Cesare Fieschi - Carlo Pozzilli

Prof. Freddi’s article illustrates in a clear and exhaustive manner the latest and most significant developments in the field of Multiple Sclerosis (MS), including possible causes and clinical and instrumental diagnosis, as well as present and future therapeutic strategies.
Among the various aspects, the article emphasises the crucial role acquired by Magnetic Resonance (MR) over the last few years and stresses its importance in the disease diagnostics, in the study of its pathogenic and prognostic aspects and in therapeutic monitoring (1). By allowing in vivo photographing of typical MS lesions, MR has in fact revolutionised the diagnostic routine for this disease. Its crucial role clearly emerges from the new Guidelines for the Diagnosis of MS recently compiled by the “International Study Group for the Diagnosis of Multiple Sclerosis”, headed by Prof. W.I. McDonald from the Royal College of Physicians in London (2) (Table 1).
The purpose of the new diagnostic criteria is to achieve early diagnosis of the disease, thus facilitating the recognition of its most typical aspects, also in monosymptomatic onset forms. All this proves particularly important today, if we consider the availability of new therapies, capable of slowing down the progression of the disease ever since its earliest stages. The guidelines provided by the new criteria supply indications as to timing and interpretation of the MR tests.
The crucial element for MS diagnosis continues to be the objective evidence of the disease “dissemination in time” and of its tendency to affect a number of functional systems (dissemination in space). Diagnostic categories are therefore reduced and the terms “clinically definite MS” and “probable MS” are no longer in use, having been replaced by “MS”, “non-MS” and “possible MS” for patients at risk of developing the disease and for whom a diagnostic doubt remains.
This simplification allows greater diagnostic clarity for medical practitioners and a greater understanding for patients. Besides offering greater support for the diagnosis of MS, the use of MR has made it possible to monitor both the natural history of MS and the effectiveness of new therapeutic products. We are now well aware that the MR images reflect the different stages of the damage affecting the Central Nervous System and that, for this reason, they have a predictive role as to clinical evolution. Indeed, it is well known that the existence of a significant lesion load upon disease onset and of “active” lesions, documented as a diagnostic strengthening factor following administration of a contrast medium, predicts a worse clinical outcome (3-6).
In this regard, a follow-up study at 10 years has shown that patients displaying a lesion load exceeding 3 cm3, at disease clinical onset, develop in 90% of cases a disability greater than 3 according to the Expanded Disability Status Scale (EDSS); on the other hand, when the lesion load at the onset is lower than 3 cm3, the risk of developing a disability greater than 3 according to the EDSS is equal to 27% (5).
Over the last years an extremely high number of MR data have been acquired on MS, especially within the numerous multicentric clinical trials conducted in Europe and North America. The International Federation of Multiple Sclerosis Societies (IFMSS) has recently funded a project for the creation of a MR Data Processing Centre, which is to work on the results of “therapeutic” researches on MS. This Centre, which is based in Munich, will be gathering clinical data relating to 20,000 patients affected by MS and will be able to process MR data relating to over 5000 people.
A statistical analysis of such data will make it possible to identify certain MR markers, which will allow prediction of disease progress in individual patients displaying similar pathologic features. These elements will in turn entitle us to decide whether a new treatment is effective without having to resort to clinical studies including control groups treated with placebo. In other words, the statistical analysis of this huge amount of data will provide us with a new methodological approach for the prediction of MS, for understanding its causes and for developing effective therapeutic strategies.
The use of MR in MS has allowed us to monitor the effectiveness of new therapeutic products, but it has also provided information as to the mechanisms underlying their therapeutic action. For instance, we have seen that current immunomodulating therapies, such as interferon beta and the copolymer, have a noticeable effect in repressing inflammatory lesions, with a reduction of the areas uptaking the means of contrast, but have little effect on axonal degeneration and atrophy processes. This can explain why these drugs can modify the evolution of the disease in the remitting-relapsing forms, but they certainly are less effective in progressive forms.
The worsening of disability in progressive forms is indeed the result of processes of a degenerative nature rather than of inflammation itself. In addition, the recent introduction of new non-conventional MR (Magnetization Transfer, Spectroscopy, Diffusion Imaging, etc.) and their employment in the study of the natural history of the disease have contributed to a greater understanding of the pathologic origins of MS. These techniques are integrated by functional MR that, compared to the traditional technique, also offers a “dynamic” evaluation of the brain areas as they relate to their specific function.
This is achieved by having the patient undergo tests aimed at stimulating/activating the areas under examination. In this way, it is possible to quantify tissue damage, provide information as to the functionality of the areas concern
ed and check on the effectiveness of tissue repairing mechanisms. This great interest and the large potentials offered by MR, especially in the field of demyelinizing diseases, has recently led the researchers of the II Faculty of Medicine of ‘La Sapienza’ University in Rome, S. Andrea Polyclinic, to engage in the establishment of a Regional MR Centre devoted to the development, improvement and application of MR techniques in the field of demyelinizing disease pathogenesis, monitoring and treatment. The MR equipment will be provided with a high field magnet (3 Tesla), granting higher sensitivity and specificity, which will be particularly useful in functional and spectroscopic MR.
The MR Centre of the S. Andrea Polyclinic, in cooperation with three other University and Hospital centres in Rome, will also be playing a leading role in welfare activities designed for MS patients of the Lazio Region, who will therefore be able to avail themselves of an organisation capable of meeting their requirements in terms of diagnostics, therapeutic monitoring and development of new researches. In conclusion, MR techniques allow the construction of new specific hypotheses in the biologic field, and leave room for an experimental medical approach in the development and evaluation of MS therapy. The sensitivity of these measures may substantially increase the possibilities of detecting significant variations in clinical trials, also conducted on limited cohorts of highly selected patients, monitored for short periods of time. Although MR tests are relatively costly, the potential they offer in terms of possible reduction of trial duration and in terms of statistical power may contribute to a substantial reduction in the general costs required for research and development of new drugs for MS.

GUIDELINES

How is a Relapse Described?
A “relapse” is a symptom or neurological sign, lasting at least 24 hours, which cannot be related to a pseudo-attack or to a single paroxysmal episode. In the event of a second clinical episode, a phase of stability or clinical improvement of at least 30 days after the first episode is required.

Which Are The Paraclinical Alterations Suggestive of MS?
1. MR (Barkhof Criteria) If at least 3 out of the 4 following criteria are met: -1 lesion uptaking gadolinium or 9 T2 hyperintense lesions with no lesions uptaking gadolinium -1 or more infratentorial lesion(s) -1 or more iuxta-cortical lesion(s) - 3 or more periventricular lesions
2. Cerebrospinal Fluid (CSF) Test (Positivity Criteria) Presence of IgG oligoclonal bands in the cerebrospinal fluid or of high IgG levels 3. Evoked Potentials Abnormal evoked potentials with wave latency delay but preserved morphology

Which Are The MR Criteria Based on Which We Can Refer To Time Dissemination?
-Presence of a new lesion uptaking gadolinium during a MR test carried out 3 months after the appearance of the first clinical episode
Or -If no new lesions uptaking gadolinium are detected during the test carried out 3 months after the appearance of the first clinical episode, presence of new lesions uptaking gadolinium or of T2 hyperintense lesions during a MR test carried out 6 months after the appearance of the first clinical episode.

Cesare Fieschi - Carlo Pozzilli
II Facoltà di Medicina
dell’Università di Roma La Sapienza
Policlinico S.Andrea