Curso Internacional de Curso Internacional de Especialización en Fibromialgia y Especialización en Fibromialgia y Síndrome de Fatiga Crónica - 2004Síndrome de Fatiga Crónica - 2004

Reproducción permitida citando la procedencia y la autora.

Research Advances in Research Advances in Chronic Fatigue Chronic Fatigue

SyndromeSyndrome20042004

Nancy Klimas, MDNancy Klimas, MD

University of Miami CFS Research University of Miami CFS Research CenterCenter

Definition - CFSDefinition - CFS

• >6 mo. debilitating fatigue, unexplained by >6 mo. debilitating fatigue, unexplained by preexisting illness or psychiatric co morbidity, preexisting illness or psychiatric co morbidity, and at least 4 of eight symptom criteria:and at least 4 of eight symptom criteria:

• post exertional relapsepost exertional relapse• concentration and cognitive complaintsconcentration and cognitive complaints• myalgiamyalgia• arthralgiaarthralgia• sore throatsore throat• painful lymph nodespainful lymph nodes• new headachesnew headaches• unrefreshing sleepunrefreshing sleep

Limitations of the Case Limitations of the Case DefinitionDefinition

1.1. Fails to define subsets for targeted Fails to define subsets for targeted interventionsinterventions

2.2. Research case definitions fail to Research case definitions fail to encompass broader groupencompass broader group

CFS/ME Clinical Case DefinitionCFS/ME Clinical Case Definition

• 1. Substantial reduction in activity level due to new onset, 1. Substantial reduction in activity level due to new onset, persistent fatiguepersistent fatigue

• 2. Post exertional malaise2. Post exertional malaise• 3. Sleep dysfunction3. Sleep dysfunction• 4. Pain – myalgia, headaches 4. Pain – myalgia, headaches • 5. Neurologic/Cognitive Manifestations5. 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, - Neuroendocrine manifestations eg. Temp intolerance,

weight changeweight change• - Immune manifestations eg. Tender lymph nodes, sore - Immune manifestations eg. Tender lymph nodes, sore

throat, flu-like symptomsthroat, flu-like symptoms

Based on the 1990 ACRBased on the 1990 ACRclassification guidelines:classification guidelines:• Historical featureHistorical feature = widespread = widespread

(axial) pain (axial) pain of 3 months or moreof 3 months or more

• Physical findingPhysical finding = pain in at least 3 = pain in at least 3 of the 4 body segments + a finding of the 4 body segments + a finding of at least 11 tender points on of at least 11 tender points on digital palpation of 18 designated digital palpation of 18 designated tender pointstender points(Merskey et al, 1994; Portenoy et al, 1996; Wall et al, 1994; Wolk M, 2002)

Fibromyalgia Fibromyalgia

Chronic or relapsing fatigue 6 months but not lifelong

(Determined during initial patient interview)

Significantly affects lifestyleor ability to work

YES

Non-syndromic chronic fatigue:Treat conservatively and follow periodically

NO

NO

6 months: Provide supportive treatment of symptoms and re-evaluate later

Lifelong: Look for other causes, including depression

YES

YES

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 painb) sore throat f) new headachesc) tender cervical or axillary g) unrefreshing sleep lymph nodes h) post-exertional malaised) muscle pain

YES

YES NO NCF

NOCFS is excluded if another plausible cause for symptoms is found. Treat confounding condition, re-evaluate as appropriate.

Diagnosis:Diagnosis:

Chronic Fatigue Chronic Fatigue SyndromeSyndrome

CFS “Caseness”CFS “Caseness”

• SubpopulationsSubpopulations

HPA

CFS

AutonomicImmune

CFS “Caseness”CFS “Caseness”

• SubpopulationsSubpopulations

HPA

CFS

AutonomicImmune

Conditions that can Conditions that can explain chronic explain chronic fatiguefatigue• CancerCancer• NarcolepsyNarcolepsy• Sleep apneaSleep apnea• Severe obesitySevere obesity• HypothyroidismHypothyroidism• Alcohol or substance abuseAlcohol or substance abuse• Chronic, active hepatitis B or CChronic, active hepatitis B or C• HIVHIV

Conditions That Can Conditions That Can Explain Chronic Explain Chronic Fatigue Fatigue

• HypogammaglobulinemiaHypogammaglobulinemia• TuberculosisTuberculosis• Lyme diseaseLyme disease• Multiple sclerosisMultiple sclerosis• Lupus Lupus • Rheumatoid arthritisRheumatoid arthritis• Iatrogenic, e.g., Iatrogenic, e.g.,

medication side effectsmedication side effects• Pain syndromePain syndrome

Conditions That Can Conditions That Can Explain Chronic Explain Chronic FatigueFatigue

• DementiaDementia• SchizophreniaSchizophrenia• Bipolar disorderBipolar disorder• Bulimia nervosaBulimia nervosa• Anorexia nervosaAnorexia nervosa• Major Depressive Major Depressive

DisorderDisorder

Initial Laboratory Work-upInitial Laboratory Work-up

• UrinalysisUrinalysis

• Complete blood count with differentialComplete blood count with differential

• Chemistry panelChemistry panel

• Thyroid function test Thyroid function test

• (TSH & free T4) (TSH & free T4)

• Alanine aminotransferaseAlanine aminotransferase

• Hepatitis B,C (HIV?)Hepatitis B,C (HIV?)

Initial Laboratory Work-Initial Laboratory Work-upup

• AlbuminAlbumin• GlobulinGlobulin• Alkaline phosphataseAlkaline phosphatase• CalciumCalcium• PhosphorusPhosphorus• GlucoseGlucose• Other studies as indicated Other studies as indicated

by health assessmentby health assessment

CFS Epidemiology: CDC CFS Epidemiology: CDC StudiesStudies• National health survey estimated 1 in 9 National health survey estimated 1 in 9

individuals report chronic fatigue(>6mo), and individuals report chronic fatigue(>6mo), and 2 in 100 would meet a phone survey based 2 in 100 would meet a phone survey based case definitioncase definition11

• Wichita random digit dialing of 1/3 the Wichita random digit dialing of 1/3 the population of this city resulted in a confirmed population of this city resulted in a confirmed case prevalence of 235/100,000; 373/100,000 case prevalence of 235/100,000; 373/100,000 womenwomen2 2

• 85% UNDIAGNOSED85% UNDIAGNOSED

• 11Bierl et al Population Health Met 2004 2(1):1Bierl et al Population Health Met 2004 2(1):12 2 Reyes et al Arch Int Med 2003 163:1530-36Reyes et al Arch Int Med 2003 163:1530-36

Epidemiology: DePaul Epidemiology: DePaul UniversityUniversity• LatinosLatinos: 726 per 100,000 : 726 per 100,000

• African AmericansAfrican Americans: 337 per 100,000: 337 per 100,000

• CaucasiansCaucasians: 224 per 100,000: 224 per 100,000

• Women:Women: 522 per 100,000 522 per 100,000 • Men:Men: 291 per 100,000 291 per 100,000

Jason et al Psychosom Med. 2000 Sep-Oct;62(5):655-63Jason et al Psychosom Med. 2000 Sep-Oct;62(5):655-63

Model of CFS PathogenesisModel of CFS Pathogenesis

Genetic PredispositionGenetic Predisposition

Triggering event / infectionTriggering event / infection

Mediators (Immune, Mediators (Immune, endocrine, neuroendocrine, endocrine, neuroendocrine,

psychosocial)psychosocial)

Health Outcome/PersistenceHealth Outcome/Persistence

Genetic Predisposition - CFSGenetic Predisposition - CFS

• HLA DR haplotypes in 112 South Florida HLA DR haplotypes in 112 South Florida CFS patients, compared to 5,000 regional CFS patients, compared to 5,000 regional and national controlsand national controls

• 4 to 6 fold increased relative risk for DR4, 4 to 6 fold increased relative risk for DR4, DR3 and DQ3. (Keller et al, 1992)DR3 and DQ3. (Keller et al, 1992)

• Seattle CFS Cooperative Research Center Seattle CFS Cooperative Research Center Twin study - genetic predisposition, Twin study - genetic predisposition, hereditability estimate of 51% (2nd World hereditability estimate of 51% (2nd World Conf)Conf)

Evidence for Triggering Evidence for Triggering event/ infection - CFS event/ infection - CFS • 60 to 80% of CFS subjects date the onset of 60 to 80% of CFS subjects date the onset of

their illness to an acute viral-like illness their illness to an acute viral-like illness (Komaroff, Buchwald)(Komaroff, Buchwald)

• Lloyd and colleagues in Australia performed a Lloyd and colleagues in Australia performed a prospective study during and after acute EBV, prospective study during and after acute EBV, Q fever or Ross River Virus -Anergy during Q fever or Ross River Virus -Anergy during acute infection predicted persistent CFS like acute infection predicted persistent CFS like symptomssymptoms

• Evengard and colleagues reported at the 4th Evengard and colleagues reported at the 4th AACFS meeting - 67% of CFS group AACFS meeting - 67% of CFS group and and controlscontrols had a negative life event in had a negative life event in the the months preceding illnessmonths preceding illness

Model of CFS PathogenesisModel of CFS Pathogenesis

Genetic PredispositionGenetic Predisposition

Triggering event / infectionTriggering event / infection

Mediators (Immune, Mediators (Immune, endocrine, neuroendocrine, endocrine, neuroendocrine,

psychosocial)psychosocial)

Health Outcome/PersistenceHealth Outcome/Persistence

Immune cascade

N atura l K iller

C ells (T h1)

C D 8 cellskill virus

H elper C D 4 cellT h1 cytokines

IL-2, IN F ac tivates C D 8

B ce llsm ake antibody

prevent and helpc lear in fec tion

H elper C D 4 cellT h2 cytokines

IL-6, IL-10ac tivates B ce lls

Macrophage presents antigen

..

Neuro/Endocrine/Immune Neuro/Endocrine/Immune BalanceBalance

Neuro/Endocrine/Immune Neuro/Endocrine/Immune BalanceBalance

..

CFS

Immune

neurologic

endocrine

Immune abnormalities in Immune abnormalities in CFSCFSImmune ActivationImmune Activation

• DR, CD26 DR, CD26 expressionexpression

• TH2 cytokine shiftTH2 cytokine shift

• Proinflammatory Proinflammatory cytokines cytokines expression TNF-a, expression TNF-a, IL-1, IL6IL-1, IL6

Functional defectsFunctional defects

NK Cell dysfunctionNK Cell dysfunction

CD8 abnormalitiesCD8 abnormalities

perphorins, granzymesperphorins, granzymes

Macrophage Macrophage abnormalitiesabnormalities

Antibody productionAntibody production

Immunology What’s New?Immunology What’s New?• Exercise induced complement activationExercise induced complement activation11

• NK phenotypes predict riskNK phenotypes predict risk 2 2

• Gene expression patterns break Gene expression patterns break population into two groups, one with population into two groups, one with increases in gene expression involved in increases in gene expression involved in immune activation, another with lower immune activation, another with lower levels of gene expression in areas levels of gene expression in areas reflecting metabolismreflecting metabolism33

1 Sorensen, Jones et al J Allergy Clin Immun 2003 112(2):397-4031 Sorensen, Jones et al J Allergy Clin Immun 2003 112(2):397-4032 Stewart et al Cytometry 2003 53(1)26332 Stewart et al Cytometry 2003 53(1)26333 Vernon, Suzanne, presentation CFS Regional Conference, Oct 20033 Vernon, Suzanne, presentation CFS Regional Conference, Oct 2003

Immune cascade

N atura l K iller

C ells (T h1)

C D 8 cellskill virus

H elper C D 4 cellT h1 cytokines

IL-2, IN F ac tivates C D 8

B ce llsm ake antibody

prevent and helpc lear in fec tion

H elper C D 4 cellT h2 cytokines

IL-6, IL-10ac tivates B ce lls

Macrophage presents antigen

..

Role of the Immune Role of the Immune System in Illness System in Illness PersistencePersistenceDirect Direct IndirectIndirect• Contribution to Contribution to

symptom complexsymptom complex• Immune Immune

competence, role in competence, role in preventing re-preventing re-activation of activation of infectionsinfections

• Long term outcomes Long term outcomes from Th2 shiftfrom Th2 shift

• Interaction with Interaction with HPA axisHPA axis

• Impact on sleepImpact on sleep

• Neurotransmitter Neurotransmitter interactionsinteractions

Activation and FluActivation and Flu--like Symptomslike Symptoms• CD2+26+% was positively associated with

reports of flu-like symptom (tender lymph nodes & sore throat) frequency (r=.347, p=.056) and severity (r=.463, p=.009)

• CD2+26+% was also associated with fatigue(FSI-Intensity; r=.383, p=.028) and daily disruption caused by fatigue (FSI-Disruption; r=.400, p=.021)

• These findings corroborate earlier work (Cruess et al., 2000) showing a relationship between CD2+26+ and lymph node symptoms

LYMPHOCYTE PROLIFERATION IN RESPONSE TO PHA: MEAN (+/- S.D.) NET CPM

IN CFS PATIENTS ABOVE OR BELOW THE MEAN ON COGNITIVE DIFFICULTIES SCALE

210000

180000

150000

120000

90000

60000

30000 LOW CDSHIGH CDS

P = .O3

Other CFS SymptomsOther 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

LowNKCCNormalNKCC

The Immune System The Immune System Influences Influences the Brain the Brain

The Immune System The Immune System Influences Influences the Brain the Brain

Cytokines

Type 1Type 2Pro-inflammatory

Neurotransmitterswithin the brain, andin the periphery

Neuroendocrinehormones, promoteantiinflammatoryresponse

Viral Viral Persistence/Reactivation Persistence/Reactivation

HHV6 virus is present in 22 to 54% of patients in HHV6 virus is present in 22 to 54% of patients in cross sectional studies (Ablashi, Krueger, cross sectional studies (Ablashi, Krueger, Knox), HHV6 virus is present in 79% of CFS Knox), HHV6 virus is present in 79% of CFS patients in longitudinal studies (HHV6 PCR patients in longitudinal studies (HHV6 PCR assay, Knox)assay, Knox)

HHV6 virus is present in the spinal fluid of 28 of HHV6 virus is present in the spinal fluid of 28 of 120 CFS patients (Peterson), and 7 of 35 CFS 120 CFS patients (Peterson), and 7 of 35 CFS samples (Knox).samples (Knox).

Enterovirus is present in 13% of CFS muscle Enterovirus is present in 13% of CFS muscle samples (Douche-Aourik, 2003)samples (Douche-Aourik, 2003)

EBV? Still a maybeEBV? Still a maybe

CNSCNS

• Viral encephalitis?Viral encephalitis?

• Neuroendocrine DysfunctionNeuroendocrine Dysfunction

• Autonomic Nervous SystemAutonomic Nervous System

• Sleep PhysiologySleep Physiology

• Blood FlowBlood Flow

• Neurotransmitter ImbalanceNeurotransmitter Imbalance

EndocrinologyEndocrinologyReduced Cortisol output via several mechanismsReduced Cortisol output via several mechanismsA) heightened negative feedbackA) heightened negative feedbackB) heightened receptor functionB) heightened receptor functionC) impaired ACTH and cortisol responses to challengeC) impaired ACTH and cortisol responses to challenge DHEA functional abnormality (early data)DHEA functional abnormality (early data)Abnormal seritonin functionAbnormal seritonin functionIL-6 increase associates with low cortisol CRH mediatedIL-6 increase associates with low cortisol CRH mediated

Many confounding factors (deconditioning, sleep, comorbid Many confounding factors (deconditioning, sleep, comorbid depression, stress, medication)depression, stress, medication)

Cleare AJ Endocr Rev 2003 24(2):236-52Cleare AJ Endocr Rev 2003 24(2):236-52Papanicolau Neuroimmunomodulation 2004 11(2)65-74Papanicolau Neuroimmunomodulation 2004 11(2)65-74

HPA Axis dysregulationHPA Axis dysregulation

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

• Dinan and colleagues - evidence of Dinan and colleagues - evidence of deficiency of hypothalamus, pituitary, deficiency of hypothalamus, pituitary, andand adrenal hypofunction.adrenal hypofunction.

• Small adrenal gland in depressed and non Small adrenal gland in depressed and non depressed CFS subjects, enlarged adrenal depressed CFS subjects, enlarged adrenal in depressed control group.in depressed control group.

• Bennett et al studied 500 FM patients with Bennett et al studied 500 FM patients with basal IGF-I levels which were significantly basal IGF-I levels which were significantly lower than controls.lower than controls.

Renin Aldosterone AxisRenin Aldosterone Axis

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

• 30 of the 33 patients had at least one value of supine or upright PRA or 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 supine or upright serum AL outside of the 95% Tolerance Interval (TI) for normal volunteers normal volunteers

• 16 patients had low serum AL and low or normal PRA, consistent with 16 patients had low serum AL and low or normal PRA, consistent with Hyporeninemic Hypoaldosteronism (HH) Hyporeninemic Hypoaldosteronism (HH)

• The underlying defect may be autonomic nervous system dysfunction The underlying defect may be autonomic nervous system dysfunction and/or a primary adrenal defect.and/or a primary adrenal defect.

Zuckerbraun, E, Kim, HS, Daigle, K, Lee, ML, Friedman, TC, Charles R. Drew UniversityZuckerbraun, E, Kim, HS, Daigle, K, Lee, ML, Friedman, TC, Charles R. Drew University

Autonomic DysfunctionAutonomic 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, Sympathetic over activation (Pagini, De Becker)De Becker)

• Study in adolescents mirrored that of Study in adolescents mirrored that of adultsadults

Balancing ActBalancing Act

sympathetic sympathetic parasympatheticparasympathetic

Autonomic Nervous SystemAutonomic Nervous System

• Haemodynamic Instability Score taken during tilt Haemodynamic Instability Score taken during tilt table testing predicts CFS with 90% sensitivity. table testing predicts CFS with 90% sensitivity. 11

• Heart Rate variability as a predictor of CFSHeart Rate variability as a predictor of CFS 2 2

• Blood flow volume of the middle cerebral artery Blood flow volume of the middle cerebral artery during tilt showed no difference between cases and during tilt showed no difference between cases and controlscontrols 3 3 (Prior studies supine have shown reduced (Prior studies supine have shown reduced regional blood flow in response to task)regional blood flow in response to task)

• 1 Naschitz QJ Med 2003 96(133-142)1 Naschitz QJ Med 2003 96(133-142)

• 2 Yamamoto2 Yamamoto Exp Biol Med 2003 228(2):167-74Exp Biol Med 2003 228(2):167-74

• 3 Razumovsky J Neuroimmun 2003 13(1)57-673 Razumovsky J Neuroimmun 2003 13(1)57-67

Autonomic DysfunctionAutonomic Dysfunction

• Drops in BP followed by CFS relapseDrops in BP followed by CFS relapse

• Exhaustive treadmill testing results in Exhaustive treadmill testing results in cognitive function decline (LaManca et cognitive function decline (LaManca et al)al)

• Perfusion abnormalities of brain stem, Perfusion abnormalities of brain stem, cerebellum (Costa et al)cerebellum (Costa et al)

• Mid cerebral reduced perfusion Mid cerebral reduced perfusion (Schwartz et al)(Schwartz et al)

Sleep PhysiologySleep Physiology

• Circadian Sleep - Wake neuroendocrine and Circadian Sleep - Wake neuroendocrine and immune functions in CFS (Modolfsky)immune functions in CFS (Modolfsky)

• altered diurnal patterns in cortisol, prolactinaltered diurnal patterns in cortisol, prolactin

• altered diurnal patterns of NK cell functionaltered diurnal patterns of NK cell function

• alpha wave intrusion on sleep EEG , reduced alpha wave intrusion on sleep EEG , reduced stage III and IVstage III and IV

• Higher %REM (Twin study, 22 discordent Higher %REM (Twin study, 22 discordent twins)twins)11

1 Watson1 Watson et al Sleep 2003 26(3):32-8et al Sleep 2003 26(3):32-8

MuscleMuscle• Cardiac muscle – cardiac output related to severity,and predicted Cardiac muscle – cardiac output related to severity,and predicted

exercise induced relapseexercise induced relapse11

Exercise testing in 189 CFS subjects resulted in clinically Exercise testing in 189 CFS subjects resulted in clinically significant subgroups 50% showing moderate to severe functional significant subgroups 50% showing moderate to severe functional impairment. Unexpected blunted HR and BP responses noted. impairment. Unexpected blunted HR and BP responses noted. 22

• Sarcoplasmic reticulum defect – conduction and calcium transport Sarcoplasmic reticulum defect – conduction and calcium transport abnormalitiesabnormalities33

• Oxidative stress study, measuring protein carbonyls suggested Oxidative stress study, measuring protein carbonyls suggested higher levels of protein oxidation than controls higher levels of protein oxidation than controls 44

1 Peckerman et al AJ Med Sci 2003 326(2)551 Peckerman et al AJ Med Sci 2003 326(2)55

22 Vaness Med Sci Sports Exerc 2003 35(6):908-13Vaness Med Sci Sports Exerc 2003 35(6):908-13

3 Fulle et al Neuromuscul3 Fulle et al Neuromuscul Disord 2003 13(6):479-84Disord 2003 13(6):479-84

4 Smirnova et al Mol Chem Biochem 2003 248(1-2):93-54 Smirnova et al Mol Chem Biochem 2003 248(1-2):93-5

Model of CFS PathogenesisModel of CFS Pathogenesis

Genetic PredispositionGenetic Predisposition

Triggering event / infectionTriggering event / infection

Mediators (Immune, Mediators (Immune, endocrine, neuroendocrine, endocrine, neuroendocrine,

psychosocial)psychosocial)

Health Outcome/PersistenceHealth Outcome/Persistence

Management of CFSManagement of CFS

Develop Individualized PlanDevelop Individualized Plan

• SupportiveSupportive• SymptomaticSymptomatic• Pathogenesis ModelsPathogenesis Models

Pathogenesis Directed Pathogenesis Directed InterventionsInterventions

• Immune - Ampligen, future Immune - Ampligen, future immunomodulators immunomodulators

• HPA axis interventions - Growth HPA axis interventions - Growth hormone, cortisol hormone, cortisol

• NMH treatments (plasma expansion, NMH treatments (plasma expansion, sympathetic and parasympathetic sympathetic and parasympathetic stimulants/inhibitors); stimulants/inhibitors);

• Sleep - pharmacologic and Sleep - pharmacologic and nonpharmacologicnonpharmacologic

Immune modulatory Immune modulatory approachesapproaches

Ampligen, a immune modulator and Ampligen, a immune modulator and antiviral (Phase 3 recently completed)antiviral (Phase 3 recently completed)

Allergy immunotherapy to down Allergy immunotherapy to down regulate allergic driveregulate allergic drive

Future immunomodulators (trials Future immunomodulators (trials underway): Isoprinosine, thalidomide, underway): Isoprinosine, thalidomide, anti- TNFa monoclonal Abanti- TNFa monoclonal Ab

Proof of concept: Autologous Proof of concept: Autologous lymphocyte studylymphocyte study

Implications for treatment - Implications for treatment - NMHNMH

• ““Pipes and a pump”, wired by the Pipes and a pump”, wired by the autonomic nervous systemautonomic nervous system

• Fill the space - fluid vs. cellsFill the space - fluid vs. cells

• compress the space - alpha 1 compress the space - alpha 1 agonistsagonists

• regulate the pump - beta blockersregulate the pump - beta blockers

HPA axis interventions -HPA axis interventions -

• Growth hormone – phase 1 (Antwerp Growth hormone – phase 1 (Antwerp study)study)

• Cortisol – conflicting phase 2 study Cortisol – conflicting phase 2 study results (London, NIH) results (London, NIH)

• Restoration of sleep cycle (circadian Restoration of sleep cycle (circadian rhythm)rhythm)

Autonomic InterventionsAutonomic Interventions

Fill the intravascular space Fill the intravascular space • Water and saltWater and salt• Fludrocortisone - retains sodium, at Fludrocortisone - retains sodium, at

the expense of potassium - need to the expense of potassium - need to monitor potassium levelsmonitor potassium levels

• Precaution - supine hypertensionPrecaution - supine hypertension• Cells - rule out anemia, consider Cells - rule out anemia, consider

blood volume studiesblood volume studies

Autonomic InterventionsAutonomic 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, Less specific agents: pseudophedrine, ephedrine, caffeine, other stimulants (may ephedrine, caffeine, other stimulants (may worsen POTS)worsen POTS)

Precaution - supine hypertensionPrecaution - supine hypertension - Compression hose- Compression hose• Increase fill time: Highly selective beta Increase fill time: Highly selective beta

blockersblockers

SleepSleep

• Re-establish circadian rhythmRe-establish circadian rhythm• Conditioned response to bed - avoid Conditioned response to bed - avoid

bed for resting, reading, use bed for bed for resting, reading, use bed for sleeping. Establish “bedtime”.sleeping. Establish “bedtime”.

• Avoid short acting hypnoticsAvoid short acting hypnotics• tricyclics, doxepan are longer acting, tricyclics, doxepan are longer acting,

and don’t trap in alpha waveand don’t trap in alpha wave• mirtazapine (Remeron) – stage 4 mirtazapine (Remeron) – stage 4

inducerinducer

University of Miami CFS University of Miami CFS Research and Clinical Research and Clinical Center– Center– Research ProtocolsResearch Protocols

SMART Energy Study (CBT)SMART Energy Study (CBT) Erythropoetin (Procrit) phase 2 Erythropoetin (Procrit) phase 2

protocolprotocol Pathogenesis of NK cell defect in CFSPathogenesis of NK cell defect in CFS Thalidomide Phase 1 protocolThalidomide Phase 1 protocol Isoprinosine Phase 2 protocol Isoprinosine Phase 2 protocol Natural history studyNatural history study

Proportion of IFN-gamma to IL-5 in PHA-stimulated cultures

300

200

100

0RA

TIO

OF

TY

PE

1 T

O T

YP

E 2

CY

TO

KIN

ES

* CLINICAL IMPROVEMENT

BASELINE

WEEK 1P = .03

for CFS patients in immunomodulation trial.

**

*

**

*

1 2 3 4 5 6 7 8 9 10 11

*

What do we need to know?What do we need to know?

• What is the nature and cause of the What is the nature and cause of the fatigue?fatigue?

• What is the incidence (new cases each What is the incidence (new cases each year) of this illness?year) of this illness?

• Sequence of events at onset – what puts a Sequence of events at onset – what puts a person at risk? person at risk?

• What are the mediators that take this from What are the mediators that take this from “self limited” to “chronic” illness?“self limited” to “chronic” illness?

• What is its natural history? Are CFS What is its natural history? Are CFS patients at a higher risk for other illnesses?patients at a higher risk for other illnesses?

What do we need to know?What do we need to know?

• Relevant subgroups – “lumping” has Relevant subgroups – “lumping” has slowed us downslowed us down

• Once the illness is established, can Once the illness is established, can its course be changed by “adjusting” its course be changed by “adjusting” the immune, neuroendocrine or the immune, neuroendocrine or autonomic nervous system?autonomic nervous system?

What do we need to know?What do we need to know?

• Is there a subgroup with a chronic Is there a subgroup with a chronic infection driving the entire illness?infection driving the entire illness?

• Is there a subgroup with an Is there a subgroup with an autoimmune process driving the entire autoimmune process driving the entire illness?illness?

• Is there a subgroup with primarily a Is there a subgroup with primarily a CNS driven illness?CNS driven illness?

• Are there available biologic markers Are there available biologic markers that define these subgroups?that define these subgroups?

What do we need to know?What do we need to know?

• More effective treatments based on More effective treatments based on the underlying pathophysiology of the underlying pathophysiology of the illness. the illness.

• Could there be an effective method Could there be an effective method to prevent this illness?to prevent this illness?

How do we get there from How do we get there from here? here? ResearchResearch• Longitudinal studies, comparing subgroups Longitudinal studies, comparing subgroups

to established illnesses and controlsto established illnesses and controls

• Clinical intervention studies, to teach us Clinical intervention studies, to teach us about effective therapies and underlying about effective therapies and underlying processes. Single interventions that are processes. Single interventions that are proven to be partially effective, then need proven to be partially effective, then need to be studied in combination.to be studied in combination.

• Rehab studies, to make standard long Rehab studies, to make standard long term rehabilitative approaches. term rehabilitative approaches.

How do we get there from How do we get there from here? here? ResearchResearch• International collaborative studies, International collaborative studies,

building bridges building bridges • Developing networks of clinicians to Developing networks of clinicians to

work together with the work together with the pharmaceutical industry to recruit pharmaceutical industry to recruit and implement intervention protocolsand implement intervention protocols

• NIH sponsored research protocolsNIH sponsored research protocols• CDC studiesCDC studies

ConclusionConclusion

• There has been significant progress There has been significant progress in our understanding of CFS .in our understanding of CFS .

• The neuroendocrine, immune, and The neuroendocrine, immune, and central nervous system are linked, central nervous system are linked, and can’t be considered separately. and can’t be considered separately.

• More effective therapies, based on More effective therapies, based on this new understanding are available, this new understanding are available, with others under study.with others under study.

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

Thank You!Thank You!

Professional links:Professional links:

AACFS on line: AACFS on line: www.aacfs.orgCDC on line: CDC on line: www.cdc.govNIH on line: NIH on line: www.nih.gov

Advocacy organizations:Advocacy organizations:

CFIDS Association of AmericaCFIDS Association of AmericaOn-line: On-line: www.cfids.org Information: Information: info@cfids.orgAmerican Fibromyalgia Syndrome Assn. American Fibromyalgia Syndrome Assn. Online: Online: www.afsafund.orgwww.afsafund.orgNational Gulf War Resource Center online: National Gulf War Resource Center online: www.ngwrc.org