AACFS 2004 Meeting Summary by Charles W. Lapp, M.D

AACFS 2004 Meeting Summary by Charles W. Lapp, M.D

The 7^th Annual Research and Clinical Conference of the American Association of Chronic Fatigue Syndrome was held October 8-10, 2004, in beautiful Madison, Wisconsin, about 2 hours northwest of Chicago. Fall was just touching the trees when we arrived, and the weather was delightful.

This year’s conference attracted 235 attendees, 39 of whom came from overseas. Fourteen foreign countries were represented, including Spain, New Zealand, Australia, Belgium, England, Switzerland, the Netherlands, Italy, Denmark, Norway, Japan, Korea, Mexico and India. Over half the attendees were medical professionals, the balance being mostly patients and caregivers.

One hundred seventy abstracts were submitted to the organization committee. The final scientific program consisted of 48 scientific presentations, 5 reviews, two philosophical approaches, and 4 workshops. Drs. Jason, Ablashi, and Bateman contributed extensively as the program organizers; Drs. Clauw and DeMeirLeir co-chaired the research section, while Drs. Lapp and Schwartz headed the clinical session.

RESEARCH SESSION (FRIDAY, OCTOBER 8)

Dr. Tony Komaroff kicked off the meeting, as usual, with his much-anticipated overview of research over the past two years. These nuggets of wisdom and understanding can best be summarized by bulleting the key points:

· The Medical Outcome Study Short-Form-36 is a reliable, validated survey that has shown substantial reductions of function in persons with CFS (PWCs) from the US, UK, and Germany.

· CFS symptoms during pregnancy improved in one third, worsened in one third, and remained unchanged in one-third.

· A recent large study of prognosis concluded that the course of CFS waxes and wanes, but only about 10% of patients achieve complete remission.

· Central nervous system involvement in CFS is supported by predictable decreases in CRH, ACTH and cortisol; elevated prolactin in response to serotonin stimulators; and growth hormone deficiency.

· While higher order skills are preserved, cognitive studies in CFS demonstrate a decline in IQ (sometimes from supranormal to normal levels), and deficits in complex information processing, processing speed, acquisition of new information, and learning or recall of complex material.

· A reduce blood volume (red blood cell mass) and prolonged acetylcholine-mediated vasodilation of the microcirculation (e.g., forearm skin) occur frequently in CFS.

· Sleep is less efficient, sleep onset is delayed, and sleep study abnormalities (apnea, leg movement, restless legs, and narcolepsy) occur in up to 50% of cases of CFS.

· Therapy of sleep abnormalities is only modestly effective in improving CFS symptoms.

· Activated lymphocytes are increased in CFS and may pass through the blood brain barrier to activate other lymphocytes and dendritic cells. This effect may persist for years.

· Activated microgliae secrete pro-inflammatory cytokines and nitrous oxide (NO) causing a chronic low level injury.

· Apoptosis (cell death) of neutrophils may lead to neutropenia in some patients.

· Inflammatory cytokines are elevated at the onset and over time in many patients infected with Parvovirus B19. Persistent fatigue is best correlated with elevated gamma-interferon.

· PCR plus Southern Blot demonstrated at least one species of mycoplasma in a 179 of 261 study subjects with CFS, compared to 2 out of 36 healthy controls. M. Hominis and M. pneumonia were most commonly identified.

· Nucleic acid gene expression techniques have demonstrated persistent deficiencies in oxidative phosphorylation, glycolysis, and glucose metabolism in PWCs.

· Reduced Vitamin D levels are seen in both CFS and FM, correlating with increased musculoskeletal pain and lower bone density.

· Endogenous levels of omega-3 fatty acids are reduced in chronic illness, and may be associated with an increase in inflammatory mediators and reduced antiviral activity. Small trials suggest that replenishment may have some value.

Komaroff was followed by Dr. Bill Reeves, Chief of Viral Exanthems and Herpesvirus Branch, NCID / Centers for Disease Control and Prevention in Atlanta. Dr. Reeves provided an entertaining and comprehensive overview of CFS epidemiologic studies performed by the CDC over the past several years.

25-50% of persons reporting to a general medical clinic complain of fatigue. According to a British study, 20% have unexplained fatigue, while 75% can be attributed to psychiatric causes and 5% to medical causes. The prevalence of CFS in two large population-based studies ranged from 235 per 100,000 (from 34,000 households with 90,000 individuals polled in Witchita, KS) to 422 per 100,000 (a study of 18,000 adult respondents in Chicago).

Data from the United States reveals:

· 2 to 5 times more women have CFS than men

· Adults have 5 times the risk of adolescents

· Minorities are at higher risk

· Lower socio-economic class is at at higher risk

· 80% of subjects report a gradual onset

· While there are no regional differences in prevalence, the prevalence is higher in rural than urban areas (for “CFS-like” cases)

It is estimated that there are approximately 800,000 cases of CFS in the US and it appears that only 10-17% of these have actually been diagnosed by a physician or provider. Approximately 25% are unemployed or on disability.

The annual economic burden from CFS alone was recently estimated to be $9-billion, roughly equivalent to all the loss from hurricanes this year in Florida, or the entire profit margin of WalMart! In the UK it is estimated that the direct cost of medical care adds an additional burden of $4-billion per year.

Finally, the goals of the CDC are to determine if CFS is a single illness; to define the natural history and clinical presentation of the disorder; to identify risk factors and diagnostic markers; and to devise both control and preventive strategies. At this point he opined, “We know more about what CFS is not than what it is.”

Dr. Dan Clauw (Chair, Department of Medicine/Rheumatology, University of Michigan) reviewed current trends in FM. The 1990 American College of Rheumatology definition is being re-examined, he explained, as researchers view FM as less of a discreet illness with focal areas of pain, and more as a continuum of illness with diffuse tenderness and associated somatic symptoms. It is also being recognized that psychological and behavioral factors play a negative role in some cases.

Tenderpoints may be less helpful than we once thought (studies indicate they correlate better with emotional distress than to disease severity), and they give the unfortunate impression that FM is mostly a muscle disorder, while most practitioners recognize that FM encompasses both rheumatic and multisystem symptoms.

Women are 1.8 times more likely to report widespread pain than men, but 10 times more likely to contract FM. The prevalence of FM is increased 8-fold in first degree relatives, according to Clauw, whereas the risk is only 2-4 fold for other rheumatic disorders such as rheumatoid arthritis and lupus, “making FM the most familial rheumatic disease.” He feels that genetic markers of FM identified to date, however, are mostly related to comorbid psychiatric illness and not FM alone.

Pain amplification is clearly present in FM and attributed to both central and peripheral abnormalities, but cannot be explained to emotional or psychological factors. Persons with FM (PFs) perceive that a given pain is more severe than do healthy controls, and the threshold for other sensations (noise, heat, and electrical stimulation, for example) is also reduced. The lower threshold for sensing pain is corroborated by functional MRI studies.

Depression has almost no role in pain processing, but “catastrophizing” or feeling “out of control” may exacerbate the perception of pain.

Abnormal pain perception is not unique to FM, but is also seen in irritable bowel syndrome, temperomandibular dysfunction, muscle contraction headaches, chronic low back pain, vulvodynia, and complex regional pain disorders, suggesting that there is some commonality among these. Two mechanisms offered for this are “wind-up” and the absence of DNIC (diffuse noxious inhibitory controls), both of which are being extensively studied.

FM therapy is commonly centered on managing pain. Three approaches to management include counseling and support, opioids, and manipulating the antinocic (serotonin- and noradrenaline-related) pathways of the central nervous system. Clauw gave examples of several drugs that modulate pain by enhancing serotonin-, noradrenalin-, or mixed-pathways.

PAPERS AND PRESENTATIONS

Over 30 papers were selected for presentation at this year’s Research Session, of which several were clearly outstanding.

Dr. Jo Nijs (Free University of Brussles) introduced the attendees to the importance of elastace in persons with CFS. Previous studies have established that persistent activation of the 2,5-OAS pathway in CFS leads to elevated levels of RNaseL, which is cleaved in turn by capsain and elastace to a more biologically active form of low molecular weight RNaseL (LMW RNaseL). Also, higher levels of RNaseL correlate with reduced exercise ability (Snell 2002).

Sixteen PWCs (no controls) underwent exercise stress testing. Oxygen uptake at a Respiratory Quotient of 1.0 (RQ = 1.0 is about equivalent to the anaerobic threshold) was reduced compared to predicted norms. Increased levels of plasma elastase activity correlated with reduced oxygen uptake, but scores on a symptom inventory, MOS SF-36 scores, RNaseL, PKR, and nitrous oxide levels did not. Elevated elastase levels could conceivably damage lung tissue and impair oxygen diffusion across alveoli in the lungs, possibly explaining decreased oxygen delivery to tissues in CFS.

Dr. Charles Raison pointed out that when interferon-alpha is administered therapeutically to persons with hepatitis C virus infection, many subjects develop a CFS-like illness. Before treatment 3% of patients met criteria for CFS, but during treatment 30% developed signs and symptoms consistent with CFS.

An interesting study from the rather isolated population of Dubbo, Australia, was described by Dr. Jim Jones of the CDC. A prospective study of persons who contracted three well-characterized illnesses (mononucleosis, Ross River Virus, and Q-Fever) demonstrated that 10-15% of victims met CFS criteria at 6 months and 5-6% continued to meet criteria at 12 months after infection. Neither the pre-morbid psychiatric profile nor any biological marker predicted who would develop CFS.

Harold Harrison, MD, PhD, proposed that procoagulant genetic factors play a role in CFS/ME and FM. His group studied tests of coagulability (such as fibrinogen and soluble fibrin monomer) and genes that control coagulability (e.g., protein C, protein S). 38 of 45 subjects (84%) had at least one positive test, a prevalence 3 times greater than the general population, according to Harrison. This group postulates that a subset of PWCs suffers with low grade coagulation (“sludge”) in the microcirculation, which could explain many symptoms of CFS.

Dr. Julian Stewart, a pediatric cardiologist from NY Medical College in Valhalla, NY presented a straightforward but elegant study of circulation changes in young adults with Postural Orthostatic Tachycardia Syndrome (POTS). He described three subsets of patients (high-, low-, and normal-flow POTS), all of whom demonstrated a marked decrease in thoracic blood volume on head up tilt table testing. Normal- and low-flow subjects also demonstrated pooling of blood in the splanchnic (abdominal) area during the same maneuver. Stewart concluded that the orthostatic intolerance can be produced by a number of mechanisms among them low blood volume, autonomic problems, and local abnormalities of blood flow and blood pressure regulation, but not necessarily an autonomic dysfunction.

CLINICAL SESSION (OCTOBER 9-10, 2004)

Over 70 abstracts were submitted to the Clinical Committee for consideration. Here are a couple of the top papers:

Anne Garcia-Quintana (Hospital Valle D’Hebron and Delfos Medical Center, Barcelona)

Dr. Quintana compared 50 persons with CFS/ME (PWCs) with 10 sedentary and 16 active young individuals by means of an arm ergometer and a bicycle ergometer. This confirmed previous studies showing that PWCs have a markedly reduced aerobic work capacity on bicycle ergometry, but demonstrated that they also have reduced upper body work capacity. Plasma lactate was also decreased in the more physically impaired.

This was a very straightforward study that was carried out well and came to a meaningful conclusion. PWCs can now understand why upper body activity is so exhausting.

Fred Friedberg (Stony Brook, LI, NY)

Patients frequently ask their doctors whether or not it would be beneficial to join a support group. Responses may be enthusiastic to discouraging, based mostly on the doctor’s own opinion, not necessarily on experience or information. This study provides some incite.

Friedberg distributed a survey to 32 active members and 135 inactive (or dropout) members of a local support group. The support group included persons with CFS (76%), FM (62%), and Multiple Chemical Sensitivities (28%). The illness course since joining the group was rated as better (52%), worse (29%), and unchanged (19%), and 80% of the sample consider the SG helpful.

The most frequently endorsed reasons for attending were illness legitimization (68%), new information (66%), and feeling understood (62%).Low endorsements were given to finding and dealing with physicians (35%, 39%). The most common reasons for dropping out were inconvenient location or time (38%, 37%), negative talk (33%) and too sick to attend (29%).

David Strayer (Hemispherx Biopharma)

Reported on a Phase III randomized, double blind placebo controlled crossover study of 234 subjects treated with parenteral Ampligen 400 mg twice weekly for 40 weeks. Demographics were similar in both groups. The dropout rate was slightly increased (24 v 16) as were the Serious Adverse Events (16 v 8) in the treatment group compared to placebo, but the differences were not statistically significant (p > 0.10).

Exercise duration in the treatment group was 16.1% greater than placebo (in completers) and 15.2% greater than placebo in all participants (intent to treat analysis, p<0.05). These increases in exercise duration were over twice the minimum considered medically significant (6.5%).

Maximum oxygen utilization was markedly improved in treated (6.07) versus placebo (0.58) subjects.

There were no significant adverse events or significant abnormalities in laboratory parameters.

Ampligen treatment in this debilitated population of CFS patients resulted in a medically and statistically significant improvement in the primary endpoint, exercise treadmill duration, compared to placebo. Ampligen may be the first drug to demonstrate safety and effectiveness in the treatment of CFS.

Dr. Kenny DeMeirleir (Vrije Universiteit Brussels, Belgium)

Dr. DeMeirleir challenged the conventional view of CFS as a disorder that has no known pathophysiology. He stated confidently that enough is known about the disorder to treat it in a scientific manner. He used two cellular anti-viral systems (oligo adenyl synthetase [OAS] and phosphokinase [PKR]) as examples.

In the OAS system, infection and mild immune dysfunction activate OAS, which then produces an enzyme RNaseL, which leads to cell death (apoptosis) and (in CFS) the production of a novel low molecular weight RNaseL.

OAS System

infection + innate immune defects à

activated 2’5′ OAS à

­ RNaseL à

­ apoptosis and truncated (LMW) RNaseL

Truncated or low molecular weight RNaseL can cause multiple symptoms (increased pain, depression, hypersensitivities, visual symptoms and hypoglycemia) via the ABC transporter system. Dr. DeMeirleir also stated that activated OAS can suppress the thyroid even though thyroid function tests appear normal.

Activation of PKR pathways, on the other hand, leads to activation of NF-kappa-B, the iNOS gene, and cyclo-oxygenase (COX2) pathways. These changes in switch the immune system to a Th2 state, suppress the hypothalamic-pituitary-adrenal axis, and cause both vasoconstriction and platelet aggregation.

PKR System

Activation of PKR pathways à

Activation of NF-kB / iNOS / COX2 à

Th2 switching, low HPA/CRH, vasoconstriction/platelet aggregation à

Multiple symptoms

DeMeirleir , therefore, sees Chronic Fatigue Syndrome as a Th2 immune disorder, with activated PKR, activated OAS, and an elevated RNaseL. He believes that effective therapeutic interventions might include restoring immune competence, treating hormonal changes, treating infections and allergies. He provided two case studies of PWCs in whom triggers were identified and focused therapy produced remarkable improvement.

Stanley Schwartz (Warren Clinic, Tulsa OK)

Dr. Schwartz is a practitioner and infectious disease specialist who tackled the difficult question of whether chronic Lyme disease and CFS are one and the same. Such questions arise because persons with previous Lyme infection may develop CFS-like symptoms. A minority of physicians attribute such symptoms to persistent borreliosis and recommend long term antibiotic therapy. The majority concludes that short term therapy is sufficient to destroy the Lyme organism .

If symptoms last longer than 6 months after a tick bite, is it chronic Lyme disease (LD) or CFS? To answer this question Schwartz reviewed the extant literature on chronic LD but he concluded that it is not clear if fatigue after LD is a form of CFS, unresolved infection, or due to an immune abnormality. Antibiotic therapy has not conclusively been shown effective in randomized controlled trials of chronic LD.

Schwartz made the important point that Lyme Disease is a clinical diagnosis, and that laboratory tests for LD may be unreliable in patients who do not have a reliable history of clinical Lyme disease.Accepted tests include the ELISA, Western Blot, skin biopsy, or synovial PCR. There are many other investigational tests, but these are unreliable and should not be relied upon for a diagnosis.

Leonard Jason, PhD (DePaul University, Chicago) & Nancy Klimas, MD (University of Miami)

Persons with CFS (PWCs) are clearly a heterogeneous group with diverse signs and symptoms. Just as there are many causes for cancer, it seems that there are various triggers and forms of CFS. This heterogeneity makes CFS difficult to define precisely. Over the years, several clinical case definitions have been suggested, but they clearly select slightly different populations. As a result, there is a lack of consistency in related studies using different criteria.

Table 1 – CFS Case Definitions

When the three case definitions were used with a group of chronically fatigued patients, the Holmes criteria selected the fewest, the Fukuda selected the highest number, and the Canadian in between.

Jason points out that the 1994 Fukuda Criteria are internationally accepted and widely used in current research. These criteria were developed by a consensus group assembled by the CDC and the NIH. In addition, the CDC meets periodically to update and revise these criteria. These recommendations are published by the CDC and are referenced on the CDC web site.

Sub typing patients was recommended by the authors of the Fukuda criteria (Fukuda, et al. Annals of IM, 1994), but they provided no specific recommendations. Subtyping could further define the patient population for research purposes and might define appropriate groups for targeted therapies. Klimas warned, however, about over-generalization. Generalizing from subgroup data requires follow-up trials to determine if the results can be extrapolated to the larger population.

Dr. Klimas suggested a number of ways to subtype patients including:

Symptoms / history subgrouping (e.g., duration, age at onset, severity, gender, ethnicity,

socioeconomic class, functional status, etc.)

Cognitive predominant versus pain predominant

Based on onset — acute versus slow

Based on systems involved (e.g., immune, autonomic, or neuroendocrine)

Based on gene expression patterns

Based on psychiatric diagnoses (depressed, anxious, compulsive, neurotic, etc.)

Based on physical findings (such as Tenderpoints, a positive Romberg, or hyperextensible joints)

Based on objective measures

Low cortisol (neuroendocrine grouping)

Abnormal tilt test (autonomic or orthostatically intolerant group)

Activation or cell markers, cytokine elevation (immune group)

Abnormal PASAT or other cognitive study (neurocognitive group)

CLINICAL MINI-SEMINARS

Three clinically relevant mini-seminars were presented at the Madison conference, including “Cognitive Behavioral Therapy,” “Exercise in Persons with CFS and FM,” and “Dysautonomias and Orthostatic Intolerance.” While it is difficult to capture these workshops entirely, the substance is summarized below.

COGNITIVE BEHAVIORAL THERAPY

A 2001 article in the Journal of the AMA reviewed the treatment literature at that time and concluded that CFS “interventions which have shown promising results include Cognitive Behavioral Therapy and exercise.” This renewed an interest in CBT, which had been explored previously both in the US and abroad.

CBT was initially brought to attention by British psychologists who subscribe to the idea that somatic symptoms in CFS and FM are perpetuated by errant illness beliefs and maladaptive coping. That is, persons with CFS/ME/FM have certain abnormal cognitions and behaviors that perpetuate their symptoms and impairments. For example, attributing CFS to a physical cause — like a virus or a metabolic disorder — is maladaptive. In this school the cognitive therapists believe that abnormal emotions and physiology are perpetuated by such “catastrophic interpretations” that lead to excessive emotion and beliefs that somatic symptoms are beyond the control of the individual.

More recently CBT has been applied to a number of supportive interventions ranging from the British approach, to supportive counseling, education and even non-pharmacologic therapies. So CBT may have become an all-encompassing, confusing, “waste basket” term.

To bring order to the chaos Dr. Lapp organized a mini-symposium on CBT that featured speakers with diverse perspectives. Dr. Friedberg was an early pioneer for CFS who has written widely and been extremely active in regional support groups. Dr. Van Hoof provides one-on-one counseling to patients at a well known CFS clinic in Brussels. Dr. Segota, on the other hand, has provided group counseling to patients at the CFS center in Miami. Their combined talents provide a wonderful framework for providers, counselors, as well as patients.

Dr. Fred Friedberg (Stony Brook, LI, NY)

Dr. Friedberg described many PWCs as hard drivers who – because of being work-focused and overextended – have difficulty coping with an illness that lacks a diagnostic test, obvious cause, and specific treatment. His experience with CBT has been positive, but he asks the question, “Does CBT improve coping or does it actually improve the patient?” The answer is unknown, of course, but Dr. Friedberg suggests that CBT does help the patient take control back over his life and health. In a 1997 paper, he points out, Rey concluded that if a patient has little sense of control then limiting activity and stress actually increases impairment because the patient feels further constrained or victimized. If the patient is given a strong sense of control, however, limiting activity and stress leads to improvement. Lack of control may come from severe illness, lack of support, and poor coping (catastrophization, denial, pessimism or “giving up”), but achieving control for the patient is fruitful.

Friedberg encourages patients to balance activity with rest, and requires that they sustain appropriate lifestyle changes if they wish to improve.

Specific therapies include relaxation techniques, sleep hygiene, anger management, pleasant mood induction, pacing (taking rest periods), and graded activity.

Dr. ElkeVan Hoof (Free University of Brussels, Belgium)

Dr. Van Hoof feels that CBT should define the patient’s cognitions and modify them so as to reduce symptoms and improve quality of life. The Brussels model utilizes a team approach, which places a priority on medical therapy first, then behavioral therapy that may include CBT and psychiatric counseling.

Van Hoof uses a “phase approach” that places patients in one of four phase groups. Ideally patients will progress through these phases, but some will linger in one phase and some will actually retrogress at times. Van Hoof feels that the phase approach provides structure for the patient, partner, and family.

In Phase I (Crisis) the patient is usually functioning poorly, chaotic, emotional, and “out of control.” In this phase Van Hoof and her team explain the biological model of CFS and introduce therapeutic strategies. Social assistants help obtain state and financial support including disability, if needed. A social framework is established by asking a partner, friend, or family members to attend sessions also. The purpose of Phase I is to return control to the patient, as well as illness insight and information.

Phase II (Stabilization) increases the patient’s adherence to therapy, motivates the caregiver to be a coach, increases self-efficacy, addresses victimization and life events, and introduces pacing and limit setting.

Phase III (Resolution) is the time to identify perpetuating factors, challenge negative thoughts, and set realistic goals.

Finally, Phase IV (Integration) attempts to reintegrate the patient with work or school, while avoiding relapse.

Mary-Catherine Segota, PhD (Behavioral Medicine Research Center,University of Miami)

Dr. Segota introduced us to a 12 week group therapy program Stress Management and Relaxation Training, or SMART, developed at the University of Miami. Each weekly 2-hour group session consists of 90 minutes of didactic learning and cognitive restructuring and 30 minutes of relaxation and guided imagery. The benefits of group versus individual therapy include extra social support and exposure to others with similar symptoms, modeling of coping strategies, and a structure that is time efficient and cost effective. Elements of instruction include education (using the biopsychosocial model), cognitive restructuring, adaptive coping skill training, quality of life enhancement, and graded exercise. Participants also do “homework” in the form of reading and keeping a journal between sessions.

Session 1 deals entirely with stress management strategies and how to identify and change negative thought patterns. .

Sessions 2-5 teach that thoughts and emotions effect how one feels, and that the individual has control over these. For example, if you were confronted by someone your brain would automatically appraise the situation and trigger various mood (concern, fright, anger, anxiety, depression) and physical (tense, teary, aggressive) changes. At this point, however, the individual can make choices to ignore the confrontation, run away, argue, or even fight. These sessions also deal with cognitive distortions such as all-or-nothing thinking, over-generalization, magnification, and “should statements.”

Sessions 6-8 are devoted to resolving interpersonal difficulties, teaching communication, assertiveness, and listening skills, as well as conflict resolution and anger management.

Sessions 9-12 focus on helping them develop more realistic expectations for themselves, reprioritize different aspects of their lives, and increase successful experiences.

EXERCISE WORKSHOP

The workshop “Exercise in CFS/ ME and FM” highlighted three slightly different approaches to exercise, all based on the understanding that persons with CFS/ME/FM suffer exercise intolerance and post-exertional malaise unless they stay within prescribed limits. Two groups (Hunter-Hopkins Center and Workwell) suggested that “the limit” was probably ones AT or “anaerobic threshold.” The AT is that time during exertion that the heart and lungs can no longer provide adequate oxygen to muscles, and muscle metabolism changes from aerobic to anaerobic. It is well known that the AT occurs unusually early in persons with CFS/ME/FM.

Charles W. Lapp, MD (Hunter-Hopkins Center, Charlotte NC)

Dr. Lapp explained the basis for the exercise prescription by demonstrating how cardio-pulmonary exercise testing is performed and how the anaerobic threshold (or AT) is determined in the laboratory. He then described one approach used in Charlotte, low level interval activity, which presumes that flares and relapses occur if patients exert beyond the anaerobic threshold. If the AT is determined to occur at 4 ½ minutes, for example, then the patient is advised to exert no more than 4 to 4.5 minutes before stopping to take a 5 minute rest. Depending on how the patient feels, he or she may perform one repetition on a “bad day” or several on a “good day.” Walking, bicycling, and swimming are the preferred forms of exercise, but interval activity applies to all daily activities of exertion, including cleaning, vacuuming, carrying groceries, gardening, etc. Clapp and others have validated this technique in debilitated PWCs who were able to walk on a treadmill for 10 repetitions of 3 minutes each (30 minutes total exercise) without triggering a flare ( Physical Therapy, 1999 )!

Staci Stevens and Mark Snell, PhD (Workwell, Ripon CA)

Staci Stevens is the CEO of Workwell Foundation, which is dedicated to research and improving quality of life for PWCs, and she is also an exercise physiologist who has designed rehabilitation programs for PWCs for over the past 15 years. Dr. Chris Snell is also an exercise physiologist and professor in the Sports Sciences Department at the University of the Pacific. He has been involved in CFS research for the past 6 years, and has published widely on exercise, cardio-pulmonary exercise testing , and disability in CFS.

Stevens and Snell see PWCs as one of two basic types: Roller Coasters or Energy Avoiders. The Roller Coasters tend to overexert then collapse, and the goal is to slow them down to a moderate pace. The Energy Avoiders tend to shun exercise, and the goal is to find activities that they can participate in safely, without triggering a flare.

After determining the type of patient and starting a basic exercise program the Workwell group follows up with three questions: (1) Did you develop post-exertional malaise? (2) Do you recover from what I recommended? (3) What are your goals for physical activity?

The group has published widely on the use of Cardio-Pulmonary Exercise Testing for impairment (disability) testing, and confirm other studies showing that there is “oxidative impairment” in CFS/ME/FM. In other words, the AT occurs prematurely in most subjects. They made the point that when a patient exceed his AT, he or she incurs an “oxygen debt” much like incurring a monetary debt by overdrawing one’s bank account. Such an oxygen deficit leads to fatigue and other symptoms in CFS/ME/FM, and for some patients even daily activities like bathing or dressing may be limited. Stevens and Snell point out that such a debt has to be paid back by resting.

Workwell defines exercise in terms of 30 second intervals. They emphasize that the initial goal is to improve functional movement, then train the short term energy system, and then improve range of motion and functional strength. Their program starts with stretching and strengthening with no resistance; then resistance training (using very light weights or elastic bands); then interval training; then a maintenance program.

Stevens and Snell emphasized 5 core concepts for exercise in CFS:

(1) Appropriate exercise is movement from which the patient can recover,

(2) Exercise needs to be restorative (i.e., help the patient to improve),

(3) Progressed must be fitted to function (i.e., don’t trigger flares),

(4) Oxygen dept must be repaid by rest and breathing exercises, and

(5) Patients must make exercise a priority.

Janice H. Hoffman (OHSU, Portland OR)

Janice H Hoffman is a clinical exercise specialist and research team member at the Oregon Health & Science University in Portland. She has conducted several studies of exercise in persons with Fibromyalgia for the OHSU team, which includes Dr.Kim Dupree Jones, Dr. Sharon Clark, and Dr. Robert Bennett, who is highly renowned for his work in Fibromyalgia and fibropain. Hoffman has co-authored several papers with Dr. Jones, involving exercise and motivation techniques for fibromyalgia research. Janice currently heads an exercise program for the OHSU Fibromyalgia Clinic in Portland, and she described the approach that is employed in that program.

The OHSU Program follows a 4-step progression, beginning with improved body alignment, breathing, and relaxation techniques, then adding flexibility exercises, followed by strength training, and finally cardio endurance training.

Body alignment addresses abnormal pain postures, most notably the tightened chest, high shouldered, head-forward, sniffing-like posture seen in most people with FM, especially when they are tired or in flare. Subjects are also advised to avoid prolonged sitting, which exacerbates such postures and increases fibropain.

Standard deep (abdominal) breathing and progressive relaxation techniques are taught next. Hoffman points out that most people with CFS/ME/FM already have tense muscles (especially in the neck and shoulders), so relaxation techniques that require first tensing the muscles and then relaxing are avoided.

Flexibility is improved with a number of prescribed stretches. Hoffman points out that these stretches should be slow, static, and gentle (rather than rhythmic or pumping) and should last less than 10 seconds. Stretches are specifically directed at the neck and shoulder, but also aim to stretch the hip-flexors, quadriceps and hamstrings in the upper leg. Patients are taught to avoid overhead activities (tolerated very poorly) and eccentric contractions (best addressed with a therapist).

Resistance exercises are then added in order to build core strength, then all the major muscle groups. These are prescribed a maximum of twice weekly, and sides are alternated during repetitions in order to rest one side while the other is being exerted.

Unlike the previous two groups, the OHSU Group uses heart rate rather than anaerobic threshold (AT) to prescribe endurance exercises. They limit exercise duration to 20-25 minutes, discourage highly repetitive movements, and encourage the patient to maintain the heart rate between 40-70% of the calculated maximum heart rate ( = 230 – age in years). Hoffman says a good benchmark for staying in a low-to-moderate aerobic zone is to tell participants they should be able to talk, but not sing.

Hoffman encourages all patients to take a warm bath after therapy, although some of her participants say they like to apply cool compresses instead; she stresses the importance of staying hydrated during and after exercise by drinking lots of fluid; and lastly, Janice encourages patients to not stop daily exercises unless absolutely necessary. She will ask her clients to move back one step in the program rather than stop altogether. “If you have to stop”, she advises, “start up the program again as soon as possible.”

Janice Hoffman also deals with Roller Coaster patients who have a tendency to push too hard then crash. She has a mantra plainly posted in her gym that she asks her participants to remember at all times:

“I could have done more today but I held back just a little, and that’s okay, because I’m in this for the long run!”

Staci Stevens can be contacted at the Workwell Foundation, Ripon, California, (Telephone 209-599-7194). Janice Hoffman’s program has several instructive video tapes, available from the Oregon FM Association at https://www.myalgia.com/

DYSAUTONOMIA AND ORTHOSTATIC INTOLERANCE IN CFS / ME / FM

Prior to 1995, autonomic and orthostatic symptoms were considered just annoyances for persons with CFS/ME/FM. In September 1995 Drs. Bou-Houlaigah, Rowe, and Calkins published a JAMA article entitled “The Relationship Between Neurally Mediated Hypotension and the Chronic Fatigue Syndrome” that demonstrated NMH occurs in up to 96% of PWCs, and 9/22 subjects (41%) improved with simple therapy.

Dr. Lapp moderated a mini-seminar on dysautonomia and orthostatic intolerance (OI), including two papers on recent investigational therapies.

Julian Stewart , MD (NY Medical College, Valhalla NY)

Stewart is professor of pediatrics and physiology at NY Medical College and has established a Center for Hypotension-Related Disease aimed at young people from childhood through young adult with neurally mediated syncope, chronic orthostatic intolerance, chronic fatigue syndrome, and orthostatic intolerance of other etiologies.

Stewart defines orthostatic intolerance (OI) as the inability to tolerate the upright position. OI may be associated with a number of symptoms including fatigue, nausea, headache, lightheadedness, abdominal pain, sweating, tremor, weakness, anxiety, and depressed feelings. He described how tilt table testing is used to distinguish the various forms of OI, namely orthostatic hypotension, postural orthostatic tachycardia syndrome (POTS), and neurally mediated hypotension (NMH).

When a person stands, gravity pulls a pint or so of blood into the lower extremities, reducing blood pressure in the upper body and brain. The heart and brain blood flow are initially not affected and blood pressure is typically maintained for at least the short term. This normally produces an increase in the heart rate of 10-15 beats per minute. In orthostatic hypotension the heart rate usually increases slightly, but the blood pressure falls by at least 20 mmHg systolic or 10 mmHg diastolic within 3 minutes of upright posture (American Autonomic Society).

POTS is defined as an increase in the heart of 30 or more beats per minute within 5 minutes of upright tilting. Stewart presented an earlier paper espousing that POTS may not be an autonomic disorder but due to decreased blood volume in the upper body or thorax.

NMH (also known as simple faint, vasovagal faint, neurocardiogenic syncope, etc.) is characterized by an initial increase in heart rate and blood pressure, followed by a rapid decline in both associated with disorientation, diaphoresis (sweating), and eventual syncope (fainting). Fainting can trigger a prolonged flare of CFS or FM.

Dr. Lapp emphasized a number of points about tilt table testing in CFS/ME/FM:

(1) Tilt table testing must be performed properly: after a prolonged supine period, in a dark quiet room, in the absence of medications and other causes for orthostatic intolerance (DM, anemia, dehydration, etc.).

(2) Passive studies (using no stimulant medications) are preferred by most.

(3) Terminating the tilt table study before frank syncope can prevent prolonged flares.

(4) Orthostatic hypotension, when present, occurs within seconds to minutes of standing upright and may occur in anyone. It is not typical of CFS/ME or FM.

(5) Normal persons do not have symptoms on standing, but the symptoms of CFS/ME and FM are promptly worsened by upright posture.

(6) Orthostatic intolerance is delayed by many minutes in PWCs, whereas it occurs promptly in other disorders (such as Addison’s disease, diabetic neuropathy, Shy-Drager Syndrome, etc.)Also, at the Hunter-Hopkins Center many persons with CFS/ME/FM have an intermediate form of orthostatic intolerance that Lapp has termed “Symptomatic Orthostatic Tachycardia Syndrome” or SOTS. This is characterized by an exacerbation of symptoms on upright tilt, an increase of >30 bpm in the heart rate, and a slowly rising diastolic blood pressure but no frank syncope.

David Bell (Lyndonville NY)

Dr. Bell is a true pioneer in the field of Chronic Fatigue Syndrome, and the pre-eminent expert on pediatric Chronic Fatigue Syndrome. He described an outbreak of about 200 cases of CFS – mostly in children – that occurred in the Rochester, NY area, starting in 1983. His work has produced at least 3 books and numerous articles on CFS. In the past few years Dr. Bell worked with the late Dr. David Streeten to study orthostatic intolerance and blood volume in PWCs. For this conference, Bell described his experience with RBC mass and ADH in PWCs.

Bell randomly measured the red blood cell mass (RBCV) and plasma volume (PV) using the Cr⁵¹ technique in 19 PWCs. Sixteen of these had significantly reduced RBC mass compared to predicted control values. Ten had reduced plasma volume, but this was not statistically significant from normal and tended to vary based on thelevel of the patient’s hydration at test time. In another study of 72 PWCs, 73% had a RBCV less than 23 ml/kg (low) while 44% had a RBCV less than 20 ml/kg (very low).

Dr. Bell then recalled a paper by Bakheit (1993) that described low antidiuretic hormone levels in nine persons with CFS. Bakheit had suggested that low ADH would lead to functional dehydration, and that volume expansion might help such patients. Bell then initiated a pilot study of 17 PWCs who were given intravenous fluids (normal saline) daily for at least 3 months. The outcome of this experiment was that 5 patients (30%) had a slight response, 10 had a good response (60%), and 2 quit the study early. While IV fluids may help, it is neither practical nor safe to use this therapy widely. Six patients developed infections from placement of the IV PICC lines.

Barry Hurwitz, PhD (University of Miami / VA Medical Center)

Dr. Hurwitz is professor of psychology at the University of Miami and a professor at the Behavioral Medicine Research Center, VA Medical Center in Miami. He has interests in CFS, AIDS, behavioral medicine, and cardiovascular risks. Hurwitz is the Principal Investigator, with Nancy Klimas, on an NIH-sponsored five year study of red blood cell mass and the autonomic nervous system in CFS. 94 subjects have been enrolled to date (42 + 8 years old, BMI 25.6 + 5, 80 % F, mostly Caucasian). One year is left in the study.

The “ProCrit Study” is a prospective, double-blinded, controlled, crossover study. PWCs with documented low RBC volume are treated with either epoetin (ProCrit™) or placebo, while PWCs with normal RBC volume are treated with placebo only. The dose of epoetin is 50 units/kg given subcutaneously three times weekly. Subjects also supplement with salt (to increase the volume of fluid in the body) and iron (needed to make new red blood cells).

Subjects undergo a number of other studies including tilt table testing, isoproterenol and phenylephrine challenges (to check beta and alpha adrenergic receptor sensitivity), an echocardiogram, an electrocardiogram, routine laboratory studies and psychological evaluation. This information helps to subtype patients, but also provides more information about persons with CFS.

Data collected so far shows that 60% of females and 15% of males have a substantial reduction in their red blood cell volumes. When compared to normal subjects, those with a low RBCV demonstrate a mild normochromic normocytic anemia and a slightly elevated erythrocyte sedimentation rate, although the differences are so small that this cannot be discriminated on a routine CBC.

The “ProCrit Study” is not completed so the double blind has not been broken and Dr. Hurwitz has no basis for predicting whether epoetin will actually help PWCs. He and Dr. Klimas report that some subjects have shown an increase in red blood cells (i.e., probably on therapy) and have required special management to maintain the hematocrit in a safe range. There is a sense that treatment has improved symptomatology in some patients, but only time will tell.

SUMMARY

Overall the conference was a great success. Over 170 abstracts were submitted for consideration by researchers all over the world. Forty-eight papers were presented at the conference, and over 75 posters were available for review between sessions.

The Research Session was superb, providing new material and approaches for the understanding and diagnosis of CFS and FM. I am confident that many researchers and clinicians left the meeting with new and exciting ideas following this session. I was particularly impressed by Dr. Komaroff’s overview of CFS / FM achievements in the past two years, and by Dr. Bill Reeves all-encompassing epidemiology review, which summarized the CDC experience over the past few years.

As in the past, my major disappointment was the lack of new papers on treatment. Only one paper – on Ampligen – specifically dealt with treatment, although several other papers dealt with the approach to CFS or FM. Most clinicians were overwhelming pleased with the Clinical Session, which focused mostly on three specific areas in which treatment modalities exist and have been successful. These were dysautonomias and orthostatic intolerance, low level progressive exercise, and behavioral therapy. Three mini-seminars highlighted these three areas, and providers left the sessions feeling that they had fresh enthusiasm and new approaches to share with their patients.

It is my hope that the next conference will emphasize therapy by highlighting specific treatment areas such as sleep, pain, and hormonal therapies; and include a lengthy open forum for clinicians to exchange ideas.

Charles W. Lapp, MD

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Charlotte, North Carolina 28210
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