MS Abstracts 01b-2g6

Objectives
Recovery to normal or near normal Visual Acuity is usual after acute DeMyelinating Optic Neuritis, despite the frequent persistence of Conduction Abnormalities as evidenced by the Visual Evoked Potential (VEP).

This raises the possibility that Cortical adaptation to a persistently abnormal input contributes to the recovery process.

The objective of this study was to investigate the pattern of Cerebral response to a simple visual stimulus in recovered patients in comparison to normal subjects.

Methods
Functional Magnetic Resonance Imaging (fMRI) was used to study the Brain activation pattern induced by a periodic monocular 8Hz photic stimulus in seven patients.

Who had recovered from a single episode of acute unilateral Optic Neuritis, and in seven normal controls. VEPs and structural Optic Nerve MRI were performed on patients.

Results
Stimulation of either eye in controls activated only the Occipital Visual Cortex.

However, in patients, stimulation of the recovered eye also induced extensive activation in other areas.

Including the Insula-Claustrum, Lateral Temporal and Posterior Parietal Cortices, and Thalamus; stimulation of the clinically unaffected eye activated Visual Cortex and Right Insula-Claustrum only.

The volume of ExtraOccipital activation in patients was strongly correlated with VEP latency (r = 0.71, p = 0.005).

Conclusions
The ExtraOccipital Areas that were activated in patients all have extensive visual connections, and some have been proposed as sites of multimodal Sensory integration.

The results indicate a functional reorganization of the Cerebral response to simple visual stimuli after Optic Neuritis that may represent an adaptive response to a persistently abnormal input.

Whether this is a necessary part of the recovery process remains to be determined.

Background And Purpose
Modern NeuroImaging has demonstrated progression of disease in Multiple Sclerosis (MS) that may not be detected by standard clinical protocols, prompting a search for new, sensitive tests.

Methods
In fifty patients with MS, we examined eye movements, with particular attention to the speed and accuracy of Saccades.

And, the Vestibulo-Ocular Reflex during small, high-speed head rotations. We also measured the Subjective Visual Vertical (SVV), using a modified laser-pointer.

Visual function was measured, and patients were graded using the Kurtzke Functional Neurological Status (FSS), and Expanded Disability Status Scale (EDSS).

Results
Our main finding was that patients showing abnormalities of eye movements (20/50) were more disabled than those with a normal examination (EDSS scores significantly different, p < 0.01).

Although the ages and duration of disease were similar in both groups. Saccadic Dysmetria and InterNuclear OphthalmoParesis were common.

SVV was abnormally large in 36 % of patients; these showed abnormal eye movements and poorer visual acuity more commonly than those with normal SVV.

In patients with the largest deviations of SVV, Kurtzke FSS Cerebellar Functions were significantly worse (p = 0.021).

Conclusions
Clinical examination of eye movements, with attention to dynamic properties of Saccades and the Vestibulo-Ocular Reflex, takes only a few minutes to perform, but may provide better information concerning the presence of BrainStem and Cerebellar involvement than Kurtzke protocols.

Measurement of SVV is possible in the clinic and is a sensitive sign of BrainStem dysfunction; our present study suggests that SVV is also affected when Cerebellar circuits are involved in MS.

Prospective studies are required to determine whether the development of abnormalities with Ocular Motor and SVV testing are predictive of disease activity and progressive disability in MS.

Background
A subset of individuals with Multiple Sclerosis (MS) endures degradation of Cognitive function during disease progression.

The purpose of this study was to compare visual Cognitive reaction time performance during three conditions of Auditory Distraction (four-talker babble; word repetition; babble combined with word repetition) to a quiet, undistracted condition.

Methods
Twenty-two patients with mild Relapsing/Remitting MS (Expanded Disability Status Scale mean of 3.0) and 17 age-matched and education-matched control subjects free of Neurologic Disease were tested.

On four Cognitive visual processing subtests of simple reaction time, choice reaction time, and Visual Working Memory for same and sequential digits concurrently during three conditions of Auditory Distraction.

Results
When reaction times for MS and control participants were pooled across all four Cognitive tests, the scores of the MS patients in quiet (528 ms) were significantly slower than those of the control subjects (459 ms).

The Auditory Distraction condition of word repetition combined with four-talker babble degraded Cognitive performance more than most of the other distraction conditions in both groups.

Conclusions
Even in mild MS, subtle visual Cognitive processing deficits may be elicited by Auditory Distraction.

The Paced Auditory Serial Addition Test (PASAT), a subtest of the Multiple Sclerosis Functional Composite Score (MSFC), is increasingly used in the evaluation of Cognitive function in Multiple Sclerosis (MS).

While patient acceptance for the PASAT is low, its visual version, the Paced Visual Serial Addition Test (PVSAT), is perceived to be better tolerated.

The aim of this study was to investigate the interchangeability of PVSAT and PASAT in the evaluation of Cognitive function in MS. Twenty-one normal controls and 50 patients with clinically definite MS were tested with PASAT and PVSAT.

Both for PASAT and PVSAT, 3 and 2-second versions of two parallel test forms were used. In the PVSAT, the PASAT stimuli were shown on a computer screen.

Patients were also tested with the other two MSFC subtests, i.e. the Nine-Hole Pegboard Test and Timed 25-Foot Walk Test, to calculate MSFC scores. PASAT-3 correlated highly with both PVSAT-3 and PVSAT-2.

MSFC-v scores calculated with PVSAT-2 and PVSAT-3 values correlated highly with MSFC scores calculated with PASAT-3 results. The results suggest that the PVSAT can be used as an alternative for the PASAT in the MSFC.

Effective therapy in the earliest stages of Multiple Sclerosis (MS) demands early correct diagnosis. Retrospective analysis included 130 patients (90 women) with a median age of 35.5 years, median duration of the disease of 2 years and median EDSS score of 3.0.

27 patients had Clinically Isolated Syndrome (CIS) suggestive of MS, 66 Relapsing/Remitting (RR) MS, 19 Secondary/Progressive (S/P) MS and 18 Primary/Progressive (PP) MS.

The predominant symptoms were Sensory in 52% of the patients with CIS compared to 27% in patients with RRMS, whereas they were more often Motor in patients with PPMS.

Patients with CIS had higher CSF cell counts than patients diagnosed in later stages of the disease and OligoClonal Bands were found in 89% of all patients without statistically significant differences between the subgroups.

Prolonged latencies of Visual Evoked Potentials (VEP) were found in only 29% of patients with CIS compared to 66% in RRMS, 75% in SPMS and 65% of PPMS patients.

Fifty-six percent of patients with CIS, 88% with RRMS, 74% with SPMS and 78% of patients with PPMS fulfilled modified the Barkhof et al. MRI criteria at the time of diagnosis.

Patients in early MS often present with Sensory symptoms. Brain MRI can be inconclusive in over 40% of patients with CIS but the elevated CSF cell count and positive OligoClonal Bands are helpful in establishing the diagnosis of CIS suggestive of MS.

In later stages of the disease the combination of clinical features, MRI, prolonged VEP latencies and positive CSF OligoClonal Bands secures the correct diagnosis.

Cognitive Dysfunction (affecting particularly Attention and Working Memory) occurs early in patients with Multiple Sclerosis.

Previous studies have focused on identifying potentially adaptive functional reorganization through recruitment of new Brain regions that could limit expression of these deficits.

However, lesion studies remind us that functional specializations in the Brain make certain Brain regions necessary for a given task.

We therefore have asked whether altered functional interactions between regions normally recruited provide an alternative adaptive mechanism with Multiple Sclerosis pathology.

We used a version of the n-back task to probe Working Memory in patients with early Multiple Sclerosis.

We applied a functional connectivity analysis to test whether relationships between relative activations in different Brain regions change in potentially adaptive ways with Multiple Sclerosis.

We studied 21 patients with Relapsing/Remitting Multiple Sclerosis and 16 age- and sex-matched healthy controls with 3T functional MRI.

The two groups performed equally well on the task. Task-related activations were found in similar regions for patients and controls.

However, patients showed relatively reduced activation in the Superior Frontal and Anterior Cingulate Gyri (P > 0.01).

Patients also showed a variable, but generally substantially smaller increase in activation than healthy controls with greater task complexity, depending on the specific Brain region assessed (P < 0.001).

Functional connectivity analysis defined further differences not apparent from the univariate contrast of the task-associated activation patterns.

Control subjects showed significantly greater correlations between Right DorsoLateral PreFrontal and Superior Frontal/Anterior Cingulate activations (P < 0.05).

Patients showed correlations between activations in the Right and Left PreFrontal Cortices, although this relationship was not significant in healthy controls (P < 0.05).

We interpret these results as showing that, while Cognitive processing in the task appears to be performed using similar Brain regions in patients and controls, the patients have reduced functional reserve for Cognition relevant to Memory.

Functional connectivity analysis suggests that altered InterHemispheric interactions between Dorsal and Lateral PreFrontal regions may provide an adaptive mechanism that could limit clinical expression of the disease distinct from recruitment of novel processing regions.

Together, these results suggest that therapeutic enhancement of the coherence of interactions between Brain regions normally recruited (functional enhancement).

As well as recruitment of alternative areas or use of complementary Cognitive strategies (both forms of adaptive functional change), may limit expression of Cognitive Impairments in Multiple Sclerosis.

Multiple Sclerosis can follow very different patterns of evolution and variable rates of disability accumulation. This raises the issue whether it represents one or several distinct diseases.

We assessed demographic and clinical characteristics in 1844 patients with Multiple Sclerosis that we categorized according to the classification of Lublin and Reingold (1996) into 1066 (58%) Relapsing/Remitting, 496 (27%) Secondary/Progressive, 109 (6%) Progressive/Relapsing and 173 (9%) Primary/Progressive cases of Multiple Sclerosis.

Relapsing/Remitting and Secondary/Progressive cases shared similar age at disease onset (median = 28.7 versus 29.5 years; P = 0.21), initial symptoms of the Relapsing/Remitting phase, degree of recovery from the first Neurological episode, and time from the first to the second episode.

By contrast, disease duration was twice as long in Secondary/Progressive than in Relapsing/Remitting cases (mean +/- SD = 17.6 +/- 9.6 versus 8.7 +/- 8.6 years; P < 0.001).

Relapsing/Progressive and Primary/Progressive cases were essentially similar in their clinical characteristics.

In patients experiencing a Progressive course, median age at onset of Progressive phase was similar in Secondary/Progressive cases and in cases who were Progressive from onset (39.1 versus 40.1 years; P = 0.47).

The proportion of cases with superimposed relapses during progression was approximately 40% in both categories.

Finally, the 1562 patients with an Exacerbating/Remitting initial course and the 282 patients with a Progressive initial course of the disease were essentially similar with respect to the time course of disability accumulation from assignment to a given disability score, and the age at assignment of disability landmarks.

These observational data suggest that the clinical phenotype and course of Multiple Sclerosis are age dependent.

Relapsing/Remitting disease can be regarded as Multiple Sclerosis in which insufficient time has elapsed for the conversion to Secondary/Progressive.

Secondary/Progressive forms as Relapsing/Remitting Multiple Sclerosis that has 'grown older'; and Progressive from onset cases as Multiple Sclerosis 'amputated' from the usual preceding Relapsing/Remitting phase.

Times to reach disability milestones, and ages at which these landmarks are reached, follow a predefined schedule not obviously influenced by relapses, whenever they may occur, or by the initial course of the disease, whatever its phenotype.

This leads to a unifying concept of the disease in which Progressive and Secondary/Progressive might be regarded as essentially similar.

From the clinical and statistical positions, Multiple Sclerosis might be considered as one disease with different clinical phenotypes rather than an entity encompassing several distinct diseases--the position of complexity rather than true heterogeneity.

Dendritic Cells (DC), as the most effective Antigen-Presenting Cells, are protagonists of the complex Immune Network involved in Multiple Sclerosis (MS) lesion formation.

Glatiramer Acetate (GA), a synthetic random copolymer, is thought to exert its therapeutical effect in MS by favoring both Th2 cell development and IL-10 production from peripheral Lymphocytes as well as by systemically affecting the Antigen-Presenting Cells.

In the present study we further analyzed the mechanisms of action of GA by using an autologous DC-Lymphocytes (Ly) coculture system from 11 MS patients and 12 matched healthy controls (HC).

We found that, in MS patients, pretreatment with GA significantly decreases the in vitro proliferative effect of DC on Lymphocytes as compared to HC and to unpulsed or Myelin Basic Protein (MBP)-pulsed DC from MS patients (P < 0.05).

In addition, GA-treated DC from both MS patients and HC significantly increase the Lymphocyte production of IL-5 and IL-13 as compared to MBP-treated DC (P < 0.05).

In conclusion our in vitro study may provide new therapeutical mechanisms of GA on Lymphocytes, antiproliferative and Th2-favouring effects, which are mediated by Monocyte-derived DC.

InterLeukin-15 (IL-15) is a novel proinflammatory Cytokine having similar biological activities to IL-2 which is implicated in the pathogenesis of Multiple Sclerosis.

It is produced by activated blood Monocytes, Macrophages and Glial Cells. There is little information about the involvement of IL-15 in the development of Multiple Sclerosis (MS).

The objective of our study was to measure IL-15 Serum and CerebroSpinal Fluid (CSF) levels in MS patients and to correlate serum and CSF IL-15 concentrations with clinical parameters of the disease.

CSF IL-15/Serum IL-15 ratio (c/s IL-15 ratio) was introduced to assess the origin of elevated IL-15 levels.

Materials And Methods
We measured Serum and CSF IL-15 levels in 52 patients with MS and 36 age and gender matched patients with Inflammatory (IND) and Non-Inflammatory Neurological Diseases (NIND) studied as control groups.

IL-15 levels were correlated with clinical parameters as duration, disability, MRI activity and clinical subtypes of the disease.

Results
MS patients were found to have significantly higher Serum IL-15 levels compared with IND (p=0.00016) and NIND patients (p=0.00045).

Elevated levels of IL-15 were also found in CSF samples from MS patients compared with patients with IND (p=0.00034) and NIND (p=0.0003).

Among MS subgroups there were no statistically different IL-15 Serum and CSF concentrations. No significant correlation of serum and CSF IL-15 concentrations with MRI activity, disability assessed by EDSS score and duration of the disease were also found.

C/S IL-15 ratio was found lower in MS patients compared with IND (p=0.01) and not significantly different compared with NIND patients (p=0.14) suggesting that systemic activation might be the source of high CSF IL-15 levels in MS patients.

Conclusions
Our findings suggest a possible role of IL-15 in the immunopathogenetic mechanisms of MS.

We evaluated the specific IgG AntiBodies against Heat Shock Proteins (HSPs) in CerebroSpinal Fluids (CSF) from patients with Multiple Sclerosis (MS).

ELISA was employed to examine IgG AntiBodies against ten HSPs (HSP27, alphaA and alphaB Crystallins, HSP60, CCT, Mycobacterium bovis HSP65, Escherichia coli GroEL, HSP70, HSC70 and HSP90) in CSF from 30 patients with MS, and 25 patients with Motor Neuron Diseases (MND).

Significantly higher AntiBody Titers against HSP70 and HSC70 proteins were found in CSF obtained from patients with MS as compared with MND independent of CSF total protein, IgG concentrations and IgG indices, respectively.

The AntiBody Titers against HSP70 were indicated to be significantly higher in the progressive cases than in cases of remission.

The results suggest that IgG AntiBodies against specific types of HSPs especially HSP70 family proteins (HSP70 and HSC70) in CSF may play an important role in the pathophysiology of MS through the modification of Immune Response and cytoprotective functions of molecular chaperons.

Objectives
MRI T₂ HypoIntensity in Multiple Sclerosis (MS) Gray Matter, suggesting Iron deposition, is associated with physical disability, disease course, lesion load, and Brain Atrophy.

Ambulatory dysfunction limits quality of life; however correlation with conventional MRI remains poor.

Methods
Normalized intensity on T₂-weighted images was obtained in the Basal Ganglia, Thalamus, Red Nucleus, and Dentate Nucleus in 47 MS patients and 15 healthy controls.

Brain T₁-HypoIntense and FLAIR-HyperIntense lesion volume, Third Ventricle width, Brain Parenchymal Fraction and timed 25 foot walk (T₂5FW) were measured in the MS group.

Results
T₂ HypoIntensity was present throughout Gray Matter in MS vs. controls (all p< 0.01).

Dentate T₂ HypoIntensity was the only MRI variable significantly correlated with T₂5FW (Pearson r=-0.355, p=0.007) and was also the best MRI correlate of physical disability (EDSS) score in regression modeling (r=-0.463, R(2)=0.223, p=0.004).

Conclusions
T₂ HypoIntensity is present in SubCortical Gray Matter Nuclei in patients with MS vs. normal controls.

Dentate Nucleus T₂ HypoIntensity is independently related to ambulatory impairment and disability, accounting for more variance than conventional lesion and Atrophy measures.

This study adds more weight to the notion that T₂ HypoIntensity is a clinically relevant marker of tissue damage in MS.

To assess the role of CSF OligoClonal Bands (OB) in determining the clinical outcome in patients with Relapsing/Remitting Multiple Sclerosis (RRMS) treated with IFN-ß.

We carried out a retrospective, multicenter, observational study recruiting 209 RRMS patients from six MS centres from northern, central and southern areas of Italy under treatment with IFN-ß-1a i.m., IFN-ß-1a s.c. and IFN-ß-1b s.c.

Twenty-two of 209 patients (10.6%) showed no OB in CSF. The patients without had, at disease onset, significantly higher frequency of visual disturbances (p=0.02) and less sensory involvement (p=0.04) than those with OB.

A statistical trend (p=0.056) towards a longer time to reach sustained disability progression during treatment was found in patients without compared to those with OB.

Thirty-six of 187 (19%) patients with OB worsened by at least 1 EDSS point compared to none of 22 (0%) OB-negative patients (p=0.017).

The delaying of disability progression in OB-negative patients during treatment was significantly dependent only on the number of baseline MRI T₂-weighted lesions (p=0.012) that was found to be significantly lower in OB-negative than in OB-positive patients (p=0.04).

The absence of OB and low number of baseline T₂-weighted lesions in this cohort of MS patients are favorable prognostic factors influencing the clinical response to IFN-ß treatment in RRMS patients.