MS Abstracts 01a-2g4

Treatment with Acetyl L-Carnitine (ALCAR) has been shown to improve Fatigue in patients with Chronic Fatigue Syndrome, but there have been no trials on the effect of ALCAR for treating Fatigue in Multiple Sclerosis (MS).

To compare the efficacy of ALCAR with that of Amantadine, one of the drugs most widely used to treat MS-related fatigue, 36 MS patients presenting fatigue were enrolled in a randomized, double-blind, crossover study.

Patients were treated for 3 months with either Amantadine (100 mg twice daily) or ALCAR (1 g twice daily). After a 3-month washout period, they crossed over to the alternative treatment for 3 months.

Patients were rated at baseline and every 3 months according to the Fatigue Severity Scale (FSS), the primary endpoint of the study. Secondary outcome variables were: Fatigue Impact Scale (FIS), Beck Depression Inventory (BDI) and Social Experience Checklist (SEC).

Six patients withdrew from the study because of adverse reactions (five on Amantadine and one on ALCAR). Statistical analysis showed significant effects of ALCAR compared with amantadine for the Fatigue Severity Scale (p = 0.039).

There were no significant effects for any of the secondary outcome variables. The results of this study show that ALCAR is better tolerated and more effective than Amantadine for the treatment of MS-related Fatigue.

Several studies have reported beneficial effects of IntraVenous ImmunoGlobulin (IVIg) in diseases of the NeuroAxis.

However, IVIg effects on Leukocyte recruitment, a hallmark feature of AutoImmunity and acute inflammation, remain largely unexplored.

Using intravital microscopy, we studied the effects of IVIg on Leukocyte recruitment in Experimental AutoImmune Encephalomyelitis, a model of Multiple Sclerosis.

In IVIg-treated mice, a significant decrease in recruitment (rolling and adhesion) was observed prior to and following disease onset, and this was concomitant with improved clinical score.

Since much of the recruitment is dependent upon alpha4-Integrin (Ligand for VCAM-1) we used an in vitro flow chamber system and demonstrated a 60% decrease in alpha4-Integrin-dependent Leukocyte adhesion to immobilized VCAM-1.

Finally, we used Leukocytes from Multiple Sclerosis patients and demonstrated that IVIg treatment decreased recruitment by 60% on human Endothelium.

However, when we visualized the role of IVIg in a second model of Brain inflammation, Cerebral Ischemia-reperfusion, IVIg actually promoted the formation of Platelet-Leucocyte aggregates in post-Ischemic Cerebral vessels.

In conclusion, we report a new mechanism of action of IVIg through interference of alpha4-Integrin-dependent Leucocyte recruitment in both an animal model and human Multiple Sclerosis.

We also report that IVIg will not be beneficial in all types of pro-adhesive states and may in fact be detrimental in a situation such as Stroke.

Background
Fatigue is experienced by most patients with Multiple Sclerosis (MS) and often is profoundly debilitating.

No large-scale studies to our knowledge have examined Circadian Rhythm abnormalities in MS patients or the relationship of Fatigue to Circadian Rhythms.

Objective
To determine if patients with MS and Fatigue have sleep disturbances or Circadian Rhythm abnormalities associated with Fatigue.

Design & Setting
Case-control study at Washington University School of Medicine, St Louis, Mo.

Patients
Fifteen patients with MS and Fatigue were compared with 15 patients with MS without Fatigue and 15 age- and sex-matched, healthy controls.

Main Outcome Measures
Sleep disturbances and Circadian Rhythm abnormalities were quantitated by Actigraphy, Fatigue by the Fatigue Descriptive Scale, and Excessive Sleepiness by the Epworth Sleepiness scale (ESS).

Results
Of the 15 Fatigued patients with MS, 2 had delayed sleep phase, 10 had disrupted sleep, and 3 had normal sleep.

One of the 15 NonFatigued MS patients had irregular sleep cycles, 2 others had disrupted sleep, and 12 had normal sleep. All 15 of the healthy controls had normal sleep.

Nine patients with MS and Fatigue scored 10 or higher on the ESS, suggesting excessive daytime Sleepiness. Only 2 patients with MS without Fatigue scored higher than 10 on the ESS. None of the healthy controls were fatigued, and 14 were not excessively sleepy.

A relationship was found between Fatigue and abnormal sleep cycles or disrupted sleep (Fisher exact test, P =.003). There was also a relationship between subjective excessive daytime Sleepiness and Fatigue in MS patients (P =.02).

Conclusion
There is a significant correlation between Fatigue in MS patients and disrupted sleep or abnormal sleep cycles.

Background/Aims
To describe the clinical characteristics and course of 16 patients with Uveitis associated with Multiple Sclerosis (MS).

Methods
The records of 1254 patients with Uveitis were reviewed. Sixteen of these patients had MS. The history, review of systems, Ocular findings, and clinical test results of each of these 16 subjects were analyzed. The mean follow-up time was 38 months.

Results
Most patients with MS-associated Uveitis were white females between 20 and 50 years of age. The diagnosis of MS preceded the onset of Uveitis in 56%, followed it in 25%, and was made concurrently in 19% of the cases.

In 94%, the Uveitis was BiLateral. Pars Planitis was the most frequent form of Uveitis in our study population (81%); concomitant anterior chamber inflammation was common and was Granulomatous in nature 56% of the time.

Forty-one percent of the eyes with MS-associated Uveitis had 20/30 or better initial Visual Acuity. Among these treated patients, significant loss of Visual Acuity was uncommon.

Conclusions
MS-associated Uveitis should be suspected in white female patients with BiLateral Uveitis, especially if Pars Planitis is present. These patients often retain useful vision for many years if treated.

Patients with Primary/Progressive Multiple Sclerosis (PPMS) typically experience a Progressive disease course from onset, leading to the accumulation of severe Neurological disability.

This is in contrast with the observation that the burden and activity of lesions on conventional Magnetic Resonance Imaging (MRI) scans of the Brain are much lower in patients with PPMS than in those with other less disabling forms of the disease.

Studies with structural and functional MRI techniques are providing relevant contributions to the understanding of the mechanisms underlying the accumulation of irreversible Neurological deficits in patients with PPMS.

The results of these studies underpin that the main factors possibly explaining the clinical/MRI discrepancy observed in patients with PPMS include the:

1. Presence of a diffuse tissue damage that is
   • beyond the resolution of conventional imaging
2. Extent of Cervical Cord damage
3. Impairment of the adaptive capacity of the Cortex
   • to limit the functional consequences of SubCortical pathology

Background
OligoClonal free kappa Bands are present as frequently as OligoClonal IgG Bands in the CerebroSpinal Fluid (CSF) from patients with Definite Multiple Sclerosis (MS) and can even occur in the absence of OligoClonal IgG.

As such, they too are markers of an ongoing Intrathecal Immune process.

Objectives
To determine how frequently OligoClonal free kappa bands are detectable in the CSF from patients with clinical signs and symptoms suggestive of MS in the absence of CSF restricted OligoClonal IgG.

Methods
An ImmunoAffinity mediated ImmunoBlotting technique specific for free kappa chains was used, after isoelectric focusing of paired CSF and Serum samples from 33 patients with clinical signs and symptoms suggestive of MS but without CSF OligoClonal IgG.

CSF data were correlated with MRI results in the context of the new diagnostic criteria from McDonald et al.

Results
Eighteen CSF samples contained OligoClonal free kappa Bands (54%), mainly from patients with motor dysfunction (83%) and Optic Neuritis (64%).

All patients with a positive MRI according to Barkhof's Criteria (n = 6) had free kappa bands in their CSF.

Conclusions

1. OligoClonal free kappa Bands in the CSF are related to the dissemination of MS lesions.
2. Such bands should be looked for in OligoClonal IgG negative CSF.
3. The presence of free kappa Bands in the CSF may be a substitute for OligoClonal IgG in the McDonald's Criteria for diagnosis of MS.

The objective of this study was to establish whether the time interval of 3 months is sufficient to detect whole-Brain Atrophy changes in patients with Relapsing/Remitting (RR) Multiple Sclerosis (MS).

Another aim was to assess the value of monthly gadolinium (Gd)-enhanced magnetic resonance imaging (MRI) and of different Gd-enhancement patterns as predictors of Brain Atrophy.

Thirty patients with RRMS (mean disease duration 4.9 years, mean age 34.4 years and mean Expanded Disability Status Scale [EDSS] 1.4) were assessed at baseline and monthly for a period of 3 months with clinical and MRI examinations.

Calculations of baseline and monthly absolute and percent changes of MRI measures have been obtained using two semiautomated (Buffalo and Trieste) and one automated (SPM99) segmentation method.

Changes of Brain Parenchymal Fraction (BPF) were investigated according to Gd-enhancement patterns. Mean absolute and percent changes of BPF did not significantly differ at any time point in the study for any of the three methods.

There was slight but not significant decrease of BPF from baseline to month 3: -0.0004 (0.05%), p=0.093 for Trieste; -0.0006 (0.07%), p=0.078 for Buffalo; and -0.0006 (0.08%), p=0.081 for SPM99 method.

In ring-enhancement positive patients, there was a significant difference between baseline and month 3 changes of BPF, EDSS, and number of relapses. Over the study period, we did not demonstrate differences between changes of BPF according to the presence of Gd enhancement.

Longitudinally, multiple regression analysis demonstrated that the only clinical or MRI parameter that predicted BPF decrease was the mean absolute change of ring-enhancing lesion load (R=0.62, p=0.003).

The noteworthy findings of this study are:
1. The observation that a significant Brain Atrophy progression cannot be detected over a 3-month period in RRMS.
2. The demonstration that the ring-enhancement pattern may contribute to more severe Brain tissue loss in the short term.
3. The lack of relationship between the presence and duration of Gd-enhancement activity and Brain Volume changes in the short term.

Two techniques that correct (normalize) Regional and Whole Brain Volumes according to head size-the proportion method (Tissue-to-IntraCranial Volume Ratio) and the residual method.

Regression-based predicted Brain tissue volumes are used pervasively in NeuroImaging research, but have received little critical evaluation or direct comparison.

Using a quantitatively derived MRI data set of patients with Multiple Sclerosis (n = 18) and age-/sex-matched normal controls (n = 18), we introduced various types of error into estimates of IntraCranial Volume (ICV) and Absolute Parenchymal Volume (APV).

To observe how this error affected the final outcome of normalized Brain measures and their ability to detect group differences, as computed by a proportion (Brain Parenchymal Fraction [BPF]) and residual method (Predicted Parenchymal Volume [PPV]).

The results indicated that systemic error in ICV and APV values considerably affected BPF means based on the proportion method, except with dependent-related systematic APV error, but essentially did not change statistical power associated with group differences in BPF.

Random error altered BPF means to a much smaller extent, but was associated with moderate reductions in statistical power.

On the other hand, PPV estimates based on the residual method were unaffected by these same ICV and APV errors, except with dependent-related systematic APV error, and were not associated with reductions in statistical power.

Our findings suggest that head size correction of Brain regions with the residual method generally may provide advantages over the proportion method.

In this review, the authors focus on clinical aspects of Central Nervous System (CNS) Atrophy in Multiple Sclerosis (MS), including the relationship between Atrophy and Disability, disease course, disease duration, quality of life, and Fatigue.

Cross-sectional studies have demonstrated a moderate but significant correlation between Brain or Spinal Cord Atrophy and physical disability in patients with MS.

Longitudinal studies (>/= 5 years) have shown that CNS Atrophy is a significant predictor of subsequent long-term Neurologic deterioration.

The clinical relevance of CNS Atrophy is reinforced by studies showing that Atrophy accounts for more variance than conventional lesion measures in predicting disability.

Impaired quality of life and both Urodynamic and Sexual Dysfunction, but not Fatigue, are associated with Brain Atrophy.

It is likely that once the level of CNS Atrophy reaches a critical threshold, patients begin to suffer clinical impairment and disease progression.

Longitudinal studies suggest that CNS Atrophy may occur in patients with Clinically Isolated DeMyelinating Syndromes who are at high risk for developing Clinically Definite MS.

Longitudinal natural history studies in Relapsing/Remitting, Secondary/Progressive, and Primary/Progressive MS have suggested that patients develop CNS Atrophy at a faster rate in the first few years of disease than later in the disease course.

Similarly, long-term follow-up studies have shown a poor relationship between disease duration and the rate of Brain Atrophy. The authors conclude that measurement of Atrophy of the CNS is emerging as a clinically relevant biomarker of the MS disease process.

For more than a century, Multiple Sclerosis was viewed as a disease process characterized by Oligodendrocyte and Myelin loss, and research into the pathogenesis of Multiple Sclerosis was mainly focused on the mechanisms of inflammation.

However, with development of more sophisticated NeuroImaging and Molecular Biology techniques, attention has shifted to new aspects of pathogenesis of Multiple Sclerosis: Axonal Loss and NeuroDegeneration.

Evidence is increasing that tissue destruction, primarily Axonal Loss and NeuroDegeneration, is a key element in the pathogenesis of Multiple Sclerosis.

In addition, it is now known that Brain and Spinal Cord Atrophy begins early in the disease process of Multiple Sclerosis and advances relentlessly throughout the course of the disease.

Cumulative data suggest that Axonal loss is the major determinant of progressive Neurologic disability in patients with Multiple Sclerosis.

Magnetic Resonance Imaging and Magnetic Resonance Spectroscopy in patients with Multiple Sclerosis for < 5 years indicate Brain Atrophy and loss of Axonal integrity.

NeuroDegeneration and Axonal Loss in patients with Multiple Sclerosis are initially accompanied by a local response from Oligodendrocyte Progenitor Cells and some ReMyelination.

However, these repair mechanisms eventually fail, and patients typically develop generalized Brain Atrophy, Cognitive decline, and permanent disability.

Although the exact mechanisms underlying Central Nervous System Atrophy in patients with Multiple Sclerosis are largely unknown.

Evidence exists that Atrophy may represent an epiphenomenon related to the effects of dynamic Inflammation within the Central Nervous System.

Including DeMyelination, Axonal injury, Neuronal Loss, Wallerian Degeneration, and possibly Iron deposition.

This article summarizes the potential mechanisms involved in Central Nervous System Atrophy in patients with Multiple Sclerosis.

Objective
To describe experience with the use of Mycophenolate Mofetil (MMF) in the treatment of Multiple Sclerosis (MS).

Background
MMF is a potent ImmunoSuppressant that is a Selective Inhibitor of Inosine 5'-Monophosphate Dehydrogenase Type II, the enzyme responsible for the de novo synthesis of the purine nucleotide guanine within activated T and B lymphocytes and macrophages.

Methods
A retrospective review of experience in treating 79 MS patients with MMF (61 with Secondary/Progressive, 14 with Relapsing/Remitting, and 4 with Primary/Progressive MS) in the authors' MS center.

Results
In most cases, MMF was added as adjunctive therapy in patients already being treated with either Interferon-beta (n = 44) or Glatiramer Acetate (n = 20).

Fifteen patients not able to use Interferon or Glatiramer Acetate were treated with MMF monotherapy.

Seventy percent of the patients continued MMF therapy. Eight patients discontinued therapy because of side effects, 7 patients continued to exhibit evidence of disease progression, 4 were denied insurance coverage, 2 were lost to follow-up.

And, 1 patient had an elevation of hepatic transaminases that resolved on discontinuation of MMF. One patient discontinued MMF therapy secondary to CytomegaloVirus Diarrhea.

Conclusion
MMF was well tolerated by the majority of patients treated. While these clinical observations were uncontrolled, the clinical course of MS was either unchanged or subjectively improved in many of the treated patients.

A randomized controlled trial of MMF in MS, either as monotherapy or in conjunction with Interferon or Glatiramer Acetate, appears warranted.

Prognosis of Multiple Sclerosis is highly variable. Clinical variables have been identified that are assessable early in the disease and are predictors of the time from the disease onset to the onset of irreversible disability.

Our objective was to determine if these clinical variables still have an effect after the first stages of disability have been reached.

We determined the dates of disease onset and assignment of scores of irreversible disability in 1844 patients with Multiple Sclerosis.

We used three scores on the Kurtzke Disability Status Scale as benchmarks of disability accumulation: 4 (limited walking but without aid); 6 (walking with unilateral aid); and 7 (wheelchair bound).

We used Kaplan-Meier analyzes and Cox regression models to determine the influence of the clinical variables on the time to disability onset.

Median times from onset of Multiple Sclerosis to assignment of a score of 4, 6 and 7 were significantly influenced by:
1. Gender
2. Age
3. Symptoms and course
4. Relapsing/Remitting or Progressive
   • at onset of the disease
5. Degree of recovery from the first relapse
6. Time to a second Neurological episode
7. Number of relapses in the first 5 years of the disease

Similarly, times from onset of Multiple Sclerosis to a score of 6 and 7 were influenced by time to a score of 4.

In contrast, none of the variables substantially affected the time from a score of 4 to a score of 6 or 7, or from a score of 6 to a score of 7.

Early assessable clinical variables significantly influence the time from the onset of Multiple Sclerosis to the assignment of a Disability score of 4, but not the subsequent progression of irreversible disability.