Multiple Sclerosis Lesions 4

Phase III definitive treatment trials of new Multiple Sclerosis (MS) therapies now routinely incorporate an annual Magnetic Resonance Imaging protocol.

With change in T₂-weighted Brain Lesion Load providing an important outcome measure.

To date the accepted strategy has been to perform a core imaging protocol on all patients in such studies. The aim of this study was to provide power calculations based on this MRI endpoint.

Serial MRI data from 128 patients with either Relapsing/Remitting (RR) or Secondary/Progressive (SP) MS were used.

To calculate sample size requirements using a repeated measures analysis of variance design. We provide sample size calculations based on various follow-up intervals and effect sizes.

Sample sizes for the SPMS cohort were substantially larger than for the RRMS group, reflecting the greater variance in lesion load changes between patients in the SPMS group.

With a follow-up of 3 years, we estimate that only 12 and 33 patients per arm are needed to show stabilization of MRI lesion load in the RRMS and SPMS groups, respectively.

Our results suggest that ongoing Phase III treatment trials are more than adequately powered to detect even subtle treatment effects. And indicate that incorporating measurements from longer follow-up durations increases power substantially.

We conclude that an annual imaging protocol provides a robust and powerful tool for assessing effects on the Radiological appearance of the disease process.

Purpose
To determine annual rates of volumetric changes in the whole-Brain Parenchyma of patients with Relapsing/Remitting and Secondary/Progressive Multiple Sclerosis (MS).

And test the hypothesis that these changes correlate with clinical Disability.

Materials And Methods
A computer-assisted segmentation technique with thin-section Magnetic Resonance (MR) imaging was used.

In 36 patients with MS (27 Relapsing/Remitting, nine Secondary/Progressive) and in 20 control subjects to quantify Brain and CerebroSpinal Fluid volumes.

To determine the degree of Brain atrophy, the percentage Brain Parenchyma Volume (PBV) relative to that of intraCranial contents was calculated.

Results
At the beginning of the study, the PBV was smaller in the MS group than in the control group (P = .007); Brain Parenchyma Volumes were similar.

The median rate of Brain Volume loss was 17.3 mL per year in patients with Relapsing/Remitting MS and 23.6 mL per year in those with Secondary/Progressive MS.

There was a negative correlation between Brain Atrophy and Expanded Disability Status Scale (EDSS) score in patients with Secondary/Progressive MS (r = -0.69, P = .004) and no correlation in patients with Relapsing/Remitting MS.

T₂ lesion volume did not correlate with Brain Atrophy in either group.

Conclusion
The correlation between Brain Atrophy and EDSS score was better in patients with Secondary/Progressive MS than in those with Relapsing/Remitting MS.

Axonal degeneration plays an important role in the accumulation of disability in patients with Multiple Sclerosis (MS).

Pathological studies have demonstrated Axonal damage, particularly in areas of acute inflammation and DeMyelination, and in chronic lesions.

Axonal loss and its progression, which is associated with Neurological Disability, has also been demonstrated by Magnetic Resonance Imaging (MRI) studies.

The mechanisms of Axonal loss are uncertain, but may involve Axonal degeneration secondary to DeMyelination, or damage to the Axonal cytoskeleton.

Inflammatory mediators, including Cytokines and ProteoLytic Enzymes may contribute to Axonal damage, as may Nitric Oxide.

Axonal destruction may also be due to Immune attack directed at Axonal components.

The realization that Axonal degeneration is a fundamental component of MS that may occur early in the disease course should alter the approach to management.

And open avenues to a more targeted ImmunoTherapy aimed at reducing the progression of disability.

We reviewed the Magnetic Resonance Imaging scans from 22 serial studies of 5 patients with Balo's Concentric Sclerosis collected during the past 3 years.

The data showed the concentric lesions did not occur simultaneously but developed step by step in a centrifugal direction.

The development of lesions was preceded by an enhancing ring relatively devoid of DeMyelination.

And was followed by progressive DeMyelination occurring mainly at the inner aspect of the enhancement.

The same process recurred on the edge of the previous enhanced zone.

Thus, an appearance of concentric rings with alternating DeMyelinated and relatively Myelin-preserved bands was formed.

Texture analysis was applied to MR images of the Spinal Cord in an attempt to quantify pathological changes that occur in Multiple Sclerosis (MS).

Texture features quantify macroscopic lesions and also the microscopic abnormalities that may be undetectable using conventional measures of lesion volume and number (Lesion Load).

Significant differences in texture between normal controls and MS patients were seen.

Texture differences were detected between normal controls and Relapsing/Remitting patients before detectable Spinal Cord Atrophy.

There was also significant correlation between texture and disability. The segmentation and texture analysis technique demonstrates intraobserver coefficients of variation ranging from 0. 6-8.2%.

Texture analysis has potential as a tool for monitoring changes associated with the development of Disability in patients with MS.

Reproducibility and sensitivity must be improved to use the technique for serial monitoring in individuals.

Magn Reson Med 42:929-935, 1999. Copyright 1999 Wiley-Liss, Inc.

The benefits of texture analysis of Magnetic Resonance images have been assessed in Multiple Sclerosis (MS) patients.

Out of thirty-two lesions identified in eight MS patients, nine were considered active, judging from their Gadolinium uptake.

Texture analysis allowed to obtain forty-two characterizing parameters for each lesion.

Using discriminant analysis as a statistical method allowed classification of lesions into two groups: active or non-active.

An attempt to classify their level of activity by using only co-occurrence matrices was unsuccessful.

Alternately, the same type of analysis performed on runlength analysis criteria allowed the accurate classification of 88% of active lesions and 96% of non-active lesions.

Using incremental discriminate analysis can reduce the number of useful parameters.

This method showed that among the 42 parameters, only 8 were highly significant and permitted an accurate classification.

Five of these parameters are runlength parameters, and three others are more directly related to global distribution.

The main interest of runlength parameters is to allow the demonstration that lesion structure is different in active and non-active plaques.

This preliminary work suggests that using texture analysis could be of interest in the follow-up of MS patients.

Because it provides an opportunity to identify active lesions without frequent Gadolinium injections.

Nuclear Magnetic Resonance (NMR) imaging is an established diagnostic medium to diagnose Multiple Sclerosis (MS).

In clinically stable MS patients, NMR detects silent disease activity, which is the reason why it is being used to monitor treatment trials, in which it serves as a secondary outcome parameter.

The absence of a clear correlation with clinical Disability, the so-called 'clinico-radiological' paradox, and the poor predictive value of NMR prohibit the use of NMR as a primary outcome parameter in clinical trials.

This is - among others - a result of the limited HistoPathological specificity of conventional, or 'T₂-weighted' imaging, the most commonly used NMR technique.

In this paper we review additional NMR techniques with higher tissue specificity. Most of which show marked heterogeneity within NMR-visible lesions, reflecting HistoPathological heterogeneity.

Gadolinium enhancement identifies the early inflammatory phase of Lesion development, with active Phagocytosis by Macrophages.

Persistently HypoIntense lesions on T₁-weighted images ('Black Holes') relate to Axonal Loss and Matrix destruction, and show a better correlation with clinical disability.

Marked prolongation of T₁ relaxation time correlates with enlargement of the ExtraCellular space, which occurs as a result of Axonal loss or Edema.

Axonal viability can also be measured using the concentration of N-AcetylAspartate (NAA) using NMR Spectroscopy.

This technique is also capable of showing Lactate and mobile Lipids in lesions with active Macrophages.

The multi-exponential behavior of T₂ relaxation time in Brain White Matter provides a tool to monitor the Myelin water component in MS lesions (short T₂ component).

As well as the expansion of the ExtraCellular space (long T₂ component).

Chemical exchange with macromolecules (e.g. Myelin) can be measured using Magnetization Transfer Imaging, and correlates with DeMyelination, Axonal loss and Matrix destruction.

Increased water Diffusion has been found in MS lesions (relating to Edema and an expanded ExtraCellular Space).

And a loss of Anisotropy may indicate a loss of Fiber orientation (compatible with DeMyelination).

Apart from the HistoPathological heterogeneity within focal MS lesions, the Normal-Appearing White Matter shows definite abnormalities with all quantifiable NMR techniques.

A decrease in the concentration of NAA, decreased Magnetization Transfer values and prolonged T₁ relaxation time values are probably all related to microscopic abnormalities, including Axonal damage.

This 'invisible' Lesion Load may constitute a significant proportion of the total lesion load but is not visible on conventional NMR.

Similarly, mechanisms for clinical recovery exist, which are not distinguished using MR imaging.

Therefore, it is highly unlikely that the clinico-radiological paradox will ever be solved completely. However, NMR provides an opportunity to sequentially measure tissue changes in vivo.

Using MR parameters with (presumed) HistoPathological specificity, the development of (irreversible) tissue damage can be monitored.

Which perhaps allows the identification of factors that determine lesional outcome in MS, since the absence of severe tissue destruction is prognostically favorable.

NMR monitoring of the extent to which such changes can be prevented by treatment will ultimately benefit the selection of future treatment strategies.

We investigated NeuroChemical abnormalities in the Normal-Appearing White Matter (NAWM) on MRI of patients with Optic Neuritis (ON) and compared them to those of patients with Multiple Sclerosis (MS).

Patients with ON (42) were classified into three groups according to abnormalities on Brain MRI. Patients with MS (55) were divided in two groups: Relapsing/Remitting MS (RRMS) and Secondary/Progressive MS (SPMS).

All patients underwent MRI of the Brain and localized Proton Magnetic Resonance Spectroscopy (MRS) of NAWM. The results were compared to those of 15 controls.

Patients with MS had significant abnormalities compared with controls and with patients with ON.

Patients with RRMS and those with ON had comparable MRS parameters, while patients with SPMS had significant SpectroScopic abnormalities in comparison with controls, but also with patients with RRMS.

These changes consisted of a decrease in N-AcetylAspartate, a Neuronal marker, which may reflect Axonal dysfunction and/or loss. MRS abnormalities were detected in 14 patients with ON (27%).

The main abnormalities consisted of a decrease in N-AcetylAspartate, an increase in Choline-containing compounds at long echo times, and the presence of free lipid peaks at short echo times.

MRS of the NAWM on MRI may prove useful for detecting NeuroChemical Brain abnormalities in ON not visible on MRI.

Purpose
To determine the relationship between T₂ lesion volume and either disability measurements or change in T₂ lesion volume over time in Multiple Sclerosis (MS).

Materials And Methods
Eighteen patients (age range, 26-53 years) with clinically proved Relapsing/Remitting MS were examined every 6 months for over 2 years.

Three-millimeter-thick contiguous images of the whole Brain were obtained. T₂ lesion volume was calculated with a highly reproducible volumetric computer method.

Results
A substantial annual increase in T₂ lesion volume, with a median annual increase of approximately 8%, was demonstrated.

However, there was no significant correlation between absolute T₂ lesion volume and either the absolute Expanded Disability Status Scale (EDSS) grade (P = .32) or the absolute Ambulation Index (AI) (P = .20).

In addition, no significant correlation between change in T₂ lesion volume and change in EDSS grade (P = .42) or AI (P = .37) was found. There was no significant correlation between T₂ lesion volume and duration of disease (P = .08).

Conclusion
There is no significant correlation between T₂ Lesion volume and standardized disability measurements despite a substantial increase in T₂ lesion volume over time.

Patients have an increase in total T₂ lesion volume in the Brain regardless of their clinical status or disability measurements.

T₂ lesion volumes as outcomes in therapeutic clinical trials on MS should be viewed as secondary outcomes rather than as surrogate markers of clinical responses.