Clinically Isolated Syndromes Abstracts - 01

Objectives
A confident and accurate diagnosis of Multiple Sclerosis (MS) is important, but a specific diagnostic test for the disease does not exist.

The traditional diagnostic criteria of Poser et al. were published in 1983, and recently, McDonald et al. recommended new criteria for the diagnosis of MS.

Patients And Methods
In this study these two diagnostic schemes were compared by prospectively applying both of them to 76 patients with clinical features suggesting a new diagnosis of MS.

Results
Using the Poser's Criteria, 29 patients (38%) were classified as Clinically Definite and 35 patients (46%) as Laboratory Definite MS.

According to the new McDonald Criteria, MS was diagnosed in 39 (52%) patients, 37 patients (48%) had 'Possible MS'. All patients with a Clinically Definite MS with the Poser Criteria were also given the diagnosis of MS as recommended by McDonald et al.

Of those 35 patients with Laboratory Definite MS according to Poser et al., four patients could be classified as having MS with the McDonald Criteria, 89% of them had 'Possible MS'.

Conversely, 75% of the 39 patients, who fulfilled the new McDonald Criteria for MS were assigned to the category of Clinically Definite MS according to the Poser's Criteria, and 83% of the patients with a 'Possible MS' using the McDonald Criteria, had a Laboratory Definite MS with the Poser criteria.

Conclusion
MS according to the McDonald Criteria was diagnosed more often than 'Clinically Definite MS' according to Poser et al., but combining the categories of Clinically and Laboratory Definite MS, the diagnosis of MS could clearly be established more frequently using the Poser's Criteria.

Copyright Blackwell Munksgaard 2003

While Brain Atrophy occurs early in the clinical course of Multiple Sclerosis, exactly how early, which tissues are affected and the rate at which early Atrophy occurs are unclear.

Regional Brain Atrophy was investigated in 58 patients recruited within 3 months of onset of a Clinically Isolated Syndrome (CIS) suggestive of Multiple Sclerosis, who were followed-up for 3 years.

At 3 years, 31 subjects had developed Multiple Sclerosis as defined by the McDonald Criteria, while 27 had not (13 had MRI-visible Brain lesions and 14 did not).

In those who developed Multiple Sclerosis, the mean decrease in Gray Matter Fractional volume (GMF, as a fraction of total IntraCranial volume) was -0.017 (-3.3%) and was significantly larger than in the combined lesion-positive and lesion-negative CIS subjects [-0.005 (-1.1%), P = 0.001].

No decrease in White Matter Fractional volumes (WMF) was seen. Change in GMF correlated only modestly with the change in T₂ lesion volume from baseline to year 3 (r = -0.428, P = 0.004).

These results suggest that progressive Gray Matter, but not White Matter Atrophy, is seen in the earliest clinically observable stages of relapse onset Multiple Sclerosis, and this is only moderately related to lesion accumulation.

Longer-term follow-up is required to determine whether early Gray Matter Atrophy is associated with subsequent disability or Cognitive Impairment.

Background
The number and volume of abnormalities on baseline Brain Magnetic Resonance images, in patients with initial findings suggestive of Multiple Sclerosis are known to predict outcome in terms of disability.

However, no long-term data exist on specific locations or types of lesions.

Objective
To assess the long-term predictive value of baseline Magnetic Resonance Imaging parameters, including location of lesions and Gadolinium-enhancing and HypoIntense lesions.

In patients with initial findings suggestive of Multiple Sclerosis for the occurrence of clinically relevant disability as defined by an Expanded Disability Status Scale score of 3.

Patients
After a median follow-up period of 8.7 years, the medical records of 42 patients were reviewed and assessed for time until patients received an Expanded Disability Status Scale score of 3.

Magnetic Resonance Imaging parameters were dichotomized according to maximum accuracy and then used to calculate hazard ratios using the Cox model for proportional hazard ratios.

Results
Conversion to Clinically Definite Multiple Sclerosis was observed in 26 patients (62%), of whom 14 (54%) progressed to an Expanded Disability Status Scale score of 3.

Two or more InfraTentorial lesions best predicted long-term disability (hazard ratio, 6.3). Gadolinium-enhancing and HypoIntense T₁-weighted lesions did not show prognostic value.

Conclusion
InfraTentorial lesions are related to long-term prognosis for patients with initial findings suggestive of Multiple Sclerosis and thus may help to identify patients at high risk for earlier occurrence of clinically relevant disability.

Background
Barkhof Criteria have been adopted to demonstrate dissemination in space in the new Multiple Sclerosis diagnostic criteria because of their high specificity for predicting conversion to Multiple Sclerosis.

One of the 4 Barkhof Criteria is the presence of an InfraTentorial lesion.

In Clinically Isolated Syndromes (CIS) of the BrainStem (CISB), the InfraTentorial criterion does not demonstrate dissemination in space, raising the possibility that the criteria may be less specific in CISB.

As compared with specificity in other CIS, in which all 4 criteria demonstrate dissemination in space.

Objective
To compare the validity indices of Barkhof Criteria in CISB with those in other CIS.

Design & Setting
Inception cohort with median follow-up of 34 months for CISB and 40 months for other CIS, in an institutional ambulatory referral center.

Patients
A sample of 51 patients with CISB and 102 patients with other CIS (46 with Myelitis and 56 with Optic Neuritis) was analyzed.

Barkhof Criteria, with a cutoff of 3 of 4, were applied to Magnetic Resonance Imaging performed at baseline. Four combinations each containing 3 parameters were also applied, with a cutoff of 2 of 3.

Main Outcome Measure
Specificity of unmodified Barkhof Criteria and of the 4 combinations to predict conversion to Clinically Definite Multiple Sclerosis.

Results
The specificity of the Criteria in CISB was 61% against 73% in other CIS.

The combinations that retained the InfraTentorial lesion parameter had lower specificities in the CISB group; in analysis of the group with other CIS, no such differences were found.

Conclusion
The InfraTentorial lesion criterion is responsible for the lower specificity of Barkhof Criteria in CISB.

This paper extends on previous data on prognosis in Multiple Sclerosis (MS), to encompass the entire course of the disease.

The first episode suggestive of MS [the Clinically Isolated Syndrome (CIS)] was included as a starting point, and the speed of secondary progression as an end point. Primary/Progressive MS was not included.

Unique preconditions, with one Neurological service covering the Goteborg district, allowed for establishing a strictly population-based, essentially untreated 15-year incidence cohort of 308 MS patients who were followed for 25 years.

Survival analysis was performed as Kaplan-Meyer graphs, and independent predictors were ascertained by Cox regression analysis. A matrix of several predictors and end points was created.

From CIS, a higher risk of Developing Clinically Definite MS (CDMS), Secondary/Progressive course and Disability Status Scale 7 (DSS 7) was predicted by Efferent Tract lesions.

However less than 25% had reached DSS 7, 25 years after CIS with pure Afferent lesions or other favorable predictors.

During the first five years, higher relapse frequency, as well as incomplete remission of early bouts, predicted higher risks of Secondary/Progressive course and DSS 7 during follow-up to 25 years.

However, these early predictors were unable to predict the rate of progression, which seems to contain an element of the disease process unassociated with its early events.

Only late predictors, such as a shorter time from onset to secondary progression (1-10 years) and a higher number of Functional Systems involved at onset of progression predicted a faster progression rate. Predictors from this study could be used to refine historically controlled trials.

In Clinically Isolated Syndromes (CIS), the new McDonald Criteria for Multiple Sclerosis diagnosis require new Gadolinium-enhancing lesions for dissemination in time at a 3-month follow-up Magnetic Resonance Imaging scan.

In a cohort of 56 patients, these Criteria were specific (95%) but less sensitive (58%) for Clinically Definite Multiple Sclerosis at 3 years.

If new T₂ lesions were allowed as an alternative for dissemination in time, sensitivity increased (74%) with maintained specificity (92%), enabling an accurate diagnosis of Multiple Sclerosis in more patients.

Background
Most patients with Multiple Sclerosis initially present with a Clinically Isolated Syndrome.

Despite the fact that Clinically Definite Multiple Sclerosis will develop in up to 80 percent of these patients, the course of the disease is unpredictable at its onset and requires long-term observation or repeated Magnetic Resonance Imaging (MRI).

We investigated whether the presence of Serum AntiBodies against Myelin Oligodendrocyte Glycoprotein (MOG) and Myelin Basic Protein (MBP) in patients with a Clinically Isolated Syndrome predicts the interval to conversion to Clinically Definite Multiple Sclerosis.

Methods
A total of 103 patients with a Clinically Isolated Syndrome, positive findings on cerebral MRI, and OligoClonal Bands in the CerebroSpinal Fluid were studied.

At base line, serum samples were collected to test for anti-MOG and anti-MBP AntiBodies with Western blot analysis, and the lesions detected by Cerebral MRI were quantified.

Neurologic Examinations for relapse or disease progression (defined as conversion to Clinically Definite Multiple Sclerosis) were performed at base line and subsequently every three months.

Results
Patients with Anti-MOG and Anti-MBP AntiBodies had relapses more often and earlier than patients without these AntiBodies. Only 9 of 39 AntiBody-SeroNegativ patients (23 percent) had a relapse, and the mean (+/-SD) time to relapse was 45.1+/-13.7 months.

In contrast, 21 of 22 patients (95 percent) with AntiBodies against both MOG and MBP had a relapse within a mean of 7.5+/-4.4 months, and 35 of 42 patients (83 percent) with only Anti-MOG AntiBodies had a relapse within 14.6+/-9.6 months (P < 0.001 for both comparisons with AntiBody-SeroNegative patients).

The adjusted hazard ratio for the development of Clinically Definite Multiple Sclerosis was 76.5 (95 percent confidence interval, 20.6 to 284.6).

Among the patients who were SeroPositive for both AntiBodies and 31.6 (95 percent confidence interval, 9.5 to 104.5) among the patients who were SeroPositive only for Anti-MOG AntiBodies, as compared with the SeroNegativ patients.

Conclusions
Analysis of AntiBodies against MOG and MBP in patients with a Clinically Isolated Syndrome (CIS) is a rapid, inexpensive, and precise method for the prediction of early conversion to Clinically Definite Multiple Sclerosis.

This finding may be important for the counseling and care of patients with a first DeMyelinating event suggestive of Multiple Sclerosis.

Copyright 2003 Massachusetts Medical Society

The baseline MRI studies from the Controlled High-Risk Subjects Avonex Multiple Sclerosis Prevention Study (CHAMPS) trial, a randomized, longitudinal, double-blind trial of 383 patients with a first acute clinical DeMyelinating event.

And, evidence of prior SubClinical DeMyelination on Magnetic Resonance Imaging (MRI) of the Brain, provides a large MRI database for patients likely in the earliest stages of Multiple Sclerosis (MS).

High-resolution baseline MRIs revealed a median of 13 T₂ lesions (maximum = 103 lesions) and 2.05 cm3 of T₂ lesion volume (maximum 35.04 cm3), with 30% of patients having one or more enhancing lesions despite receiving a standardized high-dose course of IntraVenous CorticoSteroids.

PeriVentricular, discrete, and JuxtaCortical T₂ lesions were present in 99%, 92% and 67% of the patients, respectively. Large (> 6 mm), T₁-HypoIntense, InfraTentorial, and Corpus Callosum lesions were present in 69%, 50%, 55% and 58%, respectively.

Clinical presentation groups showed differences in T₂ lesion volume, and enhancing lesion number and volume. At baseline, 97%, 81% and 72% of the patients met 'Paty', 'Fazekas', and 'Barkhof' research Criteria for MS, respectively, with the percentages similar according to clinical presentation group.

These results support and extend those of smaller and/or retrospective series, which have shown substantial SubClinical injury, based on Brain MRI, at the earliest identifiable stages of disease.

The objective of this work was to assess the effect of Interferon-ß-1a (Avonex) on the rate of development of Clinically Definite Multiple Sclerosis and Brain Magnetic Resonance Imaging changes in subgroups.

Based on type of presenting event, baseline Brain Magnetic Resonance Imaging parameters, and demographic factors in the Controlled High-Risk Subjects Avonex Multiple Sclerosis Prevention Study (CHAMPS) trial.

After the onset of a first DeMyelinating event, 383 patients with Brain Magnetic Resonance Imaging evidence of SubClinical DeMyelination were treated with CorticoSteroids and randomly assigned to receive weekly intramuscular injections of 30 microg Interferon-ß-1a or placebo.

The treatment effect within subgroups was assessed in proportional hazards models both for the development of Clinically Definite Multiple Sclerosis and for a combined outcome of development of Clinically Definite Multiple Sclerosis or >1 new or enlarging T₂ lesions on Brain Magnetic Resonance Imaging.

A beneficial effect of treatment was noted in all subgroups evaluated.

Adjusted rate ratios for the development of Clinically Definite Multiple Sclerosis in the Optic Neuritis, BrainStem-Cerebellar, and Spinal Cord Syndrome subgroups were 0.58 (p = 0.05), 0.40 (p = 0.03), and 0.30 (p = 0.01).

And, for the development of the combined Clinically Definite Multiple Sclerosis/Magnetic Resonance Imaging outcome were 0.50 (p < 0.001), 0.41 (p = 0.001), and 0.40 (p = 0.004), respectively.

A treatment benefit on both outcome measures also was seen in subgroups based on baseline Brain Magnetic Resonance Imaging parameters, gender, and age.

Interferon-ß-1a is beneficial when initiated at the first clinical DeMyelinating event (CIS) in patients with Brain Magnetic Resonance Imaging evidence of SubClinical DeMyelination.

The beneficial effect is present for Optic Neuritis, BrainStem-Cerebellar Syndromes, and Spinal Cord Syndromes.

Segmented Normal-Appearing Brain Tissue (NABT) was investigated in 40 patients with a recent onset and 13 patients with a remote onset of a Clinically Isolated Syndrome (CIS) using Magnetization Transfer Ratio (MTR) Histograms.

Abnormalities were present in patients with a high risk for MS (recent onset and T₂-weighted lesions present) and in those with a low risk for relapse (recent onset without T₂-weighted lesions).

Similar mild NABT abnormality was present with CIS and no further disease activity 14 years later. NABT MTR abnormality in CIS may indicate susceptibility to DeMyelination but not to disease progression.

Multiple sclerosis (MS) is a disease of unknown origin and for which there is no specific diagnostic test.

The diagnosis of MS is always the result of a more or less simple procedure, depending on the cases, and it remains uncertain until evidence of Anatomo-Pathological signs have been brought forward. An almost unanimous consensus does exist regarding several points.

In the presence of suggestive or, at least, compatible Neurological Signs and in the absence of any alternative diagnosis according to a Neurologist expert in MS, the diagnosis of MS is based on Three Criteria:

1. The "Space Dissemination Criterion"
   • Evidence of at least two different lesions in the White Matter of the Central Nervous System
2. The "Time Dissemination Criterion"
   • Evidence of at least two different episodes in the disease course
3. The "Infammatory Criterion"
   • Evidence of a chronic inflammation of the CNS revealed through the analysis of the CerebroSpinal Fluid, i.e.

The observation of one or several of these criteria allows to establish the diagnosis of MS with more or less certainly, likely to be reassessed according to the subsequent course of the disease.

There is a wide consensus today with Poser's Classification (Poser et al., 1983) which combines the three criteria and distinguishes five different categories.

According to Poser et al., Space Dissemination may be proved on Clinical Examination, but also with the Brain MRI and, failing that, with the Evoked Potentials.

Time Dissemination is based only on clinical signs and the Inflammatory Criterion is as significant as the two other criteria.

This classification has just been revised by an expert committee (McDonald et al., 2001) who wish to simplify it into two different categories (MS vs Possible MS).

It has been suggested that Time Dissemination should be proven by the observation of MRI signs three months, at least, after the previous clinical episode or the previous MRI.

It has also been suggested to use the Inflammatory Criterion in second position in replacement of the Space Criterion, when the latter is missing on the Clinical and ParaClinical levels. Time will say whether this new classification will replace the previous one.

This review summarizes the main contributions given by Magnetic Resonance Imaging (MRI) to predict disease evolution in patients at presentation with Clinically Isolated Syndromes (CIS) suggestive of Multiple Sclerosis (MS).

In these patients, the extent of lesions on T₂-weighted scans of the Brain is a robust predictor of the subsequent development of Clinically Definite MS (CDMS), moderate to severe disability and new MRI lesions.

The risk of developing CDMS in patients with CIS is further increased when some of these lesions are enhancing or when additional lesions are seen on T₂-weighted scans of the Spinal Cord.

Recent studies using new MRI techniques have shown that irreversible tissue disruption is an early event in the course of MS and that subtle Normal-Appearing White Matter changes occur in patients with CIS.

And, are associated with an increased risk of developing CDMS. These findings are changing our views of how to monitor early MS evolution and of early MS treatment strategy.