Magnetic Resonance Imaging (MRI)
In Multiple Sclerosis

The aim of the study was to evaluate the predictive power of baseline Gadolinium (Gd) enhanced MRI in relation to subsequent clinical and MRI activity.

Sixty eight patients with clinically definite Relapsing/Remitting Multiple Sclerosis had a baseline Gd enhanced MRI and were followed up clinically and by monthly Gd enhanced MRI for six months.

The occurrence of relapses during the follow up period was predicted by the presence of at least one enhancing Lesion on the baseline MRI (P < 0.05).

The number and volume of enhancing lesions at baseline were significantly associated with both enhancing lesions observed during the follow up period (P < 0.0001) and the accumulation of abnormality on T₂ weighted images (P < 0.0001).

Moreover, the presence of three or more enhancing lesions at baseline scan was consistently associated with the development of permanent abnormalities on T₂ weighted images six months later.

The study suggests that the number and volume of Gd enhancing lesions at a single examination are strong short term predictors of subsequent clinical and MRI activity.

Fifty-three patients with Relapsing/Remitting Multiple Sclerosis who had monthly Gd (Gadolinium) enhanced MRI (Magnetic Resonance Imaging) and clinical evaluation, were divided into two subgroups:

1) patients with a clinical relapse, treated with IVMP (IntraVenous MethylPrednisolone) and at least one enhancing lesion on MRI.

2) patients who did not have a clinical relapse but with at least one enhancing Lesion on MRI.

In group 1, we evaluated the number and volume of enhancing lesions on the scan before and three scans after IVMP therapy; in group 2, we considered the first scan with enhancing lesions and the subsequent three scans.

The mean number and volume of enhancing lesions on the first scan was significantly higher in patients with clinical relapse compared to patients without clinical relapse.

In group 1, we found a consistent reduction in the first scan following Steroid treatment which returned to initial levels at the following scan.

Both volumetric and numerical evaluation are appropriate MRI outcome measures in monitoring therapeutic trials.

In this study, 14 patients with either Relapsing/Remitting or Secondary/Progressive Multiple Sclerosis (MS) were scanned monthly using Gadolinium enhanced Magnetic Resonance Imaging (MRI).

At the start of the study and at 1 year follow up, T₂-weighted and Magnetization Transfer (MT) scans were also performed.

The correlation between the frequency and extent of enhancement and changes of lesion load over a 1 year period on T₂-weighted and MT images were assessed.

For all patients, and for the Relapsing/Remitting patients only, the number and volume of enhancing lesions per month showed no significant correlation with the change between baseline and 1 year follow up of lesion volumes on T₂ and MT images.

However, strong correlations were found between the number and volume of Gadolinium enhancing Lesions with changes of T₂ (r = 0.93, P = 0.02) and MT (r = 0.82, P = 0.04) lesion loads in patients with Secondary/Progressive MS.

Strong correlations were also found between the lesion loads on T₂-weighted scans and on MT images both at baseline and at 1 year follow up (r = 0.83, P = 0.003).

In addition, the changes in lesion load over 1 year, detected using the two techniques, were moderately correlated (r = 0.51, P = 0.05).

This study provides further evidence that the pathological processes in MS are at different stages in Relapsing/Remitting and Secondary/Progressive MS.

It also suggests that the effectiveness of recovery mechanisms within lesions might be one of the major factors responsible for such a difference.

We examined the effect of Copolymer-1 (Cop-1) on Magnetic Resonance (MR) Imaging changes in 10 patients with Relapsing/Remitting Multiple Sclerosis (RRMS).

Monthly Gadolinium (Gd)-enhanced MR imaging was performed for 9 to 27 months in the pretreatment period followed by 10 to 14 additional months during Cop-1 treatment.

MR images were evaluated by two radiologists (F.S. and R.C.P.) masked to the scan date.

We found a 57% decrease in the frequency of new Gd-enhancing lesions and in the mean area/month of new Gd-enhancing lesions in the Cop-1 treatment period compared with the pretreatment period (0.92 versus 2.20 lesions per month and 22 mm2 versus 43 mm2 area/month; p = 0.1, Wilcoxon signed rank test).

Percentage change in lesion load area on T₂-weighted images showed a decrease in the accumulation of Lesion area during treatment, which was significant for the patient group with a longer pretreatment period (p = 0.05, Friedman test).

These results demonstrate a reduction in the number of new Gd-enhancing lesions and in the lesion load during Cop-1 treatment compared with the preceding period without therapy and are suggestive of an effect of Cop-1 on MR abnormalities observed in Multiple Sclerosis.

Magnetic Resonance Imaging (MRI) provides a powerful tool for assessing disease activity in Multiple Sclerosis (MS), and its role as a surrogate marker for monitoring treatment efficacy is now becoming established.

The most commonly used MRI parameters in treatment trials:

1. Monthly Gadolinium-enhanced MRI
   • with the number of active lesions serving as the outcome measure
2. Annual lesion load quantification
   • in which change in MS lesion volume provides the MRI endpoint

We evaluated clinical/MRI correlations and the relationship between these two markers of disease activity in 73 patients with Clinically Definite MS.

Quantification of T₂ lesion load was performed at study entry and exit, with a median study duration of 11 months (range, 9 to 14 months).

Monthly post Gadolinium T₁-weighted images were acquired between these time points.

Lesion load at study entry was significantly correlated with the baseline Expanded Disability Status Scale (EDSS) score, but no significant longitudinal correlation was demonstrated.

The number of enhancing Lesions on the entry scan was predictive of subsequent relapse rate over the study duration and also correlated with the subsequent enhancing lesion activity over the study period.

A significant correlation was found between change in lesion load and disease activity on the monthly scans.

Our results suggest that annual lesion load quantification provides an efficient measure of ongoing disease activity, and this supports its application as a surrogate marker of disease evolution in Phase III Treatment Trials.

Six patients with early, mild, Relapsing/Remitting Multiple Sclerosis were studied with monthly Gadolinium-enhanced Magnetic Resonance Imaging scans for 8 to 11 months.

Numerous enhancing lesions were observed irrespective of clinical activity. Four of the 6 patients had one or more enhancing lesions present on each examination.

The other 2 patients had enhancing lesions noted in 7 and 9 of 11 months. In contrast, only two clinical exacerbations were observed during the study period.

Neither the exacerbations nor other changes in symptoms or signs correlated with occurrence of the enhancing Lesions. Enhancement generally persisted for less than 1 month.

The opening of the Blood-Brain Barrier as reflected by Gd enhancement on Magnetic Resonance Imaging may represent ongoing disease activity (Clinically Silent MS lesions) in patients with mild, Relapsing/Remitting Multiple Sclerosis who are clinically stable.

The frequency of these lesions appears to be sufficient to use as an outcome measure in clinical trials testing clinical efficacy in patients with early, Relapsing/Remitting Multiple Sclerosis.

Comment in: Ann Neurol 1992 Jan;31(1):116-7

Objective
Sequential MR imaging frequently shows disease activity (clinically silent new Brain lesions) in subgroups of patients with Multiple Sclerosis and therefore is valuable in monitoring the effects of treatment.

Monitoring of disease activity in patients being treated for Relapsing/Remitting Multiple Sclerosis will increase in importance as new and safe therapies are developed.

We studied sequential enhanced MR images of patients with early Relapsing/Remitting Multiple Sclerosis to define the MR features that indicate disease activity in this subgroup of patients and to compare MR imaging and clinical findings for this purpose.

Subjects And Methods
Seven patients with Relapsing/Remitting Definite Multiple Sclerosis were examined monthly for 4-12 months.

For each image, a standard repositioning protocol consisting of three images was used to ensure reproducibility of Axial (double oblique) image planes, planned according to internal landmarks.

A total of 58 unenhanced T₂-weighted and enhanced T₁-weighted MR images were obtained.

Results
MR images showed new enhancing lesions in six of the seven patients.

On 25 (43%) of the 58 enhanced T₁-weighted MR images, a total of 50 new enhancing lesions were observed, and on one image a re-enhancing lesion was seen.

The unenhanced T₂-weighted images showed corresponding abnormalities for 92% of the new enhancing lesions.

At follow-up, most lesions (86%) were enhanced on only one occasion: 4% were enhanced on more than two consecutive monthly MR examinations.

Forty-nine percent of the lesions seen on T₂-weighted images "disappeared" (beyond the resolution of the imaging system) after a mean follow-up of 3.5 months, especially Lesions that were initially smaller than 5 mm.

During the study, only five clinical relapses occurred in three patients (all at times when MR images showed contrast-enhancing lesions), and fixed disability did not increase.

On 21 additional occasions, MR images showed new enhancing or re-enhancing lesions in patients who were clinically stable at the time (4.2 times more clinically silent disease activity).

Conclusion
Our results suggest that contrast-enhanced MR imaging is more sensitive than clinical monitoring for detecting new disease activity in patients with Relapsing/Remitting Multiple Sclerosis and that MR imaging might be useful in the evaluation of therapeutic regimens.

Objective
To evaluate whether recombinant human Interferon-ß-1a significantly affects disease activity as measured by a reduction in the number and volume of Gd enhancing lesions on monthly MRI.

The study also evaluated the effect on six-monthly T₂ weighted abnormality and relapse frequency.

Methods
After a baseline scan and a six month pretreatment period, 68 patients were randomly assigned to receive either 3 MIU or 9 MIU of Interferon-ß-1a by subcutaneous injection three times a week for six months.

All patients were examined by Gd enhanced MRI every month in both pretreatment and treatment periods. The evaluation of Gd enhancing lesions was performed blind at the end of the study.

Results
The mean number of Gd enhancing lesions was higher during the pretreatment period than during treatment.

This difference was statistically significant for the two different dose subgroups (3.5 v 1.8, P < 0.001 for the 3 MIU group and 2.4 v 0.9, P < 0.001 for the 9 MIU group, corresponding to a reduction of 49% and 64% respectively).

The mean volume of Gd enhancing lesions also significantly decreased by 61% (3 MIU group) and 73% (9 MIU group).

These reductions were evident only after the first month of treatment. The six-monthly rate of new lesions as seen in T₂ weighted images showed a similar trend of reduction with treatment (65% and 70% respectively).

Lesion volume on T₂ scans significantly increased during the pretreatment period whereas it remained almost stable during the treatment period in both groups.

Clinical relapse rate was significantly reduced by treatment (53% for the 3 MIU group, P < 0.001; 69% for the 9 MIU group, P < 0.001).

Conclusion
Interferon-ß-1a seemed effective in reducing disease activity in Relapsing/Remitting Multiple Sclerosis at both the doses used.

Comment in: J Neurol NeuroSurg Psychiatry 1996 Sep;61(3):239-41

Introduction
We performed this study to define the sensitivity of delayed Gadolinium-enhanced Magnetic Resonance Imaging (MRI) in detecting active lesions in the Brains of patients with Multiple Sclerosis (MS).

Material And Methods
T₁-weighted images were obtained in 27 patients with Relapsing/Remitting or Secondary/Progressive MS before, 5-7 min and 20-30 min after the injection of 0.1 mmol/kg Gadolinium-DTPA.

Results
One-hundred-and-three enhancing lesions were found on the early and 110 on the delayed scans (increase=6.4%).

Six patients had 8 additional lesions in the delayed scans, while 1 patient had 1 more lesion on the early scan.

Two of the 12 (17%) patients with no enhancing lesions on the early scans had 2 enhancing lesions on the delayed scans.

The average increase of enhancing Lesion detection with delayed scanning was 14.5% for those patients who already had enhancing lesions on the early post-contrast scans.

A significant increase of the enhancing Lesion volume was found with delayed scanning (P=0.004).

Conclusion
These data indicate that it is possible to increase MRI sensitivity in detecting MS active lesions by delaying the scanning after Gadolinium injection.

Treatment with MethylPrednisolone reduces the duration and severity of clinical relapses in Multiple Sclerosis (MS), while reducing the number of Gadolinium-enhancing lesions on T₁-weighted MRI.

We performed serial MRI imaging after MethylPrednisolone treatment to see whether suppression of enhancement persists and whether related abnormalities on T₂-weighted images disappear at follow-up.

Thirteen patients with definite MS received a total of 31 courses of MethylPrednisolone over an average period of 50 weeks.

Gadolinium-enhanced MRI was obtained before and after treatment, then at monthly intervals, using a standardized repositioning and imaging protocol.

Two experienced readers in conference defined the number of active (Gadolinium-enhancing and new or enlarging nonenhancing) lesions. We detected 609 active lesions on 195 examinations.

Directly after treatment the reduction in the number of enhancing lesions was 78%, indicating restoration of the BBB and suppression of Inflammation.

It was uncommon for a Lesion which stopped enhancing to show enhancement on a subsequent examination.

No beneficial effect was observed on the rate of disappearance of related abnormalities on T₂-weighted images, indicating persistent change such as Edema, cellular infiltration or DeMyelination.

Moreover, in 89% of cases, an increase in the number of active lesions was observed before new clinical activity, if any, was observed (on average 52% earlier).

MRI enabled us to demonstrate that the duration of the effect of MethylPrednisolone treatment is temporary (on average 9.7 weeks).

It is now well established that clinically stable patients with Relapsing/Remitting Multiple Sclerosis have ongoing disease activity when evaluated by serial Gadolinium-enhanced (Gd-DTPA) Magnetic Resonance Imaging (MRI) scans.

Despite this, the relationship between clinical disease and MRI lesions, though suspected, has not been extensively documented.

The relationship between Gd-DTPA MRI lesions and clinical disease was examined in this study of 9 patients with mild Relapsing/Remitting Multiple Sclerosis (Expanded Disability Status Scale [EDSS] < 3.5) who had 24 to 37 monthly Gd-DTPA MRI scans, Neurological Examinations, and EDSS score assignments.

The area and frequency of Gd-DTPA Lesions were examined during months with and without clinical worsening as measured by EDSS. Forty-one episodes of clinical worsening were noted during the study.

A significant association was observed between these periods of clinical worsening and MRI parameters, including increases in total number, number of new lesions, and the total area of enhancement.

Logistic regression analysis showed a significant effect of the number and area of Gd-DTPA MRI lesions on both the onset and continuation of clinical worsening, confirming an important relationship between clinical disease and an increase in Cerebral Gd-DTPA MRI activity.

A relationship with long-term disability was suggested, but cannot be confirmed without longer follow-up of these patients.

Serial Brain MRI scanning is widely used for assessing Multiple Sclerosis disease activity in the evaluation of new therapies.

Traditionally, the Net Change in T₂-weighted lesion volume between paired scans has been used as a measure of disease progression and as a secondary endpoint in definitive clinical trials.

However, as the Net Change in T₂-weighted lesion volume reflects only the Difference between New and Resolved T₂-weighted lesions, this measure significantly under-represents the total T₂-weighted lesion activity.

Difference images produced by subtracting labelled T₂-weighted lesion volumes from Serial registered T₂-weighted scans, allows separate measurements of individual volumes of New and Resolving T₂-weighted lesions.

This may reflect underlying disease activity more sensitively.

We generated T₂-weighted difference images to define T₂-weighted lesion changes over 1 year for 19 patients with Relapsing Multiple Sclerosis.

The mean New T₂-weighted lesion volume change was three times greater than the mean Net T₂-weighted lesion volume change over the study period.

New T₂-weighted lesion volumes were more strongly correlated with T₁-weighted Gadolinium-enhancing lesion volumes (r = 0.72, P = 0.001) than were the Net T₂-weighted lesion volume changes (r = 0.45, P = 0.01).

Baseline T₂-weighted Lesion volume was more highly correlated with New T₂-weighted lesion volumes (r = 0.89, P < 0.0001) than with Net T₂-weighted lesion change (r = 0.47, P < 0.001).

There was a trend for patients who showed sustained clinical progression over the year to have a greater New T₂-weighted lesion volume than those who did not.

This difference was not seen with Net T₂-weighted lesion volume change. T₂-weighted lesion difference images should provide an additional and sensitive tool for monitoring disease activity in Multiple Sclerosis.