Regional brain atrophy in primary fatigued patients with multiple sclerosis
Introduction
Fatigue is experienced by the majority of patients with multiple sclerosis (MS) (Lerdal et al., 2007), predicts poor quality of life and is described as a subjective lack of physical and/or mental energy (Benedict et al., 2005). Cortico-subcortical circuit disruption involving frontal cortex and basal ganglia (Roelcke et al., 1997) is suggested to play a pathogenetic role for the development of MS-fatigue. Regional cortical- and white matter atrophy in the frontal and parietal lobes (Sepulcre et al., 2009) with involvement of thalamus, putamen and caudate nucleus (Inglese et al., 2004, Inglese et al., 2007, Niepel et al., 2006, Tellez et al., 2008) has been related to MS-fatigue. But also a relation between diffuse injury of normal appearing white matter (NAWM) and MS-fatigue has been described (Codella et al., 2002, Tartaglia et al., 2004).
The aim of the present study was to investigate the role of MRI brain correlates in MS-fatigue. We hypothesized that fatigue in MS patients with moderate disease severity is associated with regional cortical atrophy and diffuse NAWM damage. Multiple aetiologies of MS-fatigue are linked in a model encompassing biological and psychological aspects, suggesting that the disease process with inflammation and demyelination is the primary trigger of MS-fatigue with cognitive-behavioural variables as exaggerating factors (van Kessel and Moss-Morris 2006). As physical disability, sleep disturbances, pain, stress, depression and self-efficacy has been found to contribute to MS-fatigue by approximately 50% (Strober and Arnett, 2005, Trojan et al., 2007), we carefully excluded patients with fatigue related to other causes of fatigue then MS itself. Subjective fatigue scores and objective measures of motor function (Andreasen et al., 2009a) and cognition (Andreasen et al., 2009b) were studied in relations to quantitative MRI measures, using an advanced high resolution technique, tensor based morphometry (TBM), to investigate regional brain atrophy in fatigued MS-patients.
Section snippets
Subjects
Between May 2006 and October 2007 forty patients attending the MS-outpatient-clinic at Aarhus University Hospital and Viborg County Hospital were recruited. Inclusion criteria were relapsing-remitting MS, age 18–55 years and an Expanded Disability Status Scale score (EDSS score) ≤ 3.5 (Kurtzke 1983). Exclusion criteria were MRI contra-indications, clinical attack between day of enrolment and MRI acquisition, dementia, pregnancy, concomitant major medical illness and “secondary fatigue” related
Recruitment
Medical records of 906 patients were screened. One hundred ninety-five patients fulfilled the inclusion criteria and were sent a letter. One hundred sixteen patients responded and 29 were excluded following interview (Fig. 1). Further 53 patients were excluded due to predefined criteria for secondary fatigue. Eventually, a total of 17 primary fatigued (PF), 17 non-fatigued (NF) patients and seven healthy controls (HC) were scanned (Table 1).
Clinical and laboratory characteristics
Age and distribution of gender were similar among the
Discussion
In the present study high quality neuro-imaging techniques and advanced methods of analysis were applied which makes the outcome highly dependent on the quality of the spatial normalization. The co-registration was performed at a 2 mm level which is superior to the degree of details achieved with a voxel based morphometry method. The drawback of such a high degree of details is the increase of error at lower resolution regions such as the sulci. TBM is highly sensitive to small changes of brain
Conflict of interest statement
No authors have conflicts of interests.
Acknowledgments
We are grateful to Ryan Sangill, M.Sc PhD, for MRI protocol design; Dora Zeidler, RT, and Michael Geneser, RT, for MRI acquisition; Anders Rodell, M.Sc. PhD, and Jesper Frandsen, M.Sc., for data analysis. Also we are grateful to Hans Jacob Hansen, MD, nurse Vivi Brandt and secretary Lisbeth Petersen for clinical suggestions and contacts to participants. We thank nurse Helle Krogh, at the MS out-patient clinic Viborg County Hospital for recruitment of participants. This study was supported by
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