AACFS 2004 Meeting Summary by Charles W. Lapp, M.D
The 7th
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.
|
Serotonin-enhancing |
Mixed |
Noradrenalin-enhancing |
|
citalopram |
amitriptyline |
duloxetine |
|
fluvoxamine |
imipramine |
venlafaxine |
|
sertraline |
milnacipran |
|
|
paroxetine |
|
|
|
fluoxetine |
|
|
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
|
Definition |
Substance |
Comments
|
|
Ramsey Definition
(1981) |
Fatigue occurs after minimal exertion and there
may be a delay.
Symptoms of circulatory impairment.
Symptoms of CNS impairment.
At least 6 months duration. |
The first true case definition. |
|
London Criteria
(Goudsmit, 1992)
|
Exercise induced fatigue.
Neurological disturbance.
Fluctuation of symptoms.
Ongoing symptoms for > 6 months. |
Selects more symptomatic patients than 1994
Fukuda criteria (below). |
|
Australian Case
Definition |
Exercise induced fatigue, disrupting daily
activities, of > 6 months duration.
Neuropsychatric dysfunction and new short term
memory loss.
No alternative diagnoses. |
Post-exertional malaise and neurocognitive
problems are the major symptoms, not fatigue. |
|
1988 US Criteria
(Holmes, et alia)
|
Chronic unexplained fatigue.
No other plausible explanation.
At least 8 symptoms or 2 physical findings and
4 symptoms. |
Physical findings were difficult to document,
and symptoms were ill-defined. |
|
1994 US Criteria
(Fukuda, et
alia.) |
Chronic unexplained fatigue that is not
lifelong but at least 6 months duration.
No other plausible explanation.
At least 4 of 8 symptoms (myalgias, arthralgias,
new headache, non-exudative pharyngitis, lymphadenopathy, cognitive
dysfunction, post-exertional malaise, sleep disorder) |
Internationally accepted and used. Selects
fewer symptoms than 1988 Criteria, but more impaired subjects (based
on MOS SF-36).
Exclusions are specified.
Requires a psychiatric interview and
standardized instruments to define symptoms.
. |
|
Canadian
Consensus Definition (2004) |
Marked fatigue that reduces activity
(required).
Post-exertional malaise (required).
Non-restorative sleep or disturbance (or acute
onset required if not present).
At least 2 neurocognitive symptoms.
At least 2 symptoms from autonomic,
neuroendocrine, or immune categories..
|
Selects reduced psychiatric morbidity compared
to 1994 Fukuda criteria, but more severe physical impairment,
fatigue or weakness, and neurocognitive symptoms.
|
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
http://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
0344 Park Road, Suite 300
Charlotte, North Carolina 28210
Tel. (704) 543 9692
·
Fax. (704) 543 8547