1.Multiple sclerosis related fatigue Gavin Giovannoni Barts and The London
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. 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 medicationsFatigue 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. WHICH ARE YOUR MOST DISABLING MS SYMPTOMS?www.ms-res.org
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. 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. The reflex arc: the basic architecture of the nervous systemcortical areas “perception”sub-cortical areas modulation“afferent or sensory limb” sensory receptors e.g. stretch / temperature receptor+-+ local modulationintegrator 1integrator 2-Response e.g. muscle contraction / behavioural response “efferent or motor limb”“memory” hard-wired or acquired
9. The reflex arc: the basic architecture of the nervous systemcortical areas “perception”sub-cortical areas modulation“afferent or sensory limb” sensory receptors e.g. stretch / temperature receptor+-+ local modulationintegrator 1integrator 2-Response e.g. muscle contraction / behavioural response “efferent or motor limb”“memory” hard-wired or acquired
10. PerceptsBushnell M C et al. PNAS 1999;96:7705-7709
11. Emotional response to unpleasant perceptsVogt. Pain and emotion interactions in subregions of the cingulate gyrus. Nat Rev Neurosci. 2005 Jul;6(7):533-44.
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. WHICH OF THE FOLLOWING AFFECT YOUR SLEEP?www.ms-res.org
16. Circadian and hypothermia-induced effects on visual and auditory evoked potentials in multiple sclerosisRomani et al. Clinical Neurophysiology 111 (2000) 1602-1606.
17. Body temperature is elevated and linked to fatigue in RRMS, even without heat exposureSumowski & Leavitt. Arch Phys Med Rehabil. 2014 Feb 19. pii: S0003-9993(14)00126-9. doi:
18. A randomized controlled crossover trial of aspirin for fatigue in MSWingerchuk, NEUROLOGY 2005;64:1267–1269
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 shownMitchell G , Lust A Biol. Lett. 2008;4:415-418
20. Mitchell G , Lust A Biol. Lett. 2008;4:415-418
27. Sustained-release oral fampridine in multiple sclerosis: a randomised, double-blind, controlled trialGoodman et al. Lancet 2009; 373: 732–38.
28. Fampridine responders
29. Fampridine responders
30. Impact of MS: cognitive functioning in the CIS stage 60%Patients failing ≥ 2 cognitive tests40%57%20%Deficits were found mainly in memory, speed of information processing, attention and executive functioning7%0%p < 0.0001-20%CIS Patients n = 40Healthy Controls n = 30Feuillet et al. MSJ 2007
31. Cortical plasticity makes it difficult to use motor and other functional systems to study focal MS lesionsIpsilateral premotorSupplementary motor areaContralateral primary sensorimotorNon-dominant left hand, 75% max rate, grouped 4-finger tapping Slide courtesy Prof. Paul Matthews, Imperial College.
32. Functional MRI correlates of Fatigue in MSFilipi et al. NeuroImage 15, 559–567 (2002)
33. Staying SMARTwww.stayingsmart.org.uk
34. Sickness BehaviourDantzer et al. Inflammation to sickness and depression: when the immune system subjugates the brain Nature Reviews Neuroscience 2008; 9:46-56 .
35. Sickness BehaviourDantzer et al. Inflammation to sickness and depression: when the immune system subjugates the brain Nature Reviews Neuroscience 2008; 9:46-56 .
36. Evolution of interleukin-1bS. Bird et al. Cytokine & Growth Factor Reviews 13 (2002) 483–502
37. Assessing Relapses in Multiple SclerosisRoss et al. Mult Scler Int 2013;2013:470476.
38. Natalizumab reduces fatigue in MS: TYNERGY TrialSvenningsson et al PLoS One. 2013;8(3):e58643.
39. Fatigue in multiple sclerosis: an example of cytokine mediated sickness behaviour?Heesen et al. J Neurol Neurosurg Psychiatry 2006;77:34–39.
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. Psychological Health Depression Anxiety Stress Alcohol abuse Social IsolationSickness Behaviour MS disease activity InfectionsPhysical Health Deconditioning Co-morbidities (hypothyroidism, obesity, medication side effects, etc.)Pathological FatigueEnvironmental Factors Temperature Social isolationSleep Disorders Primary Secondary to MSMultiple Sclerosis Cognitive Impairment Physical disability Temperature sensitivity Exercise-related conduction block