’s dashboard). When one has an injury, the cause of pain is often obvious. When the pain comes from chronic muscle shortening (caused by the decreased energy production—think writer’s cramp where muscles lock in the shortened position), the cause of the pain may not be obvious. In addition, this causes “trigger points” in the belly of the muscles (those “tender knots” patients feel in their muscles) as well as “central sensitization.” This occurs when chronic pain causes the pain centers in the brain to amplify and even generate the pain. Fortunately, treating the underlying cause of the pain will often make the pain resolve, just like putting oil in the car makes the oil light go out.

Although most CFS patients’ pain will often resolve within three months of simply treating with the SHINE protocol, it is also critical to eliminate pain directly. Many studies show a marked analgesic and anti-inflammatory effect from adequate doses of two herbals, willow bark and boswellia, which have been shown to be as or more effective than NSAIDs and COX 2 inhibitors, but without the GI or other toxicity. These herbals are excellent for arthritic, inflammatory, and other pains as well.

Natural remedies
Natural remedies that are helpful to improving immune function include the following:
 * Willow bark
 * Boswellia
 * Herbal preparations containing a mix of valerian root, wild lettuce, Jamaican Dogwood, passionflower, hops and theanine.

Medication
Medications particularly effective for CFS/FMS patients include the following:


 * Gabapentin (for example, Neurontin marketed in the U.S.).
 * Tramadol (for example, Ultram marketed in the U.S.).
 * Metaxalone (for example, Skelaxin marketed in the U.S. by King Pharmaceuticals).
 * Pregabalin (for example, Lyrica marketed in the U.S. by Pfizer).
 * Duloxetine (for example, Cymbalta marketed in the U.S.).

Medications that should be avoided by CFS/FMS patients (unless clearly more helpful to the patient than other alternatives):


 * Ibuprofen (for example, Motrin and Advil marketed in the U.S.). Ibuprofen has been shown to be not effective in 90% of CFS/FMS patients and is much more dangerous than the medications noted above.

Psychological well-being
Many illnesses are associated with various psychological profiles. In CFS/FMS, a common profile is a “mega-type-A” overachiever who, because of childhood low self esteem, overachieves to get approval. They tend to be perfectionists and have difficulties protecting their boundaries—that is, they say “yes” to requests when they feel like saying “no.” Instead of responding to their bodies’ signal of fatigue by resting, they redouble their efforts. Taking time to rest, and getting and staying out of abusive personal and work environments is critical.

Notable Experts
Jacob Teitelbaum, M.D. Physician, medical researcher and best-selling author on the subject of CFS/FMS.

Other Resources
Online CFS diagnostic program (free) analyzes symptoms and provides a printout of probable diagnoses and a recommended personalized treatment protocol.

Related Problems
There are a number of diseases and syndromes that have features in common with chronic fatigue syndrome. The conditions may exist together.


 * Fibromyalgia
 * Hypothyroidism
 * Hypopituitarism
 * Systemic Lupus Erythematosus
 * Sjögren Syndrome
 * Myofascial Pain Syndrome

Clinical Trials
More information about clinical trials can be found at ClinicalTrials.gov.