A Preliminary Diffusion Tensor and Magnetization Transfer Magnetic Resonance Imaging Study of Early-Onset Multiple Sclerosis | Demyelinating Disorders | JAMA Neurology | JAMA Network
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MTR and MD Histogram-Derived Metrics of the NABT and MTR Histogram-Derived Metrics of the Cervical Cord*2
MTR and MD Histogram-Derived Metrics of the NABT and MTR Histogram-Derived Metrics of the Cervical Cord*
Original Contribution
March 2004

A Preliminary Diffusion Tensor and Magnetization Transfer Magnetic Resonance Imaging Study of Early-Onset Multiple Sclerosis

Author Affiliations

From the Neuroimaging Research Unit (Drs Mezzapesa, Rocca, and Filippi) and the Departments of Neurology (Drs Mezzapesa, Rocca, Rodegher, Comi, and Filippi) and Neuroradiology (Dr Falini), Scientific Institute and University Hospital San Raffaele, Milan, Italy; and the Multiple Sclerosis Center, Ospedale di Gallarate, Gallarate, Italy (Dr Ghezzi). The authors have no relevant financial interest in this article.

Arch Neurol. 2004;61(3):366-368. doi:10.1001/archneur.61.3.366

Background  Early-onset multiple sclerosis (MS) typically has a more favorable course than adult-onset disease.

Objective  To assess the extent of microscopic tissue damage in the brain and cervical cord of patients with early-onset MS.

Design  During a single magnetic resonance imaging session, images of the brain and spinal cord were obtained using diffusion tensor and magnetization transfer magnetic resonance imaging.

Patients  We studied 13 patients with early-onset MS and 10 healthy volunteers.

Results  Compared with control subjects, patients with early-onset MS showed only a slight increase of the average mean diffusivity of the normal-appearing brain tissue.

Conclusion  The relatively modest central nervous system damage detected in these patients might explain why early-onset MS typically has a more favorable clinical course than adult-onset MS.

In about 3% to 12% of cases, multiple sclerosis (MS) has an onset before 16 years of age.1 Several natural history studies1,2 have demonstrated that early-onset MS typically has a more favorable clinical course than the more common adult-onset disease. A plausible explanation for such a finding might be that the overall amount of tissue damage occurring in the central nervous systems of patients with early-onset MS is only mild. Previous studies,3,4 however, did not show any difference between early- and adult-onset MS in terms of conventional magnetic resonance imaging (MRI) metrics. This is likely owing to the poor specificity of conventional MRI to the heterogeneous substrates of MS and to its limited accuracy in estimating the actual amount of central nervous system tissue damage. In adult-onset MS, diffusion tensor (DT) and magnetization transfer (MT) MRI have enabled researchers to obtain reliable estimates of tissue damage, and show that it is not limited to lesions visible in T2-weighted images, but that it involves diffusely the normal-appearing brain tissue (NABT).5 To our knowledge, no previous study has attempted to quantify tissue damage in the brain and spinal cord of patients with early-onset MS. In this study, we obtained MT- and DT-MR images from these patients, with the goal of improving our understanding of the pathophysiology of early-onset MS.


We studied 10 girls and 3 boys with early-onset MS (mean age, 14.1 years [range, 7-16 years]; mean disease duration, 17.6 months [range, 8-36 months]; median Expanded Disability Status Scale score, 1.5 [range, 1.0-2.5]; and mean number of relapses per patient, 2.7 [range, 2-4]). Ten healthy volunteers (7 girls and 3 boys; mean age, 14.8 years [range, 9-16 years]) served as control subjects. At the time MRI was performed, all patients had been relapse- and steroid-free for at least 6 months. Eight patients were taking disease-modifying treatments (interferon beta-1a [n = 5] and glatiramer acetate [n = 3]). Local ethical committee approval and written informed consent from all patients were obtained before study initiation.

Using a 1.5-T scanner, we obtained the following sequences in the brain: (1) dual-echo turbo spin echo (repetition time/echo time, 3300/16-98 milliseconds; 24 axial 5-mm-thick sections with 256 × 256 matrix; and 250 × 250-mm2 field of view); (2) 2-dimensional gradient echo (repetition time/echo time, 600/12 milliseconds; flip angle, 20°; 20 axial 5-mm-thick sections with 256 × 256 matrix; and 250 × 250-mm2 field of view) with and without a saturation pulse (off-resonance radio-frequency pulse centered 1.5 kHz below the water frequency, with a gaussian envelope of duration of 7.68 milliseconds and α = 500°); and (3) pulsed gradient spin echo echo planar (interecho spacing, 0.8; echo time, 123 milliseconds; 10 axial 5-mm-thick sections with 128 × 128 matrix; and 250 × 250-mm2 field of view), with diffusion gradients applied in 8 noncollinear directions. Additional information about this sequence is given elsewhere.5 For the cervical cord, we obtained the following sequences: (1) fast–short-time inversion recovery (repetition time/echo time/inversion time, 2288/60/110 milliseconds; echo train length, 11, 8; 3-mm-thick sagittal sections with an intersection gap of 0.3 mm; matrix size, 264 × 512; field of view, 280 × 280 mm2; and number of signal averages, 4); and (2) 2-dimensional gradient echo with the same acquisition parameters used for the brain.

All MRI postprocessing was performed by a single observer (D.M.M.) masked to the subjects' identity. Lesions were identified on the dual-echo scans, and lesion volumes were measured using a segmentation technique based on local thresholding.5 After coregistration of the 2 gradient-echo scans using a surface-matching technique based on mutual information, the MT ratio (MTR) images were derived pixel by pixel, as described elsewhere.5 Extracerebral tissue was removed from MTR maps,5 and the resulting images were coregistered with the T2-weighted images. The pulsed gradient spin echo images were first corrected for distortion induced by eddy currents using an algorithm that maximizes mutual information between the diffusion-unweighted and -weighted images. Then, we calculated the DT and mean diffusivity (MD) derived for every pixel, as previously described.5 The diffusion images were interpolated to the same image matrix size as the dual echo, and then the b = 0 step of the pulsed gradient spin echo scans were coregistered with the dual-echo T2-weighted images.5 The final step consisted of automatic transfer of lesion outlines onto the MTR and MD maps to calculate the average lesion MTR and MD. To study the MTR and MD of NABT, pixels inside lesion outlines were masked out, and MTR and MD histograms of the NABT were produced.5 Cervical cord lesions were identified by the same observer on the fast–short-time inversion recovery scans. From the 2 gradient-echo images, with and without the saturation pulse, MTR maps and histograms were derived, as previously described.6 For each histogram, the average MTR and MD and the peak height were measured. Given the strong correlation existing between average histogram measures and the histogram peak location, the latter quantity was not considered for this study, to reduce the risk for type I errors.

We used a 2-tailed t test for unpaired data to compare MTR and MD histogram-derived metrics from the 2 groups of subjects. Univariate correlations were explored using the Spearman rank correlation coefficient.


In patients with early-onset MS, mean T2-weighted volume of brain lesions was 11.1 mL (range, 0.0-61.5 mL), average lesion MTR was 39.2% (SD, 2.0%), and average lesion MD was 1.01 × 103mm2/s (SD, 0.08 × 103 mm2/s). The median number of cervical cord lesions was 1.6 (range, 0-6).

In Table 1, MTR and MD histogram-derived metrics of the NABT and MTR histogram-derived metrics of the cervical cord from patients and controls are reported. Compared with controls, patients with MS had significantly increased average MD of the NABT only. No correlation was found between dual-echo lesion load and MD and MTR histogram-derived metrics.


Several studies have shown a more favorable course in patients with an onset of MS before 16 years of age than those with a typical onset in adulthood.1,2 However, the reasons for such a difference have not been fully elucidated yet. Cerebrospinal fluid3 and conventional MRI findings3 at disease onset have been found to be similar in both populations. Longitudinal MRI studies have also shown that the accumulation of disease burden on brain dual-echo scans is similar between these 2 groups of patients.4

In this preliminary study, we used MT- and DT-MRI to quantify the extent of NABT damage in patients with early-onset MS. Previous quantitative MRI studies5,6 showed significant and widespread NABT damage in adult patients with MS and clinical characteristics similar to those of our patient cohort (relapsing-remitting course, number of relapses, Expanded Disability Status Scale score). On the contrary, the present study shows that the brain and cervical cord of patients with early-onset MS are relatively spared, because these patients did not differ from matched controls in terms of relative proportions of free and bound water (as measured by MTR), and had only modest increase of average MD. These findings are in agreement with those of a previous study showing a lower rate of development of hypointense lesions and brain atrophy in early-onset MS.7 We also quantified the number of cervical cord lesions and the extent of microscopic cord damage. We found no MT histogram abnormalities in patients with early-onset MS, confirming that spinal cord damage has a major role in the development of disability in MS. Another factor that might contribute to the modest central nervous system damage found in this cohort of patients with early-onset MS is the relatively short disease duration. However, this factor is likely to have only a marginal role, because significant MTR abnormalities have been found in the NABT of patients with relapsing-remitting MS or patients with clinically isolated syndromes, and disease durations that were even shorter than those of the present study.8,9

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Article Information

Corresponding author and reprints: Massimo Filippi, MD, Neuroimaging Research Unit, Department of Neurology, Scientific Institute and University Hospital San Raffaele, Via Olgettina, 60, 20132 Milan, Italy (e-mail: m.filippi@hsr.it).

Accepted for publication October 27, 2003.

Author contributions: Study concept and design (Dr Filippi); acquisition of data (Drs Mezzapesa, Rodegher, and Ghezzi); analysis and interpretation of data (Drs Mezzapesa, Rocca, Falini, and Comi); drafting of the manuscript (Drs Mezzapesa, Rocca, and Filippi); critical revision of the manuscript for important intellectual content (Drs Rocca, Falini, Rodegher, Ghezzi, Comi, and Filippi); study supervision (Drs Comi and Filippi).

Simone  ILCarrara  DTortorella  C  et al Course and prognosis in early-onset MS: comparison with adult-onset forms.  Neurology.2002;59:1922-1928.PubMedGoogle Scholar
Confavreux  CVukusic  SAdeleine  P Early clinical predictors and progression of irreversible disability in multiple sclerosis: an amnesic process.  Brain.2003;126:770-782.PubMedGoogle Scholar
Sindern  EHaas  JStark  EWurster  U Early onset MS under the age of 16: clinical and paraclinical features.  Acta Neurol Scand.1992;86:280-284.PubMedGoogle Scholar
Ebner  FMillner  MMJustich  E Multiple sclerosis in children: value of serial MR studies to monitor patients.  AJNR Am J Neuroradiol.1990;11:1023-1027.PubMedGoogle Scholar
Rocca  MAFalini  AColombo  BScotti  GComi  GFilippi  M Adaptive functional changes in the cerebral cortex of patients with nondisabling multiple sclerosis correlate with the extent of brain structural damage.  Ann Neurol.2002;51:330-339.PubMedGoogle Scholar
Filippi  MBozzali  MHorsfield  MA  et al A conventional and magnetization transfer MRI study of the cervical cord in patients with MS.  Neurology.2000;54:207-213.PubMedGoogle Scholar
Balassy  CBernert  GWober-Bingol  C  et al Long-term MRI observations of childhood-onset relapsing-remitting multiple sclerosis.  Neuropediatrics.2001;32:28-37.PubMedGoogle Scholar
Iannucci  GTortorella  CRovaris  MSormani  MPComi  GFilippi  M 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.2000;21:1034-1038.PubMedGoogle Scholar
De Stefano  NNarayanan  SFrancis  SJ  et al Diffuse axonal and tissue injury in patients with multiple sclerosis with low cerebral lesion load and no disability.  Arch Neurol.2002;59:1565-1571.PubMedGoogle Scholar