MS Abstracts 03c-2g6

Reliable prognostic markers of Primary/Progressive (PP) Multiple Sclerosis evolution are still needed. Diffusion Tensor (DT) MRI can quantify Normal-Appearing White Matter (NAWM) and Gray Matter (GM) damage in Multiple Sclerosis patients.

We investigated whether conventional and DT-MRI-derived measures can predict the long-term clinical evolution of PP Multiple Sclerosis.

In 54 PP Multiple Sclerosis patients, conventional and DT-MRI scans of the Brain and T₁-weighted scans of the Cervical Cord were acquired at baseline and after a median follow-up of 15 months.

Another clinical evaluation was performed, 56 months after baseline, in 52 patients. Measures of lesion load, Brain and Cord Atrophy were obtained.

Histograms of the Mean Diffusivity (MD) and Fractional Anisotropy (FA) values from the NAWM and GM were analyzed. At follow-up, 35 patients (65%) experienced a confirmed disability progression.

Baseline Expanded Disability Status Scale score and average GM MD were independent predictors of subsequent clinical deterioration in a multivariable model (Nagelkerke R2: 0.44; discriminating ability: 81%).

A lower level of disability and a more severe GM damage identify PP Multiple Sclerosis patients with an increased risk of disease progression over the subsequent 5 years. These data may be relevant to select patients for future exploratory phase II trials.

This study aimed to determine regional pattern of tissue Perfusion in the Normal-Appearing White Matter (NAWM) of patients with Primary/Progressive (PP), Relapsing/Remitting (RR) Multiple Sclerosis (MS) and healthy controls.

And to investigate the association between Perfusion abnormalities and clinical disability.

Using Dynamic Susceptibility Contrast (DSC) Perfusion MRI at 3 T, we studied 22 patients with clinically definite MS, 11 with PP-MS and 11 with RR-MS and 11 age- and gender-matched healthy volunteers.

The MRI protocol included axial dual-echo, Dynamic Susceptibility Contrast enhanced (DSC) T₂*-weighted and post-contrast T₁-weighted images.

Absolute Cerebral Blood Flow (CBF), Cerebral Blood Volume (CBV) and Mean Transit Time (MTT) were measured in the PeriVentricular, Frontal, Occipital NAWM and in the Splenium of the Corpus Callosum.

Compared to controls, CBF and CBV were significantly lower in all NAWM regions in both PP-MS patients (p values from < 0.0001 to 0.001) and RR-MS (p values from < 0.0001 to 0.020).

Compared to RR-MS, PP-MS patients showed significantly lower CBF in the PeriVentricular NAWM (p=0.002) and lower CBV in the PeriVentricular and Frontal NAWM (p values: 0.0029 and 0.022).

EDSS was significantly correlated with the PeriVentricular CBF (r=-0.48, p=0.0016) and with the PeriVentricular and Frontal CBV (r=-0.42, p=0.015; r=-0.35, p=0.038, respectively).

This study suggests that the hemodynamic abnormalities of NAWM have clinical relevance in patients with MS. DSC Perfusion MRI might provide a relevant objective measure of disease activity and treatment efficacy.

Background And Purpose
Perfusion measurement in Multiple Sclerosis (MS) may cast light on the disease pathogenesis and lesion development since Vascular pathology is frequently demonstrated in the disease.

This study was performed to investigate the perfusion characteristics in MS lesions using Dynamic Susceptibility Contrast MR Imaging (DSC-MRI) to better understand the HemoDynamic changes in MS.

Methods
Seventeen patients with Relapsing/Remitting MS were studied with DSC-MRI.

Perfusion measurements included Cerebral Blood Flow (CBF), Cerebral Blood Volume (CBV), and Mean Transit Time (MTT), were obtained in enhancing, non-enhancing lesions covered by DSC-MRI and ContraLateral Normal-Appearing White Matter (NAWM) in patients as well as normal White Matter in seventeen control subjects.

Results
DSC-MRI data demonstrated reduced perfusion with significantly prolonged MTT (P < 0.001) in lesions and NAWM in patients compared with normal White Matter in controls.

Compared to ContraLateral NAWM, enhancing lesions demonstrate increased CBF (P = 0.007) and CBV (P < 0.0001), indicating inflammation-mediated VasoDilatation.

A K means cluster analysis was performed and identifies approximately 63.8% of non-enhancing lesions (Class 1) with significantly decreased perfusion (P < or = 0.0001) when compared with ContraLateral NAWM.

In contrast, the remainder 36.2% non-enhancing lesions (Class 2) show increased CBV (P = 0.02) in a similar fashion to enhancing lesions and can be observed on quantitative color-coded maps even without Blood-Brain Barrier breakdown.

Conclusion
DSC-MRI measurements demonstrate potential for investigating HemoDynamic abnormalities that are associated with inflammatory activity, lesion reactivity and Vascular compromise in MS lesions.

Non-enhancing lesions showed both low and high perfusion suggesting MicroVascular abnormalities with HemoDynamic Impairment and inflammatory reactivity that cannot be seen on conventional MRI.

Objective
To determine whether Memory Loss in patients with Multiple Sclerosis (MS) results from faulty Encoding or Retrieval.

We correlated extent of T₂-weighted lesion involvement with Brain activation patterns on fMRI scans obtained while patients performed a Verbal Episodic Memory task.

Methods
We performed a Neurologic Examination, NeuroPsychological testing, and an event-related fMRI scan on 36 patients with Relapsing/Remitting MS.

In addition, we obtained T₂-weighted structural MRI scans to measure lesion volume.

We performed a regression analysis to examine the association between lesion volume and Regional Brain activation.

Results
Increasing lesion volume correlated with increasing magnitude of Brain activation, primarily in the Left Frontal and Parietal Association Cortices.

Significant correlations of function with lesion volume were primarily observed during the Memory Retrieval phase of the task.

Conclusions
These results extend previous fMRI studies in Multiple Sclerosis (MS) by demonstrating an association between greater disease burden and increased Neural recruitment during Episodic Memory.

In addition, the stronger correlations observed between lesion volume and Brain activation during retrieval than Encoding would suggest that Retrieval processes are more affected by MS-related Cerebral pathology.

By combining all the data available from the Genetic Analysis of Multiple Sclerosis in EuropeanS (GAMES) project, we have been able to identify 17 microsatellite markers showing consistent evidence for apparent association.

As might be expected five of these markers map within the Major Histocompatibility Complex (MHC) and are in LD with HLA-DRB1. Individual genotyping of the 12 non-MHC markers confirmed association for three of them--D11S1986, D19S552 and D20S894.

Association mapping across the candidate genes implicated by these markers in 937 UK trio families revealed modestly associated haplotypes in JAG1 (p=0.019) on Chromosome 20p12.2 and POU2AF1 (p=0.003) on Chromosome 11q23.1.

Objective
To study sleep-wake and Body Core Temperature (BCT) Circadian rhythms in patients with Multiple Sclerosis (MS)-associated with chronic Fatigue.

Methods
Six Relapsing/Remitting MS patients with chronic Fatigue underwent 48 consecutive hours PolySomnoGraphy (PSG) with BCT measurement, followed by a Multiple Sleep Latency Test (MSLT).

All patients were relapse- and drug-free. Mood depression, Brain and Cervical Cord enhanced MRI, dynamic spirometry and Fatigue Severity Scale (FSS) were assessed just before PSG.

Results
In all patients mood depression was absent and dynamic spirometry normal, but FSS confirmed Fatigue. MRI showed non-enhancing lesions.

Nocturnal sleep was characterized by normal architecture and mean sleep efficiency was only slightly reduced.

Arousal index was normal and periodic limb movements during sleep (PLMS) were present in four patients, with an increased index (PLMS-I) in only two of them.

Upon MSLT, mean sleep latency was normal in all patients with one sleep onset REM period in one patient. All patients displayed a normal BCT 24-h rhythm.

Mesor, amplitude and acrophase of BCT rhythm did not show significant differences between MS and controls.

Conclusions
We found substantially normal sleep-wake and BCT rhythmicity in six patients with MS and Fatigue.

Non-restorative sleep and abnormal BCT regulation were unlikely mechanisms of chronic Fatigue in our MS patients.

Significance
Subjective Fatigue and abnormal sleep and BCT can be independent manifestation in MS patients.

The findings support the notion that objective measures of Fatigue comparable to the MSLT for sleepiness do not exist.

Multiple Sclerosis (MS) is a chronic NeuroDegenerative Disease of the CNS in which an unrelenting attack from the Innate and Adaptive arms of the Immune System results in extensive DeMyelination, loss of Oligodendrocytes and Axonal Degeneration.

This review summarizes advances in the understanding of the cellular and molecular pathways involved in NeuroDegeneration following Autoimmune-mediated inflammation in the CNS.

The mechanisms underlying Myelin and Axonal destruction and the equally important interaction between degenerative and repair mechanisms are discussed.

Recent studies have revealed that the failure of CNS regeneration may be in part a result of the presence of Myelin-associated growth inhibitory molecules in MS lesions.

Successful therapeutic intervention in MS is likely to require suppression of the inflammatory response, in concert with blockade of growth inhibitory molecules and possibly the mobilization or transplantation of Stem Cells for regeneration.

The function of Oligodendrocytes is to myelinate CNS Axons. Oligodendrocytes and the Axons they myelinate are functional units, and NeuroTransmitters released by Axons can influence all stages of Oligodendrocyte development via Calcium dependent mechanisms.

Some of the clearest functional evidence is for Adenosine, ATP, and Glutamate, which are released by electrically active Axons and regulate the migration and proliferation of Oligodendrocyte Progenitor Cells and their differentiation into myelinating Oligodendrocytes.

Glutamate and ATP, released by both Axons and Astrocytes, continue to mediate Ca⁺ signaling in mature Oligodendrocytes, acting via AMPA and NMDA Glutamate Receptors, and heterogeneous P2X and P2Y Purinoceptors.

Physiological signalling between Axons, Astrocytes, and Oligodendrocytes is likely to play an important role in Myelin maintenance throughout life.

Significantly, ATP- and Glutamate-mediated Ca⁺ signaling are also major components of Oligodendrocyte and Myelin damage in numerous pathologies, most notably Ischemia, injury, PeriVentricular Leukomalacia, and Multiple Sclerosis.

In addition, NG2-expressing Glia (Synantocytes) in the adult CNS are highly reactive cells that respond rapidly to any CNS insult by a characteristic Gliosis, and are able to regenerate Oligodendrocytes and possibly Neurons.

Glutamate and ATP released by Neurons and Astrocytes evoke Ca⁺ signaling in NG2-Glia (Synantocytes), and it is proposed these regulate their differentiation capacity and response to injury.

In summary, clear roles have been demonstrated for NeuroTransmitter-mediated Ca⁺ signaling in Oligodendrocyte development and pathology.

A key issue for future studies is to determine the physiological roles of NeuroTransmitters in mature Oligodendrocytes and NG2-Glia (Synantocytes).

Background
Damage of the Blood-Brain Barrier and invasion of Immunocompetent cells into the Central Nervous System represent key events in the ImmunoPathogenesis of Multiple Sclerosis.

Mitoxantrone hydrochloride reduces progression of disability and clinical exacerbations in patients with Multiple Sclerosis. Its precise mode of action is unclear.

Objective & Design
To investigate the effects of Mitoxantrone on the migratory capacity of ImmunoCompetent Cells ex vivo and in vitro. A case-control study.

Setting
Heinrich Heine University, Department of Neurology, Dusseldorf, Germany.

Participants
Peripheral Blood Mononuclear Cells (PBMCs) were obtained from 11 patients with Multiple Sclerosis before and after intravenous Mitoxantrone treatment; PBMCs from 5 healthy control donors were treated with Mitoxantrone in vitro.

Main Outcome Measures
The migratory capacity was studied in an in vitro Boyden chamber assay; cells and their rates of migration were analyzed by light microscopy and flow cytometry.

To determine the specificity of our findings, PBMCs were treated with Perfosfamide in vitro.

Results
Mitoxantrone decreased the migratory capacity of CD14⁺ Monocytes and (to a lesser degree) of CD4⁺ and CD8⁺ T-Lymphocytes.

These observations were confirmed when control PBMCs were treated with an equivalent dose of Mitoxantrone in vitro. Similar effects were seen when PBMCs were preincubated with Perfosfamide.

The inhibitory effects of Mitoxantrone on the migratory capacity of PBMCs were mediated by reduced Matrix MetalloProteinase-9 activity, as demonstrated by zymography, polymerase chain reaction, and inhibitory studies.

Conclusion
Mitoxantrone may inhibit the migration of inflammatory cells into and within the Central Nervous System.

Background
Interferon Inhibitory Activity (IIA) is a logical candidate for explaining Neutralizing AntiBody-negative partial responsiveness to Interferon-ß in Multiple Sclerosis (MS), but its role has not been evaluated.

Objective & Design
To investigate the role of IIA and soluble Interferon-/ß receptor (sIFNR) in determining response of patients with MS to Interferon-beta therapy. A parallel-group, open-label study.

Setting
Baird Multiple Sclerosis Center, Buffalo, NY.

Patients Blood was obtained before and 24 hours after injection of Interferon-ß-1a from 38 Anti-Interferon-ß Neutralizing AntiBody-negative patients with Relapsing/Remitting MS and 16 untreated healthy controls.

On the basis of clinical parameters of response to Interferon-ß therapy, the patients were divided into stable or good-responder (n = 20) and active or partial-responder (n = 18) groups.

Main Outcome Measures
Quantitative analyses of Magnetic Resonance Imaging were obtained; the IIA and sIFNR levels were measured using bioassay and enzyme-linked immunosorbent assay, respectively.

Results
The IIA and sIFNR levels were elevated in MS patients compared with controls (P < .001).

The IIA levels were higher in active or partial responders compared with stable or good responders (P < .001); the sIFNR levels were not different between groups.

The Extended Disability Status Score and T₂ lesion volumes were higher in the active or partial-responder group compared with the stable or good-responder group.

Interferon-ß-1a did not have short-term effects on the IIA and sIFNR levels.

In univariate general linear model and stepwise regression analyses, IIA levels were associated with T₂ lesion volume.

Conclusion
The levels of IIA are associated with increased MS disease activity and with responsiveness to Interferon-ß therapy in Anti-Interferon-ß Neutralizing AntiBody-negative MS patients.

To evaluate the effect of Interferon-beta-1b (IFN-ß-1b) on Multiple Sclerosis (MS) with severe Optic Nerve and Spinal Cord DeMyelination.

We examined the relationship between IFN-ß-1b treatment outcome and the clinical and genetic characteristics of three types of DeMyelinating Diseases of the Central Nervous System, i.e., NeuroMyelitis Optica (NMO), MS and MS with severe Optic-Spinal DeMyelination.

Japanese MS frequently carried HLA DPB1()0501, which is associated with NMO.

MS with DPB1()0501 showed severe Optic-Spinal DeMyelination represented by longitudinally extensive Spinal Cord lesion, blindness and CSF Pleocytosis.

IFN-ß-1b treatment did not succeed in these patients because of the increase of Optic Nerve and Spinal Cord relapse and other severe side effects.

IFN-ß-1b should not be administered to DeMyelinating patients with genetic and clinical characteristics mimicking NMO such as HLA DPB1()0501 allele, longitudinally extensive Spinal Cord lesion, blindness and CSF Pleocytosis even if they have symptomatic Cerebral lesions as typically seen in MS.

The present study strongly suggests that these patients should be diagnosed as having NMO.

Background
The authors previously proposed diagnostic criteria for NeuroMyelitis Optica (NMO) that facilitate its distinction from prototypic Multiple Sclerosis (MS).

However, some patients with otherwise typical NMO have additional symptoms not attributable to Optic Nerve or Spinal Cord inflammation or have MS-like Brain MRI lesions.

Furthermore, some patients are misclassified as NMO by the authors' earlier proposed criteria despite having a subsequent course indistinguishable from prototypic MS.

A Serum AutoAntiBody marker, NMO-IgG, is highly specific for NMO. The authors propose revised NMO diagnostic criteria that incorporate NMO-IgG status.

Methods
Using final clinical diagnosis (NMO or MS) as the reference standard, the authors calculated sensitivity and specificity for each criterion and various combinations using a sample of 96 patients with NMO and 33 with MS.

The authors used likelihood ratios and logistic regression analysis to develop the most practical and informative diagnostic model.

Results
Fourteen patients with NMO (14.6%) had extra-Optic-Spinal CNS symptoms.

NMO-IgG SeroPositivity was 76% sensitive and 94% specific for NMO. The best diagnostic combination was 99% sensitive and 90% specific for NMO.

And consisted of at least two of three elements: longitudinally extensive Cord lesion, onset Brain MRI nondiagnostic for MS, or NMO-IgG SeroPositivity.

Conclusions
The authors propose revised diagnostic criteria for definite NeuroMyelitis Optica (NMO) that require Optic Neuritis, Myelitis, and at least two of three supportive criteria:

MRI evidence of a contiguous Spinal Cord lesion 3 or more segments in length, onset Brain MRI nondiagnostic for Multiple Sclerosis, or NMO-IgG SeroPositivity.

CNS involvement beyond the Optic Nerves and Spinal Cord is compatible with NMO.