CFSFM: Recent Research Progress

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CFS/FMRecent Research Progress

• Benjamin H. Natelson, MD
• Professor of Neurosciences,
• UMDNJ-New Jersey Medical School

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CDC CFS case definition

• CFS subset of prolonged fatigue 1 month duration

Onset of fatigue
DX CFS
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1988 1994 CFS Case Definitions

• 1988 - ? in activity by at least 50
• 1994 substantial decrease in activity
• Minor symptoms
• Rheumatological infectious neuropsychiatric
• Exclusions
• Obesity any medical cause of fatigue
• Bipolar eating disorder schizophreniform
  alcohol or drug abuse
  
• 1994 Prevalence 0.4 of general population FM

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Minor Criteria to Diagnose CFS

• 1994
• ?
• ?
• ?
• ?
• ?
• ?
• ?
• ?
• no
• no

• 1988
• sore throat
• tender lymph glands
• myalgia
• arthralgia
• unrefreshing sleep
• headache
• cognitive problems
• ? Sx after exertion
• weakness
• fever/chills

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Pathophysiological Possibilities

• Forme fruste of depression or somatization
• Endocrinopathy
• Viral or immunological
• Chronobiological disorder
• Subtle encephalopathy
• Cardiovascular

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Comparing Case Definitions

• 45 patients fulfilling both 1988 and 1994 case
  definitions by self report
  
• 26 patients fulfilling 1994 but not 1988
• Age and gender not different
• Sudden onset 84 vs 58 1988 more
• ? activity 70 vs 54 1988 worse
• Duration 55 vs 36 mo 1994 longer

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Clinical profile of 94 vs 88 CFS

• Percent reporting each symptom

1994 1988
Memory-concentration 92 96
Unrefreshing sleep 89 100
Post-exertional fatigue 81 98
Muscle pain 77 100
Weakness 69 96
Headache 46 89
Joint pain 39 87
Swollen lymph nodes 31 87
Sore throat 23 89
Feverishness 23 89
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Tentative Conclusion

• Patients with milder CFS (i.e., 94 but not 88)
  appear to be less likely to have had an
  infectious trigger and/or a continuing
  immunological problem.
• Brimacombe et al. J Clin Psychol Med Settings,
  9309, 2002
  

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Unexplained Illness

• Diagnosis given to patients varies with referral
  process. Flu-like malaise is CFS. Diffuse pain
  is FM. Sensitivity to odors is MCS. Bowel
  complaints are IBS. All these OVERLAP!

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Widespread Pain and Multiple Tender Points

• Primary FM there are no exclusions so
  prevalence is much higher than in CFS
  
• 5 compared to 0.4 FM
• Secondary FM rates are higher yet ? 20
• The widespread pain is still medically
  unex-plained but is presumed to be on an organic
  basis
  
• Allows one to design a study comparing 1 to 2
  FM to determine risk factors

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CFSFM is Worse than CFS only
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Exercise Capacity
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Rate of Axis I Diagnoses (163 consecutive female
patients with CFS)
CFS CFS/MCS CFS/FM CFS/FM/MC
S Axis I Dx 0 35/62
(56) 14/31 (45) 17/44 (39) 4/26
(15) 1 18/62 (29) 4/31 (13
) 13/44 (30) 8/26 (31)
1 9/62 (15) 13/31 (42)
14/44 (32) 14/26 (54) Ciccone et al. Ps
ychosom Med, 65268, 2003


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Rate of Diagnosis of IBS (Subset of women for wh
om we had data)
CFS CFS/MCS CFS/FM CFS/FM/MCS
4/26 (15) 2/11 (18)
12/32 (38) 10/18 (56)
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What does this mean (suggest)?

• CFS without other medically unexplained illnesses
  may be a different process than CFS with comorbid
  illness syndromes.
  
• Critical to repeat with an FM alone group

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Stratification Strategies to Reduce Heterogeneity

• Sudden vs gradual
• No psychiatric diagnosis vs diagnosis after
  illness onset (usually depression)
  
• With or without other illnesses such as FM
• Cognitive impairment vs normal cognition
• Very severe vs less severe
• Severity is the best stratifier
• Twice as much FM, n-p impairment and psych Dx

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Dates of Onset for Sudden GroupZhang et al.
Chronobiology International, 1795-100, 2000
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Post Exertional Fatigue

• One argument is that CFS is a variant of
  depression. However, post-exertional fatigue,
  although common in CFS, is not seen in depression.

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Pre- and Post-treadmill Average Activity
CFS HEALTHY
Pre-treadmill Post-treadmill
Pre-treadmill Post-treadmill
Sisto et al. QJM, 91365, 1998
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Hormonal Responses to Exercise
Ottenweller et al., Neuropsychobiol 4334, 2001.
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Symbol Digit Modalities Test(Mean SEM)
LaManca et al. AJM 10559S, 1998
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Cardiovascular Stress Reactivity
LaManca et al. Psychosom Med., 63756, 2001
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Poor Reactivity Predicts Symptom Burden
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Suggests a relation between ability to react to
stress and magnitude of symptoms

• Could be responsible in part for post-exertional
  symptom worsening.
  
• Could aggregate over entire day to produce longer
  lasting symptoms.

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Baroreflex plays a role
Peckerman et al. Psychosom Med 65889, 2003
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A Different Question

• Could CFS be a chronobiological disorder i.e.,
  chronic internal desynchronization or a disorder
  of entrainment?

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Negative Evidence

• Dutch actigraph data collected for 12 consecutive
  days
  
• Analysis drops first and last days
• Data collected every 10 minutes
• 19 CFS
• 10 with markedly diminished activity
• 9 with relatively normal activity
• 8 healthy controls

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Circadian period and acrophase
Pwith t-test (variance controlled) for the mean a
nd F-test for the S.D..
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Mean Circadian Period ? variability
Ohashi et al. Physiol Behav. 7739, 2002
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Mean Circadian Period ? variability
Ohashi et al. Physiol. Behav. 7739, 2002
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Interpretation

• Sleep is further disturbed by vigorous exertion
  to alter circadian phase

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New RO1 on Sleep Cytokines

• About 75 of CFS patients have poor sleep
  efficiency
  
• Ho Sleep disrupting cytokines (IL-4, IL10) are
  increased while sleep producing cytokines (TNF-a,
  INF-?) decrease
  
• Compare cytokines of sleep-matched controls to
  CFS
  
• Same after exercise
• Same after sleep deprivation

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Ultradian Cytokine Secretion in a Normal
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How About Depression as a Cause?
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Compare CFS-Dep to DEP on BDI
Johnson et al. J. Affective Dis 3921, 1996
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Conclusion

• CFS is probably not a variant of major depression

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Overlap with Sjögrens Syndrome

• Complaints of sicca common in CFS
• May in part be due to use of TCAs
• Presence of Sjögrens antibodies very rare
• Lip biopsy is definitive way to Dx Sjögrens
• We inquired about sicca, did Schirmers tests,
  and biopsied 18 healthy controls and 25 CFS

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Overlap with Sjögrens Syndrome
25 CFS Subjects
18 Controls
Symptom of Mucosal Dryness
Symptom of Mucosal Dryness
Symptom of Mucosal Dryness
Gland Pathol Score
Low Schirmer
Low Schirmer
Low Schirmer
Normal Schirmer
Normal Schirmer
Normal Schirmer
0
0
0
Normal
0
0
1
2
3
0
12
1
16
8
0
0
0
0
0
?1
Sirois et al. J Rheum 28126, 2001
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Viral/Immunological Hypotheses of CFS

• Some persistent or reactivated viral infection
  causes the symptom profile of CFS
  
• Some process (perhaps an original viral
  infection) triggers a persistent immuno-logical
  response which remains ongoing and produces the
  symptoms of CFS

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Data are not Confirmatory

• No evidence for herpesvirus reactivation in CFS1
  
  
• No consistent evidence for immune dysfunction in
  blood with exception of reduced NK cell count
  and/or activity2
  
• May reflect inactivity rather than illness

1Wallace et al. CDLI 6216, 1999
2Natelson et al. CDLI 9747, 2002

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The Question

• The symptoms of fatigue, unrefreshing sleep and
  cognitive problems point to a central neural
  origin to CFS
  
• One major polemic dividing the field is the
  argument that CFS is somatization
  
• An exaggeration of normal human feelings
• One alternative explanation is that some CFS
  patients have a neurological disease

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Is CFS Somatization Disorder?

• Prevalence rates for SD in CFS vary from 0 to 98
  depending on whether symptoms are coded as being
  due to physical or psychiatric cause
  
• Incidence of SD is 2.3 when strict DSM III-R or
  IV criteria are utilized
  
• Johnson et al., Psychosom Med 5850,1996

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Just What is Somatisation?

• The same as neurasthenia
• A word that carries the connotation of the
  illness being functional
  
• Psychiatric nosology for medically unexplained
  illness
  
• Driven by belief rather than data

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Consider the alternative hypothesis

• Some CFS patients may have an occult
  encephalopathy despite having no neurological
  findings other than occasional balance problems

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DeLuca et al. Arch Neurol 50301, 1993
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Neuropsychological Function

• CFS patients function worse than controls on
  complex attentional tasks
  
• Stratification strategy
• Those with Axis I similar to controls
• Those without Axis I most impaired
• This group could have underlying encephalopathy

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If this dysfunction were relevant to the symptom
complex of CFS, it should relate to functional
status. If it is an epiphenomon, its presence
should not relate to functional status

• PLAN Evaluate relation between presence of
  neuropsych abnormalities and physical function on
  the SF-36

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Days of General Inactivity in CFS patients who
failed zero (n 19), one (n 20), or two or
more (n 14) cognitive tests

0 1 2 Numbe
r of Failing Test Scores JNNP, 64431,
1998
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Brain MRIs in CFS

• Do MRIs on CFS and sedentary controls
• Test hypothesis that the patients with no Axis I
  pathology will be the group with the highest
  frequency of brain MRI abnormalities

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Percent of subjects with brain MRI abnormalities
Lange et al. J. Neurol. Sci.1713-7, 1999.
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If these lesions were relevant to the symptom
complex of CFS, they should relate to functional
status. If they are epiphenoma, their presence
should not affect functional status

• PLAN Evaluate relation between presence of
  abnormalities and physical function on the SF-36

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Cook et al. Intl J Neurosci. 1071-6, 2001
Cook et al. Intl J Neurosci. 1071-6, 2001
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NJ Case Definition for Severe CFS (Modification
of 1988 CDC case definition)

• Insert an intensity dimension
• - Uses a 0-5 Likert scale
• (3 substantial, 4 severe, 5 very
  severe)
  
• Patients must report severities of 3 or
• greater for at least 7 Sx in the prior month

Natelson et al. Clin. Infec. Dis. 211204-10, 1995
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CFS Severity and Ventric Volume
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Conclusions

• Stratification of CFS subjects is important to
  understand pathophysiology of illness
  
• CFS subjects without concurrent Axis I
  psychiatric disorder show significantly more
  
• small abnormal MRI signal changes
• in subcortical white matter of frontal lobes
• CFS patients in severe category have biggest
  ventricles
  
• Supports conclusion that some CFS patients may
  have underlying encephalopathy
  

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Where to go from here?

• Examination of spinal fluid

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• We reasoned that we would find abnormal-ities of
  spinal fluid in some CFS patients
  
• Those with no co-morbid depression more than in
  those with no psychopathology
  
• In those with the most marked cognitive impairment

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Results

• LPs successfully done on 13 controls
• None had protein 40 or 3 WBCs/HPF
• LPs were successfully done on 44 CFS
• 8 had elevated protein ( 45 mg/dl)
• 4 had increased numbers of WBCs ( 5/HPF)
• 1 had both elevated protein and increased cells
• Thus 30 of taps were outside of nl range!!

Natelson et al. CDLI, 1253, 2005
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Cognitive function not different in high
protein group
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CFS Abnormality Psychopath

• Rates of current depression
• 0 in those with abnormal CSF
• 27 in those with normal CSF
• p .04 one tailed
• Rates of lifetime depression
• 46 in those with abnormal CSF
• 48 in those with normal CSF

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CSF IL-10, a pro-inflammatory cytokine
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CSF IL-8
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Conclusion

• 30 of all CFS patients tapped had spinal fluids
  outside of laboratory norms
  
• Supports our inference that some patients with
  CFS have an occult encephalopathy
  
• Could relate to elevated levels of IL-10
• One confounding variable may be drugs -- ???
• We again found most CFS abnormalities in the
  group with no psychopathology
  
• Continues to support our stratification strategy
• We did not find a relation with n-p impairment

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Use fMRI to Assess Brain Activity

• fMRI assesses Hb-O2/Hb ratios to provide an
  indirect measure of neuronal activity
  
• This technique allows one to see the brain
  during various tasks and states
  
• Study 1 Brain activation during warm and painful
  stimuli
  
• FM and controls
• Study 2 Brain activation during PASAT, a
  complex attentional task
  
• CFS and controls with normal cognitive function

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Warm non-painful stimulus
FM Group
Control Group
Cook et al., J. Rheumatology, in press.
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Information Processing Task
Lange et al, JNNP, in press.
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What These Studies Tell Us

• FM patients feel warm as if it were hot
• CFS patients process information as if it were
  substantially harder than it really is
  
• The two studies suggest that CFS/FM brain
  requires additional neural resources to deal with
  mental processes that we take for granted
  
• Is this the process responsible for mental
  fatigue?
  
  
  
  
  
  
  
  
  
  
  

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A primary brain problem or not?

• Look at the heart and determine if abnormalities
  exist and, if present, if they relate to any
  index of brain dysfunction

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Non-Invasive CV Evaluation

• Assessed heart rate, blood pressure, and stroke
  volume in 17 CFS patients and 24 sedentary
  controls while supine, standing, and sitting
  
• Used impedance cardiography used to measure
  stroke volume -- an index of cardiac blood flow
  

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Cardiac Output in CFS
Peckerman et al. Am J Med Sci, 32655, 2003
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CO and postexertional fatigue
Peckerman et al. Am J Med Sci, 32655, 2003
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Suggests Problem with Cardiac Output for Severe
CFS Patients

• Do radionucleid MUGA study to evaluate cardiac
  function during exercise stress EF should
  increase

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Ejection Fraction and CFS Severity
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Suggests that cardiac function is not normal at
least in the most severely affected patients
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Research Question

• Are CNS lesions secondary to perfusion problem or
  primary?

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New Experiment

• Determine resting cardiac output (Q)
• Use functional neuro-imaging to determine
  cerebral blood flow during orthostatic challenge
  via LBNP
  
• Research questions
• What is resting CBF in patients vs controls
• What is relation between Q and CBF at rest
• How does CFS severity fit in
• How does orthostatic challenge affect this
  relation

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LBNP in the magnet
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Conclusion

• Data collected to this point supports our major
  hypothesis that CFS is for some a neurological
  disorder the pathophysiological role of the
  heart is under active investigation

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Please refer potential study patients to the
CFS/FM Center

• [phone]
• or
• www.umdnj.edu//cfs

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CFS/FM Center Researchers

• Dr. Kyoko Ahashi
• Dr. Michael Brimacombe
• Dr. Kim Busichio
• Dr. Don Ciccone
• Dr. Helena Chandler
• Dr. Neil Cherniack
• Dr. Dane Cook
• Dr. John DeLuca
• Dr. Drew Helmer
• Dr. Susan Johnson
• Dr. Gudrun Lange

• Dr. John LaManca
• Dr. John Ottenweller
• Dr. Arnold Peckerman
• Dr. Karen Quigley
• Dr. Rick Servatius
• Dr. SueAnn Sisto
• Dr. Lana Tiersky
• Dr. Chin-Lin Tseng
• Dr. Yoshi Yamamoto
• Dr. Kazu Yoshiuchi
• Dr. Shelley Weaver
• Dr. Quan Wu Zhang

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Rate of Diagnosis of IBS (Subset of women for wh
om we had data)
CFS CFS/MCS CFS/FM CFS/FM/MCS
4/26 (15) 2/11 (18)
12/32 (38) 10/18 (56)