the role of autonomic function in the symptom of fatigue Julia - - PowerPoint PPT Presentation

w o r k i n g t o g e t h e r a s N e w c a s t l e A c a d e m i c H e a l t h P a r t n e r s

Standing up for fatigue – the role of autonomic function in the symptom of fatigue

Julia Newton Professor of Ageing and Medicine, Newcastle University Deputy Medical Director

Newcastle Hospitals NHS Foundation Trust

Medical Director Academic Health Science Network NENC

w o r k i n g t o g e t h e r a s N e w c a s t l e A c a d e m i c H e a l t h P a r t n e r s

Outline of talk

• What is fatigue
• What is autonomic dysfunction
• Recent and current work from Newcastle
• Potential future work

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What is CFS(ME)?

• Classified by WHO in ICD-10 as a neurological disorder G93.3
• Medical unexplained

– Physiologically distinct from depression – Identifiable immunological, neurological, endocrine abnormalities that are consistent

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• Severe debilitating fatigue causing interference with normal

functions.

• Duration of at least 4 months
• No evidence for other medical or psychiatric problems.
• Typical history
• No pointers on examination to alternative diagnoses.
• Blood tests are normal

What is CFS(ME)?

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What is fatigue?

• Fatigue is not the same as tiredness and is not relieved by

sleep or rest.

• It is common to a broad range of chronic medical illnesses.
• Our understanding and recognition of the importance of fatigue

in chronic illness is improving.

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Fatigue

Fatigue

Chronic infection Connective tissue disease Autoimmune disease Sleep disturbance

Lupus Rheumatoid arthritis Polymyositis EBV Toxoplasma HCV, HIV (AIDS) Brucella Coeliac disease Thyroid disease Addison’s disease PBC Sleep apnoea Sleep deprivation narcolepsy

Organic brain disease

Alzheimer’s MS Parkinson’s Disease Primary psychiatric

Also consider other organ-based disease (lung (COPD), heart, liver, kidney, bowel), malignancy and chemotherapy/radiotherapy, brain injury, PTSD, diabetes

w o r k i n g t o g e t h e r a s N e w c a s t l e A c a d e m i c H e a l t h P a r t n e r s

Liver Neurology Endocrine Rheumatology Cardiovascular Respiratory

Primary Biliary Cirrhosis Non-alcoholic fatty liver disease Multiple sclerosis Parkinson’s disease Mitochondrial myopathy Hypo- thyroidism Type 2 diabetes Sjogrens Rheumatoid arthritis SLE Pre- dialysis Post- dialysis Heart failure Autonomic dysfunction Bronchi- ectasis COPD Chronic Fatigue Syndrome Ageing

Newcastle Fatigue Consortium

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Perceived fatigue is comparable across chronic disease groups

Jones & Newton, QJM 2009

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Epidemiology of CFS

• CFS - Prevalence of 0.2-0.4%

– Average primary care practice of 10,000 will have up to 40 patients

• Estimated annual prevalence 4000 cases per

million population

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How common is Fatigue

• 25% of all primary care consultations are attributable to

fatigue.

• Main reason for attendance in 6.5% of consultations.
• UK community surveys show that over 10% of adults had had

substantial fatigue for over a month.

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The cost of fatigue

• In the US; fatigue occurs in 40% of workers resulting in lost

productive time in 65% of these workers (26% in those without fatigue).

• Workers with fatigue cost employers $136.4 billion annually,

an excess of $101 billion compared with workers without fatigue.

• When fatigue co-occurred with other conditions the condition

specific lost productive time increased three-fold.

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Is it a real illness?

• Medically unexplained ≠ patient is mad or bad!
• Almost all patients are devastated by their illness

and suffer depression as a result.

• Most will suffer severe hardship with loss of

income, job, loss of hobbies, marital difficulties.

• Difficult to conceive that the majority of patients

would wish to continue in this state

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Is it a real illness?

• Scientific evidence now points to underlying

physiological abnormalities.

• Psychiatric symptoms are secondary.

– Anger – Frustration – Reactive depression and anxiety

w o r k i n g t o g e t h e r a s N e w c a s t l e A c a d e m i c H e a l t h P a r t n e r s Genetic predisposition Psychosocial background Triggering event (infection) Endocrine disturbance (adrenocortical axis) Autonomic dysfunction Chronic cytokine abnormalities POTS, postural hypotension, abnormal muscle and skin blood flow Mitochondrial abnormality? Dysfunctional immunological response

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What is autonomic dysfunction?

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CFS Controls NAFLD PBC PSC OLT VVS ITP Sjogren 4 8 12 16 20 24

Orthostatic Grading Scale

Symptoms of autonomic dysfunction

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Orthostatic intolerance

CFS – 89% NAFLD - 56% (Newton et al., CAR 2009) PBC – 69% (Newton et al., Hepatology 2008) In all cases fatigue severity associates with increased

• rthostatic intolerance.

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Dysautonomia-Associated Fatigue (DAF) CFS/ME Chronic Disease

DAF Fatigue Non-DAF Fatigue

Fatigued Non-Fatigued

Newton et al., QJM 2007

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Objective autonomic abnormalities

Controls CFS 100 125 150

p<0.0001 Mean SBP over 24 hours

Controls PBC 100 125 150

Mean SBP over 24 hours p=0.04

Newton et al., Psychosom Med 2009 Newton et al., CAR 2009

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Fatigued Non-Fatigued 10 100 1000 10000

HRV

p=0.01

Newton et al. Liver Int 2006 Newton et al. EJGH 2006 Newton et al. Hepatology 2006

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Consequences of autonomic dysfunction

Head up tilt testing - 57% of NAFLD group have neurally- mediated hypotension (vasovagal syncope and/or

• rthostatic hypotension)

(p=0.006 v controls).

Newton et al., CAR 2009

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CFS/ME Controls P N 64 64 Age mean ± SD 46 ± 12 48 ± 15 0.5 Males (%) 23 (36) 23 (36) Ns FIS 97 ± 28 12 ± 20 <0.0001 Hx of loss of consciousness (%) 27 (40%) 15 (23%) 0.04 HUT positive (in those able to tolerate the test) 19 7 0.004 Systolic OH 24 26 0.6 Delayed OH 2 0.5 POTS 20 4 0.0005

Those with LOC - HUT was positive in 15 (56%) which is comparable to previous studies of the predictive value of head up tilt in those with unexplained syncope.

Hollingsworth et al., EJCI 2010

Consequences of autonomic dysfunction

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What might the mechanisms be?

• Upstream
• Downstream

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Upstream

Controls CFS 10 15 20

p=0.0013

Symbol Search Scaled Score

80 90 100 110 120 130 140 1.00 1.01 1.02 1.03 1.04 1.05 p=0.02;r2=0.4

Full IQ T score Max Valsalva Phase 1-3

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Muscle MR spectroscopy – 2 mins exercise

Jones & Newton JIM, 2009

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Downstream

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Human muscle cell cultures

Myoblast culture Day 7 myotube culture

10 biopsies obtained from chronic fatigue patients

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C-Pace EP

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35

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Cardiac MR

CFS Controls 1.00 1.25 1.50 1.75 2.00 2.25

PCr/ATP

Hollingsworth et al., EJCI 2010 & JIM 2011

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Background

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1.00 1.25 1.50 1.75 2.00 2.25 2 4 6

p=0.03 PCr/ATP Change in LVWI on standing

Functional and symptom associated consequences

Controls CFS 2 3 4 5

LVWI on standing p=0.05

LVWI normal LVWI abnormal 5 10 15

Orthostatic Grading Scale p=0.04

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MRC Cohort Results

• Cardiac MR was performed in 47

CFS participants matched case-by- case for age and sex to 47 controls.

• Mean±SD length of history (yrs) for

CFS was 14±10.

• CFS patients had significantly

reduced end systolic and diastolic volumes together with reduced end diastolic wall masses (all p<0.0001)

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Plasma and Red Cell volume

• 41 CFS patients and 10 controls matched group-

wise also had PV and RCV assessed.

• RCV was 1565±443 ml with 26/47 (55%) having

values below 95% of normal expected values. PV was 2659±529 ml with 13/47 (28%) <95% expected mean value.

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• There were strong positive

correlations between total volume and end diastolic wall mass with both increasing RCV and PV also associating with increased end diastolic wall mass.

Plasma volume ml ED Wall Pap Mass

1000 2000 3000 4000 50 100 150

p<0.0001;r2=0.4 Plasma volume ml ED Wall Mass

1000 2000 3000 4000 50 100 150

p=0.0002;r2=0.4

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• There was a significant negative

relationship between increasing fatigue severity and lower PV.

• There were no relationships

between any of the MR or volume measurements and length of history suggesting that deconditioning was unlikely to be the cause of these abnormalities.

40 80 120 160 1000 2000 3000 4000

FIS Plasma volume (ml)

p=0.04;r2=0.1

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• Brain natriuretic peptide (BNP) is a 32-amino acid polypeptide

secreted by the ventricles of the heart in response to excessive stretching of heart muscle cells.

• Release of BNP is modulated by calcium ions.
• BNP is named as such because it was originally identified in

extracts of porcine brain, although in humans it is produced mainly in the cardiac ventricles.

• The physiologic actions of BNP include decrease in systemic

vascular resistance and central venous pressure as well as an increase in natriuresis.

• The net effect of these peptides is a decrease in blood pressure

due to the decrease in systemic vascular resistance and, thus,

• afterload. Additionally, the actions of BNP result in a decrease in

cardiac output due to an overall decrease in central venous pressure and preload as a result of the reduction in blood volume that follows natriuresis and diuresis.

C F S C

• n

t r

• l

s 2 0 0 4 0 0 6 0 0 8 0 0 1 0 0 0

B N P (p g /m l) p = 0 .0 1 3

N=42 CFS compared to N=10 Controls

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B N P < 4 B N P > 4 6 0 8 0 1 0 0 1 2 0

E D V o l p = 0 .0 5

B N P < 4 0 0 B N P > 4 0 0 2 0 3 0 4 0 5 0

E S V o l p = 0 .0 5

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Conclusion

• CFS/ME is a chronic disabling disease with a genetic background, triggered by

infection and with a link to psychosocial stressors

• Fatigue is a common problem that affects patients with a range of chronic diseases
• There is increasing evidence of very specific physiological abnormalities
• Symptoms suggestive of autonomic dysfunction are common.
• Autonomic dysfunction is associated with fatigue severity and a range of other often

considered to be insignificant symptoms.

• Studies have detected brain, cardiac and muscle abnormalities in CFS and fatigue

associated diseases, the severity of which frequently associates with the severity of autonomic symptoms

• There are still no curative treatments
• Patients have major problems with disbelief within medical and

benefits/insurance/pensions systems

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Thanks to Muscle work Newcastle: Dr Audrey Brown Prof Mark Walker Ms Cara Tomas Oxford: Dr Karl Morten MR work Newcastle: Dr Andreas Finkelmeyer Prof Andrew Blamire Dr Kieran Hollingsworth Mr Tim Hodgson Dr Guy MacGowan Cardiac work Newcastle Dr Guy MacGowan MRC Cohort Newcastle: Dr Laura Maclachlan Dr Stuart Watson Dr Peter Gallagher Dr Lucy Robinson The patients …..