by Dr. Charles W. Lapp

[Moderator's Note: This report on the 8th International IACFS
Conference on CFS, FM, and Related Illnesses was written by
Charles W. Lapp, M.D., and is distributed here with his
permission.]

8th International IACFS Conference on CFS, FM, and Related
Illnesses Fort Lauderdale, Florida January 12-14, 2007

The 2007 meeting of the IACFS (formerly AACFS) has set new
records for attendance, including more than 250 professionals
and over 300 patients.  An effort has been made to expand
internationally, and over 21 countries were represented at this
meeting!

Even before the meeting began, big changes were occurring.
The IACFS Board voted to change the name of the organization
to the International Association of CFS and ME  in recognition of
the term  ME  used by many other English-speaking nations, and
thereby tendering an alternate name for this illness.  Later in the
week, an ad hoc Name Change Committee, put together by
ProHealth CEO Rich Carson, also recommended using the term
ME (or Mylagic Encephalopathy) in lieu of CFS.  CFS will
probably remain the scientific term for the illness, but it is hoped
that ME will become the common designation.

Another key event at this meeting was the introduction of the new
Pediatric Case Definition.  A working committee of the IACFS
has hammered out a proposed manner of diagnosing children
and adolescents with this disorder.  Research has been
hampered in the past by the absence of unifying diagnostic
criteria. The committee has provided a summary paper, a
questionnaire for clinical use, and a summary "scoring sheet,"
which should help both clinicians and researchers to understand
pediatric CFS/ME better.

In reviewing the papers submitted for presentation, it soon
became clear that the amount and quality of research in
CFS/ME has increased significantly over the past two years,
and that many researchers are looking into specific aspects of
the illness (such as fatigue, or pain, or sleep disruption) rather
than attempting to study the syndrome as a whole.

It seems that each year a new aspect of research is introduced,
and this year that aspect is "genomics and proteomics."
Genomics is defined as the study of function and interactions of
genetic material in the genome, while proteomics is the study of
proteins made in the cell. Both of these fields are contributing
substantially to our understanding of CFS/ME and FM. As Dr.
Suzanne Vernon of the CDC pointed out, it is hopeful that these
studies will lead to a better understanding of the illness, perhaps
a specific marker, and possibly even therapy.

Unlike previous conferences, clinical and research papers were
inter-mingled this year but organized by general topic such as
fatigue, sleep disorders, clinical trials, pain, epidemiology, brain
function, behavioral health, pediatrics, gender aspects, and
genetics/proteomics.

Fatigue Session

Seiki Tajima of Osaka, Japan, launched the meeting with a
study of activity monitoring and autonomic responses in sleep.
Patients wore an activity monitor (similar to a pedometer, but
worn on the wrist), which was able to discriminate periods of
activity, rest, and sleep during a 24 hour period.  Tajima was
able to identify at least 5 types of abnormal sleep patterns in
PWCs, including a long sleeping type, severe insomnia,
hypersomnia, and sleep phase shifting.   Autonomic (that is, R-R
spectrum) analysis revealed that poor sleep may be due to a
lack of parasympathetic activity during attempted sleep periods.
Nicole Porter (DePaul University, Chicago) queried PWCs and
healthy individuals about their experience of fatigue. She was
then able to define at least 5 different fatigue states:

Wired fatigue  feels over-stimulated but low energy

Brain fog fatigue  mental or cognitive impairment is associated
with fatigue

Molasses fatigue  heaviness and immobilization, unable to
prolong activity

Flu-like fatigue  weakness with flu-like symptoms

Post-exertional fatigue  a lack of energy following minor activity

Healthy individuals experienced only one type of fatigue (typically
flu-like), while PWCs experienced fatigue in diverse ways.


Elizabeth Mahoney described a CDC-sponsored study of the
effect of allostatic load.  One's "allostatic load" is essentially your
accumulated stressors.  However, the CDC used objective
measures (such as heart rate, blood pressure, c-reactive protein
levels, waist-to-hip ratio, lipid levels, blood sugar, insulin levels,
etc.) as a measure of "load."  Based on this premise, women
with a high allostatic load were 5 times more likely to develop
CFS/ME compared to those with low allostatic loads. This did
not hold true for men, however.  Mahoney also pointed out that
this study demonstrated a high prevalence of metabolic
syndrome in PWCs.  [Metabolic syndrome is characterized by
central obesity, elevated cholesterol and triglycerides, elevated
blood sugar; and the presence of metabolic syndrome frequently
predicts later diabetes and cardiovascular disorders such as
heart attack and stroke.]

Margaret Chicorella, both an exercise physiologist and an
attorney from University of the Pacific,  Stockton, CA,
demonstrated how disability could be better defined using a
two-part exercise test.  When cardio-pulmonary exercise testing
is repeated 24+ hours after the first test, oxygen consumption
and the maximum achievable heart rate both decrease
substantially. This is objective evidence of post-exertional
malaise --  a sine qua non of CFS/ME/FM  and could be very
useful in disability determinations.

Paul Nestadt (Mt.Sinai School of Medicine, NYC) used Magnetic
Resonance Spectroscopy (1H-MRS) to show that lactate is
increased and N-acetyl-aspartate (NAA) is reduced in the brains
of PWCs (Persons with CFS/ME).  Lactate levels correlated with
the level of fatigue, and were not abnormal in persons with
depression or anxiety.  These findings are further evidence that
CFS/ME is not psychiatric in origin, and that mitochondrial
function and neuronal density (or metabolism) are reduced in
PWCs.

Dubbo is small city in the northwest corner of New South Wales,
Australia, and has been the site of several epidemiological
studies concerning the clinical course of EBV mononucleosis  (a
DNA virus) and Q-fever (a rickettsial infection). Toni Whistler of
the CDC described genetic findings in persons who developed
PIFS, or Post-Infectious Fatigue Syndrome, which is very similar
to CFS/ME.   30,000 genes were studied, and more than 40% of
the pathways were found related to regulatory and metabolic
pathways.  Cell cycle regulation, gene regulation, and signaling
were most commonly involved; and apoptotic, metabolic, and
inflammatory (IL 10) pathways were prominent in the sickest
patients.  Whistler concluded that there is a subset of PIFS in
which immune abnormalities play a significant role.


Clinical Trials

Barry Hurwitz, a colleague of Dr. Nancy Klimas at the University
of Miami, presented the findings of their famous "ProCrit
Study."   57 PWCs were studied for anemia and low red blood
cell volume (RBCV). About 70% of the cohort actually had a low
RBC volume.  These were given either ProCrit (n=30) or
placebo (n=10), while those with normal RBC volume were given
placebo injections for 4 months. All were administered iron and
dietary salt supplements also.  80% of treated subjects
responded to 10,000 units per week of ProCrit, and their RBC
volume increased about 26% on average. Orthostatic
intolerance (by tilt table testing) improved in treated subjects, but
exercise tolerance, fatigue, and other measures did not change.
Thus, ProCrit therapy might be modestly helpful for patients with
orthostatic intolerance and low RBCV, but not for the general
symptoms of CFS/ME.

José Montoya (Stanford University School of Medicine)
described his recent valgancyclovir (Valcyte™) studies in 12
persons with virally induced fatigue and cognitive dysfunction.
Subjects were treated with valgancyclovir for 6 months (one for 3
months only), and 9 had significant improvement in fatigue and
cognition.  Five of these had elevated EBV titers (VCA-IgG,
EBNA, or EBV-EA), 3 had both elevated EBV and HHV6
serologies, one had neither. None had HHV6 elevations alone.
Comment:   It is not at all clear if any of these patients had
CFS/ME.  We can only say that a subset of persons with
Post-Infectious Viral Syndrome may respond to prolonged
therapy with valgancyclovir. Dr. Montoya warned that
valgancyclovir is a dangerous drug and must be used with great
caution.  A study of valgancyclovir specifically in persons with
CFS/ME is slated to start this month, and we all anxiously await
the outcome!

Martin Lerner (Wayne State University, Detroit) described a
subset of patients with persistent EBV and/or cytomegalovirus
(CMV), electrocardiographic changes, and symptoms of
CFS/ME.  In addition to having elevated IgM (or EBV-EA) titers,
all 37 patients had an elevated heart rate at rest, recurrent
T-wave inversions on Holter monitoring, cardiac abnormalities
and/or biopsy proven cardiomyopathy.  Subjects with EBV
positivity were treated with high dose valcyclovir (VCV or
Valtrex™) 14mg/kg daily, and subjects with CMV positivity were
treated with valgancyclovir (VGCV or Valcyte™) for 3 to 3.5
years with improvement in fatigue, tachycardia, chest pain,
syncope, flu-like symptoms, EBV titers, and cardiac wall motion.
No serious adverse effects were seen.


Pain

Dan Clauw (University of Michigan, Ann Arbor) provided his
usual elegant and fascinating presentation, this time on "Pain
Processing and Therapy in Fibromyalgia."   Clauw explained
that each of us has a "volume control" for controlling the severity
of pain, and that this controller is affected by both genetics and
environment (or experience).  Studies have shown that persons
with FM (PWFs) have a normal "detection threshold" for pain,
but a decreased "noxious threshold" to a variety of stimuli,
including pressure, heat, noise, and electrical stimulation. Thus,
PWFs sense the onset of pain the same as other individuals, but
are much more sensitive to pain. This is independent of
expectancy or hypervigilance.

Such findings can be demonstrated by a functional MRI scan (
fMRI), which senses deoxygenated blood and thereby detects
parts of the brain that are activated. Using this technique,
Clauw's group has demonstrated that healthy individuals have a
minimal response to a modest pain stimulus, while PWFs have
a very strong response to the same modest stimulus.   This
proves, Clauw explains, that "when FM patients say they hurt,
they really do hurt!"

Studies have also shown that pain is unrelated to co-morbid
depression, but persons who catastrophize (negative thoughts,
magnification of symptoms, "glass-half-empty") tend to
experience more pain.

Clauw's management of pain parallels The Stepwise Approach
espoused at the Hunter-Hopkins Center:  education,
pharmacologic therapy, aerobic exercise, alternative therapies
(such as hypnotherapy, biofeedback, acupuncture, chiropracty,
electrostimulation) and Cognitive Behavioral Therapy (or
coaching).  He reports good evidence that the following are
helpful: Tricyclic antidepressants (amitriptyline, cyclobenzaprine)
SNRIs (venlafaxine, duloxetine) and possibly SSRIs Tramadol

There is weak evidence for using growth hormone,
5-hydroxy-tryptane, tropisetron, and SAMe; and NO evidence
supports the use of NSAIDs (ibuprofen, naproxen, etc.),
corticosteroids, or guiafenesin. Clauw is not a fan of opioids,
narcotics, or sleep medications in the treatment of FM.   Newer
possible therapies for fibropain include GHB (Xyrem™),
dopamine agonists (roprinolole, pramipexole), and
neuromodulators.

Lastly, Clauw pointed out that there is a strong familial
predisposition to fibromyalgia, with first degree relatives having
8 times the risk of developing FM.  Also, Diatchenko has linked
abnormalities in the COMT haplotype (which controls serotonin
in the body and brain) to TMJ. This means that at least one gene
codes for pain, and possibly the tendency to develop FM.


Epidemiology

Rosemary Underhill of the New Jersey CFS Association studied
the prevalence of chronic fatigue and CFS in the offspring of
mothers with CFS/ME.   A questionnaire to members of the
NJCFSA identified 108 mothers with physician-documented
CFS/ME.   These woman were contacted for details. There were
220 offspring.  24% of mothers had an offspring with
documented CFS/ME or chronic fatigue (CF). CFS/ME
occurred in 5.5%, and 11.4% had chronic fatigue. Both sons and
daughters were affected about equally, and half developed
illness after age 18.   42% of the offspring with CFS/ME had
already recovered, as had one-third of those with CF.

Leonard Jason (DePaul University, Chicago) calculated the
economic impact of  CFS/ME using both community-based and
tertiary sample pools.   Indirect costs (that is, loss of production)
were estimated to occur in 27%, or an annual loss of $20,000
per person with CFS/ME.  Direct costs (drugs, medical tests,
office visits, etc.) were ascertained to be $8764 per person in
the tertiary sample and $2341 in the community sample.
(Patients identified from tertiary care tend to be more ill than
those in the community.)

Thus, the combined direct and indirect costs were $22,341 per
person in the community sample and $28,674 in the tertiary
sample, for an annual cost to the US economy of 19.6 to
25.2-billion dollars.


Ampligen

Dr. William Carter, CEO of Hemispherx Biopharma, reported
the Ampligen experience to a crowd of interested providers
before sessions began on Saturday, January 13.  He stated that
since the 1980's about 1000 individuals have been treated with
Ampligen, using about 80,000 doses of this experimental drug.
Phase III studies have been positive -- showing a 16% increase
in exercise ability in treated subjects  and preliminary data has
been submitted to the FDA toward the New Drug Application for
Ampligen.  There was no speculation when this process will be
complete or when Ampligen might be available to patients.


Brain Function

The current status of researching brain function in CFS/ME was
reviewed by Gudrun Lange (University of Medicine and Dentistry
of New Jersey  UMDNJ).  She described some of the
neurocognitive tests used to demonstrate cognitive dysfunction
in CFS/ME, and pointed out that testing is much more positive in
bedridden subjects (presumably sicker) and after maximal
exertion (say on a bicycle or treadmill).

Radiological tools that demonstrate positive findings are MRI,
CT scanning, SPECT and PET scanning (which measure
cerebral blood flow), Proton Magnetic SPECT or Magnetic
Resonance Spectroscopy (they measure brain metabolites such
as glucose), and blood oxygen level dependent Functional MRI
(or fMRI, which measures activation in areas of the brain, say to
pain).

Studies so far have demonstrated that:

PWCs perform as accurately as healthy controls, but require
more regions of the brain (that is, PWCs have to work harder to
get the same results);

The key cognitive deficit in PWC's is their speed of information
processing; and,

Metabolic findings have been variable, depending on the
metabolite and the group studying it.

Doctors from Barcelona, Spain, and Santiago, Chile, presented
their results of SPECT scanning in PWCs compared to patients
with depression.  Dr. Garcia-Quintana showed that cerebral
blood flow is decreased in the frontal lobes (only) of depressed
patients, but reduced in frontal lobes and brainstem in PWCs.
PWCs also have an increase of blood flow in the thalamus (a
pain control center).   Following exercise (or mental strain such
as puzzles, short stories, or cubing numbers) the cerebral blood
flow was markedly decreased in frontal, pre-frontal, anterior
temporal, and cingulated regions in more than 87% of subjects
studied.  Increased blood levels of the enzymes elastace and
RNaseL correlated with more severe loss of cerebral blood
flow.  Comment:  This is old news, but confirms previous studies
in the US.  We have known for over a decade that frontal,
temporal lobe, and brainstem blood flow is reduced in PWCs,
which is thought to cause problems with
creativity/motivation/memory (frontal lobes), mood and memory
(temporal lobes), and the sleep/fatigue/autonomic centers of the
brainstem. We also knew that both exercise and mental exertion
exacerbate this reduced blood flow for up to 72 hours!  The new
twist is that elevated elastase and RNaseL levels correlate with
reduced blood flow.

Fumihara Togo (UMDNJ) presented a short but elegant paper
that studied motor tasks and performance time in PWCs.
Subjects would focus on a target  in this case an arrow pointing
left or right  and touch one key for left, another for right. Togo
demonstrated that motor performance was normal in CFS/ME,
but that PWCs were slower to perform.  In contrast, depressed
patients had difficulty with both motor skills and speed.

A similar kind of finger-tapping study was described by Mark
Van Ness, Christopher Snell, and Staci Stevens (University of
the Pacific). They measured simple reaction time (the response
to a simple target) and complex reaction time (response to a
target hidden within other information) at rest, and then 30
minutes and 24 hours after an exercise test.  They found that
PWCs were a bit slower to respond than matched controls even
at rest, worst 30 minutes after exercise, and still delayed 24
hours later. This held for simple or complex reaction time.

Hiro Kuratsune (Kansai University, Japan) concluded this
session with a summary of what is known about brain function in
CFS. We know: The MRI is abnormal in the majority of PWCs
due to numerous T2 weighted hyperintense spots or foci, and
evidence of demyelination PWCs with more brain abnormalities
tend to be more physically impaired The volume of gray matter is
reduced in proportion to reduced physical activity (that is, the
brain shrinks in PWCs who are inactive!) Cerebral blood flow is
diminished, especially in the cingulate area (controls attention,
autonomic nervous system), temporal lobes (control mood,
motivation), and frontal lobes (motivation, creativity, and short
term memory)

The concentration of acetyl-carnitine is reduced, particularly in
the cingulate, and supplementing acetyl-carnitine may increase
neurotransmitters such as GABA. glutamine, and aspartate
Acetyl-carnitine supplementation may also improve attention
5-HT (serotonin) transporter binding was reduced in the rostral
cingulate area in PWCs, which may help explain fatigue and
pain


Behavioral Health

Cognitive Behavioral Therapy (CBT) and Graded Exercise
Therapy (GET) are commonly thought to be the only effective
treatments for CFS/ME, mostly due to the influence of two
meta-analyses of the treatment literature.  (In actuality, these
were the only two effective modalities that had been studied
extensively, but other treatments may be helpful). Unfortunately,
many practitioners concluded erroneously that psychiatric care
and vigorous exercise were "the cure" for CFS/ME.  Dr. Ellie
Stein, a psychiatrist from Calgary, Canada, eloquently
addressed this in her introductory remarks.

Stein pointed out that CFS/ME and FM are chronic,
heterogeneous conditions that are unlikely to respond to any
single approach. It is understandable that both have high rates of
psychiatric co-morbidity (such as depressed mood and anxiety),
yet neither is considered a psychiatric disorder. Since no
medication is known to cure CFS/ME or FM, behavioral
interventions are a reasonable consideration.

The earliest CBT/GET programs were based on the false
assumptions that avoidance of activity, illness severity,
increased attention to symptoms, and autonomic arousal
("hyper," or hyper-excitable behavior) were causing or
perpetuating symptoms, when in actuality they were the result of
the illness.  Of seven controlled studies using early CBT
techniques,  only 4 were positive and most were inconclusive or
poorly done.

Five studies of graded exercise in CFS/ME showed a modest
decrease in fatigue, but improvement in pain, sleep, autonomic,
immune, and cognitive symptoms have not been shown.

It has long been suspected that persons with "pure FM" (i.e.,
less fatigue and cognitive dysfunction) can exert more easily,
and several studies have shown temporary improvement in pain
and quality of life, but many effects have worn off within a year.
CBT has not been proven helpful in "pure FM."

No study has measured the effect of CBT or exercise in the
severely ill.

Stein points out that CBT and GET don't work well because
many patients do not have dysfunctional illness beliefs, many are
already functioning at maximum activity levels, and the exercise
makes some people worse!    She recommends "The Stanford
Model," a program for persons with chronic illness that is based
on education, encouragement, and shared responsibility
between patient and professional.  The Stanford Model
addresses low level exercise, cognitive symptom management,
nutrition, energy and sleep management, the use of medication
and community resources, managing emotions, and dealing with
health care professionals.  This program has proven success in
MS, rheumatoid arthritis, and other chronic illnesses.   Dr. Pat
Fennell has also developed a proprietary chronic illness
approach, based on her proposed Four Phases of Coping in
CFS/ME. This model encourages patients to collect data, take
control of symptoms, grieve losses, and search for a new
identity.  Comment:  Dr. Bruce Campbell's CFIDS and FM Self
Help Book and his online CFIDS and FM Self Help Course (both
available at www.cfidsselfhelp.org) are based on the Stanford
Model, and highly recommended!  Patricia Fennell's books are
available from Barnes & Noble and other booksellers.

Stein went on to point out that self-efficacy (that is, the perceived
ability to control illness) and acceptance of illness are both
associated with positive physical and psychological outcomes.
Therefore, CBT and GET are the most studied behavioral
interventions, but results are short lived and many do not benefit.
Stein urges alternative approaches such as the Stanford Model
that are more patient friendly and have a good record of
success.

Professor Fred Friedberg (Stony Brook University) presented a
short course on CFS/ME and FM to his students, and found that
even a brief exposure to factual information about these
illnesses led to more favorable attitudes by fourth year medical
students. Two points that students endorsed strongly were, "It is
important for physicians to understand CFS," and "Patients are
[NOT] to blame for their illness."


Pediatric Session

Although CFS/ME is known to occur in children and
adolescents, pediatricians have been hampered by the absence
of a case definition for children.  The adult research definition
(Fukuda, et al. Annals of IM, 1994)  traditionally has been used,
but children have age-specific issues and generally report
different symptoms than adults. With this problem in mind, the
IACFS developed the Pediatric Case Definition Working Group
(Drs. Jason, Bell, DeMeirleir, Gurwitt, Jordan, Lapp, Miike,
Torres-Harding and Van Hoof) to study the problem.  For more
than a year the committee studied various approaches to
diagnosis, and developed a new definition, questionnaires, and
a scoring sheet for pediatricians. This new definition combines
the best aspects of the Fukuda definition with the best aspects
of the Canadian Clinical Definition of ME/CFS  (Carruthers, et
al, JCFS 11(1):7-115, 2003), and has produced two
questionnaires with queries that are age-appropriate (for under
11 years old, and 11-18 years old).

To establish a diagnosis of pediatric CFS/ME the following five
symptom categories must be satisfied:

Post-exertional malaise

Unrefreshing sleep, or a disturbance of sleep quantity or rhythm

Myofascial, joint, abdominal, or headache pain

Two or more neurocognitive manifestations; and

At least one symptom from two of the following three categories:
(1) autonomic manifestations, (

2) neuroendocrine manifestations, or

(3) immune manifestations.


It is hoped that this pediatric case definition will lead to more
appropriate identification of children and adolescents with
CFS/ME.  An article on the development and use of the
definition will appear in the Journal of Chronic Fatigue
Syndrome shortly.  The article, questionnaires, and scoring
sheet are available online at www.cfstreatment.info , and will
soon be available on www.aacfs.org  and www.drlapp.net.

Elke Van Hoof (Vrije Universiteit Brussel, Belgium)  reported on
how adolescents with CFS/ME perceive their social
environment. She studied 27 Belgian adolescents (mean age 16
+ 3 years), three-quarters of whom were female. Onset of illness
was sudden in 48% of cases, and it took about 1 years to
receive a diagnosis.  Only 22% were able to attend school full
time, and more than half (52%) reported conflicts in school. One
third (33%) got help from a teacher or classmate in order to
keep up, 82% had to skip classes frequently, and 70% got
failing grades. Forty percent were involved in extracurricular
activities once in a while, but 48% experienced no activities
outside of school.   Van Hoof concluded that CFS/ME in
adolescence can lead to social isolation, grades that fall below
true capability, and poor attendance at school.  Thus the
adolescent with CFS/ME is vulnerable to a poor self image and
low self efficacy.


Poster Presentations

Each year dozens of prospective papers are submitted to the
scientific review committee for consideration. Typically the best
papers are presented to the entire assembly, and less solid
studies are relegated to "posters" in a side room or along the
walls of the auditorium.  This year the quality of papers was so
good that several poster authors were asked to give a brief
summary of their findings to the assembly.

C. Lennartsson of the Karolinska Institute (Sweden) confirmed
previous reports that low level interval training is well tolerated in
CFS/ME.   She was followed by Mark Van Ness (University of
the Pacific) whose exercise physiology group measured
metabolic and immune responses to exercise.  They confirmed
that maximum aerobic capacity (VO2  peak) was reduced in
PWCs compared to sedentary controls (24.3 ml/min/kg
compared to 31.4), and the oxygen capacity at the Anaerobic
Threshold was also reduced. They introduced a new measure,
DVO2 / D workload that is also much lower in PWCs than
controls (7.7 in CFS/ME compared to 8.9 in controls, where <8
is clearly abnormal). Serum lactate was elevated in PWCs,
suggesting an abnormally early shift to anaerobic metabolism.

Pat Fennell (CEO of Albany Health Management) described a
paradigm shift that she is seeing in the patient population,
namely a shift from acute care to chronic care needs. She briefly
discussed her Four Phase Model and the Wagner model of
chronic illness management. She urged providers to focus on
whether the patient is responding to therapy; whether
psychological support is needed; whether disability was
inevitable; and whether interventions were appropriately
matched to the phase of illness.

Garth Nicholson hypothesized that mitochondrial function is
reduced in CFS/ME, and that replacement of essential
mitochondrial lipids could improve mitochondrial function and
reduce reactive oxygen species in the patient. In two studies,
patients treated with glycophospholipids and "good" bacteria
(NTFactor ™) reportedly achieved up to a 43% reduction in
fatigue.

Daniel Blockmans (Leuven, Belgium) reported a randomized
placebo controlled crossover study of methylphenidate
(Ritalin™), 20mg daily, in 60 PWCs. Subjects received either
stimulant or placebo for 4 weeks, then treatment was crossed for
another 4 weeks. Using the SF-36, the Hospital Depression and
Anxiety Scale, and visual analog scales for pain, cognition,
fatigue and other symptoms, Blockmans showed that stimulant
medication improved fatigue and concentration significantly in
17% of cases.  F. Garcia-Fructosa (Clínica CIMA, Barcelona)
also provided a poster on the effect of modafanil (Provigil™,
another type of stimulant) in PWCs.  Modafanil was able to
reduce daytime sleepiness by an average of 25% in 31 PWCs.
However, 65% of patients reported some adverse effects
(mostly anxiety, panic, irritability or palpitations), and 5 had to
withdraw from the study. The drug did not interfere with sleep,
however.  Comment:  We have also noted that PWCs with
hypersomnolence and/or excessive daytime sleepiness respond
very well to stimulant medications.  Some report improvement in
concentration and focus as well.  In our experience adverse
effects are usually mild if patients start with a low dose and build
up slowly.

Staci Stevens (Workwell, University of the Pacific) used the
SF-36 survey to monitor post-exertional malaise after 10
minutes of exercise on a bicycle ergometer. Although patients
and controls had similar results before exercise and 7 days
afterward, it took controls only 1 day to recover, while no PWCs
had recovered in 2 days and 50% required 5-6 days to recover.

Kenny DeMeirleir (Vrije Universeteit Brussels, Belgium)
reported that 20-25% of Belgians typically suffer with lactose
and fructose intolerance, respectively, whereas 71% of PWCs
have intolerance to fructose (fruit sugars, beans, cauliflower,
cabbage, and yes, brussel sprouts). Lactose intolerance was
similar (20%) in PWCs and the general population.

Jonathan Kerr (St. George's University, London) has done
extensive genomic and proteomic studies in PWCs. This time
he reports on miRNA  short non-coding RNA sequences that are
produced in the nucleus, migrate to the cytoplasm, and regulate
translation (cellular protein production).  Studying 15 PWCs and
30 controls, Kerr found 4 unique miRNAs in PWCs.

Paul Cheney reported that PWCs demonstrate evidence of
diastolic dysfunction by tilt-echocardiography. This seems to
confirm his previous finding of diastolic dysfunction on
impedence cardiography, and is consistent with known
deficiencies of mitochondrial or cellular energy in patients with
CFS/ME and FM.  Comment:   Our office has obtained
impedance cardiograms on at least 8 PWCs, and have seen
only trivial diastolic dysfunction, a condition that is reported in
even healthy individuals. Confirmatory echocardiography in
several subjects (but not tilt-echocardiography) has
demonstrated NO significant abnormalities.


Genetic / Proteomics Session

Suzanne Vernon, Human Genomics Team Leader at the CDC,
defines genomics as the study of function and interactions of
genetic material in the genome, including interactions with
environmental factors. Genetics on the other hand is the study of
a single gene.  She then described several gene profiling
techniques such as microarrays, gene chips, and RT-PCR.
Such advanced techniques are used by the CDC and other to
unravel the CFS puzzle.

One of the most helpful techniques recognizes fine variations in
the gene, known as Single Nucleotide Polymorphisms or SNPs
(pronounced "snips").  For example, a health gene sequence of
nucleotides may look like this to a geneticist:...TGCCGAT…
An abnormal gene may look like:......................TTCCGAT…

That one small change is referred to as a SNP and can be used:
(1) to understand who is predisposed to CFS/ME, (2) as a
marker for the illness, or possibly (3) as a clue to a treatment.

Certain polymorphisms are associated with specific groups. For
example, Vernon and her group have been able to identify
normal healthy patients, persons with general fatigue, and
PWCs just on the basis of specific polymorphism patterns.
PWCs have then been subclassified into several distinct,
genetically defined groups.

CFS/ME is difficult to study, however, because it does not
appear to be controlled by a single gene, and the genes change
over time (i.e. they are "epigenetic").

Proteomics is the study of intracellular proteins, particularly their
structures and functions. While the genome is a rather constant
entity, the proteome differs from cell to cell and is constantly
changing through its interactions with the genome and the
environment.


Genetic Profiles in Severe Forms of FM and CFS was
presented by Estibaliz Olano.  She and her colleagues at
Progenika Biopharma (Barcelona) hypothesized that persons
with CFS and FM could be differentiated genetically. From a
pool of 2000 subjects they assessed 186 women with FM and
217 women with CFS/ME.  These subjects were stratified by
special questionnaires into "severe" or "mild-to-moderate"
cases.   SNP profiling was able to discriminate the severe
cases from less severe cases of CFS/ME.  These SNPs were
related to 6 major genetic areas that fit the clinical understanding
of CFS/ME:

COMT, THP, DOPA, 5HT (these genes control
neurotransmitters)

POMC  (produces adrenocorticotropin, melanotropes, and
melanocyte-stimulating hormone)

Glucocorticoid and corticotrophin receptors

Interleukins (cytokine production)

NOS (nitrous oxide production)

TNF (more cytokine production)

Also 15 SNPs were identified that separated PWCs from
persons with FM with 53% sensitivity and 95% specificity.

Comment:   This work by a commercial lab in Spain is
consistent with findings from the CDC (see below) and other
genomic studies.  Such corroboration makes it more likely that
genomics can help us understand CFS/ME/FM, and perhaps will
provide a marker for these illnesses.

M.S.Rajeevan reported results from one of the CDC genomic
studies. This concluded that SNPs link CFS/ME to HPA axis
dysregulation, immune dysfunction, and high levels of allostatic
load (that is, chronic stress). 137 subjects were selected from
the CDC's Wichita Hospital Study, and these individuals were
able to be differentiated into 5 unique classes.  Five genomic
markers for glucocorticoid receptors were more common in
PWCs than in persons with chronic fatigue alone and those who
were not fatigued; there were 3 serotonin receptor markers that
were associated with CFS as opposed to chronic fatigue or
non-fatigued individuals.

James Baraniuk (Georgetown University, Washington DC)
studied the proteomics of CFS/ME. He defined a proteome as
"a set of proteins in one cell, compartment or person."  His
hypothesis was that Central Nervous System dysfunction was
common in CFS, FM, and Gulf War Syndrome, so abnormal
proteins would probably appear in cerebrospinal fluid (CSF). He
studied the CSF of 52 subjects, most of whom met international
criteria for CFS/ME.

In his first experiment, 10 proteins were identified as shared
between CFS/ME and GWS, but totally absent from healthy
individuals. The second experiment demonstrated that keratins
(which are rare) and orosomucoids were seen in PWCs, but not
in controls. Ten proteins found in the first cohort of PWCs
matched the protein abnormalities in the second cohort.
Baraniuk estimated that the chance of this occurrence was
about one in one million!

Baraniuk found proteomic evidence for:  protease-anti-protease
imbalance, structural injury, oxidant injury, vascular deregulation,
leptomeningeal activation, and structural repair.  In conclusion,
the common "CFS-related proteome" in cerebrospinal fluid
suggests shared pathophysiology in CFS, FM, and GWS. This
proteome is NOT found in healthy control samples.

Lastly, Frederick Albright (University of Utah) used geneology to
provide evidence of a heritable contribution in CFS/ME.  The
Mormon geneology database includes 2.2-million Utah Mormon
pioneers and their descendants over 10 generations, and health
records have been linked to the geneology since 1994. Thus it is
possible to follow the inheritance of CFS over at least 16 years.
Albright identified 551 descendents with CFS (65% female,
35% male).

He first hypothesized that if CFS is heritable, it should occur at
higher frequency in close relatives of CFS cases. In fact, the risk
of a first degree relative contracting CFS was 7.68X, while the
risk for a second degree relative was 2.54X. This suggests that
CFS is indeed heritable.

The second hypothesis was that if CFS is familial, CFS cases
should be more closely related than controls. Using
sophisticated analysis, he demonstrated that case-relatedness
was 4.13 units and control relatedness was 2.81, which was
statistically significant. Thus CFS/ME appears to be familial as
well as heritable.


New Methods

One of the most fascinating and practical papers was given by
Akikazu Sakudo of Osaka University, where he works with H.
Karutsune,Y. Watanabe, and others.  Sakudo described using
visible and near-infrared spectroscopy (which is typically used to
examine fruit for ripeness and quality) to discriminate PWCs
from normal healthy controls. Both serum scan and a simple
scan of the thumb were obtained and then analyzed using
"principal component analysis" (PCA) and "soft independent
modeling of class analogy" (SIMCA) statistical techniques. The
result was a clear separation of normal healthy persons from
persons defined by international (Fukuda or CDC) criteria to
have CFS/ME.


Comment:   This is like Star Trek!  Using a simple handheld
gun-like apparatus, Japanese researchers scanned a test tube
of serum or simply scanned the patient's thumb, and
immediately the Vis-NIR Spectroscope could predict whether or
not the patient had CFS/ME. This technique takes less than one
second to perform, and requires no skill on the part of the
examiner!  Although the spectroscope identified 100% of healthy
individuals and 42 of 45 PWCs (93%), it is not known yet if the
technique can separate PWCs from persons with other illnesses
like MS, rheumatoid arthritis, and depression.  If successful, this
relatively inexpensive (US $3000-8000) and harmless device
could provide rapid definitive diagnosis and finally silence the
skeptics. [Thank goodness Vir-NIS spectroscopy can't treat, or I
might be put out of a job by a machine!]


Viral and Immune Interactions

Viral infections have long been suspected as the cause of
CFS/ME, but no infectious agent has ever been identified.  A
related viewpoint is that a virus may trigger CFS/ME, but then an
abnormal biochemical change perpetuates the illness.  This has
been referred to as the "hit-and-run theory." Ron Glaser (Ohio
State University) examined another possibility, that latent viruses
(or even parts of viruses) could be producing abnormal proteins
within the cells of our patients, causing immune dysregulation,
cytokine production, and inefficient T-cell or NK-cell function.
Viruses (or parts of viruses) can induce cells to manufacture
proteins and enzymes, some of which may be injurious to the
call.  Glaser's group injected into mice an enzyme (dUPTase)
that is encoded by the EB virus. Immune function and behavior
were then monitored.  Lymphocytes in the injected mice were
less able to replicate, and the treated animals lost weight, had
elevated temperatures, and were slow-moving.

Glaser's group also elegantly demonstrated that stress and age
affect latent virus activation. Geriatric patients, for example, had
much higher titers of antibodies to Epstein-Barr Early Antigen
(EA) and Capsid IgG (VCA-IgG) than young adults.  And when
antibody titers were measured in young students at various
times during the school year, titers were noted to rise as much
as four-fold during exam periods, and drop to more moderate
levels during Summer vacation.  Comment:   This is no surprise
to anybody who has experienced the recurrence of herpetic
mouth ulcers or recurrent shingles (zoster) following periods of
stress. The point, however, is that latent viruses (like VZV, EBV,
and HHV6) can reactivate during periods of stress, causing
immune changes and even symptoms of illness.  Since EBV is
an oncogenic virus, Glaser raises concerns that such
reactivation could conceivably cause B-cell lymphomas. To my
knowledge the latter has not been confirmed in CFS/ME.

One question that arises frequently is, "Which test should we use
to detect chronic reactivation of viruses such as HHV6 and
EBV?"    Dharam Ablashi (HHV6 Foundation, Nevada) pointed
out that viral re-activation is  more closely associated with
CFS/ME than just titers of latent antibodies. He examined
several techniques for measuring viral presence.  Qualitative
PCR on whole blood did not differentiate between active and
latent infection, and there was too little virus in serum to make
this assay useful. Active infection can be inferred by quantitative
PCR, serum nested PCR, and analysis of cytopathic effect, but
these techniques are difficult, expensive, and not readily
available to clinicians. On the other hand, Ablashi provided
evidence that highly elevated titers (>1:320 or 1:640) of
commercially available IFA assays for IgG can be used to
identify patients suspected of having active infection.
Comment:   Now we know that high titers of EBV or HHV6 IgG
are likely due to reactivation, and possibly amenable for antiviral
therapy.

Susan Levine (private practice in NY City) and others measured
IgG levels to HHV6  and early antigen titers of EBV in persons
with CFS/ME.  45% of PWCs had titers of >1:320 to EBV and
35% had titers of >1:320 to HHV6, whereas none of 11 controls
had such elevated titers.  This suggests that a subset of PWCs
suffer from chronic infections with EBV and/or HHV6.

Cytokines are immunologically-based chemicals that can cause
viral symptoms such as fever, sore throat, swollen glands,
achiness, etc.  Brian Gurbaxani (CDC, Atlanta) described a
simple but helpful study that demonstrated increased levels of
one pro-inflammatory cytokine, Interleukin 6 (IL6), in PWCs.  His
group demonstrated that increased levels of IL6 were
proportionate to CFS/ME symptom severity, but also correlated
with waist-to-hip ratio (one measure of allosteric load, or
"stress") and C-reactive protein (CRP), which is a marker of
inflammation.   This finding supports the hypothesis that an
ongoing inflammatory process could be contributing to CFS
symptoms.

John Chia (EV Med Research, California) reported on
enterovirus infections in PWCs with GI distress. Enteroviruses (a
genus of RNA viruses that includes echovirus, coxsackie virus,
and poliovirus) have been reported in CFS/ME patients by the
British, but have not been explored much in the US. Chia
obtained gastric biopsies on 108 PWCs with upper
gastrointestinal complaints plus 12 normal healthy subjects and
9 subjects with other GI disorders.  100 of the patient biopsies
revealed at least mild chronic inflammation, of which 5
demonstrated infection with H.pylori.   Eighty-six (86/108=80%)
were positive for the VP1 (enteroviral capsid protein), while only
2/21 (10%) of controls were positive.  Enteroviral RNA was
detected in 5 of the 15 biopsy specimens studied (33%).  Thus
enteroviral infections may play a role in a subset of PWCs with
upper gastrointestinal complaints.

While the evidence is not as compelling as with other infectious
organisms, Garth Nicholson (Institute for Molecular Medicine,
Calfornia) and colleagues continue to report positive PCR
results for Mycoplasma species in PWCs and Gulf War
Syndrome victims.


Additional Posters

Tae Park (Seoul, South Korea) reported once again on his
remarkable success in treating PWCs with one gram of
intravenous gamma globulin weekly for 6 months.   In addition
Park attends to diet, sufficient salt and water intake, regular
exercise, and sleep management.  He reported on 50 patients
(28M, 22F), all of who were severely ill and disabled with
CFS/ME.  Twenty-five of the 28 males improved enough to
return to work (Karnofsky Performance Score from 40 to 90;
Fatigue Impact Scale from 120 to 20-40). Eighteen of 22
females remarkably improved also (KPS 40 to 80; FIS 125 to
40-50).   Comment:  Four major studies using IVGG for the
treatment of CFS/ME have shown variable results   two were
successful, two were not. Park has abundant and continued
success with his regimen, but possibly his adjunctive therapy or
regular IV fluid administration contributes to some of his
success?

Lastly, Jacob Teitelbaum (Annapolis Research Center,
Maryland) provided a poster on his most recent vogue,
d-ribose.  Ribose is a sugar (not at all like table sugar!) that is
used by the cell and specifically by the mitochondria in the
production of energy.  Other studies have suggested that
d-ribose supplementation may improve cellular energy in heart
and skeletal muscles. Teitelbaum's pilot study included 41
PWCs who took 5 grams of d-ribose thrice daily for about two
weeks. Using visual analog scales, 66% of the patients reported
significant improvement during the study, with an average
increase of 42% in energy and 30% in well-being.  Comment:   If
confirmed, this is great news!  I am concerned, however, over
the short treatment period, which is well within the placebo effect
range.  Also, subjective improvement is one thing, but do any
objective parameters improve?   Teitelbaum states that a
randomized controlled trial is underway, so perhaps we will find
out soon.


Conclusions

This was an excellent and exciting meeting, perhaps the best
CFS/ME conference yet.  Information was so overwhelming that
two weeks later I am still trying to sort it out!

It is clear from the number and quality of papers submitted that
CFS/ME research is beginning to thrive, and that several other
nations now rival the US in this field.  Particularly productive this
year were Japan, Belgium, Spain, Sweden and the United
Kingdom.

Two salient events during the conference were the IACFS vote
to change the name to CFS/ME, and the introduction of the
Pediatric Case Definition.  I am sure that these
recommendations will have both profound and positive
consequences.

There were several themes that ran through the conference:
Researchers are looking more at specific symptoms such as
fatigue, pain, and sleep, rather than the syndrome as a whole.

Genomics and proteomics are clearly confirming previous
theories of pathophysiology, and look hopeful as a means
toward a marker for the illness, clues as to causation, and a way
of subtyping subjects. As research becomes "deeper" or more
molecular the differences between CFS/ME and FM are more
distinct.

The importance of subtyping is more recognized. At this time
many researchers consider such subtypes as male/female,
acute/insidious onset, severity, and whether fibromyalgia is
present or not.

The Center for Disease Control is strongly encouraging specific
instruments for documenting symptoms, function, and
compliance with the Fukuda Criteria, but these are not yet widely
used. As a result, it is not clear what is meant when an author
states that his subjects "meet international (or CDC) criteria."
And clearly the concept of viruses or latent infections as
perpetuators of CFS/ME are back in favor.

So what have I learned personally that will aid me in diagnosis
and treatment? First of all, I will recommend testing for elastase,
RNaseL, C-reactive protein, selected cytokines, and NK Cell
Activity, because they are objective markers of pathophysiology
and severity, and they can monitor response to therapy.

I will recommend a test-retest approach to cardio-pulmonary
exercise testing, because it confirms for disability purposes
reduced functional capacity as well as post-exertional malaise.

I will recommend more overnight sleep studies because a
majority of PWCs and PWFs have treatable sleep disorders that
can be identified and monitored only by polysomnography.

I will encourage a more multi-disciplinary approach, especially
supportive counselors for those who are deeply depressed or
catastrophizing I will look for lipid abnormalities and evidence of
metabolic syndrome in our patients, and address these
problems more aggressively.

I will recommend exploration of chronic illness models (such as
Bruce Campbell's Self Help Course) as a means for group
counseling and support. While graded exercise programs may
be too aggressive for many patients, interval exercise and
heart-rate-limited exercise programs are safe and effective
therapies.

I will test more for HHV6a and EBV reactivation, and consider
cautious administration of valgancyclovir and/or high dose
valcyclovir. I will be recommending trials of acetyl carnitine,
d-ribose, replacement lipids (such as NTFactor™), and
antioxidants based on favorable reports presented at this
conference.

Charles W. Lapp, MD, Director
Hunter-Hopkins Center, P.A., Charlotte, North Carolina
January 29, 2007

The above information reflects the personal opinions of the
author only, and is not meant to be an exact or exhaustive review
of the IACFS conference. This material is copyrighted, but may
be reprinted with permission of the author and with appropriate
credit.   Contact:  drlapp@drlapp.net .   (© 2007)