MS Abstracts 06d-2g5

Objectives
Therapy of acute exacerbations of Multiple Sclerosis (MS) with high-dose Intravenous MethylPrednisolone (IVMP) has shortened the recovery period after relapses.

But the mechanisms responsible for the beneficial effects of IVMP in attacks have not been clearly established.

Our purpose was to analyze the effect of IVMP on the expression of Chemokine Receptor 5 (CCR5) protein in blood in acute MS exacerbation.

Materials And Methods
Blood samples were collected from 10 patients with an acute MS exacerbation and the levels of CCR5 on CD4⁺ and CD8⁺ T-Cells and CD14⁺ Monocytes were analyzed by using flow cytometry before IVMP, 24 h, 1 and 3 weeks after commencement of treatment.

Results
During the 3-week period the percentages of CCR5-expressing CD4⁺ T -Cells and CD8⁺ T-Cells tended to decrease (P = 0.09 and 0.05, respectively), but the effect did not reach statistical significance.

No marked changes were found in the percentage of CCR5-expressing CD14⁺ Cells.

Conclusions
A tendency to a reduction of CCR5-expressing CD4⁺ and CD8⁺ blood cells induced by IVMP suggests inhibition of their potential to transmigrate into the Central Nervous System, which is consistent with the short-term beneficial effect of IVMP in acute exacerbation of MS.

Objective
Many patients with Multiple Sclerosis (MS) are currently receiving treatment with Interferon-beta (IFN-ß). Early identification of nonresponder patients is crucial to try different therapeutic approaches.

We investigated various criteria of treatment response to assess which criterion better identifies patients with a poor response.

Methods
We studied Relapsing/Remitting MS (RRMS) patients treated with IFN-ß and followed them up for at least 2 years.

Expanded Disability Status Score was scored every 3 months and relapses were recorded. We analyzed various criteria based on relapses, disability progression, or both.

Results
Three hundred ninety-three patients were included. After 2 years of treatment, we observed a proportion of nonresponders, ranging from 7 to 49% depending on the stringency of the criteria used.

Criteria based in disability progression had higher sensitivity, specificity, and accuracy.

The hazard ratio for the development of marked disability after 6 years of treatment was 39.6 (95% confidence interval, 16.6-94.4) among the patients who fulfilled the criterion based only in disability progression.

Interpretation
Criteria of response to IFN-ß therapy in RRMS using disability progression are more clinically relevant than those based only in relapse rate.

This finding may be important for the counseling and care of RRMS patients treated with IFN-ß.

Ann Neurol 2006;59:344-352.

A growing literature reports that stressful life events are associated with exacerbation and the subsequent development of Brain lesions in patients with Multiple Sclerosis (MS).

The evolution an MS exacerbation occurs over a period of many months and involves many different biological processes that change over time.

Likewise, the experience of stress also occurs over time, with an onset, a shift from acute to chronic in some cases, and resolution. Each of these phases is associated with unique biological features.

Thus, the impact of stress on MS exacerbation may depend on the temporal trajectories of stress and MS exacerbation, and when the intersection between these two trajectories occurs.

This paper presents a temporal model, along with three different temporal relationships and associated mechanisms by which stress may impact MS exacerbation.

These include the onset of a stressor, which may be mediated by Mast Cell activation, the point that a stressor begins to become chronic.

Which may be mediated by GlucoCorticoid resistance in Immune Cells, and the resolution of the stressor, which may be mediated by a drop in Cortisol.

These three hypotheses are not necessarily mutually exclusive.

Data on psychosocial mediators and moderators are also briefly reviewed and future research directions are discussed.

Objectives
Previous studies have shown that Upper Cervical Cord Atrophy (UCCA) occurs in Multiple Sclerosis (MS), particularly in those disabled and with Primary or Secondary/Progressive disease.

It is less clear how early it can be detected in Relapsing/Remitting (RR) MS, and whether early Cord Atrophy relates to the concurrent or future clinical course.

Methods
Twenty seven RR MS patients (median disease duration 1.7 years, in all cases < 3 years from onset) were recruited along with 20 controls.

They were followed for up to 3 years with a yearly assessment of UCCA and clinical function measured by the Expanded Disability Status Scale (EDSS) and MS Functional Composite Score (MSFC).

Clinical and MRI correlations were investigated. Statistical models adjusted for covariates including total IntraCranial volume.

Results
Longitudinal analysis showed a significant decrease in UCCA in patients both within the patient cohort (p < 0.001) and in comparison with controls (p = 0.001).

There was a significant increase in EDSS (p = 0.008) but no significant change in MSFC. The rate of UCCA loss did not correlate with clinical change or with change in Brain Volume.

Conclusions
In summary, serial UCCA measurement detects the development of Spinal Cord Atrophy in clinically early RR MS.

Background
Certain Stem Cell Transplantation procedures might slow down inflammatory pathology in Multiple Sclerosis (MS).

Aims
To halt disease progression in aggressive MS by a Bone Marrow Transplantation (BMT) protocol aimed at maximum T-Cell suppression.

Methods
Autologous BMT was performed in 14 patients with rapid Secondary/Progressive MS (median EDSS score at baseline, 6; median disease duration, five years).

To accomplish rigorous T-Cell ablation, a strong conditioning protocol was chosen-Cyclophosphamide, total body irradiation, and AntiThymocyte Globulin.

To minimize the possibility of reinfusing mature T-Cells in the graft, bone marrow, not peripheral blood, was used as the CD34+ stem cell source.

Results
Median follow up was 36 months (range, 7-36). Post-transplant haemopoietic recovery was successful in all patients.

Early toxicity included Epstein-Barr Virus related post-transplantation Lymphoproliferative disorder.

Longterm effects were development of AntiThyroid AntiBodies (three) and Myelodysplastic Syndrome (one). One patient died of progressive disease five years after transplantation.

Treatment failure, defined by EDSS increase sustained for six months or more, was seen in nine patients and stabilization or improvement in five.

Other clinical parameters generally showed the same outcome. No Gadolinium enhanced lesions were seen on post-treatment Magnetic Resonance Imaging, in either Cerebral or Spinal Cord scans. However, CerebroSpinal Fluid OligoClonal Bands remained positive in most cases.

Conclusions
This strong ImmunoSuppressive regimen did not prevent clinical progression in patients with aggressive Secondary MS.

The lack of efficacy, together with some serious side effects, does not favor the use of similar rigorous T-Cell depleting protocols in the future.

Background
Fatigue is a major complaint of Multiple Sclerosis (MS) patients. However, little is known about its pathophysiological mechanisms.

Evidence from Chronic Fatigue Syndrome and studies on sickness behavior suggest that Immune and NeuroEndocrine factors may play a causative role in the development of Fatigue.

Methods
We compared whole blood stimulatory capacity for pro- (TNF-, IFN-γ) and Anti-Inflammatory Cytokines (IL-10) as well as Hypothalamo-Pituitary-Adrenal (HPA) Axis function in 15 MS patients with marked Fatigue and 15 patients without Fatigue as determined by the Fatigue Severity Scale (FSS).

Results
Proinflammatory Cytokines were significantly higher (TNF-: 478.9 v 228.2 pg/ml, p = 0.01; IFN-γ: 57.6 v 27.8 pg/ml; p = 0.01) in MS patients with Fatigue.

Furthermore, TNF- values significantly correlated with daytime sleepiness as measured by the Epworth Sleepiness Scale (r = 0.64, p = 0.001).

Controlling for disease activity (as measured by the Cambridge Multiple Sclerosis Basic Score), disease duration, Expanded Disability Status Scale, and Depression further increased the correlation of Cytokine production and Fatigue.

HPA Axis activity was not related to Fatigue but was modestly correlated with Cognitive Impairment.

Conclusion
Our data suggest that Fatigue in MS is at least partially mediated through activation of ProInflammatory Cytokines.

In line with earlier findings, HPA Axis dysfunction seems not to be relevant in MS Fatigue pathogenesis but appears to be linked to Cognitive Impairment.

Our findings suggest that increased levels of inflammatory Cytokines may be involved in MS Fatigue. Investigation of Cytokine profiles may increase the understanding of Fatigue pathogenesis in MS.

Available ImmunoModulatory and conventional Steroid treatment regimens provide a limited symptomatic benefit for patients with Progressive Multiple Sclerosis (MS).

We performed an open trial on the short-term efficacy of repeated Intrathecal application of the sustained release Steroid TriamCinolone Acetonide (TCA) in 27 Progressive MS patients.

Six TCA administrations, performed every third day, reduced the Expanded Disability Status Scale (EDSS) score [initial: 5.4 +/- 1.3, 3-7.5 (mean +/- SD, range); end: 4.9 +/- 1.1; 2.5-6.5; P < 0.001] and significantly increased the walking distance and speed in particular after the fourth TCA injection.

Concomitantly serially determined CerebroSpinal Fluid (CSF) markers of cell injury, Neuron-specific Enolase, total tau-protein, S-100, and beta-Amyloid did not significantly change within the interval of TCA treatment. No serious side effects appeared.

We conclude that repeat Intrathecal injection of 40 mg TCA provides a substantial benefit in Progressive MS patients with predominant Spinal symptoms and does not alter CSF markers of Neuronal Cell injury.

Background
Patients with Primary/Progressive Multiple Sclerosis (PPMS) often develop severe disability despite low levels of abnormality on conventional Magnetic Resonance Imaging (MRI).

This may relate to diffuse pathological processes occurring in Normal Appearing Brain Tissue (NABT) involving both White Matter (NAWM) and Gray Matter (NAGM).

Magnetization Transfer Imaging (MTI) is capable of identifying these processes and may be particularly informative when applied to patients with early PPMS.

Aim
To assess the relationship between abnormalities in NABT identified by MTI and disability and other radiological data in patients with early PPMS.

Methods
We studied 43 patients within 5 years of disease onset and 43 controls.

The Expanded Disability Status Scale (EDSS) and the Multiple Sclerosis Functional Composite (MSFC) were scored.

Magnetization Transfer Ratios (MTR) of NABT, NAWM, and NAGM were calculated and the following MTR parameters were measured: mean, peak height, peak location, and MTR value at the 25th, 50th, and 75th percentiles.

Proton density, T₂, T₁, and Gadolinium enhancing lesion loads were also calculated.

Results
Differences were found between patients and controls in mean, peak height, and peak location of NAWM and NAGM (p < /=0.001).

Weak to moderate correlations were found between MTR parameters and disability in both NAWM and NAGM. Strong correlations between MTR parameters and lesion loads were found, particularly in NAWM.

Conclusion
MTR abnormalities are seen in NAWM and NAGM in early PPMS and both are associated with disability.

NAWM MTR abnormalities are more closely related to conventional MRI measures than those seen in NAGM.

Knowledge about the balance between heritable and nonheritable risk in Multiple Sclerosis (MS) is based on twin studies in high-prevalence areas.

In a study that avoided ascertainment limitations and directly compared continental Italy (medium-prevalence) and Sardinia (high-prevalence).

We ascertained 216 pairs from 34,549 patients. This gives a twinning rate of 0.62% among MS patients, significantly less than that of the general population.

In continental Italy, probandwise concordance was 14.5% (95% confidence interval, 5.1-23.8) for monozygotic and 4.0% (95% confidence interval, 0.8-7.1) for dizygotic twins.

Results in Sardinia resemble those in northern populations but in limited numbers.

Monozygotic concordance was 22.2% (95% confidence interval, 0-49.3) probandwise, but no concordant dizygotic pairs were identified.

A questionnaire on 80 items possibly related to disease cause was administered to 70 twin pairs, 135 sporadic patients, and 135 healthy volunteers.

Variables positively (7) or negatively (2) associated with predisposition and concordance in twins largely overlapped and were mainly linked to infection.

If compared with previous studies, our data demonstrate that penetrance in twins appears to correlate with MS prevalence.

They highlight the relevance of nonheritable variables in Mediterranean areas. The apparent underrepresentation of MS among Italian twins draws attention to protective factors, shared by twins, that may influence susceptibility.

Ann Neurol 2005.

Objective
To explore the potential of Dexrazoxane to suppress subclinical CardioToxicity in MS patients receiving Mitoxantrone.

Methods
An open-label study was performed to evaluate possible subclinical CardioToxicity in Multiple Sclerosis patients treated quarterly with Mitoxantrone (48mg/m(2) cumulative), with and without concomitant Dexrazoxane, using blinded serial Radionucleide Ventriculography.

Results
No patient experienced symptoms of heart failure. Patients receiving Dexrazoxane, which is Cardioprotective for Anthracyclines, exhibited a significantly lesser decline in Left Ventricular ejection fraction (mean change, -3.80% vs -8.55%, p < 0.001).

Interpretation
These results support a Cardioprotective effect of Dexrazoxane in Mitoxantrone treated Multiple Sclerosis patients.

Ann Neurol 2006;59:206-209.

This study examines the current knowledge of physiological and clinical effects of TetraHydroCannabinol (THC) and Cannabidiol (CBD) and presents a rationale for their combination in pharmaceutical preparations.

Cannabinoid and vanilloid receptor effects as well as non-receptor mechanisms are explored, such as the capability of THC and CBD to act as anti-inflammatory substances independent of Cyclo-Oxygenase (COX) inhibition.

CBD is demonstrated to antagonise some undesirable effects of THC including intoxication, sedation and tachycardia, while contributing Analgesic, Anti-Emetic, And Anti-Carcinogenic properties in its own right.

In modern clinical trials, this has permitted the administration of higher doses of THC, providing evidence for clinical efficacy and safety for Cannabis based extracts in treatment of Spasticity, Central Pain and Lower Urinary Tract symptoms in Multiple Sclerosis.

As well as sleep disturbances, peripheral Neuropathic Pain, Brachial Plexus Avulsion symptoms, Rheumatoid Arthritis and intractable Cancer pain.

Prospects for future application of whole Cannabis extracts in NeuroProtection, drug dependency, and neoplastic disorders are further examined.

The hypothesis that the combination of THC and CBD increases clinical efficacy while reducing adverse events is supported.

Hematopoietic Stem Cell (HSC) transplantation is a potential therapy that can offer Multiple Sclerosis patients a radical, potentially curative treatment.

Using Experimental Autoimmune Encephalomyelitis (EAE) as a model, we previously reported that retrovirally transduced B-Cells expressing Myelin Basic Protein (MBP), MBP Ac1-11, or Myelin Oligodendrocyte Glycoprotein p35-55 induced tolerance and reduced symptoms.

Here, we extend our tolerance approach using Bone Marrow (BM) cells expressing full-length PhosphoLipid Protein (PLP) in a model for Relapsing/Remitting EAE.

Using GFP expression as a marker, we found that up to 50% of cells were positive for transgene expression in peripheral blood after 900 rad irradiation and transduced BM transplantation, and expression was stable in hematopoietic lineages for over 10 weeks.

Upon challenge, T-Cell proliferation in response to PLP p139-151 was reduced and EAE was completely abolished in a pretreatment protocol.

In addition, protection from EAE could be achieved with PLP-transduced BM cells given on day 12 after immunization, a potential therapeutic protocol.

Finally, the protective effect of PLP-expressing BM could also be observed using a nonmyeloablative protocol, albeit with lower efficacy.

Our results suggest that HSC may be useful to achieve long-lasting tolerance to protect mice from EAE and possibly to promote CNS repair in ongoing EAE.