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.

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.

No evidence of JC virus reactivation in natalizumab treated multiple sclerosis patients: an 18 month follow-up study.

BACKGROUND AND AIM: Natalizumab, used as therapy for multiple sclerosis (MS), has been associated with progressive multifocal leucoencephalopathy (PML), a potentially fatal disease caused by JC virus (JCV), which is not predictable by specific markers. This study evaluated whether JCV reactivation occurred in the urine and/or plasma in 42 MS patients treated with natalizumab over 18 months, and followed by a thorough monitoring programme. METHODS: 42 patients (F/M: 24/18, mean age 34.4±8.9 years) were followed-up by: urine and plasma JCV-DNA PCR assay, immune cell subsets analysis, clinical and MRI evaluation, quality of life, fatigue and mood assessment. RESULTS: JCV data. At baseline, 11/42 (26%) patients had JCV viruria, persistent at serial controls. One patient acquired viruria at month 1 and one patient at month 12. No patient had JCV viraemia at baseline; three patients acquired viraemic (one at month 6, one at month 13 (both transiently) and one at month 12 (persistently viraemic)). The prevalence of JCV in both urine and plasma did not change significantly from baseline to months 12 and 18. No patient had clinical or MRI evidence of PML. Immunological data. Circulating B cells showed greater expansion (300% increase in absolute number) since the first infusion. NK cell count doubled with no change in percentage while T cell count increased with a reduced percentage, reflecting a clear redistribution in the lymphocyte compartment. CD4+ and CD8+ T cells increased proportionally, with no change in their percentage. Clinical data. 27 patients (64%) were disease free after 1 year. A marked improvement in quality of life was reported by 72% of patients. CONCLUSIONS: No evidence of subclinical JCV reactivation was found in our natalizumab treated MS patients up to 18 months of therapy, notwithstanding the marked increase in circulating B cells observed. Moreover, the efficacy of natalizumab, its tolerability and the positive impact on quality of life were confirmed in this study.

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.

Extensive cortical inflammation is associated with epilepsy in multiple sclerosis.

INTRODUCTION: Epilepsy is three to six times more frequent in MS than in the general population. Previous studies based on conventional magnetic resonance (MR) imaging have suggested a possible correlation between cortical inflammatory pathology and epileptic seizures. However, pure intracortical lesions (ICLs) are unlikely to be demonstrated with conventional MR. We applied the double inversion recovery (DIR) sequence in relapsing remitting MS (RRMS) patients with or without epileptic seizures in order to clarify the relationship between ICLs and epilepsy in MS in vivo. METHODS: Twenty RRMS patients who had epileptic seizures (RRMS/E) during the course of the disease were studied for the presence of ICLs. A group of 80 RRMS patients with no history of seizures and matched for gender, age, disease duration, Expanded Disability Status Scale (EDSS) grading, and T2 lesion volume (T2-WMLV) was selected as reference population. ICLs were detected by applying the DIR sequence. RESULTS: ICLs were observed in 18/20 (90%) RRMS/E and in 39/80 (48%) RRMS (p = 0.001). RRMS/E showed five times more ICLs (7.2 +/- 8.4) than RRMS (1.5 +/- 2.4; p = 0.015). The total ICLs volume was 6 times larger in RRMS/E than in RRMS (1.2 +/- 1.7 cm3 versus 0.2 +/- 0.2 cm3, p = 0.016). No significant difference was observed between RRMS and RRMS/E with regard to the number and volume of juxtacortical lesions and T2-WMLV. DISCUSSION: Our findings indicate that RRMS/E have more extensive cortical inflammation than RRMS patients with no history of epilepsy. Inflammatory ICLs may be responsible for epilepsy in MS.

Detection of cortical inflammatory lesions by double inversion recovery magnetic resonance imaging in patients with multiple sclerosis.

BACKGROUND: A significant inflammatory pathologic disorder in the cortex of patients with multiple sclerosis (MS) has been demonstrated by ex vivo studies. OBJECTIVE: To determine the frequency, time of appearance, and clinical relevance of intracortical lesions (ICLs) in MS in vivo. DESIGN: Double inversion recovery sequence study. SETTING: Multiple Sclerosis Centre of the Veneto Region. Patients We enrolled 380 patients (116 with clinically isolated syndrome [CIS], 163 with relapsing-remitting MS [RRMS], and 101 with secondary progressive MS [SPMS]) and 40 age- and sex-matched healthy volunteers between May 1, 2005, and December 31, 2006. MAIN OUTCOME MEASURES: We assessed the frequency and number of ICLs and brain parenchyma fraction, white matter T2 lesion volume, and clinical disability. RESULTS: Although never observed in healthy volunteers, ICLs were detected in 58% of patients (36% of patients with CIS, 64% of patients with RRMS, and 73% of patients with SPMS). The number of ICLs was higher in patients with SPMS than in those with CIS or RRMS (P <.001), and patients with ICLs had a higher Expanded Disability Status Scale score (P = .004), a higher white matter T2 lesion volume (P = .008), a lower brain parenchyma fraction (P = .009), and a higher frequency of IgG oligoclonal bands (IgGOBs) (P <.001) than patients without ICLs. Patients positive for IgGOBs had more ICLs than patients negative for IgGOBs (P = .02). The number of ICLs correlated with the Expanded Disability Status Scale score (r = 0.48, P <.001), white matter T2 lesion volume (r = 0.38, P = .001), and brain parenchyma fraction (r = -0.47, P = .001). A significant association between ICLs and male sex was observed. CONCLUSIONS: Although more frequent in patients with SPMS, ICLs were observed from the early disease stages. The ICLs were more frequently detected in patients with IgGOBs and were associated with a higher clinical disability score and male sex. The ICLs may help to define MS clinical heterogeneity and prognosis in clinical settings.