Retinal degeneration in primary-progressive multiple sclerosis: A role for cortical lesions?

BACKGROUND: Retinal atrophy in multiple sclerosis (MS) is secondary to optic nerve focal inflammation and to injury of the posterior visual pathway. OBJECTIVES: To investigate the contribution of cortical lesions (CLs) to retinal pathology in primary-progressive multiple sclerosis (PPMS). METHODS: We performed a cross-sectional evaluation of 25 patients and 20 controls, relating magnetic resonance imaging (MRI) metrics of visual pathway integrity with parameters derived from spectral-domain optical coherence tomography (peripapillary retinal nerve fiber layer (RNFL) thickness, ganglion cell + inner plexiform layer (GCIPL) thickness, and macular volume (MV)). RESULTS: Mean RNFL, GCIPL thickness, and MV were significantly reduced in patients compared to controls. MV and GCIPL thickness were significantly correlated with visual acuity. RNFL thinning was associated with thalamus and visual cortex volume (respectively, p = 0.01 and p < 0.05). In addition to thalamic volume, GCIPL thinning was associated with CLs and intracortical lesion number and volume, leucocortical lesion volume (all p ⩽ 0.05) while MV decrease was associated with CLs volume ( p = 0.05) and intracortical lesion number and volume ( p < 0.05). CONCLUSION: Our results suggest that RNFL thinning and GCIPL thinning/MV decrease may be explained by alternative mechanisms including retrograde trans-synaptic degeneration and/or a common pathophysiologic process affecting both the brain with CLs and the retina with neuronal loss.

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.

Quantitative Measurement of tissue damage and recovery within new T2w lesions in pediatric- and adult-onset multiple sclerosis.

BACKGROUND: Children and adolescents with relapsing-remitting multiple sclerosis (RRMS) have a similar T2 lesion burden as adults matched for disease duration. However, it is unknown whether the degree of tissue destruction within lesions is also similar. Persistent reduced T1-weighted signal intensity within lesions indicates loss of tissue integrity. OBJECTIVE: We aimed to compare change over a 2-year period in T1 intensity within new T2 lesions, from pre-lesion levels to chronic post-lesion levels, between pediatric and adult-onset MS. METHODS: A two-point intensity-normalization method was used to generate normalized T1-weighted (NT1) images from T1-weighted data in 29 pediatric MS patients (age(mean±SD, years), disease duration (years)=15.7±2.4, 3.9±2.6) and 24 adult MS patients (36.7±8.9, 6.9±4.8). Subjects were imaged at three consecutive timepoints, 1 year apart. For each subject, a 'new-T2' lesion mask was created and the NT1 intensities 'pre-lesion', 'peri-lesion' and 'post-lesion' were determined. A longitudinal model was used to capture NT1 changes. RESULTS: The NT1 in both groups failed to recover to pre-lesion values by 1 year post-lesion (p=0.0002), with children showing significantly better recovery than adults (p=0.0089). CONCLUSIONS: Both groups showed a significant chronic reduction of T1 intensity within new T2 lesions. However, children showed a significantly greater recovery of T1 intensity, suggesting that MS lesions in the pediatric MS population are less destructive, or that pediatric patients have greater reparative capacity.

Normalization of white matter intensity on T1-weighted images of patients with acquired central nervous system demyelination.

BACKGROUND: Intensity variation between magnetic resonance images (MRI) hinders comparison of tissue intensity distributions in multicenter MRI studies of brain diseases. The available intensity normalization techniques generally work well in healthy subjects but not in the presence of pathologies that affect tissue intensity. One such disease is multiple sclerosis (MS), which is associated with lesions that prominently affect white matter (WM). OBJECTIVE: To develop a T1-weighted (T1w) image intensity normalization method that is independent of WM intensity, and to quantitatively evaluate its performance. METHODS AND SUBJECTS: We calculated median intensity of grey matter and intraconal orbital fat on T1w images. Using these two reference tissue intensities we calculated a linear normalization function and applied this to the T1w images to produce normalized T1w (NT1) images. We assessed performance of our normalization method for interscanner, interprotocol, and longitudinal normalization variability, and calculated the utility of the normalization method for lesion analyses in clinical trials. RESULTS: Statistical modeling showed marked decreases in T1w intensity differences after normalization (P < .0001). CONCLUSIONS: We developed a WM-independent T1w MRI normalization method and tested its performance. This method is suitable for longitudinal multicenter clinical studies for the assessment of the recovery or progression of disease affecting WM.

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

INTRODUCTION: 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. OBJECTIVE: To compare the frequency, volume and distribution of T2 and T1 lesions in children and adults with relapsing-remitting multiple sclerosis (RRMS). METHODS: Lesions were segmented on T2- and T1-weighted MRI images from 29 children and 29 adults with RRMS, matched for disease duration. RESULTS: 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). DISCUSSION: 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.

Lesion distribution in children with clinically isolated syndromes.

We evaluated the incidence, volume, and spatial distribution of T2-weighted magnetic resonance imaging lesions in 58 children with clinically isolated syndromes at risk for multiple sclerosis compared with 58 adults with relapsing-remitting multiple sclerosis. Pediatric patients with clinically isolated syndromes who had brain lesions had supratentorial lesion volumes similar to adult multiple sclerosis patients, but greater infratentorial lesion volumes (p < 0.009), particularly in the pons of male patients. The predilection for infratentorial lesions the pediatric patients with clinically isolated syndromes may reflect immunological differences or differences in myelin, possibly related to the caudorostral temporal gradient in myelin maturation.