Multiple Sclerosis Manifestations

Objective
To examine the relationship between inflammation and Brain Atrophy in patients with a Clinically Isolated Syndrome (CIS) suggestive of Multiple Sclerosis (MS).

Methods
Monthly triple-dose Gadolinium (Gd/DTPA)-enhanced MRI scans over 6 months were obtained in 62 consecutive CIS patients with an abnormal baseline MRI scan. Subsequently MRI was performed at months 12 and 18.

Patients who developed a Clinically Definite MS (i. e., a second clinical episode) ended the study at the time of the relapse.

For each scan, the number and volume of newly active lesions (Gd-enhancement/new or newly enlarging T₂ lesion that did not enhance), and the number and volume of T₂ HyperIntense lesions (T₂-LL) and T₁-black holes (T₁-LL) were calculated.

The Percentage of Brain Volume Changes (PBVC) was assessed using a fully automated technique (SIENA; Structural Image Evaluation using Normalization of Atrophy).

Results
Twenty-four (39%) developed Clinically Definite MS by month 18. Thirty-eight (61%) were relapse-free 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].

Conclusions
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.

We investigated the relationship between emotional changes, Brain lesion burden and development of Multiple Sclerosis (MS).

Thirty-seven consecutive patients with Clinically Isolated Syndrome (CIS) were prospectively assessed with the Expanded Disability Status Scale (EDSS), the 21-item Beck Depression Inventory (BDI), the State-Trait Anxiety Inventory (STAI) and Gadolinium enhanced (Gd⁺) MRI scans.

BDI and STAI were also administered to 36 age-matched controls. Conversion to MS was defined as the occurrence of a clinical relapse. CIS patients were more likely to endorse symptoms of Anxiety and Depression than controls.

Baseline scores for Depression and Anxiety did not correlate with the Total Lesion Load (i.e., volume of Gd⁺, T₂ and T₁ lesions) and the number of Gd⁺+ lesions during the first six months of follow-up.

A positive correlation was found between severity of Depressive Scores and the lesion load in the Right Temporal region (P = 0.005).

After 33⁺/^-6 months of the study entry, patients who had a clinical relapse were more frequently Depressed (P = 0.001) than those relapse free.

Emotional disturbances are frequently observed in CIS patients and show a tendency towards a normalization in relapse-free patients.

The increased rate of Depressive Symptoms observed in patients who developed MS seems to result from a combination of Psychological and organic features.

The Lesion Load in the Right Temporal region is confirmed as a key area for developing Depressive Symptoms, even in the early phase of the disease.

The correlation between conventional MRI lesion load accumulation and Multiple Sclerosis clinical evolution is only modest.

The assessment of Brain Parenchymal Volume and of its changes over time may provide adjunctive MRI markers reflecting the more disabling aspects of Multiple Sclerosis pathology.

Magnetization Transfer (MT) MRI is sensitive to 'occult' Multiple Sclerosis-related Brain damage and might also contribute to overcome the clinical/MRI paradox.

In this study, we assessed the value of conventional and MT MRI-derived metrics in predicting the medium-term clinical evolution of patients with different Multiple Sclerosis phenotypes.

We studied 73 patients, with Relapsing/Remitting Multiple Sclerosis (n = 34), Secondary/Progressive Multiple Sclerosis (n = 19) and Clinically Isolated Syndromes suggestive of Multiple Sclerosis (n = 20), and 16 healthy subjects.

Brain dual-echo, T₁-weighted (only in patients) and MT MRI scans were obtained at baseline and after 12 months.

T₂-HyperIntense and T₁-HypoIntense lesion volumes, normalized Brain Volume and average lesion MT Ratio (MTR) were measured.

MTR Histograms from the Whole Brain Tissue were also obtained. Clinical Multiple Sclerosis evolution and Neurological disability were re-assessed in all patients after a median follow-up of 4.5 years.

A multivariate analysis was performed to establish which clinical and MRI-derived variables were significant predictors of Neurological deterioration at the end of the study period. At the end of follow-up, 34 patients showed significant Neurological deterioration.

The final multivariable model included average Brain MTR percentage change after one year [P = 0.02, odds ratio (OR) = 0.86] and baseline T₂-HyperIntense lesion volume (P = 0.04, OR=1.04) as independent predictors of medium-term disability accumulation (r2 = 0.23).

In this cohort of patients, abnormal values of average Brain MTR changes showed a relatively high specificity (76.9%) and positive predictive value (59.1%) for Expanded Disability Status Scale score deterioration in individual cases.

In patients with Multiple Sclerosis, a comprehensive estimation of the short-term changes of both conventional and MT MRI-detectable lesion burden might provide useful prognostic information for the medium-term clinical disease evolution.

Multiple Sclerosis is an Immune-mediated Inflammatory DeMyelinating Disease of the Central Nervous System clinically characterized by relapses and remissions of Neurological Disturbance.

A typical relapse, exemplified by Optic Neuritis, increases in severity over a week or two and after approximately one month begins to remit. Resolution takes place over the course of two to three months.

In the early stages, clinical recovery is virtually complete, though persistent abnormalities of Conduction can usually be detected by Evoked Potential techniques and persistent structural abnormalities can be detected by Magnetic Resonance Imaging (MRI).

These techniques, together with CerebroSpinal Fluid examination for OligoClonal Bands IgG, provide supporting evidence for the diagnosis which, in the absence of a specific test, nevertheless remains primarily clinical.

The course of the disease is very variable, but after a number of years Neurological Deficit begins to accumulate after each relapse.

In most patients, the Relapsing/Remitting phase of the disease is followed by a phase of continuous progression of Disability.

Cognitive Disturbances can be detected in many patients even quite early in the course of the illness.

• Deficits in Attention, Memory and Executive Skills may be prominent and tend to become increasingly prominent as Neurological Deficit increases, although this is not always the case.

There is some correlation between the extent of MRI abnormalities in the Cerebral White Matter and the severity of Cognitive Deficit.

Depression and Anxiety are commonly experienced but are poorly correlated to the Lesion Load seen on MRI.

In contrast, the much rarer Psychotic Symptoms: Euphoria and Emotional Lability are closely linked to the severity of White Matter Disease.

Background
Magnetization Transfer (MT) Magnetic Resonance Imaging (MRI) can provide in vivo quantitative estimates of microscopic tissue damage in Normal-Appearing White Matter (NAWM) and Gray Matter (GM) from patients with Multiple Sclerosis (MS).

Objective
To determine whether a one-time MT MRI can provide markers of short-term disease evolution in patients with Relapsing/Remitting MS.

Design, Setting, & Patients
Eighteen-month observational study. NeuroImaging Research Unit, Scientific Institute and University Ospedale San Raffaele. Twenty-two patients with untreated Relapsing/Remitting MS.

Main Outcome Measures
Relapse rate; disability according to the Expanded Disability Status Scale (EDSS); dual-echo, 2-dimensional gradient echo with and without a saturation MT pulse and T₁-weighted MRIs of the Brain; and MT Ratio (MTR) Histograms for NAWM and GM.

Results
During the study period, 13 patients (59%) experienced 25 relapses. The median EDSS score was 1.25 (range, 0-3.5) at study entry and 1.75 (range, 0-3) at study exit.

Significant, although moderate, correlations were found between average GM MTR values at baseline and EDSS changes during the study period (r = -0.44; P = .04).

A trend was observed for the correlation between NAWM MTR values at baseline and the EDSS changes throughout 18 months (r = -0.42; P = .05).

For the relation between EDSS changes and baseline GM MTR, the slope of the regression line was -0.5 (95% confidence interval, -1.0 to 0.0), indicating that a decrease in the baseline GM MTR of 1% predicted an increase in the EDSS score of 0.5 point throughout the 18 months.

Conclusion
This study indicates that a "snapshot" MT MRI assessment detects subtle Brain tissue changes that are associated with short-term disability accumulation in patients with Relapsing/Remitting MS.

Background And Purpose
A Triple-Dose (TD) of Gadolinium chelate is highly sensitive approach for detecting lesion activity in Multiple Sclerosis (MS).

However, individual TD injections do not provide data on the severity of the pathologic process in a population of lesions, and its clinical use is limited by the cost-benefit considerations.

Our aim was to determine whether the use of three subsequent single doses (SD) of a Gadolinium chelate in Brain MR imaging is useful in detecting MS lesions with different patterns of enhancement.

Methods
In 10 patients, T₁-weighted spin-echo images were acquired before and after three intravenous administrations of 0.1 mmol/kg of Gadodiamide.

Results
In all patients, SD images showed six enhancing lesions; double-dose (DD) images, 13; and TD images, 22. Differences between SD and TD and between DD and TD were significant (P < .018).

Six lesions (27%) enhanced with all the three doses; seven (32%), with both DD and TD; and nine (41%), with only TD.

Proportions of patients with at least one enhancing lesion were, for SD, four of 10; DD, seven of 10; and TD, nine of 10.

In defining active disease in these nine patients, we needed only 19 SDs versus the 30 SDs that would have been needed if individual TD injections were used.

Conclusion
With three subsequent SD injections, the number of enhancing lesions progressively increases.

This approach allows the distinction of three levels of enhancement, and it reduces the amount of contrast agent needed to distinguish patients with active MS from those with nonactive MS.

Objective
To assess the time course of Brain Atrophy and the difference across clinical subtypes in Multiple Sclerosis (MS).

Methods
The percent Brain Volume Change (PBVC) was computed on existing longitudinal (2 time points) T₁-weighted MRI from untreated (trial and nontrial) patients with MS.

Patients (n = 963) were classified as Clinically Isolated Syndromes suggestive of MS (CIS, 16%), Relapsing/Remitting (RR, 60%), Secondary/Progressive (SP, 15%), and Primary/Progressive (PP, 9%) MS.

The median length of follow-up was 14 months (range 12-68).

Results
There was marked heterogeneity of the annualized PBVC (PBVC/y) across MS subtypes (p = 0.003), with higher PBVC/y in SP than in CIS (p = 0.003).

However, this heterogeneity disappeared when data were corrected for the baseline Normalized Brain Volume.

When the MS population was divided into trial and nontrial subjects, the heterogeneity of PBVC/y across MS subtypes was present only in the second group.

Due to the higher PBVC/y values found in trial data in CIS (p = 0.01) and RR (p < 0.001).

The estimation of the sample sizes required for demonstrating a reduction of Brain Atrophy in patients in a placebo-controlled trial showed that this was larger in patients with early MS than in those with the Progressive forms of the disease.

Conclusions
This first large study in untreated patients with Multiple Sclerosis (MS) with different disease subtypes shows that Brain Atrophy proceeds relentlessly throughout the course of MS.

With a rate that seems largely independent of the MS subtype, when adjusting for baseline.