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

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 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

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 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

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 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

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. 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

Fatigue Fatigue Connective tissue Autoimmune Sleep Organic brain Chronic infection disease disease disturbance disease Alzheimer ’ s EBV Coeliac disease Lupus Sleep apnoea Toxoplasma Thyroid disease MS Rheumatoid arthritis Sleep deprivation Addison ’ s disease Parkinson ’ s Disease HCV, HIV (AIDS) Polymyositis narcolepsy Brucella PBC 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 Non-alcoholic Multiple fatty Primary Biliary sclerosis Parkinson’s liver disease Cirrhosis disease Mitochondrial Sjogrens myopathy Rheumatology Hypo- thyroidism Rheumatoid Endocrine arthritis Newcastle Type 2 diabetes Fatigue SLE Consortium Heart failure Pre- dialysis Autonomic Cardiovascular Post- dysfunction dialysis Bronchi- Chronic Fatigue ectasis Syndrome Ageing COPD Respiratory 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

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

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 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

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. 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

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. 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

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 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

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) Dysfunctional immunological response Chronic cytokine abnormalities Endocrine disturbance (adrenocortical axis) Autonomic dysfunction POTS, postural hypotension, abnormal muscle and skin blood flow Mitochondrial abnormality? 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

What is autonomic dysfunction? 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

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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

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

Symptoms of autonomic dysfunction 24 Orthostatic Grading 20 16 Scale 12 8 4 0 CFS Controls NAFLD PBC PSC OLT VVS ITP Sjogren 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

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. 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

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

Objective autonomic abnormalities p=0.04 p<0.0001 150 150 Mean SBP over 24 Mean SBP over 24 hours hours 125 125 100 100 Controls PBC Controls CFS Newton et al., Psychosom Med 2009 Newton et al., CAR 2009 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

p=0.01 10000 1000 HRV 100 10 Fatigued Non-Fatigued Newton et al. Liver Int 2006 Newton et al. EJGH 2006 Newton et al. Hepatology 2006 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

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

Consequences of autonomic dysfunction CFS/ME Controls P N 64 64 Age mean ± SD 46 ± 12 48 ± 15 0.5 Males (%) 23 (36) 23 (36) Ns <0.0001 FIS 97 ± 28 12 ± 20 Hx of loss of 27 (40%) 15 (23%) 0.04 consciousness (%) HUT positive (in 19 7 0.004 those able to tolerate the test) Systolic OH 24 26 0.6 Those with LOC - HUT was positive in 15 Delayed OH 2 0 0.5 (56%) which is comparable to previous studies of the predictive value of head up POTS 20 4 0.0005 tilt in those with unexplained syncope. Hollingsworth et al., EJCI 2010 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

What might the mechanisms be? • Upstream • Downstream 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

Upstream 1.05 p=0.02;r 2 =0.4 Symbol Search Scaled Score 20 Max Valsalva Phase 1-3 p=0.0013 1.04 1.03 15 1.02 1.01 10 1.00 80 90 100 110 120 130 140 Controls CFS Full IQ T score 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

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

Downstream 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

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

C-Pace EP 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