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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. =. 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

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  1. CFS/FM:Recent Research Progress Benjamin H. Natelson, MD Professor of Neurosciences, UMDNJ-New Jersey Medical School

  2. = 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 Onset of fatigue DX CFS

  3. 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

  4. 1988 sore throat tender lymph glands myalgia arthralgia unrefreshing sleep headache cognitive problems  Sx after exertion weakness fever/chills 1994         no no Minor Criteria to Diagnose CFS

  5. Pathophysiological Possibilities • Forme fruste of depression or somatization • Endocrinopathy • Viral or immunological • Chronobiological disorder • Subtle encephalopathy • Cardiovascular

  6. 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

  7. 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

  8. 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

  9. 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!

  10. 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

  11. CFS+FM is Worse than CFS only

  12. Exercise Capacity

  13. Rate of Axis I Diagnoses (163 consecutive female patients with CFS) CFS CFS/MCS CFS/FM CFS/FM/MCS # 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

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

  15. 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

  16. 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

  17. Dates of Onset for Sudden GroupZhang et al. Chronobiology International, 17:95-100, 2000

  18. 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.

  19. Pre- and Post-treadmill Average Activity CFS HEALTHY Pre-treadmill Post-treadmill Pre-treadmill Post-treadmill Sisto et al. QJM, 91:365, 1998

  20. Hormonal Responses to Exercise Ottenweller et al., Neuropsychobiol 43:34, 2001.

  21. Symbol Digit Modalities Test(Mean & SEM) LaManca et al. AJM 105:59S, 1998

  22. Cardiovascular Stress Reactivity LaManca et al. Psychosom Med., 63:756, 2001

  23. Poor Reactivity Predicts Symptom Burden

  24. 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.

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

  26. 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

  27. 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..

  28. Mean Circadian Period  variability Ohashi et al. Physiol & Behav.77:39, 2002

  29. Mean Circadian Period  variability Ohashi et al. Physiol. Behav. 77:39, 2002

  30. Interpretation Sleep is further disturbed by vigorous exertion to alter circadian phase

  31. 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

  32. Ultradian Cytokine Secretion in a Normal

  33. How About Depression as a Cause?

  34. Compare CFS-Dep to DEP on BDI Johnson et al. J. Affective Dis 39:21, 1996

  35. Conclusion CFS is probably not a variant of major depression

  36. 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

  37. Overlap with Sjögren’s Syndrome 25 CFS Subjects 18 Controls + Symptom of Mucosal Dryness – Symptom of Mucosal Dryness – Symptom of Mucosal Dryness Gland Pathol Score Low Schirmer Normal Schirmer Low Schirmer Normal Schirmer Low Schirmer Normal Schirmer 0 0 0 Normal 0 0 1 <1 2 3 0 12 1 16 8 0 0 0 0 0 1 Sirois et al. J Rheum 28:126, 2001

  38. 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

  39. 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

  40. 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

  41. 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

  42. 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

  43. Consider the alternative hypothesis Some CFS patients may have an occult encephalopathy despite having no neurological findings other than occasional balance problems

  44. DeLuca et al. Arch Neurol 50:301, 1993

  45. 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

  46. 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

  47. 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

  48. 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

  49. Percent of subjects with brain MRI abnormalities Lange et al. J. Neurol. Sci.171:3-7, 1999.

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