MS-Related Fatigue

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MS-Related Fatigue

  1. 1. Multiple sclerosis related fatigue Gavin Giovannoni Barts and The London
  2. 2. 1. Patients with a raised serum CRP level had higher KFSS, but not FQS, scores than patients with normal CRP. 2. Patients with benign MS were as fatigued as patients with non-benign disease. 3. The pathogenesis of fatigue in MS is complex and does not appear to be directly related to systemic markers of inflammatory disease activity. 4. Patients with PP MS were less fatigued than patients with RR disease.
  3. 3. Defining the problem 1. 2. 3. 4. Between 65-97% of MSers experience significant fatigue Presenting symptom in approximately one-third of MSers 15-40% of MSers describe fatigue as their most disabling symptom Fatigue is associated with: a. b. c. d. e. f. 5. 6. 7. depression & anxiety sleep disorders deconditioning temperature sensitivity infections and ongoing inflammation side effect of medications Fatigue is a common reason for unemployment in MSers. Fatigue is a ‘non-specific’ symptom There are several different physiological mechanisms underlying the presentation of fatigue.
  4. 4. WHICH ARE YOUR MOST DISABLING MS SYMPTOMS? www.ms-res.org
  5. 5. J Neurol Neurosurg Psychiatry. 2006 Jan;77(1):2-3.
  6. 6. What is fatigue? How we define fatigue remains as controversial today as it did 40 years ago: “True fatigue and ….. tiredness are plainly different.” Fatigue. Lancet. 1966 ;1(7437):585-6. Fatigue is more than tiredness and has recently been referred to as “pathological exhaustion”. Editorial. Barnett R. Fatigue. Lancet. 2005;366(9479):21.
  7. 7. More on fatigue ……. the term “pathological” would, for example, classify the physical fatigue which athletes’ experience, as part of voluntary effort, as being abnormal. ……. Fatigue, therefore, must surely be a normal phenomenon; a subjective feeling of tiredness or exhaustion, which could refer to both physical (motor activities) and mental (cognitive or emotional) processes…… …... Fatigue is only pathological if it is disabling, i.e. it impacts on the social, physical and occupational wellbeing of a subject……
  8. 8. The reflex arc: the basic architecture of the nervous system cortical areas “perception” sub-cortical areas modulation “afferent or sensory limb” sensory receptors e.g. stretch / temperature receptor + - + local modulation integrator 1 integrator 2 - Response e.g. muscle contraction / behavioural response “efferent or motor limb” “memory” hard-wired or acquired
  9. 9. The reflex arc: the basic architecture of the nervous system cortical areas “perception” sub-cortical areas modulation “afferent or sensory limb” sensory receptors e.g. stretch / temperature receptor + - + local modulation integrator 1 integrator 2 - Response e.g. muscle contraction / behavioural response “efferent or motor limb” “memory” hard-wired or acquired
  10. 10. Percepts Bushnell M C et al. PNAS 1999;96:7705-7709
  11. 11. Emotional response to unpleasant percepts Vogt. Pain and emotion interactions in subregions of the cingulate gyrus. Nat Rev Neurosci. 2005 Jul;6(7):533-44.
  12. 12. Case study • A 28-year old woman with early RR-MS. Little neurological impairment but suffering from severe fatigue, worse during menstruation. Recently split up with long-term partner. Has had to stop work as a bank clerk because of the fatigue. • How are you going to manage her fatigue? 1. 2. 3. 4. 5. . Is she depressed or anxious? Does she have a sleep disorder? Is she cognitively impaired? Are any medications contributing to the fatigue? Does she have a metabolic disorder (e.g. hypothyroidism)?
  13. 13. WHICH OF THE FOLLOWING AFFECT YOUR SLEEP? www.ms-res.org
  14. 14. Rationale for sodium channel blockade Videos courtesy Hugh Bostock, Inst. Neurol., UCL Waxman SG. Nat Rev Neurosci. 2006 Dec;7(12):932-41.
  15. 15. Wilhelm Uhthoff
  16. 16. Circadian and hypothermia-induced effects on visual and auditory evoked potentials in multiple sclerosis Romani et al. Clinical Neurophysiology 111 (2000) 1602-1606.
  17. 17. Body temperature is elevated and linked to fatigue in RRMS, even without heat exposure Sumowski & Leavitt. Arch Phys Med Rehabil. 2014 Feb 19. pii: S0003-9993(14)00126-9. doi:
  18. 18. A randomized controlled crossover trial of aspirin for fatigue in MS Wingerchuk, NEUROLOGY 2005;64:1267–1269
  19. 19. The relationship between Tempbrain and Tempcarotid in: (a) (b) (c) (d) (e) (f) wildebeest (Jessen et al. 1994) zebra (Fuller et al. 1999) oryx (Maloneyet al. 2002) horse (Mitchell et al. 2006) pronghorn in summer (Lustet al. 2007) pronghorn in winter (from Hébert et al. 2008). Tbrain(squares) and its 95% confidence limits are shown Mitchell G , Lust A Biol. Lett. 2008;4:415-418
  20. 20. Mitchell G , Lust A Biol. Lett. 2008;4:415-418
  21. 21. Born to Run
  22. 22. Menstrual Cycle ‘catamenial fatigue’
  23. 23. Cooling Vests
  24. 24. Butchers Fridge
  25. 25. Ice Baths
  26. 26. Rationale for sodium channel blockade Videos courtesy Hugh Bostock, Inst. Neurol., UCL Waxman SG. Nat Rev Neurosci. 2006 Dec;7(12):932-41.
  27. 27. Sustained-release oral fampridine in multiple sclerosis: a randomised, double-blind, controlled trial Goodman et al. Lancet 2009; 373: 732–38.
  28. 28. Fampridine responders
  29. 29. Fampridine responders
  30. 30. Impact of MS: cognitive functioning in the CIS stage 60% Patients failing ≥ 2 cognitive tests 40% 57% 20% Deficits were found mainly in memory, speed of information processing, attention and executive functioning 7% 0% p < 0.0001 -20% CIS Patients n = 40 Healthy Controls n = 30 Feuillet et al. MSJ 2007
  31. 31. Cortical plasticity makes it difficult to use motor and other functional systems to study focal MS lesions Ipsilateral premotor Supplementary motor area Contralateral primary sensorimotor Non-dominant left hand, 75% max rate, grouped 4-finger tapping Slide courtesy Prof. Paul Matthews, Imperial College.
  32. 32. Functional MRI correlates of Fatigue in MS Filipi et al. NeuroImage 15, 559–567 (2002)
  33. 33. Staying SMART www.stayingsmart.org.uk
  34. 34. Sickness Behaviour Dantzer et al. Inflammation to sickness and depression: when the immune system subjugates the brain Nature Reviews Neuroscience 2008; 9:46-56 .
  35. 35. Sickness Behaviour Dantzer et al. Inflammation to sickness and depression: when the immune system subjugates the brain Nature Reviews Neuroscience 2008; 9:46-56 .
  36. 36. Evolution of interleukin-1b S. Bird et al. Cytokine & Growth Factor Reviews 13 (2002) 483–502
  37. 37. Assessing Relapses in Multiple Sclerosis Ross et al. Mult Scler Int 2013;2013:470476.
  38. 38. Natalizumab reduces fatigue in MS: TYNERGY Trial Svenningsson et al PLoS One. 2013;8(3):e58643.
  39. 39. Fatigue in multiple sclerosis: an example of cytokine mediated sickness behaviour? Heesen et al. J Neurol Neurosurg Psychiatry 2006;77:34–39.
  40. 40. Fatigue • • • . Pathogenesis is complex - demyelination, reduced safety factor of conduction, temperature sensitivity, poor sleep, co-morbidities, side effects of medication, inflammation and alterations in mood. Detailed history (pattern of fatigue, mood, sleep, disease activity, deconditioning, diet) Treatment individualised – Sickness behaviour = DMTs – Lifestyle management (incorporate self-discipline induced reward) • Behavioural therapy • Exercise – CBT & anti-depressants (desipramine, SNARI, NARI, MAOI) – Improve sleep hygiene & correct any sleep disorders – Stimulants • Amantadine - limited efficacy & significant side effects 100mg/day,  max = 200 mg BD • Modafinil – 100-200mg BD – Methyphenidate, dexamphetamine, pemoline, selegiline – Conduction block • Aminopyridines (3,4- and 4) – Cooling (cooling suits, anti-pyretics, life-style changes)
  41. 41. Psychological Health Depression Anxiety Stress Alcohol abuse Social Isolation Sickness Behaviour MS disease activity Infections Physical Health Deconditioning Co-morbidities (hypothyroidism, obesity, medication side effects, etc.) Pathological Fatigue Environmental Factors Temperature Social isolation Sleep Disorders Primary Secondary to MS Multiple Sclerosis Cognitive Impairment Physical disability Temperature sensitivity Exercise-related conduction block

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