Benign Multiple Sclerosis - 2g6

Background
The definition of Benign Multiple Sclerosis (B-MS) is still controversial.

This mainly takes into account the subject's motor ability, with little or no relevance to other important features such as Cognition.

Moreover, no paraclinical markers are currently available to reliably identify patients who will remain Benign in the long term.

Objectives
To assess, by using quantitative Magnetic Resonance (MR) metrics, differences in tissue damage between B-MS patients after dividing them into two groups on the basis of their Cognitive performance.

Methods
Forty-seven B-MS patients (Expanded Disability Status Scale score < / = 3.0 and disease duration >/=15 years) underwent NeuroPsychological Assessment through the Rao Brief Repeatable Battery and the Stroop Test.

At that time, B-MS patients underwent conventional Brain MR and Magnetization Transfer (MT) imaging.

White Matter lesion load, global and Regional Brain Volumes, and MT Ratio (MTR) in lesions and Normal-Appearing Brain were measured.

Quantitative MR measures were compared in Cognitively Impaired (CI-MS) and Cognitively Preserved (CP-MS) patients and in 24 demographically matched healthy controls.

Test performance was correlated with MR changes in specific Cortical regions.

Results
Eleven patients were classified as CI-MS, and 36 were classified as CP-MS. Both T₂-weighted and T₁-weighted lesion loads were higher (p = 0.05 and 0.001) in CI-MS than in CP-MS patients.

Furthermore, CI-MS patients were characterized by more pronounced decrease in NeoCortical Volume (p = 0.005) and Cortical MTr (p = 0.02) values than CP-MS patients.

Finally, test performance correlated significantly with MR changes in relevant Cortical regions.

Conclusions
Cognitive Assessment and quantitative Magnetic Resonance can help to reliably identify Benign Multiple Sclerosis patients.

Background
Cognitive Impairment is one of the frequent and early findings in Multiple Sclerosis (MS).

Objective
To determine the relation between Cognitive abnormalities and the extent of macroscopic and microscopic tissue damage in the Corpus Callosum (CC), revealed by conventional Magnetic Resonance Imaging (MRI), Magnetization Transfer Imaging (MTI) and Diffusion Tensor Imaging (DTI).

Methods
Conventional dual-echo, DTI and MTI of the Brain were obtained from 36 patients with Relapsing/Remitting (RR) MS, and 13 age and gender matched normal controls.

Voxels from CC were identified using a Tractography based algorithm. Mean Apparent Diffusion Coefficient (mean trace ADC(av)) and MT Ratio were measured for the CC as defined by Tractography.

Corpus Callosum Area (CCA) was measured using edge detection on the mid-sagittal slice on high resolution MRI images.

The Expanded Disability Status Scale (EDSS) and Paced Auditory Serial Addition Test (PASAT) were scored.

Results
Nine patients (25%) were found to be Cognitively Impaired.

The CCA was not significantly different in the whole cohort of patients from controls (608.2 (428.6-713.0) mm² vs 674.2 (585.8-754.4) mm², p = 0.1).

But, was smaller in Cognitively Impaired than unimpaired group (417 (290-634) mm² vs 652 (511-718) mm², p = 0.04).

The mean MT Ratio of CC in patients was lower than in controls (0.41 (0.39-0.042) vs 0.43 (0.42-0.43), p < 0.001).

The mean trace ADC(av) in the CC in patients was higher than in controls (0.94 (0.89-0.99) vs 0.87 (0.85-0.89), p < 0.001).

PASAT was correlated with mean MT Ratio (r = 0.47, p = 0.0046), ADC(av) (r = -0.53, p = 0.0012), CCA (r = 0.42, p = 0.01) and total T₂ lesion load (r = -0.4, p = 0.017).

But, not with T₂ lesion load within the CC (r = -0.24, p = 0.16), disease duration (r = -0.2, p = 0.24) or EDSS (r = -0.27, p = 0.12).

Conclusions
mean trace ADC(av), MTR and Atrophy measures in the CC may offer a sensitive method detecting subtle macroscopic and microscopic changes associated with Cognitive Impairment in MS.

Corpus Callosum (CC), the largest compact White Matter fiber bundle of the human Brain involved in InterHemispheric transfer, is frequently damaged in the course of Multiple Sclerosis (MS).

Cognitive Impairment is one of the factors affecting quality of life of patients with Benign MS (BMS).

The aim of this study was to investigate the relationship between the Cognitive profile of BMS patients and the extent of tissue damage in the CC.

Brain conventional and DT MRI scans were acquired from 54 BMS patients and 21 healthy controls. NeuroPsychological Tests (NPT) exploring Memory, Attention, and Frontal Lobe Cognitive Domains were administered to the patients.

DT Tractography was used to calculate the Mean Diffusivity (MD) and Fractional Anisotropy (FA) of the CC Normal-Appearing White Matter (NAWM). An index of CC Atrophy was also estimated.

Nine (17%) BMS patients fulfilled criteria for Cognitive Impairment. Compared with controls, BMS had significantly different CC Diffusivity and Volumetry (P < 0.001).

Compared with Cognitively Preserved patients, those with CI had significantly higher CC lesion volume (LV) (P = 0.02) and NAWM MD (P = 0.02).

The scores obtained at PASAT were significantly correlated with CC T₂ LV, and NAWM FA and MD (r values ranging from -0.31 to 0.66, P values ranging from 0.04 to < 0.001).

Cognitive Impairment in BMS is associated with the extent of CC damage in terms of both focal lesions and diffuse fiber bundle injury.

MRI assessment of topographical distribution of tissue damage may represent a rewarding strategy for understanding the subtle clinical deficits of patients with BMS.

Hum Brian Mapp 2009. (c) 2008 Wiley-Liss, Inc.

Objective
Although in Benign Multiple Sclerosis (BMS) locomotor disability is absent or only minimal, subclinical Cognitive Impairment seems to occur in many cases.

Diffusion Tensor (DT) MRI enables us to quantify the extent of "actual" tissue damage, which goes undetected when using conventional MRI.

Against this background, we investigated the extent of structural Brain damage underlying Cognitive Dysfunction in BMS, with the ultimate aim to move a first step toward a more reliable definition of this disease phenotype.

Methods
Conventional and DT MRI scans of the Brain were acquired from 62 BMS patients. Thirty-six Secondary/Progressive Multiple Sclerosis (SPMS) patients and 19 healthy subjects served as controls.

In BMS patients, NeuroPsychological tests exploring Memory, Attention, and Frontal Lobe functions were administered.

Normalized Brain Volume (NBV), Mean Diffusivity (MD), and Fractional Anisotropy (FA) of the Normal-Appearing White Matter (NAWM) and MD of the Gray Matter (GM) were computed.

Results
Twelve BMS patients (19%) fulfilled predefined criteria for Cognitive Impairment. BMS patients had abnormal MD and FA values from both NAWM and GM.

Whereas BMS patients without Cognitive Impairment had lower T₂ LV (p = 0.03), higher NBV (p = 0.006), and lower average GM MD (p = 0.03) than SPMS patients, BMS patients with Cognitive Impairment did not significantly differ from SPMS patients for any MRI-derived metric.

Conclusions
In Benign Multiple Sclerosis (BMS), Cognitive Dysfunction is associated with severe structural Brain damage, which resembles that of patients with a much more disabling disease course.

A reliable definition of BMS should, therefore, include the preservation of Cognitive functioning as an additional requisite.

The objective of this study was to assess the functional and structural substrates of Cognitive Network changes in patients with Benign Multiple Sclerosis (BMS), using an analysis of effective connectivity and MR Tractography.

Using a 3-Tesla scanner, we acquired Dual-Echo, Diffusion Tensor (DT) and Functional MRI during the performance of the Stroop task from 15 BMS patients and 19 healthy controls.

DT MR Tractography was used to calculate DT derived metrics from several White Matter (WM) fiber bundles, thought to be involved in Cognitive performance.

DT MRI metrics from WM fiber bundles not directly related with Cognitive performance were also derived. Effective connectivity analysis was performed using statistical parametric mapping.

MS patients had significantly abnormal DT MRI metrics in all the structures analyzed. Compared with controls, MS patients had more significant activations of several areas of the Cognitive Network involved in Stroop performance, bilaterally.

Compared with controls, BMS patients also had increased connectivity strengths between several Cortical Areas of the SensoriMotor Network and the Right (R) Inferior Frontal Gyrus and the R Cerebellum, as well as decreased connectivity strengths with the Anterior Cingulate Cortex.

Coefficients of altered connectivity were moderately correlated with structural MRI metrics of tissue damage within Intra- and Inter-Hemispheric Cognitive-related WM fiber bundles.

While no correlations were found with the remaining fiber bundles studied, suggesting that Functional Cortical Changes in patients with BMS might represent an adaptive response driven by damage of specific WM structures.

(c) 2007 Wiley-Liss, Inc.

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

1. Forty-eight patients with BMS (Expanded Disability Status Scale [EDSS] score < or = 3.0 and disease duration > or = 15 years) and
2. 96 patients with non-disabling, early Relapsing/Remitting (RRMS) (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 ? 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.

Objective
The term Benign Multiple Sclerosis (BMS) is referred to patients who have a mild or absent disability several years after disease clinical onset. Axonal Damage can be measured in vivo using proton MR Spectroscopy ((1)H-MRS).

In this study, we quantified the severity of "global" Axonal Damage in BMS and early Relapsing/Remitting (RR) MS patients, using Whole Brain N-AcetylAspartate (WBNAA) (1)H-MRS, to better elucidate the structural correlates of a non-disabling disease evolution.

Methods
WBNAA concentration was measured in 37 patients with BMS (mean disease duration 22.3 years) and 17 patients with early RRMS (mean disease duration 4.0 years), using an unlocalized (1)H-MRS sequence.

Dual echo and T₁-weighted scans were also obtained to measure T₂-HyperIntense Lesion Volume (TLV) and Normalized Brain Volume (NBV).

Results
TLV was higher in BMS (mean TLV = 13.1 mL) than in early RRMS patients (mean TLV = 7.2 mL) (P = 0.018).

Whereas neither NBV (mean NBV: 1491.0 mL in BMS vs 1520.3 mL in RRMS) nor WBNAA concentration (mean WBNAA: 10.5 mmol in BMS vs 11.4 mmol in RRMS) significantly differed between the two groups.

In MS patients, no correlation was found between WBNAA concentration and Expanded Disability Status Scale (EDSS), TLV and NBV.

Conclusions
The similar WBNAA concentrations seen in BMS and early RRMS patients fit with the notion.

That a non-disabling long-term evolution of MS may be due, at least in part, to non-progression of pathology. Such a condition seems to be independent from MRI-visible lesions burden.

It is well known that the current classification of patients with Benign Multiple Sclerosis (BMS), i.e., those with absent or minimal locomotor disability several years after disease onset, suffers from not having any prognostic value for the subsequent evolution of Multiple Sclerosis (MS).

The identification of markers predictive of the longer-term course of MS will help define BMS more reliably and would allow better counseling of patients, particularly when advising on the initiation of a Disease-Modifying Treatment.

MRI-based evidence suggests that there are three potential, but not mutually exclusive, explanations for the scarce clinical impact of BMS:
1. The paucity of tissue damage within and outside MS lesions;
2. The relative sparing of clinically eloquent regions; and
3. The presence of effective compensatory mechanisms.

In addition, the results of correlative MRI/NeuroPsychology studies underpin the need for a new definition of BMS, which should consider the maintenance of a normal Cognitive profile as an additional criterion.

Cervical Cord damage is likely to contribute to the accumulation of disability in Multiple Sclerosis (MS) and can be quantified in vivo using MRI.

We used conventional and Diffusion Tensor (DT) MRI to:
1. Define the temporal evolution of intrinsic Tissue Injury and Atrophy in the Cervical Cord from MS patients
2. Investigate how these two aspects of Cord damage are interrelated and

3. Assess the correlation of Cord MRI metrics with concomitant Brain damage and disability

Conventional and DT MRI of the brain and Cervical Cord were obtained from 42 MS patients and 9 healthy controls at baseline and after a mean follow-up of 2.4 years.

At each time-point, we measured: Cervical Cord lesion number, cross-sectional area, Mean Diffusivity (MD) and Fractional Anisotropy (FA).

Brain T2 lesion volume, Gray Matter MD, Normal-Appearing White Matter (NAWM) MD and FA, as well as longitudinal normalized percentage Brain Volume changes were also measured.

In MS patients, Cervical Cord Cross-Sectional Area (P < 0.001) and FA (P = 0.01) decreased, and Cervical Cord MD increased (P < 0.001) during follow-up.

Cord FA decrease, but not Cord Cross-Sectional Area and MD, was significantly higher (P = 0.05) in Primary/Progressive MS patients than in those with either Relapsing/Remitting or Secondary/Progressive MS.

At baseline and follow-up, moderate correlations were found between intrinsic Cord Diffusivity abnormalities and Cord Cross-Sectional Area (r values ranging from 0.34 to 0.58), but not between their changes over time.

No cross-sectional and longitudinal correlations were found between these MRI metrics and the number of Cord T2-visible lesions.

Brain NAWM MD (P = 0.03) and Brain Volume (P < 0.001) also changed in patients.

There was no significant correlation between Cord and Brain MRI metrics at both time-points, as well as between their changes occurred over the follow-up.

Baseline Cord Cross-Sectional Area (r = -0.40, P = 0.01) and FA (r = -0.40, P = 0.03) correlated with increase in disability at follow-up.

This study shows that both progressive tissue loss and injury to the remaining tissue occur in the Cervical Cord of MS patients.

And that these two components of Cord damage are not strictly interrelated, thus suggesting that a multiparametric MRI approach is needed to achieve more accurate estimates of such a damage.

MS Cord pathology also seems to be independent of concomitant Brain changes, to develop at different rates according to disease phenotype, and to be associated to medium-term disability accrual.

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Updated On: 7/16/2009