Multiple sclerosis related fatigue

Gavin Giovannoni

Barts and The London

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.

Defining the problem 1. Between 65-97% of MSers experience significant fatigue

2. Presenting symptom in approximately one-third of MSers

3. 15-40% of MSers describe fatigue as their most disabling symptom

4. Fatigue is associated with:

a. depression & anxiety

b. sleep disorders

c. deconditioning

d. temperature sensitivity

e. infections and ongoing inflammation

f. side effect of medications

5. Fatigue is a common reason for unemployment in MSers.

6. Fatigue is a ‘non-specific’ symptom

7. There are several different physiological mechanisms underlying the presentation of fatigue.

www.ms-res.org

WHICH ARE YOUR MOST DISABLING MS SYMPTOMS?

J Neurol Neurosurg Psychiatry. 2006 Jan;77(1):2-3.

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.

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……

sensory receptors e.g. stretch / temperature receptor

Response e.g. muscle contraction / behavioural response

integrator 1 integrator 2

modulation

local modulation

+ -

+

-

The reflex arc: the basic architecture of the nervous system

“afferent or sensory limb”

“efferent or motor limb”

“memory” hard-wired or acquired

cortical areas “perception”

sub-cortical areas

sensory receptors e.g. stretch / temperature receptor

Response e.g. muscle contraction / behavioural response

integrator 1 integrator 2

modulation

local modulation

+ -

+

-

The reflex arc: the basic architecture of the nervous system

“afferent or sensory limb”

“efferent or motor limb”

“memory” hard-wired or acquired

cortical areas “perception”

sub-cortical areas

Bushnell M C et al. PNAS 1999;96:7705-7709

Percepts

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.

.

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. Is she depressed or anxious?

2. Does she have a sleep disorder?

3. Is she cognitively impaired?

4. Are any medications contributing to the fatigue?

5. Does she have a metabolic disorder (e.g. hypothyroidism)?

www.ms-res.org

WHICH OF THE FOLLOWING AFFECT YOUR SLEEP?

Rationale for sodium channel blockade

Waxman SG. Nat Rev Neurosci. 2006 Dec;7(12):932-41. Videos courtesy Hugh Bostock, Inst. Neurol., UCL

Wilhelm Uhthoff

Circadian and hypothermia-induced effects on visual and auditory evoked potentials in multiple sclerosis

Romani et al. Clinical Neurophysiology 111 (2000) 1602-1606.

Sumowski & Leavitt. Arch Phys Med Rehabil. 2014 Feb 19. pii: S0003-9993(14)00126-9. doi:

Body temperature is elevated and linked to fatigue in RRMS, even without heat exposure

A randomized controlled crossover trial of aspirin for fatigue in MS

Wingerchuk, NEUROLOGY 2005;64:1267–1269

Mitchell G , Lust A Biol. Lett. 2008;4:415-418

(a) wildebeest (Jessen et al. 1994)

(b) zebra (Fuller et al. 1999)

(c) oryx (Maloneyet al. 2002)

(d) horse (Mitchell et al. 2006)

(e) pronghorn in summer (Lustet al.

2007)

(f) pronghorn in winter (from Hébert et

al. 2008).

Tbrain(squares) and its 95% confidence

limits are shown

The relationship between Tempbrain and Tempcarotid in:

Mitchell G , Lust A Biol. Lett. 2008;4:415-418

Born to Run

Menstrual Cycle

‘catamenial fatigue’

Cooling Vests

Butchers Fridge

Ice Baths

Rationale for sodium channel blockade

Waxman SG. Nat Rev Neurosci. 2006 Dec;7(12):932-41. Videos courtesy Hugh Bostock, Inst. Neurol., UCL

Sustained-release oral fampridine in multiple sclerosis: a randomised, double-blind, controlled trial

Goodman et al. Lancet 2009; 373: 732–38.

Fampridine responders

Fampridine responders

Impact of MS: cognitive functioning in the CIS stage

Feuillet et al. MSJ 2007

CIS Patients n = 40

57%

7%

-20%

0%

20%

40%

60%

Healthy Controls n = 30

p < 0.0001

Deficits were found mainly in memory, speed of

information processing, attention and executive

functioning

Patients failing ≥ 2 cognitive

tests

Ipsilateral premotor

Contralateral primary sensorimotor

Supplementary motor area

Non-dominant left hand, 75% max rate, grouped 4-finger tapping

Slide courtesy Prof. Paul Matthews, Imperial College.

Cortical plasticity makes it difficult to use motor and other functional systems to study focal MS lesions

Functional MRI correlates of Fatigue in MS

Filipi et al. NeuroImage 15, 559–567 (2002)

Staying SMART

www.stayingsmart.org.uk

Sickness Behaviour

Dantzer et al. Inflammation to sickness and depression: when the immune system subjugates the brain

Nature Reviews Neuroscience 2008; 9:46-56 .

Sickness Behaviour

Dantzer et al. Inflammation to sickness and depression: when the immune system subjugates the brain

Nature Reviews Neuroscience 2008; 9:46-56 .

Evolution of interleukin-1b

S. Bird et al. Cytokine & Growth Factor Reviews 13 (2002) 483–502

Assessing Relapses in Multiple Sclerosis

Ross et al. Mult Scler Int 2013;2013:470476.

Natalizumab reduces fatigue in MS: TYNERGY Trial

Svenningsson et al PLoS One. 2013;8(3):e58643.

Fatigue in multiple sclerosis: an example of cytokine mediated sickness behaviour?

Heesen et al. J Neurol Neurosurg Psychiatry 2006;77:34–39.

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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)

Pathological Fatigue

Sickness Behaviour MS disease activity

Infections

Psychological Health Depression

Anxiety Stress

Alcohol abuse Social Isolation

Physical Health Deconditioning Co-morbidities

(hypothyroidism, obesity, medication side effects, etc.)

Environmental Factors Temperature

Social isolation

Multiple Sclerosis Cognitive Impairment

Physical disability Temperature sensitivity

Exercise-related conduction block

Sleep Disorders Primary

Secondary to MS