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Nicola De Stefano, MD; Sridar Narayanan, MSc; Gordon S. Francis, MD; Rozie Arnaoutelis, BSc; Maria C. Tartaglia, BSc; Jack P. Antel, MD; Paul M. Matthews, MD; Douglas L. Arnold, MD

Arch Neurol. 2001;58:65-70.

Objective  To assess axonal damage and its contribution to disability at different stages of multiple sclerosis (MS).

Background  Recent in vivo imaging and in situ pathologic studies have demonstrated that substantial axonal damage accompanies the inflammatory lesions of MS. However, the relation of axonal damage to the duration of MS and its contribution to disability at different stages of the disease remain poorly defined.

Design  We performed proton magnetic resonance spectroscopic imaging in 88 patients with a wide range of clinical disability and disease duration to measure N-acetylaspartate (NAA, an index of axonal integrity) relative to creatine (Cr) in a large central brain volume that included mostly normal-appearing white matter on magnetic resonance imaging.

Results  We observed that the NAA/Cr values were abnormally low in the early stages of MS, even before significant disability (measured using the Expanded Disability Status Scale [EDSS]) was evident clinically, and declined more rapidly with respect to EDSS at lower than at higher EDSS scores (P<.001). The correlation of NAA/Cr values with EDSS score was significantly (P<.03) stronger in patients with mild disability (EDSS score <5, Spearman rank order correlation = –0.54, P< .001) than in patients with more severe disability (EDSS score 5, Spearman rank order correlation = -0.1, P<.9). When similar analyses were performed in patients with MS grouped for duration of disease, the subgroup with early disease duration (<5 years) also showed central brain NAA/Cr resonance intensity ratios significantly lower than healthy controls (P<.001).

Conclusion  Cerebral axonal damage begins and contributes to disability from the earliest stages of the disease.

From the Department of Neurology and Neurosurgery, Montreal Neurological Institute and Hospital, Montreal, Quebec (Drs De Stefano, Francis, Antel, Matthews, and Arnold; Mr Narayanan; and Mss Arnaoutelis and Tartaglia); Institute of Neurological Sciences and NMR Centre, University of Siena, Siena, Italy (Dr De Stefano); and Centre for Functional Magnetic Resonance Imaging of the Brain, Department of Clinical Neurology, University of Oxford, Oxford, England (Dr Matthews).

Corresponding author: Nicola De Stefano, MD, Institute of Neurological Science, Viale Bracci 2, 53100, Siena, Italy (e-mail: destefano{at}unisi.it).

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