Enlarged Virchow Robin spaces associate with cognitive decline in multiple sclerosis.

The clinical significance of Virchow Robin spaces (VRS) in inflammatory brain disorders, especially in multiple sclerosis (MS), is still undefined. We analysed enlarged VRS (eVRS) by means of phase sensitive inversion recovery (PSIR) MRI sequence and investigated their association with inflammation or brain atrophy, and to clinical or physical disability. Forty-three MS patients (21 clinically isolated syndrome suggestive of MS [CIS], 15 RRMS, 7 progressive [PMS]) and 10 healthy controls (HC) were studied. 3DT1, 3DFLAIR and 2DPSIR images were obtained with a 3T MRI scanner. eVRS number and volume were calculated by manual segmentation (ITK-SNAP). Freesurfer was used to assess brain parenchymal fraction (BPF). All patients underwent clinical (EDSS) and cognitive (Rao's BRB and DKEFS) evaluation. eVRS number and volume resulted significantly higher on 2D-PSIR compared to both 3D-T1 (p<0.001) and 3D-FLAIR (p<0.001) and were significantly increased in CIS compared to HC (p<0.05), in PMS and RRMS compared to CIS (p<0.001) and in male versus female patients (p<0.05). eVRS volume increased significantly with disease duration (r = 0.6) but did not correlate with EDSS. eVRS significantly correlated with SPARTd (r = -0.47) and DKEFSfs (r = -0.46), especially when RRMS and PMS were merged in a single group (r = 0.89, p = 0.002 and r = 0.66, p = 0.009 respectively), while no correlation was found with BPF (r = 0.3), gadolinium-enhancing lesions (r = 0.2) and WMT2 lesion volume (r = 0.2). 2DPSIR allowed the detection of an impressive higher number of eVRS compared to 3DT1 and 3DFLAIR. eVRS associate with SPARTd and DKEFSfs failure in relapse-onset MS, suggesting they may contribute to cognitive decline in MS.

MRI-detectable cortical lesions in the cerebellum and their clinical relevance in multiple sclerosis.

BACKGROUND: The demonstration of cortical lesions (CL) in the cerebellum by magnetic resonance imaging (MRI) is hampered by technical and anatomical constraints. OBJECTIVE: To investigate the occurrence of cerebellar CL and their correlation with cerebellar-related disability by combining Double Inversion Recovery (DIR) and Phase Sensitive Inversion Recovery (PSIR) MRI images in multiple sclerosis (MS) patients. MATERIAL AND METHODS: 40 MS patients (10 CIS/eRRMS, 24 RRMS, 6 SPMS), having a wide range of disability and disease duration, were enrolled. DIR and PSIR images were obtained with a 3T-MRI. RESULTS: Cerebellar white matter lesions (WML) and/or CL were observed in 33/40 patients (82.5%) among which 14/40 had only CL. CL were demonstrated in 26/40 patients by DIR and in 31/40 by PSIR, and their number increased from CIS/eRRMS to SPMS. PSIR disclosed a significantly higher number of CL compared to DIR (RRMS: p=0.0008; SPMS: p=0.002). CL number correlates with the cerebellar Expanded Disability Status Score (EDSS) score (r=0.72, p<0.0001). No correlation was observed between supra-tentorial and cerebellar CL. CONCLUSIONS: CL are detected by PSIR in the cerebellum of the majority of MS patients, are more than WML, increase with disease progression and strongly correlate with the cerebellar EDSS. Thus, the observation of CL in the cerebellum of MS at clinical onset might be useful for prognostic and therapeutic aims.

The Parallel Analysis of Phase Sensitive Inversion Recovery (PSIR) and Double Inversion Recovery (DIR) Images Significantly Improves the Detection of Cortical Lesions in Multiple Sclerosis (MS) since Clinical Onset.

BACKGROUND: Double inversion recovery (DIR) detects only a minority (<20%) of cortical lesions (CL) in multiple sclerosis (MS). Phase-sensitive inversion recovery (PSIR) was suggested to be substantially superior to DIR in the detection of cortical lesions (CL). These two sequences might be complementary. OBJECTIVES: To analyze CL frequency and type in MS patients having different disease duration and disability, including patients at clinical onset, and to discern more correctly the artifacts, by combining DIR and PSIR images. PATIENTS AND METHODS: 40 patients were enrolled in the study: 10 clinically isolated syndrome/early relapsing remitting MS (CIS/eRRMS), 24 relapsing remitting MS (RRMS), 6 secondary progressive MS (SPMS). DIR and PSIR images were jointly used to classify lesions as purely intracortical (IC), leukocortical (LC) and juxtacortical (JC). RESULTS: PSIR disclosed CL in 100% of the patients and was capable of identifying more than four times lesions (455.5%, p<0.00001), especially IC (mean numbers: 36.5 in CIS/eRRMS, 45.0 in RRMS and 52.3 in SPMS) and LC (mean numbers: 10.9 in CIS/eRRMS, 20.1 in RRMS and 25.3 in SPMS), compared to DIR (p<0.00001). CL number was significantly higher in SPMS compared to RRMS (p<0.0001). Artifacts were more accurately identified by comparing the two sequences. CONCLUSIONS: Our study confirms the higher ability of PSIR in disclosing and classifying CL. The presence of CL in all CIS patients further points out the relevance of cortical pathology in MS. Whether the parallel analysis of DIR and PSIR images may be useful for diagnostic purposes, especially when a diagnosis of MS is suspected but not confirmed by routine MRI, needs to be evaluated in larger patient series. The analysis of the cortex by DIR and PSIR may also allow a better stratification of the patients for prognostic and counseling purposes, as well as for their inclusion in clinical studies.

Disease-modifying drugs reduce cortical lesion accumulation and atrophy progression in relapsing-remitting multiple sclerosis: results from a 48-month extension study.

Cortical lesions (CLs) and atrophy are pivotal in multiple sclerosis (MS) pathology. This study determined the effect of disease modifying drugs (DMDs) on CL development and cortical atrophy progression in patients with relapsing-remitting MS (RRMS) over 48 months. Patients (n = 165) were randomized to sc IFN ß-1a 44 µg, im IFN ß-1a 30 µg, or glatiramer acetate 20 mg. The reference population comprised 50 DMD-untreated patients with RRMS. After 24 months, 43 of the untreated patients switched to DMDs. The four groups of patients were followed up for an additional 24 months. At 48 months the mean standard deviation number of new CLs was significantly lower in patients treated with sc IFN ß-1a (1.4 ± 1.0, range 0-5) compared with im IFN ß-1a (2.3 ± 1.3, range 0-6, P = 0.004) and glatiramer acetate (2.2 ± 1.5, range 0-7, P = 0.03). Significant reductions in CL accumulation and new white matter and gadolinium-enhancing lesions were also observed in the 43 patients who switched to DMDs after 24 months, compared with the 24 months of no treatment. Concluding, this study confirms that DMDs significantly reduce CL development and cortical atrophy progression compared with no treatment.

The changing clinical course of multiple sclerosis: a matter of gray matter.

OBJECTIVE: Clinical and neuroimaging parameters predictive of the changing clinical course of multiple sclerosis (MS) from relapsing-remitting to secondary progressive have not been clarified yet. We specifically designed a prospective 5-year longitudinal study aimed at assessing demographic, clinical, and magnetic resonance imaging (MRI) parameters that could predict the changing clinical course of MS. METHODS: At study entry and after 5 years, clinical and MRI (ie, gray matter and white matter lesions, including spinal cord lesions, and global and regional cortical thinning) parameters were assessed in a training set of 334 consecutive relapsing-remitting MS patients and in an independent validation set of 84 relapsing-remitting MS patients. RESULTS: Sixty-six (19.7%) relapsing-remitting MS patients changed their clinical course during the study and entered into the secondary progressive phase. Age (p = 0.001, odds ratio [OR] = 1.2), cortical lesion volume (p < 0.001, OR = 1.7), and cerebellar cortical volume (p < 0.001, OR = 0.2) at study entry were found to predict the changing clinical course. The model including only these 3 variables correctly identified 252 of 268 (94.0%) patients who maintained the relapsing-remitting course and 58 of 66 (87.8%) patients who became secondary progressive (cross-validated error rate = 7.2%). When applied on the validation set, the model obtained a similar error rate (8.4%). INTERPRETATION: A prediction model based on age, cortical lesion load, and cerebellar cortical volume suitably explains the probability of relapsing-remitting MS patients evolving into the progressive phase. Gray matter damage appears to play a pivotal role in determining the changing clinical course of MS.

Low degree of cortical pathology is associated with benign course of multiple sclerosis.

BACKGROUND: Although a more favorable course of multiple sclerosis is associated with a low degree of cortical pathology, only longitudinal studies could definitely confirm this association. MATERIALS AND METHODS: We followed 95 early relapsing-remitting MS (RRMS; median Expanded Disability Status Scale (EDSS) = 1.5, mean disease duration = 3.1 ± 1.3 years) and 45 benign MS patients (EDSS ≤ 3.0, disease duration ≥ 15 years, normal cognition) for 6 years, with EDSS evaluations every 6 months and brain magnetic resonance imaging (MRI) at baseline and then yearly. RESULTS: At baseline, we detected 406 cortical lesions (CLs) in 67/95 (70.5%) early RRMS and in 24/45 (53.3%) benign MS patients (p = 0.046). After 6 years, the appearance of new CLs was observed in 80/95 (84.2%; 518 CLs) of our early RRMS and in 25/45 (55.5%; 63 CLs; p < 0.001) benign MS patients. At baseline, after corrections for age and disease duration, we observed a cortical thinning of several frontal and temporal regions in our RRMS study patients, compared to the benign MS patients (p ranging between 0.001-0.05). After 6 years, the cortical thinning had increased significantly in several cortices of RRMS patients, but only in the occipital-temporal (p = 0.036) and superior parietal gyrus (p = 0.035) of those with benign MS. Stepwise regression analysis revealed the CL volume (p = 0.006) and the cortical thickness of the temporal middle (p < 0.001), insular long (p < 0.001), superior frontal (p < 0.001) and middle frontal gyri (p < 0.001) as the most sensitive independent predictors of a favorable disease course. CONCLUSIONS: Our data confirmed that a significantly milder cortical pathology characterizes the most favorable clinical course of MS. Measures of focal and diffuse grey matter should be combined to increase the accuracy in the identification of a benign MS course.

Heterogeneity of cortical lesions in multiple sclerosis: an MRI perfusion study.

In this study, dynamic susceptibility contrast-magnetic resonance imaging (DSC-MRI) was used to quantify the cerebral blood flow (CBF), the cerebral blood volume (CBV), and the mean transit time (MTT) and to analyze the changes in cerebral perfusion associated with the cortical lesions in 44 patients with relapsing-remitting multiple sclerosis. The cortical lesions showed a statistically significant reduction in CBF and CBV compared with the normal-appearing gray matter, whereas there were no significant changes in the MTT. The reduced perfusion suggests a reduction of metabolism because of the loss of cortical neurons. A small population of outliers showing an increased CBF and/or CBV has also been detected. The presence of hyperperfused outliers may imply that perfusion could evolve during inflammation. These findings show that perfusion is altered in cortical lesions and that DSC-MRI can be a useful tool to investigate more deeply the evolution of cortical lesions in multiple sclerosis.

Grey matter lesions in MS: from histology to clinical implications.

Although multiple sclerosis (MS) is a chronic inflammatory-demyelinating disease of the white matter (WM) of the central nervous system, several pathological and magnetic resonance imaging (MRI) studies have shown that a large amount of lesions are located in the cortical and deep gray matter. The histopathological and immunological characteristics of cortical lesions differ significantly from those located in the WM, which suggests a location-dependent expression of the MS immunopathological process. More recently, the availability of not-conventional MRI sequences having higher sensitivity for the gray matter has allowed to depict in vivo a portion of such lesions. The available MRI data obtained on large cohorts of patients, having different clinical forms of the disease, indicate that cortical lesions can be detected early in the disease course, sometimes even before the appearance of WM lesions, and correlate with the severity of physical disability and cognitive impairment, and with the evolution of the disease toward the secondary progressive phase. This review provides a summary of the main histopathological and MRI findings of cortical lesions in MS and discusses their possible clinical implications.

Cortical lesion load associates with progression of disability in multiple sclerosis.

Cortical inflammatory lesions have been correlated with disability and cortical atrophy in multiple sclerosis. The extent to which cortical lesion load is associated with longer-term physical and cognitive disability in different multiple sclerosis phenotypes has not yet been investigated. Thus, a 5-year prospective longitudinal study was carried on in a large group of patients with multiple sclerosis. Three hundred and twelve consecutive patients suffering from multiple sclerosis (157 relapsing remitting, 35 paediatric, 45 benign, 44 primary progressive and 31 secondary progressive) were enrolled in a 5-year prospective clinical and neuroimaging study. Several magnetic resonance parameters (including cortical lesion number and volume, contrast-enhancing cortical lesions and grey matter atrophy) were analysed to find associations with clinical and cognitive outcomes. Patients with high cortical lesion load had higher Expanded Disability Status Scale increase (median = 1.5; range = 0-3) during the study than both patients with low cortical lesion load (median = 1.0; range = 1-3, P < 0.001) and without cortical lesions (median = 0.5; range = -1 to 2, P < 0.001). Compared with clinically stable patients, 101 (32.4%) patients showing clinical progression at 5 years had the highest rate of cortical lesion accumulation (P < 0.001). Stepwise regression analysis revealed significant and independent contributions from age (ß = 0.55), cortical lesion volume (ß = 0.58), T(2) white matter lesion volume (ß = 0.34) and grey matter fraction (ß = 0.42) as predictors (final model with r(2 )= 0.657, P < 0.001) of Expanded Disability Status Scale change. Disease duration (ß = 0.52, P < 0.001), cortical lesion volume (ß = 0.67, P < 0.001), grey matter fraction (ß = 0.56, P < 0.001) and T(2) white matter lesion volume (ß = 0.31, P = 0.040) at baseline were found to be independent predictors of cognitive status at the end of the study. While confirming the relevance of cortical pathology in all multiple sclerosis phenotypes, but benign, our study suggests that grey matter and white matter changes in multiple sclerosis occur, at least, partly independently, and that grey matter, more than white matter, damage is associated with physical and cognitive disability progression. Thus, the combination of grey and white matter parameters gives a more comprehensive view of multiple sclerosis pathology and allows a better understanding of the progressive phase of the disease, which, however, seems more related to cortical damage than to subcortical white matter changes.

No MRI evidence of cortical lesions in neuromyelitis optica.

BACKGROUND: Neuromyelitis optica (NMO) is a severe inflammatory demyelinating disease of the CNS in which a pathogenic role of anti-aquaporin-4 (AQP4) antibodies has been suggested. Although AQP4 is expressed in human cortex, recent histologic studies have failed to find any evidence of cortical demyelination in NMO. OBJECTIVE: To evaluate, in vivo, the occurrence of focal and diffuse cortical pathology in NMO. METHODS: We studied 30 patients with NMO, 30 patients with relapsing-remitting multiple sclerosis (RRMS), and 30 normal controls (NC). RRMS and NC were age- and gender-matched to NMO. The presence of cortical lesions (CLs) was evaluated on double inversion recovery sequence and cortical thickness (CTh) by the application of Freesurfer on 3 volumetric fast field echo T1-weighted images. RESULTS: No CL was observed in NC or in NMO, while 83 CLs were identified in 20/30 (66.7%) patients with RRMS. Although NMO did not differ from NC in the global CTh, a mild thinning was observed in some cortical areas (postcentral [p = 0.018], precentral [p = 0.009], and calcarine [p = 0.015] gyri) and in the thalamus (p = 0.036). Global and regional cortical thickness was significantly decreased in RRMS compared to both NMO and NC. DISCUSSION: Our in vivo data further suggest that the immune-mediated pathologic process occurring in NMO spares most of the cortex. NMO differs from multiple sclerosis, where CLs and atrophy are frequently found, even in early disease phases. Thus, MRI analysis of the cortex may be a potential diagnostic tool, especially in ambiguous cases.

The association of intrathecal immunoglobulin synthesis and cortical lesions predicts disease activity in clinically isolated syndrome and early relapsing-remitting multiple sclerosis.

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.

Cortical diffusion-tensor imaging abnormalities in multiple sclerosis: a 3-year longitudinal study.

PURPOSE: To evaluate whether diffusion-tensor imaging can be combined with double inversion recovery to improve the detection of structural changes occurring in the cortex of patients with multiple sclerosis (MS). MATERIALS AND METHODS: Once local ethics committee approval and informed consent were obtained, 168 patients with relapsing-remitting MS and 45 sex- and age-matched control subjects were included in a 3-year longitudinal study. Expanded Disability Status Scale (EDSS) and magnetic resonance (MR) imaging examinations were performed at study entry and after 3 years. Number and volume of cortical lesions, T2 white matter lesion volume (WMLV), and fractional anisotropy (FA) and mean diffusivity (MD) of normal-appearing gray matter (NAGM) and cortical lesions were analyzed. Between-group differences in terms of NAGM-FA and NAGM-MD were assessed with analysis of variance followed by Tukey test correction. RESULTS: At baseline, NAGM-FA was higher in patients (mean ± standard deviation, 0.149 ± 0.011) than in control subjects (0.125 ± 0.008; P < .001) and higher in patients with cortical lesions (0.154 ± 0.011) than in those without (0.138 ± 0.010; P < .001). Moreover, FA was higher in cortical lesions than in NAGM (P < .001). After 3 years, NAGM-FA was unchanged in control subjects and increased in patients (0.154 ± 0.012; P < .001), especially in patients with worsened EDSS score (0.170 ± 0.011; P < .001). The same behavior was observed for NAGM-MD. At baseline, NAGM-FA significantly correlated with EDSS score (r = 0.75; P < .001) and cortical lesion volume (r = 0.850; P < .001). Multivariate analysis identified NAGM-FA (B = 0.654; P < .001) and T2 WMLV (B = 0.310; P < .001) as independent predictors of EDSS score, while NAGM-FA change (B = 0.523; P < .001) and disease duration (B = 0.342; P < .001) were independent predictors of EDSS change. CONCLUSION: Compared with control subjects, patients with RRMS had an increase in FA of NAGM that strongly correlated with cortical lesion volume and clinical disability.

Basal ganglia and frontal/parietal cortical atrophy is associated with fatigue in relapsing-remitting multiple sclerosis.

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.

A 3-year magnetic resonance imaging study of cortical lesions in relapse-onset multiple sclerosis.

OBJECTIVE: We assessed the occurrence, extent, and frequency of formation of cortical lesions (CLs) in patients with relapsing-remitting (RR) and secondary progressive (SP) multiple sclerosis (MS), and their relationship with cortical atrophy and disability progression. METHODS: One-hundred seven MS patients (76 RRMS and 31 SPMS), enrolled in a prospective, longitudinal magnetic resonance imaging (MRI) study, were assessed clinically and by brain MRI (including a double inversion recovery sequence) 3 years after study initiation. CL number and volume, T2 white matter (WM) lesion volume, gray matter fraction, and expanded disability status scale (EDSS) were measured. RESULTS: At baseline, CLs were detected in 64.4% of RRMS and 74.2% of SPMS patients. During follow-up, 132 new CLs were found in 44 RRMS patients (57.9%; 0.8 new CL/patient/yr) and 61 in 15 SPMS patients (48.4%; 1.0 new CL/patient/yr). Among these patients, only 31 also showed at least 1 new WM lesion. CL number and volume increases were higher in the 52 patients with a clinical worsening compared with those without (p < 0.001). Baseline CL volume correlated with baseline EDSS (r = 0.36, p < 0.001) and EDSS changes over time (r = 0.51, p < 0.001). Baseline CL volume was an independent predictor of EDSS accumulation and GM volume change at follow-up in both patient groups. In SPMS patients, baseline T2 WM lesion volume was another independent predictor of EDSS worsening. INTERPRETATION: In relapse-onset MS, CLs accumulate over time and are associated with disability progression. The quantification of CLs might represent an additional useful paraclinical tool to monitor MS evolution.

Magnetic resonance evidence of cerebellar cortical pathology in 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.

Cortical lesions and atrophy associated with cognitive impairment in relapsing-remitting multiple sclerosis.

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.

Morphology and evolution of cortical lesions in multiple sclerosis. A longitudinal MRI study.

Cortical lesions (CLs) can be detected in the majority of patients with established multiple sclerosis (MS), but little is known about their evolution over time. This study was performed to investigate the short-term MRI evolution of CLs, with the ultimate aim to achieve a better in vivo understanding of their nature. Seven hundred and sixty-eight CLs from 107 MS patients (76 with relapsing-remitting [RR] and 31 with secondary progressive [SP] MS) were followed with brain MR examinations, including a double inversion recovery (DIR) sequence, every 6 months for 1 year. CLs' number, volume and morphological features were assessed at each time-point. Six hundred and eighty CLs (88.5%) remained morphologically unchanged during the follow-up period, while 74 (9.6%) showed an increase in size. Only 6 (0.8%) CLs seen at baseline (all in RRMS patients) disappeared at follow-up MRI scans. No enlarging CLs spread into the subcortical white matter. No CLs ever showed gadolinium enhancement. At baseline, the mean number of CLs was higher in SPMS than in RRMS patients (p<0.001), whereas the mean number of new CLs per patient after 1 year did not differ between the two groups. Over a one-year period, CLs can increase their number and size in a relevant proportion of MS patients, without spreading into the subcortical white matter or showing inflammatory features similar to those of white matter lesions. The short-term rate of CLs accumulation does not seem to vary according to the clinical stage of MS.