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CFS/FM: Recent Research Progress. Benjamin H. Natelson, MD Professor of Neurosciences, UMDNJ-New Jersey Medical School. =. Level of Activity. 0. 1. 2. 3. 4. 5. 6. Duration of Fatigue (mo.). CDC CFS case definition. CFS subset of prolonged fatigue > 1 month duration.

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cfs fm recent research progress

CFS/FM:Recent Research Progress

Benjamin H. Natelson, MD

Professor of Neurosciences,

UMDNJ-New Jersey Medical School

cdc cfs case definition


Level of Activity








Duration of Fatigue (mo.)

CDC CFS case definition
  • CFS subset of prolonged fatigue > 1 month duration

Onset of fatigue


1988 1994 cfs case definitions
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 F>M

minor criteria to diagnose cfs

sore throat

tender lymph glands



unrefreshing sleep


cognitive problems

 Sx after exertion






Minor Criteria to Diagnose CFS
pathophysiological possibilities
Pathophysiological Possibilities
  • Forme fruste of depression or somatization
  • Endocrinopathy
  • Viral or immunological
  • Chronobiological disorder
  • Subtle encephalopathy
  • Cardiovascular
comparing case definitions
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
clinical profile of 94 vs 88 cfs
Clinical profile of ‘94 vs ‘88 CFS

1994 1988

Percent reporting each symptom

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

tentative conclusion

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, 9:309, 2002

unexplained illness

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!

widespread pain and multiple tender points
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%; F>>M
  • 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 1⁰ to 2⁰ FM to determine risk factors

Rate of Axis I Diagnoses

(163 consecutive female patients with CFS)


# 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. Psychosom Med, 65:268, 2003


Rate of Diagnosis of IBS

(Subset of women for whom we had data)


4/26 (15%) 2/11 (18%) 12/32 (38%) 10/18 (56%)

what does this mean suggest

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

stratification strategies to reduce heterogeneity
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
post exertional fatigue

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.


Pre- and Post-treadmill Average Activity


Pre-treadmill Post-treadmill Pre-treadmill Post-treadmill

Sisto et al. QJM, 91:365, 1998

hormonal responses to exercise
Hormonal Responses to Exercise

Ottenweller et al., Neuropsychobiol 43:34, 2001.

symbol digit modalities test mean sem
Symbol Digit Modalities Test(Mean & SEM)

LaManca et al. AJM 105:59S, 1998

cardiovascular stress reactivity
Cardiovascular Stress Reactivity

LaManca et al. Psychosom Med., 63:756, 2001

suggests a relation between ability to react to stress and magnitude of symptoms

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.

a different question

A Different Question

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

negative evidence
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
circadian period and acrophase
Circadian period and acrophase

* P<0.05 from controls; ** P<0.05 from active CFS with

t-test (variance controlled) for the mean and F-test for the S.D..

mean circadian period variability
Mean Circadian Period  variability

Ohashi et al. Physiol & Behav.77:39, 2002

mean circadian period variability30
Mean Circadian Period  variability

Ohashi et al. Physiol. Behav. 77:39, 2002



Sleep is further disturbed by vigorous exertion to alter circadian phase

new ro1 on sleep cytokines
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-α, INF-γ) decrease
  • Compare cytokines of sleep-matched controls to CFS
  • Same after exercise
  • Same after sleep deprivation
compare cfs dep to dep on bdi
Compare CFS-Dep to DEP on BDI

Johnson et al. J. Affective Dis 39:21, 1996



CFS is probably not a variant of major depression

overlap with sj gren s syndrome
Overlap with Sjögren’s Syndrome
  • Complaints of sicca common in CFS
    • May in part be due to use of TCAs
  • Presence of Sjögren’s antibodies very rare
  • Lip biopsy is definitive way to Dx Sjögren’s
    • We inquired about sicca, did Schirmer’s tests, and biopsied 18 healthy controls and 25 CFS
overlap with sj gren s syndrome38
Overlap with Sjögren’s Syndrome

25 CFS Subjects

18 Controls

+ Symptom of

Mucosal Dryness

– Symptom of

Mucosal Dryness

– Symptom of

Mucosal Dryness





































Sirois et al. J Rheum 28:126, 2001

viral immunological hypotheses of cfs
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
data are not confirmatory
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 6:216, 1999

2Natelson et al. CDLI 9:747, 2002

the question
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
is cfs somatization disorder
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 58:50,1996

just what is somatisation
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
consider the alternative hypothesis

Consider the alternative hypothesis

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

neuropsychological function
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

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

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

Number of Failing Test Scores JNNP, 64:431, 1998

brain mris in cfs
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
percent of subjects with brain mri abnormalities
Percent of subjects with brain MRI abnormalities

Lange et al. J. Neurol. Sci.171:3-7, 1999.

plan evaluate relation between presence of abnormalities and physical function on the sf 36

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


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. 21:1204-10, 1995

  • 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

where to go from here

Where to go from here?

Examination of spinal fluid

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
  • 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, 12:53, 2005

cfs abnormality psychopath
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
  • 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
use fmri to assess brain activity
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

Warm non-painful stimulus

FM Group

Control Group

Cook et al., J. Rheumatology, in press.


Information Processing Task

Lange et al, JNNP, in press.

what these studies tell us
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?
a primary brain problem or not

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

non invasive cv evaluation
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
suggests problem with cardiac output for severe cfs patients

Suggests Problem with Cardiac Output for Severe CFS Patients

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

research question

Research Question

Are CNS lesions secondary to perfusion problem or primary?

new experiment
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


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

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

CFS/FM Center Researchers

Rate of Diagnosis of IBS

(Subset of women for whom we had data)


4/26 (15%) 2/11 (18%) 12/32 (38%) 10/18 (56%)