MS Abstracts 04d-2g7

Objective
To quantify Axonal Loss in the Retinal Nerve Fiber Layer (RNFL) in patients with Multiple Sclerosis (MS), with and without a history of Optic Neuritis, by means of ocular imaging technologies.

Methods
This cross-sectional study enrolled 50 patients with MS and 25 age- and sex-matched healthy controls.

All patients underwent Neurologic assessment and a complete Ophthalmic examination that included Visual Acuity, Visual Field Examination, Optical Coherence Tomography (OCT), Scanning Laser Polarimetry (GDx) and Visual Evoked Potentials (VEPs).

Visual parameters and RNFL measurements were evaluated in MS eyes with a prior Optic Neuritis episode (MS-ON), with no prior episode (MS-NON) and control subjects.

Results
There were significant differences (p < 0.05, analysis of variance) between MS-ON (n = 25 eyes) and healthy eyes (n = 25 eyes) for all RNFL parameters measured by OCT and GDx.

Significant differences between MS-NON (n = 75 eyes) and healthy eyes were also found for most of these parameters.

RNFL thickness in the temporal quadrant was the parameter with the greatest differences between groups (71.79 microm in healthy eyes, 60.29 microm in MS-NON and 53.92 microm in MS-ON, p < 0.0005).

Although there was a highly significant but moderate correlation between RNFL thickness and duration of the disease, no correlation was observed between RNFL thickness and Neurologic impairment (Expanded Disability Status Scale).

Conclusions
Axonal Loss was detected not only in MS eyes with a previous acute Optic Neuritis, but also in MS eyes with no known Optic Neuritis episode.

Structural abnormalities correlate with functional assessments of the Optic Nerve.

Studies in Canada have provided strong evidence that environmental factors act at a population level to influence the unusual geographical distribution of Multiple Sclerosis (MS).

However, the available data accommodate more than one type of environmental effect. Migration studies show that changes to early environment can greatly affect risk, and there are recent indications that risk can be altered in situ.

The rising incidence rates of MS in Canada implied by longitudinal increases in sex ratio place this effect in temporal context and narrow the candidates for mediating the effect of environment.

Similarly, geographical patterns in Australia imply that modifiable environmental factors hold the key to preventing some 80% of cases.

Genetic epidemiology provides overwhelming evidence that genetic background has an important complementary role. If genetic factors are held constant, the environment sets the disease threshold.

Although these could be independent additive risk factors, it seems more likely that susceptibility is mediated by direct interactions between the environment and genes.

Campath 1-H (Alemtuzumab) is a humanized MonoClonal AntiBody which targets the CD52 Antigen.

A low molecular weight glycoprotein present on the surface of most Lymphocyte lineages, causing Complement mediated lysis and rapid and prolonged T-Lymphocyte depletion.

Following encouraging initial data from other centres we report our open label experience of using Campath 1-H as a treatment in aggressive Relapsing Multiple Sclerosis:

In a consecutive series of 39 highly selected patients treated across three regional centres and followed for a mean of 1.89 years.

The mean annualized relapse rate fell from 2.48 pre treatment to 0.19 post treatment with 29% of documented relapses observed in the 12 weeks following initial infusion.

Mean change in EDSS was -0.36 overall and -0.15 in those patients completing >/=1 year of follow- up.

Eighty-three per cent of patients had stable or improved disability following treatment. Infusion related side effects were common including rash, headache and pyrexia but were usually mild and self limiting.

Transient worsening of pre-existing Neurological deficits during infusion was observed in 3 patients.

12 patients developed biochemical evidence of Autoimmune Dysfunction, 2 patients developed Thyroid Disease and 1 patient Autoimmune skin disease.

We conclude that relapse rates fall following Campath 1-H. While side effects were common these were normally self limiting or easily managed, suggesting Campath 1-H may be of use in the treatment of very active Relapsing/Remitting Multiple Sclerosis.

Understanding the neuropathology of Multiple Sclerosis (MS) is essential for improved therapies. Therefore, identification of targets specific to pathological types of MS may have therapeutic benefits.

Here we identify, by laser-capture microdissection and proteomics, proteins unique to three major types of MS lesions: acute plaque, chronic active plaque and chronic plaque.

Comparative proteomic profiles identified tissue factor and protein C inhibitor within chronic active plaque samples, suggesting dysregulation of molecules associated with coagulation.

In vivo administration of hirudin or recombinant activated protein C reduced disease severity in Experimental Autoimmune Encephalomyelitis and suppressed Th1 and Th17 Cytokines in Astrocytes and Immune cells.

Administration of mutant forms of recombinant activated protein C showed that both its anticoagulant and its signalling functions were essential for optimal amelioration of Experimental Autoimmune Encephalomyelitis.

A proteomic approach illuminated potential therapeutic targets selective for specific pathological stages of MS and implicated participation of the coagulation cascade.

Background
The few controlled longitudinal studies of Cognitive performance in MS patients all provide evidence of deterioration in at least a subset of the patients sampled.

Only one of these studies has focused on Primary/Progressive MS, and little attention has been paid to the specific domains of Cognitive functioning that change over time.

The present study examined three principal Cognitive Domains in samples of Primary/Progressive MS patients and healthy controls followed over a period of 3 years.

Methods
A battery of NeuroPsychological tests that included measures of Strategic Problem Solving, Verbal Memory, and Information Processing Speed was administered annually to 24 MS patients and 25 controls.

Results
MS patients' performance on measures of Processing Speed showed significantly greater decline over the 3-year period than did that of controls. Similar results were not observed in the case of problem solving or Verbal Memory.

There was no evidence of more dramatic decline occurring in patients who were initially classified as Cognitively impaired relative to those who were unimpaired at baseline.

However, this failure may have been influenced by differential attrition from the sample; more impaired patients were less likely to complete the study.

Conclusion
Overall the results support the contention that Information Processing Speed is the domain most sensitive to the impact of Multiple Sclerosis on Cognitive functioning over time.

Objective
To investigate the pattern of Cognitive Impairment in patients with Relapsing/Remitting (RR), Secondary/Progressive (SP), Primary/Progressive (PP) Multiple Sclerosis, and patients with Clinically Isolated Syndrome (CIS) suggestive of MS, relative to control participants in the Greek population.

Methods
RR patients (N=75), SP patients (N=29), PP patients (N=23), CIS patients (N=33), and healthy control participants (N=43) were assessed by the Brief Repeatable Battery of NeuroPsychological Tests (BRBN).

Results
The overall prevalence of Cognitive Dysfunction in our patients was 52.8% with CIS patients excluded and 47.5% with CIS patients included.

All MS patients differed significantly from controls in all BRBN measures.

Similar was the pattern of Cognitive Dysfunction in patients with CIS suggestive of MS, although Verbal Learning/Memory Capacity (as measured by the Selective Reminding Test) remained relatively spared.

The comparisons between patient groups revealed some differences in the performance mainly in favor of CIS and RRMS patients. These differences largely disappeared after controlling for physical disability (EDSS).

Conclusion
All MS subtypes patients exhibit a pattern of Cognitive Impairment running across the studied Cognitive domains.

The pattern of Cognitive Dysfunction in patients with CIS is similar with relative sparing of Verbal Learning.

Gadolinium-DTPA (Gd-DTPA) is routinely used as a marker for inflammation in MRI to visualize breakdown of the Blood-Brain Barrier (BBB) in Multiple Sclerosis.

Recent data suggest that Ultra-Small Superparamagnetic Particles of Iron Oxide (USPIO) can be used to visualize cellular infiltration, another aspect of inflammation.

This project aimed to compare the novel USPIO particle SHU555C to the longitudinal pattern of Gd-DTPA enhancement in Multiple Sclerosis. Nineteen Relapsing/Remitting patients were screened monthly using Gd-enhanced MRI.

In case of new enhancing lesions, USPIO were injected and 24 h later, MRI was performed and blood was collected to confirm USPIO loading of circulating Monocytes.

Lesion development was monitored by 3 monthly Gd-DTPA-enhanced scans and a final scan 7-11 months after injection.

USPIO-enhancement was observed as HyperIntensity on T₁-weighted images, whereas no signal changes were observed on T₂-weighted-gradient-echo images.

In 14 patients with disease activity, 188 USPIO-positive lesions were seen, 144 of which were Gd-negative. By contrast, there were a total of 59 Gd-positive lesions, 15 of which were USPIO negative.

Three patterns of USPIO-enhancement were seen:
1. Focal enhancement
2. Ring-like enhancement and
3. Return to IsoIntensity of a previously HypoIntense lesion

The latter pattern was most frequently observed for lesions that turned out to be transiently HypoIntense on follow-up scans.

And ring-enhancing lesions were less likely to evolve into black holes at follow-up than lesions without ring-like USPIO-enhancement; we speculate this to be associated with repair.

In 4% of the USPIO-positive/Gd negative lesions, USPIO-enhancement preceded Gd-enhancement by 1 month.

USPIO-enhancement remained visible for up to 3 months in 1.5% of all USPIO-positive lesions. In 29% of the lesions enhancing with both contrast agents, USPIO-enhancement persisted whereas Gd-enhancement had already resolved.

In conclusion, the new nano-particle SHU555C provides complementary information to Gd-enhanced MRI, probably related to Monocyte infiltration.

The use of USPIO-enhanced MRI is likely to lead to more insight in the pluriformity of inflammation in Multiple Sclerosis.

Uric Acid (UA), a product of purine metabolism, may be an antioxidant, perhaps acting as a scavenger of Peroxynitrite. Patients with Gout have a reduced incidence of Multiple Sclerosis (MS).

A number of studies found that patients with MS have low serum levels of UA, although it has not been established whether this represents a primary deficit or a secondary effect.

UA has also been proposed as a marker of disease activity and response to ImmunoSuppressive or ImmunoModulatory treatment.

We retrospectively reviewed 83 Relapsing/Remitting or Secondary/Progressive MS patients (64 females and 19 males) followed in our Neurology Unit.

We collected data concerning demographic variables as age and sex, and clinical variables as age of onset, clinical type, disease duration, EDSS score and total number of relapses.

We considered UA levels in three different situations: during a relapse, during remission period and during remission period under ImmunoModulatory treatment Interferon-beta-1a im (Avonex; Biogen Idec Inc., Cambridge, MA, USA).

Interferon-beta-1a sc (Rebif; Serono Europe Limited, London, UK), Interferon-beta-1b (Betaferon; Bayer Schering Pharma AG, Berlin, Germany) or Glatiramer Acetate (Copaxone; TEVA Neuroscience LLC, Kansas City, MO, USA).

A Wilcoxon matched pairs test was carried out to determine differences between groups. A P-value less than 0.05 was considered statistically significant.

In 33 patients, we were able to compare at least one UA value obtained during a relapse with at least one when remission without treatment. Mean serum UA levels were significantly lower when measured during a relapse (r: 0.39, P: 0.024).

In 27 cases, we compared at least one remission value without treatment with at least one obtained during remission and ImmunoModulatory treatment.

Mean serum UA levels significantly increased when determined during Interferon-beta or Glatiramer Acetate therapy (r: 0.84, P < 0.001).

Although we do not know exactly whether and how UA is involved in MS pathogenesis, our data suggest that UA might reflect disease activity or treatment response in MS.

Objective
To compare the effect of two types of Acupuncture on the quality of life of individuals with Secondary/Progressive Multiple Sclerosis and provide preliminary evidence regarding the safety of this intervention for this population.

Design & Setting
Preliminary single-blind randomized controlled trial. Outpatient attendance at rehabilitation unit.

Participants
Fourteen participants with Secondary/Progressive Multiple Sclerosis.

Interventions
Chinese medical Acupuncture or minimal Acupuncture. Participants received 10 treatments over five weeks.

Measures
Multiple Sclerosis Impact Scale 29, Fatigue Severity Scale and General Health Questionnaire 12 were measured pre and post intervention. Adverse events and other responses during treatment were recorded prospectively.

Results
Participants receiving minimal Acupuncture demonstrated statistically significant greater improvement in the Multiple Sclerosis Impact Scale.

29 psychological subscale compared with those receiving Chinese medical Acupuncture in an intention-to-treat analysis (P=0.04), with mean change in Chinese Acupuncture group of 6.0 (SD 13.9).

And in minimal Acupuncture group of 23.0 (SD 21.0). No other statistically significant difference between the groups was found.

No major adverse events were noted. Minor adverse events such as lower limb muscle spasms or pain were noted in some participants in both intervention groups.

Conclusion
Minimal Acupuncture resulted in greater improvement of Multiple Sclerosis Impact Scale 29 psychological subscale compared with Chinese medical acupuncture.

No other differences between the groups were found. In view of the small sample these results are not conclusive.

This study provides preliminary evidence to suggest that Acupuncture is safe for people with Secondary/Progressive Multiple Sclerosis. A large-scale trial is required to provide more definitive evidence.

We evaluated the incidence, volume, and spatial distribution of T₂-weighted Magnetic Resonance Imaging lesions in 58 children.

With Clinically Isolated Syndromes at risk for Multiple Sclerosis compared with 58 adults with Relapsing/Remitting Multiple Sclerosis.

Pediatric patients with Clinically Isolated Syndromes who had Brain lesions had SupraTentorial lesion volumes similar to adult Multiple Sclerosis patients, but greater InfraTentorial lesion volumes (p < 0.009), particularly in the Pons of male patients.

The predilection for InfraTentorial lesions the pediatric patients with Clinically Isolated Syndromes may reflect Immunological differences or differences in Myelin, possibly related to the CaudoRostral temporal gradient in Myelin maturation.

Ann Neurol 2008.

Background
Several studies have reported lower focal DeMyelination and inflammatory activity in Primary/Progressive Multiple Sclerosis (PPMS) than in Relapsing/Remitting MS (RRMS).

However, very little is known about possible differences in damage and distribution that may occur within lesions visible on Magnetic Resonance Imaging in the 2 forms of the disease.

Objective
To evaluate differences in spatial distribution and structural damage of focal DeMyelinating lesions in patients with PPMS and RRMS.

Design:
We acquired conventional Magnetic Resonance and Magnetization Transfer images in 24 PPMS and 36 RRMS patients (matched for sex, age, and disease duration) and 23 healthy sex- and age-matched controls.

In each participant, we measured T₂- and T₁-weighted lesion volumes and Magnetization Transfer Ratios in lesional and nonlesional Brain Tissues.

The spatial distribution of focal DeMyelination was assessed using T₂- and T₁-weighted lesion probability maps in each patient group. Voxel-based procedures were performed.

Setting
University hospital.

Results
Patients with PPMS had greater disability than those with RRMS, with 70% of PPMS patients and 11% of RRMS patients having relevant motor symptoms.

The T₁- and T₂-weighted lesion volumes were higher in PPMS than in RRMS patients (P < .001).

T₁- and T₂-weighted lesion probability maps showed that the maximum probability for lesions was higher in PPMS (peak probability, 45% and 29%, respectively) than in RRMS (peak probability, 33% and 19%, respectively).

Patients and was localized in the Corona Radiata. Voxelwise analysis of lesional Magnetization Transfer Ratios gave overlapping results.

Conclusions
Differences in Cerebral pathologic involvement exist between RRMS and PPMS and contribute to variations in clinical disability.

Interferon-beta (IFN-ß) reduces disease activity in a subgroup of patients with Relapsing/Remitting Multiple Sclerosis (MS). The mechanism of action as well as the PathoPhysiological basis of responsiveness to IFN-ß is not well understood.

Since T-Cell activation plays an important part in the pathophysiology of MS, we here investigated the effect of IFN-ß on the expression of co-signaling pathways (CD28-CD80/CD86, CD154-CD40, ICOS-ICOSL, PD-1-PD-L1/2).

In MS patients and correlated the results with the clinical response to IFN-ß in individual patients.

Expression of co-signaling molecules was measured by flow cytometry in vitro on Peripheral Blood MonoNuclear Cells after incubation with IFN-ß, and in vivo in whole blood samples of 32 untreated and 24 IFN-ß treated MS patients, including 13 patients longitudinal.

IFN-ß treatment induced upregulation of CD40, CD80, CD86, PD-L1 and PD-L2 on Monocytes as well as PD-L1 on CD4(1)-T-Cells in vitro and in vivo.

IFN-ß treated MS patients were grouped into responders and non-responders on the basis of Kurtzke's EDSS (Expanded Disability Status Scale) progression and relapse rate.

Upregulation of CD40, CD86 and PD-L2 on Monocytes was associated with treatment response to IFN-ß (P < 0.001, P = 0.028 and P = 0.028, respectively).

Our results show that IFN-ß upregulates co-stimulatory as well as co-inhibitory molecules in vitro and in vivo implicating that modulation of the balance between positive and negative co-stimulatory signals might be an important part of the mechanism of action of IFN-ß in MS.

Upregulation of the expression of CD40, CD86 and PD-L2 may be useful as a predictive marker for clinical response to IFN-ß treatment at early timepoints during IFN-ß therapy.