The Berlin Treatment Algorithm: recommendations for tailored innovative therapeutic strategies for multiple sclerosis-related fatigue

Christian Veauthier, Helge Hasselmann, Stefan M Gold, Friedemann Paul, Christian Veauthier, Helge Hasselmann, Stefan M Gold, Friedemann Paul

Abstract

More than 80% of multiple sclerosis (MS) patients suffer from fatigue. Despite this, there are few therapeutic options and evidence-based pharmacological treatments are lacking. The associated societal burden is substantial (MS fatigue is a major reason for part-time employment or early retirement), and at least one out of four MS patients view fatigue as the most burdensome symptom of their disease. The mechanisms underlying MS-related fatigue are poorly understood, and objective criteria for distinguishing and evaluating levels of fatigue and tiredness have not yet been developed. A further complication is that both symptoms may also be unspecific indicators of many other diseases (including depression, sleep disorders, anemia, renal failure, liver diseases, chronic obstructive pulmonary disease, drug side effects, recent MS relapses, infections, nocturia, cancer, thyroid hypofunction, lack of physical exercise). This paper reviews current treatment options of MS-related fatigue in order to establish an individualized therapeutic strategy that factors in existing comorbid disorders. To ensure that such a strategy can also be easily and widely implemented, a comprehensive approach is needed, which ideally takes into account all other possible causes and which is moreover cost efficient. Using a diagnostic interview, depressive disorders, sleep disorders and side effects of the medication should be identified and addressed. All MS patients suffering from fatigue should fill out the Modified Fatigue Impact Scale, Epworth Sleepiness Scale, the Beck Depression Inventory (or a similar depression scale), and the Pittsburgh Sleep Quality Index (or the Insomnia Severity Index). In some patients, polygraphic or polysomnographic investigations should be performed. The treatment of underlying sleep disorders, drug therapy with alfacalcidol or fampridine, exercise therapy, and cognitive behavioral therapy-based interventions may be effective against MS-related fatigue. The objectives of this article are to identify the reasons for fatigue in patients suffering from multiple sclerosis and to introduce individually tailored treatment approaches. Moreover, this paper focuses on current knowledge about MS-related fatigue in relation to brain atrophy and lesions, cognition, disease course, and other findings in an attempt to identify future research directions.

Keywords: Cognitive behavioral therapy; Depression; Fatigue; Multiple sclerosis; Obstructive sleep apnea; Patient stratification; Personalized medicine; Polysomnography; Resistance training; Restless legs syndrome; Tiredness.

Figures

Fig. 1
Fig. 1
Distinction between primary fatigue, secondary fatigue, and sleepiness. This figure displays possibilities for distinguishing the primary fatigue from secondary fatigue, tiredness, and sleepiness. Whereas primary motor fatigue can be distinguished objectively from tiredness and secondary fatigue by gait recording, primary cognitive fatigue indeed cannot be distinguished objectively from tiredness and secondary fatigue. Sleepiness can clearly be distinguished from primary and secondary fatigue and motor fatigue and tiredness—as sleepiness can be measured objectively by the multiple sleep latency test
Fig. 2
Fig. 2
The Berlin Treatment Algorithm. Please note: Restless legs syndrome can be diagnosed on the basis of the following four minimal criteria: an urge to move the legs (usually accompanied by uncomfortable sensations), which begin or worsen during rest and are relieved by movement predominantly in the evening or night. Depression can be diagnosed by structured interviews. Self-report scales (e.g., Beck Depression Inventory (BDI)) can be useful to screen for depression. Abbreviations: MFIS Modified Fatigue Impact Scale, PSQI Pittsburgh Sleep Quality Index, ESS Epworth Sleepiness Scale, COPD chronic obstructive pulmonary disease, SSRIs selective serotonin reuptake inhibitors, CBT cognitive behavioral therapy

References

    1. Borisow N, Döring A, Pfueller CF, Paul F, Dörr J, Hellwig K. Expert recommendations to personalization of medical approaches in treatment of multiple sclerosis: an overview of family planning and pregnancy. EPMA J. 2012;3(1):9. doi: 10.1186/1878-5085-3-9.
    1. Veauthier C, Paul F. Sleep disorders in multiple sclerosis and their relationship to fatigue. Sleep Med. 2014;15(1):5–14. doi: 10.1016/j.sleep.2013.08.791.
    1. Konieczka K, Koch S, Binggeli T, Schoetzau A, Kesselring J. Multiple sclerosis and primary vascular dysregulation (Flammer syndrome). EPMA J. 2016;7(1). Available from: .
    1. Krupp LB, Alvarez LA, LaRocca NG, Scheinberg LC. Fatigue in multiple sclerosis. Arch Neurol. 1988;45(4):435–7. doi: 10.1001/archneur.1988.00520280085020.
    1. Berger JR, Pocoski J, Preblick R, Boklage S. Fatigue heralding multiple sclerosis. Mult Scler. 2013;19(11):1526–32. doi: 10.1177/1352458513477924.
    1. Chua AS, Glanz BI, Guarino AJ, Cook SL, Greeke EE, Little GE, et al. Patient-reported outcomes in multiple sclerosis: relationships among existing scales and the development of a brief measure. Mult Scler Relat Disord. 2015;4(6):598–606. doi: 10.1016/j.msard.2015.09.004.
    1. Moore P, Harding KE, Clarkson H, Pickersgill TP, Wardle M, Robertson NP. Demographic and clinical factors associated with changes in employment in multiple sclerosis. Mult Scler. 2013;19(12):1647–54. doi: 10.1177/1352458513481396.
    1. Coyne KS, Boscoe AN, Currie BM, Landrian AS, Wandstrat TL. Understanding drivers of employment changes in a multiple sclerosis population. Int J MS Care. 2015;17(5):245–52. doi: 10.7224/1537-2073.2014-051.
    1. Paralyzed Veterans of America, editor. Fatigue and multiple sclerosis: evidence-based management strategies for fatigue in multiple sclerosis. Washington, DC; 1998. Available from: .
    1. Veauthier C, Paul F. Therapie der Fatigue bei Multipler Sklerose, ein Behandlungsalgorithmus. Nervenarzt. 2016, doi:10.1007/s00115-016-0128-7.
    1. Krupp LB, LaRocca NG, Muir-Nash J, Steinberg AD. The fatigue severity scale. Application to patients with multiple sclerosis and systemic lupus erythematosus. Arch Neurol. 1989;46(10):1121–3. doi: 10.1001/archneur.1989.00520460115022.
    1. Fisk JD, Ritvo PG, Ross L, Haase DA, Marrie TJ, Schlech WF. Measuring the functional impact of fatigue: initial validation of the fatigue impact scale. Clin Infect Dis. 1994;18(Suppl 1):S79–83. doi: 10.1093/clinids/18.Supplement_1.S79.
    1. Fischer JS, LaRocca NG, Miller DM, Ritvo PG, Andrews H, Paty D. Recent developments in the assessment of quality of life in multiple sclerosis (MS) Mult Scler. 1999;5(4):251–9. doi: 10.1191/135245899678846177.
    1. Veauthier C. Younger age, female sex, and high number of awakenings and arousals predict fatigue in patients with sleep disorders: a retrospective polysomnographic observational study. Neuropsychiatr Dis Treat. 2013;9:1483. doi: 10.2147/NDT.S50763.
    1. Flachenecker P, Kümpfel T, Kallmann B, Gottschalk M, Grauer O, Rieckmann P, et al. Fatigue in multiple sclerosis: a comparison of different rating scales and correlation to clinical parameters. Mult Scler. 2002;8(6):523–6. doi: 10.1191/1352458502ms839oa.
    1. Stankoff B, Waubant E, Confavreux C, Edan G, Debouverie M, Rumbach L, et al. Modafinil for fatigue in MS: a randomized placebo-controlled double-blind study. Neurology. 2005;64(7):1139–43. doi: 10.1212/01.WNL.0000158272.27070.6A.
    1. Veauthier C, Radbruch H, Gaede G, Pfueller C, Dorr J, Bellmann-Strobl J, et al. Fatigue in multiple sclerosis is closely related to sleep disorders: a polysomnographic cross-sectional study. Mult Scler. 2011;17(5):613–22. doi: 10.1177/1352458510393772.
    1. Penner I, Raselli C, Stocklin M, Opwis K, Kappos L, Calabrese P. The Fatigue Scale for Motor and Cognitive Functions (FSMC): validation of a new instrument to assess multiple sclerosis-related fatigue. Mult Scler. 2009;15(12):1509–17. doi: 10.1177/1352458509348519.
    1. Greim B, Benecke R, Zettl UK. Qualitative and quantitative assessment of fatigue in multiple sclerosis (MS) J Neurol. 2007;254(S2):II58–64.
    1. American Academy of Sleep Medicine, editor. International Classification of Sleep Disorders. 3rd ed. Darien, IL: American Academy of Sleep Medicine; 2014.
    1. Marti I, Valko PO, Khatami R, Bassetti CL, Baumann CR. Multiple sleep latency measures in narcolepsy and behaviourally induced insufficient sleep syndrome. Sleep Med. 2009;10(10):1146–50. doi: 10.1016/j.sleep.2009.03.008.
    1. Johns MW. Reliability and factor analysis of the Epworth Sleepiness Scale. Sleep. 1992;15(4):376–81.
    1. Popp RFJ, Fierlbeck AK, Knüttel H, König N, Rupprecht R, Weissert R, et al. Daytime sleepiness versus fatigue in patients with multiple sclerosis: a systematic review on the Epworth sleepiness scale as an assessment tool. Sleep Med Rev. 2016, doi:10.1016/j.smrv.2016.03.004.
    1. Aguillard RN, Riedel BW, Lichstein KL, Grieve FG, Johnson CT, Noe SL. Daytime functioning in obstructive sleep apnea patients: exercise tolerance, subjective fatigue, and sleepiness. Appl Psychophysiol Biofeedback. 1998;23(4):207–17. doi: 10.1023/A:1022257514209.
    1. Hossain JL, Ahmad P, Reinish LW, Kayumov L, Hossain NK, Shapiro CM. Subjective fatigue and subjective sleepiness: two independent consequences of sleep disorders? J Sleep Res. 2005;14(3):245–53. doi: 10.1111/j.1365-2869.2005.00466.x.
    1. Kluger BM, Krupp LB, Enoka RM. Fatigue and fatigability in neurologic illnesses: proposal for a unified taxonomy. Neurology. 2013;80(4):409–16. doi: 10.1212/WNL.0b013e31827f07be.
    1. Severijns D, Octavia JR, Kerkhofs L, Coninx K, Lamers I, Feys P. Investigation of fatigability during repetitive robot-mediated arm training in people with multiple sclerosis. PLoS One. 2015;10(7):e0133729. doi: 10.1371/journal.pone.0133729.
    1. Behrens J, Pfüller C, Mansow-Model S, Otte K, Paul F, Brandt AU. Using perceptive computing in multiple sclerosis—the Short Maximum Speed Walk test. J Neuroeng Rehabil. 2014;11:89. doi: 10.1186/1743-0003-11-89.
    1. Behrens JR, Mertens S, Krüger T, Grobelny A, Otte K, Mansow-Model S, et al. Validity of visual perceptive computing for static posturography in patients with multiple sclerosis. Mult Scler. 2016;22(12):1596–1606. doi: 10.1177/1352458515625807.
    1. Sehle A, Mündermann A, Starrost K, Sailer S, Becher I, Dettmers C, et al. Objective assessment of motor fatigue in multiple sclerosis using kinematic gait analysis: a pilot study. J Neuroeng Rehabil. 2011;8:59. doi: 10.1186/1743-0003-8-59.
    1. Filippi M, Rocca MA, Colombo B, Falini A, Codella M, Scotti G, et al. Functional magnetic resonance imaging correlates of fatigue in multiple sclerosis. NeuroImage. 2002;15(3):559–67. doi: 10.1006/nimg.2001.1011.
    1. Manconi M, Rocca MA, Ferini-Strambi L, Tortorella P, Agosta F, Comi G, et al. Restless legs syndrome is a common finding in multiple sclerosis and correlates with cervical cord damage. Mult Scler. 2008;14(1):86–93. doi: 10.1177/1352458507080734.
    1. Veauthier C, Gaede G, Radbruch H, Sieb J-P, Wernecke K-D, Paul F. Periodic limb movements during REM sleep in multiple sclerosis: a previously undescribed entity. Neuropsychiatr Dis Treat. 2015;11:2323. doi: 10.2147/NDT.S83350.
    1. Kurtzke JF. Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS) Neurology. 1983;33:1444–52. doi: 10.1212/WNL.33.11.1444.
    1. Patrick E, Christodoulou C, Krupp L, on behalf of the New York State MS Consortium Longitudinal correlates of fatigue in multiple sclerosis. Mult Scler. 2008;15(2):258–61. doi: 10.1177/1352458508097466.
    1. Merkelbach S, Schulz H, Kölmel HW, Gora G, Klingelhöfer J, Dachsel R, et al. Fatigue, sleepiness, and physical activity in patients with multiple sclerosis. J Neurol. 2011;258(1):74–9. doi: 10.1007/s00415-010-5684-3.
    1. Colosimo C, Millefiorini E, Grasso MG, Vinci F, Fiorelli M, Koudriavtseva T, et al. Fatigue in MS is associated with specific clinical features. Acta Neurol Scand. 1995;92(5):353–5. doi: 10.1111/j.1600-0404.1995.tb00145.x.
    1. Mills RJ, Young CA. The relationship between fatigue and other clinical features of multiple sclerosis. Mult Scler. 2011;17(5):604–12. doi: 10.1177/1352458510392262.
    1. Runia TF, Jafari N, Siepman DAM, Hintzen RQ. Fatigue at time of CIS is an independent predictor of a subsequent diagnosis of multiple sclerosis. J Neurol Neurosurg Psychiatry. 2015;86(5):543–6. doi: 10.1136/jnnp-2014-308374.
    1. Marrie RA, Reingold S, Cohen J, Stuve O, Trojano M, Sorensen PS, et al. The incidence and prevalence of psychiatric disorders in multiple sclerosis: a systematic review. Mult Scler. 2015;21(3):305–17. doi: 10.1177/1352458514564487.
    1. Chiaravalloti ND, DeLuca J. Cognitive impairment in multiple sclerosis. Lancet Neurol. 2008;7(12):1139–51. doi: 10.1016/S1474-4422(08)70259-X.
    1. Rao SM, Leo GJ, Bernardin L, Unverzagt F. Cognitive dysfunction in multiple sclerosis. I. Frequency, patterns, and prediction. Neurology. 1991;41(5):685–91. doi: 10.1212/WNL.41.5.685.
    1. Urbanek C, Weinges-Evers N, Bellmann-Strobl J, Bock M, Dörr J, Hahn E, et al. Attention Network Test reveals alerting network dysfunction in multiple sclerosis. Mult Scler. 2010;16(1):93–9. doi: 10.1177/1352458509350308.
    1. DeLuca J, Johnson SK, Natelson BH. Information processing efficiency in chronic fatigue syndrome and multiple sclerosis. Arch Neurol. 1993;50(3):301–4. doi: 10.1001/archneur.1993.00540030065016.
    1. Demaree HA, DeLuca J, Gaudino EA, Diamond BJ. Speed of information processing as a key deficit in multiple sclerosis: implications for rehabilitation. J Neurol Neurosurg Psychiatry. 1999;67(5):661–3. doi: 10.1136/jnnp.67.5.661.
    1. McCarthy M, Beaumont JG, Thompson R, Peacock S. Modality-specific aspects of sustained and divided attentional performance in multiple sclerosis. Arch Clin Neuropsychol. 2005;20(6):705–18. doi: 10.1016/j.acn.2005.04.007.
    1. Weinges-Evers N, Brandt AU, Bock M, Pfueller CF, Dörr J, Bellmann-Strobl J, et al. Correlation of self-assessed fatigue and alertness in multiple sclerosis. Mult Scler. 2010;16(9):1134–40. doi: 10.1177/1352458510374202.
    1. Guimarães J, Sá MJ. Cognitive dysfunction in multiple sclerosis. Front Neurol. 2012;3:74. doi:10.3389/fneur.2012.00074.
    1. Bellmann-Strobl J, Wuerfel J, Aktas O, Dörr J, Wernecke KD, Zipp F, et al. Poor PASAT performance correlates with MRI contrast enhancement in multiple sclerosis. Neurology. 2009;73(20):1624–7. doi: 10.1212/WNL.0b013e3181c1de4f.
    1. Johnson SK, Lange G, DeLuca J, Korn LR, Natelson B. The effects of fatigue on neuropsychological performance in patients with chronic fatigue syndrome, multiple sclerosis, and depression. Appl Neuropsychol. 1997;4(3):145–53. doi: 10.1207/s15324826an0403_1.
    1. Kujala P, Portin R, Revonsuo A, Ruutiainen J. Attention related performance in two cognitively different subgroups of patients with multiple sclerosis. J Neurol Neurosurg Psychiatry. 1995;59:77–82. doi: 10.1136/jnnp.59.1.77.
    1. Krupp LB, Elkins LE. Fatigue and declines in cognitive functioning in multiple sclerosis. Neurology. 2000;55(7):934–9. doi: 10.1212/WNL.55.7.934.
    1. Parmenter BA, Denney DR, Lynch SG. The cognitive performance of patients with multiple sclerosis during periods of high and low fatigue. Mult Scler. 2003;9(2):111–8. doi: 10.1191/1352458503ms859oa.
    1. Geisler MW, Sliwinski M, Coyle PK, Masur DM, Doscher C, Krupp LB. The effects of amantadine and pemoline on cognitive functioning in multiple sclerosis. Arch Neurol. 1996;53(2):185–8. doi: 10.1001/archneur.1996.00550020101021.
    1. Schwartz CE, Coulthard-Morris L, Zeng Q. Psychosocial correlates of fatigue in multiple sclerosis. Arch Phys Med Rehabil. 1996;77(2):165–70. doi: 10.1016/S0003-9993(96)90162-8.
    1. Bailey A, Channon S, Beaumont JG. The relationship between subjective fatigue and cognitive fatigue in advanced multiple sclerosis. Mult Scler. 2007;13(1):73–80. doi: 10.1177/1352458506071162.
    1. Siegert RJ, Abernethy DA. Depression in multiple sclerosis: a review. J Neurol Neurosurg Psychiatry. 2005;76(4):469–75. doi: 10.1136/jnnp.2004.054635.
    1. Arnett PA, Barwick FH, Beeney JE. Depression in multiple sclerosis: review and theoretical proposal. J Int Neuropsychol Soc. 2008;14(5):691–724. doi: 10.1017/S1355617708081174.
    1. Arnett PA, Higginson CI, Voss WD, Wright B, Bender WI, Wurst JM, et al. Depressed mood in multiple sclerosis: relationship to capacity-demanding memory and attentional functioning. Neuropsychology. 1999;13(3):434–46. doi: 10.1037/0894-4105.13.3.434.
    1. Arnett PA, Higginson CI, Voss WD, Bender WI, Wurst JM, Tippin JM. Depression in multiple sclerosis: relationship to working memory capacity. Neuropsychology. 1999;13(4):546–56. doi: 10.1037/0894-4105.13.4.546.
    1. Arnett PA, Higginson CI, Randolph JJ. Depression in multiple sclerosis: relationship to planning ability. J Int Neuropsychol Soc. 2001;7(6):665–74. doi: 10.1017/S1355617701766027.
    1. Diamond BJ, Johnson SK, Kaufman M, Graves L. Relationships between information processing, depression, fatigue and cognition in multiple sclerosis. Arch Clin Neuropsychol. 2008;23(2):189–99. doi: 10.1016/j.acn.2007.10.002.
    1. DeLuca J, Chelune GJ, Tulsky DS, Lengenfelder J, Chiaravalloti ND. Is speed of processing or working memory the primary information processing deficit in multiple sclerosis? J Clin Exp Neuropsychol. 2004;26(4):550–62. doi: 10.1080/13803390490496641.
    1. Archibald CJ, Fisk JD. Information processing efficiency in patients with multiple sclerosis. J Clin Exp Neuropsychol. 2000;22(5):686–701. doi: 10.1076/1380-3395(200010)22:5;1-9;FT686.
    1. Gaudino EA, Chiaravalloti ND, DeLuca J, Diamond BJ. A comparison of memory performance in relapsing-remitting, primary progressive and secondary progressive, multiple sclerosis. Neuropsychiatry Neuropsychol Behav Neurol. 2001;14(1):32–44.
    1. Benedict RHB, Cookfair D, Gavett R, Gunther M, Munschauer F, Garg N, et al. Validity of the minimal assessment of cognitive function in multiple sclerosis (MACFIMS) J Int Neuropsychol Soc. 2006;12(4):549–58. doi: 10.1017/S1355617706060723.
    1. Langdon D, Amato M, Boringa J, Brochet B, Foley F, Fredrikson S, et al. Recommendations for a Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS) Mult Scler. 2012;18(6):891–8. doi: 10.1177/1352458511431076.
    1. Kaminska M, Kimoff R, Benedetti A, Robinson A, Bar-Or A, Lapierre Y, et al. Obstructive sleep apnea is associated with fatigue in multiple sclerosis. Mult Scler. 2012;18(8):1159–69. doi: 10.1177/1352458511432328.
    1. Veauthier C, Gaede G, Radbruch H, Gottschalk S, Wernecke K-D, Paul F. Treatment of sleep disorders may improve fatigue in multiple sclerosis. Clin Neurol Neurosurg. 2013;115(9):1826–30. doi: 10.1016/j.clineuro.2013.05.018.
    1. Cote I, Trojan D, Kaminska M, Cardoso M, Benedetti A, Weiss D, et al. Impact of sleep disorder treatment on fatigue in multiple sclerosis. Mult Scler. 2013;19(4):480–9. doi: 10.1177/1352458512455958.
    1. Braley TJ, Segal BM, Chervin RD. Hypnotic use and fatigue in multiple sclerosis. Sleep Med. 2015;16(1):131–7. doi: 10.1016/j.sleep.2014.09.006.
    1. Veauthier C. Hypnotic use and multiple sclerosis related fatigue: a forgotten confounder. Sleep Med. 2015;16(3):319. doi: 10.1016/j.sleep.2014.11.012.
    1. Baglioni C, Spiegelhalder K, Nissen C, Riemann D. Clinical implications of the causal relationship between insomnia and depression: how individually tailored treatment of sleeping difficulties could prevent the onset of depression. EPMA J. 2011;2(3):287–93. doi: 10.1007/s13167-011-0079-9.
    1. Manconi M, Ferini-Strambi L, Filippi M, Bonanni E, Iudice A, Murri L, et al. Multicenter case-control study on restless legs syndrome in multiple sclerosis: the REMS study. Sleep. 2008;31(7):944–52.
    1. Li Y, Munger KL, Batool-Anwar S, De Vito K, Ascherio A, Gao X. Association of multiple sclerosis with restless legs syndrome and other sleep disorders in women. Neurology. 2012;78(19):1500–6. doi: 10.1212/WNL.0b013e3182553c5b.
    1. Braley TJ, Segal BM, Chervin RD. Sleep-disordered breathing in multiple sclerosis. Neurology. 2012;79(9):929–36. doi: 10.1212/WNL.0b013e318266fa9d.
    1. Habukawa M, Uchimura N, Kakuma T, Yamamoto K, Ogi K, Hiejima H, et al. Effect of CPAP treatment on residual depressive symptoms in patients with major depression and coexisting sleep apnea: contribution of daytime sleepiness to residual depressive symptoms. Sleep Med. 2010;11(6):552–7. doi: 10.1016/j.sleep.2010.02.007.
    1. Schwartz DJ, Karatinos G. For individuals with obstructive sleep apnea, institution of CPAP therapy is associated with an amelioration of symptoms of depression which is sustained long term. J Clin Sleep Med. 2007;3(6):631–5.
    1. Hasselmann H, Bellmann-Strobl J, Ricken R, Oberwahrenbrock T, Rose M, Otte C, et al. Characterizing the phenotype of multiple sclerosis-associated depression in comparison with idiopathic major depression. Mult Scler. 2016;22(11):1476–84. doi: 10.1177/1352458515622826.
    1. Mahajan ST, Patel PB, Marrie RA. Under treatment of overactive bladder symptoms in patients with multiple sclerosis: an ancillary analysis of the NARCOMS patient registry. J Urol. 2010;183(4):1432–7. doi: 10.1016/j.juro.2009.12.029.
    1. Buysse DJ, Reynolds CF, Monk TH, Berman SR, Kupfer DJ. The Pittsburgh Sleep Quality Index: a new instrument for psychiatric practice and research. Psychiatry Res. 1989;28(2):193–213. doi: 10.1016/0165-1781(89)90047-4.
    1. Veauthier C, Paul F. Fatigue in multiple sclerosis: which patient should be referred to a sleep specialist? Mult Scler. 2012;18(2):248–9. doi: 10.1177/1352458511411229.
    1. Sinnecker T, Mittelstaedt P, Dörr J, Pfueller CF, Harms L, Niendorf T, et al. Multiple sclerosis lesions and irreversible brain tissue damage: a comparative ultrahigh-field strength magnetic resonance imaging study. Arch Neurol. 2012;69(6):739–45. doi: 10.1001/archneurol.2011.2450.
    1. Bakshi R, Yeste A, Patel B, Tauhid S, Tummala S, Rahbari R, et al. Serum lipid antibodies are associated with cerebral tissue damage in multiple sclerosis. Neurol Neuroimmunol Neuroinflamm. 2016;3(2):e200. doi: 10.1212/NXI.0000000000000200.
    1. Azevedo CJ, Overton E, Khadka S, Buckley J, Liu S, Sampat M, et al. Early CNS neurodegeneration in radiologically isolated syndrome. Neurol Neuroimmunol Neuroinflamm. 2015;2(3):e102. doi: 10.1212/NXI.0000000000000102.
    1. Zivadinov R, Cerza N, Hagemeier J, Carl E, Badgett D, Ramasamy DP, et al. Humoral response to EBV is associated with cortical atrophy and lesion burden in patients with MS. Neurol Neuroimmunol Neuroinflamm. 2016;3(1):e190. doi: 10.1212/NXI.0000000000000190.
    1. Pérez-Miralles FC, Sastre-Garriga J, Vidal-Jordana A, Río J, Auger C, Pareto D, et al. Predictive value of early brain atrophy on response in patients treated with interferon β. Neurol Neuroimmunol Neuroinflamm. 2015;2(4):e132. doi: 10.1212/NXI.0000000000000132.
    1. Paul F. Pathology and MRI: exploring cognitive impairment in MS. Acta Neurol Scand. 2016;134(Suppl 200):24–33. doi: 10.1111/ane.12649.
    1. Tartaglia MC, Narayanan S, Francis SJ, Santos AC, De Stefano N, Lapierre Y, et al. The relationship between diffuse axonal damage and fatigue in multiple sclerosis. Arch Neurol. 2004;61(2):201–7. doi: 10.1001/archneur.61.2.201.
    1. Calabrese M, Rinaldi F, Grossi P, Mattisi I, Bernardi V, Favaretto A, et al. Basal ganglia and frontal/parietal cortical atrophy is associated with fatigue in relapsing-remitting multiple sclerosis. Mult Scler. 2010;16(10):1220–8. doi: 10.1177/1352458510376405.
    1. Pellicano C, Gallo A, Li X, Ikonomidou VN, Evangelou IE, Ohayon JM, et al. Relationship of cortical atrophy to fatigue in patients with multiple sclerosis. Arch Neurol. 2010;67(4).
    1. Yaldizli O, Penner I-K, Frontzek K, Naegelin Y, Amann M, Papadopoulou A, et al. The relationship between total and regional corpus callosum atrophy, cognitive impairment and fatigue in multiple sclerosis patients. Mult Scler. 2014;20(3):356–64. doi: 10.1177/1352458513496880.
    1. Nygaard GO, Walhovd KB, Sowa P, Chepkoech J-L, Bjornerud A, Due-Tonnessen P, et al. Cortical thickness and surface area relate to specific symptoms in early relapsing-remitting multiple sclerosis. Mult Scler. 2015;21(4):402–14. doi: 10.1177/1352458514543811.
    1. Gobbi C, Rocca M, Riccitelli G, Pagani E, Messina R, Preziosa P, et al. Influence of the topography of brain damage on depression and fatigue in patients with multiple sclerosis. Mult Scler. 2014;20(2):192–201. doi: 10.1177/1352458513493684.
    1. Sepulcre J, Masdeu J, Goni J, Arrondo G, Velez de Mendizabal N, Bejarano B, et al. Fatigue in multiple sclerosis is associated with the disruption of frontal and parietal pathways. Mult Scler. 2009;15(3):337–44. doi: 10.1177/1352458508098373.
    1. Damasceno A, Damasceno BP, Cendes F. Atrophy of reward-related striatal structures in fatigued MS patients is independent of physical disability. Mult Scler. 2016;22(6):822–9. doi: 10.1177/1352458515599451.
    1. Roelcke U, Kappos L, Lechner-Scott J, Brunnschweiler H, Huber S, Ammann W, et al. Reduced glucose metabolism in the frontal cortex and basal ganglia of multiple sclerosis patients with fatigue: a 18F-fluorodeoxyglucose positron emission tomography study. Neurology. 1997;48(6):1566–71. doi: 10.1212/WNL.48.6.1566.
    1. Finke C, Schlichting J, Papazoglou S, Scheel M, Freing A, Soemmer C, et al. Altered basal ganglia functional connectivity in multiple sclerosis patients with fatigue. Mult Scler. 2015;21(7):925–34. doi: 10.1177/1352458514555784.
    1. Rocca MA, Meani A, Riccitelli GC, Colombo B, Rodegher M, Falini A, et al. Abnormal adaptation over time of motor network recruitment in multiple sclerosis patients with fatigue. Mult Scler. 2016;22(9):1144–53. doi: 10.1177/1352458515614407.
    1. Dantzer R, O’Connor JC, Freund GG, Johnson RW, Kelley KW. From inflammation to sickness and depression: when the immune system subjugates the brain. Nat Rev Neurosci. 2008;9:46–56. doi: 10.1038/nrn2297.
    1. Schedlowski M, Engler H, Grigoleit J-S. Endotoxin-induced experimental systemic inflammation in humans: a model to disentangle immune-to-brain communication. Brain Behav Immun. 2014;35:1–8. doi: 10.1016/j.bbi.2013.09.015.
    1. Jin S, Kim JG, Park JW, Koch M, Horvath TL, Lee BJ. Hypothalamic TLR2 triggers sickness behavior via a microglia-neuronal axis. Sci Rep. 2016;6:29424. doi: 10.1038/srep29424.
    1. Hanken K, Eling P, Kastrup A, Klein J, Hildebrandt H. Integrity of hypothalamic fibers and cognitive fatigue in multiple sclerosis. Mult Scler Relat Disord. 2015;4(1):39–46. doi: 10.1016/j.msard.2014.11.006.
    1. Giovannoni G, Thompson AJ, Miller DH, Thompson EJ. Fatigue is not associated with raised inflammatory markers in multiple sclerosis. Neurology. 2001;57(4):676–81. doi: 10.1212/WNL.57.4.676.
    1. Rudick RA, Barna BP. Serum interleukin 2 and soluble interleukin 2 receptor in patients with multiple sclerosis who are experiencing severe fatigue. Arch Neurol. 1990;47(3):254–5. doi: 10.1001/archneur.1990.00530030018008.
    1. Flachenecker P, Bihler I, Weber F, Gottschalk M, Toyka KV, Rieckmann P. Cytokine mRNA expression in patients with multiple sclerosis and fatigue. Mult Scler. 2004;10(2):165–9. doi: 10.1191/1352458504ms991oa.
    1. Heesen C, Nawrath L, Reich C, Bauer N, Schulz K-H, Gold SM. Fatigue in multiple sclerosis: an example of cytokine mediated sickness behaviour? J Neurol Neurosurg Psychiatry. 2006;77(1):34–9. doi: 10.1136/jnnp.2005.065805.
    1. Gold SM, Krüger S, Ziegler KJ, Krieger T, Schulz K-H, Otte C, et al. Endocrine and immune substrates of depressive symptoms and fatigue in multiple sclerosis patients with comorbid major depression. J Neurol Neurosurg Psychiatry. 2011;82(7):814–8. doi: 10.1136/jnnp.2010.230029.
    1. Malekzadeh A, Van de Geer-Peeters W, De Groot V, Teunissen CE, Beckerman H, TREFAMS-ACE Study Group Fatigue in patients with multiple sclerosis: is it related to pro- and anti-inflammatory cytokines? Dis Markers. 2015;2015:758314. doi: 10.1155/2015/758314.
    1. Gottschalk M, Kümpfel T, Flachenecker P, Uhr M, Trenkwalder C, Holsboer F, et al. Fatigue and regulation of the hypothalamo-pituitary-adrenal axis in multiple sclerosis. Arch Neurol. 2005;62(2):277. doi: 10.1001/archneur.62.2.277.
    1. Téllez N, Comabella M, Julià E, Río J, Tintoré M, Brieva L, et al. Fatigue in progressive multiple sclerosis is associated with low levels of dehydroepiandrosterone. Mult Scler. 2006;12(4):487–94. doi: 10.1191/135248505ms1322oa.
    1. Powell DJH, Moss-Morris R, Liossi C, Schlotz W. Circadian cortisol and fatigue severity in relapsing-remitting multiple sclerosis. Psychoneuroendocrinology. 2015;56:120–31. doi: 10.1016/j.psyneuen.2015.03.010.
    1. Jongen PJ, Lehnick D, Koeman J, Frequin S, Heersema D, Kornips B, et al. Fatigue and health-related quality of life in relapsing-remitting multiple sclerosis after 2 years glatiramer acetate treatment are predicted by changes at 6 months: an observational multi-center study. J Neurol. 2014;261(8):1469–76. doi: 10.1007/s00415-014-7363-2.
    1. Melanson M, Grossberndt A, Klowak M, Leong C, Frost EE, Prout M, et al. Fatigue and cognition in patients with relapsing multiple sclerosis treated with interferon beta. Int J Neurosci. 2010;120(10):631–40. doi: 10.3109/00207454.2010.511732.
    1. Ziemssen T. Multiple sclerosis beyond EDSS: depression and fatigue. J Neurol Sci. 2009;277:S37–41. doi: 10.1016/S0022-510X(09)70011-5.
    1. Patti F, Amato MP, Trojano M, Bastianello S, Tola MR, Picconi O, et al. Quality of life, depression and fatigue in mildly disabled patients with relapsing-remitting multiple sclerosis receiving subcutaneous interferon beta-1a: 3-year results from the COGIMUS (COGnitive Impairment in MUltiple Sclerosis) study. Mult Scler. 2011;17(8):991–1001. doi: 10.1177/1352458511401943.
    1. Kunkel A, Fischer M, Faiss J, Dähne D, Köhler W, Faiss JH. Impact of natalizumab treatment on fatigue, mood, and aspects of cognition in relapsing-remitting multiple sclerosis. Front Neurol. 2015;6:97. doi:10.3389/fneur.2015.00097. eCollection 2015.
    1. Penner I-K, Sivertsdotter EC, Celius EG, Fuchs S, Schreiber K, Berkö S, et al. Improvement in fatigue during natalizumab treatment is linked to improvement in depression and day-time sleepiness. Front Neurol. 2015;6:18.
    1. Montalban X, Comi G, O’Connor P, Gold S, de Vera A, Eckert B, et al. Oral fingolimod (FTY720) in relapsing multiple sclerosis: impact on health-related quality of life in a phase II study. Mult Scler. 2011;17(11):1341–50. doi: 10.1177/1352458511411061.
    1. Calkwood J, Cree B, Crayton H, Kantor D, Steingo B, Barbato L, et al. Impact of a switch to fingolimod versus staying on glatiramer acetate or beta interferons on patient- and physician-reported outcomes in relapsing multiple sclerosis: post hoc analyses of the EPOC trial. BMC Neurol. 2014;14(1):220. doi: 10.1186/s12883-014-0220-1.
    1. Riera R, Porfírio GJ, Torloni MR. Alemtuzumab for multiple sclerosis. Cochrane Database Syst Rev. 2016;4:CD011203.
    1. Kappos L, Gold R, Miller DH, MacManus DG, Havrdova E, Limmroth V, et al. Efficacy and safety of oral fumarate in patients with relapsing-remitting multiple sclerosis: a multicentre, randomised, double-blind, placebo-controlled phase IIb study. Lancet. 2008;372(9648):1463–72. doi: 10.1016/S0140-6736(08)61619-0.
    1. O’Connor P, Wolinsky JS, Confavreux C, Comi G, Kappos L, Olsson TP, et al. Randomized trial of oral teriflunomide for relapsing multiple sclerosis. N Engl J Med. 2011;365(14):1293–303. doi: 10.1056/NEJMoa1014656.
    1. Lerdal A, Bakken LN, Kouwenhoven SE, Pedersen G, Kirkevold M, Finset A, et al. Poststroke fatigue—a review. J Pain Symptom Manage. 2009;38(6):928–49. doi: 10.1016/j.jpainsymman.2009.04.028.
    1. Friedman JH, Brown RG, Comella C, Garber CE, Krupp LB, Lou J-S, et al. Fatigue in Parkinson’s disease: a review. Mov Disord. 2007;22(3):297–308. doi: 10.1002/mds.21240.
    1. Thames AD, Castellon SA, Singer EJ, Nagarajan R, Sarma MK, Smith J, et al. Neuroimaging abnormalities, neurocognitive function, and fatigue in patients with hepatitis C. Neurol Neuroimmunol Neuroinflamm. 2015;2(1):e59–9. doi: 10.1212/NXI.0000000000000059.
    1. Achiron A, Givon U, Magalashvili D, Dolev M, Liraz Zaltzman S, Kalron A, et al. Effect of alfacalcidol on multiple sclerosis-related fatigue: a randomized, double-blind placebo-controlled study. Mult Scler. 2015;21(6):767–75. doi: 10.1177/1352458514554053.
    1. Moller F, Poettgen J, Broemel F, Neuhaus A, Daumer M, Heesen C. HAGIL (Hamburg Vigil Study): a randomized placebo-controlled double-blind study with modafinil for treatment of fatigue in patients with multiple sclerosis. Mult Scler. 2011;17(8):1002–9. doi: 10.1177/1352458511402410.
    1. Branas P. Treatments for fatigue in multiple sclerosis: a rapid and systematic review. Health Technol Assess. 2000;4(27):1-61. .
    1. Shaygannejad V, Janghorbani M, Ashtari F, Zakeri H. Comparison of the effect of aspirin and amantadine for the treatment of fatigue in multiple sclerosis: a randomized, blinded, crossover study. Neurol Res. 2012;34(9):854–8. doi: 10.1179/1743132812Y.0000000081.
    1. Ashtari F, Fatehi F, Shaygannejad V, Chitsaz A. Does amantadine have favourable effects on fatigue in Persian patients suffering from multiple sclerosis? Neurol Neurochir Pol. 2009;43(5):428–32.
    1. Rossini PM, Pasqualetti P, Pozzilli C, Grasso MG, Millefiorini E, Graceffa A, et al. Fatigue in progressive multiple sclerosis: results of a randomized, double-blind, placebo-controlled, crossover trial of oral 4-aminopyridine. Mult Scler. 2001;7(6):354–8. doi: 10.1191/135245801701567050.
    1. Weinshenker BG, Penman M, Bass B, Ebers GC, Rice GP. A double-blind, randomized, crossover trial of pemoline in fatigue associated with multiple sclerosis. Neurology. 1992;42(8):1468–71. doi: 10.1212/WNL.42.8.1468.
    1. Cohen RA, Fisher M. Amantadine treatment of fatigue associated with multiple sclerosis. Arch Neurol. 1989;46(6):676–80. doi: 10.1001/archneur.1989.00520420096030.
    1. A randomized controlled trial of amantadine in fatigue associated with multiple sclerosis. The Canadian MS Research Group. Can J Neurol Sci. 1987;14(3):273–8.
    1. Asano M, Finlayson ML. Meta-analysis of three different types of fatigue management interventions for people with multiple sclerosis: exercise, education, and medication. Mult Scler Int. 2014;2014:1–12. doi: 10.1155/2014/798285.
    1. Lange R, Volkmer M, Heesen C, Liepert J. Modafinil effects in multiple sclerosis patients with fatigue. J Neurol. 2009;256(4):645–50. doi: 10.1007/s00415-009-0152-7.
    1. Krupp LB, Coyle PK, Doscher C, Miller A, Cross AH, Jandorf L, et al. Fatigue therapy in multiple sclerosis: results of a double-blind, randomized, parallel trial of amantadine, pemoline, and placebo. Neurology. 1995;45(11):1956–61. doi: 10.1212/WNL.45.11.1956.
    1. Rosenberg GA, Appenzeller O. Amantadine, fatigue, and multiple sclerosis. Arch Neurol. 1988;45(10):1104–6. doi: 10.1001/archneur.1988.00520340058012.
    1. Tomassini V, Pozzilli C, Onesti E, Pasqualetti P, Marinelli F, Pisani A, et al. Comparison of the effects of acetyl l-carnitine and amantadine for the treatment of fatigue in multiple sclerosis: results of a pilot, randomised, double-blind, crossover trial. J Neurol Sci. 2004;218(1–2):103–8. doi: 10.1016/j.jns.2003.11.005.
    1. Peuckmann-Post V, Elsner F, Krumm N, Trottenberg P, Radbruch L. Pharmacological treatments for fatigue associated with palliative care. Cochrane Database Syst Rev. 2010;11:CD006788.
    1. Mücke M. Mochamat, Cuhls H, Peuckmann-Post V, Minton O, Stone P, et al. Pharmacological treatments for fatigue associated with palliative care. Cochrane Database Syst Rev. 2015;5:CD006788.
    1. Pucci E, Branãs P, D’Amico R, Giuliani G, Solari A, Taus C. Amantadine for fatigue in multiple sclerosis. Cochrane Database Syst Rev. 2007;1:CD002818.
    1. Tejani AM, Wasdell M, Spiwak R, Rowell G, Nathwani S. Carnitine for fatigue in multiple sclerosis. Cochrane Database Syst Rev. 2010;2:CD007280.
    1. Wingerchuk DM, Benarroch EE, O’Brien PC, Keegan BM, Lucchinetti CF, Noseworthy JH, et al. A randomized controlled crossover trial of aspirin for fatigue in multiple sclerosis. Neurology. 2005;64(7):1267–9. doi: 10.1212/01.WNL.0000156803.23698.9A.
    1. Macdonell R, Nagels G, Laplaud D-A, Pozzilli C, de Jong B. Martins da Silva A, et al. Improved patient-reported health impact of multiple sclerosis: The ENABLE study of PR-fampridine. Mult Scler. 2016;22(7):944–54. doi: 10.1177/1352458515606809.
    1. Applebee A, Goodman AD, Mayadev AS, Bethoux F, Goldman MD, Klingler M, et al. Effects of dalfampridine extended-release tablets on 6-minute walk distance in patients with multiple sclerosis: a post hoc analysis of a double-blind, placebo-controlled trial. Clin Ther. 2015;37(12):2780–7. doi: 10.1016/j.clinthera.2015.10.014.
    1. Allart E, Benoit A, Blanchard-Dauphin A, Tiffreau V, Thevenon A, Zephir H, et al. Sustained-released fampridine in multiple sclerosis: effects on gait parameters, arm function, fatigue, and quality of life. J Neurol. 2015;262(8):1936–45. doi: 10.1007/s00415-015-7797-1.
    1. Pavsic K, Pelicon K, Ledinek AH, Sega S. Short-term impact of fampridine on motor and cognitive functions, mood and quality of life among multiple sclerosis patients. Clin Neurol Neurosurg. 2015;139:35–40. doi: 10.1016/j.clineuro.2015.08.023.
    1. Grossman P, Kappos L, Gensicke H, D’Souza M, Mohr DC, Penner IK, et al. MS quality of life, depression, and fatigue improve after mindfulness training: a randomized trial. Neurology. 2010;75(13):1141–9. doi: 10.1212/WNL.0b013e3181f4d80d.
    1. Hebert JR, Corboy JR, Manago MM, Schenkman M. Effects of vestibular rehabilitation on multiple sclerosis-related fatigue and upright postural control: a randomized controlled trial. Phys Ther. 2011;91(8):1166–83. doi: 10.2522/ptj.20100399.
    1. Rietberg MB, Brooks D, Uitdehaag BM, Kwakkel G. Exercise therapy for multiple sclerosis. Cochrane Database Syst Rev. 2005;1:CD003980.
    1. Döring A, Pfueller CF, Paul F, Dörr J. Exercise in multiple sclerosis—an integral component of disease management. EPMA J. 2011;3(1):2. doi: 10.1007/s13167-011-0136-4.
    1. Moss-Morris R, McCrone P, Yardley L, van Kessel K, Wills G, Dennison L. A pilot randomised controlled trial of an Internet-based cognitive behavioural therapy self-management programme (MS Invigor8) for multiple sclerosis fatigue. Behav Res Ther. 2012;50(6):415–21. doi: 10.1016/j.brat.2012.03.001.
    1. van Kessel K, Moss-Morris R, Willoughby E, Chalder T, Johnson MH, Robinson E. A randomized controlled trial of cognitive behavior therapy for multiple sclerosis fatigue. Psychosom Med. 2008;70(2):205–13. doi: 10.1097/PSY.0b013e3181643065.
    1. Mohr DC, Hart SL, Goldberg A. Effects of treatment for depression on fatigue in multiple sclerosis. Psychosom Med. 2003;65(4):542–7. doi: 10.1097/01.PSY.0000074757.11682.96.
    1. Thomas PW, Thomas S, Kersten P, Jones R, Slingsby V, Nock A, et al. One year follow-up of a pragmatic multi-centre randomised controlled trial of a group-based fatigue management programme (FACETS) for people with multiple sclerosis. BMC Neurol. 2014;14(1):109. doi: 10.1186/1471-2377-14-109.
    1. Veauthier C, Gaede G, Radbruch H, Wernecke K-D, Paul F. Sleep disorders reduce health-related quality of life in multiple sclerosis (Nottingham Health Profile Data in Patients with Multiple Sclerosis) Int J Mol Sci. 2015;16(7):16514–28. doi: 10.3390/ijms160716514.
    1. Berrigan LI, Fisk JD, Patten SB, Tremlett H, Wolfson C, Warren S, et al. Health-related quality of life in multiple sclerosis: direct and indirect effects of comorbidity. Neurology. 2016;86(15):1417–24. doi: 10.1212/WNL.0000000000002564.
    1. Tanigawa T. Obstructive sleep apnea: its prevention and screening may contribute to the prevention of hypertension, diabetes and cardiovascular diseases. EPMA J. 2011;2(1):83–9. doi: 10.1007/s13167-011-0073-2.
    1. Tuleta I, Pabst S, Juergens UR, Nickenig G, Skowasch D. Obstructive sleep apnoea as a risk factor for atherosclerosis—implication for preventive and personalised treatment. EPMA J. 2011;2(1):39–47. doi: 10.1007/s13167-011-0070-5.
    1. Olson L, Cole M, Ambrogetti A. Correlations among Epworth Sleepiness Scale scores, multiple sleep latency tests and psychological symptoms. J Sleep Res. 1998;7(4):248–53. doi: 10.1046/j.1365-2869.1998.00123.x.
    1. Bastien C. Validation of the Insomnia Severity Index as an outcome measure for insomnia research. Sleep Med. 2001;2(4):297–307. doi: 10.1016/S1389-9457(00)00065-4.
    1. Walters AS, Frauscher B, Allen R, Benes H, Chaudhuri KR, Garcia-Borreguero D, et al. Review of diagnostic instruments for the restless legs syndrome/Willis-Ekbom Disease (RLS/WED): critique and recommendations. J Clin Sleep Med. 2014;10(12):1343–9.
    1. Flachenecker P, Meissner H. Fatigue in multiple sclerosis presenting as acute relapse: subjective and objective assessment. Mult Scler. 2008;14(2):274–7. doi: 10.1177/1352458507082480.
    1. Allen RP, Picchietti DL, Garcia-Borreguero D, Ondo WG, Walters AS, Winkelman JW, et al. Restless legs syndrome/Willis–Ekbom disease diagnostic criteria: updated International Restless Legs Syndrome Study Group (IRLSSG) consensus criteria—history, rationale, description, and significance. Sleep Med. 2014;15(8):860–73. doi: 10.1016/j.sleep.2014.03.025.
    1. Wang J, Yin G, Li G, Liang W, Wei Q. Efficacy of physical activity counseling plus sleep restriction therapy on the patients with chronic insomnia. Neuropsychiatr Dis Treat. 2015;11:2771. doi: 10.2147/NDT.S94724.
    1. Lee CS, Lee SD, Kang S-H, Park HY, Yoon I-Y. Comparison of the efficacies of oral iron and pramipexole for the treatment of restless legs syndrome patients with low serum ferritin. Eur J Neurol. 2014;21(2):260–6. doi: 10.1111/ene.12286.
    1. Buchfuhrer MJ. Strategies for the treatment of restless legs syndrome. Neurotherapeutics. 2012;9(4):776–90. doi: 10.1007/s13311-012-0139-4.
    1. Allen R, Chen C, Soaita A, Wohlberg C, Knapp L, Peterson BT, et al. A randomized, double-blind, 6-week, dose-ranging study of pregabalin in patients with restless legs syndrome. Sleep Med. 2010;11(6):512–9. doi: 10.1016/j.sleep.2010.03.003.
    1. Abetz L, Arbuckle R, Allen RP, Garcia-Borreguero D, Hening W, Walters AS, et al. The reliability, validity and responsiveness of the International Restless Legs Syndrome Study Group rating scale and subscales in a clinical-trial setting. Sleep Med. 2006;7(4):340–9. doi: 10.1016/j.sleep.2005.12.011.
    1. Kyle SD, Aquino MRJ, Miller CB, Henry AL, Crawford MR, Espie CA, et al. Towards standardisation and improved understanding of sleep restriction therapy for insomnia disorder: a systematic examination of CBT-I trial content. Sleep Med Rev. 2015;23:83–8. doi: 10.1016/j.smrv.2015.02.003.
    1. Taylor DJ, Schmidt-Nowara W, Jessop CA, Ahearn J. Sleep restriction therapy and hypnotic withdrawal versus sleep hygiene education in hypnotic using patients with insomnia. J Clin Sleep Med. 2010;6(2):169–75.
    1. Miller CB, Espie CA, Epstein DR, Friedman L, Morin CM, Pigeon WR, et al. The evidence base of sleep restriction therapy for treating insomnia disorder. Sleep Med Rev. 2014;18(5):415–24. doi: 10.1016/j.smrv.2014.01.006.
    1. Morin AK, Jarvis CI, Lynch AM. Therapeutic options for sleep-maintenance and sleep-onset insomnia. Pharmacotherapy. 2007;27(1):89–110. doi: 10.1592/phco.27.1.89.
    1. Ancoli-Israel S, Bliwise DL, Nørgaard JP. The effect of nocturia on sleep. Sleep Med Rev. 2011;15(2):91–7. doi: 10.1016/j.smrv.2010.03.002.
    1. Depressive disorders. In: Diagnostic and Statistical Manual of Mental Disorders. Fifth Edition. American Psychiatric Association; 2013 [cited 2016 May 19]. Available from:.
    1. World Health Organization . International Statistical Classification of Diseases and Related Health Problems (ICD) 10. Geneva: World Health Organization; 1994.
    1. Beck AT, Steer RA. Internal consistencies of the original and revised Beck Depression Inventory. J Clin Psychol. 1984;40(6):1365–7. doi: 10.1002/1097-4679(198411)40:6<1365::AID-JCLP2270400615>;2-D.
    1. Patten SB, Burton JM, Fiest KM, Wiebe S, Bulloch AGM, Koch M, et al. Validity of four screening scales for major depression in MS. Mult Scler. 2015;21(8):1064–71. doi: 10.1177/1352458514559297.
    1. Minden SL, Feinstein A, Kalb RC, Miller D, Mohr DC, Patten SB, et al. Evidence-based guideline: assessment and management of psychiatric disorders in individuals with MS Report of the Guideline Development Subcommittee of the American Academy of Neurology. Neurology. 2014;82(2):174–81. doi: 10.1212/WNL.0000000000000013.
    1. Golubnitschaja O, Costigliola V, EPMA General report & recommendations in predictive, preventive and personalised medicine 2012: white paper of the European Association for Predictive, Preventive and Personalised Medicine. EPMA J. 2012;3(1):14. doi: 10.1186/1878-5085-3-14.
    1. Pérez LP, González RS, Lázaro EB. Treatment of mood disorders in multiple Sclerosis. Curr Treat Options Neurol. 2015;17(1):323. doi: 10.1007/s11940-014-0323-4.
    1. Koch MW, Glazenborg A, Uyttenboogaart M, Mostert J, De Keyser J. Pharmacologic treatment of depression in multiple sclerosis. Cochrane Database Syst Rev. 2011;2:CD007295.
    1. Fiest KM, Walker JR, Bernstein CN, Graff LA, Zarychanski R, Abou-Setta AM, et al. Systematic review and meta-analysis of interventions for depression and anxiety in persons with multiple sclerosis. Mult Scler Relat Disord. 2016;5:12–26. doi: 10.1016/j.msard.2015.10.004.
    1. Paul F, Veauthier C. Fatigue in multiple sclerosis: a diagnostic and therapeutic challenge. Expert Opin Pharmacother. 2012;13(6):791–3. doi: 10.1517/14656566.2012.667075.
    1. Bove R, White CC, Giovannoni G, Glanz B, Golubchikov V, Hujol J, et al. Evaluating more naturalistic outcome measures: a 1-year smartphone study in multiple sclerosis. Neurol Neuroimmunol Neuroinflamm. 2015;2(6):e162. doi: 10.1212/NXI.0000000000000162.
    1. Mathiowetz VG, Finlayson ML, Matuska KM, Chen HY, Luo P. Randomized controlled trial of an energy conservation course for persons with multiple sclerosis. Mult Scler. 2005;11(5):592–601. doi: 10.1191/1352458505ms1198oa.
    1. Kos D, Duportail M, D’hooghe M, Nagels G, Kerckhofs E. Multidisciplinary fatigue management programme in multiple sclerosis: a randomized clinical trial. Mult Scler. 2007;13(8):996–1003. doi: 10.1177/1352458507078392.
    1. Hugos C, Copperman L, Fuller B, Yadav V, Lovera J, Bourdette D. Clinical trial of a formal group fatigue program in multiple sclerosis. Mult Scler. 2010;16(6):724–732. doi: 10.1177/1352458510364536.
    1. Finlayson M, Preissner K, Cho C, Plow M, et al. Randomized trial of a teleconference-delivered fatigue management program for people with multiple sclerosis. Mult Scler. 2011;17(9):1130–1140. doi: 10.1177/1352458511404272.

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