A longitudinal study of MR diffusion changes in normal appearing white matter of patients with early multiple sclerosis

doi:10.1016/S0730-725X(02)00519-2

Magnetic Resonance Imaging

Volume 20, Issue 5, June 2002, Pages 383-388

https://doi.org/10.1016/S0730-725X(02)00519-2 Get rights and content

Abstract

Background and purpose: The stage at which normal appearing white matter (NAWM) abnormalities first appear in multiple sclerosis (MS) is not clear. The aim of our study was to monitor water diffusion changes over time in NAWM of patients with early MS.

Methods: Out of a consecutive series of patients enrolled in a MR study on clinically isolated syndrome (CIS), we selected 19 subjects who had completed a one year follow-up. The MR scans obtained at baseline and at 12 months were reviewed according to the new criteria on the diagnosis of MS. Lesion load on T2 and T1 weighted images and the trace of the apparent diffusion coefficient in NAWM were measured both at baseline and at 12 months in patients and in 12 healthy controls.

Results: In three patients the diagnosis of MS was done at baseline based on MR. Thirteen patients developed MS during the study and in three patients the diagnosis remained “possible MS.” TADC in NAWM in patients was significantly higher than in controls at the 12 months’ follow-up but not at baseline (controls mean tADC ± sd = 0.745 ± 0.02 mm²/sec × 10⁻³; patients mean tADC₁₂ ± sd = 0.767 ± 0.02 mm²/sec × 10⁻³; p < 0.02). TADC and T2 lesion load at 12 months were significantly correlated (p < 0.01). Patients exhibiting tADC₁₂ above a confidence interval had a significantly greater EDSS score at the same time period (EDSS₁₂ ± sd = 1.9 ± 0.5 and = 1.1 ± 0.4 respectively; p < 0.01).

Conclusions: This study suggests that diffusion MR cannot detect alterations in NAWM of patients with a CIS suggestive of MS. After one year, when most patients develop MS, diffusion MR abnormalities in NAWM become apparent. These abnormalities are correlated with T2 lesion load and may contribute to neurological impairment.

Introduction

Diffusion weighted imaging allows to measure tissue water diffusion in the brain which is affected by the size and integrity of structures that normally restrict diffusion. The trace of the apparent diffusion coefficient (tADC) can be increased as a result of pathologic processes that modify tissue integrity, thus reducing “restricting” barriers [1]. Several reports have demonstrated increased tADC in multiple sclerosis (MS) in the white matter that appears normal on studies obtained with conventional techniques [2], [3], [4], [5], [6], [7], [8], [9]. This finding is consistent with histopathologic studies, which have showed abnormalities in macroscopically normal-appearing white matter (NAWM) in MS [10].

In vivo detection of white matter abnormalities that are beyond the resolution of conventional MR techniques is becoming the focus of great attention.

The stage at which NAWM abnormalities first appear in MS is not clear. The time of onset, particularly in relation to clinical parameters and to lesion development, is relevant in understanding disease pathogenesis and may have an impact on disability.

The earliest clinical event in many patients with MS is a clinically isolated syndrome (CIS). Several reports have attempted to detect subtle alterations in NAWM in CIS. The results are however, contradictory. MR spectroscopy (MRS) studies have demonstrated little or no changes in NAA in NAWM in CIS patients [11], [12].

Some authors have demonstrated subtle changes of magnetization transfer ratio (MTR) outside lesions in CIS patients and a significant correlation between the extent of such abnormalities and the risk of developing MS [13]. On the other hand other studies have found no difference in magnetization transfer parameters among control subjects and patients with a CIS [14], [15]. These contradictory results may be due to the fact that changes of NAWM outside MR visible lesions may be small in an early phase of the disease, and beyond the resolution of the techniques so far implemented.

Therefore we investigated NAWM in CIS patients using diffusion weighted imaging, which provides an independent measure of tissue ultrastructural damage. We monitored tADC in NAWM over time, aiming at identifying the stage at which white matter changes occur outside MR visible lesions. Furthermore, in order to elucidate the pathophysiology underlying NAWM in MS and the impact on disability, we investigated whether changes outside MR visible lesions are somehow linked to the amount of MR visible lesions and whether they correlate with clinical parameters.

Section snippets

Subjects

Diffusion weighted imaging was introduced into an ongoing prospective, longitudinal multi-sequence MR and clinical study on patients with CIS consecutively enrolled at the MS Center at our institution.

Inclusion criteria for this study were: 1) a single clinical episode suggestive of MS and positive MR findings according to Fazekas’ criteria [16]; 2) age between 18 and 50 years; 3) no steroid treatment for at least 60 days before entry in the study. All patients gave written informed consent to

Results

According to the recommended diagnostic criteria for MS of the International panel [18], of the nineteen patients included in the study, in 16 (84.2%) the diagnosis was “possible MS,” based on the presence of a single clinical episode and of dissemination in space demonstrated by the baseline MR. Three patients (15.8%) were classified as MS due to evidence of both dissemination in time and space of MR lesions. At the 12 months’ follow-up, 16 (84.2%) patients had MS, based on the evidence of new

Discussion

This study using diffusion MR suggests that NAWM outside T2-visible lesions of patients with CIS undergo microscopic changes over time. In particular DWI may help identifying the stage at which ultra-structural changes occur in NAWM in MS patients.

No significant alterations were found in the NAWM at the baseline MR scan despite the presence of T2 visible lesions; subtle changes as compared to mean values in controls were observed at the 12 months’ follow-up. At this time, although no patients

Conclusions

In conclusion, these preliminary results shed some light on the controversy regarding NAWM in CIS patients. Our study was conducted on a cohort of patients who were selected on the basis of an isolated clinical episode and a positive MR and who were followed-up for one year. By doing so we were able to detect subtle changes in NAWM, beyond the resolution of conventional MR techniques. The importance of these changes is highlighted by the correlation with the extent of T2 lesion load, a

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A longitudinal study of MR diffusion changes in normal appearing white matter of patients with early multiple sclerosis

Abstract

Introduction

Section snippets

Subjects

Results

Discussion

Conclusions

Magn Reson Imaging

J Neurol Sci

J Neurol Sci

Magn Reson Imaging

J Neurol Sci

Imaging of diffusion and microcirculation with gradient sensitizationdesign, strategy, and significance

J Magn Reson Imaging

Increased water self-diffusion in chronic plaques and in apparently normal white matter in patients with multiple sclerosis

Acta Neurol Scand

Apparent diffusion coefficients in benign and secondary progressive multiple sclerosis by nuclear magnetic resonance

Magn Reson Med

Pathologic damage in MS assessed by diffusion-weighted and magnetization transfer MRI

Neurology

The pathogenesis of lesions and normal-appearing white matter changes in multiple sclerosisa serial diffusion MRI study

Brain

A quantitative study of water diffusion in multiple sclerosis lesions and normal-appearing white matter using echo-planar imaging

Arch Neurol

Magnetic resonance diffusion tensor imaging for characterizing diffuse and focal white matter abnormalities in multiple sclerosis

Magn Reson Med

Quantitative diffusion weighted magnetic resonance imaging, cerebral atropy, and disability in multiple sclerosis

J Neurol Neurosurg Psychiatry

Normal-appearing white matter in optic neuritis and multiple sclerosisa comparative proton spectroscopy study

Neuroradiology

Prognostic value of MR and magnetization transfer imaging findings in patients with clinically isolated syndromes suggestive of multiple sclerosis at presentation

AJNR Am J Neuroradiol

Magnetization transfer histogram analysis of monosymptomatic episodes of neurologic dysfunctionpreliminary findings

AJNR Am J Neuroradiol

Magnetization transfer imaging in patients with clinically isolated syndromes suggestive of multiple sclerosis

AJNR Am J Neuroradiol

Criteria for an increased specificity of MRI interpretation in elderly subjects with suspected multiple sclerosis

Neurology

Fast magnetic resonance diffusion-weighted imaging of acute human stroke

Neurology