Transcript Treatment of CFS: the USA Experience

Research Advances in
Chronic Fatigue
Syndrome
Nancy Klimas, MD
University of Miami
CFS and GWI Research Center
Miami VA Medical Center
Definition - CFS
>6 mo. debilitating fatigue, unexplained by
preexisting illness or psychiatric co morbidity,
and at least 4 of eight symptom criteria:
post exertional relapse
concentration and cognitive complaints
myalgia
arthralgia
sore throat
painful lymph nodes
new headaches
unrefreshing sleep
CFS/ME Clinical Case Definition
1. Substantial reduction in activity level due to new
onset, persistent fatigue
2. Post exertional malaise
3. Sleep dysfunction
4. Pain – myalgia, headaches
5. Neurologic/Cognitive Manifestations
6. At least one symptom from 2 of the following:
- Autonomic manifestations eg. OI, IBS
- Neuroendocrine manifestations eg. temperature
intolerance, weight change
- Immune manifestations eg. tender lymph nodes, sore
throat, flu-like symptoms
Link to full report www.iacfs.net
CFS “Caseness”
Subpopulations
CFS
Immune
Autonomic
HPA
CFS “Caseness”
Subpopulations
Autonomic
Immune
HPA
Other overlapping conditions
Fibromyalgia
Gulf War Illness (VA CSP 16 fold increased
risk of CFS in Gulf War veterans)
Eisen et al Ann Int Med 2005 7;142(11):881
Multiple Chemical Sensitivity
Epidemiology: DePaul
University
• Latinos: 726 per 100,000
• African Americans: 337 per 100,000
• Caucasians: 224 per 100,000
• Women: 522 per 100,000
• Men:
291 per 100,000
CDC Wichita study: 85% undiagnosed,
50% reduction in household income – 9 billion/yr US loss
productivity
Jason et al Psychosom Med. 2000 Sep-Oct;62(5):655-63
Reeves et al Biomed Central 2005
Attitudes of Physicians
Of 811 GP’s 44% did not feel confident making
the diagnosis, 41% did not feel confident treating
More likely to have confidence if they had a
friend or family member with CFS, having more
patients with CFS.
Concludes that education emphasizing
acceptance of CFS as a real entity results in
improved confidence in treatment
Bowen J et al Family Pract 2005 April 1
Model of CFS
Pathogenesis
Genetic Predisposition
Triggering event / infection
Mediators (Immune, endocrine,
neuroendocrine, psychosocial)
Health Outcome/Persistence
Genetic Predisposition - CFS
HLA DR haplotypes in 112 South Florida CFS
patients, compared to 5,000 regional and
national controls
4 to 6 fold increased relative risk for DR4, DR3
and DQ3. (Keller et al, 1992)
Seattle CFS Cooperative Research Center Twin
study - genetic predisposition, hereditability
estimate of 51% (2nd World Conf)
Evidence for Triggering
event/ infection - CFS
60 to 80% of CFS subjects date the onset of
their illness to an acute viral-like illness
(Komaroff, Buchwald) Less so in population
based studies. (Reeves, Jason)
Andrew Lloyd and colleagues in Australia
performed a prospective study during and after
acute EBV, Q fever or Ross River Virus -Anergy
during acute infection predicted persistent CFS
like symptoms
Peter White described post EBV illness in a
prospective trial
Model of CFS
Pathogenesis
Genetic Predisposition
Triggering event / infection
Mediators (Immune, endocrine,
neuroendocrine, psychosocial)
Health Outcome/Persistence
CRF
CNS Symptoms
• Altered perceptions
- fatigue
- pain
• Cognitive changes
- concentration
- memory
• Mood alterations
- depression
- anxiety
• Sleep disturbances
- unrefreshing sleep
- altered sleep-wake cycle
Physical stress activates
immune system and HPA
axis
Emotional stress activates
immune system and HPA
axis
Hypothalamic-PituitaryAdrenal Axis
• Relative Hypocortisolemia
Musculoskeletal System
• Myalgia & Arthralgia
Gastrointestinal Tract
• Altered bowel habits
• Abdominal pain
Heart and Blood Vessels
• Altered blood pressure
responses
• Dizziness
Immune System
• Lymph node tenderness
• Sore throat
• Enhanced Cytokines
Immune cascade
Macrophage presents antigen
Natural Killer
Cells(Th1)
Helper CD4 cell
Th1 cytokines
IL-2, INF
activates CD8
.
Helper CD4 cell
Th2 cytokines
IL-6, IL-10
activates B cells
CD8 cells
kill virus
B cells
make antibody
prevent and help
clear infection
Immune abnormalities in CFS
Immune Activation
DR, CD26 expression
TH2 cytokine shift
Proinflammatory
cytokines expression
TNF-a, IL-1, IL6
Functional defects
NK Cell dysfunction
CD8 abnormalities
perforins, granzymes
Macrophage abnormalities
Antibody production
Immunology What’s New?
Exercise induced complement activation1
NK phenotypes predict risk 2
Lower mRNA and TGF-beta1 production 3
Increased neutrophil apoptosis 4
Autoantibodies - anti-microtubule-associated
protein 2, sDNA5
CTL defect equals that of NK cells
1 Sorensen, Jones et al J Allergy Clin Immun 2003 112(2):397-403
2 Stewart et al Cytometry 2003 53(1)2633
3 Tomoda A et al Psychiatry Res 2005 134(1):101
4 Kennedy et al J Clin Parhol 2004 57(8) 891
5 Vernon and Reeves, J Autoimmune Dis 2005 25:2:5
6 Maher Fletcher and Klimas 2006
Viral Persistence/Reactivation
HHV6 virus is present in 22 to 54% of patients in
cross sectional studies (Ablashi, Krueger, Knox),
HHV6 virus is present in 79% of CFS patients in
longitudinal studies (HHV6 PCR assay, Knox)
HHV6 virus is present in the spinal fluid of 28 of 120
CFS patients (Peterson), and 7 of 35 CFS
samples (Knox).
Enterovirus is present in 13% of CFS muscle samples
(Douche-Aourik, 2003)
EBV – dUTPase as a immune modulator, up
regulating inflammatory cytokines (Glaser, 2005)
(Glaser et al Brain Behavior and Immunity 2005 19(2):91-103)
HPA Axis dysregulation
Demitrack low basal cortisols in CFS subjects,
hypothalamic dysfunctionDinan and colleagues - evidence of deficiency
of hypothalamus, pituitary, and adrenal
hypofunction.
Small adrenal gland in depressed and non
depressed CFS subjects, enlarged adrenal in
depressed control group.
Bennett et al studied 500 FM patients with
basal IGF-I levels which were significantly
lower than controls.
Endocrinology
Reduced Cortisol output via several mechanisms
A) heightened negative feedback
B) heightened receptor function
C) impaired ACTH and cortisol responses to challenge
DHEA functional abnormality (early data)
Abnormal seritonin function
IL-6 increase associates with low cortisol CRH
mediated
Many confounding factors (deconditioning, sleep,
comorbid depression, stress, medication)
Cleare AJ Endocr Rev 2003 24(2):236-52
Papanicolau Neuroimmunomodulation 2004 11(2)65-74
Maes M Neuro Endocrinol Lett 2005 Oct 30;26(5)
Renin Aldosterone Axis
High Prevalence of Renin-Aldosterone Axis
Abnormalities in Patients with Chronic Fatigue Syndrome
(CFS)
30 of the 33 patients had at least one value of supine or
upright PRA or supine or upright serum AL outside of the
95% Tolerance Interval (TI) for normal volunteers
16 patients had low serum AL and low or normal PRA,
consistent with Hyporeninemic Hypoaldosteronism (HH)
The underlying defect may be autonomic nervous
system dysfunction and/or a primary adrenal defect.
Zuckerbraun, E, Kim, HS, Daigle, K, Lee, ML, Friedman, TC, Charles R. Drew University
Autonomic Dysfunction
Neurally mediated hypotension (Rowe)
Orthostatic hypotension (Streeten)
Parasympathetic dysfunction(Sisto)
Sympathetic over activation (Pagini, De
Becker)
Study in adolescents mirrored that of
adults
Balancing Act
sympathetic
parasympathetic
Autonomic Nervous System
Haemodynamic Instability Score taken during tilt
table testing predicts CFS with 90% sensitivity. 1
Heart Rate variability as a predictor of CFS 2
Gastric emptying delayed in 23/32 CFS subjects 3
1 Naschitz QJ Med 2003 96(133-142)
2 Yamamoto Exp Biol Med 2003 228(2):167-74
3 Burnet BMC Gastrenterol 2004 (1):32
Autonomic Dysfunction
Drops in BP followed by CFS relapse
Exhaustive treadmill testing results in
cognitive function decline (LaManca et al)
Perfusion abnormalities of brain stem,
cerebellum (Costa et al)
Mid cerebral reduced perfusion (Schwartz
et al)
Neuropeptides
Seritonin and its precursers: abnormalities
of CSF tryptophan levels
Badawy et al J Psychopharm 2005 19(4):385
PET scan – 5HT1A receptor binding reduced in
CFS, particularly in the hippocampus
Cleare AJ et al Biol Psychiatry 2005 1;57(3):239-46
Reduction of seritonin transporters (5HTTs)
most pronounced in the anterior cingulate by
PET scan. Yamamoto S et al Neuroreport 2004 15(17):2571
Neuroimaging
Reductions in global grey matter
associated with reductions in physical
activity (28 subjects, 28 matched controls).
deLange et al Neuroimage 200526(3):777
Utilization of more extensive regions of the
brain to process tasks using fMRI and
mPASAT. Lange G et al Neuroimage 2005 26(2):513
Sleep Physiology
Circadian Sleep - Wake neuroendocrine and
immune functions in CFS (Modolfsky)
altered diurnal patterns in cortisol, prolactin
altered diurnal patterns of NK cell function
alpha wave intrusion on sleep EEG , reduced
stage III and IV
Higher %REM (Twin study, 22 discordant twins)1
1 Watson et al Sleep 2003 26(3):32-8
Muscle
Oxidative stress study, measuring protein carbonyls
suggested higher levels of protein oxidation than
controls 1
Exercise testing in 189 CFS subjects resulted in
clinically significant subgroups 50% showing
moderate to severe functional impairment.
Unexpected blunted HR and BP responses noted. 2
Sarcoplasmic reticulum defect – conduction and
calcium transport abnormalities3
1 Smirnova et al Mol Chem Biochem 2003 248(1-2):93-5
2 Vaness Med Sci Sports Exerc 2003 35(6):908-13
3 Fulle et al Neuromuscul Disord 2003 13(6):479-84
Muscle
Cardiac muscle – cardiac output related to
severity,and predicted exercise induced relapse1
Subset of CFS patients with IgM EBV or CMV Ab at
risk for cardiac motility abnormalities and
occassionally true cardiomyopathy 2
Raises the issue of incomplete viral replication,
activating immune responses as suggested by
Glaser et al 3
1 Peckerman et al AJ Med Sci 2003 326(2)55
2 Lerner M et al In Vivo 2004(18) 4:417
3 Glaser R Brain Behavior Immun 2005 19(2):91
Exercise – new studies
No association between pain related fear of
movement and exercise capacity and disability
Nijs J et al Phys Ther 2004 84(8):696
Exercise induced pain thresholds increase in
controls and decrease in CFS subjects Whiteside A et
al Pain 109(3):497
Exercise – new studies
A subset of fit healthy controls deprived of exercise
develop symptoms similar to CFS/FM. The subset is
predicted by baseline abnormalities of autonomic,
immune and HPA axis abnormalities.1
Patients with Rnase L abnormalities have abnormal
exercise physiology which is mediated in part by
immune dysfunction 2
Response to exercise shows accentuated oxidative
stress, and marked alterations of muscle membrane
excitablility, sufficient to explain muscle pain and post
exertional malaise. 3
1Glass
JM et al J Psychosom res 2004 57(4):391
2
Snell CR In Vivo 2005 19(2)387, Nijs J et al Med Sci Sports Exerc 2005 Oct 37(10):1647
3
Jammes Y et al J Intern Med 2005 257(3):229
Model of CFS
Pathogenesis
Genetic Predisposition
Triggering event / infection
Mediators (Immune, endocrine,
neuroendocrine, psychosocial)
Health Outcome/Persistence
Molecular Epidemiology Laboratory
Strategy
DNA
mRNA Protein
Abundance
Genomics
Proteomics
Protein
Function
Activity-based
Protein Profiling
Microarray Technology
Microarray Production
DNA clones
oligonucleotides
PCR amplification
Purification
Robotic printing
Sample Preparation
Plasma
Blood
PBMCs
PBMCs
Lymphoprep
Erythrocytes +
Granulocytes
Total RNA
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Labelled cDNA
Hybridization
Gradual onset
Sudden onset
23 women with CFS from Wichita
Measure expression of 3,800 genes
Question:
Could gene expression profiles and
differentially expressed genes
distinguish subtypes of CFS? Of the
3,800 genes, 117 were significantly
Different between gradual vs sudden
onset
Differentially Expressed Genes
in Numerous Pathways
Genetic studies
Differential expression of 35 genes of 9522 tested.
T Cell activation, neuronal and mitochondrial
regulatory abnormalities Kaushik J Clin pathol 2005 58(8):826
Abnormalities of Immune response genes in postinfection fatigue suggest genetic variations in
susceptibility to persistent fatigue. Helbig QJM 2005 98(8):565
Pre-post exercise challenge gene studies saw
differences in genes that regulate ion transport,
intracellular cell functions. Challenge studies such
as these may be more useful than single cross
sectional studies. Whistler et al BMC Physiol 2005 24;5(1):5
CFS is a Complex Illness
Illness represents
alterations in complex
systems of homeostasis
Not a result of a single
mutation or single
environmental factor
Arise from a combined
action of many genes,
environmental factors
and risk-conferring
behavior
Treatment
Pathogenesis based approaches
Pathogenesis Directed
Interventions
Immune - Ampligen, future
immunomodulators
HPA axis interventions - Growth hormone,
cortisol
NMH treatments (plasma expansion,
sympathetic and parasympathetic
stimulants/inhibitors);
Sleep - pharmacologic and
nonpharmacologic
Immune cascade
Macrophage presents antigen
Natural Killer
Cells(Th1)
Helper CD4 cell
Th1 cytokines
IL-2, INF
activates CD8
.
Helper CD4 cell
Th2 cytokines
IL-6, IL-10
activates B cells
CD8 cells
kill virus
B cells
make antibody
prevent and help
clear infection
Immune modulatory approaches
Ampligen, a immune modulator and
antiviral (Phase 3 recently completed)
Allergy immunotherapy to down
regulate allergic drive
 Future immunomodulators (trials
underway): Isoprinosine, thalidomide,
anti-TNFa monoclonal Ab
Proof of concept: Autologous
lymphocyte study
Treating HHV6a?
Association vs. causation
Blood PCR HHV6 a did not predict HHV6 virus is present
in the spinal fluid
CSF did not predict blood
Of 120 CSF samples, 44 had abnormalities of protein,
glucose or cells. Of the 44 , 28 were positive for
HHV6(26), EBV (1), or CMV(1).
5 of 8 CSF PCR positive treated until CSF cleared returned
to full time employment (Peterson); in his experience TK
inhibitors did not clear CSF, patients required foscarnet or
cidofovir
Open label valgancyclovir 9 of 12 responders in high titer
EBV plus HHV6 selected cohort , (Jose Montoya of
Stanford)
Placebo control trials have not been completed
Autonomic Dysfunction
Neurally mediated hypotension (Rowe)
Orthostatic hypotension (Streeten)
Parasympathetic dysfunction (Sisto)
Sympathetic over activation (Pagini, De Becker)
Balancing Act
sympathetic
parasympathetic
Implications for treatment - NMH
“Pipes
and a pump”, wired by the
autonomic nervous system
Fill the space - fluid vs. cells
compress the space - alpha 1
agonists (e.g. midodrine),
anti-phlebitic stockings
regulate the pump - beta blockers
HPA axis interventions Growth hormone – phase 1
(Antwerp study)
Cortisol – conflicting phase 2
study results (London, NIH)
Restoration of sleep cycle
(circadian rhythm)
Sleep
Re-establish circadian rhythm
Conditioned response to bed - avoid bed for
resting, reading, use bed for sleeping.
Establish “bedtime”.
Avoid short acting hypnotics (alpha trappers)
tricyclics, doxepan are longer acting, and don’t
trap in alpha wave
mirtazapine (Remeron), sodium oxybate or
gamma hydroxybutyrate, (Xyrem) act as stage
4 inducers
Pain and Sleep
pregabulin (Lyrica) 529 subjects, placebo
control trial in fibromyalgia
Significant improvement in pain, sleep and
fatigue (48% improved vs 27% placebo),
450 mg dose had greater reduction in pain
scores.
Nutritional interventions
Oxidative stress studies suggest
interventions such as glutathione, Nacytylcysteine, alpha lipoic acid,
NADH
Vitamin studies suggest B vitamins,
Vitamin C, magnesium, sodium,
zinc, l-tryptophan, L carnitine, coQ10, and essential fatty acids
highlighted interventions have phase 2 studies published
Nutritional interventions
Dangers:
Licorice root – potassium deficiencies
“supplements” that are actually hormones
“supplements” that have iffy contents – eg.
St John’s wort, melatonin
Products that make unsubstantiated
claims
Under and over hydration
Reconditioning
Poor orthostatic resilience leads to
substantial changes in usual
reconditioning programs
Limit upright head up time to 5 minutes
alternating with 5 minutes flat, use flat
or near flat aerobic conditions
(swimming, recumbent bike)
Concentrate on muscle bulking
exercises, increasing metabolic ate
(weight training, light weights)
Flexibility , stretching and balance as
core component.
Recent reports - interventions
Brewers Yeast Extract - in a mouse model , using a chronic
immune activation model, the BYE prep quieted the immune
response and prevented further over activation in subsequent
immune challenges. Activity level increased in the treated
animals as compared to placebo
Use of antibiotics for Coxiella burnetii infection(Q fever). TCN
was given to 4 CFS patients and 58 ICFS PCR positive
patients: all cleared the infection, CFS patients failed to
improve, ICFS patients improved in performance and in
temperature and headaches scores.
Neurotropin - 6 mo treatment resolved all symptoms.
Neurotropin is a immune modulator that is currently used in
Japan to treat RSD and other painful conditions.
Toda Hiroshima J Med Sci 2006 mar 55(1) 35-77.
Takasha Evid based Compl Alt Med 2006 mar 3(1)109
Twakami et al Intern Med 2005 Dec 44(12):1258-63
Recent reports - interventions
Melatonin 29 patients, 5mg open label study, 8 of 27
normalized fatigue scores. Measured patients dim
light melatonin onset, patients whose result was later
than 22 hours were more likely to respond to
treatment.
Methylphenidate (ritalin) in CFS 10 mg BID study in
60 patients, placebo control: 17% reported decreased
fatigue, 22% improvement in concentration. ..further
studies needed.
Modafinil not helpful (N=14 cross over study) – mixed
effect on cognitive testing, some dose effect.
Van Heukelom et al Eur J neurol 2006 Jan 13(1):55-60
Blockman D et al Am J Med 2006 feb 119(2):167
Randall DC et al J Psychopharm 2005 nov 19(6): 647-60
Recent reports - interventions
Walking program notes an initial ability to meet
goals (4 to 10 days), then develop exercise
intolerance and worsening symptomatology
Patients report: of 155 patients taking
everything under the sun, most helpful
supplements coQ10 (69%) DHEA (65%),
ginsing (56%) by self report. Vitamins,
exercise, yoga, predicted improvement. Yoga
seemed the most helpful.
Black CD and McCully KK. Dyn Med 2005 Oct 28;3:10
Bentler SE J Clin Psychiatry 2005 may 66(5):625
University of Miami CFS Research
and Clinical Center–
Research Protocols
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SMART Energy Study (CBT)
Erythropoetin (Procrit) phase 2 protocol
Pathogenesis of NK cell defect in CFS
Thalidomide Phase 1 protocol
Isoprinosine Phase 2 protocol
Natural history study
Gene expression with exercise challenge in
CFS and GWI
Conclusion
There has been significant progress in our
understanding of CFS .
The neuroendocrine, immune, and central
nervous system are linked, and can’t be
considered separately.
More effective therapies, based on this
new understanding are available, with
others under study.
All CFS patients can
experience a better quality of
life with compassionate care
and a multidisciplinary
approach.
Thank You!
Professional links:
AACFS on line: www.aacfs.org
CDC on line: www.cdc.gov
NIH on line: www.nih.gov
Advocacy organizations:
CFIDS Association of America
On-line: www.cfids.org Information: [email protected]
American Fibromyalgia Syndrome Assn.
Online: www.afsafund.org
National Gulf War Resource Center online: www.ngwrc.org
New Zealand: Associated Myalgic Encephalopathy Society Inc
www.anzmes.org.nz
Photo by Leventhal, Karnovsky and Martz