Your patients’ lives

Between
Relapses

MS fatigue feels like being stuck in a bubble with really
thick air around you that constantly pushes you down.

Annika, age 25
Diagnosed with MS 2 years ago




MS Overview

Multiple sclerosis impacts the central nervous system in several ways1,2

In multiple sclerosis (MS), accumulation of the damage in the central nervous system (CNS) overtakes the brain’s limited capacity to repair itself. This can eventually lead to decreased efficiency and altered connectivity between regions of the brain.1,2








Damage

Damage from MS can affect the whole CNS. Autoimmune and inflammatory components can damage myelin, white matter, neurons, axons, and blood vessels. This damage can begin early in the disease.1,2





Lesions

Peripheral immune cells are present in MS lesions. Lesions are a common occurrence in MS and are caused by immune cells crossing the blood–brain barrier.3*





Remodeling

Remodeling can occur in MS but may have limited effectiveness. Remodeling in the CNS may partially restore or retain function and has multiple potential mechanisms.1,2,4





Signaling

Signaling can be altered in the CNS in MS. The signaling of various molecules can be affected in MS.3,6





Connectivity

Connectivity in neural networks can be affected by MS. In MS, lesions can affect either the function of a brain region or communication between brain regions and networks. Changes in connectivity and network organization can occur in MS.16




The clinical course of MS is heterogeneous2,3

Prediagnosis, patients can experience radiologically isolated syndrome (RIS) or clinically isolated syndrome (CIS). Once diagnosed, MS can be relapsing-remitting (RRMS), secondary progressive (SPMS), or primary-progressive (PPMS).2,3

RRMS affects approximately 85% of patients with MS and is characterized by recurring relapses. Of those with RRMS, 80% will eventually progress to SPMS. PPMS affects approximately 10% to 15% of newly diagnosed patients with MS.2,3

Relapses are reversible episodes of neurologic deficits that can coincide with lesions.2,3 Relapse intensity can vary from mild to severe, and the symptoms they cause can vary from patient to patient.20

  • Prediagnosis, patients can experience radiologically isolated syndrome (RIS) or clinically isolated syndrome (CIS). Once diagnosed, MS can be relapsing-remitting (RRMS), secondary progressive (SPMS), or primary-progressive (PPMS).2,3

  • RRMS affects approximately 85% of patients with MS and is characterized by recurring relapses. Of those with RRMS, 80% will eventually progress to SPMS. PPMS affects approximately 10% to 15% of newly diagnosed patients with MS.2,3

  • Relapses are reversible episodes of neurologic deficits that can coincide with lesions.2,3 Relapse intensity can vary from mild to severe, and the symptoms they cause can vary from patient to patient.20






Like the disease itself, the symptoms of MS
are heterogeneous and unpredictable3

MS can be challenging to manage due to the variability in symptoms between patients. Though each person living with MS can experience the disease in different ways, some of the most common symptoms of MS include21,22:
  • Fatigue
  • Numbness/
    tingling
  • Weakness
  • Dizziness and vertigo
  • Sexual problems
  • Emotional changes
  • Difficulty walking/gait issues
  • Vision problems
  • Bladder/bowel problems
  • Cognitive changes


Of these, fatigue is one of the most prevalent. In a large study of MS patients
(N = 25,728), about 81% experienced fatigue within their first year of diagnosis.

This high prevalence is consistent with other studies of MS fatigue.23,24






MS Fatigue Overview

Like MS itself, MS fatigue has
a variety of potential mechanisms25,26

MS fatigue is unique to people living with MS and different than other types
of fatigue. If patients experience MS fatigue, it doesn’t mean they aren’t
trying to push through it.25,27,28




Compared with normal fatigue, MS fatigue can25,27:
  • Occur on a daily basis
  • Come on suddenly and more severely
  • Be aggravated by heat and humidity
  • Interfere with physical function
  • Interfere with cognitive function

There are a number of factors that are thought to contribute to your patients’ experience of MS fatigue.


  • Primary factors contributing to MS fatigue are thought to be linked to the pathophysiology of the disease itself. There are several distinct hypotheses for the pathophysiological mechanisms of primary fatigue in MS.26

    These include26:

    • Structural damage to white and gray matter
    • Inflammatory processes
    • Maladaptive network recruitment due to lesions or inflammation
    • Metacognitive mechanisms

    This demonstrates the complexity of MS fatigue pathophysiology.

    As all of these potential CNS mechanisms underlying fatigue may eventually lead to changes in neural network function, measuring brain connectivity with neuroimaging may be of importance.26

    Studies have found that the brains of people with MS fatigue may have altered connectivity at rest compared with the brains of people without MS.29,30 Other studies have shown altered activation when performing fatiguing tasks in the brains of people with MS compared with the brains of people without MS.31-33

    Studies also suggest that changes in connectivity or activation within neural networks may lead to reduced efficiency in the brains of patients with MS fatigue.16,33







MS FATIGUE AND YOUR PATIENTS

MS fatigue can worsen over time23

MS fatigue is highly prevalent, can occur early in the disease
course, and may worsen over time.23,24






Though pharmacologic agents can be used to treat MS fatigue symptoms, there is currently insufficient evidence to support these agents for the management of MS fatigue.25


 

Nonpharmacologic strategies might include exercise, simplifying work-related tasks, cognitive behavioral therapies, or alternative treatments such as acupuncture.25,34




Since MS affects every patient differently, these pharmacologic and
nonpharmacologic treatment options may not work for everyone.25,34







MS fatigue can affect many aspects of life25,35

Like other MS symptoms, MS fatigue can negatively affect patients’ lives.25,35


MS fatigue has been associated with25,35:

Difficulties in
physical
functioning

Difficulties in
cognitive
functioning

Reduced ability to
complete activities of
daily living (ADLs)

Reduced ability
to work

Anxiety and
depression

Difficulties with
relationships and
social integration



MS fatigue can also impact care partners of patients living with MS.

In a study evaluating the effects of MS on care partners, nearly half of care
partners (N = 654 of 1,333) rated fatigue as the most stressful MS symptom.36



How real patients experience MS fatigue


Quotes were collected from real MS patients.



How does MS fatigue impact your patients?






TALK TO YOUR Patients

Why bring up MS fatigue?

Like MS itself, MS fatigue is complex and can impact
patients in a variety of ways.25,26,35





MS fatigue has a variety of defining characteristics. There are several hypotheses as to its potential underlying mechanisms.25,26

MS fatigue is highly prevalent, can occur early in the disease course, and may worsen over time.23,24

An often “hidden” symptom 37, MS fatigue has been associated with a variety of negative effects on patients. These can include physical and cognitive difficulties, inability to work or complete activities of daily living, and more.25,35




Ask your patients living with MS directly about their fatigue
to help you understand how it’s affecting them.



Additional resources


Clinical papers on fatigue

Read more research about
MS fatigue from your peers.



Manjaly 2019

Penner 2016

Bisecco 2017


MS fatigue flashcard

A brief resource on how patients experience fatigue and the impact it can have on their lives.


Download Now

  • Clinical papers on fatigue

    Read more research about
    MS fatigue from your peers.



    Manjaly 2019

    Penner 2016

    Bisecco 2017


  • MS fatigue flashcard

    A brief resource on how patients experience fatigue and the impact it can have on their lives.


    Download Now






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References: 1. Cerqueira JJ, Compston DAS, Geraldes R, et al. Time matters in multiple sclerosis: can early treatment and long-term follow-up ensure everyone benefits from the latest advances in multiple sclerosis? J Neurol Neurosurg Psychiatry. 2018;89(8):844-850. doi:10.1136/jnnp-2017-317509. 2. Filippi M, Bar-Or A, Piehl F, et al. Multiple sclerosis. Nat Rev Dis Primers. 2018;4(1):43. doi:10.1038/s41572-018-0041-4. 3. Dendrou CA, Fugger L, Friese MA. Immunopathology of multiple sclerosis. Nat Rev Immunol. 2015;15(9):545-558. doi:10.1038/nri3871. 4. Kerschensteiner M, Bareyre FM, Buddeberg BS, et al. Remodeling of axonal connections contributes to recovery in an animal model of multiple sclerosis. J Exp Med. 2004;200(8):1027-1038. doi:10.1084/jem.20040452. 5. Abu-Rub M, Miller RH. Emerging cellular and molecular strategies for enhancing central nervous system (CNS) remyelination. Brain Sci. 2018;8(6):111. doi:10.3390/brainsci8060111. 6. Mandolesi G, Gentile A, Musella A, et al. Synaptopathy connects inflammation and neurodegeneration in multiple sclerosis. Nat Rev Neurol. 2015;11(12):711-724. doi:10.1038/nrneurol.2015.222. 7. Chaudhry BZ, Cohen JA, Conway DS. Sphingosine 1-phosphate receptor modulators for the treatment of multiple sclerosis. Neurotherapeutics. 2017;14(4):859-873. doi:10.1007/s13311-017-0565-4. 8. Fischer I, Alliod C, Martinier N, Newcombe J, Brana C, Pouly S. Sphingosine kinase 1 and sphingosine 1-phosphate receptor 3 are functionally upregulated on astrocytes under pro-inflammatory conditions. PLoS One. 2011;6(8):e23905. doi:10.1371/journal.pone.0023905. 9. Van Doorn R, Van Horssen J, Verzijl D, et al. Sphingosine 1-phosphate receptor 1 and 3 are upregulated in multiple sclerosis lesions. Glia. 2010;58(12):1465-1476. doi:10.1002/glia.21021. 10. Fincher J, Whiteneck C, Birgbauer E. GPCR cell signaling pathways mediating embryonic chick retinal growth cone collapse induced by LPA and S1P. Dev Neurosci. 2014;36(6):443-453. doi:10.1159/000364858. 11. Jaillard C, Harrison S, Stankoff B, et al. Edg8/S1P5: an oligodendroglial receptor with dual function on process retraction and cell survival. J Neurosci. 2005;25(6):1459-1469. doi:10.1523/JNEUROSCI.4645-04.2005. 12. Postma FR, Jalink K, Hengeveld T, Moolenaar WH. Sphingosine-1-phosphate rapidly induces Rho-dependent neurite retraction: action through a specific cell surface receptor. EMBO J. 1996;15(10):2388-2392. 13. Meacci E, Garcia-Gil M. S1P/S1P receptor signaling in neuromuscular disorders. Int J Mol Sci. 2019;20(24):6364. doi:10.3390/ijms20246364. 14. Silver J, Miller JH. Regeneration beyond the glial scar. Nat Rev Neurosci. 2004;5(2):146-156. doi:10.1038/nrn1326. 15. Garris CS, Blaho VA, Hla T, Han MH. Sphingosine-1-phosphate receptor 1 signalling in T cells: trafficking and beyond. Immunology. 2014;142(3):347-353. doi:10.1111/imm.12272. 16. Tahedl M, Levine SM, Greenlee MW, Weissert R, Schwarzbach JV. Functional connectivity in multiple sclerosis: recent findings and future directions. Front Neurol. 2018;9:828. doi:10.3389/fneur.2018.00828. 17. Shu N, Liu Y, Li K, et al. Diffusion tensor tractography reveals disrupted topological efficiency in white matter structural networks in multiple sclerosis. Cereb Cortex. 2011;21(11):2565-2577. doi:10.1093/cercor/bhr039. 18. Li Y, Jewells V, Kim M, et al. Diffusion tensor imaging based network analysis detects alterations of neuroconnectivity in patients with clinically early relapsing-remitting multiple sclerosis. Hum Brain Mapp. 2013;34(12):3376-3391. doi:10.1002/hbm.22158. 19. Fleischer V, Koirala N, Droby A, et al. Longitudinal cortical network reorganization in early relapsing–remitting multiple sclerosis. Ther Adv Neurol Disord. 2019;12:1756286419838673. doi:10.1177/1756286419838673. 20. Managing relapses. National Multiple Sclerosis Society. Accessed June 29, 2020. https://www.nationalmssociety.org/Treating-MS/Managing-Relapses. 21. MS symptoms. National Multiple Sclerosis Society. Accessed June 29, 2020. https://www.nationalmssociety.org/Symptoms-Diagnosis/MS-Symptoms. 22. Giovannoni G, Butzkueven H, Dhib-Jalbut S, et al. Brain health: time matters in multiple sclerosis. Mult Scler Relat Disord. 2016;9 Suppl 1:S5-S48. doi:10.1016/j.msard.2016.07.003. 23. Kister I, Bacon TE, Chamot E, et al. Natural history of multiple sclerosis symptoms. Int J MS Care. 2013;15(3):146-158. doi:10.7224/1537-2073.2012-053. 24. Kobelt G, Thompson A, Berg J, Gannedahl M, Eriksson J, MSCOI Study Group; European Multiple Sclerosis Platform. New insights into the burden and costs of multiple sclerosis in Europe. Mult Scler. 2017;23(8):1123-1136. doi:10.1177/1352458517694432. 25. Khan F, Amatya B, Galea M. Management of fatigue in persons with multiple sclerosis. Front Neurol. 2014;5:177. doi:10.3389/fneur.2014.00177. 26. Manjaly ZM, Harrison NA, Critchley HD, et al. Pathophysiological and cognitive mechanisms of fatigue in multiple sclerosis. J Neurol Neurosurg Psychiatry. 2019;90(6):642-651. doi:10.1136/jnnp-2018-320050. 27. Fatigue. National Multiple Sclerosis Society. Accessed June 29, 2020. https://www.nationalmssociety.org/Symptoms-Diagnosis/MS-Symptoms/Fatigue. 28. Cook KF, Bamer AM, Roddey TS, Kraft GH, Kim J, Amtmann D. Multiple sclerosis and fatigue: understanding the patient's needs. Phys Med Rehabil Clin N Am. 2013;24(4):653-661. doi:10.1016/j.pmr.2013.06.006. 29. Bisecco A, Di Nardo F, Docimo R, et al. Fatigue in multiple sclerosis: the contribution of resting-state functional connectivity reorganization. Mult Scler. 2018;24(13):1696-1705. doi:10.1177/1352458517730932. 30. Finke C, Schlichting J, Papazoglou S, et al. Altered basal ganglia functional connectivity in multiple sclerosis patients with fatigue. Mult Scler. 2015;21(7):925-934. doi:10.1177/1352458514555784. 31. Tartaglia MC, Narayanan S, Arnold DL. Mental fatigue alters the pattern and increases the volume of cerebral activation required for a motor task in multiple sclerosis patients with fatigue. Euro J Neurol. 2008;15(4):413-419. doi:10.1111/j.1468-1331.2008.02090.x. 32. Engström M, Flensner G, Landtblom AM, Ek AC, Karlsson T. Thalamo-striato-cortical determinants to fatigue in multiple sclerosis. Brain Behav. 2013;3(6):715-728. doi:10.1002/brb3.181. 33. Chen MH, Wylie GR, Sandroff BM, Dacosta-Aguayo R, DeLuca J, Genova HM. Neural mechanisms underlying state mental fatigue in multiple sclerosis: a pilot study. J Neurol. Published online April 29, 2020. doi:10.1007/s00415-020-09853-w 34. Ayache SS, Chalah MA. Fatigue in multiple sclerosis—insights into evaluation and management. Neurophysiol Clin. 2017;47(2):139-171. doi:10.1016/j.neucli.2017.02.004. 35. Lerdal A, Gulowsen Celius E, Krupp L, Dahl AA. A prospective study of patterns of fatigue in multiple sclerosis. Eur J Neurol. 2007;14(12):1338-1343. doi:10.1111/j.1468-1331.2007.01974.x. 36. McKenzie T, Quig ME, Tyry T, et al. Care partners and multiple sclerosis: differential effect on men and women. Int J MS Care. 2015;17(6):253-260. doi:10.7224/1537-2073.2014-083. 37. Penner IK. Evaluation of cognition and fatigue in multiple sclerosis: daily practice and future directions. Acta Neurol Scand. 2016;134(Suppl 200):19-23. doi:10.1111/ane.12651

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Inflammation is more pronounced in the acute stages of MS but can continue into later stages of the disease as well. Early lesions show invading peripheral immune cells, which can include macrophages, T cells, B cells, and plasma cells. At later stages of the disease, these cells, along with activated CNS-resident microglia and astrocytes, promote gray and white matter damage.3

*A network of vessels and tissue that restricts entry of certain substances into the brain.

Reestablishing or rearranging neural connections.

Cell type that creates myelin in the CNS.

§Specialized end of an axon that determines and guides the direction of growth.

In a 1-year longitudinal study, patients with early RRMS meeting criteria for no evidence of disease activity (NEDA-3; n = 56) and those with evidence of disease activity (n = 36) showed increases in local cortical connections. This change was not observed in healthy controls (n = 101) over the same period.19

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