lessons from research in chronic fatigue syndrome · nkcv. polarised discussions between •doctors...
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NKCV
Lessons from research in
Chronic Fatigue syndrome
Jos WM van der Meer
MD PhD FRCP(Lon) FRCP(Edin) FIDSA MAE
Emeritus Professor of Medicine
Radboud umc Nijmegen
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NKCV
• Secondary to other disease
- a most common complaint
- commonly ignored by the doctor
• Chronic fatigue syndrome (CFS)
Incapacitating chronic
fatigue
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NKCV
CFS
• Chronic incapacitating fatigue
• > 6 months
• Medically unexplained
• Associated symptoms myalgia/ arthralgia/ concentration
disturbances/ memory disturbances/
sleep disturbances/
See also CDC criteria (Fukuda et al)
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NKCV
Reasons for negative
medical view on CFS:
• information from outdated psychiatric textbooks
• Inability to diagnose and treat
• irritation about selfdiagnosis “ME”*
• strong physical attributions
*Myalgic encephalomyelitis
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NKCV
Polarised discussions
between • Doctors who deny the existence of CFS/ME
• Doctors who are convinced it is a psychiatric illness.
• Patients, lay people and doctors who adhere to unscientific and uncritical explanations for CFS.
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NKCV
Can we measure fatigue?
• Questionnaires
(CIS, SIP)
• Actometer
• Neuropsycholo-
gic assessment
• Exercise
assessment
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NKCV
CFS etiology & pathogenesis
Perpetu-ating factors
Complaints
Predisposing factors
Precipitating factors
Prognostic factors
Prins et al Lancet 2006
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NKCV
Predisposing factors
Somatic factors
genetic (no convicing candidate genes)
metabolic (no evidence)
Psychological factors
physical inactivity in childhood
trauma in childhood
physical hyperactivity in adulthood
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NKCV
Precipitating factors
Patients attribute CFS to:
• Infection (e.g., EBV mononucleosis)
• Intoxication
• Surgery
• Anaesthesia
• Delivery
• Traumatic events
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NKCV
Precipitating factors
• Infection
So far, no unifying cause has been found, hence:
– either: various causative organisms
– or: unknown micro-organism
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NKCV
Model perpetuating factors in CFS Vercoulen et al Psychosom Res 1998
Physical Activity Somatic attributies
Focus on complaints
Fatigue Sense of control
Somatic
factors?
Substrate? impairment
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NKCV
Somatic perpetuating factors
Causality? Association?
Largely irreproducible
Many investigations into the pathophysiology are flawed by the lack of adequate controls
Adequate controls:
• robust matching
• control for actual stress effects
• the same pre-analytical procedures
Neighbourhood controls (Nijmegen); Twins (Seattle)
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TGFbeta-1 in CFS
Roerink et al unpublished
cfs controls cohort 1 cohort 2
c1 c2
All patients & controls All patients controls
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NKCV
Substrate Central fatigue, hence in the CNS
• Functional studies
• Blood (not where the action is)
• CSF
• Neuro-imaging
• Animal experiments
• Interventions
Netea et al 2007
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brainfunction
Affective/Motivational
error-related response is disturbed
Cognitive error-related responses are not disturbed
De Lange et al Brain 2004
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NKCV
Brain structure
* *
Independent
confirmation in
2 other papers,
but:
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Recent large study
(Van der Schaaf et al Biol Prsychiatry 2015)
CFS controls CFS controls
2016 cohort 2006 cohort revisited
Gre
y m
atte
r vo
lum
e
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NKCV
Pain is related to decreased grey
matter
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NKCV
CFS, a perceptional
disorder
• Sleep
• Exercise tolerance
• Concentration
• Memory
• Movement registration
Buchwald et al, Vercoulen et al, Bazelmans et al
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NKCV
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NKCV
Natural course of CFS over 18 months
recovery 3%
improved 17%
unchanged 60%
worse 20%
Vercoulen et al 1996
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NKCV
INTERVENTIONS
• Fluoxetine (Prozac®) - no effect*
• Galantamine - no effect
• Food supplement - no effect
• Low dose steroids - effect?
• Cognitive behavioural therapy - effect
• Acclydine: no effect
• Ondansetron: no effect*
• Tryptophane depletion: no effect*
• Anakinra results pending
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NKCV
CBT for CFS effect on fatigue severity
35
40
45
50
55
0 mnth 8 mnth 14 mnth
cis
-fati
gu
e
CBT
support groups
natural course
CBT-SG p =.0001 CBT-SG p =.0015
CBT-NC p =.0001 CBT-NC p =.0016
Prins et al Lancet 2004
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NKCV
1. Fewer or no symptoms 73%
2. No physical impairment 64%
3. No social impairment 57%
4. No substantial impairment 58%
5. No serious fatigue 58%
6. No serious fatigue and not impaired 51%
7. Positive attitude to fatigue 45%
Recovery after CBT
Knoop, Bleijenberg, et al 2007
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NKCV
Institute of Medicine Consensus:
Systemic exertion intolerance disease
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NKCV
Prevalence of Postural Orthostatic
tachycardia syndrome (POTS)
Adult
CFS (n=331) 5.7%
non-CFS (n=318) 6.9%
Adolescent
CFS (n= 88) 18.2%
non CFS (NM=23) 17.4%
Roerink et al J Int Med 2016
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NKCV
Acknowledgement
Gijs Bleijenberg Joep Galama Hans Knoop Caroline Swanink Jan Vercoulen Ellen Bazelmans Judith Prins Maaike de Vries Petra Servaes Jan Fennis Syberen van der Werf Patricia Soetekouw Maurice Albers Frederique Brouwers Eufride Klein Rouweler Lammy Elving Lieke de Jong Jacques Lenders Ria te Winkel Berna de Vree Floris de Lange Megan Roerink Ivan Toni Marieke van der Schaaf Peter Hagoort