Multiple Sclerosis Abstracts 03d-2g6

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.

Multiple Sclerosis (MS) is a complex Neurological Disorder characterized by inflammation and degeneration of the Central Nervous System, primarily involving the White Matter.

On the basis of a wide body of evidence in experimental models and in affected patients, several attempts to treat MS using drugs which modulate Immune reactions have been performed or are currently ongoing.

However, it should be stressed that inflammation does not have only a detrimental effect in MS.

In fact, parts of the inflammatory events are crucial for the control and conclusion of the acute phase of damage and it is probable that they actually favor regeneration and recovery.

Due to the above, several trials with ImmunoSuppressant drugs failed or were suspended because of unexpected worsening of the course of MS.

The knowledge of MS ImmunoPathogenesis is so rapidly evolving that any attempt to review it is in some way frustrating. On the other hand, this evolution is at the basis of the several new treatment options which can be hypothesized for this disease.

The current status of ImmunoSuppression in MS and the possible future development of MS treatment will be reviewed, with particular reference to those treatments which have already been tested in clinical trials.

And which are based on sound evidence of a putative interference with specific events occurring in MS, with the sparing of general immunity.

Background
Parenterally administered Glatiramer Acetate reduces the frequency of relapses and the formation of active Brain lesions seen with MRI in Multiple Sclerosis.

This study assessed whether two doses of Glatiramer Acetate given orally could improve clinical and MRI measures of inflammation and NeuroDegeneration in a large cohort of patients with Relapsing/Remitting Multiple Sclerosis.

Methods
1912 patients with Relapsing/Remitting Multiple Sclerosis were screened and 1651 were randomized to receive 50 mg or 5 mg of Glatiramer Acetate or placebo by daily oral administration over 14 months.

The intention-to-treat cohort consisted of 1644 patients who took at least one dose of study medication (50 mg Glatiramer Acetate [n=543], 5 mg Glatiramer Acetate [n=553], placebo [n=548]).

After baseline investigation, clinical assessments were done every 2 months and MRI was obtained for all patients at baseline and at study exit.

Additionally, MRI was undertaken every 2 months for a cohort of 486 patients. The primary outcome was the total number of confirmed relapses observed during the study period.

Several prespecified clinical and MRI secondary and tertiary outcomes assessed treatment efficacy on inflammation and NeuroDegeneration due to Multiple Sclerosis.

Findings
The cumulative number of confirmed relapses did not differ between the two active treatment groups and the placebo group.

Relative to placebo, the rate ratio for the 50 mg Glatiramer Acetate treated group was 0.92 (95% CI 0.77-1.08, p=0.30) and for the 5 mg Glatiramer Acetate treated group was 0.98 (0.83-1.15, p=0.76).

No drug effect was seen for any of the secondary and tertiary endpoints. The study drug was safe and well tolerated.

Interpretation
5 mg and 50 mg Glatiramer Acetate administered orally on a daily basis do not affect relapse rate or other clinical and MRI parameters of disease activity and burden in patients with Relapsing/Remitting Multiple Sclerosis.

Treatment with oral formulations of Glatiramer Acetate at the doses tested cannot be recommended.

Background
Cognitive compensatory mechanisms may limit the Cognitive Dysfunction due to Cerebral tissue destruction in Multiple Sclerosis (MS).

Objective
To explore the effect of educational status on Cognitive performances in early Relapsing/Remitting (RR) MS.

Methods
43 RRMS patients were individually matched for age, sex and educational level with 43 healthy controls.

Each patient underwent NeuroPsychological tests, clinical assessment and Magnetic Resonance Imaging (MRI).

Cognitive scores of MS patients were compared to those of their paired controls according to educational level.

Results
Less educated patients had low performances on all but two NeuroPsychological tests, while more educated patients had low scores only for three tests.

Cognitive performances of more educated patients but not those of less educated ones were strongly correlated with MRI parameters and decreased with the severity of Cerebral tissue destruction.

Conclusion
These different Cognitive patterns suggest the existence of a Cognitive compensation in more educated patients which is limited by the accumulation of tissue damage.

Saltatory Conduction in Myelinated fibers depends on the specific molecular organization of highly specialized Axonal domains at the Node of Ranvier, the ParaNodal and the JuxtaParaNodal regions.

Voltage-gated Sodium Channels (Na(v)) have been shown to be deployed along the naked DeMyelinated Axon in experimental models of CNS DeMyelination and in Multiple Sclerosis lesions.

Little is known about aggregation of Nodal, ParaNodal and JuxtaParaNodal constituents during the repair process.

We analyzed by ImmunoHistoChemistry on free-floating sections from Multiple Sclerosis Brains the expression and distribution of Nodal (Na(v) Channels), ParaNodal (ParaNodin/Caspr) and JuxtaParaNodal (K(v) channels and Caspr2) molecules in DeMyelinated and ReMyelinated lesions.

Whereas in DeMyelinated lesions, ParaNodal and JuxtaParaNodal proteins are diffusely distributed on denuded Axons, the distribution of Na(v) channels is heterogeneous, with a diffuse ImmunoReactivity but also few broad Na(v) Channel aggregates in all DeMyelinated lesions.

In contrast to the DeMyelinated plaques, all ReMyelinated lesions are characterized by the detection of aggregates of Na(v) Channels, ParaNodin/Caspr, K(v) channels and Caspr2.

Our data suggest that these aggregates precede ReMyelination, and that Na(v) channel aggregation is the initial event, followed by aggregation of ParaNodal and then JuxtaParaNodal Axonal proteins.

ReMyelination takes place in Multiple Sclerosis tissue but Myelin repair is often incomplete, and the reasons for this ReMyelination deficit are many.

We suggest that a defect of Na(v) channel aggregation might be involved in the ReMyelination failure in DeMyelinated lesions with spared Axons and Oligodendroglial cells.

Considering the association of sleep disturbance and Fatigue in Multiple Sclerosis (MS), we investigated the presence of sleep disturbances that may be related to Fatigue by using objective and subjective measures.

We included 27 MS patients with Fatigue, 10 MS patients without Fatigue and 13 controls. The Pittsburgh sleep quality index score showed significant differences between patient groups and controls.

Beck Depression inventory scores were significantly higher in Fatigued than Non-Fatigued patients.

Comparison of patient groups and controls revealed significant differences for time in bed, sleep efficiency index, sleep continuity index, wake time after sleep onset, total arousal index and periodic limb movement arousal index.

Our study confirms that MS causes sleep fragmentation in terms of both macro and microstructure. Fatigue in MS could be partially explained by disruption of sleep microstructure, poor subjective sleep quality and depression.

Brain Atrophy as determined by quantitative MRI can be used to characterize disease progression in Multiple Sclerosis. Many studies have addressed White Matter (WM) alterations leading to Atrophy, while changes of the Cerebral Cortex have been studied to a lesser extent.

In vivo, the Cerebral Cortex has been difficult to study due to its complex structure and regional variability. Measurement of Cerebral Cortex thickness at different disease stages may provide new insights into Gray Matter (GM) pathology.

In the present investigation, we evaluated in vivo Cortical thickness and its relationship to disability, disease duration, WM T₂ hyper-intense and T₁ HypoIntense lesion volumes.

High-resolution MRI Brain scans were obtained in 20 patients with clinically definite Multiple Sclerosis and 15 age-matched normal subjects.

A novel method of automated surface reconstruction yielded measurements of the Cortical thickness for each subject's entire Brain and computed cross-subject statistics based on the Cortical anatomy.

Statistical thickness difference maps were generated by performing t-tests between patient and control groups and individual thickness measures were submitted to analyses of variance to investigate the relationship between Cortical thickness and clinical variables.

The mean overall thickness of the Cortical ribbon was reduced in Multiple Sclerosis patients compared with controls [2.30 mm (SD 0.14) versus 2.48 mm (SD 0.11)], showing a significant main effect of group (controls versus patients).

In patients, we found significant main effects for disability, disease duration, T₂ and T₁ lesion volumes.

The visualization of statistical difference maps of the Cortical GM thickness on inflated Brains across the Cortical surface revealed a distinct distribution of significant focal thinning of the Cerebral Cortex in addition to the diffuse Cortical Atrophy.

Focal Cortical thinning in Frontal [2.37 mm (SD 0.17) versus 2.73 mm (SD 0.25)] and in Temporal [2.65 mm (SD 0.15) versus 2.95 mm (SD 0.11)] Brain regions was observed, even early in the course of the disease or in patients with mild disability.

Patients with longstanding disease or severe disability, however, presented additionally with focal thinning of the Motor Cortex Area [2.35 mm (SD 0.19) versus 2.74 mm (SD 0.15)].

We conclude that in vivo measurement of Cortical thickness is feasible in patients suffering from Multiple Sclerosis.

The data provide new insight into the Cortical pathology in Multiple Sclerosis patients, revealing focal Cortical thinning beside an overall reduction of the Cortical thickness with disease progression.

A mathematical model was applied to new lesion formation in Multiple Sclerosis, as apparent on frequent T₂-weighted MRI.

The pathophysiologically motivated two-process model comprises two opposing nonlinear self-limiting processes, intended to represent degenerative and reparatory processes, respectively, investigating T₂ activity from a dynamic/temporal rather than a spatial/static perspective.

Parametric maps were obtained from the model to characterize the MRI dynamics of lesion development, answering the questions of:

1. How long new T₂ lesion activity persists
2. How much residual damage/HyperIntensity remains
3. How the T₂ dynamics compare to those of contrast-enhancing MRI indicating active inflammation

997 MRI examinations were analyzed, acquired weekly to monthly from 45 patients over a 1-year period.

The model was applied to all pixels within 332 new lesions, capturing the time profiles with excellent fidelity (r = 0.89 +/- 0.03 average correlation between model and image data).

From this modeling perspective, the observed dynamics in new T₂ lesions are in agreement with two opposing processes of longitudinal intensity change, such as inflammation and degeneration versus resorbtion and repair.

On average, about one third of a new lesion consisted of transient signal change with little or no residual HyperIntensity and activity of 10 weeks or less.

Global lesion burden as MRI surrogate of disease activity may therefore be confounded by large amounts of transient HyperIntensity.

T₂ activity also persisted significantly beyond the period of contrast enhancement, thereby defining MRI sensitivity toward a subacute phase of lesion development beyond Blood-Brain Barrier patency.

Concentric patterns of dynamic properties within a lesion were observed, consistent with concentric histological appearance of resulting MS plaques.

Multiple Sclerosis (MS) is the most common cause of Neurological disability in young adults.

Recent studies have implicated specific Sodium ChannelSodium Channel isoforms as having an important role in several aspects of the pathophysiology of MS.

Including the restoration of Impulse Conduction after DeMyelination, Axonal Degeneration and the mistuning of Purkinje Neurons that leads to Cerebellar dysfunction.

By manipulating the activity of these channels or their expression, it might be possible to develop new therapeutic approaches that will prevent or limit disability in MS.

Axonal Degeneration is a major contributor to NonRemitting deficits in Multiple Sclerosis, and there is thus considerable current interest in the development of strategies that might prevent Axonal Loss in NeuroInflammatory Disease.

DysRegulation of Sodium Ion homeostasis has been implicated in mechanisms leading to Axonal Degeneration, and several studies have shown that blockade of Sodium Channels can ameliorate Axon damage following Anoxic, Traumatic and Nitric Oxide-induced CNS injury.

Two Sodium Channel Blockers, Phenytoin and Flecainide, have been reported to protect Axons in Experimental Autoimmune Encephalomyelitis (EAE) for 30 days, but long-term protective effects have not been studied.

We demonstrate here that oral administration of Phenytoin provides long-term (up to 180 days) protection for Spinal Cord CorticoSpinal Tract (CST) and Dorsal Column (DC) Axons in both monophasic (C57/BL6 mice) and Chronic/Relapsing (Biozzi mice) murine EAE.

Untreated C57/BL6 mice exhibit a 40-50% loss of CST and DF Axons at 90 and 180 days post-EAE induction via Myelin-Oligodendrocyte Glycoprotein (MOG) injection.

In contrast, only 4% of DF Axons are lost at 90 days, and only 8% are lost at 180 days in Phenytoin-treated C57/BL6 mice with EAE; only 21-29% of CST Axons are lost at 90 and 180 days in Phenytoin-treated C57/BL6 mice with EAE.

Attenuation of Dorsal Column compound Action Potentials was ameliorated and clinical status was also significantly enhanced with Phenytoin treatment at 90 and 180 days in this model.

In addition, inflammatory cell infiltration into the Dorsal Columns was reduced in Phenytoin-treated mice with EAE compared with untreated mice with EAE.

Similar results were obtained in Biozzi mice with Chronic/Relapsing EAE followed for 120 days post-injection.

These observations demonstrate that Phenytoin provides long-term protection of CNS Axons and improves clinical status in both Monophasic and Chronic/Relapsing models of NeuroInflammation.

Background
The activity of the Immune System displays a Circadian rhythm.

In diseases characterized by aberrant Immune activity, ChronoTherapy - treatment regimen tailored to diurnal body rhythms - may increase medication efficiency, safety, and tolerability.

The goal of this study was to compare the outcomes of IntraVenous CorticoSteroid administration during the day or night, for treatment of acute Multiple Sclerosis (MS) relapses.

Methods
Seventeen MS patients were included in the study.

Clinical assessment of disability was performed at trial entry, and at days 7 and 30 from therapy initiation.

Adverse events and preference of nighttime versus daytime therapy were assessed at the end of the treatment course.

Results
After nighttime treatment, clinical recovery was significantly enhanced and the mean number of side effects was significantly lower.

Furthermore, the majority of patients expressed a preference for nighttime versus daytime treatment.

Conclusions
The study suggests a potential benefit for implementation of chronotherapy using Steroid treatment for acute MS relapse, with implications for other Immune- mediated Disorders.

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.