1. Curso Internacional de Especialización en Fibromialgia y Síndrome de Fatiga Crónica - 2004 Reproducción permitida citando la procedencia y la autora.

2. Research Advances in Chronic Fatigue Syndrome 2004 Nancy Klimas, MD University of Miami CFS Research Center

3. Definition - CFS >6 mo. debilitating fatigue, unexplained by preexisting illness or psychiatric co morbidity, and at least 4 of eight symptom criteria: >6 mo. debilitating fatigue, unexplained by preexisting illness or psychiatric co morbidity, and at least 4 of eight symptom criteria: post exertional relapse post exertional relapse concentration and cognitive complaints concentration and cognitive complaints myalgia myalgia arthralgia arthralgia sore throat sore throat painful lymph nodes painful lymph nodes new headaches new headaches unrefreshing sleep unrefreshing sleep

4. Limitations of the Case Definition 1. Fails to define subsets for targeted interventions 2. Research case definitions fail to encompass broader group

5. CFS/ME Clinical Case Definition 1. Substantial reduction in activity level due to new onset, persistent fatigue 1. Substantial reduction in activity level due to new onset, persistent fatigue 2. Post exertional malaise 2. Post exertional malaise 3. Sleep dysfunction 3. Sleep dysfunction 4. Pain – myalgia, headaches 4. Pain – myalgia, headaches 5. Neurologic/Cognitive Manifestations 5. Neurologic/Cognitive Manifestations 6. At least one symptom from 2 of the following: 6. At least one symptom from 2 of the following: - Autonomic manifestations eg. OI, IBS - Autonomic manifestations eg. OI, IBS - Neuroendocrine manifestations eg. Temp intolerance, weight change - Neuroendocrine manifestations eg. Temp intolerance, weight change - Immune manifestations eg. Tender lymph nodes, sore throat, flu-like symptoms - Immune manifestations eg. Tender lymph nodes, sore throat, flu-like symptoms

6. Based on the 1990 ACR classification guidelines: Historical feature = widespread (axial) pain Historical feature = widespread (axial) pain of 3 months or more Physical finding = pain in at least 3 of the 4 body segments + a finding of at least 11 tender points on digital palpation of 18 designated tender points Physical finding = pain in at least 3 of the 4 body segments + a finding of at least 11 tender points on digital palpation of 18 designated tender points (Merskey et al, 1994; Portenoy et al, 1996; Wall et al, 1994; Wolk M, 2002)Fibromyalgia

7. Chronic or relapsing fatigue  6 months but not lifelong (Determined during initial patient interview) Significantly affects lifestyle or ability to work YES Non-syndromic chronic fatigue:Treat conservatively and follow periodically NO  6 months: Provide supportive treatment of symptoms and re- evaluate later Lifelong: Look for other causes, including depression YES

8. 1. History & Physical (including neurological & psychiatric tests) 2. Exclusionary lab tests Meets  4 of the 8 Symptom Criteria a) impaired memory or concentration e) multi-joint pain b) sore throat f) new headaches c) tender cervical or axillary g) unrefreshing sleep lymph nodes h) post-exertional malaise d) muscle pain YES NO NCF NO CFS is excluded if another plausible cause for symptoms is found. Treat confounding condition, re-evaluate as appropriate.

9. Diagnosis: Chronic Fatigue Syndrome

10. CFS “Caseness” Subpopulations Subpopulations HPA CFS Autonomic Immune

11. CFS “Caseness” Subpopulations Subpopulations HPA CFS Autonomic Immune

12. Conditions that can explain chronic fatigue Cancer Cancer Narcolepsy Narcolepsy Sleep apnea Sleep apnea Severe obesity Severe obesity Hypothyroidism Hypothyroidism Alcohol or substance abuse Alcohol or substance abuse Chronic, active hepatitis B or C Chronic, active hepatitis B or C HIV HIV

13. Conditions That Can Explain Chronic Fatigue Hypogammaglobulinemia Hypogammaglobulinemia Tuberculosis Tuberculosis Lyme disease Lyme disease Multiple sclerosis Multiple sclerosis Lupus Lupus Rheumatoid arthritis Rheumatoid arthritis Iatrogenic, e.g., medication side effects Iatrogenic, e.g., medication side effects Pain syndrome Pain syndrome

14. Conditions That Can Explain Chronic Fatigue Dementia Dementia Schizophrenia Schizophrenia Bipolar disorder Bipolar disorder Bulimia nervosa Bulimia nervosa Anorexia nervosa Anorexia nervosa Major Depressive Disorder Major Depressive Disorder

15. Initial Laboratory Work-up Urinalysis Urinalysis Complete blood count with differential Complete blood count with differential Chemistry panel Chemistry panel Thyroid function test Thyroid function test (TSH & free T4) (TSH & free T4) Alanine aminotransferase Alanine aminotransferase Hepatitis B,C (HIV?) Hepatitis B,C (HIV?)

16. Initial Laboratory Work-up Initial Laboratory Work-up Albumin Albumin Globulin Globulin Alkaline phosphatase Alkaline phosphatase Calcium Calcium Phosphorus Phosphorus Glucose Glucose Other studies as indicated by health assessment Other studies as indicated by health assessment

17. CFS Epidemiology: CDC Studies National health survey estimated 1 in 9 individuals report chronic fatigue(>6mo), and 2 in 100 would meet a phone survey based case definition 1 National health survey estimated 1 in 9 individuals report chronic fatigue(>6mo), and 2 in 100 would meet a phone survey based case definition 1 Wichita random digit dialing of 1/3 the population of this city resulted in a confirmed case prevalence of 235/100,000; 373/100,000 women 2 Wichita random digit dialing of 1/3 the population of this city resulted in a confirmed case prevalence of 235/100,000; 373/100,000 women 2 85% UNDIAGNOSED 85% UNDIAGNOSED 1 Bierl et al Population Health Met 2004 2(1):1 1 Bierl et al Population Health Met 2004 2(1):1 2 Reyes et al Arch Int Med 2003 163:1530-36

18. Epidemiology: DePaul University Latinos: 726 per 100,000 Latinos: 726 per 100,000 African Americans: 337 per 100,000 African Americans: 337 per 100,000 Caucasians: 224 per 100,000 Caucasians: 224 per 100,000 Women: 522 per 100,000 Women: 522 per 100,000 Men: 291 per 100,000 Men: 291 per 100,000 Jason et al Psychosom Med. 2000 Sep-Oct;62(5):655-63

19. Model of CFS Pathogenesis Genetic Predisposition Triggering event / infection Mediators (Immune, endocrine, neuroendocrine, psychosocial) Health Outcome/Persistence

20. Genetic Predisposition - CFS HLA DR haplotypes in 112 South Florida CFS patients, compared to 5,000 regional and national controls 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) 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) Seattle CFS Cooperative Research Center Twin study - genetic predisposition, hereditability estimate of 51% (2nd World Conf)

21. 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) 60 to 80% of CFS subjects date the onset of their illness to an acute viral-like illness (Komaroff, Buchwald) 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 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 Evengard and colleagues reported at the 4th AACFS meeting - 67% of CFS group and controls had a negative life event in the months preceding illness Evengard and colleagues reported at the 4th AACFS meeting - 67% of CFS group and controls had a negative life event in the months preceding illness

22. Model of CFS Pathogenesis Genetic Predisposition Triggering event / infection Mediators (Immune, endocrine, neuroendocrine, psychosocial) Health Outcome/Persistence

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24. Neuro/Endocrine/Immune Balance. CFS Immune neurologic endocrine

25. Immune abnormalities in CFS Immune Activation DR, CD26 expression DR, CD26 expression TH2 cytokine shift TH2 cytokine shift Proinflammatory cytokines expression TNF-a, IL-1, IL6 Proinflammatory cytokines expression TNF-a, IL-1, IL6 Functional defects NK Cell dysfunction CD8 abnormalities perphorins, granzymes perphorins, granzymes Macrophage abnormalities Antibody production

26. Immunology What’s New? Exercise induced complement activation 1 Exercise induced complement activation 1 NK phenotypes predict risk 2 NK phenotypes predict risk 2 Gene expression patterns break population into two groups, one with increases in gene expression involved in immune activation, another with lower levels of gene expression in areas reflecting metabolism 3 Gene expression patterns break population into two groups, one with increases in gene expression involved in immune activation, another with lower levels of gene expression in areas reflecting metabolism 3 1 Sorensen, Jones et al J Allergy Clin Immun 2003 112(2):397-403 2 Stewart et al Cytometry 2003 53(1)2633 3 Vernon, Suzanne, presentation CFS Regional Conference, Oct 2003

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28. Role of the Immune System in Illness Persistence Direct Indirect Contribution to symptom complex Contribution to symptom complex Immune competence, role in preventing re- activation of infections Immune competence, role in preventing re- activation of infections Long term outcomes from Th2 shift Long term outcomes from Th2 shift Interaction with HPA axis Interaction with HPA axis Impact on sleep Impact on sleep Neurotransmitter interactions Neurotransmitter interactions

31. Other CFS Symptoms Low NKCC participants reported more cognitive difficulties (Multidimensional Fatigue Symptoms Inventory–Mental); p=.001 0 2 4 6 8 10 12 14 16 MFSI-Mental Low NKCC Normal NKCC

32. The Immune System Influences the Brain Cytokines Type 1 Type 2 Pro-inflammatory Neurotransmitters within the brain, and in the periphery Neuroendocrine hormones, promote antiinflammatory response

33. 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? Still a maybe

34. CNS Viral encephalitis? Viral encephalitis? Neuroendocrine Dysfunction Neuroendocrine Dysfunction Autonomic Nervous System Autonomic Nervous System Sleep Physiology Sleep Physiology Blood Flow Blood Flow Neurotransmitter Imbalance Neurotransmitter Imbalance

35. 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

36. HPA Axis dysregulation Demitrack low basal cortisols in CFS subjects, hypothalamic dysfunction- Demitrack low basal cortisols in CFS subjects, hypothalamic dysfunction- Dinan and colleagues - evidence of deficiency of hypothalamus, pituitary, and adrenal hypofunction. 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. 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. Bennett et al studied 500 FM patients with basal IGF-I levels which were significantly lower than controls.

37. Renin Aldosterone Axis High Prevalence of Renin-Aldosterone Axis Abnormalities in Patients with Chronic Fatigue Syndrome (CFS) 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 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) 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. 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

38. Autonomic Dysfunction Neurally mediated hypotension (Rowe) Neurally mediated hypotension (Rowe) Orthostatic hypotension (Streeten) Orthostatic hypotension (Streeten) Parasympathetic dysfunction(Sisto) Parasympathetic dysfunction(Sisto) Sympathetic over activation (Pagini, De Becker) Sympathetic over activation (Pagini, De Becker) Study in adolescents mirrored that of adults Study in adolescents mirrored that of adults

39. Balancing Act sympathetic parasympathetic

40. Autonomic Nervous System Haemodynamic Instability Score taken during tilt table testing predicts CFS with 90% sensitivity. 1 Haemodynamic Instability Score taken during tilt table testing predicts CFS with 90% sensitivity. 1 Heart Rate variability as a predictor of CFS 2 Heart Rate variability as a predictor of CFS 2 Blood flow volume of the middle cerebral artery during tilt showed no difference between cases and controls 3 (Prior studies supine have shown reduced regional blood flow in response to task) Blood flow volume of the middle cerebral artery during tilt showed no difference between cases and controls 3 (Prior studies supine have shown reduced regional blood flow in response to task) 1 Naschitz QJ Med 2003 96(133-142) 1 Naschitz QJ Med 2003 96(133-142) 2 Yamamoto Exp Biol Med 2003 228(2):167-74 2 Yamamoto Exp Biol Med 2003 228(2):167-74 3 Razumovsky J Neuroimmun 2003 13(1)57-67 3 Razumovsky J Neuroimmun 2003 13(1)57-67

41. Autonomic Dysfunction Drops in BP followed by CFS relapse Drops in BP followed by CFS relapse Exhaustive treadmill testing results in cognitive function decline (LaManca et al) Exhaustive treadmill testing results in cognitive function decline (LaManca et al) Perfusion abnormalities of brain stem, cerebellum (Costa et al) Perfusion abnormalities of brain stem, cerebellum (Costa et al) Mid cerebral reduced perfusion (Schwartz et al) Mid cerebral reduced perfusion (Schwartz et al)

42. Sleep Physiology Circadian Sleep - Wake neuroendocrine and immune functions in CFS (Modolfsky) Circadian Sleep - Wake neuroendocrine and immune functions in CFS (Modolfsky) altered diurnal patterns in cortisol, prolactin altered diurnal patterns in cortisol, prolactin altered diurnal patterns of NK cell function altered diurnal patterns of NK cell function alpha wave intrusion on sleep EEG, reduced stage III and IV alpha wave intrusion on sleep EEG, reduced stage III and IV Higher %REM (Twin study, 22 discordent twins) 1 Higher %REM (Twin study, 22 discordent twins) 1 1 Watson et al Sleep 2003 26(3):32-8

43. Muscle Cardiac muscle – cardiac output related to severity,and predicted exercise induced relapse 1 Cardiac muscle – cardiac output related to severity,and predicted exercise induced relapse 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 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 abnormalities 3 Sarcoplasmic reticulum defect – conduction and calcium transport abnormalities 3 Oxidative stress study, measuring protein carbonyls suggested higher levels of protein oxidation than controls 4 Oxidative stress study, measuring protein carbonyls suggested higher levels of protein oxidation than controls 4 1 Peckerman et al AJ Med Sci 2003 326(2)55 2 Vaness Med Sci Sports Exerc 2003 35(6):908-13 3 Fulle et al Neuromuscul Disord 2003 13(6):479-84 4 Smirnova et al Mol Chem Biochem 2003 248(1-2):93-5

44. Model of CFS Pathogenesis Genetic Predisposition Triggering event / infection Mediators (Immune, endocrine, neuroendocrine, psychosocial) Health Outcome/Persistence

45. Management of CFS Develop Individualized Plan Supportive Supportive Symptomatic Symptomatic Pathogenesis Models Pathogenesis Models

46. Pathogenesis Directed Interventions Immune - Ampligen, future immunomodulators Immune - Ampligen, future immunomodulators HPA axis interventions - Growth hormone, cortisol HPA axis interventions - Growth hormone, cortisol NMH treatments (plasma expansion, sympathetic and parasympathetic stimulants/inhibitors); NMH treatments (plasma expansion, sympathetic and parasympathetic stimulants/inhibitors); Sleep - pharmacologic and nonpharmacologic Sleep - pharmacologic and nonpharmacologic

47. Immune modulatory approaches uAmpligen, a immune modulator and antiviral (Phase 3 recently completed) uAllergy immunotherapy to down regulate allergic drive u Future immunomodulators (trials underway): Isoprinosine, thalidomide, anti- TNFa monoclonal Ab uProof of concept: Autologous lymphocyte study

48. Implications for treatment - NMH “Pipes and a pump”, wired by the autonomic nervous system “Pipes and a pump”, wired by the autonomic nervous system Fill the space - fluid vs. cells Fill the space - fluid vs. cells compress the space - alpha 1 agonists compress the space - alpha 1 agonists regulate the pump - beta blockers regulate the pump - beta blockers

49. HPA axis interventions - Growth hormone – phase 1 (Antwerp study) Growth hormone – phase 1 (Antwerp study) Cortisol – conflicting phase 2 study results (London, NIH) Cortisol – conflicting phase 2 study results (London, NIH) Restoration of sleep cycle (circadian rhythm) Restoration of sleep cycle (circadian rhythm)

50. Autonomic Interventions Fill the intravascular space Water and salt Water and salt Fludrocortisone - retains sodium, at the expense of potassium - need to monitor potassium levels Fludrocortisone - retains sodium, at the expense of potassium - need to monitor potassium levels Precaution - supine hypertension Precaution - supine hypertension Cells - rule out anemia, consider blood volume studies Cells - rule out anemia, consider blood volume studies

51. Autonomic Interventions Compress the veins: Alpha 1 agonists Compress the veins: Alpha 1 agonists - Midodrine (Proamitine) 2.5 to 10 mg - Midodrine (Proamitine) 2.5 to 10 mg (q4h, upright) (q4h, upright) –Less specific agents: pseudophedrine, ephedrine, caffeine, other stimulants (may worsen POTS) Precaution - supine hypertension - Compression hose - Compression hose Increase fill time: Highly selective beta blockers Increase fill time: Highly selective beta blockers

52. Sleep Re-establish circadian rhythm Re-establish circadian rhythm Conditioned response to bed - avoid bed for resting, reading, use bed for sleeping. Establish “bedtime”. Conditioned response to bed - avoid bed for resting, reading, use bed for sleeping. Establish “bedtime”. Avoid short acting hypnotics Avoid short acting hypnotics tricyclics, doxepan are longer acting, and don’t trap in alpha wave tricyclics, doxepan are longer acting, and don’t trap in alpha wave mirtazapine (Remeron) – stage 4 inducer mirtazapine (Remeron) – stage 4 inducer

53. 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

55. What do we need to know? What is the nature and cause of the fatigue? What is the nature and cause of the fatigue? What is the incidence (new cases each year) of this illness? What is the incidence (new cases each year) of this illness? Sequence of events at onset – what puts a person at risk? Sequence of events at onset – what puts a person at risk? What are the mediators that take this from “self limited” to “chronic” illness? What are the mediators that take this from “self limited” to “chronic” illness? What is its natural history? Are CFS patients at a higher risk for other illnesses? What is its natural history? Are CFS patients at a higher risk for other illnesses?

56. What do we need to know? Relevant subgroups – “lumping” has slowed us down Relevant subgroups – “lumping” has slowed us down Once the illness is established, can its course be changed by “adjusting” the immune, neuroendocrine or autonomic nervous system? Once the illness is established, can its course be changed by “adjusting” the immune, neuroendocrine or autonomic nervous system?

57. What do we need to know? Is there a subgroup with a chronic infection driving the entire illness? Is there a subgroup with a chronic infection driving the entire illness? Is there a subgroup with an autoimmune process driving the entire illness? Is there a subgroup with an autoimmune process driving the entire illness? Is there a subgroup with primarily a CNS driven illness? Is there a subgroup with primarily a CNS driven illness? Are there available biologic markers that define these subgroups? Are there available biologic markers that define these subgroups?

58. What do we need to know? More effective treatments based on the underlying pathophysiology of the illness. More effective treatments based on the underlying pathophysiology of the illness. Could there be an effective method to prevent this illness? Could there be an effective method to prevent this illness?

59. How do we get there from here? Research Longitudinal studies, comparing subgroups to established illnesses and controls Longitudinal studies, comparing subgroups to established illnesses and controls Clinical intervention studies, to teach us about effective therapies and underlying processes. Single interventions that are proven to be partially effective, then need to be studied in combination. Clinical intervention studies, to teach us about effective therapies and underlying processes. Single interventions that are proven to be partially effective, then need to be studied in combination. Rehab studies, to make standard long term rehabilitative approaches. Rehab studies, to make standard long term rehabilitative approaches.

60. How do we get there from here? Research International collaborative studies, building bridges International collaborative studies, building bridges Developing networks of clinicians to work together with the pharmaceutical industry to recruit and implement intervention protocols Developing networks of clinicians to work together with the pharmaceutical industry to recruit and implement intervention protocols NIH sponsored research protocols NIH sponsored research protocols CDC studies CDC studies

61. Conclusion There has been significant progress in our understanding of CFS. 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. 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. More effective therapies, based on this new understanding are available, with others under study.

62. All CFS patients can experience a better quality of life with compassionate care and a multidisciplinary approach.

63. Thank You! Professional links: AACFS on line: www.aacfs.org www.aacfs.org CDC on line: www.cdc.gov www.cdc.gov NIH on line: www.nih.gov www.nih.gov Advocacy organizations: CFIDS Association of America On-line: www.cfids.org Information: info@cfids.org www.cfids.orginfo@cfids.orgwww.cfids.orginfo@cfids.org American Fibromyalgia Syndrome Assn. Online: www.afsafund.org National Gulf War Resource Center online: www.ngwrc.org www.ngwrc.org