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Fortschr Neurol Psychiatr 2015; 83(04): 211-220
DOI: 10.1055/s-0034-1399353
Übersicht
© Georg Thieme Verlag KG Stuttgart · New York

Fatigue bei Patienten mit Multipler Sklerose – Pathogenese, Klinik, Diagnostik und Therapie

Fatigue in Patients with Multiple Sclerosis – Pathogenesis, Clinical Picture, Diagnosis and Treatment
R. Patejdl
1   Institut für Physiologie, Universitätsmedizin Rostock
,
I. K. Penner
2   Kognitive Psychologie und Methodologie, Universität Basel
,
T. K. Noack
1   Institut für Physiologie, Universitätsmedizin Rostock
,
U. K. Zettl
3   Klinik für Neurologie und Poliklinik, Universitätsmedizin Rostock
› Author Affiliations
Further Information

Publication History

Publication Date:
20 April 2015 (online)

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Zusammenfassung

Fatigue ist ein sehr häufiges und subjektiv stark belastendes Symptom der Multiplen Sklerose (MS). Ausgehend von der Komplexität der pathogenetischen Mechanismen wird im vorliegenden Artikel ein Ansatz zur systematischen diagnostischen Einordnung der Fatigue erarbeitet. Insbesondere durch den Einsatz funktioneller Bildgebungsverfahren konnten in den letzten Jahren wichtige Beiträge zur Differenzierung der verschiedenen klinischen Erscheinungsformen der MS-Fatigue geleistet werden. Durch die verbesserte Einsicht in den Zusammenhang zwischen der Immunpathologie der MS und der Ausbildung von Fatigue rückt die Wechselwirkung zwischen Fatigue und immunmodulierender Basistherapie der MS vermehrt in den Blickpunkt. Auf der Grundlage der aktuell verfügbaren empirischen Daten werden in dieser Arbeit daher nicht nur die medikamentöse, physikalische und psychologische symptomatische Therapie referiert, sondern darüber hinaus wird auch die aktuelle Datenlage zu den Effekten der etablierten sowie der zahlreichen neuen MS-Immuntherapeutika auf die MS-Fatigue dargestellt.

Abstract

Fatigue is a frequent and restricting symptom of multiple sclerosis (MS). Starting from its pathogenetic mechanisms, the article develops an approach to the differential diagnosis of fatigue in MS patients. Over the past years, the use of functional imaging techniques has given important information on the mechanisms of this highly variable clinical picture. Considering our improved understanding of the interdependency of immune pathology and the clinical presentation of neuropsychological disorders, the relationship between immunomodulatory treatments and fatigue is receiving increased attention. Therefore, this article not only reports on the most recent data on pharmacological, physical and psychological interventions in the symptomatic treatment of fatigue, but also puts a special accent on data concerning the interactions between the rapidly growing number of immunomodulatory treatments in MS.

Schlüsselwörter

Multiple Sklerose - Fatigue - immunmodulatorische Therapie

Key words

multiple sclerosis - fatigue - immunomodulatory therapy
 

  • Literatur

  • 1 Nagaraj K, Taly AB, Gupta A et al. Prevalence of fatigue in patients with multiple sclerosis and its effect on the quality of life. J Neurosci Rural Pract 2013; 4: 278-282
    Article in Thieme ConnectPubMedGoogle Scholar
  • 2 Kister I, Bacon TE, Chamot E et al. Natural history of multiple sclerosis symptoms. Int J MS Care 2013; 15: 146-158
    CrossrefPubMedGoogle Scholar
  • 3 Runia TF, Jafari N, Siepman DAM et al. Fatigue at time of CIS is an independent predictor of a subsequent diagnosis of multiple sclerosis. J Neurol Neurosurg Psychiatry 2014; DOI: 10.1136/jnnp-2014-308374.
    PubMedGoogle Scholar
  • 4 Mills RJ, Young CA. A medical definition of fatigue in multiple sclerosis. QJM 2008; 101: 49-60
    CrossrefPubMedGoogle Scholar
  • 5 Iriarte J, Subirá ML, Castro P. Modalities of fatigue in multiple sclerosis: correlation with clinical and biological factors. Mult Scler 2000; 6: 124-130
    CrossrefPubMedGoogle Scholar
  • 6 Stadelmann C, Wegner C, Brück W. Inflammation, demyelination, and degeneration – recent insights from MS pathology. Biochim Biophys Acta 2011; 1812: 275-282
    CrossrefPubMedGoogle Scholar
  • 7 Zettl UK, Stüve O, Patejdl R. Immune-mediated CNS diseases: A review on nosological classification and clinical features. Autoimmun Rev 2012; 11: 267-179
    CrossrefPubMedGoogle Scholar
  • 8 Codella M, Rocca MA, Colombo B et al. A preliminary study of magnetization transfer and diffusion tensor MRI of multiple sclerosis patients with fatigue. J Neurol 2002; 249: 535-537
    CrossrefPubMedGoogle Scholar
  • 9 van der Werf SP, Jongen PJ, Lycklama à Nijeholt GJ et al. Fatigue in multiple sclerosis: interrelations between fatigue complaints, cerebral MRI abnormalities and neurological disability. J Neurol Sci 1998; 160: 164-170
    CrossrefPubMedGoogle Scholar
  • 10 Bakshi R, Miletich RS, Henschel K et al. Fatigue in multiple sclerosis: cross-sectional correlation with brain MRI findings in 71 patients. Neurology 1999; 53: 1151-1153
    CrossrefPubMedGoogle Scholar
  • 11 Rocca MA, Parisi L, Pagani E et al. Regional but not global brain damage contributes to fatigue in multiple sclerosis. Radiology 2014; 273: 511-520
    CrossrefPubMedGoogle Scholar
  • 12 Pellicano C, Gallo A, Li X et al. Relationship of cortical atrophy to fatigue in patients with multiple sclerosis. Arch Neurol 2010; 67: 447-453
    PubMedGoogle Scholar
  • 13 Tedeschi G, Dinacci D, Lavorgna L et al. Correlation between fatigue and brain atrophy and lesion load in multiple sclerosis patients independent of disability. J Neurol Sci 2007; 263: 15-19
    CrossrefPubMedGoogle Scholar
  • 14 Nygaard GO, Walhovd KB, Sowa P et al. Cortical thickness and surface area relate to specific symptoms in early relapsing-remitting multiple sclerosis. Mult Scler 2014; Epub ahead of print
    PubMedGoogle Scholar
  • 15 Gobbi C, Rocca MA, Riccitelli G et al. Influence of the topography of brain damage on depression and fatigue in patients with multiple sclerosis. Mult Scler 2014; 20: 192-201
    CrossrefPubMedGoogle Scholar
  • 16 Calabrese M, Rinaldi F, Grossi P et al. Basal ganglia and frontal/parietal cortical atrophy is associated with fatigue in relapsing-remitting multiple sclerosis. Mult Scler 2010; 16: 1220-1228
    CrossrefPubMedGoogle Scholar
  • 17 Bester M, Lazar M, Petracca M et al. Tract-specific white matter correlates of fatigue and cognitive impairment in benign multiple sclerosis. J Neurol Sci 2013; 330: 61-66
    CrossrefPubMedGoogle Scholar
  • 18 Cruz Gómez ÁJ, Ventura Campos N, Belenguer A et al. Regional brain atrophy and functional connectivity changes related to fatigue in multiple sclerosis. PLoS One 2013; 8: e77914
    CrossrefPubMedGoogle Scholar
  • 19 Sepulcre J, Masdeu JC, Goñi J et al. Fatigue in multiple sclerosis is associated with the disruption of frontal and parietal pathways. Mult Scler 2009; 15: 337-344
    CrossrefPubMedGoogle Scholar
  • 20 Pardini M, Bonzano L, Mancardi GL et al. Frontal networks play a role in fatigue perception in multiple sclerosis. Behav Neurosci 2010; 124: 329-336
    CrossrefPubMedGoogle Scholar
  • 21 Reddy H, Narayanan S, Arnoutelis R et al. Evidence for adaptive functional changes in the cerebral cortex with axonal injury from multiple sclerosis. Brain 2000; 123 (11) 2314-2320
    CrossrefPubMedGoogle Scholar
  • 22 Rocca MA, Absinta M, Valsasina P et al. Abnormal cervical cord function contributes to fatigue in multiple sclerosis. Mult Scler 2012; 18: 1552-1559
    CrossrefPubMedGoogle Scholar
  • 23 Niepel G, Bibani RH, Vilisaar J et al. Association of a deficit of arousal with fatigue in multiple sclerosis: effect of modafinil. Neuropharmacology 2013; 64: 380-388
    CrossrefPubMedGoogle Scholar
  • 24 Newman J. Putting the puzzle together. Part I and II: towards a general theory of the neural correlates of consciousness. J Consciousness Stud 1997; 4: 47-66 ; 100–121
    PubMedGoogle Scholar
  • 25 Feinstein A. Is there a cognitive signature for multiple sclerosis-related fatigue?. Mult Scler 2014; Epub ahead of print
    PubMedGoogle Scholar
  • 26 Hanken K, Eling P, Hildebrandt H. Is there a cognitive signature for MS-related fatigue?. Mult Scler 2014; Epub ahead of print
    PubMedGoogle Scholar
  • 27 Ng AV, Miller RG, Kent-Braun JA. Central motor drive is increased during voluntary muscle contractions in multiple sclerosis. Muscle Nerve 1997; 20: 1213-1218
    CrossrefPubMedGoogle Scholar
  • 28 Specogna I, Casagrande F, Lorusso A et al. Functional MRI during the execution of a motor task in patients with multiple sclerosis and fatigue. Radiol Med 2012; 117: 1398-1407
    CrossrefPubMedGoogle Scholar
  • 29 Scheidegger O, Kamm CP, Humpert SJ et al. Corticospinal output during muscular fatigue differs in multiple sclerosis patients compared to healthy controls. Mult Scler 2012; 18: 1500-1506
    CrossrefPubMedGoogle Scholar
  • 30 Park H, Friston K. Structural and functional brain networks: from connections to cognition. Science 2013; 342: 1238411
    CrossrefPubMedGoogle Scholar
  • 31 Minagar A, Barnett MH, Benedict RHB et al. The thalamus and multiple sclerosis: modern views on pathologic, imaging, and clinical aspects. Neurology 2013; 80: 210-219
    CrossrefPubMedGoogle Scholar
  • 32 Harbuz M. Neuroendocrine function and chronic inflammatory stress. Exp Physiol 2002; 87: 519-525
    CrossrefPubMedGoogle Scholar
  • 33 Zellini F, Niepel G, Tench CR et al. Hypothalamic involvement assessed by T1 relaxation time in patients with relapsing-remitting multiple sclerosis. Mult Scler 2009; 15: 1442-1449
    CrossrefPubMedGoogle Scholar
  • 34 Huitinga I, Erkut ZA, van Beurden D et al. Impaired hypothalamus-pituitary-adrenal axis activity and more severe multiple sclerosis with hypothalamic lesions. Ann Neurol 2004; 55: 37-45
    CrossrefPubMedGoogle Scholar
  • 35 Gottschalk M, Kümpfel T, Flachenecker P et al. Fatigue and regulation of the hypothalamo-pituitary-adrenal axis in multiple sclerosis. Arch Neurol 2005; 62: 277-280
    CrossrefPubMedGoogle Scholar
  • 36 Flachenecker P, Bihler I, Weber F et al. Cytokine mRNA expression in patients with multiple sclerosis and fatigue. Mult Scler 2004; 10: 165-169
    CrossrefPubMedGoogle Scholar
  • 37 Heesen C, Koehler G, Gross R et al. Altered cytokine responses to cognitive stress in multiple sclerosis patients with fatigue. Mult Scler 2005; 11: 51-57
    CrossrefPubMedGoogle Scholar
  • 38 White AT, Light AR, Hughen RW et al. Differences in metabolite-detecting, adrenergic, and immune gene expression after moderate exercise in patients with chronic fatigue syndrome, patients with multiple sclerosis, and healthy controls. Psychosom Med 2012; 74: 46-54
    CrossrefPubMedGoogle Scholar
  • 39 Fleming WE, Pollak CP. Sleep disorders in multiple sclerosis. Semin Neurol 2005; 25: 64-68
    Article in Thieme ConnectPubMedGoogle Scholar
  • 40 Chwastiak LA, Gibbons LE, Ehde DM et al. Fatigue and psychiatric illness in a large community sample of persons with multiple sclerosis. J Psychosom Res 2005; 59: 291-298
    CrossrefPubMedGoogle Scholar
  • 41 Gobbi C, Rocca M, Pagani E et al. Forceps minor damage and co-occurrence of depression and fatigue in multiple sclerosis. Mult Scler 2014; 20: 1633-1640
    CrossrefPubMedGoogle Scholar
  • 42 Fisk JD, Pontefract A, Ritvo PG et al. The impact of fatigue on patients with multiple sclerosis. Can J Neurol Sci 1994; 21: 9-14
    CrossrefPubMedGoogle Scholar
  • 43 Krupp LB, LaRocca NG, Muir-Nash J et al. The fatigue severity scale. Application to patients with multiple sclerosis and systemic lupus erythematosus. Arch Neurol 1989; 46: 1121-1123
    CrossrefPubMedGoogle Scholar
  • 44 Penner IK, Raselli C, Stöcklin M et al. The Fatigue Scale for Motor and Cognitive Functions (FSMC): validation of a new instrument to assess multiple sclerosis-related fatigue. Mult Scler 2009; 15: 1509-1517
    CrossrefPubMedGoogle Scholar
  • 45 Dahl O, Stordal E, Lydersen S et al. Anxiety and depression in multiple sclerosis. A comparative population-based study in Nord-Trøndelag County, Norway. Mult Scler 2009; 15: 1495-1501
    CrossrefPubMedGoogle Scholar
  • 46 Zigmond AS, Snaith RP. The hospital anxiety and depression scale. Acta Psychiatr Scand 1983; 67: 361-370
    CrossrefPubMedGoogle Scholar
  • 47 Bonnier G, Roche A, Romascano D et al. Advanced MRI unravels the nature of tissue alterations in early multiple sclerosis. Ann Clin Transl Neurol 2014; 1: 423-432
    CrossrefPubMedGoogle Scholar
  • 48 Daams M, Geurts JJG, Barkhof F. Cortical imaging in multiple sclerosis: recent findings and 'grand challenges'. Curr Opin Neurol 2013; 26: 345-352
    CrossrefPubMedGoogle Scholar
  • 49 Calabrese M, Filippi M, Gallo P. Cortical lesions in multiple sclerosis. Nat Rev Neurol 2010; 6: 438-444
    CrossrefPubMedGoogle Scholar
  • 50 Veauthier C, Radbruch H, Gaede G et al. Fatigue in multiple sclerosis is closely related to sleep disorders: a polysomnographic cross-sectional study. Mult Scler 2011; 17: 613-622
    CrossrefPubMedGoogle Scholar
  • 51 MSTKG. Symptomatische Therapie der Multiplen Sklerose. Nervenarzt 2004; 75: 2-39
    PubMedGoogle Scholar
  • 52 Sumowski JF, Leavitt VM. Body temperature is elevated and linked to fatigue in relapsing-remitting multiple sclerosis, even without heat exposure. Arch Phys Med Rehabil 2014; 95: 1298-1302
    CrossrefPubMedGoogle Scholar
  • 53 Nilsagård Y, Denison E, Gunnarsson L. Evaluation of a single session with cooling garment for persons with multiple sclerosis--a randomized trial. Disabil Rehabil Assist Technol 2006; 1: 225-233
    CrossrefPubMedGoogle Scholar
  • 54 Schwid SR, Petrie MD, Murray R et al. A randomized controlled study of the acute and chronic effects of cooling therapy for MS. Neurology 2003; 60: 1955-1960
    CrossrefPubMedGoogle Scholar
  • 55 Schmidt S, Wonneberger M. Long-term endurance exercise improves aerobic capacity in patients with relapsing-remitting multiple sclerosis: impact of baseline fatigue. J Neurol Sci 2014; 336: 29-35
    CrossrefPubMedGoogle Scholar
  • 56 Mostert S, Kesselring J. Effects of a short-term exercise training program on aerobic fitness, fatigue, health perception and activity level of subjects with multiple sclerosis. Mult Scler 2002; 8: 161-168
    CrossrefPubMedGoogle Scholar
  • 57 Pfitzner A, Flachenecker P, Zettl U. Effects of endurance training under normobaric, hypoxic conditions on fatigue in patients with MS: Results of a randomized, prospective study. PLOS ONE submitted
    PubMedGoogle Scholar
  • 58 Evans WJ, Lambert CP. Physiological basis of fatigue. Am J Phys Med Rehabil 2007; 86: S29-S46
    CrossrefPubMedGoogle Scholar
  • 59 Mathiowetz VG, Finlayson ML, Matuska KM et al. Randomized controlled trial of an energy conservation course for persons with multiple sclerosis. Mult Scler 2005; 11: 592-601
    CrossrefPubMedGoogle Scholar
  • 60 Thomas PW, Thomas S, Hillier C et al. Psychological interventions for multiple sclerosis. Cochrane Database Syst Rev 2006; CD004431
    PubMedGoogle Scholar
  • 61 Bisht B, Darling WG, Grossmann RE et al. A multimodal intervention for patients with secondary progressive multiple sclerosis: feasibility and effect on fatigue. J Altern Complement Med 2014; 20: 347-355
    CrossrefPubMedGoogle Scholar
  • 62 Coote S, Gallagher S, Msetfi R et al. A randomised controlled trial of an exercise plus behaviour change intervention in people with multiple sclerosis: the step it up study protocol. BMC Neurol 2014; 14: 241
    CrossrefPubMedGoogle Scholar
  • 63 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: 798285
    PubMedGoogle Scholar
  • 64 Apel A, Greim B, Zettl UK. How frequently do patients with multiple sclerosis use complementary and alternative medicine?. Complement Ther Med 2005; 13: 258-263
    CrossrefPubMedGoogle Scholar
  • 65 Kochs L, Wegener S, Sühnel A et al. The use of complementary and alternative medicine in patients with multiple sclerosis: a longitudinal study. Complement Ther Med 2014; 22: 166-172
    CrossrefPubMedGoogle Scholar
  • 66 Yadav V, Narayanaswami P. Complementary and alternative medical therapies in multiple sclerosis-the american academy of neurology guidelines: a commentary. Clin Ther 2014; 36: 1972-1978
    CrossrefPubMedGoogle Scholar
  • 67 Piatkowski J, Kern S, Ziemssen T. Effect of BEMER magnetic field therapy on the level of fatigue in patients with multiple sclerosis: a randomized, double-blind controlled trial. J Altern Complement Med 2009; 15: 507-511
    CrossrefPubMedGoogle Scholar
  • 68 Haase R, Piatkowski J, Ziemssen T. Long-term effects of Bio-Electromagnetic-Energy Regulation therapy on fatigue in patients with multiple sclerosis. Altern Ther Health Med 2011; 17: 22-28
    PubMedGoogle Scholar
  • 69 Ziemssen T, Hoffman J, Apfel R et al. Effects of glatiramer acetate on fatigue and days of absence from work in first-time treated relapsing-remitting multiple sclerosis. Health Qual Life Outcomes 2008; 6: 67
    CrossrefPubMedGoogle Scholar
  • 70 Putzki N, Yaldizli O, Tettenborn B et al. Multiple sclerosis associated fatigue during natalizumab treatment. J Neurol Sci 2009; 285: 109-113
    CrossrefPubMedGoogle Scholar
  • 71 Putzki N, Kollia K, Katsarava Z et al. Multiple sclerosis related fatigue improves after treatment initiation with natalizumab. Multiple Sclerosis 2007; 13 (Suppl. 02) Poster 228
    PubMedGoogle Scholar
  • 72 Yildiz M, Tettenborn B, Borgwardt S. Trajectory of fatigue severity in natalizumab treated multiple sclerosis patients. Clin Neurol Neurosurg 2013; 115: 902-903
    CrossrefPubMedGoogle Scholar
  • 73 Polman CH, O'Connor PW, Havrdova E et al. A randomized, plazebo-controlled trial of natalizumab for relapsing multiple sclerosis. N Engl J Med 2006; 354: 899-910
    CrossrefPubMedGoogle Scholar
  • 74 Khademi M, Stol D, Olsson T et al. Induction of systemic TNFalpha in natalizumab-treated multiple sclerosis. Eur J Neurol 2008; 15: 309-312
    CrossrefPubMedGoogle Scholar
  • 75 Montalban X, Comi G, O'Connor P 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: 1341-1350
    CrossrefPubMedGoogle Scholar
  • 76 Kappos L, Gold R, Miller DH et al. Efficacy and safety of oral fumarate in patients with relapsing-remitting multiple sclerosis: a multicentre, randomised, double-blind, plazebo-controlled phase IIb study. Lancet 2008; 372: 1463-1472
    CrossrefPubMedGoogle Scholar
  • 77 Calkwood J, Cree B, Crayton H 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: 220
    CrossrefPubMedGoogle Scholar
  • 78 Vermersch P, Czlonkowska A, Grimaldi LME et al. Teriflunomide versus subcutaneous interferon beta-1a in patients with relapsing multiple sclerosis: a randomised, controlled phase 3 trial. Mult Scler 2014; 20: 705-716
    CrossrefPubMedGoogle Scholar
  • 79 Thibault M, Havdrova E, Giovannoni G et al. Alemtuzumab improves quality of live in RRMS – patients who relapsed in prior therapy: Three-year follow-up of CARE-MS II. ACTRIMS/ECTRIMS; 2014 (Poster) 2014;
    PubMedGoogle Scholar
  • 80 Pucci E, Branãs P, D'Amico R et al. Amantadine for fatigue in multiple sclerosis. Cochrane Database Syst Rev 2007; CD002818
    PubMedGoogle Scholar
  • 81 Rossini A, Bergamaschi R, Gandeloro E et al. Fatigue in multiple sclerosis: multidimensional assessment and response to symptomatic treatment. Multiple Sclerosis 2004; 10: 462-468
    CrossrefPubMedGoogle Scholar
  • 82 Solari A, Uitdehaag B, Giuliani G et al. Aminopyridines for symptomatic treatment in multiple sclerosis. Cochrane Database Syst Rev 2001; CD001330
    PubMedGoogle Scholar
  • 83 Zifko UA, Rupp M, Schwarz S et al. Modafinil in treatment of fatigue in multiple sclerosis. Results of an open-label study. J Neurol 2002; 249: 983-987
    CrossrefPubMedGoogle Scholar
  • 84 Stankoff B, Waubant E, Confavreux C et al. Modafinil for fatigue in MS: a randomized plazebo-controlled double-blind study. Neurology 2005; 64: 1139-1143
    CrossrefPubMedGoogle Scholar
  • 85 Rammohan KW, Rosenberg JH, Lynn DJ et al. Efficacy and safety of modafinil (Provigil) for the treatment of fatigue in multiple sclerosis: a two centre phase 2 study. J Neurol Neurosurg Psychiatry 2002; 72: 179-183
    CrossrefPubMedGoogle Scholar
  • 86 Mitler M, Harsh J, Hirshkowitz M et al. Long-term efficacy and safety of modafinil (PROVIGIL((R))) for the treatment of excessive daytime sleepiness associated with narcolepsy. Sleep Med 2000; 1: 231-243
    CrossrefPubMedGoogle Scholar
  • 87 Wingerchuk DM, Benarroch EE, O'Brien PC et al. A randomized controlled crossover trial of aspirin for fatigue in multiple sclerosis. Neurology 2005; 64: 1267-1269
    CrossrefPubMedGoogle Scholar
  • 88 Tomassini V, Pozzilli C, Onesti E 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: 103-108
    CrossrefPubMedGoogle Scholar
  • 89 Colombo B, Martinelli Boneschi F, Rossi P et al. MRI and motor evoked potential findings in nondisabled multiple sclerosis patients with and without symptoms of fatigue. J Neurol 2000; 247: 506-509
    CrossrefPubMedGoogle Scholar
  • 90 Mainero C, Faroni J, Gasperini C et al. Fatigue and magnetic resonance imaging activity in multiple sclerosis. J Neurol 1999; 246: 454-458
    CrossrefPubMedGoogle Scholar
  • 91 Tartaglia MC, Narayanan S, Francis SJ et al. The relationship between diffuse axonal damage and fatigue in multiple sclerosis. Arch Neurol 2004; 61: 201-207
    CrossrefPubMedGoogle Scholar
  • 92 Filippi M, Valsasina P, Rocca M. Magnetic resonance imaging of grey matter damage in people with MS. Int MS J 2007; 14: 12-21
    PubMedGoogle Scholar
  • 93 Bermel R, Stone L, Marrie R et al. Decreased Volume of Subcortical Activation during complex finger tapping correlates with increasing level of fatigue in Patients with MS. Neurology 2008; 70 (11) (Suppl. 01) A208
    PubMedGoogle Scholar
  • 94 Leocani L, Colombo B, Magnani G et al. Fatigue in multiple sclerosis is associated with abnormal cortical activation to voluntary movement--EEG evidence. Neuroimage 2001; 13: 1186-1192
    PubMedGoogle Scholar
  • 95 Petajan JH, White AT. Motor-evoked potentials in response to fatiguing grip exercise in multiple sclerosis patients. Clin Neurophysiol 2000; 111: 2188-2195
    CrossrefPubMedGoogle Scholar
  • 96 Liepert J, Mingers D, Heesen C et al. Motor cortex excitability and fatigue in multiple sclerosis: a transcranial magnetic stimulation study. Mult Scler 2005; 11: 316-321
    CrossrefPubMedGoogle Scholar
  • 97 Roelcke U, Kappos L, Lechner-Scott J 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: 1566-1571
    CrossrefPubMedGoogle Scholar
  • 98 Schubert M, Wohlfarth K, Rollnik JD et al. Walking and fatigue in multiple sclerosis: the role of the corticospinal system. Muscle Nerve 1998; 21: 1068-1070
    CrossrefPubMedGoogle Scholar
  • 99 Morris ME, Cantwell C, Vowels L et al. Changes in gait and fatigue from morning to afternoon in people with multiple sclerosis. J Neurol Neurosurg Psychiatry 2002; 72: 361-365
    CrossrefPubMedGoogle Scholar
  • 100 Rocca MA, Matthews PM, Caputo D et al. Evidence for widespread movement-associated functional MRI changes in patients with PPMS. Neurology 2002; 58: 866-872
    CrossrefPubMedGoogle Scholar
  • 101 Heesen C, Nawrath L, Reich C et al. Fatigue in multiple sclerosis: an example of cytokine mediated sickness behaviour?. J Neurol Neurosurg Psychiatry 2006; 77: 34-39
    CrossrefPubMedGoogle Scholar
  • 102 Téllez N, Comabella M, Julià E et al. Fatigue in progressive multiple sclerosis is associated with low levels of dehydroepiandrosterone. Mult Scler 2006; 12: 487-494
    CrossrefPubMedGoogle Scholar
  • 103 Heesen C, Gold SM, Raji A et al. Cognitive impairment correlates with hypothalamo-pituitary-adrenal axis dysregulation in multiple sclerosis. Psychoneuroendocrinology 2002; 27: 505-517
    CrossrefPubMedGoogle Scholar
  • 104 Lin JS, Hou Y, Jouvet M. Potential brain neuronal targets for amphetamine-, methylphenidate-, and modafinil-induced wakefulness, evidenced by c-fos immunocytochemistry in the cat. Proc Natl Acad Sci U S A 1996; 93: 14128-14133
    CrossrefPubMedGoogle Scholar
  • 105 Ishizuka T, Sakamoto Y, Sakurai T et al. Modafinil increases histamine release in the anterior hypothalamus of rats. Neurosci Lett 2003; 339: 143-146
    CrossrefPubMedGoogle Scholar
  • 106 Kos D, Kerckhofs E, Nagels G et al. Origin of fatigue in multiple sclerosis: review of the literature. Neurorehabil Neural Repair 2008; 22: 91-100
    PubMedGoogle Scholar
  • 107 Merlino G, Fratticci L, Lenchig C et al. Prevalence of 'poor sleep' among patients with multiple sclerosis: An independent predictor of mental and physical status. Sleep Med 2009; 10: 26-34
    CrossrefPubMedGoogle Scholar
  • 108 Stanton BR, Barnes F, Silber E. Sleep and fatigue in multiple sclerosis. Mult Scler 2006; 12: 481-486
    CrossrefPubMedGoogle Scholar
  • 109 McAuley E, Motl RW, Morris KS et al. Enhancing physical activity adherence and well-being in multiple sclerosis: a randomised controlled trial. Mult Scler 2007; 13: 652-659
    CrossrefPubMedGoogle Scholar
  • 110 Pasquinelli S, Solaro C. Nutritional assessment and malnutrition in multiple sclerosis. Neurol Sci 2008; 29 (Suppl. 04) S367-S369
    PubMedGoogle Scholar
  • 111 Willerding-Möllmann S, Wilkens L, Schlegelberger B et al. Azathioprine-associated myelodysplastic syndrome with cytogenetic aberrations. Dtsch Med Wochenschr 2004; 129: 1246-1248
    Article in Thieme ConnectPubMedGoogle Scholar
  • 112 Capobianco M, Malucchi S, Ulisciani S et al. Acute myeloid leukemia induced by mitoxantrone treatment for aggressive multiple sclerosis. Neurol Sci 2008; 29: 185-187
    CrossrefPubMedGoogle Scholar
  • 113 Taylor L, Hughes RAC, McPherson K. The risk of cancer from azathioprine as a treatment for multiple sclerosis. Eur J Neurol 2004; 11: 141
    PubMedGoogle Scholar
  • 114 Lebrun C, Debouverie M, Vermersch P et al. Cancer risk and impact of disease-modifying treatments in patients with multiple sclerosis. Mult Scler 2008; 14: 399-405
    CrossrefPubMedGoogle Scholar
  • 115 Bombardier CH, Blake KD, Ehde DM et al. Alcohol and drug abuse among persons with multiple sclerosis. Mult Scler 2004; 10: 35-40
    CrossrefPubMedGoogle Scholar
  • 116 Funakawa I, Hara K, Yasuda T et al. Intractable hiccups and sleep apnea syndrome in multiple sclerosis: report of two cases. Acta Neurol Scand 1993; 88: 401-405
    CrossrefPubMedGoogle Scholar
  • 117 Petek-Balci B, Yayla V, Ozer F. Multiple sclerosis and Hashimoto thyroiditis: two cases. Neurologist 2005; 11: 301-304
    CrossrefPubMedGoogle Scholar
  • 118 Flachenecker P, Müller G, König H et al. "Fatigue" in multiple sclerosis. Development and and validation of the "Würzburger Fatigue Inventory for MS". Nervenarzt 2006; 77: 165-166 , 168–170, 172–174
    CrossrefPubMedGoogle Scholar
  • 119 Savci S, Inal-Ince D, Arikan H et al. Six-minute walk distance as a measure of functional exercise capacity in multiple sclerosis. Disabil Rehabil 2005; 27: 1365-1371
    CrossrefPubMedGoogle Scholar
  • 120 Greim B, Engel C, Apel A et al. Fatigue in neuroimmunological diseases. J Neurol 2007; 254 (Suppl. 02) II102-II106
    CrossrefPubMedGoogle Scholar
  • 121 DeLuca J, Genova HM, Hillary FG et al. Neural correlates of cognitive fatigue in multiple sclerosis using functional MRI. J Neurol Sci 2008; 270: 28-39
    CrossrefPubMedGoogle Scholar
  • 122 Schlaeger R, Fuhr P. Symptomatische medikamentöse Behandlung des Fatigue. Bad Honnef: Hippocampus Verlag 2009; 145-151
    PubMedGoogle Scholar