Multiple Sclerosis Research Repository

1. “Conversion from clinically isolated syndrome to multiple sclerosis: A large multicentre study”: J Kuhle et al

-”At median follow-up of 4.31 years, 623 CIS cases converted to CDMS. Predictors of conversion in multivariable analyses were OCB (HR = 2.18, 95% CI = 1.71-2.77, p < 0.001), number of T2 lesions (two to nine lesions vs 0/1 lesions: HR = 1.97, 95% CI = 1.52-2.55, p < 0.001; >9 lesions vs 0/1 lesions: HR = 2.74, 95% CI = 2.04-3.68, p < 0.001) and age at CIS (HR per year inversely increase = 0.98, 95% CI = 0.98-0.99, p < 0.001). Lower 25-OH-D levels were associated with CDMS in univariable analysis, but this was attenuated in the multivariable model. OCB positivity was associated with higher EBNA-1 IgG titres”

2. “The relationship between inflammation and atrophy in clinically isolated syndromes suggestive of multiple sclerosis: a monthly MRI study after triple-dose gadolinium-DTPA”: Andrea Paolillo

-”Twenty-four (39%) developed clinically definite MS by month 18. Thirty-eight (61%) were relapsefree and completed the MRI follow-up. Relapse-free patients showed a progressive median increase between baseline and month 18 in T1-LL (25%, p<0.001), but not in T2-LL (8.5%, p=ns). PBVC decreased by 1.1% (p<0.001) in a time-dependent pattern (Kendall coefficient of concordance=0.85). Exploratory subgroup analyses showed a trend towards progressive decreases in brain volume in active patients (i. e., those with at least one newly active lesion during monthly MRI scanning; Spearman’s R=-0.61; p<0.001), but not among inactive patients (Spearman’s R=-0.10; p=0.53). Significant differences in median brain volume changes between the active and inactive patient groups were found at months 12 and 18; the difference detected at month 6 was not significant. The cumulative number and volume of new Gd-enhancing lesions developed during the 6 months of frequent MRI scanning were highly correlated with PBVC over the 18-month period (Spearman R values were 0.73 and 0.85, respectively). The strongest predictor of PBVC at 18 months was the cumulative volume of newly active lesions during frequent MRI scanning [ss=-0. 83, standard error (SE)=0.07, p<0.001].”

-”This study shows that visible inflammation as detected by monthly, triple-dose Gd-enhanced MRI is an important factor in the pathogenesis of brain tissue loss in CIS patients. However, inflammation and brain atrophy do not proceed in parallel: atrophy appeared only after a delay of months following acute inflammation. Frequent MRI scanning allows for the detection of CIS patients who will develop brain atrophy in the short-term.”

3. “Disability and T2 MRI lesions: a 20-year follow-up of patients with relapse onset of multiple sclerosis”: L K Fisniku et al

-”Clinically isolated syndromes (CIS), such as optic neuritis, brainstem or spinal cord syndromes are frequently the first clinical presentations of multiple sclerosis. However, not all CIS patients develop multiple sclerosis and in those who do, disability is highly variable. In previous follow-up studies, brain lesions on T2-weighted MRI are associated with increased risk of multiple sclerosis and to an extent disability. We evaluated the longitudinal relationships between the MRI lesions and clinical course over a period of 20 years. CIS patients were recruited between 1984 and 1987 and previously followed up after 1, 5, 10 and 14 years. Of the 140 subjects who were initially recruited with a CIS for a baseline MRI study, we followed up 107 patients after a mean of 20.2 years (range 18-27.7). Multiple sclerosis was diagnosed as clinically definite on clinical grounds only and disability determined using the Expanded Disability Status Scale (EDSS) and Multiple Sclerosis Functional Composite (MSFC) score. Clinically definite multiple sclerosis developed in 67 out of 107 (63%) overall: 60 out of 73 (82%) with abnormal and 7 out of 34 (21%) with normal baseline MRI. Multiple sclerosis was still relapsing-remitting in 39 (58%)–including 26 (39%) with a ‘benign’ course (EDSS < or = 3)–whilst 28 (42%) had developed secondary progression.”

4. “Treatment with disease-modifying drugs for people with a first clinical attack suggestive of multiple sclerosis”: G Filippini

-”Authors’ conclusions: Very low-quality evidence suggests a small and uncertain benefit with early treatment compared with placebo in reducing disability-worsening and relapses. The advantage of early treatment compared with delayed on disability-worsening was heterogeneous depending on the actual drug used and based on very low-quality evidence. Low-quality evidence suggests that the chances of relapse are less with early treatment compared with delayed. Early treatment reduced the hazard of conversion to CDMS compared either with placebo, no treatment or delayed treatment, both in short- and long-term follow-up. Low-quality evidence suggests that early treatment is associated with fewer participants with at least one serious AE compared with placebo. Very low-quality evidence suggests that, compared with placebo, early treatment leads to more withdrawals or treatment discontinuation due to AEs. Difference between drugs on short-term benefit and safety was uncertain because few studies and only indirect comparisons were available. Long-term safety of early treatment is uncertain because of inadequately reported or unavailable data.”

5. “Treatment with disease-modifying drugs for people with a first clinical attack suggestive of multiple sclerosis (Review): Filippini G (Cochrane Review, 2017)

-”There was a small, non-significant advantage of early treatment compared with placebo in disability worsening (6.4% fewer (13.9 fewer to 3 more) with Rebif

-”We did not find evidence of differences between early and delayed treatments for disability-worsening at a maximum of five years follow up)

-”Very low quality evidence suggests a small and uncertain benefit with early treatment compared with placebo in reducing disability-worsening and relapses.”

-”is early treatment better than later treatment”; Avonex, Betaferon, Copaxone or Rebif; “the great variability between the studies and the low quality of the evidence makes our confidence in this result low”

6. “MRI characteristics are predictive for CDMS in monofocal but not in multifocal patients with a clinically isolated syndrome:: Jessica M Nielsen et al

-”in monofocal patients, the risk for CDMS over 2 years was significantly higher when greater than or equal to 9T2 lesions or at least one Gd-enhancing lesion were present at the first even tor 3 or 6 months after the first event” (*This is M’s situation*)

7. “The Prognostic Utility of MRI in Clinically Isolated Syndrome: A Literature Review” by C. Odenthal et al

-”Published rates of conversion CIS to CDMS differ according to length of study follow-up.  Five studies were identified in which subjects were followed for greater than 6 years.  For follow up of 6.9, 7.2, 7.3, 14 and 20 years, total conversion rates were 48%, 60%, 85%, 68%, and 63%.  

-”The risk of conversion to CDMS is greater in patients presenting with abnormal T2WI.  Subjects with CIS subjects in the range of 50-70% with abnormal T2WI.” 

-”Fisniku et al followed 107 subjects with CIS to 20.2 years; 82% with abnormal baseline MRI converted to CDMS, compared with 21% with normal MRI imaging”

-”In another study, 88% of subjects with abnormal MR imaging converted by 14 years, compared to 19% of those with normal scans”

-”A recent meta-analysis concluded that abnormal T2WI, regardless of lesion number, was associated with increased risk of conversion”

-”In addition to T2 lesions, increased risk of conversion to MS is associated with the presence of gadolinium-enhancing lesions”

-”The presence of at least 1 Gd-enhancing lesion is predictive of time to CDMS in monofocal but not in multifocal presentations”

-”the prognostic significance of T1 lesions has been infrequently addressed.  Summers et al found that in addition to Gd-enhancing lesions, T1 lesions were predictive of cognitive dysfunction after 7 years”

-”Baseline T2 lesion number is associated with EDSS at long-term follow up to 14 years”

-”while baseline T2 lesion number was not associated with disability, the increase in T2 lesion number over the first year after presentation was predictive of EDSS at 6 years”

-”The risk of disease progression is associated with lesion location, with periventricular, callosal and cerebellar distributions being most associated with conversion to CDMS”

-”Infratentorial lesion location may be associated with increased risk of disease and disability.  Since infratentorial lesions are likely to affect clinically eloquent areas, they may have greater contribution to future disability.” 

-”In a large multicenter study of 468 subjects with CIS, infratentorial lesions (including the brainstem and cerebellum) were not associated with increased risk of conversion”

-”It is uncertain whether neurodegeneration is present in subjects with CIS”

-”Subjects with CIS who convert to CDMS demonstrate a greater T2LV at presentation compared with those who do not convert”

-”baseline T2LV was an independent predictor of conversion to MS by 4 years”

-”T2LV is associated with the development of future disability”

-”the rate of increase in T2LV in the first year is associated with greater long-term disability”

-”T2 lesion volume may be better suited to the prediction of disability scores other than EDSS….(T1 lesion volume) did correlate with the Multiple Sclerosis Functional Composite at 6 years. Another study found that both T1 lesion number and volume were predictive of future cognitive dysfunction” 

-”reported volume reduction in a number of deep GM structures of subjects with CIS, compared with controls, including the thalamus and caudate nucleus.

-”cerebellar volume was associated with baseline tests of cerebellar function” 

-”A recent study of 212 subjects did find that increased T2LV was associated with reduced volume of a number of deep GM structures”

-”In a longitudinal study of 24 subjects with CIS, Audoin et al found that the midsagittal corpus callosal area was significantly reduced at 12 months.  Callosal area also correlated with progression in EDSS….in a larger cohort of 220 subjects with CIS, change in callosal area in the first 6 months after presentation was predictive of conversion to CDMS by 2 years”

-”patients with CIS had increased mean diffusivity in all WM tracts”

-”widespread reduced fractional anistropy in the WM of subjects with CIS”

-”the magnetization transfer ratio of patients with CIS differed significantly from healthy controls”

-”magnetization transfer ratio has been shown to be predictive of conversion to CDMS”

-”NAA is a metabolite considered to be exclusive to neurons”

-”Other studies found that only those patients with clinical progression demonstrated reduced NAA at presentation” 

-”Myo-inositol (MIns or Ins) is a metabolite primarily concentrated in glial cells

–”They demonstrated baseline reduced NAA and increased choline”

-”The rate of increase in MIns concentration in normal-appearing WM over the first year was predictive of poor executive function at 7.2 years”

-”Functional cortical changes are present from the earliest stages of CIS.  Compared with healthy controls, subjects with CIS demonstrate increased cortical activation in both cerebral hemispheres”

-”T2 hypointensity, attributable to iron deposition, is a frequent finding in subjects with MS”

-”While regional atrophy is not present at patient presentation (CIS), changes in DTI and MR spectroscopy parameters demonstrate that there is functional change occurring in normal-appearing brain tissue.  Widespread increased motor cortical activation visualized on fMRI suggests that neuroplasticity is already a factor at initial presentation”

-”subjects with CIS demonstrate brain iron deposition, a feature that is characteristic of MS” 

8. “Evidence for widespread axonal damage at the earliest clinical stage of multiple sclerosis”: M Filippi

-”Although axonal pathology is recognized as one of the major pathological features of multiple sclerosis, it is less clear how early in its course it occurs and how it correlates with MRI-visible lesion loads. To assess this early axonal pathology, we quantified the concentration of whole-brain N-acetylaspartate (WBNAA) in a group of patients at the earliest clinical stage of the disease and compared the results with those from healthy controls. Conventional brain MRI and WBNAA using unlocalized proton magnetic resonance spectroscopy were obtained from 31 patients at presentation with clinically isolated syndromes suggestive of multiple sclerosis and paraclinical evidence of dissemination in space, and from 16 matched controls. An additional conventional MRI scan was obtained in all patients 4-6 months later to detect dissemination of lesions in time. The mean WBNAA concentration was significantly lower in patients compared with the controls (P < 0.0001). It was not significantly different between patients with and without enhancing lesions at the baseline MRI or between patients with and without lesion dissemination in time. No correlation was found between WBNAA concentrations and lesion volumes. Widespread axonal pathology, largely independent of MRI-visible inflammation and too extensive to be completely reversible, occurs in patients even at the earliest clinical stage of multiple sclerosis. This finding lessens the validity of the current concept that the axonal pathology of multiple sclerosis is the end-stage result of repeated inflammatory events, and argues strongly in favour of early neuroprotective intervention.”

9. “Combined analysis of global and compartmental brain volume changes in early multiple sclerosis in clinical practice:  A Pichler

-”At baseline, all the brain volume metrics, except cGMV, were significantly lower; and the T2-LL was significantly higher, in patients with MS rather than CIS. During the follow-up, only the PBVC was higher in MS (p = 0.008) and this difference was driven by converters from CIS to MS. Quartiles of PBVC did not allow us to predict conversion to MS, but were associated with the degree of disability.”

10.  “Cognitive impairment in clinically isolated syndrome: A systematic review”: Carolina Fiorin Anhoque

-”Seven studies fulfilled the selection criteria adopted in this review. The pattern of cognitive abnormalities in CIS resembles that found in patients with MS and is characterized by attention deficit, reduced information processing speed and impaired working memory and executive functions. The frequency of cognitive impairment in CIS seems to be lower than in MS.”

11.  “Cognitive impairment in patients with clinically isolated syndrome”: 

Carolina Fiorin Anhoque

-” CIS patients had significantly worse performance on the Paced Auditory Serial Addition Test (PASAT) 2 seconds (P=0.009) and on verbal fluency tests (P=0.0038) than controls.”

-”CIS patients had worse cognitive performance than controls on neuropsychological tests evaluating executive functioning”

12.   “Cortical involvement determines impairment 30 years after a clinically isolated syndrome”: Lukas Haider

-”Many studies report an overlap of MRI and clinical findings between patients with relapsing-remitting multiple sclerosis (RRMS) and secondary progressive multiple sclerosis (SPMS), which in part is reflective of inclusion of subjects with variable disease duration and short periods of follow-up. To overcome these limitations, we examined the differences between RRMS and SPMS and the relationship between MRI measures and clinical outcomes 30 years after first presentation with clinically isolated syndrome suggestive of multiple sclerosis. Sixty-three patients were studied 30 years after their initial presentation with a clinically isolated syndrome; only 14% received a disease modifying treatment at any time point. Twenty-seven patients developed RRMS, 15 SPMS and 21 experienced no further neurological events; these groups were comparable in terms of age and disease duration. Clinical assessment included the Expanded Disability Status Scale, 9-Hole Peg Test and Timed 25-Foot Walk and the Brief International Cognitive Assessment For Multiple Sclerosis. All subjects underwent a comprehensive MRI protocol at 3 T measuring brain white and grey matter (lesions, volumes and magnetization transfer ratio) and cervical cord involvement. Linear regression models were used to estimate age- and gender-adjusted group differences between clinical phenotypes after 30 years, and stepwise selection to determine associations between a large sets of MRI predictor variables and physical and cognitive outcome measures. At the 30-year follow-up, the greatest differences in MRI measures between SPMS and RRMS were the number of cortical lesions, which were higher in SPMS (the presence of cortical lesions had 100% sensitivity and 88% specificity), and grey matter volume, which was lower in SPMS. Across all subjects, cortical lesions, grey matter volume and cervical cord volume explained 60% of the variance of the Expanded Disability Status Scale; cortical lesions alone explained 43%. Grey matter volume, cortical lesions and gender explained 43% of the variance of Timed 25-Foot Walk. Reduced cortical magnetization transfer ratios emerged as the only significant explanatory variable for the symbol digit modality test and explained 52% of its variance. Cortical involvement, both in terms of lesions and atrophy, appears to be the main correlate of progressive disease and disability in a cohort of individuals with very long follow-up and homogeneous disease duration, indicating that this should be the target of therapeutic interventions.”

12)  “Differential Gray Matter Vulnerability in the 1 Year Following a Clinically Isolated Syndrome”: Ismail Koubiyr et al

-At baseline, GM volumes did not differ between PwCIS and HC, but hippocampal MD (mean diffusivity) was higher in PwCIS than HC (p < 0.01). Over 1 year, GM alterations became more widespread with putamen and hippocampus volumes decreasing in PwCIS (p < 0.01), and cortical thinning in different parts of the cortex along with a significant increase of MD. Hippocampus MD at baseline could predict its volume loss (R² = 0.159; p < 0.05) and cortical thinning was associated to microstructural damage (Spearman’s rho ranging from −0.424 to −0.603 with p < 0.003).

-Along with MS being a diffuse inflammatory disease, GM showed a differential vulnerability at the early stage spreading from hippocampus to the cortex. Hippocampus volume loss could be predicted by its MD at baseline.

13.  “A 30-Year Clinical and Magnetic Resonance Imaging Observational Study of Multiple Sclerosis and Clinically Isolated Syndromes” by Karen K Chung, MBBS et al

-used 2010 McD criteria

-120 participants over 30 years; 80 developed MS by 30 years; in terms of EDSS: 

42% remained full ambulatory (EDSS scores less than or equal to 3.5), all of 

whom had RRMS; 4% had RRMS and EDSS greater than 3.5; 34% had SPMS with 

EDSS greater than 3.5; and MS contributed to death in 20%

-the strongest early predictors (within 5 years of presentation) of secondary 

progressive MS at 30 years were presence of baseline infratentorial lesions and 

deep white matter lesions at 1 year

-people presenting with a brainstem CIS were at greater risk than those 

presenting with either ON or transverse myelitis; this was consistent with the higher proportion of brainstem subjects with baseline IT lesion present compared to ON and transverse myelitis; the change in EDSS scores from nadir to 5 years was also largest in the brainstem CIS group

–Baseline EDSS scores were not significantly associated with 30-year outcome

-5-year EDSS scores greater than or equal to 2.5 was a significant predictor of SPMS following a CIS

-13 of 14 (93%) of people who progressed by greater than or equal to 2 EDSS points between nadir and 5 years had transitioned to SPMS

-for predicting 30-year EDSS score less than or equal to 3.5 vs EDSS score greater than 3.5 outcome, EDSS scores at nadir and 5 years were significant, more so than EDSS changes between these time points, and the predictive value of EDSS scores at 5 years was, unsurprisingly, greater than at earlier time points

-a greater proportion of people with nadir EDSS scores greater than or equal to 2.5 progressed to 3 year EDSS scores greater than 3.5

-the strongest early MRI predictors of 30-year EDSS scores greater than 3.5 were the presence of (1) baseline IT lesions, with 86% progressing to EDSS scores greater than 3.5 by 30 years vs 34% of those without and (2) 1 year DWM lesions, with 60% reaching EDSS scores greater than 3.5 vs 13% of those without

-30 year outcomes could, in part, be predicted by early EDSS scores and more robustly by MRI-derived regional lesion counts

-MRI lesion counts provided to be better predictors than EDSS scores and lesion location was more important than lesion number

-it was early IT and DWM lesions that had the greatest long term prognostic value…in people with baseline IT and DWM lesions by 1 year, the chances of having SPMS were 94%…those with 1 or more IT lesions by 1 year were 5 times more likely to have died due to MS than the rest of the cohort

-IT lesions have previously been linked with less favorable outcomes in people with MS after a mean follow-up of 7.7 years

14.  “Differential Gray Matter Vulnerability in the 1 Year Following a Clinically Isolated Syndrome” by Ismail Koubiyr et al

-at baseline, GM volumes did not differ between PwCIS and HC, but hippocampal MD (mean diffusivity) was higher in PwCIS than HC

-over 1 year, GM alterations became more widespread with putamen and hippocampal volumes decreasing in PwCIS and cortical thinning in different parts of the cortex along with a significant increase of MD

-Hippocampus MD at baseline could predict its volume loss and cortical thinning was associated to microstructural damage

-GM showed a differential vulnerability at the early stage spreading from hippocampus to the cortex; hippocampus volume loss could be predicted by its MD at baseline

-in order to study the selective vulnerability of GM, diffusion tensor imaging (DTI) allows to explore the microstructural integrity of the structures; a few studies used this technique in CIS, showing abnormal results in the thalamus, hippocampus, and cerebellum, suggesting microstructural changes from the early stages of MS

-there was a differential vulnerability of the hippocampus compared to the rest of the GM

-in PwCIS lateral ventricles volumes increased, reflecting deep brain atrophy, whereas putamen and hippocampus volumes significantly decreased

-the mean CTh significantly decreased in 1 year; regionally, multiple brain areas of significant cortical thinning in both hemispheres were observed; this cortical thinning was noticed in the bilateral frontal and temporal lobes, left insula and right parietal lobe

-regarding microstructural changes, PwCIS showed significantly higher MD in the left frontal, left temporal, left cingulate and bilateral parietal lobes

-baseline hippocampus MD was able to predict hippocampus volume loss after 1 year; T2 LL was taken into account in this model and was not responsible for the volume loss

-mean diffusivity change from year 0 to year 1 was strongly correlated to the cortical thinning in the left frontal lobe, the right parietal lobe, and the left temporal lobe

-no correlation found between EDSS and MRI (volumetric and DTI) abnormalities; these abnormalities were not able to predict the conversion to MS after 1 year

-the present study showed differential GM vulnerability as microstructural damage spread from the deep gray matter (hippocampus) to the cortex 1 year after the CIS; this microstructural damage occurred before irreversible gray matter atrophy

-at baseline, there was no sign of GM atrophy in PwCIS compared to HC; however, microstructural damage was already present and the hippocampus was the first and only GM structure altered; the hippocampus showed increased MD compared to controls

-the damage occurring to the hippocampus was further confirmed by a significant volume loss after 1 year of follow up; the putamen showed also a significant volume loss at follow up

-the hippocampus MD was able to predict its volume loss independently of lesion volume

-microstructural abnormalities as detected by DTI in the hippocampus, preceding volume loss and predicting it, suggested that a primary tissue alteration within this structure is involved in the neurodegenerative process

-activation of microglia/macrophages, associated with demyelination and neurodegeneration, has been pathologically observed in DGM, including the hippocampus, in MS

-in EAE, microglial activation within the hippocampus has been observed in association with neuronal dysfunction and memory impairment independently of demyelination

-the persistence of the prediction after adjustment on lesion load suggests an independent mechanism

-it is well-established that GM atrophy including cortical and DGM atrophy is mainly responsible for the development of the whole brain atrophy

-it has also been suggested that meningeal inflammation and microglial activation could lead to direct pathology of the GM and some evidence of this mechanism has been observed in progressive MS

-in 1 study showing some level of DGM atrophy, lesion volume was superior to 2 cm cubed

-in another study, CIS patients with lesion load superior to 4.49 cm cubed had lower DGM volumes than those with a median lesion load inferior to 4.49cm cubed

-this suggests that in the CIS samples with lower lesion load, the pre-clinical stage developed before CIS was shorter, explaining why atrophy was not developed

-we did not observe significant cortical thinning at baseline

-we observed some cortical thinning during the follow-up period in bilateral frontal lobes, bilateral temporal lobes and left insular and right parietal lobes; these results are in line with the study by Rocca et al showing GM atrophy of frontal, temporal, and parietal lobes in CIS patients 1 year after the onset of the disease; microstructural abnormalities in the cortex appeared only after 1 year of follow up as opposed to hippocampuses 

-MD of bilateral parietal lobes, left frontal, left temporal and left cingulate lobes was not only significantly increased after 1 year in PwCIS; this result did not only reflect atrophy because of CSF contamination

-A recent studying using 7 Tesla MRI showed the existence of a gradient of pathology in the cortex of MS patients, suggesting that the pathological process was driven from the pial surface and supported the role of inflammation within the cortex in relation with meningeal inflammation

-cortical volume loss seems to parallel DGM volume loss at these very early stages of MS; however, microstructural damage starts within the hippocampus first

15.  “Cortical involvement determines impairment 30 years after a clinically isolated syndrome” by Lukas Haider et al

-63 patients were studied 30 years after their initial presentation with a clinically isolated syndrome; 27 developed RRMS; 15 SPMS; and 21 experienced no further neurological events

-at the 30-year follow-up, the greatest differences in MRI measures between SPMS and RRMS were the number of cortical lesions, which were higher in SPMS (the presence of cortical lesions had 100% sensitivity and 88% specificity), and grey matter volume, which was lower in SPMS

-across all subjects, cortical lesions, grey matter volume and cervical cord volume explained 60% of the variance of the EDSS; cortical lesions alone explained 43%

-grey matter volume cortical lesions and gender explained 43% of the variance of T25FW

-reduced cortical magentization transfer ratios emerged as the only significant explanatory variable for the SDMT and explained 52% of its variance

-cortical involvement, both in terms of lesions and atrophy, appears to be the main correlate of progressive disease and disability in a cohort of individuals with very long follow-up and homogenous disease duration

-cortical MTR emerged as the strongest significant predictive factor in all models to explain cognitive outcome measures

-cortical lesions were the clearest determinant of a progressive disease course and that cortical involvement 30 years after symptom onset was the dominant factor explaining both physical and cognitive outcomes

-cortical lesions were absent in all individuals who remained CIS; found in 3 of 27 who developed RRMS; present in all 15 individuals who developed SPMSe

-subpial demyelination accounted quantitatively for most of the cortical involvement

-leukocortical lesions only reveal the tip of the iceberg

-primary cortical demyelination is highly specific for MS

-disability measures were frequently explained by grey matter related to MRI measures 

-a dominant role for cortical involvement for prediction of current and future disability 

-current structural MRI sequences are relatively insensitive to biologically and clinically relevant aspects of tissue injury, and the networked nature of the brain

-thalamic atrophy has been repeatedly suggested as an early correlate of present and subsequent disability in MS; group differences for thalamic volume in our study were significant comparing CIS and RRMS and CIS and SPMS, RRMS compared with SPMS was far from the significance level

-cortical involvement was the main MRI feature that distinguished SPMS from RRMS

16. “Lesion location across diagnostic regions in multiple sclerosis” by Viola Pongratz et al

-in patients with CIS, lesion clusters in white matter tracts in the subcortical area have been shown to predict conversion to RRMS as did lesion clusters in the diagnostic regions

-a new subcortical lesion in a follow up MRI of a patient with CIS demonstrates dissemination in time according to the diagnostic criteria and has also been interpreted as active disease in pivotal clinical trials

-supratentorial white matter lesions neither directly abutting the ventricles nor the cortical ribbon were classified as subcortical lesions

-at baseline: subcortical lesions found in 93%

-follow up EDSS correlated with total lesion numbers in all regions but not with the number of new lesions; EDSS at baseline correlated with periventricular lesion volume only