MS Abstracts 02d-2g7

The highly diversified variable regions of ImmunoGlobulin (Ig) molecules contain Immunogenic determinants denoted idiotopes.

We have previously reported that T-Cells from Multiple Sclerosis (MS) patients recognize IgG from autologous CerebroSpinal Fluid (CSF), and mapped a T-Cell Epitope to an IgG idiotope.

To test the ability of CSF IgG molecules to elicit a broad polyclonal T-Cell response in MS, we have analyzed T-Cell responses in the blood and CSF against idiotope Peptides.

Spanning Complementarity Determining Region (CDR) 3 and somatic mutations within the variable regions of MonoClonal CSF IgG.

Consistent with a diversified idiotope-specific T-Cell repertoire, CD4⁺ T-Cells from both patients recognized several idiotope Peptides presented by HLA-DR molecules.

Mutations were critical for T-Cell recognition, as T-Cells specific for a mutated CDR1 Peptide did not recognize corresponding germline-encoded Peptides.

One T-Cell clone recognized both an idiotope Peptide and the B-Cell clone expressing this idiotope, compatible with endogenous processing and presentation of this idiotope by B-Cells.

These results suggest that mutated CSF IgG from MS patients carry several T-Cell Epitopes, which could mediate Intrathecal IgG production and inflammation in MS through idiotope-driven T-B-Cell collaboration.

Objective
To determine the prognostic value of NeuroMyelitis Optica (NMO)-ImmunoGlobulin G (IgG) in patients with recurrent Optic Neuritis (ON).

The Aquaporin-4-specific Serum AutoAntiBody, NMO-IgG, is a biomarker for NMO and Relapsing Transverse Myelitis.

Recurrent ON may herald Multiple Sclerosis (MS) or NMO, or it may occur as an isolated syndrome. The prognosis and response to therapy differs in each of these contexts.

Methods
We evaluated 34 patients who were tested for NMO-IgG between 2000 and 2007 and who had two or more episodes of ON without satisfying a diagnosis of MS or NMO prior to Serologic testing.

Clinical data were available for 25 Mayo Clinic patients (5 NMO-IgG positive and 20 NMO-IgG negative) and for an additional 9 SeroPositive patients whose Serum was referred to the Mayo Clinic NeuroImmunology laboratory for testing.

Results
Twenty percent of the patients with recurrent ON seen at Mayo Clinic were SeroPositive.

All NMO-IgG-positive patients (vs 65% NMO-IgG-negative patients) had at least one attack with Visual Acuity in the affected eye worse than 20/200 (p = 0.05).

In SeroPositive patients for whom long-term follow-up was possible (median 8.9 years after the initial ON), 6 of 12 (50%) experienced an episode of Myelitis and fulfilled criteria for NMO.

In contrast, 1 of 15 SeroNegative patients (6.7%) fulfilled McDonald Criteria for MS (p = 0.03). SeroPositive patients had a final visual score which was worse than that of SeroNegative patients (p = 0.02).

Conclusion
NeuroMyelitis Optica (NMO)-ImmunoGlobulin G SeroPositivity predicts poor visual outcome and development of NMO. SeroPositive recurrent Optic Neuritis is a limited form of NMO.

Background
Studies on the prevalence of Multiple Sclerosis have been carried out worldwide, showing a heterogeneous distribution between countries and even between the different regions of the same country.

Methods
We estimated the regional and national prevalence of Multiple Sclerosis in France on 1 January 2003, based on the computerised database of the national farmer health insurance system ("Mutualité Sociale Agricole").

Results
There were 2667 cases of Multiple Sclerosis registered on the prevalence date, out of 4,098,477 affiliates.

After standardization on age, estimates for the national prevalence of Multiple Sclerosis in French farmers were 65.0 per 100,000 inhabitants (95% confidence interval 62.5 to 67.5), 41.9 per 100,000 in men (39.1 to 44.7) and 96.3 per 100,000 in women (92.0 to 100.6).

The prevalence of Multiple Sclerosis was significantly higher in the NorthEastern regions (approximately 100 per 100,000 inhabitants) compared with the SouthWestern regions (around 50 per 100,000 inhabitants).

Conclusion
Our study is the first to evaluate the overall prevalence of Multiple Sclerosis in France and its 22 regions using the same methodology.

Our results may be generalized to the whole French population as there is no convincing evidence of an increased or decreased susceptibility to Multiple Sclerosis.

Among farmers or persons living in the countryside. This places France among the countries of medium to high prevalence.

Confirming the uneven distribution of Multiple Sclerosis that correlates with latitude, raises once more the question of the role of genetic and environmental factors in the susceptibility to Multiple Sclerosis.

The clinical signs grouped under the concept of Apathy are a common feature of PreFrontal and Basal Ganglia lesions or dysfunctions and can therefore help to improve our understanding of the functional anatomy of the PreFrontal-Basal Ganglia System.

Apathy is here defined as a quantitative reduction of voluntary, goal-directed behaviors. The underlying mechanisms responsible for Apathy can be divided into three subtypes of disrupted processing:
1. Emotional-Affective
2. Cognitive
3. Auto-Activation

Apathy due to the disruption of 'Emotional-Affective' processing refers to the inability to establish the necessary linkage between Emotional-Affective signals and the ongoing or forthcoming behavior.

It may be related to lesions of the Orbital-Medial PreFrontal Cortex or to the related subregions (Limbic territory) within the Basal Ganglia (e.g. Ventral Striatum, Ventral Pallidum).

Apathy due to the disruption of 'Cognitive' processing refers to difficulties in elaborating the plan of actions necessary for the ongoing or forthcoming behavior.

It may be related to lesions of the DorsoLateral PreFrontal Cortex and the related subregions (associative territory) within the Basal Ganglia (e.g. Dorsal Caudate Nucleus).

The disruption of 'auto-activation' processing refers to the inability to self-activate thoughts or self-initiate actions contrasting with a relatively spared ability to generate externally driven behavior.

It is responsible for the most severe form of Apathy and in most cases the lesions affect BiLaterally the Associative and Limbic territories of the internal portion of the Globus Pallidus.

It characterizes the syndrome of 'auto-activation deficit' (also known as 'Psychic Akinesia' or 'Athymormia').

This syndrome implies that direct lesions of the Basal Ganglia output result in a loss of amplification of the relevant signal, consequently leading to a diminished extraction of this signal within the Frontal Cortex.

Likewise, Apathy occurring in Parkinson's Disease could be interpreted as secondary to the loss of Spatial and Temporal focalization of the signals transferred to the Frontal Cortex.

In both situations (direct Basal Ganglia lesions and Nigro-Striatal Dopaminergic loss), the capacity of the Frontal Cortex to select, initiate, maintain and shift programs of actions is impaired.

The mutual involvement of Dopamine and its metabolites in the Nervous and Immune Systems has the potential to provide information on the interaction of these two systems.

During a 24-hour period, we used capillary electrophoresis with electrochemical detection to repeatedly measure the IntraCellular CatecholAmine concentrations in the peripheral blood Lymphocytes of Relapsing/Remitting Multiple Sclerosis (RRMS) patients.

Receiving Interferon-beta-1b (IFN-ß-1b) (n = 13), and those of IFN-naïve RRMS patients receiving their first IFN-ß-1a injection (n = 19) during this study, and compared them with the levels in healthy controls (n = 12).

At baseline, the NorEpinephrine level was significantly decreased (P =0.003) in the long-term IFN MS patients compared with the controls.

The Time x Group interactions for Dopamine (P=0.5854) and NorEpinephrine (P=0.6192) were not significant. The group effects for the individual drugs were P=0.3529 and 0.1282, respectively.

The lower NorEpinephrine level at baseline in the long-term IFN MS group suggests an Immunologically stable phase, in line with our previous findings.

This is the first report of the effects of IFN-ß administration on IntraCellular Catecholamines in MS patients.

Further studies are necessary to elucidate the Immune reactions affected by the CatecholAmines in MS and to evaluate the roles of these potential ImmunoTransmitters.

Objectives
A study of Cognitive, Psychological and social aspects in Benign Multiple Sclerosis (MS).

Methods
One hundred and sixty three patients with Benign MS (defined as disease duration > or = 15 years and Expanded Disability Status Scale (EDSS) score < or = 3.0 ) underwent NeuroPsychological testing on the Rao's Brief Repeatable Battery (BRB).

And the Stroop test, evaluation of Depression on the Montgomery and Asberg Depression Rating Scale (MADRS), of Fatigue on the Fatigue Severity Scale (FSS) and of handicap on the Environmental Status Scale (ESS).

Patients' Cognitive performance was compared with that of 111 demographically matched healthy controls. Cognitive Impairment was defined as the failure in at least 3 tests, using the fifth percentile of controls' performance as the cut-off point.

Clinical correlates of Cognitive Impairment were determined by multiple logistic regression analysis.

Results
Cognitive assessment led to the identification of 74 subjects (45%) with Cognitive Impairment.

Significant Fatigue was found in 80 subjects (49%) and Depression in 88 patients (54%).

In comparison with Cognitively preserved subjects, Cognitively Impaired patients exhibited higher handicap scores on the EDSS (p = 0.005).

In the regression analysis, only EDSS scores were significantly associated with Cognitive Impairment (OR 1.8, 95%CI 1.2-2.6).

Conclusion
Current definitions of Benign MS may overestimate this entity, since they are mainly weighted for the patients' motor abilities and fail to capture relevant disease-related Cognitive, Psychological and Social problems.

Aim
To propose a simple tool for early prediction of unfavorable long term evolution of Multiple Sclerosis (MS).

Methods
A Bayesian model allowed us to calculate, within the first year of disease and for each patient, the Bayesian Risk Estimate for MS (BREMS) score that represents the risk of reaching Secondary/Progression (SP).

Results
The median BREMS scores were higher in 158 patients who reached SP within 10 years compared with 1087 progression free patients (0.69 vs 0.30; p < 0.0001).

The BREMS value was related to SP risk in the whole cohort (p < 0.0001) and in the subgroup of 535 patients who had never been treated with Immune therapies, thus reasonably representing the natural history of the disease (p < 0.000001).

Conclusions
The BREMS score may be useful both to identify patients who are candidates for early or for more aggressive therapies and to improve the design and analysis of clinical therapeutic trials and of observational studies.

AntiBody-mediated inflammation is believed to contribute to tissue injury in Multiple Sclerosis (MS).

The majority of patients with MS have OligoClonal Bands (OCB), corresponding to AntiBodies against a variety of antigens, in their CerebroSpinal Fluid (CSF). The relation of CSF OCB and disease progression in MS is uncertain.

To investigate whether there is a relation between CSF OCB and a more aggressive disease course of MS, 143 patients with definite MS according to the Poser diagnostic criteria and CSF analysis at time of diagnosis were followed over a period of 5 years.

There were no differences in presence or number of CSF OCB between patients with significant worsening of disability and stable patients.

There were no differences in presence or number of CSF OCB between patients with stable Relapsing/Remitting MS and patients developing secondary progression during follow-up.

The presence or number of CSF OCB does not seem to influence early disease progression in MS.

Natalizumab is a powerful new therapy with a novel mechanism of action for the treatment of Multiple Sclerosis.

In a randomized, double-blind, Phase III study (the AFFIRM [Natalizumab Safety and Efficacy in Relapsing/Remitting Multiple Sclerosis] study):

Natalizumab MonoTherapy 300 mg intravenous every 4 weeks reduced the risk of sustained disability progression by 42% and annualized relapse rate by 68% over 2 years (both p < 0.001 versus placebo).

Natalizumab was approved in the US in November 2004 for the treatment of Relapsing Multiple Sclerosis, but was voluntarily withdrawn in February 2005 due to three cases of Progressive Multifocal Leukoencephalopathy.

Following a safety evaluation and regulatory review, the US FDA approved natalizumab as monotherapy for the treatment of Relapsing Multiple Sclerosis in June 2006 generally for patients who have had an inadequate response to, or are unable to tolerate, alternative treatments.

Functional MRI (fMRI) studies have shown increased activation of IpsiLateral Motor Areas during hand movement in patients with Multiple Sclerosis (MS).

We hypothesized that these changes could be due to disruption of TransCallosal Inhibitory Pathways.

We studied 18 patients with Relapsing/Remitting MS. Conventional T₁- and T₂-weighted images were acquired and Lesion Load (LL) measured.

Diffusion Tensor Imaging (DTI) was performed to estimate Fractional Anisotropy (FA) and Mean Diffusivity (MD) in the body of the Corpus Callosum (CC).

fMRI was obtained during a right-hand motor task. Patients were studied to evaluate TransCallosal Inhibition (TCI, latency and duration) and Central Conduction Time (CCT).

Eighteen normal subjects were studied with the same techniques. Patients showed increased MD (P < 0.0005) and reduced FA (P < 0.0005) in the body of the CC.

Mean latency and duration of TCI were altered in 12 patients and absent in the others.

Between-group analysis showed greater activation in patients in BiLateral PreMotor, Primary Motor (M1), and Middle Cingulate Cortices and in the IpsiLateral Supplementary Motor Area, Insula, and Thalamus.

A multivariate analysis between activation patterns, structural MRI, and NeuroPhysiological findings demonstrated positive correlations between T₁ LL, MD in the body of CC, and activation of the IpsiLateral Motor Cortex (iM1) in patients.

Duration of TCI was negatively correlated with activation in the iM1.

Our data suggest that functional changes in iM1 in patients with MS during a motor task partially represents a consequence of loss of TransCallosal Inhibitory Fibers.

Hum Brain Mapp, 2006. (c) 2006 Wiley-Liss, Inc.

Purpose
To prospectively assess sensitivity and specificity of Diffusion indexes of the Corpus Callosum (CC) for differentiating Relapsing NeuroMyelitis Optica (RNMO) from Relapsing/Remitting Multiple Sclerosis (RRMS), by using final clinical diagnosis as the reference standard.

Materials and Methods
Participants provided informed consent; the study was approved by the institutional review board.

Forty-six consecutive patients with RRMS (18 men, 28 women; mean age, 37.7 years; range, 18-58 years) and 26 consecutive patients with RNMO (two men, 24 women; mean age, 38.6 years; range, 19-59 years) underwent Diffusion-Tensor Magnetic Resonance Imaging.

Mean Diffusivity (MD) and Fractional Anisotropy (FA) of the Region Of Interest (ROI) of the CC in the midsagittal plane were measured and used as discriminative indexes.

Bayesian classification with leave-one-out cross-validation was used to determine diagnostic accuracy.

Differences in Diffusion indexes of ROIs among groups were evaluated by using the Kruskal-Wallis test, followed by the Mann-Whitney U test for multiple comparisons and Bonferroni correction.

Results
Mean MD (8.48 x 10(-4) mm(2)/sec) and FA (0.729) of the ROI in patients with RNMO were significantly (P < .001) different from those (MD = 10.64 x 10(-4) mm(2)/sec, FA = 0.599) in patients with RRMS.

Sensitivity and specificity for differentiation were 92.3% (24 of 26 patients with RNMO) and 93.5% (43 of 46 patients with RRMS) for FA and 88.5% (23 of 26 patients with RNMO) and 89.1% (41 of 46 patients with RRMS) for MD, respectively.

Conclusion
Measurement of Diffusion indexes of the CC may be useful for distinguishing patients with RNMO from those with RRMS.

Supplemental material: (c) RSNA, 2007.

Background
The role of ApoliPoprOtein E (APOE) polymorphism has been well recognized in other Cognitive NeuroDegenerative Disorders, such as Alzheimer Disease.

Its role in Multiple Sclerosis (MS) is less clear, though studies indicate that 40% to 60% of patients with MS have evidence of Cognitive Impairment.

Objective
To determine whether there is an association between APOE epsilon4 and Cognitive deficits in MS.

Methods
We performed a standardized battery of NeuroPsychological tests investigating the Four Cognitive Domains commonly impaired in MS and assessed the association of the presence of APOE epsilon4 with Cognition in MS.

Results
A strong association was found between the presence of APOE epsilon4 and Cognitive Deficits in patients with MS, particularly in the domains of Learning and Memory.

This association was strongest in our youngest cohort (age 31 to 40) of patients with MS.

Conclusions
APOE epsilon4 is significantly associated with Cognitive Impairment in patients with Multiple Sclerosis (MS).

However, the modest effects do not justify APOE genotyping of patients with MS in clinical practice.