Periventricular lesions and MS diagnostic criteria in young adults with typical clinically isolated syndromes.

In patients who present with a clinically isolated syndrome (CIS), whose features are suggestive of multiple sclerosis (MS), fulfilling McDonald 2010 magnetic resonance imaging (MRI) criteria for dissemination in space (DIS) and dissemination in time (DIT) enables a diagnosis of MS. While ⩾1 periventricular lesion is included in the 2010 DIS criteria, earlier McDonald criteria required ⩾3 periventricular lesions to confirm DIS and recent Magnetic Resonance Imaging in Multiple Sclerosis (MAGNIMS)-recommended DIS criteria also require ⩾3 lesions. We investigated the effect of varying the required number of periventricular lesions and found that the best combination of specificity and sensitivity for clinically definite MS was seen for ⩾1 periventricular lesion using both the McDonald 2010 and MAGNIMS 2016 criteria

Grey matter involvement by focal cervical spinal cord lesions is associated with progressive multiple sclerosis.

BACKGROUND: The in vivo relationship of spinal cord lesion features with clinical course and function in multiple sclerosis (MS) is poorly defined. OBJECTIVE: The objective of this paper is to investigate the associations of spinal cord lesion features on MRI with MS subgroup and disability. METHODS: We recruited 120 people: 25 clinically isolated syndrome, 35 relapsing-remitting (RR), 30 secondary progressive (SP), and 30 primary progressive (PP) MS. Disability was measured using the Expanded Disability Status Scale. We performed 3T axial cervical cord MRI, using 3D-fast-field-echo and phase-sensitive-inversion-recovery sequences. Both focal lesions and diffuse abnormalities were recorded. Focal lesions were classified according to the number of white matter (WM) columns involved and whether they extended to grey matter (GM). RESULTS: The proportion of patients with focal lesions involving at least two WM columns and extending to GM was higher in SPMS than in RRMS (p = 0.03) and PPMS (p = 0.015). Diffuse abnormalities were more common in both PPMS and SPMS, compared with RRMS (OR 6.1 (p = 0.002) and 5.7 (p = 0.003), respectively). The number of lesions per patient involving both the lateral column and extending to GM was independently associated with disability (p < 0.001). CONCLUSIONS: More extensive focal cord lesions, extension of lesions to GM, and diffuse abnormalities are associated with progressive MS and disability

ADvanced IMage Algebra (ADIMA): a novel method for depicting multiple sclerosis lesion heterogeneity, as demonstrated by quantitative MRI.

BACKGROUND: There are modest correlations between multiple sclerosis (MS) disability and white matter lesion (WML) volumes, as measured by T2-weighted (T2w) magnetic resonance imaging (MRI) scans (T2-WML). This may partly reflect pathological heterogeneity in WMLs, which is not apparent on T2w scans. OBJECTIVE: To determine if ADvanced IMage Algebra (ADIMA), a novel MRI post-processing method, can reveal WML heterogeneity from proton-density weighted (PDw) and T2w images. METHODS: We obtained conventional PDw and T2w images from 10 patients with relapsing-remitting MS (RRMS) and ADIMA images were calculated from these. We classified all WML into bright (ADIMA-b) and dark (ADIMA-d) sub-regions, which were segmented. We obtained conventional T2-WML and T1-WML volumes for comparison, as well as the following quantitative magnetic resonance parameters: magnetisation transfer ratio (MTR), T1 and T2. Also, we assessed the reproducibility of the segmentation for ADIMA-b, ADIMA-d and T2-WML. RESULTS: Our study's ADIMA-derived volumes correlated with conventional lesion volumes (p < 0.05). ADIMA-b exhibited higher T1 and T2, and lower MTR than the T2-WML (p < 0.001). Despite the similarity in T1 values between ADIMA-b and T1-WML, these regions were only partly overlapping with each other. ADIMA-d exhibited quantitative characteristics similar to T2-WML; however, they were only partly overlapping. Mean intra- and inter-observer coefficients of variation for ADIMA-b, ADIMA-d and T2-WML volumes were all < 6 % and < 10 %, respectively. CONCLUSION: ADIMA enabled the simple classification of WML into two groups having different quantitative magnetic resonance properties, which can be reproducibly distinguished

HLA-DRB1*15 influences the development of brain tissue damage in early PPMS

OBJECTIVES To investigate whether (1) there were differences between HLA-DRB1*15-positive and -negative patients at baseline, and (2) HLA-DRB1*15-positive patients showed a greater development of brain and spinal cord damage, as assessed by MRI, and greater progression of disability, during a 5-year follow-up, compared with HLA-DRB1*15-negative patients. METHODS HLA-DRB1*15 typing was performed in 41 patients with primary progressive multiple sclerosis (PPMS) who were recruited within 5 years of symptom onset. All patients and 18 healthy controls were studied clinically and with MRI at baseline, and every 6 months for 3 years, and then at 5 years. Magnetization transfer ratio parameters and volumes for brain gray matter and normal-appearing white matter, brain T2 lesion load, and spinal cord cross-sectional area were obtained. Patient disability was assessed at each visit using the Expanded Disability Status Scale and Multiple Sclerosis Functional Composite subscores. RESULTS There were no significant differences between HLA-DRB1*15-positive and -negative patients at baseline. HLA-DRB1*15-positive patients showed a greater decline in brain magnetization transfer ratio for gray matter and normal-appearing white matter (both p = 0.005) than HLA-DRB1*15-negative patients over 5 years, while the same parameters did not change over time in healthy controls. HLA-DRB1*15-positive patients also showed a trend toward a faster increase in brain T2 lesion load than HLA-DRB1*15-negative patients (0.29 [95% confidence interval 0.20-0.38] vs 0.21 [0.13-0.30] mL/mo, p = 0.085) and higher T2 lesion volumes at all time points (average difference [95% confidence interval]: 10.58 mL [7.09-14.07], p < 0.001) during the follow-up, after adjusting for disease duration. CONCLUSIONS These findings suggest that HLA-DRB1*15 influences the progression of brain pathology in PPMS

MS in South Asians in England: early disease onset and novel pattern of myelin autoimmunity.

BACKGROUND: Epidemiological studies describe a latitude gradient for increased MS prevalence and a preponderance of disease in Caucasian individuals. However, individuals from other ethnic backgrounds and low-risk regions can acquire a raised risk through migration. Nearly a fifth of the London population is of Asian/Asian-British origin and a significant proportion of referrals are from this group. METHODS: We investigated whether there were differences in timing, presentation, severity, and immunology of disease (with respect to CD4 myelin epitope recognition) between individuals in London with MS who were either of S. Asian or Caucasian origin. Individuals of S. Asian origin with MS were compared with healthy S. Asian controls, individuals with MS and of Caucasian origin and Caucasian controls. RESULTS: Age at MS onset is significantly lower in the S. Asian group, attributable to earlier onset specifically in UK-born individuals, though clinical presentation is similar. Analysis of CD4 autoimmunity to myelin antigens shows disease in S. Asian individuals to encompass recognition of novel epitopes; immunity to MBP116-130 in S. Asian individuals was highly disease-specific. CONCLUSIONS: These findings emphasize the need to define disease profiles across ethnicities and identify environmental triggers conferring acquired risk. Such findings must inform choices for immunotherapeutic interventions suitable for all, across ethnicities

Diffusion tensor imaging of post mortem multiple sclerosis brain.

Magnetic resonance imaging (MRI) is being used to probe the central nervous system (CNS) of patients with multiple sclerosis (MS), a chronic demyelinating disease. Conventional T(2)-weighted MRI (cMRI) largely fails to predict the degree of patients' disability. This shortcoming may be due to poor specificity of cMRI for clinically relevant pathology. Diffusion tensor imaging (DTI) has shown promise to be more specific for MS pathology. In this study we investigated the association between histological indices of myelin content, axonal count and gliosis, and two measures of DTI (mean diffusivity [MD] and fractional anisotropy [FA]), in unfixed post mortem MS brain using a 1.5-T MR system. Both MD and FA were significantly lower in post mortem MS brain compared to published data acquired in vivo. However, the differences of MD and FA described in vivo between white matter lesions (WMLs) and normal-appearing white matter (NAWM) were retained in this study of post mortem brain: average MD in WMLs was 0.35x10(-3) mm(2)/s (SD, 0.09) versus 0.22 (0.04) in NAWM; FA was 0.22 (0.06) in WMLs versus 0.38 (0.13) in NAWM. Correlations were detected between myelin content (Tr(myelin)) and (i) FA (r=-0.79, p<0.001), (ii) MD (r=0.68, p<0.001), and (iii) axonal count (r=-0.81, p<0.001). Multiple regression suggested that these correlations largely explain the apparent association of axonal count with (i) FA (r=0.70, p<0.001) and (ii) MD (r=-0.66, p<0.001). In conclusion, this study suggests that FA and MD are affected by myelin content and - to a lesser degree - axonal count in post mortem MS brain

Constraints on Natural MNS Parameters from |U_e3|

The MNS matrix structure emerging as a result of recent neutrino measurements strongly suggests two large mixing angles (solar and atmospheric) and one small angle (|U_e3| << 1). Especially when combined with the neutrino mass hierarchy, these values turn out to impose rather stringent constraints on possible flavor models connecting the three active fermion generations. Specifically, we show that an extremely small value of |U_e3| would require fine tuning of Majorana mass matrix parameters, particularly in the context of seesaw models.Comment: 21 pages, ReVTeX, 2 .eps figure files, updated references and acknowledgment