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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.

Background: The intrathecal production of immunoglobulin (Ig) is a major biological feature of multiple sclerosis (MS), and immunopathological studies have suggested a primary role of the humoral immune response in causing irreversible brain damage., Objective: To evaluate whether, in the early phases of MS, intrathecal Ig synthesis correlates with the presence of cortical lesions (CLs), and if their association could predict the clinical course of the disease., Methods: Eighty-six patients presenting with symptoms and signs suggestive of MS underwent a diagnostic work-up that included magnetic resonance imaging and cerebrospinal fluid examination. The risk ratios (RR) for conversion to MS and for a new disease activity were calculated., Results: Patients with clinically isolated syndromes (CIS) having CLs and intrathecal synthesis of Ig had the highest risk of conversion to MS (RR = 3.4; Wald 95% CI = 1.7-7.0, p < 0.001) whereas CIS patients without CLs and intrathecal synthesis of Ig had the lowest risk of conversion to MS (RR = 0.1, Wald 95% CI = 0.02-0.7, p < 0.001). The highest risk of having disease-related activity during the follow-up was observed in CIS and relapsing-remitting MS patients showing CLs and intrathecal Ig synthesis (RR = 2.1; Wald 95% CI = 1.5-3.1, p < 0.001) while the lowest in CIS and relapsing-remitting MS patients without CLs and intrathecal Ig synthesis (RR = 0.3; Wald 95% CI = 0.1-0.7, p < 0.001)., Conclusion: We observed that the association of intrathecal immunoglobulin synthesis and CLs was highly predictive of an earlier CIS conversion to MS as well as of a higher disease activity.

Background: Fatigue is one of the most frequent symptoms suffered by patients affected by multiple sclerosis. The patho-physiological basis of multiple sclerosis-related fatigue remains to be elucidated., Objective: Our aim was to investigate whether a particular pattern of deep and/or cortical grey matter atrophy is associated with fatigue in patients with multiple sclerosis., Methods: A total of 152 patients with relapsing-remitting multiple sclerosis were evaluated with the Expanded Disability Status Scale, the Fatigue Severity Status Scale (FSS), the Modified Fatigue Impact Scale and the Beck Depression Inventory. The thalamic and basal ganglia volume and the regional cortical thickness were analysed by means of FreeSurfer., Results: Based on Fatigue Severity Status Scale score, patients were divided into fatigued (FSS ≥ 4, 71 patients, 46.6%) and non-fatigued (FSS < 4, 81 patients, 53.4%). A significant atrophy of striatum, thalamus, superior frontal gyrus and inferior parietal gyrus was observed in fatigued patients compared with non-fatigued patients. The cognitive domain of Modified Fatigue Impact Scale significantly correlated with the volume of the striatum and with the cortical thickness of the posterior parietal cortex and middle frontal gyrus (R = 0.51-0.61), while the physical domain of Modified Fatigue Impact Scale significantly correlated with striatum volume and superior frontal gyrus cortical thickness (R = 0.50-0.54)., Conclusions: The regional analysis of deep and cortical grey matter atrophy suggests an association between the neurodegenerative process taking place in the striatum-thalamus-frontal cortex pathway and the development of fatigue in relapsing-remitting multiple sclerosis. The inclusion of the posterior parietal cortex as one of the best predictors of the Modified Fatigue Impact Scale cognitive domain suggests the major role of the posterior attentional system in determining cognitive fatigue in relapsing-remitting multiple sclerosis.

Background: Although neuropathological observations suggest that cerebellar cortex is a major site of demyelination in multiple sclerosis (MS), only a few MRI studies on cerebellar cortical pathology in MS are available., Objective: To analyse cerebellar cortical volume (CCV) and leucocortical lesions (CL) in MS, and their impact on clinical disability., Methods: The authors studied 125 patients divided into 38 Clinical Isolated Syndrome (CIS), 35 relapsing remitting multiple sclerosis (RRMS), 27 secondary progressive multiple sclerosis (SPMS) and 25 primary progressive multiple sclerosis, and 32 normal controls (NC). CCV and cerebellar CL number and volume were evaluated by means of Freesurfer software and Double Inversion Recovery, respectively., Results: Compared with NC (mean 113.2 + or - 2.6 cm(3)), the CCV was significantly reduced in CIS (105.4 + or - 2.2 cm(3), p=0.018), RRMS (104.0 + or - 2.0 cm(3), p=0.012), SPMS (98.8 + or - 2.0 cm(3), p<0.001) and PPMS (100.6 + or - 2.2 cm(3), p<0.001), even after age, gender and mean cortical volume correction. CL were observed in all patient groups and were an independent predictor of CCV and cerebellar dysfunction., Discussion: The authors confirm that the cerebellar cortex is severely and early affected by MS pathology. The monitoring of cerebellar cortical atrophy and CL may help to understand the mechanism underlying disability progression in MS.

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.

Background: Neuropsychological deficits in patients with multiple sclerosis (MS) have been shown to be associated with the major pathological substrates of the disease, ie, inflammatory demyelination and neurodegeneration. Double inversion recovery sequences allow cortical lesions (CLs) to be detected in the brain of patients with MS. Modern postprocessing techniques allow cortical atrophy to be assessed reliably., Objective: To investigate the contribution of cortical gray matter lesions and tissue loss to cognitive impairment in patients with relapsing-remitting MS., Design: Cross-sectional survey., Setting: Referral, hospital-based MS clinic. Patients Seventy patients with relapsing-remitting MS., Main Outcome Measures: Neuropsychological performance was tested using the Rao Brief Repeatable Battery of Neuropsychological Tests, version A. Patients who scored 2 SDs below the mean normative values on at least 1 test of the Rao Brief Repeatable Battery of Neuropsychological Tests, version A, were considered to be cognitively impaired. A composite cognitive score (the cognitive impairment index) was computed. T2 hyperintense white matter lesion volume, contrast-enhancing lesion number, CL number and volume, normalized brain volume, and normalized neocortical gray matter volume were also assessed., Results: Twenty-four patients with relapsing-remitting MS (34.3%) were classified as cognitively impaired. T2 hyperintense white matter lesion volume and contrast-enhancing lesion number were not different between cognitively impaired and cognitively unimpaired patients. Cognitively impaired patients had a higher CL number (P = .01) and volume (P < .001) and decreased normalized brain volume (P = .02) and normalized neocortical gray matter volume (P = .002) when compared with cognitively unimpaired patients. Multivariate analysis revealed that age (beta = 0.228; P = .02), CL volume (beta = 0.452; P < .001), and normalized neocortical gray matter volume (beta = 0.349; P < .001) were independent predictors of the cognitive impairment index (r(2) = 0.55; F = 23.903; P < .001)., Conclusion: The burden of CLs and tissue loss are among the major structural changes associated with cognitive impairment in relapsing-remitting MS.

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.

Introduction: Increasing evidence suggests relevant cortical gray matter pathology in patients with Multiple Sclerosis (MS), but how early this pathology begins; its impact on clinical disability and which cortical areas are primarily affected needs to be further elucidated., Methods: 115 consecutive patients (10 Clinically Isolated Syndrome (CIS), 32 possible MS (p-MS), 42 Relapsing Remitting MS (RR-MS), 31 Secondary Progressive MS (SP-MS)), and 40 age/gender-matched healthy volunteers (HV) underwent a neurological examination and a 1.5 T MRI. Global and regional Cortical Thickness (CTh) measurements, brain parenchyma fraction and T2 lesion load were analyzed., Results: We found a significant global cortical thinning in p-MS (2.22 +/- 0.09 mm), RR-MS (2.16 +/- 0.10 mm) and SP-MS (1.98 +/- 0.11 mm) compared to CIS (2.51 +/- 0.11 mm) and HV (2.48 +/- 0.08 mm). The correlations between mean CTh and white matter (WM) lesion load was only moderate in MS (r = -0.393, p = 0.03) and absent in p-MS (r = -0.147, p = 0.422). Analysis of regional CTh revealed that the majority of cortical areas were involved not only in MS, but also in p-MS. The type of clinical picture at onset (in particular, pyramidal signs/symptoms and optic neuritis) correlated with atrophy in the corresponding cortical areas., Discussion: Cortical thinning is a diffuse and early phenomenon in MS already detectable at clinical onset. It correlates with clinical disability and is partially independent from WM inflammatory pathology.