Comprehensive Treatment of Fibromyalgia--Advice from an FM Expert

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Last Updated: 03 January 2016 03 January 2016

by Robert Bennett M.D., FRCP

The Massachusetts CFIDS/ME & FM Association Fall 2002 UPDATE

Editor's Note, 2015: We suggest you pass this article on to your treating physicians. Much of Dr. Bennett's treatment protocol also applies to individuals with ME/CFS, as the two conditions closely parallel each other. There has been some change in the medications recommended for FM pain since this article was written in 2002. For updated information go to the Fibromyalgia Information Foundation website maintained by Dr. Bennett's research group and click on Treatment. Also see More resources below.

If you are reading this you probably have a common syndrome of chronic musculoskeletal pain called fibromyalgia (FM). This chronic pain state is caused by abnormalities of sensory processing within the spinal cord and brain. As such you will usually experience a bewildering array of bodily and psychological problems that can seldom be "cured". However, armed with both patience and knowledge, many FM patients can be helped to live with less pain and be more productive. In my own evolving experience of dealing with this problem, I can identify seven aspects of management that are of importance for your doctor to successfully manage your FM.

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My advice to doctors who care for FM patients

1. Realize that FM patients are going to be a chronic challenge.

2. Be non-judgmental and prepared to be an advocate.

3. Understand the pathophysiological basis for symptoms.

4. Analyze and treat pain complaints in a systemic approach.

5. Recognize and treat psychological problems at an early stage.

6. Recognize associated syndromes of disordered sensory processing.

7. Involve all FM patients in a program of stretching and gentle aerobic exercise.

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Treatment of Pain

Pain is the primary over-riding problem for most of you. Many of the problems you experience are largely a secondary consequence of having chronic pain. When pain is even partly relieved, FM patients experience a significant improvement in psychological distress, cognitive abilities, sleep and functional capacity. A total elimination of pain is currently not possible in the majority of FM patients. However, worthwhile improvements can nearly always be achieved by a careful systematic analysis of the pain complaints.

As a generalization, FM-related pain can be divided into general pain (i.e., the chronic background pain experience) and focal pain (i.e., the intensification of pain in a specific region—usually aggravated by movement). The latter is probably a potent driving force in the generation of central sensitization. Attempts to break the pain cycle, to enable patients to be more functional are especially important.

In general, most FM patients do not derive a great deal of benefit from non-steroidal anti-inflammatory drugs (NSAID) preparations or acetaminophen, although NSAIDs are very useful in the treatment of associated joint pain problems such as osteoarthritis. Prednisone and other steroids have been shown to be ineffective in the long-term treatment of FM.

General pain

The use of NSAIDs (e.g., ibuprofen, aspirin, etc.) is usually disappointing. It is unusual for FM patients to experience more than a 20% relief of their pain, but many consider this to be worthwhile.  Narcotics (propoxyphene, codeine, and oxycodone) often provide a worthwhile relief of pain. In most patients, concerns about addiction, dependency and tolerance are ill-founded. Ultram (Tramadol) and Ultracet (Tramadol + Tylenol), are the most useful pain medications in many patients. They both have the advantages of having a low abuse potential and are not a prostaglandin inhibitor. Tramadol reduces the epileptogenic threshold and it should not be used in patients with seizure disorders.

Currently, opiates are the most effective medications for managing most chronic pain states (Friedman OP 1990, Portenoy 1996). Their use is often condemned out of ignorance regarding their propensity to cause addiction, physical dependence and tolerance (Melzack 1990, Portenoy et al 1997, Wall 1997).

While physical dependence (defined as a withdrawal syndrome on abrupt discontinuation) is inevitable, this should not be equated with addiction (Portenoy 1996). Addiction is a dysfunctional state occurring as a result of the unrestrained use of a drug for its mind-altering properties. Manipulation of the medical system and the acquisition of narcotics from non-medical sources are common accompaniments. Addiction should not be confused with "pseudo-addiction". This is a drug-seeking behavior generated by attempts to obtain appropriate pain relief in the face of under-treatment of pain.

Opiates should never be the first choice for pain relief in FM, but they should not be withheld if less powerful analgesics have failed. In my experience many FM patients want to try opioid medications, but then give up on them due to unacceptable side effects, such as mental fog, increased tiredness, dizziness, constipation and itching.

Local pain

Although you are experiencing widespread body pain—a manifestation of central sensitization—you will also have multiple areas of tenderness in muscles—so called "myofascial trigger points." The severity of pain and the location of these "hot spots" typically varies from month to month, and the judicious use of myofascial trigger point injections and spray and stretch (see section on focal pain) is worthwhile in selected patients. It is often worthwhile for your physician to identify the most symptomatic points for myofascial therapy. The steps involved in the injection of trigger points are:

1. Accurate identification of the trigger point.

2. Identification and elimination of aggravating factors.

3. The precise injection of the myofascial trigger points with 1% procaine (a local anesthetic).

4. Passive stretching of the involved muscle after the local anesthetic has taken effect; this is often aided by spraying the overlying skin with an ethyl chloride spray. In most FM patients, this myofascial therapy needs to be repeated over a period of several weeks and occasionally over several months.

Unresponsiveness is usually due to failure to eliminate an aggravating factor, imprecise injection of the trigger point, or failure to inject satellite trigger points. Trigger points are usually injected with 3 to 5 ml of 1-% procaine. Please note that these are not "steroid shots."

Performing "myofascial spray and stretch" often enhances the efficacy of trigger point injections immediately after the injections. Spray and stretch consists of an application of a vapocoolant spray, such as ethyl chloride over the muscle with simultaneous passive stretching. A fine stream of the spray is aimed toward the skin directly overlying the muscle with the active trigger point. A few sweeps of the spray are passed over the trigger point and the zone of reference. This is followed by a progressively increasing passive stretch of the muscle.

Evaluation by an occupational and physical therapist often provides worthwhile advice on improved ergonomics, biomechanical imbalance and the formulation of a regular stretching program. Hands-on physical therapy treatment with heat modalities is reserved for major flares of pain, as there is no evidence that long-term therapy alters the course of the disorder. The same comments can be made for acupuncture, TENS units and various massage techniques.

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Treatment of Sleep Disorders

Non-restorative sleep is a problem for most of you and contributes to your feelings of fatigue and seems to intensify your experience of pain. Effective management involves:

1. ensuring an adherence to the basic rules of sleep hygiene,
2. regular low grade exercise,
3. adequate treatment of associated psychological problems (depression, anxiety etc.)
4. the prescription of low dose tricyclic antidepressants or TCAs (amitryptiline, trazadone, doxepin, imipramine etc.).

Some FM patients cannot tolerate TCAs due to unacceptable levels of daytime drowsiness or weight gain. In these patients, benzodiazepine-like medications such as Ambien (zolpidem) are usually very useful.

Some FM patients suffer from a primary sleep disorder, which requires specialized management. About 25% of male and 15% of female FM patients have sleep apnea. Unless specific questions about this possibility are asked, sleep apnea will often be missed. Patients with sleep apnea usually require treatment with positive airway pressure (CPAP) or surgery.

 By far the most common sleep disorder in FM patients is restless leg syndrome. This can be effectively treated with L-Dopa/ carbidopa (Sinemet 10/100 mg at suppertime) or clonazepam (Klonopin 0.5 or 1.0 mg at bedtime).

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Exercise for FM

FM patients cannot afford not to exercise as de-conditioned muscles are more prone to microtrauma and inactivity begets dysfunctional behavioral problems. However, musculoskeletal pain and severe fatigue are powerful conditioners for inactivity. All FM patients need to have a home program with muscle stretching and gentle strengthening, and aerobic conditioning.

There are several points that need to be stressed about exercise in FM patients:

(1) Exercise is health training, not sport's training;

(2) Exercise should be non-impact loading;

(3) Aerobic exercise should be done for 30 minutes each day. This may be broken down into three 10-minute periods or other combinations, such as two 15 minute periods, to give a cumulative total of 30 minutes. This should be the aim—it may take 6-12 months to achieve this level.

(4) Strength training should emphasize on concentric work and avoid eccentric muscle contractions.

(5) Regular exercise needs to become part of the usual lifestyle; it is not merely a 3-6 month program to restore you to health.

Suitable aerobic exercise includes: regular walking, the use of a stationery exercycle or Nordic track (initially not using the arm component). Patients who are very de-conditioned or incapacitated should be started with water therapy using a buoyancy belt (Aqua-jogger). [We highly recommend ongoing pool exercise programs for both FM and ME/CFS patients to reduce pain and to safely increase conditioning.—Ed]

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Recognition of secondary distress

As you suffer from chronic pain there is a distinct possibility that you may develop secondary psychological disturbances, such as depression, anger, fear, withdrawal and anxiety. Sometimes these secondary reactions become the "major problem" for some patients. The prompt diagnosis and treatment of these secondary features is essential to effective overall management of FM patients. 

Some FM patients develop a reduced functional ability and have difficulty being competitively employed. In such cases your doctor will hopefully act as an advocate in sanctioning a reduced or modified load at work and at home.

Unless you have a severe psychiatric illness (e.g., major depressive illness or a psychosis), referral to psychiatrists is usually non-productive.

Psychological counseling, particularly the use of techniques such as cognitive restructuring and biofeedback, may benefit some patients who are having difficulties coping with the realities of living with their pain and associated problems.

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Fibromyalgia-associated syndromes

It is not unusual for FM patients to have an array of bodily complaints other than musculoskeletal pain. It is now thought that these symptoms are a result of the abnormal sensory processing as described in the previous section. Recognition and treatment of these associated problems are important in the overall management of your FM.

• Chronic fatigue
• Restless Leg Syndrome
• Irritable Bowel Syndrome
• Irritable bladder syndrome
• Cognitive dysfunction
• Cold intolerance
• Multiple Sensitivities
• Dizziness
• Neurally Mediated Hypotension
• Non-restorative sleep (above)

1. Chronic fatigue—The common treatable causes of chronic fatigue in FM patients are: (1) inappropriate dosing of medications (TCAs, drugs with antihistamine actions, benzodiazepines etc.); (2) depression; (3) aerobic deconditioning; (4) a primary sleep disorder (e.g. sleep apnea); (5) non-restorative sleep (see above); and (6) neurally mediated hypotension. A new drug called Provigil is of some help when used intermittently for management of fatigue.

2. Restless leg syndrome—This strictly refers to daytime (usually maximal in the evening) symptoms of (1) unusual sensations in the lower limbs (but can occur in arms or even scalp) that are often described as paresthesia (numbness, tingling, itching, muscle crawling); and (2) a restlessness, in that stretching or walking eases the sensory symptoms. This daytime symptomatology is nearly always accompanied by a sleep disorder—now referred to as periodic limb movement disorder (formerly nocturnal myoclonus). Treatment is simple and very effective—DOPA / Levodopa (Sinemet) in an early evening dose of 10/100 (a minority require a higher dose or use of the long acting preparations).

3. Irritable bowel syndrome—This common syndrome of GI distress that occurs in about 20% of the general population is found in about 60% of FM patients. The symptoms are those of abdominal pain, distension with an altered bowel habit (constipation, diarrhea or an alternating disturbance). Typically the abdominal discomfort is improved by bowel evacuation. Due to abnormal sensory processing these symptoms may be quite distressing to FM patients. Treatment involves (1) elimination of foods that aggravate symptoms; (2) minimizing psychological distress; (3) adhering to basic rules for maintaining a regular bowel habit; (4) prescribing medications for specific symptoms; constipation (stool softener, fiber supplementation and gentle laxatives such as bisacodyl), diarrhea (loperamide or diphenoxylate) and antispasmodics (dicyclomine or anticholinergic /sedative preparations such as Donnatal).

4. Irritable bladder syndrome—This is found in 40-60% of FM patients. The initial incorrect diagnoses are usually recurrent urinary tract infections, interstitial cystitis or a gynecological condition. Once these possibilities have been ruled out a diagnosis of irritable bladder syndrome (also called female urethral syndrome) should be considered. The typical symptoms are those of suprapubic discomfort with an urgency to void, often accompanied by frequency and dysuria. In a sub-population of FM patients this is related to a myofascial trigger point in the pubic insertion of the rectus abdominus muscles and may be helped by a procaine myofascial trigger point injection. Treatment involves: (1) increasing intake of water; (2) avoiding bladder irritants such as fruit juices (especially cranberry); (3) pelvic floor exercises (e.g. Kegel exercises); and (4) the prescription of antispasmodic medications (e.g. oxybutinin, flavoxate, hyoscamine).

5. Cognitive dysfunction—This is a common problem for many FM patients. It adversely affects the ability to be competitively employed and may cause concern as to an early dementing type of neurodegenerative disease. In practice the latter concern has never been a problem and patients can be reassured. The cause of poor memory and problems with concentration is, in most patients, related to the distracting effects of chronic pain and mental fatigue. Thus the effective treatment of cognitive dysfunction in FM is dependent on the successful management of the other symptoms.

6. Cold intolerance—About 30% of FM patients complain of cold intolerance. In most cases this amounts to needing warmer clothing or turning up the heat in their homes. Some patients develop a true primary Raynaud's phenomenon (which may mislead an unknowing physician to consider diagnoses such as Lupus (SLE) or scleroderma). Many FM patients have cold hands and feet, and some have cutis marmorata (a lace like pattern of purple discoloration of their extremities on cold exposure). Treatment involves: (1) keeping warm; (2) low-grade aerobic exercise (which improves peripheral circulation); (3) treatment of neurally-mediated hypotension; and (4) the prescription of vasodilators such as the calcium channel blockers (but these may aggravate the problem in patients with hypotension).

7. Multiple sensitivities—One result of disordered sensory processing is that many sensations are amplified in FM patients. In general FM patients are less tolerant of adverse weather, loud noises, bright lights and other sensory overloads. Treatment involves being aware that this is an FM-related problem and employing avoidance tactics.

8. Dizziness—This is a common complaint of FM patients. Before this symptom is attributable to FM a thorough evaluation for other neurological causes should be pursued (e.g. postural vertigo, vestibular disorders, 8th nerve tumors, demyelinating disorders, brain stem ischemia and cervical myelopathy). In many cases no obvious cause is found, despite sophisticated testing. Treatable causes related to FM include: (1) proprioceptive (awareness of posture, movement, changes in equilibrium) dysfunction secondary to muscle deconditioning; (2) proprioceptive dysfunction secondary to myofascial trigger points in the sterno-cleido-mastoids and other neck muscles; (3) neurally mediated hypotension (see below); and (4) medication side effects. Treatment is dependent on making an accurate diagnosis. In patients in whom no obvious cause is found a trial of physical therapy, concentrating on proprioceptive awareness may prove worthwhile relief.

9. Neurally mediated hypotension—Patients with this problem usually have a low blood pressure that does not go up normally on standing or on exercise. Although such patients often have a low ambient BP with postural changes, these findings are not a prerequisite for diagnosis. A tilt table test (sometimes with the infusion of isproterenol) is the most reliable way to confirm this diagnosis. Treatment involves: (1) education as to the triggering factors and their avoidance; (2) increasing plasma volume (increased salt intake, prescription of florinef); (3) avoidance of drugs that aggravate hypotension (e.g. TCA's, anti-hypertensives); (4) prevent the involuntary response (prescribe beta-adrenergic antagonists e.g. propranolol (inderal) or metoprolol (lopressor) or disopyramide (norpace), but these agents are only used as a last resort because they reduce exercise tolerance); and (5) minimize the efferent limb of the involuntary response (prescribe alpha-adrenergic agonists e.g. midodrine (proamatine) or anti-cholinergic agents.

 

Dr. Bennett is an internationally known FM specialist, Professor of Medicine at Oregon Health Sciences University (OHSU), and Chairman of Arthritis and Rheumatic Diseases Division.  Permission was granted to publish this article from the Oregon Fibromyalgia Foundation's website: www.myalgia.com. © 2002 Robert Bennett M.D., FRCP.

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More resources

Chronic Pain Control by Dr. David Bell

Clinical Guides for Fibromyalgia

Complementary and Mainstream Treatment Approaches  by Dr. Jeanne Hubbuch

Conventional Medicine —an overview by symptoms of classes of drugs used to treat them

Developments in Fibromyalgia Treatments

Drugs that may cause FM by Dr. Byron Hyde

Dr. Lapp's Stepwise Approach to Managing FM

Guaifenesin protocol of Dr. St. Amand

Lapp-Campbell talk on Pacing

Milnaciprin Beneficial for Fibromyalgia in Patients with Inadequate Response to Duloxetine

Important articles on Treatment

Insights about FM and Chronic Pain

Pharmacological Therapies Approved for FM

Review of Nutritional Supplements Used for ME/CFS/FM

Supplements 

2003 AACFS Clinical Conference Report: Overview of Epidemiology, Characteristics and Treatment of CFS

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Last Updated: 02 December 2015 02 December 2015

by Dr. Rosamund Vallings, MB BS, ME specialist, Auckland, New Zealand

I attended the AACFS 6th International Conference on the Chronic Fatigue Syndrome (CFS), fibromyalgia (FM) and related syndromes, held at Chantilly, Virginia from 1/31-2/2/03. The first day was a clinical conference for physicians working in the field of CFS, followed by a day and a half of research presentations. 

Overview of the Characteristics and Epidemiology of CFS

The clinical conference opened with an introduction and overview by Charles Lapp M.D. and Leonard Jason Ph.D. Lapp ran through the history of CFS, which was described by Hammurabi as early as 2000 BC. Jason reviewed the problem of CFS and its definition, citing that 50 million Americans suffer from fatigue, of which 14 million have prolonged fatigue and 8 million have a diagnosis of chronic fatigue (not CFS). CFS fitting the research case definition probably affects 800,000 in the USA. 

Epidemiologically, a major study showed that there is a predominance of females with CFS, and almost double the number of Latinos compared to American whites or Afro-Americans. There was no history of abuse in the majority of cases and in 50% of the cases there was a family history of autoimmune disease.

Those with CFS were found to be more functionally impaired than those with Type-2 diabetes, congestive heart failure, MS or end-stage renal disease. Many do however show improvement over 2 years, though the majority do remain significantly impaired. 

Various physical and psychological scales were discussed to measure outcomes and co-morbidity, including wearing a device to produce actigraphs showing daily activity. Those with CFS particularly showed reduced activity and non-restorative sleep.

He then reviewed physical examination in CFS pointing out particularly that lymph glands and skin may be very tender. Laboratory findings in CFS were usually essentially normal, though there may be abnormal immune complexes, atypical lymphocytes, lowered IgG, small increase in alkaline phosphatase, elevations in cholesterol and small increases in ANA and thyroid antibodies. MRI studies of the brain have demonstrated high intensity T2 weighted lesions, but these do occur in other diseases and are non-diagnostic. SPECT scans to demonstrate function show decreases in cerebral blood flow with exercise, often worse 24 hours later.

There was acute onset in 85% cases, and in 72% the main precipitating factor was infection, with a small number of cases following trauma, surgery, childbirth, allergic reaction and emotional trauma. He reviewed possible causes of CFS, including various infectious agents, immunological defects leading to T-cell activation, increases in cytokines and decreased NK-cell function, HPA-axis dysfunction with lowered cortisol levels and orthostatic intolerance. 92% of patients with CFS can become syncopal with orthostatic intolerance, and, as well as having a drop in BP, symptoms may come on after a delay of 15 minutes.

The differential diagnosis covered a very wide range of diseases, and the audience participated in discussion of the characteristic diagnostic features of other conditions such as:

• Evidence of a tick bite and presence of arthritis in Lyme disease
• Optic neuritis and ocular nerve disorders in MS
• Butterfly rash and arthritis in SLE
• Genital infection followed by arthritis (particularly in heel and lower spine) in Reiter's disease
• Skin discoloration and immediate light headedness on tilt in Addison's disease
• SSA antibodies in Sjorgren's syndrome
• Hypercalcemia with polyuria in parathyroidism
• High ferritin levels in hemochromatosis
• Gluten sensitivity and low ferritin in coeliac disease
• Raised SGOT in hepatitis etc

Lab tests for all of the above should be performed according to the symptoms and history. Further investigation should be pursued if the ESR is elevated as that is not characteristic of CFS, where it tends to be low.

Fibromyalgia

A diagnosis of fibromyalgia (FM) is made if there is widespread pain of at least 3 months' duration coupled with tenderness in 11 of the 18 classical tender point. Gulf War Illness (GWI) tends to overlap with CFS but there are important differences, such as gastrointestinal, respiratory and skin symptoms, which are uncommon in CFS. The 1999 case definition for Multiple Chemical Sensitivity (MCS) was presented. The main symptoms are cognitive impairment, mood disorder, disequilibrium, respiratory problems, headaches, nausea and fatigue. Symptoms are reproducible with repeated exposure and tend to improve when incitants are removed. There is considerable overlap between MCS and CFS with 30% of those with MCS fulfilling the criteria for CFS.

Management Approach to CFS

Lapp then presented his stepwise approach to the management of CFS. These steps include Patient Education; Activity—balancing light activity with rest and increasing the level of activity slowly over time; and Nutrition—avoiding malnutrition, minimizing sugar, caffeine, alcohol and tobacco, keeping fats low if suffering from diarrhea and avoiding dairy products and or/gluten for 5 days to see if there is any improvement.

Specific Symptom Therapy:

Sleep Management—Initially try melatonin, phototherapy or OTC medication, then clonazepam 0.5mg and/or doxepin 10mg (clonazepam is habituating but not addictive). Trazadone 50mg can give improvement in levels 3 - 4 sleep. Hypnotics may be needed by some patients, and flexeril can be considered in combination with any of the above.

Central Activation—reduced levels of dopamine and serotonin can lead to sleep disturbance, low pain threshold, loss of motivation and depressed mood. SSRIs (seratonin reuptake inhibitors) and SNIs (seratonin/ norepinephrine inhibitors, e.g. venlafaxine/ effexor) can be useful as can dopamine agonists such as wellbutrin.

Autonomic Nervous System dysfunction—treatment aimed at volume expansion with 2 quarts (2.5L) fluid per day with 1-2 teaspoons of salt daily. Some will benefit from fluodrocortisone 0.1-0.3 mg daily. Vasoconstrictors such as ephedrine and midodrine can be useful.

Pain Control—presented by Ben Natelson MD:

Stage 1:
NSAIDS—celebrex 200mg 2x/day - often not much help.
Plaquenil—raises pain threshold, but has side effects
Tricyclics—amitriptyline 20-50mg, particularly if there is a sleep problem
Flexeril, other muscle relaxants
EffexorXR 75 -225 mg daily if depressed

Stage 2: Anti-epileptics drugs:
Neurontin 100mg daily, increasing to 300mg, can possibly go up to 3 gm daily
Lamotrigine 25mg daily initially rising to 100mg 3x/day
Trileptal 150mg 2x/day, rising to 600mg 2x/day
Topamax—good if there is a weight problem

Stage 3:
Plaquenil —6 month trial
Tizanidine—2-4mg 2x/day (very expensive)
Mexelitine—150 - 300mg daily (a local anesthetic)
Lidocaine patches maybe useful for focal pain.
Tramadol—50mg daily.

Stage 4:
Opiates—morphine up to 30mg 2x/day
Methadone (cheap but has long half life)
Prednisone—does not work in FM, but hydrocortisone 25mg daily is often helpful (keep in mind side-effects). A four-week trial is worthwhile.

Treatment for Fatigue—drugs with stimulant effects were reviewed: dexamphetamine (dexadrine), eldepryl (selegiline), cylert (pemoline), methylphenindate (ritalin), modafinil (provigil) and a new drug used for ADD called amoxetine (atomoxetine).

Disability Evaluation of those with CFS was then discussed by Dr. Lapp. He pointed out that in the US, primary care physicians are faced with the task of advocating for 800,000 patients with CFS and more than 2 million with FM. Up to 50% of these people are unable to work. Evaluation needs to be done by a physician familiar with CFS. Standardized psychometric and functional testing instruments need to be used. For presentation to Social Security in the US, CFS patients must fit the 1994 Fukuda definition, with one or more specific medical signs clinically evaluated over at least 6 consecutive months (eg swollen or tender nodes, tender points etc)—and certain specific lab findings are acceptable. (eg NMH by tilt table testing, abnormal cranial MRI). Documentation of cognitive and emotional difficulties is also important. Physicians world-wide should be aware of the requirements to keep good notes on relevant issues for these patients.

Dr. Natelson's preliminary findings of protein changes in the spinal fluid of CFIDS patients

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Last Updated: 02 December 2015 02 December 2015

June 2005

Dr. Benjamin Natelson, M.D., professor of neurosciences at the University of New Jersey Medical School, is a highly respectedMyalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) researcher. He recently, using a new technology called proteomic profiling, has found abnormal proteins in the spinal fluid of ME/CFS patients.

The purpose of his research is to seek possible causes and diagnostic markers for ME/CFS.

In the early stages of this research, he has already found at least 5 "CFS-related alterations... in both the high and low molecular weight ranges." One of the proteins "that is present in all healthy controls... appears absent or reduced in 81% of CFIDS patients." Dr. Natelson, in the next phase of his research, is seeking to identify this protein. Likely candidates are a thryroid hormone transport protein and a brain-derived neurotrophic factor. The protein alterations could explain various ME/CFS symptoms, including exhaustion, cognition and memory problems, and neural aberrations.

Dr. Natelson wishes to continue and broaden his research to test the spinal fluids of more ME/CFS patients and controls to determine if a CFIDS-specific altered protein profile exists and if such a profile can be used as a diagnostic marker.

Although his work is in its early stages, it seems like a valuable line of research since the spinal fluid may provide access to determining organic changes in the brain.

Researchers in the Netherlands Find Reduced Brain Gray Matter in Patients with CFS

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Last Updated: 02 December 2015 02 December 2015

The following is a summary of : "Gray Matter Volume Reduction in the Chronic Fatigue Syndrome," by de Lange F.P. et al.,  NeuroImage July 26 (3) (2005): 777-781.

The team conducted this important research at the Centre for Neuroimaging at Radboud University in Nijmegen in the Netherlands. They used "...an unbiased morphometric technique to test whether CFS patients display structural cerebral abnormalities (in the brain)."

Structural cerebral morphology (physical character) and volume were mapped in two separate groups of Chronic Fatigue Syndrome (CFS) patients (in total 28 patients) and healthy controls (also totaling 28 patients). This mapping was conducted using high-resolution structural magnetic resonance images "...using voxel-based morphometry (VBM). Additionally, we recorded physical activity levels to explore the relation between severity of CFS symptoms and cerebral anamolies." [Massachusetts CFIDS/ME & FM Association emphasis].

An important aspect of the research was the use "...of a fully automated, observer independent procedure [VBM, which]...provides an unbiased and validated...technique for measuring cerebral volume and tissue concentration..."

The team also used actigraphic assessment to measure the physical activity levels of patients as well as that of a portion of the healthy controls.

Methods:

The study was restricted to women for several reasons—including the fact that more women than men suffer from CFS and also because of the differences in brain size and morphology between the sexes.

The first cohort consisted of 13 CFS patients (mean age: 28.9 years) and 15 healthy controls (mean age: 25.7 years). The two groups were matched for age, sex, and education. The second cohort consisted of "...15 older CFS patients (mean age 43.9 years)..." and an appropriately matched group of healthy controls. Two weeks prior to the scanning, 26 of the CFS patients and 14 of the healthy controls were evaluated for their physical activity level. This was done using a motion-sensing device that fits on the ankle. The device provides an activity score for each 5 min. of movement (multi-directional). This device was worn continuously day and night for at least the 14-day period.

Only patients meeting the 1994 CDC diagnostic criteria were included in the study—but, significantly, any patient exhibiting depression was excluded. (Note: while many patients with ME/CFS actually show secondary depression, the exclusion increased the likelihood that more patients who really do have ME/CFS were included in the study.)

Two other measures of the patient group were included: self-reported disease severity (measured by the Checklist of Individual Strength—a questionnaire that measures fatigue), and self-reported disease duration.

Imaging protocol:

Images of the whole brain were analyzed "...for computational analysis of differences in global and local gray and/or white matter volume." Highly sophisticated techniques were used to provide valid comparisons by normalizing a variety of variables (including population-specific biases). Then, in a second stage, statistical methods were used to correct for non-uniformities in "...signal intensity and partitioned into gray and white matter, cerebrospinal fluid, and background."

In the statistical analysis, "Global differences in gray and white matter between groups were assessed..." taking into account age as a confounding covariant." Statistical methods were also used to assess, correct and correlate physical activity and gray matter volume, and regional differences (in the brain) in gray matter between groups taking into account age and other variables.

Results:

"Both cohorts of CFS patients showed significant reductions in gray matter volume...compared to healthy controls." Even when the two cohorts are put together the reduction of gray matter in patients remains "highly significant", amounting to a reduction of "approximately 8%".

The study, interestingly, did not find a difference in gray matter reduction by brain region— the reduction in gray matter was only significant globally. There were also no local foci of reduced gray matter.

"White matter volume was not significantly different between groups."

Correlation with physical activity

There was a positive correlation between daily physical activity and gray matter within the CFS patients. At the same time, there was no such correlation in the control group. The age variable was found not to affect the physical activity level in the CFS group. This means that the positive correlation between gray matter and physical activity in the CFS population is not countered by the age variable. "There were no significant correlations between gray matter and...illness duration or CFS severity...as measured by the Checklist of individual Stength."

Conclusion:

"Our findings appear to provide a reliable somatic marker for CFS." The authors suggest the finding may corroborate the primary involvement of the central nervous system in ME/CFS. However, the authors acknowledge that the meaning of the findings may not be "straightforward". The correlation between reduced global gray matter and reduced physical activity in CFS cohorts might be causative—that is the reduced gray matter might be influencing the ability to conduct physical activity.

Alternatively, the reduction of physical activity caused by ME/CFS might be itself having the effect of reducing gray matter in the brain.

There is some research that lends credence to the effect of reduced physical activity on the amount of gray matter in the brain. However, interestingly, in this study illness duration was not found to affect the gray matter decrease in the CFS subjects. This would, obviously, suggest that the reduction of gray matter in the CFS subjects was not due to reduced physical activity.

The study found "...substantial and consistent reductions in gray matter volume...in CFS patients... This GM reduction was associated to the decline in physical activity in the CFS patients..."

Genetic and Evironmental Factors Impact CFS Patients

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Last Updated: 02 December 2015 02 December 2015

Press Release
For Immediate Release: April 20, 2006
Contact: CDC Media Relations
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People who suffer from Chronic Fatigue Syndrome (CFS) have a genetic make up that affects the body's ability to adapt to change, according to a series of papers released today by the Centers for Disease Control & Prevention (CDC). These papers, which analyze the most detailed and comprehensive clinical study on CFS to date, are published in the April issue of Pharmacogenomics.

Over the past year, CDC scientists have worked with experts in medicine, molecular biology, epidemiology, genomics, mathematics, engineering, and physics to analyze and interpret information gathered from 227 CFS patients. The information was gathered during a study in which volunteers spent two days in a hospital research ward. During this time, they underwent detailed clinical evaluations, measurement of sleep physiology, cognitive function, autonomic nervous system function, and extensive blood evaluations, including an assessment of the activity of 20,000 genes, in an attempt to identify factors that potentially cause or are related to CFS.

"This study demonstrates that the physiology of people with CFS is not able to adapt to the many challenges and stresses encountered throughout life, such as infection, injury and other adverse events during life," said Dr. William C Reeves, who heads CDC's CFS public health research program. "These findings are important because they will help to focus our research efforts to identify diagnostic tools and more effective treatments which ultimately could alleviate a lot of pain and suffering."

The multidisciplinary approach to this study, which has been termed C3 or the CFS Computational Challenge, was developed by the CDC's Dr. Suzanne Vernon, Molecular Epidemiology Team Leader for the CFS Research Laboratory. It is an approach that could lead to advances with other diseases and disorders. "We put together four teams of different experts and challenged them to develop ways to integrate and analyze a wide range of medical data so as to identify those things that could improve the diagnosis, treatment, or understanding of CFS," Dr. Vernon said. "There is a clear biologic basis for CFS, and knowing the molecular damage involved will help us devise effective therapeutic intervention and control strategies."

It's estimated that over one million people in the United States alone are sick with CFS. The condition takes a tremendous personal and social toll—approximately $9 billion a year to the nation and $20,000 per family. It occurs most frequently in women ages 40-60 and can be as disabling as multiple sclerosis and chronic obstructive pulmonary disease.

The CDC is the principal agency in the United States for protecting the health and safety of all Americans. CDC is promoting CFS awareness through a national media and education campaign set to kick off later this spring.

The April issue of Pharmacogenomics, published by Future Medicine, includes 14 research papers, the culmination of C3. The journal Pharmacogenomics is dedicated to the rapid publication of original research on basic pharmacogenomics research and its clinical applications. Published eight times a year, the journal covers the effects of genetic variablity on drug toxicity and efficacy, the characterization of genetic mutations relevant to drug action, and the identification of novel genomic targets for drug development.