Chronic Fatigue Encephalomyelitis (CFS/ME) Guidelines Analyst
Group on Scientific Research into ME: Neuroendocrinology of CFS/ME
-
Upload
wade-finch -
Category
Documents
-
view
39 -
download
2
description
Transcript of Group on Scientific Research into ME: Neuroendocrinology of CFS/ME
![Page 1: Group on Scientific Research into ME: Neuroendocrinology of CFS/ME](https://reader036.fdocuments.in/reader036/viewer/2022062502/5681358b550346895d9cf0d2/html5/thumbnails/1.jpg)
Group on Scientific Research into ME:
Neuroendocrinology of CFS/ME
Dr Anthony CleareReader, Kings College London,
Institute of Psychiatry
![Page 2: Group on Scientific Research into ME: Neuroendocrinology of CFS/ME](https://reader036.fdocuments.in/reader036/viewer/2022062502/5681358b550346895d9cf0d2/html5/thumbnails/2.jpg)
Background
• Series of studies from our research group into the neuroendocrinology of CFS/ME, beginning in 1994
• Focussing on the role of cortisol, the end product of the hypothalamo-pituitary-adrenal axis
• Original theory came from the known effects of low cortisol in other illnesses, including fatigue
![Page 3: Group on Scientific Research into ME: Neuroendocrinology of CFS/ME](https://reader036.fdocuments.in/reader036/viewer/2022062502/5681358b550346895d9cf0d2/html5/thumbnails/3.jpg)
NEGATIVE FEEDBACK
METABOLIC EFFECTS
![Page 4: Group on Scientific Research into ME: Neuroendocrinology of CFS/ME](https://reader036.fdocuments.in/reader036/viewer/2022062502/5681358b550346895d9cf0d2/html5/thumbnails/4.jpg)
Questions addressed
• Is cortisol low? • Is there abnormal control of cortisol?• Is cortisol related to symptoms?• When does cortisol change in the natural
history of CFS? • What are the causes of altered cortisol?
![Page 5: Group on Scientific Research into ME: Neuroendocrinology of CFS/ME](https://reader036.fdocuments.in/reader036/viewer/2022062502/5681358b550346895d9cf0d2/html5/thumbnails/5.jpg)
1. Is there low cortisol output in CFS?
![Page 6: Group on Scientific Research into ME: Neuroendocrinology of CFS/ME](https://reader036.fdocuments.in/reader036/viewer/2022062502/5681358b550346895d9cf0d2/html5/thumbnails/6.jpg)
24 h Urinary Free Cortisol Output
0
20
40
60
80
100
nmol
/h/2
4h
'Pure' CFSn=89
CFS + Psychn=32
Controlsn=64
UFC
Cleare et al, Am J Psych, 2001
![Page 7: Group on Scientific Research into ME: Neuroendocrinology of CFS/ME](https://reader036.fdocuments.in/reader036/viewer/2022062502/5681358b550346895d9cf0d2/html5/thumbnails/7.jpg)
S a l iv a ry c o rtiso l
0
2
4
6
8
1 0
1 2
1 4
1 6
0 6 0 0 0 9 0 0 1 2 0 0 1 5 0 0 1 8 0 0 2 1 0 0
C lo c k tim e
nmol
/lC o n t ro ls
C F S s u b je c t s
* * *
* * *
* * **
* *
Salivary Cortisol in CFSSalivary Cortisol in CFS
Jerjes et al, 2005
![Page 8: Group on Scientific Research into ME: Neuroendocrinology of CFS/ME](https://reader036.fdocuments.in/reader036/viewer/2022062502/5681358b550346895d9cf0d2/html5/thumbnails/8.jpg)
Summary of literature
• Basal Studies Urine – 4/6 low cortisol Serial blood samples – 3/6 low cortisol Serial saliva samples – 2/5 low cortisol
• About 50% studies support low cortisol
Cleare, Endo Rev, 2003
![Page 9: Group on Scientific Research into ME: Neuroendocrinology of CFS/ME](https://reader036.fdocuments.in/reader036/viewer/2022062502/5681358b550346895d9cf0d2/html5/thumbnails/9.jpg)
2. Is there an abnormal control of cortisol release?
![Page 10: Group on Scientific Research into ME: Neuroendocrinology of CFS/ME](https://reader036.fdocuments.in/reader036/viewer/2022062502/5681358b550346895d9cf0d2/html5/thumbnails/10.jpg)
HPA axis in CFSHPA axis in CFS
050
100150200250300350
-30 -15 0 15 30 45 60 75 90Cor
tisol
cha
nge
from
bas
elin
e (n
mol
/l)
CFS (n=37)
Controls (n=30)
Cleare et al, J Clin Endocrinol Metab, 2001
CRH Test - cortisol responseCRH Test - cortisol response
-1
0
1
2
3
4
5
0 10 20 30 40 50 60Cor
tisol
cha
nge
from
bas
elin
e (n
mol
/l)
CFS (n=56)
Controls (n=35)
Roberts et al, Br J Psychiatry, 2004
Salivary cortisol response to Salivary cortisol response to awakeningawakening
![Page 11: Group on Scientific Research into ME: Neuroendocrinology of CFS/ME](https://reader036.fdocuments.in/reader036/viewer/2022062502/5681358b550346895d9cf0d2/html5/thumbnails/11.jpg)
Summary of Literature
• Challenge Studies (ACTH and/or cortisol response to a variety of challenges) Overall - 11/16 blunted, none enhanced
Cleare, Endo Rev, 2003
![Page 12: Group on Scientific Research into ME: Neuroendocrinology of CFS/ME](https://reader036.fdocuments.in/reader036/viewer/2022062502/5681358b550346895d9cf0d2/html5/thumbnails/12.jpg)
3. Is low cortisol is related to the symptom of fatigue in
CFS?
Randomised, double blind, placebo-controlled trial of a low dose cortisol replacement strategy (hydrocortisone 5-10mg) to raise levels of cortisol
![Page 13: Group on Scientific Research into ME: Neuroendocrinology of CFS/ME](https://reader036.fdocuments.in/reader036/viewer/2022062502/5681358b550346895d9cf0d2/html5/thumbnails/13.jpg)
Hydrocortisone therapy in Hydrocortisone therapy in CFSCFS
Effect on fatigueEffect on fatigue
-30
-25
-20
-15
-10
-5
0
baseline 1 month 2 months
% C
hang
e in
fatig
ue Placebo-active
Active-placebo
Cleare et al, Lancet, 1999
![Page 14: Group on Scientific Research into ME: Neuroendocrinology of CFS/ME](https://reader036.fdocuments.in/reader036/viewer/2022062502/5681358b550346895d9cf0d2/html5/thumbnails/14.jpg)
4. When do patients develop low cortisol levels in the evolution of the illness?
![Page 15: Group on Scientific Research into ME: Neuroendocrinology of CFS/ME](https://reader036.fdocuments.in/reader036/viewer/2022062502/5681358b550346895d9cf0d2/html5/thumbnails/15.jpg)
Prospective Cohort Studies Prospective model of a fatigue syndrome
using high risk cohorts – post-viral (EBV infection) and postoperative
naturalistic salivary cortisol profiles. Cohort followed up after EBV infection
No relation of low cortisol to fatigue (acute, 3 and 6 months)
Cohort assessed pre and post major surgery No relation of low cortisol to fatigue (acutely, 3
weeks and 6 months) Low cortisol not a risk factor pre-operatively
Candy et al, Psychol Med, 2003; Rubin et al, Psychosom Med, 2004
![Page 16: Group on Scientific Research into ME: Neuroendocrinology of CFS/ME](https://reader036.fdocuments.in/reader036/viewer/2022062502/5681358b550346895d9cf0d2/html5/thumbnails/16.jpg)
Phase of IllnessConclusions
• Acute/sub acute fatigue – No link to cortisol• Early chronic fatigue (6 months) – No link to
cortisol• Late chronic fatigue – Low cortisol
Cortisol does not appear to be a primary cause of fatigue in these cohorts
But – studies are of CF, and too small to exclude a different pattern in tightly defined CFS
![Page 17: Group on Scientific Research into ME: Neuroendocrinology of CFS/ME](https://reader036.fdocuments.in/reader036/viewer/2022062502/5681358b550346895d9cf0d2/html5/thumbnails/17.jpg)
5. What causes changes in cortisol levels and regulation?
• Are they a primary feature of the illness or secondary to some of the consequences of being ill with CFS?
• If some HPA axis disturbance is secondary to effects of the illness – e.g. physical inactivity, sleep disturbance, stress levels etc. – then therapy targeting these (e.g. CBT) should reverse the HPA axis changes
![Page 18: Group on Scientific Research into ME: Neuroendocrinology of CFS/ME](https://reader036.fdocuments.in/reader036/viewer/2022062502/5681358b550346895d9cf0d2/html5/thumbnails/18.jpg)
CBT in CFS:CBT in CFS:Endocrine EffectsEndocrine Effects
0102030405060708090
Baseline Follow Up
All significant at P<0.05
Daily cortisol output,Daily cortisol output,(saliva) unchallenged(saliva) unchallenged
0
50
100
150
200
250
300
350
Baseline Follow Up
Response to CRH challenge: Cortisol
(a) (b)
![Page 19: Group on Scientific Research into ME: Neuroendocrinology of CFS/ME](https://reader036.fdocuments.in/reader036/viewer/2022062502/5681358b550346895d9cf0d2/html5/thumbnails/19.jpg)
Lower cortisol pre-treatment predicted a worse response to CBT
Responders 100 (70) nmol/day Non-responders 70 (44) nmol/day (P<0.05)(urinary free cortisol)
![Page 20: Group on Scientific Research into ME: Neuroendocrinology of CFS/ME](https://reader036.fdocuments.in/reader036/viewer/2022062502/5681358b550346895d9cf0d2/html5/thumbnails/20.jpg)
Cognitive Behavioural Therapy in Cognitive Behavioural Therapy in CFSCFS
ConclusionsConclusions
CBT has biological effects - normalisation of the HPA axis
Most likely exerts HPA axis effects via normalisation of factors mediating HPA axis disturbance such as sleep, deconditioning, inactivity, stress, etc.
![Page 21: Group on Scientific Research into ME: Neuroendocrinology of CFS/ME](https://reader036.fdocuments.in/reader036/viewer/2022062502/5681358b550346895d9cf0d2/html5/thumbnails/21.jpg)
Proposed multidimensional model of HPA axis changes in
CFS Illness phaseSleepPsychiatric IllnessPast AbuseMedicationStressPhysical ActivityDiet/weight changeOther trait – e.g. geneticUnknown factor(s)
HPA axis change(heterogeneous)
Contributes to fatigue maintenance
![Page 22: Group on Scientific Research into ME: Neuroendocrinology of CFS/ME](https://reader036.fdocuments.in/reader036/viewer/2022062502/5681358b550346895d9cf0d2/html5/thumbnails/22.jpg)
Future research
• Aetiological work– Longitudinal, prospective studies– High risk cohorts– Large enough to detect subgroups (if present)– Multidisciplinary – integrative understanding of
different factors• Treatment studies
– Improving therapies and therapy options– Targeting the right patients