Chronic Fatigue Syndrome Pathophysiology

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					 Chronic Fatigue Syndrome
     Pathophysiology
            Dr Anthony Cleare

          Reader in Affective Disorders
Head of Section of Neurobiology of Mood Disorders
              Institute of Psychiatry
The population

                        Population with
                        chronic fatigue



                 Overlapping
                   disorders
                 (e.g. atypical   CFS
                  depression,
                 fibromyalgia)
                     CFS

                                     PMS
       FM



            Anxiety and
            depression
                                     IBS



Cluster together – patients often have elements of several
  Predisposing factors (‘vulnerability’)

                                       Precipitating factors
                                       (‘triggers’)



 Acute or sub-acute fatigue

                                       Perpetuating factors



  Chronic fatigue or CFS
i.e Multifactorial – all need to be assessed
Predisposing factors in CFS/FM
  Female gender
  Past psychological illness
  Illness in close family members
  History of fatigue/other medically
        unexplained symptoms
  Genetic
  Childhood Trauma/Abuse
Childhood and Adult Abuse in Fibromyalgia
Walker et al, 1997
                   Fibromyalgia   Rheumatoid         P
                   (n=36)         Arthritis (n=33)



Childhood abuse
Physical assault   41.7%          16.7%              <0.05
Penetration        33.3%          13.3%              0.06

Adult assault
Penetration        66.7%          23.3%              <0.001
Physical assault   47.2%          16.7%              <0.01
Precipitating factors in CFS/FM

  Serious viral illness
  Life events
  Operative stress
  Depression/anxiety
  Medication
  Cancer treatment
      Severe Viral Infections
 Risk of Chronic Fatigue at 6 months

Viral Meningitis              25%
EBV Glandular Fever           16%
Viral Hepatitis               20%
Common viruses          1% (same as baseline risk)

Risk factors:
Past psychiatric illness (OR 5.5)
Prolonged convalescence (OR 5.4)
Pre-illness fatigue
Perpetuating factors: Psychosocial
Cognitive factors
e.g. loss of control; belief that exercise is harmful;
 symptom focussing
Behavioural factors
e.g. use of avoidance
Psychiatric illness
e.g. depression, anxiety
Social Factors
e.g. social support, response of doctors
Perpetuating factors: Biological

Reduced cortisol levels
Hypothalamic disturbance
Circadian rhythm and sleep disruption
Neurochemical – e.g. Increased central 5-HT
Autonomic changes
Physical effects of prolonged or intermittent
inactivity
Myths about biology and CFS
 Psychiatrists are not interested in finding biological causes
 of CFS
 Most of the work in leading journals has come from
 psychiatrists either directly or via collaborations
 If there are biological factors found, then psychological
 factors are no longer important and are “trumped”
 Optimal understanding and effective treatment for most
 biological illnesses needs a psychological approach too
 Trying to understand psychological factors means ignoring
 biological factors and minimises the illness
 No – although there is still a stigma about psychological
 factors.
Multifactorial approach to understanding
     HPA axis dysfunction in CFS
Chronic Fatigue Syndrome
=
Adrenal Fatigue Syndrome?
NEGATIVE
FEEDBACK




           METABOLIC
            EFFECTS
Basal HPA axis function in CFS

 Is there low cortisol output in CFS?
24 h Urinary Free Cortisol Output

              100

              80
 nmol/h/24h




              60
                                                                   UFC
              40

              20

               0
                    'Pure' CFS (n=89)    Controls (n=64)


                                   Cleare et al, Am J Psychiatry, 2001
Salivary Cortisol in CFS



                      Salivary cortisol

         16                               Controls

         14
                     ***                  CFS subjects

         12

         10                  ***
              ***
nmol/l




         8                          *
         6
                                           **
         4
         2

         0
              0600   0900   1200   1500   1800   2100
                            Clock time


                                                         Jerjes et al 2006
Overnight ACTH in CFS and healthy controls
– 15 minute blood sampling


               140


               120                                                       Controls
               100
                                                                         CFS
  ACTH pg/ml




                80


                60
                                                                                     CFS patients
                40                                                                   have lower
                20
                                                                                     morning surge
                                                                                     in ACTH
                    0
                           00


                                   00


                                           00


                                                   00


                                                           00
                    0




                                                                     0
                :0




                                                                 :0
                        0:


                                2:


                                        4:


                                                6:


                                                        8:
               22




                                                                10




                                           Tim e
                                                                         Di Giorgio et al, Psychosom Med 2004
            Summary of literature
•   Basal Studies
       UFC – 4/6 low cortisol
       Serial blood samples – 3/6 low cortisol
       Serial saliva samples – 2/5 low cortisol
•   Overall 9/17 studies found low cortisol
•   Different samples, different results?
•   Note that studies using single blood samples unreliable
    (and very inconsistent)

                                               Cleare 2003, Endo Rev
Dynamic Endocrine Testing

  Is there an abnormal HPA axis
   response to challenge/stress?
                                                           HPA axis in CFS
                                                      CRH Test - cortisol response
Cortisol change from baseline (nmol/l)




                                         350                                                CFS (n=37)

                                         300                                                Controls (n=30)

                                         250
                                         200
                                         150
                                         100
                                          50
                                          0
                                               -30   -15   0   15   30      45      60     75      90

                                                                         Cleare et al, J Clin Endocrinol Metab, 2001
              Salivary cortisol response to awakening
C o rtis o l c h a n g e fro m b as elin e



                                         5                                           CFS
                                                                                     Controls
                                         4
                                                                                                200
                                         3
                 (n m o l/l)




                                                                                                150
                                         2
                                                                                                100
                                         1
                                                                                                 50

                                         0
                                                                                                  0

                                  -1                                                                  AUC
                                             0   10   20      30        40      50      60
                                                           Time (min)
                                                                        Cleare et al, Br J Psychiatry, 2004
         Summary of Literature
•   Challenge Studies (ACTH and/or cortisol
    response)
      CRH – 3/3 blunted
      AVP – 1/1 blunted
      ACTH (synacthen) – 1/1 (high dose); 1/3 (low
      dose)
      IST – 1/4 blunted
      Naloxone – 1/1 blunted
      Exercise – 2/2 blunted
      Social stress – 1/1 blunted
      Overall - 11/16 blunted, none enhanced
                            Cleare AJ, Endocrine Reviews, 2003
Controlling for confounders
24 h Urinary Free Cortisol Output

              100

              80
 nmol/h/24h




              60

              40                                                 UFC

              20

               0
                    'Pure' CFS   CFS + Psych   Controls
                       n=89         n=32        n=64


                                 Cleare et al, Am J Psychiatry, 2001
24 h Urinary Free Cortisol Output
              100
               90
               80
               70
 nmol/h/24h




               60
               50
               40                                              UFC
               30
               20
               10
                0
                    'Pure' CFS   CFS +   Controls   Inactive
                                 Psych              Controls
                                                           HPA axis in CFS
                                                     CRH Test - effect of inactivity
Cortisol change from baseline (nmol/l)




                                                                                   CFS
                                         300
                                                                                   Controls
                                         250                                       Inactive Controls

                                         200

                                         150
                                         100
                                          50

                                          0
                                               -30   -15   0   15   30   45   60   75    90
Effects of Sleep Disturbance in CFS

  Strong HPA axis effects
  Leese et al (1996) studied the effect of 5
  days of night shift working v day shift
  working:
    lowered basal cortisol levels
    blunted ACTH response to CRH
    similar to the pattern seen in CFS
Clinical Significance

 Does low cortisol matter?
   Hydrocortisone therapy in CFS
           37 CFS Patients
              Drug-Free
       No Psychiatric Comorbidity

            35 randomised

        placebo       hydrocortisone
         n=16             n=16
                                       Hydrocortisone Dose
                                       5mg - 14 patients
     hydrocortisone      placebo       10mg - 18 patients
         n=16             n=16


32 completed both hydrocortisone and placebo phases
32 completed both hydrocortisone and placebo phases
                            Hydrocortisone therapy in CFS
                                    Effect on fatigue

                       0                         Placebo-active
% Change in fatigue




                       -5                        Active-placebo

                      -10
                      -15
                      -20
                      -25
                      -30
                      baseline        1 month           2 months

                                                Cleare et al, Lancet, 1999
                     Hydrocortisone therapy in CFS
                                    Disability
                     20
% improvement- WSA




                     15


                     10                                    Home
                                                           Social leisure
                                                           Relationships
                     5                                     Private leisure
                                                           Work

                     0


                     -5
                          Placebo          Active
                                                    Cleare et al, Lancet, 1999
                             Hydrocortisone therapy in CFS
                           CRH Test in responders to hydrocortisone

                                       Controls
                           300         CFS baseline
                                       CFS active
Cortisol change (nmol/l)




                           250         CFS placebo
                                                                                 450
                                                                                 400
                           200                                                   350
                                                                                 300
                           150                                                   250
                                                                                 200

                           100                                                   150
                                                                                 100
                                                                                  50
                            50
                                                                                   0

                            0                                                            AUC
                                 -30   0     15       30   45     60      90

                                                           Cleare et al 2001, J Clin Endocrinol Metab
Phase of illness and cortisol

 When do cortisol changes occur?

    Prospective cohort studies
Predisposing factors (‘risk factors’)

                                        Precipitating factors
                                        (‘triggers’)



Acute or sub-acute fatigue

                                        Perpetuating factors



Chronic fatigue or CFS
EBV Study
 71 subjects with clinically and
 immunologically defined EBV
 Followed up for 6 months
 Rate of fatigue 40% at 6 months (11%
 continuously for 6 months)
 Salivary cortisol profiles (0800, 1200, 1600,
 2000) at time of diagnosis, 3 months and 6
 months later
EBV Study – cross sectional results
    Cortisol output (AUC – nmol/l.h)

               Fatigue     Non-cases
               Cases
Baseline       95.4 (31.8) 90.1 (14.6)

3 months       99.4 (37.8) 84.5 (20.7)

6 months       94.5 (33.0) 93.9 (26.8)

• Non-significant differences
• Also no effect of change in AUC cortisol between baseline
        and 6 months and fatigue status at 6 months
Post Operative Fatigue Study
 Prospective model of a fatigue syndrome
 Assessments
   Pre-operatively
   Day 2-3
   1 month
   6 months post operatively
 4 groups of surgery – minor, gynaecological,
 major abdominal, cardiac
 184 participants
 Salivary cortisol profiles at 0800, 1200, 1600 and
 2000 h

                                     Rubin et al, 2003
                30




                25




                20
Fatigue score




                15




                10




                5




                0
                     -20    0        20       40     60      80     100   120     140    160    180    200       220

                                                              Time (days)

                     Minor surgery        Major abdominal surgery    Gynaecological surgery    Cardiac surgery
 Mean Differences (95% CI) in Cortisol Values (AUC: nmol/l.h) Between
                     Fatigue Cases and Non-Cases

Cortisol   Fatigue pre-   Fatigue day     Fatigue        Fatigue
value      op             2-3             1 month        6 months


Pre-op     4.2            7.6             -6.5           12.9
           (-5.8, 14.3)   (-6.9, 22.0)    (-18.2, 5.2)   (1.3, 24.5)*


Day 2-3    18.3           26.1            14.6           41.2
           (-4.3, 40.8)   (-3.6, 55.8)    (-9.8, 38.9)   (17.7, 64.6)**


1 month    -9.0           -0.2            9.7            5.9
           (-19.7, 1.6)   (-16.6, 16.1)   (-1.5, 20.9)   (-3.9, 15.7)


6 months   3.1            3.3             4.0            9.5
           (-5.7, 11.9)   (-10.0, 16.5)   (-5.8, 13.8)   (0.5, 18.5)*
               Phase of Illness
                   Conclusions

•   Acute/sub acute fatigue – No link to low
    cortisol
•   Early chronic fatigue (6 months) – No link
    to low cortisol
•   Late chronic fatigue – Low cortisol

Higher cortisol may also act as a risk factor – stress,
  depression, neurotoxicity, early experiences
 Multidimensional model of HPA
          axis in CFS
Illness phase
Sleep
Psychiatric Illness
                       HPA axis change
Past Abuse
                       (heterogeneous)
Medication
Psychosocial Stress
Physical Activity
Diet                      Contributes to
                       fatigue maintenance
Genetics
                      Cleare 2004, Trends Endocrinol Metab
  Cognitive Behavioural Therapy
             in CFS
If some HPA axis disturbance is related to inactivity,
sleep disturbance etc., then therapy targeting these
should reverse the HPA axis changes
CBT involves elements of:
  Balancing rest and activity
  Graded return to activity
  Sleep hygeine
  Cognitive restructuring (e.g. attitudes to symptoms, attitudes
  to exercise)
  Problem solving
Strong evidence of efficacy in CFS
Cognitive Behavioural Therapy
           in CFS
     Effects on Adrenal Function

Neuroendocrine testing at baseline and after
6 months of cognitive behavioural therapy
N = 107 subjects
UFC
Salivary cortisol profile
CRH test
                                       CBT in CFS
                                Salivary cortisol profile

                           Baseline
                    16
                    14     Follow-up
Cortisol (nmol/l)




                    12                                             90
                                                                   80
                    10                                             70
                     8                                             60
                                                                   50
                     6
                                                                   40
                     4                                             30

                     2                                             20
                                                                   10
                     0                                              0
                     800       1200                 1600   2000
                                                                          AUC
                                      Time of Day


                                                                  Significant at P<0.05
CBT in CFS
       CRH test

      AUC cortisol
350

300

250

200

150

100

 50

  0

 Baseline   Follow Up

  Significant at P<0.05
Response rate and pre-CBT
     endocrine status
43% responders (CGI much improved or
very much improved)
Low basal cortisol output (UFC) predicted
poor treatment response
  Responders 100 (70) nmol/day
  Non-responders 70 (44) nmol/day (P<0.05)
Cognitive Behavioural Therapy in
             CFS
              Conclusions
 CBT has biological effects, even in the
 presence of modest clinical effects in this
 sample
 CBT leads to normalisation of the HPA axis
 Most likely exerts HPA axis effects via
 normalisation of factors mediating HPA
 axis disturbance such as sleep,
 deconditioning, etc.
Conclusions re HPA axis
HPA axis is changed in direction of
  Low cortisol output
  Blunted response to challenge
Not a uniform change
  Related to several factors
  Occurs later in illness course
Does have symptomatic significance
  Maintaining factor
Reversible by CBT
Serotonergic Function
                             Prolactin responses after 30mg
                                     D-fenfluramine
                   290

                   270
PROLACTIN (iu/L)




                   250

                   230
                                                           CFS
                   210                                     CONTROLS
                                                           DEPRESSED
                   190

                   170

                   150

                   130
                         0     1   2        3      4   5
                                    TIME (hours)
        [11C]WAY-100635 in CFS
Areas of decreases in 5-HT1A
 binding in CFS v controls




 SPM Analysis
                    Hippocampal 5-HT1A Receptor Binding

                    10

                     8
Binding Potential




                     6                           Controls
                                                 CFS
                     4

                     2

                     0
                           Left      Right
In Summary
 Several emerging areas of interest that may be relevant in
 pathophysiology of CFS
 Understanding must be part of a multifactorial model
 including predisposing, precipitating and perpetuating
 factors: biological factors may operate at each of these
 levels
 Biological models of CFS are complementary to
 psychosocial models (as in all biopsychosocial medicine)
 Unlikely to be one biological process, and unclear where
 the boundary will lay between CFS and other fatigue states

				
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