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

Transcription

1 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

2 Outline of talk What is fatigue What is autonomic dysfunction Recent and current work from Newcastle Potential future work

3 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

4 What is CFS(ME)? 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

5 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.

6 Fatigue Fatigue Chronic infection Connective tissue disease Autoimmune disease Sleep disturbance Organic brain disease EBV Toxoplasma HCV, HIV (AIDS) Brucella Lupus Rheumatoid arthritis Polymyositis Coeliac disease Thyroid disease Addison s disease PBC Sleep apnoea Sleep deprivation narcolepsy 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

7 Liver Neurology Rheumatology Sjogrens Primary Biliary Cirrhosis Non-alcoholic fatty liver disease Multiple sclerosis Parkinson s disease Mitochondrial myopathy Rheumatoid arthritis Endocrine Newcastle Fatigue Consortium SLE Hypothyroidism Predialysis Type 2 diabetes Heart failure Chronic Fatigue Syndrome Ageing COPD Postdialysis Bronchiectasis Autonomic dysfunction Cardiovascular Respiratory

8 Perceived fatigue is comparable across chronic disease groups Jones & Newton, QJM 2009

9 Epidemiology of CFS CFS - Prevalence of % Average primary care practice of 10,000 will have up to 40 patients Estimated annual prevalence 4000 cases per million population

10 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.

11 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.

12 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

13 Is it a real illness? Scientific evidence now points to underlying physiological abnormalities. Psychiatric symptoms are secondary. Anger Frustration Reactive depression and anxiety

14 Genetic predisposition Psychosocial background Triggering event (infection) Dysfunctional immunological response Chronic cytokine abnormalities Endocrine disturbance (adrenocortical axis) Autonomic dysfunction Mitochondrial abnormality? POTS, postural hypotension, abnormal muscle and skin blood flow

15 What is autonomic dysfunction?

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20 Symptoms of autonomic dysfunction 24 Orthostatic Grading Scale CFS ControlsNAFLD PBC PSC OLT VVS ITP Sjogrens

21 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 orthostatic intolerance.

22 Fatigued Non-Fatigued CFS/ME Chronic Disease Dysautonomia-Associated Fatigue (DAF) DAF Fatigue Newton et al., QJM 2007 Non-DAF Fatigue

23 Objective autonomic abnormalities 150 p= p< Mean SBP over 24 hours 125 Mean SBP over 24 hours Controls PBC 100 Controls CFS Newton et al., Psychosom Med 2009 Newton et al., CAR 2009

24 10000 p=0.01 HRV Fatigued Non-Fatigued Newton et al. Liver Int 2006 Newton et al. EJGH 2006 Newton et al. Hepatology 2006

25 Consequences of autonomic dysfunction Head up tilt testing - 57% of NAFLD group have neurallymediated hypotension (vasovagal syncope and/or orthostatic hypotension) (p=0.006 v controls). Newton et al., CAR 2009

26 Consequences of autonomic dysfunction CFS/ME Controls P N Age mean ± SD 46 ± ± Males (%) 23 (36) 23 (36) Ns FIS 97 ± ± 20 < Hx of loss of 27 (40%) 15 (23%) 0.04 consciousness (%) HUT positive (in 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. those able to tolerate the test) Systolic OH Delayed OH POTS Hollingsworth et al., EJCI 2010

27 What might the mechanisms be? Upstream Downstream

28 Upstream Symbol Search Scaled Score Controls p= CFS Max Valsalva Phase p=0.02;r 2 = Full IQ T score

29 Muscle MR spectroscopy 2 mins exercise Jones & Newton JIM, 2009

30 Downstream

31 Human muscle cell cultures Myoblast culture Day 7 myotube culture 10 biopsies obtained from chronic fatigue patients

32 C-Pace EP

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36 Cardiac MR PCr/ATP CFS Controls Hollingsworth et al., EJCI 2010 & JIM 2011

37 Background

38 Functional and symptom associated consequences Change in LVWI on standing 6 4 p= PCr/ATP LVWI on standing Orthostatic Grading Scale p=0.05 Controls CFS p=0.04 LVWI normal LVWI abnormal

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40 MRC Cohort Results Cardiac MR was performed in 47 CFS participants matched case-bycase 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)

41 Plasma and Red Cell volume 41 CFS patients and 10 controls matched groupwise 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.

42 150 p<0.0001;r2=0.4 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. ED Wall Pap Mass ED Wall Mass Plasma volume ml 150 p=0.0002;r2= Plasma volume ml

43 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. Plasma volume (ml) p=0.04;r2= FIS

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45 B N P (p g /m l) 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. p = C F S C o n tr o ls N=42 CFS compared to N=10 Controls

46 E D V o l E S V o l p = p = B N P < B N P > B N P < B N P > 4 0 0

47 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

48 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..