The contribution of Magnetic Resonance Imaging techniques to the clinical prognosis of Multiple Sclerosis.

Magnetic Resonance Imaging (MRI) is a diagnostic technique with a high sensitivity for the detection of lesions, but with a poor pathological specificity.

In the case of Multiple Sclerosis (MS), the improvement of diagnostic efficacy depends on a careful analysis of the clinical presentation.

And the use of increasingly stringent MRI criteria aimed at improving the specificity of the conventional MRI T₂ sequences.

New sequences such as Fast Spin-Echo (also called Turbo Spin-Echo) and FLAIR (Fluid Attenuated Inversion Recovery, a method derived from inversion recovery) have improved the visualization of Lesions.

MRI can under certain conditions be used to monitor the evolution of MS. Acute-phase monitoring is focused on observed changes in disease activity.

Such as the appearance, recurrence or extension of lesions after i.v. injection of contrast medium, i.e., Gadolinium (Gd)-enhanced MRI.

In the chronic phase, the lesion is the aspect used as the monitoring criterion. However, MRI is still only a secondary criterion in Phase III Therapeutic Trials due to its insufficient correlation with the disability.

In Neurological daily practice, conventional MRI is only of limited interest at the individual level in patient follow-up, as its prognostic value is poor.

Moreover, the difficulty in determining the Lesion Load can only be excluded in the context of clinical trials, in which certain methodological precautions are taken.

This is why techniques other than MRI are being investigated to obtain a better correlation with the clinical course of the disease.

For instance the quantification of 'Black Holes' on T₁ weighted images, and the measurement of Cerebral and Spinal Atrophy.

Adapted MRI techniques allow a weighted signal to be obtained:

1. Diffusion Imaging - via the movement of water
2. Magnetization Transfer Imaging - by the complexity of the molecular structure
3. Spectroscopic Imaging - by chemical shift
4. Functional MRI - by local Oxygenation

These new MRI techniques allow a more precise assessment of the pathological mechanisms involved in MS.

Such as Edema, Blood-Brain Barrier break-down, DeMyelination, Gliosis, Cellular infiltration and Axonal Loss.

They provide a better means of establishing the correlation between clinical impact and the destructive nature of the MS lesion.

The importance of Axonal Loss has recently been confirmed in MS by analyzing MRI Spectroscopic and NeuroPathological findings.

In addition to Magnetization Transfer Imaging, MR Diffusion Imaging and Functional MRI are being intensively studied in order to assess their contribution to the study of reversibility of the degenerative process.

Magnetization Transfer Imaging (MTI) is a Magnetic Resonance Imaging (MRI) technique that is now used in Multiple Sclerosis (MS) studies, and is thought to have a higher pathological specificity than conventional T₂-weighted imaging.

This review outlines the correlations between Magnetization Transfer (MT) metrics and other MRI abnormalities in the study of individual MS lesions and in the assessment of MS disease burden.

MTI studies of individual MS Lesions confirm the pathological heterogeneity of T₂-weighted MRI abnormalities and the potential role of unenhanced T₁-weighted HypoIntensities as specific markers of localized severe White Matter disruption.

Correlative cross-sectional and longitudinal studies using MTI and Gadolinium (Gd)-enhanced MRI reveal that MTI findings may vary in lesions with different patterns of enhancement.

And that MTI abnormalities are closely related to the onset and recovery of Blood-Brain Barrier disruption in new MS Plaques.

MTI lesion load (LL) is highly correlated with T₂-weighted MRI LL, but it has a limited reliability as a measure of MS disease burden.

On the contrary, measures obtained from MTI scans using whole-Brain Histogram analysis are highly correlated with the extent of MS abnormalities on conventional MRI scans, and predict patients' clinical Disability well.

Since they are sensitive to the amounts of both macro- and microscopic MS disease burden in the whole Brain and in specific regions.

The correlations between MTI metrics and conventional MRI findings suggest that:

1. MTI is sensitive to different stages of lesion pathology and pathological evolution in MS patients
2. MT Histogram analysis can provide a more global assessment of MS disease burden, since it encompasses both macro- and microscopic MS pathology

MRI is very sensitive in showing MS lesions throughout the CNS. Using MRI for diagnostic purposes, however useful, is a complex issue.

Because of limited specificity of findings and a variety of options as to when, how, and which patients to examine. Comparability of data and a common view regarding the impact of MRI are needed.

Following a review of the typical appearance and pattern of MS Lesions including differential diagnostic considerations, we suggest economic MRI examination protocols for the Brain and Spine.

Recommendations for referral to MRI consider the need to avoid misdiagnosis and the probability of detecting findings of diagnostic relevance.

We also suggest MRI classes of evidence for MS to determine the diagnostic weight of findings and their incorporation into the clinical evaluation.

These proposals should help to optimize and standardize the use of MRI in the diagnosis of MS.

Initial enthusiasm about the role of Magnetic Resonance Imaging (MRI) in the diagnosis of Multiple Sclerosis decreased substantially with the notion that:

1. Lesions of various pathological origins may resemble DeMyelinating plaques.

2. A dissemination of Lesions throughout the Brain is not unique for Multiple Sclerosis but may even be a "normal" finding.

Current experience still does not allow the identification of the Etiology of a single HyperIntensity but has identified multiple features of Multiple Sclerosis related signal abnormalities which, in combination, provide rather high diagnostic accuracy.

Useful characteristics include the distribution of lesions such as a strictly PeriVentricular, InfraTentorial or JuxtaCortical location, and involvement of the Corpus Callosum.

The presence of contrast enhancement in some but not all lesions - that is, evidence of both old and new lesions - provides additional diagnostic support. Improved instrumentation for imaging of the Spine further extends the diagnostic options.

IntraMedullary signal abnormalities are detected with increased sensitivity and may disclose the presence of multiple lesions even in patients with an equivocal or a Negative MRI of the Brain.

The high sensitivity to plaques and the opportunity to simultaneously rule out other gross morphological damage justifies the use of MRI as the primary diagnostic modality in the evaluation of Multiple Sclerosis.

Magnetic Resonance (MR) Diffusion imaging is a useful technique with which to increase our understanding of pathologic damage to the Central Nervous System.

To fully quantitate Diffusion and Anisotropy in the Spinal Cord, as in other tissues, it is necessary to determine the Diffusion Tensor.

If Spinal Cord Diffusion is assumed to be cylindrically symmetric and the orientation of the Cord in the gradient frame is known, then it is shown that full quantification is possible from only three images, two of which are Diffusion-weighted.

Mean Diffusivity and volume ratio were determined in the normal Cord of four healthy volunteers and in seven Cord lesions of three patients with Clinically Definite Multiple Sclerosis (MS), who had locomotor disability suggesting the presence of Spinal pathology.

MS Cord Lesions exhibited Increased Mean Diffusivity reflecting structural damage to the Cord White Matter.

Quantification of Diffusion and Anisotropy using Spinal Cord Diffusion imaging provides new structural information in relation to Spinal Cord pathology in vivo.

Small Spinal Cord lesions, even if clinically significant, can be due to the low sensitivity of some pulse sequences.

We compared T₂-weighted Fast (FSE), and Conventional (CSE) Spin-Echo and Short-Tau Inversion Recovery (STIR)-FSE overlooked on MRI sequences to evaluate their sensitivity to and specificity for lesions of different types.

We compared the three sequences in MRI of 57 patients with Cervical Spinal symptoms. The image sets were assessed by two of us individually for final diagnosis, lesion detectability and image quality.

Both readers arrived at the same final diagnoses with all sequences, differentiating four groups of patients.

• Group 1: (30 patients, 53%), with a final diagnosis of Multiple Sclerosis (MS). DeMyelinating lesions were better seen on STIR-FSE images.

  On which the number of lesions was significantly higher than on FSE, while the FSE and CSE images showed approximately equal numbers of lesions; additional lesions were found in 9 patients.

  The Contrast-To-Noise Ratio (CNR) of 17 DeMyelinating lesions was significantly higher on STIR-FSE images than with the other sequences.

• Group 2: 19 patients (33%) with Cervical pain, 15 of whom had disc protrusion or herniation.

  Herniated discs were equally well delineated with all sequences, with better Myelographic effect on FSE.

  In five patients with intrinsic Spinal Cord abnormalities, the conspicuity and demarcation of the Lesions were similar with STIR-FSE and FSE.

• Group 3: 4 patients (7%) with Acute Myelopathy of unknown Etiology. In two patients, STIR-FSE gave better demarcation of lesions and in one a questionable additional lesions.

• Group 4: 4 patients (7%) with miscellaneous final diagnoses.

STIR-FSE had high sensitivity to DeMyelinating lesions, can be considered quite specific and should be included in Spinal MRI for assessment of suspected DeMyelinating Disease.

Magnetic Resonance Spectroscopy allows in vivo NeuroChemical exploration of Multiple Sclerosis (MS) lesions and Normal-Appearing White Matter (NAWM) on MRI.

It gives insights into PathoPhysiology:
1. Inflammation
   • increase of Choline
2. Recent DeMyelination
   • Increase in Lipids & Choline
3. Axonal Dysfunction
   • Decrease of NAA
4. Gliosis
   • Increase of MyoInositol

The Spectroscopic profile of Lesions is not specific to MS. Therefore MRI remains the first investigation to perform when MS is suspected.

However, Spectroscopy is a sensitive, reproducible, non invasive tool which may provide an index of activity.

In the future, Spectroscopy may contribute in homogenizing patient selection for clinical trials and might be used, in association with MRI, to evaluate therapeutic efficiency.

Spectroscopy might also influence therapeutic choices by identifying the prevailing lesional mechanism: Inflammatory, DeMyelination, Axonal destruction, or Gliosis.

Objectives
Leber's Hereditary Optic Neuropathy (LHON) is a Mitochondrial Disease leading to bilateral loss of Central Vision and severe Optic Nerve Atrophy.

A subtype of LHON presents additional clinical and MRI aspects indistinguishable from those of Multiple Sclerosis (MS) (LHON-MS). In patients with LHON or LHON-MS an assessment was made of:

1. Severity of Optic Nerve damage
   - using MRI and Magnetization Transfer Imaging (MTI).

2. Presence and extent of macroscopic & microscopic pathology in the Brain and Cervical Cord
   - using MRI and MT Ratio (MTR) and Mean Diffusivity () Histogram analysis.

Methods
Ten patients with LHON, four with LHON-MS, and 20 age and sex matched healthy controls were studied.

For the Optic Nerve and the Brain, dual-echo Turbo Spin Echo (TSE), T₁ weighted spin echo, and MT images were obtained.

For the Brain, fast Fluid Attenuated Inversion Recovery (fast-FLAIR) and Diffusion weighted images were also obtained.

For the Cervical Cord, fast Short Tau Inversion Recovery (STIR) and MT images were obtained. The volume and the average MTR value of both the Optic Nerves were measured.

MTR and Histograms of the Normal Appearing Brain Tissue (NABT) and MTR Histograms of the whole Cervical Cord tissue were created.

Results
The mean values of Optic Nerve volumes and MTR were significantly lower in patients with LHON than in healthy controls.

Mean NABT-MTR Histogram peak height was significantly lower in patients with LHON than in controls, whereas no significant difference was found for any of the Cervical Cord MTR Histogram derived measures.

Average Diffusivity () was higher in patients with LHON than in controls. Optic Nerve volume and MTR value and mean NABT-MTR were lower in patients with LHON-MS than in those with LHON.

Conclusions
The severity of Optic Nerve pathology in LHON is measurable in vivo using MRI and MTI.

MTR and Histogram analysis suggests that microscopic Brain damage occurs in LHON and that it is more severe in the MS-like form of the disease.

Magnetization Transfer (MT) imaging is a technique that enables measurements to be extended beyond those in conventional MR imaging sequences.

Since its introduction, MT imaging has become a popular tool, partly because of its potential to change tissue contrasts, and partly because of its capacity to characterize tissues in a quantitative manner.

MT imaging also has become particularly popular in the field of Multiple Sclerosis. Using this technique, a wealth of information has been generated on the natural history of the disease.

This article explains the physical basis of MT imaging, describes applications of the technique in MS patients, and discusses the limitations of the technique in terms of standardization.

Objective
To explore the value of Magnetization Transfer Imaging (MTI) in judging microscopic lesions in Normal-Appearing White Matter of Multiple Sclerosis (MS).

Methods
Forty-one patients with Brain MS, 17 males and 24 females, aged 13 approximately 65, and 21 healthy people, 8 males and 13 females, aged 18 approximately 57, used as controls underwent Magnetic Resonance Imaging (MRI) using 3D-spoiled grass (3D-SPGR) series, to scan the Whole Brain with saturated pulses on and off respectively.

The signal values were measured directly in the pictures of these 2 series.

The formula MTR = (M(0)-MS)/M(0) x 100% was used, where M0 represents the signal value of region of interest with the saturated pulses off, and MS represents signal value of region of interest with the saturated pulses on, to calculate the MTR value.

With reference to T₂ WI imaging, the MTR values of 17 Regions Of Interest (ROI) in the Normal-Appearing Brain White Matter, including:

The White Matter of Pons, Bilateral Cerebellar Peduncles, Knees of Internal Capsules, Splenium and Genu of Corpus Callosum, and the White Matter by the Anterior Horn and Posterior Horn of Lateral Ventricle, Body of Lateral Ventricle, and deep in the Frontal and Parietal Lobes, were measured.

The average MTR value of the 17 ROI was used to represent the MTR value of the Whole Normal-Appearing Brain and used to make comparison with that of the healthy samples statistically.

Results
Compared with those of the healthy samples, the average MTR values of each ROI of the MS patients were lower at different degrees.

The difference in the MTR values of the White Matter of Splenium of Corpus Callosum, and by Lateral Ventricles and deep in Parietal Lobe were especially bigger.

The MTR value of the Whole Brain White Matter in the healthy persons ranged from 22.76% to 25.42%, with an average value of 23.97%, both significantly higher than those of the MS patients (19.45% to 24.15%, and 22.44% respectively, both P < 0.05).

Conclusion
MTI can be used to detect the microchange of Normal-Appearing White Matter in MS. MTR is a sensitive indicator to reflect the damage of structure of tissues.

Introduction
Multiple Sclerosis (MS) is a chronic DeMyelinating disorder of the Central Nervous System, characterized by the presence of inflammatory lesions.

To analyze the BioChemical profile of the DeMyelinating lesions of the initial forms of MS (Remitting/Relapsing).

By analyzing the Proton Magnetic Resonance Spectra (₁H MRS) to characterize the process of DeMyelination and relate it to the metabolites and clinical variables analyzed.

Patients And Methods
We analyzed the largest DeMyelinating lesions in eight patients with Remitting/Relapsing MS (RRMS) using the technique of single volume ₁H MRS (VOI) with short echo time.

The Spectra of the White Matter of two healthy control were used as reference.

Results
NAA/Cr and NAA/Cho value ratios decrease and mI/Cr one increase in all Spectra lesions as compared to healthy controls. In four of the eight patients, the Cho/Cr was higher than in the controls.

Qualitative and quantitative differences in the resonances of MacroMolecules were observed, related to the BioChemistry of the process of DeMyelination.

These differences in NAA/Cr, Cho/Cr, mI/Cr and MacroMolecules probably represent different stages in the evolution of the plaques.

Conclusion
MRS is a non invasive technique able to observe biochemical variations related to the evolution process of DeMyelination.

Activity of the lesion is shown by the increment of resonances around 0.9 1.3 ppm. An increase in mI seems to occur at an early stage of DeMyelination and later the NAA is reduced.

The initial forms of MS show metabolic alterations in the plaques which are similar to the most advanced forms of MS.

The Brain Water Fraction (R), the Brain Water Transverse Relaxation Time (T₂), the Atrophy index (alpha) and the absolute concentration of the principal Brain metabolites (NAA, Cho and Cr) were measured.

By localized Proton Magnetic Resonance Spectroscopy in the Occipito-Parietal Cortex (mainly Gray Matter) of 15 Relapsing/Remitting (R-R) Multiple Sclerosis (MS) patients, 15 Secondary/Progressive (SP) MS patients and 8 healthy subjects.

Significantly lower values of N-AcetylAspartate (NAA), Creatine (Cr) and the NAA/Cr ratio in the Occipito-Parietal Cortex were detected in SP MS patients than in R-R MS and control subjects (p < 0.01).

Moreover, MS patients showed shorter T₂ water relaxation times and reduced Brain water fraction compared with controls.

Higher Atrophy indices were also detected in the mainly Occipito-Parietal Gray Matter of MS patients, particularly in those with the Progressive form.

These findings suggest that the pathological process in MS is not limited to either White Matter lesions or Normal-Appearing White Matter but extends into the Cortical Gray Matter (Occipito-Parietal), particularly in the Progressive form of the disease.

This can involve changes in Neural metabolism or Neural shrinkage and Neuron loss.

The significant increase in Atrophy indices could be the expression of the relatively higher CerebroSpinal Fluid signal from the Occipito-Parietal Cortex, even in the absence of obvious Cortical Atrophy.