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Nicola De Stefano, MD; Sridar Narayanan, MSc; Simon J. Francis, BSc; Steve Smith, DPhil; Marzia Mortilla, MD; M. Carmela Tartaglia, BSc; Maria L. Bartolozzi, MD; Leonello Guidi, MD; Antonio Federico, MD; Douglas L. Arnold, MD

Arch Neurol. 2002;59:1565-1571.

Background  Although in situ pathological studies and in vivo magnetic resonance (MR) investigations have shown that axonal injury can be significant in the early stages of multiple sclerosis (MS), diffuse axonal injury is generally considered a secondary event. Cerebral axonal damage can be specifically assessed in vivo by measuring levels of brain N-acetylaspartate (NAA, a specific index of axonal integrity detected by MR spectroscopy). Other new MR measurements such as magnetization transfer ratio (MTr) or computed estimation of brain volume can provide less specific indexes of tissue damage.

Objective  To determine whether diffuse axonal and tissue injury is present in patients with definite MS who do not show clinically significant disability.

Methods  We measured brain NAA levels (normalized to creatine [Cr]), MTr values, and cerebral volumes in patients with definite MS who had low T2-weighted MR imaging lesion volumes and no clinical disability, and also in age-matched healthy control subjects.

Results  Values of central brain NAA/Cr and MTr in normal-appearing white matter were significantly lower in the MS patients than in controls (P<.001). In contrast, total brain volumes were not significantly different between these groups. Similar results were found for MS patients with early disease (duration, <3 years) and with a particularly low cerebral T2-weighted MR imaging lesion load (2 cm³).

Conclusions  Cerebral NAA/Cr and MTr values are diffusely decreased in MS patients with early disease, low demyelinating lesion load, and no significant disability. This suggests that axonal and/or tissue injury begins very early in the course of MS and might be at least partially independent of cerebral demyelination.

From the Institute of Neurological Sciences and NMR Centre, University of Siena, Siena, Italy (Drs De Stefano, Mortilla, and Federico); Department of Neurology and Neurosurgery, Montreal Neurological Institute and Hospital, Montreal, Quebec (Messrs Narayanan and Francis, Ms Tartaglia, and Dr Arnold); Centre for Functional Magnetic Resonance Imaging of the Brain, Department of Clinical Neurology, University of Oxford, Oxford, England (Dr Smith); and Neurology Unit, Hospital of Empoli, Empoli, Italy (Drs Bartolozzi and Guidi).

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