Research Advances in Chronic Fatigue Syndrome

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Research Advances in Chronic Fatigue Syndrome

• Nancy Klimas, MD
• University of Miami
• CFS and GWI Research Center
• Miami VA Medical Center

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Definition - CFS

• gt6 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

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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

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CFS Caseness

• Subpopulations

CFS
Autonomic
Immune
HPA
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CFS Caseness

• Subpopulations

HPA
Autonomic
Immune
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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 7142(11)881
• Multiple Chemical Sensitivity

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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-Oct62(5)655-63
• Reeves et al Biomed Central 2005

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Attitudes of Physicians

• Of 811 GPs 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
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Model of CFS Pathogenesis

• Genetic Predisposition
• Triggering event / infection
• Mediators (Immune, endocrine, neuroendocrine,
  psychosocial)
• Health Outcome/Persistence

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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)

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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

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Model of CFS Pathogenesis

• Genetic Predisposition
• Triggering event / infection
• Mediators (Immune, endocrine, neuroendocrine,
  psychosocial)
• Health Outcome/Persistence

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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-Pituitary-Adrenal 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

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.
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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

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Immunology Whats 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 2525
• 6 Maher Fletcher and Klimas 2006

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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)

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HPA Axis dysregulation

• Demitrack low basal cortisols in CFS subjects,
  hypothalamic dysfunction-
• Dinan 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.

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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 3026(5)

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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
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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

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Balancing Act

• sympathetic parasympathetic

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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

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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)

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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
  157(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

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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

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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

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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

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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) 4417 3 Glaser R
Brain Behavior Immun 2005 19(2)91
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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

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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
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Model of CFS Pathogenesis

• Genetic Predisposition
• Triggering event / infection
• Mediators (Immune, endocrine, neuroendocrine,
  psychosocial)
• Health Outcome/Persistence

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Molecular Epidemiology Laboratory Strategy
DNA
Protein Abundance
Protein Function
mRNA
Genomics
Proteomics
Activity-based Protein Profiling
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Microarray Technology
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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
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Differentially Expressed Genes in Numerous
Pathways
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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
  post-infection 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 245(1)5

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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

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Treatment

• Pathogenesis based approaches

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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

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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

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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

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Balancing Act
Autonomic Dysfunction
Neurally mediated hypotension (Rowe) Orthostatic
hypotension (Streeten) Parasympathetic
dysfunction (Sisto) Sympathetic over activation
(Pagini, De Becker)

• sympathetic parasympathetic

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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

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HPA axis interventions -

• Growth hormone phase 1 (Antwerp study)
• Cortisol conflicting phase 2 study results
  (London, NIH)
• Restoration of sleep cycle (circadian rhythm)

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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 dont
  trap in alpha wave
• mirtazapine (Remeron), sodium oxybate or gamma
  hydroxybutyrate, (Xyrem) act as stage 4 inducers

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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.

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Nutritional interventions

• Oxidative stress studies suggest interventions
  such as glutathione, N-acytylcysteine, alpha
  lipoic acid, NADH
• Vitamin studies suggest B vitamins, Vitamin C,
  magnesium, sodium, zinc, l-tryptophan, L
  carnitine, co-Q10, and essential fatty acids
• highlighted interventions have phase 2 studies
  published

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Nutritional interventions

• Dangers
• Licorice root potassium deficiencies
• supplements that are actually hormones
• supplements that have iffy contents eg. St
  Johns wort, melatonin
• Products that make unsubstantiated claims
• Under and over hydration

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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.

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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

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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 (N14 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

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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 28310
• Bentler SE J Clin Psychiatry 2005 may 66(5)625

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University of Miami CFS Research and Clinical
Center Research Protocols

• 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

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Conclusion

• There has been significant progress in our
  understanding of CFS .
• The neuroendocrine, immune, and central nervous
  system are linked, and cant be considered
  separately.
• More effective therapies, based on this new
  understanding are available, with others under
  study.

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All CFS patients can experience a better quality
of life with compassionate care and a
multidisciplinary approach.
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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 info_at_cfids.org 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
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Photo by Leventhal, Karnovsky and Martz