Effect of disease-modifying drugs on cortical lesions and atrophy in relapsing-remitting multiple sclerosis.

OBJECTIVE: To measure the effects of disease-modifying drugs (DMDs) on the development of cortical lesions (CL) and cortical atrophy in patients with relapsing-remitting multiple sclerosis (RRMS). METHODS: RRMS patients (n = 165) were randomized to subcutaneous (sc) interferon (IFN) beta-1a (44 mcg three times weekly), intramuscular (im) IFN beta-1a (30 mcg weekly) or glatiramer acetate (GA; 20 mg daily). The reference population comprised 50 untreated patients. Clinical and MRI examinations were performed at baseline, 12 months and 24 months. RESULTS: One hundred and forty-one treated patients completed the study. After 12 months, 37/50 (74%) of untreated patients developed ≥ 1 new CL (mean 1.6), compared with 30/47 (64%) of im IFN beta-1a-treated patients (mean 1.2, p = 0.021), 24/48 (50%) of GA-treated patients (mean 0.8, p = 0.001) and 12/46 (26%) of sc IFN beta-1a-treated patients (mean 0.4, p < 0.001). After 24 months, ≥ 1 new CL was observed in 41/50 (82%) of untreated (mean 3.0), 34/47 (72%) of im IFN beta-1a-treated (mean 1.6, p < 0.001), 30/48 (62%) of GA-treated (mean 1.3, p < 0.001) and 24/46 (52%) of sc IFN beta-1a-treated patients (mean 0.8, p < 0.001). Mean grey matter fraction decrease in DMD-treated patients at 24 months ranged from 0.7 to 0.8 versus 1.0 in untreated patients (p = 0.023). CONCLUSIONS: Disease-modifying drugs significantly decreased new CL development and cortical atrophy progression compared with untreated patients, with faster and more pronounced effects seen with sc IFN beta-1a than with im IFN beta-1a or GA.

The predictive value of gray matter atrophy in clinically isolated syndromes.

BACKGROUND: Although gray matter (GM) atrophy is recognized as a common feature of multiple sclerosis (MS), conflicting results have been obtained in patients with clinically isolated syndromes (CIS). Methodologic and clinical constraints may take account for literature discrepancies. METHODS: A total of 105 patients presenting with CIS and 42 normal controls (NC) were studied. At baseline, 65/105 patients with CIS met the criterion of dissemination in space of lesions (DIS+). All patients were clinically assessed by means of the Expanded Disability Status Scale every 6 months and underwent MRI evaluation at study entry and then annually for 4 years. Global and regional cortical thickness and deep GM atrophy were assessed using Freesurfer. RESULTS: No significant reduction in GM atrophy was observed between the entire CIS group and the NC, excepting for the cerebellum cortical volume. When the 59 patients with CIS (46 DIS+, 13 DIS-) who converted to MS during the follow-up were compared to the NC, a significant atrophy in the precentral gyrus, superior frontal gyrus, thalamus, and putamen was observed (p ranging from 0.05 to 0.001). The multivariate analysis identified the atrophy of superior frontal gyrus, thalamus, and cerebellum as independent predictors of conversion to MS. CIS with atrophy of such areas had a double risk of conversion compared to DIS+ (odds ratio 9.6 vs 5.0). CONCLUSION: Selective GM atrophy is relevant in patients with CIS who convert early to MS. The inclusion of GM analysis in the MS diagnostic workup is worthy of further investigation.

Imaging distribution and frequency of cortical lesions in patients with multiple sclerosis.

BACKGROUND: The presence of cortical lesions (CLs) and their topographic distribution in the brains of patients with multiple sclerosis (MS) have been clearly shown by recent histopathologic studies. CLs can also be assessed in vivo, with less sensitivity, by using specific MRI sequences. MRI-based lesion probability maps (LPMs) may partially overcome this lack of sensitivity and provide unique information on the spatial distribution and frequency of CLs in MS. METHODS: A total of 149 patients with MS (103 relapsing-remitting [RR] and 46 primary progressive [PP]) underwent an MRI examination, which included the double inversion recovery (DIR) sequence for CL assessment. CL masks were then obtained for each patient and a cortical LPM (cLPM) was created for each MS subtype. RESULTS: CLs were mainly distributed in the frontal (RR = 51.8%; PP = 50.5%) and temporal (RR = 30.4%; PP = 35.5%) lobes, with a prominent involvement of the motor (RR = 37.8%; PP = 30.6%) and anterior cingulate (RR = 9.2%; PP = 10.6%) cortices. The extent of brain lobe affected by CLs was higher in RR than in PP patients. The frequency of CL occurrence was higher in PP than in RR patients. Both measurements, however, did not show differences between the 2 MS subtypes at voxel-wise analysis. CONCLUSIONS: Patients with RRMS and PPMS share more similarities than differences in terms of CL number, volume, topographic distribution, and frequency. The similarities between histopathologic data and the findings reported here suggest that DIR images can accurately illustrate the focal pathology occurring in the cortical regions of patients with MS, providing clinically relevant information.

Widespread cortical thinning characterizes patients with MS with mild cognitive impairment.

BACKGROUND: Although cognitive dysfunction affects a relevant portion of patients with multiple sclerosis (MS), its pathologic substrate has not been clarified and it does not seem entirely explained by white matter changes. METHODS: A total of 100 consecutive patients with relapsing remitting MS (RRMS) and 42 normal controls (NC) were enrolled in the study. Cognitive performance was assessed by Rao's Brief Repeatable Battery of Neuropsychological Tests (BRB). Regional cortical thickness (CTh) was evaluated by Freesurfer. RESULTS: Thirty-one patients with RRMS failed 1 or 2 tests of BRB and were considered to have a mild cognitive impairment (mCI-RRMS), while 8 patients failed at least 3 tests and were classified as markedly impaired (sCI-RRMS). The mean CTh of mCI-RRMS and sCI-RRMS group was significantly lower than in NC (p < 0.001) and cognitively normal patients with RRMS (CN-RRMS) (p < 0.001). The regional analysis revealed significant cortical thinning in frontal and temporal regions (frontotemporal thinning) of CN-RRMS compared to NC, while a widespread pattern of cortical thinning was observed in mCI-RRMS and in sCI-RRMS compared to both CN-RRMS and NC. A correlation was observed between cognitive score (CS) and the mean CTh (r = -0.69, p < 0.001) and between CS and CTh of almost all the cortical areas analyzed (r value between -0.20 and -0.65, p < 0.01). A correlation was found between T2-WM-LV and mean CTh (r = -0.31, p = 0.004) or CS (r = 0.21, p = 0.031). The multivariate analysis confirmed a widespread cortical thinning as the best predictor of cognitive impairment. CONCLUSIONS: A widespread pattern of cortical thinning characterizes patients with cognitive dysfunction, suggesting such dysfunction as expression of a more aggressive and widespread cortical pathology.

Cortical lesions in primary progressive multiple sclerosis: a 2-year longitudinal MR study.

BACKGROUND: In primary progressive multiple sclerosis (PPMS), a discrepancy exists between the modest brain white matter (WM) lesion burden and the severity of neurologic disability. Double-inversion recovery (DIR) sequences have improved MRI sensitivity in the detection of cortical lesions (CLs) in patients with relapsing-onset MS. OBJECTIVE: This 2-year longitudinal study was designed to assess the frequency, extent, and rate of formation of CLs in PPMS and their relationship with T2 lesion volume (LV), gray matter (GM) atrophy, and disability. METHODS: Forty-eight patients with PPMS underwent clinical and magnetic resonance examinations at baseline and after 2 years. The number and volume of CLs, WM T2 LV, and GM fraction (GMf) were assessed at baseline and at follow-up. RESULTS: At baseline, CLs were detected in 81.2% of patients with PPMS. At least one new CL was found in 28 patients during the follow-up. In patients with PPMS, CL and T2 WM LVs increased over the follow-up. At baseline, CL number and volumes were significantly correlated with T2 WM LV, GMf, disease duration, and Expanded Disability Status Scale score, as well as with increasing GM atrophy and disability during the follow-up. A multivariate analysis showed that CL volume at baseline was an independent predictor of percentage GM volume change and disability accumulation during the subsequent 2-year period. CONCLUSIONS: Cortical lesions are a frequent finding in primary progressive multiple sclerosis. The extent of such abnormalities is associated with the extent of cortical atrophy and clinical disability, and is able to predict their changes over a medium time period.

Evidence for relative cortical sparing in benign multiple sclerosis: a longitudinal magnetic resonance imaging study.

BACKGROUND: Using double inversion recovery (DIR) MRI, cortical lesions can be seen in the brain of patients with multiple sclerosis (MS). The burden of such lesions seems to be well correlated with the severity of MS-related disability. OBJECTIVE: To investigate whether the extent of cortical damage in patients with benign MS (BMS) might contribute to explain their favorable clinical status. METHODS: Forty-eight patients with BMS (Expanded Disability Status Scale [EDSS] score < or =3.0 and disease duration > or =15 years) and 96 patients with non-disabling, early relapsing-remitting (RR) MS (EDSS score < or =3.0 and disease duration < or =5 years) were studied. Brain MRI, including a DIR and a fluid-attenuated inversion recovery (FLAIR) sequence, was acquired at baseline and after 12 months. On DIR images, intracortical (ICL) and cortical-subcortical lesions (CSL) were identified and their number and volume calculated. Total white matter (WM) lesion volume was quantified on FLAIR images. RESULTS: Compared with early RRMS, patients with BMS had lower number of ICL at both study time points (P < or = 0.001 for both comparisons). At one-year follow-up, a significant increase of ICL and CSL number and total volume was observed only in early patients with RRMS. The number and volume of cortical lesions was not correlated with WM lesion volume. Total ICL number at baseline, total cortical lesion volume at baseline, and total cortical lesion volume change were independent predictors of MS phenotype. CONCLUSION: In patients with BMS, the selective sparing of the cortex from disease-related focal pathology might be one of the factors associated to their favorable clinical status, independently of the (possible) accrual of WM lesions.