Journal of Neurology

, Volume 258, Issue 12, pp 2199–2205 | Cite as

Fatigue and progression of corpus callosum atrophy in multiple sclerosis

  • Özgür YaldizliEmail author
  • Stephanie Glassl
  • Dietrich Sturm
  • Athina Papadopoulou
  • Achim Gass
  • Barbara Tettenborn
  • Norman Putzki
Original Communication


Fatigue is one of the most disabling symptoms in multiple sclerosis (MS) patients. There is no or only weak correlation between conventional magnetic resonance imaging (MRI) parameters and level of fatigue. The aim of this study was to investigate the relationship between progression of corpus callosum (CC) atrophy and fatigue in MS patients. This was a cohort study in 70 patients with relapsing form of MS (RRMS) and serial MRIs over a mean follow-up of 4.8 years [67% female, mean age 42 ± 11 years, mean disease duration 9.7 ± 7.6 years, mean Expanded Disability Status Scale (EDSS) 2.8 ± 1.6]. Fatigue was assessed by the Fatigue Severity Scale (FSS). CC size was measured with the CC index (CCI). In total, 40% of the patients suffered from fatigue (mean FSS score 5.3 ±1.1) and 60% patients had no fatigue (mean FSS score of 2.1 ± 1). Patients with fatigue had higher EDSS scores (p = 0.01) and CC atrophy was more pronounced in patients with fatigue (−21.8 vs. −12.1%, p = 0.005). FSS correlated with CCI change over time (r = −0.33; p = 0.009) and EDSS (p = 0.008; r = 0.361). The association between annualized CCI change and FSS was independent from EDSS, disease duration, gender and age in a multivariate linear regression analysis (p < 0.001). Progression of CC atrophy may play a role in the evolution of MS-related fatigue.


Corpus callosum index Corpus callosum atrophy Brain atrophy Fatigue Multiple sclerosis 


Conflict of interest

OY reports receiving travel grants, advisory, consulting and lecture fees from Bayer Schering, Biogen Idec, Novartis and Merck Serono which are exclusively used for research at the University of Basel, department of neurology. NP reports that he is now an employee of Biogen Idec. He had previously received honoraria, travel grants, research grants and personal compensation from Bayer Healthcare, Biogen Idec, GSK, TEVA, Sanofi Aventis, Merck Serono and Novartis. BT has received travel grants and honoraria from Merck Serono, Biogen Idec and Bayer Healthcare. AG and AP had nothing to disclose.

Supplementary material

415_2011_6091_MOESM1_ESM.doc (34 kb)
Fatigue severity scale. Each patient is asked to respond to the following nine statements by choosing a number between one and seven, where one indicates strongly disagree and seven indicates strongly agree. FSS mean score >4 indicates severe fatigue [21]


  1. 1.
    Anderson VM, Fox NC, Miller DH (2006) Magnetic resonance imaging measures of brain atrophy in multiple sclerosis. J Magn Reson Imaging 23:605–618PubMedCrossRefGoogle Scholar
  2. 2.
    Bakshi R, Miletich RS, Henschel K, Shaikh ZA, Janardhan V, Wasay M, Stengel LM, Ekes R, Kinkel PR (1999) Fatigue in multiple sclerosis: cross-sectional correlation with brain MRI findings in 71 patients. Neurology 53:1151–1153PubMedGoogle Scholar
  3. 3.
    Bakshi R, Shaikh ZA, Miletich RS, Czarnecki D, Dmochowski J, Henschel K, Janardhan V, Dubey N, Kinkel PR (2000) Fatigue in multiple sclerosis and its relationship to depression and neurologic disability. Mult Scler 6:181–185PubMedGoogle Scholar
  4. 4.
    Barkhof FJ, Elton M, Lindeboom J, Tas MW, Schmidt WF, Hommes OR, Polman CH, Kok A, Valk J (1998) Functional correlates of callosal atrophy in relapsing-remitting multiple sclerosis patients. A preliminary MRI study. J Neurol 245:153–158PubMedCrossRefGoogle Scholar
  5. 5.
    Beck AT, Brown GK, Steer RA (1997) Psychometric characteristics of the Scale for Suicide Ideation with psychiatric outpatients. Behav Res Ther 35:1039–1046PubMedCrossRefGoogle Scholar
  6. 6.
    Chard DT, Griffin CM, Rashid W, Davies GR, Altmann DR, Kapoor R, Barker GJ, Thompson AJ, Miller DH (2004) Progressive grey matter atrophy in clinically early relapsing-remitting multiple sclerosis. Mult Scler 10:387–391PubMedCrossRefGoogle Scholar
  7. 7.
    Chaudhuri A, Behan PO (2004) Fatigue in neurological disorders. Lancet 363:978–988PubMedCrossRefGoogle Scholar
  8. 8.
    Codella M, Rocca MA, Colombo B, Martinelli-Boneschi F, Comi G, Filippi M (2002) Cerebral grey matter pathology and fatigue in patients with multiple sclerosis: a preliminary study. J Neurol Sci 194:71–74PubMedCrossRefGoogle Scholar
  9. 9.
    Codella M, Rocca MA, Colombo B, Rossi P, Comi G, Filippi M (2002) A preliminary study of magnetization transfer and diffusion tensor MRI of multiple sclerosis patients with fatigue. J Neurol 249:535–537PubMedCrossRefGoogle Scholar
  10. 10.
    Colombo B, Martinelli BF, Rossi P, Rovaris M, Maderna L, Filippi M, Comi G (2000) MRI and motor evoked potential findings in nondisabled multiple sclerosis patients with and without symptoms of fatigue. J Neurol 247:506–509PubMedCrossRefGoogle Scholar
  11. 11.
    Figueira FF, Santos VS, Figueira GM, Silva AC (2007) Corpus callosum index: a practical method for long-term follow-up in multiple sclerosis. Arq Neuropsiquiatr 65:931–935PubMedCrossRefGoogle Scholar
  12. 12.
    Filippi M, Rocca MA, Colombo B, Falini A, Codella M, Scotti G, Comi G (2002) Functional magnetic resonance imaging correlates of fatigue in multiple sclerosis. Neuroimage 15:559–567PubMedCrossRefGoogle Scholar
  13. 13.
    Fisk JD, Pontefract A, Ritvo PG, Archibald CJ, Murray TJ (1994) The impact of fatigue on patients with multiple sclerosis. Can J Neurol Sci 21:9–14PubMedGoogle Scholar
  14. 14.
    Ford H, Trigwell P, Johnson M (1998) The nature of fatigue in multiple sclerosis. J Psychosom Res 45:33–38PubMedCrossRefGoogle Scholar
  15. 15.
    Freal JE, Kraft GH, Coryell JK (1984) Symptomatic fatigue in multiple sclerosis. Arch Phys Med Rehabil 65:135–138PubMedGoogle Scholar
  16. 16.
    Ge Y, Grossman RI, Udupa JK, Babb JS, Nyul LG, Kolson DL (2001) Brain atrophy in relapsing-remitting multiple sclerosis: fractional volumetric analysis of gray matter and white matter. Radiology 220:606–610PubMedCrossRefGoogle Scholar
  17. 17.
    Gean-Marton AD, Vezina LG, Marton KI, Stimac GK, Peyster RG, Taveras JM, Davis KR (1991) Abnormal corpus callosum: a sensitive and specific indicator of multiple sclerosis. Radiology 180:215–221PubMedGoogle Scholar
  18. 18.
    Giovannoni G, Thompson AJ, Miller DH, Thompson EJ (2001) Fatigue is not associated with raised inflammatory markers in multiple sclerosis. Neurology 57:676–681PubMedGoogle Scholar
  19. 19.
    Hardmeier M, Wagenpfeil S, Freitag P, Fisher E, Rudick RA, Kooijmans-Coutinho M, Clanet M, Radue EW, Kappos L (2003) Atrophy is detectable within a 3-month period in untreated patients with active relapsing remitting multiple sclerosis. Arch Neurol 60:1736–1739PubMedCrossRefGoogle Scholar
  20. 20.
    Krupp LB, Alvarez LA, LaRocca NG, Scheinberg LC (1988) Fatigue in multiple sclerosis. Arch Neurol 45:435–437PubMedGoogle Scholar
  21. 21.
    Krupp LB, LaRocca NG, Muir-Nash J, Steinberg AD (1989) The fatigue severity scale. Application to patients with multiple sclerosis and systemic lupus erythematosus. Arch Neurol 46:1121–1123PubMedGoogle Scholar
  22. 22.
    Krupp LB, Pollina DA (1996) Mechanisms and management of fatigue in progressive neurological disorders. Curr Opin Neurol 9:456–460PubMedCrossRefGoogle Scholar
  23. 23.
    Mainero C, Faroni J, Gasperini C, Filippi M, Giugni E, Ciccarelli O, Rovaris M, Bastianello S, Comi G, Pozzilli C (1999) Fatigue and magnetic resonance imaging activity in multiple sclerosis. J Neurol 246:454–458PubMedCrossRefGoogle Scholar
  24. 24.
    Marrie RA, Fisher E, Miller DM, Lee JC, Rudick RA (2005) Association of fatigue and brain atrophy in multiple sclerosis. J Neurol Sci 228:161–166PubMedCrossRefGoogle Scholar
  25. 25.
    Martola J, Stawiarz L, Fredrikson S, Hillert J, Bergstrom J, Flodmark O, Kristoffersen WM (2007) Progression of non-age-related callosal brain atrophy in multiple sclerosis: a 9-year longitudinal MRI study representing four decades of disease development. J Neurol Neurosurg Psychiatry 78:375–380PubMedGoogle Scholar
  26. 26.
    Mesaros S, Rocca MA, Riccitelli G, Pagani E, Rovaris M, Caputo D, Ghezzi A, Capra R, Bertolotto A, Comi G, Filippi M (2009) Corpus callosum damage and cognitive dysfunction in benign MS. Hum Brain Mapp 30:2656–2666PubMedCrossRefGoogle Scholar
  27. 27.
    Niepel G, Tench C, Morgan PS, Evangelou N, Auer DP, Constantinescu CS (2006) Deep gray matter and fatigue in MS: a T1 relaxation time study. J Neurol 253:896–902PubMedCrossRefGoogle Scholar
  28. 28.
    Nocentini U, Rossini PM, Carlesimo GA, Graceffa A, Grasso MG, Lupoi D, Oliveri M, Orlacchio A, Pozzilli C, Rizzato B, Caltagirone C (2001) Patterns of cognitive impairment in secondary progressive stable phase of multiple sclerosis: correlations with MRI findings. Eur Neurol 45:11–18PubMedCrossRefGoogle Scholar
  29. 29.
    Pelletier J, Suchet L, Witjas T, Habib M, Guttmann CR, Salamon G, Lyon-Caen O, Cherif AA (2001) A longitudinal study of callosal atrophy and interhemispheric dysfunction in relapsing-remitting multiple sclerosis. Arch Neurol 58:105–111PubMedCrossRefGoogle Scholar
  30. 30.
    Pittion-Vouyovitch S, Debouverie M, Guillemin F, Vandenberghe N, Anxionnat R, Vespignani H (2006) Fatigue in multiple sclerosis is related to disability, depression and quality of life. J Neurol Sci 243:39–45PubMedCrossRefGoogle Scholar
  31. 31.
    Polman CH, Reingold SC, Edan G, Filippi M, Hartung HP, Kappos L, Lublin FD, Metz LM, McFarland HF, O’Connor PW, Sandberg-Wollheim M, Thompson AJ, Weinshenker BG, Wolinsky JS (2005) Diagnostic criteria for multiple sclerosis: 2005 revisions to the “McDonald Criteria”. Ann Neurol 58:840–846PubMedCrossRefGoogle Scholar
  32. 32.
    Rao SM, Leo GJ, Haughton VM, St Aubin-Faubert P, Bernardin L (1989) Correlation of magnetic resonance imaging with neuropsychological testing in multiple sclerosis. Neurology 39:161–166PubMedGoogle Scholar
  33. 33.
    Riccitelli G, Rocca M, Forn C, Colombo B, Comi G, Filippi M (2010) Definition of regional distribution of grey matter loss in multiple sclerosis patients with fatigue: a voxel-based morphometry study. J Neurol 257:S1–S246Google Scholar
  34. 34.
    Rocca MA, Agosta F, Colombo B, Mezzapesa DM, Falini A, Comi G, Filippi M (2007) fMRI changes in relapsing-remitting multiple sclerosis patients complaining of fatigue after IFNbeta-1a injection. Hum Brain Mapp 28:373–382PubMedCrossRefGoogle Scholar
  35. 35.
    Roelcke U, Kappos L, Lechner-Scott J, Brunnschweiler H, Huber S, Ammann W, Plohmann A, Dellas S, Maguire RP, Missimer J, Radu EW, Steck A, Leenders KL (1997) Reduced glucose metabolism in the frontal cortex and basal ganglia of multiple sclerosis patients with fatigue: a 18F-fluorodeoxyglucose positron emission tomography study. Neurology 48:1566–1571PubMedGoogle Scholar
  36. 36.
    Schreiber K, Sorensen PS, Koch-Henriksen N, Wagner A, Blinkenberg M, Svarer C, Petersen HC (2001) Correlations of brain MRI parameters to disability in multiple sclerosis. Acta Neurol Scand 104:24–30PubMedCrossRefGoogle Scholar
  37. 37.
    Simioni S, Ruffieux C, Bruggimann L, Annoni JM, Schluep M (2007) Cognition, mood and fatigue in patients in the early stage of multiple sclerosis. Swiss Med Wkly 137:496–501PubMedGoogle Scholar
  38. 38.
    Simon JH, Holtas SL, Schiffer RB, Rudick RA, Herndon RM, Kido DK, Utz R (1986) Corpus callosum and subcallosal-periventricular lesions in multiple sclerosis: detection with MR. Radiology 160:363–367PubMedGoogle Scholar
  39. 39.
    Tartaglia MC, Narayanan S, Francis SJ, Santos AC, De SN, Lapierre Y, Arnold DL (2004) The relationship between diffuse axonal damage and fatigue in multiple sclerosis. Arch Neurol 61:201–207PubMedCrossRefGoogle Scholar
  40. 40.
    Van Der Werf SP, Jongen PJ, Nijeholt GJ, Barkhof F, Hommes OR, Bleijenberg G (1998) Fatigue in multiple sclerosis: interrelations between fatigue complaints, cerebral MRI abnormalities and neurological disability. J Neurol Sci 160:164–170PubMedCrossRefGoogle Scholar
  41. 41.
    Yaldizli O, Atefy R, Gass A, Sturm D, Glassl S, Tettenborn B, Putzki N (2010) Corpus callosum index and long-term disability in multiple sclerosis patients. J Neurol 257:1256–1264PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Özgür Yaldizli
    • 1
    • 3
    Email author
  • Stephanie Glassl
    • 1
  • Dietrich Sturm
    • 1
  • Athina Papadopoulou
    • 2
  • Achim Gass
    • 2
  • Barbara Tettenborn
    • 1
  • Norman Putzki
    • 1
  1. 1.Department of NeurologyCantonal Hospital St. GallenSt. GallenSwitzerland
  2. 2.Department of Neurology/NeuroradiologyUniversity of BaselBaselSwitzerland
  3. 3.Department of NeurologyUniversity of BaselBaselSwitzerland

Personalised recommendations