MRI measures of brain injury in children with Multiple Sclerosis

Multiple sclerosis (MS) is thought to be an autoimmune disease that affects the central nervous system of young adults. Although an uncommon disease in children, recent research has examined the effect of this disease upon a younger demographic group. This patient population has attracted the attention of MS researchers, as it promises a better understanding of the pathophysiology of MS at its earliest stage. Magnetic resonance imaging (MRI), a sensitive tool for detecting white matter (WM) pathology, has improved the diagnosis and appreciation of the pathogenesis of MS in adults. However, little is known about its use in children. Therefore, the main objective of this thesis is to contribute and to increase knowledge in this important new area. For this purpose, specific image processing methodologies were developed, and pathology on MRI was compared between patients with adult- and pediatric-onset MS. Comparing the spatial distribution, frequency, and volume of lesions on T2-weighted (T2w) MR images among patients with pediatric- and adult-onset MS, who had similar disease duration, showed a similar total T2w lesions between the two groups. However, children exhibited a higher T2w lesion volume and frequency in the infratentorial region, particularly in the pontine region. Persistent T1-weighted (T1w) lesions, a marker of permanent tissue damage and axonal loss, were assessed to determine whether MS lesions in children are as destructive as those in adults. To obtain a fair comparison using the scans available, normalization of intensity was essential. We showed the limitations of the currently available techniques for intensity normalization, and the need for a WM independent methodology. We proposed and developed a novel WM-independent intensity normalization method for T1w images and assessed inter-scanner, between-scanner and within subject variation before and after normalization. We also calculated the sample size required for detecting recovery of T1w intensity using our methodology and the most commonly used intensity normalization method. Then we used our methodology to assess recovery of normalized T1w intensity within new lesions in children with relapsing remitting MS (RRMS) compared to adults. We found that MS lesions recover better in children, suggesting a greater reparative capacity in younger patients. We also used our intensity normalization method to perform a quantitative comparison of T1w intensity recovery in new lesions between children with MS and children with monophasic inflammatory demyelinating syndromes (monoADS). We found that new MS lesions recover more poorly than of those in children with monoADS. This may suggest that new MS lesions are more destructive than new lesions in monophasic inflammatory demyelinating diseases.La sclérose en plaques (MS) est considérée comme une maladie auto-immune qui affecte le système nerveux central de l'adulte jeune. Bien que d'une maladie rare chez les enfants, des recherches récentes ont examiné l'effet de cette maladie sur une population plus jeune. Cette population de patients a attiré l'attention des chercheurs en SP, car elle promet une meilleure compréhension de la physiopathologie de la SEP au stade le plus précoce . Imagerie par résonance magnétique (IRM), un outil sensible pour la détection de la substance blanche (WM) pathologie, a amélioré le diagnostic et l'appréciation de la pathogenèse de la SEP chez les adultes. Cependant, peu a été connu au sujet de son utilisation chez les enfants. Par conséquent, l'objectif principal de cette thèse est de contribuer et d'accroître les connaissances dans ce nouveau domaine important. A cet effet, des méthodologies spécifiques de traitement d'image ont été développés, et de la pathologie à l'IRM ont été comparées entre les patients atteints de l'adulte et pédiatrique apparition MS. La comparaison de la répartition spatiale, la fréquence et le volume des lésions sur T2 (en T2) images IRM chez les patients atteints de la SP pédiatrique et adulte-début, qui ont eu la durée de la maladie similaire , ont montré un nombre total de lésions en T2 similaires entre les deux groupes. Cependant, les enfants présentaient un volume plus élevé de lésion en T2 et la fréquence dans la région infratentorial, en particulier dans la région pontique. (T1) des lésions pondérées en T1 persistants, un marqueur des dommages permanents aux tissus et la perte axonale, ont été évalués pour déterminer si les lésions de SP chez les enfants sont aussi destructrices que celles des adultes. Pour obtenir une comparaison équitable en utilisant les analyses disponibles, la normalisation de l'intensité était essentiel. Nous avons montré les limitations des techniques disponibles actuellement pour la normalisation de l'intensité, et le besoin d'une méthode indépendante WM. Nous avons proposé et développé une nouvelle méthode de normalisation de l'intensité WM- indépendante pour les images T1 et évalué inter- scanner, entre - scanner et dans l'objet variation avant et après normalisation. Nous avons également calculé la taille de l'échantillon nécessaire pour détecter la reprise de l'intensité T1w utilisant notre méthodologie et la méthode de normalisation de l'intensité la plus couramment utilisée. Ensuite, nous avons utilisé notre méthode pour tester notre hypothèse et la récupération assesed d'intensité T1w normalisée dans de nouvelles lésions chez les enfants sclérose en plaques rémittente (SEP-RR) par rapport aux adultes. Nous avons constaté que les lésions de SP mieux récupérer les enfants qui peuvent suggérer une plus grande capacité réparatrice chez les patients plus jeunes. Nous avons également utilisé notre méthode de normalisation de l'intensité pour effectuer une comparaison quantitative de la récupération de l'intensité T1w dans de nouvelles lésions entre enfants atteints de SP et les enfants atteints de syndromes inflammatoires démyélinisantes monophasiques (de monoADS). Nous avons constaté que de nouvelles lésions de SP récupérer plus mal que de ceux des enfants avec monoADS. Cela peut suggérer que les lésions New MS sont plus destructeur que de nouvelles lésions dans les maladies démyélinisantes inflammatoires monophasique

Quantitative determination of regional lesion volume and distribution in children and adults with relapsing-remitting multiple sclerosis.

Onset of MS occurs during childhood in about 5% of cases. It is unclear whether very young age at MS onset, when the nervous system is still myelinating, affects MS lesion accrual or regional distribution.To compare the frequency, volume and distribution of T2 and T1 lesions in children and adults with relapsing-remitting multiple sclerosis (RRMS).Lesions were segmented on T2- and T1-weighted MRI images from 29 children and 29 adults with RRMS, matched for disease duration.All subjects exhibited T2-weighted brain lesions. Children had higher whole-brain T2-weighted-lesion-volume (T2LV) compared to adults (mean (SD) in cm(3): 12.76(2.7) vs. 10.03(3.4), p<0.0013). The supratentorial-T2LV was similar in children and adults (8.45(1.7) vs. 7.94(1.7), mean (SD), p = 0.2582), but adults were more likely to have supratentorial lesions (96.5% vs. 68.9%, p<0.012). Children were more likely to have infratentorial-T2-weighted lesions (75.9% vs. 43.4%, p<0.03), specifically in the brainstem (62.1% vs. 26.7%, p<0.019) and the pons (48.3% vs. 17.24%, p<0.024), had higher infratentorial-T2-weighted-lesion counts (4.1(5.6) vs. 1.45(2.3), p<0.021), a greater infratentorial-T2LV (4.31(2.7) vs. 2.08(2.4), p<0.0013), and a greater infratentorial-T1-weighted-lesion-volume (T1LV) (3.7(2.5) vs. 1.08(1.9), p<0.0007). Whole-brain-T1LV was higher in children (9.3(2.5) vs. 6.43(2.1), p>0.001). Adult MS patients had higher supratentorial-T1LV (5.5(0.92) vs. 6.41(2.1), mean (SD), p<0.034), whereas children were more likely to have infratentorial-T1-weighted lesions (58.6% vs. 23.3%, p<0.015).Onset of MS during childhood is associated with a higher volume of brain lesions in the first few years of disease relative to adults. Children with MS are more likely than adults to have T2 and T1 lesions in the infratentorial white matter, raising the possibility of preferential immune targeting of more mature myelin. Children with MS have a lower supratentorial T1 lesion burden, possibly reflecting more effective remyelination and repair in brain regions that are still engaged in active primary myelination

Association of deep gray matter damage with cortical and spinal cord degeneration in primary progressive multiple sclerosis

IMPORTANCE: The investigation of cortical gray matter (GM), deep GM nuclei, and spinal cord damage in patients with primary progressive multiple sclerosis (PP-MS) provides insights into the neurodegenerative process responsible for clinical progression of MS. OBJECTIVE: To investigate the association of magnetic resonance imaging measures of cortical, deep GM, and spinal cord damage and their effect on clinical disability. DESIGN, SETTING, AND PARTICIPANTS: Cross-sectional analysis of 26 patients with PP-MS (mean age, 50.9 years; range, 31-65 years; including 14 women) and 20 healthy control participants (mean age, 51.1 years; range, 34-63 years; including 11 women) enrolled at a single US institution. Clinical disability was measured with the Expanded Disability Status Scale, 9-Hole Peg Test, and 25-Foot Walking Test. We collected data from January 1,2012, through December 31, 2013. Data analysis was performed from January 21 to April 10, 2015. MAIN OUTCOMES AND MEASURES: Cortical lesion burden, brain and deep GM volumes, spinal cord area and volume, and scores on the Expanded Disability Status Scale (score range, 0 to 10; higher scores indicate greater disability), 9-Hole Peg Test (measured in seconds; longer performance time indicates greater disability), and 25-Foot Walking Test (test covers 7.5 m; measured in seconds; longer performance time indicates greater disability). RESULTS: The 26 patients with PP-MS showed significantly smaller mean (SD) brain and spinal cord volumes than the 20 control group patients (normalized brain volume, 1377.81 [65.48] vs 1434.06 [53.67] cm3 [P =.003]; normalized white matter volume, 650.61 [46.38] vs 676.75 [37.02] cm3 [P =.045]; normalized gray matter volume, 727.20 [40.74] vs 757.31 [38.95] cm3 [P =.02]; normalized neocortical volume, 567.88 [85.55] vs 645.00 [42.84] cm3[P =.001]; normalized spinal cord volume for C2-C5, 72.71 [7.89] vs 82.70 [7.83] mm3[P <.001]; and normalized spinal cord volume for C2-C3, 64.86 [7.78] vs 72.26 [7.79] mm3[P =.002]). The amount of damage in deep GM structures, especially with respect to the thalamus, was correlated with the number and volume of cortical lesions (mean [SD] thalamus volume, 8.89 [1.10] cm3; cortical lesion number, 12.6 [11.7]; cortical lesion volume, 0.65 [0.58] cm3; r =-0.52; P <.01). Thalamic atrophy also showed an association with cortical lesion count in the frontal cortex (mean [SD] thalamus volume, 8.89 [1.1] cm3; cortical lesion count in the frontal lobe, 5.0 [5.7]; r =-0.60; P <.01). No association was identified between magnetic resonance imaging measures of the brain and spinal cord damage. CONCLUSIONS AND RELEVANCE In this study, the neurodegenerative process occurring in PP-MS appeared to spread across connected structures in the brain while proceeding independently in the spinal cord. These results support the relevance of anatomical connectivity for the propagation of MS damage in the PP phenotype

Demographic data in the pediatric and adult groups.

<p>The pediatric and adult MS groups were matched for disease duration (t-test, p = 0.78) and proportion of females (Fisher's exact test, p = 0.76).</p

Figure 1

<p>Lesion frequency maps (axial (left), sagittal (middle) and coronal (right) views) in the hot metal color scale showing the infratentorial (A) and supratentorial (B) T2-weighted lesion distributions in children with RRMS (rows 1 and 3) vs. adults with RRMS (rows 2 and 4), superimposed on the average T2-weighted structural images (in grey scale) for each group. The intensity of each voxel in the overlay represents the group frequency for lesions at each location.</p

Supratentorial and infratentorial incidence and volume of T2 and T1-weighted lesions.

1<p>measured using Fisher's exact test;</p>2<p>measured using two-tailed t-test,</p>3<p>measured using non-parametric Wilcoxon test.</p