MS Abstracts 04d-2g5

Background
Genetic Epidemiological studies suggest both Genetic and Environmental factors have a role in Multiple Sclerosis (MS). Environmental effects are strongly suggested from geographical gradients, migration data, and discordance rates in twins.

In Epidemiological studies, risk of MS in offspring of small families and in those with an early birth-order position has been reported and interpreted in the context of the hygiene hypothesis, which is that infections at an early age, introduced by older siblings, are protective. We aimed to study the effect of birth order on MS risk.

Methods
A longitudinal, population-based sample of individuals with MS and their healthy siblings were identified from the Canadian Collaborative Project on Genetic Susceptibility to MS.

Data were grouped according to single (simplex) or multiple (multiplex) siblings with MS in a sibship. Separate analyses were done for each sibship size.

Findings
We studied 10 995 individuals with MS and 26 336 healthy siblings, and found no relation between MS risk and birth-order position.

In simplex sibships of at least seven siblings, slightly more siblings who were born late in the birth order had MS; the same was found for the first-born sibling with MS in a multiplex sibship.

Siblings with MS were slightly younger (p < 0.0001) than those without MS, contrary to the expected age at onset bias.

Interpretation
These findings do not support the hygiene hypothesis and could be due to a cohort effect resulting from increasing MS incidence.

Birth order has no effect on MS risk in most families, and there is no support for the hypothesis that having older siblings protects against MS.

Background
Movement-associated Cortical reorganization is known to occur in Multiple Sclerosis (MS). We aimed to define the development of such Cortical reorganization by comparing data from patients with different disease phenotypes.

Methods
We studied patients with different phenotypes of MS: 16 patients with a Clinically Isolated Syndrome (CIS), 14 patients with Relapsing/Remitting MS (RRMS) and no disability, 15 patients with RRMS and mild clinical disability, and 12 patients with Secondary/Progressive MS (SPMS).

Patients did a simple Motor Task with their unimpaired dominant hand during MRI, which was compared across the phenotype groups.

Findings
Patients with a CIS activated more of the ContraLateral Primary SensoriMotor Cortex than those with RRMS and no disability, whereas patients with RRMS and no disability activated more of the Supplementary Motor Area than those with a CIS.

Patients with RRMS and no disability activated more of the Primary SensoriMotor Cortex, BiLaterally, and more of the IpsiLateral Supplementary Motor Area than patients with RRMS and mild clinical disability.

Conversely, patients with RRMS and mild clinical disability activated more of the ContraLateral Secondary SomatoSensory Cortex and Inferior Frontal Gyrus, and the IpsiLateral Precuneus.

Patients with RRMS and mild clinical disability activated more of the ContraLateral Thalamus and of the IpsiLateral Secondary SomatoSensory Cortex than those with SPMS.

However, patients with SPMS activated more of the Inferior Frontal Gyrus, BiLaterally, the Middle Frontal Gyrus, BiLaterally, the ContraLateral Precuneus, and the IpsiLateral Cingulate Motor Area and Inferior Parietal Lobe.

Interpretation
Movement-associated Cortical reorganization in patients with MS seems to vary across individuals at different stages of disease.

Our study suggests that early in the disease course, more areas typically devoted to Motor Tasks are recruited. Then BiLateral activation of these regions is seen, and late in the disease course, areas that healthy people recruit to do novel or complex tasks are activated.

Multiple Sclerosis (MS) is associated with a variety of symptoms and functional deficits that result in a range of progressive impairments and handicap.

Symptoms that contribute to loss of independence and restrictions in social activities lead to continuing decline in quality of life.

Our aim is to give an updated overview on the management of symptoms and rehabilitation measures in MS. Appropriate use of these treatment options might help to reduce long-term consequences of MS in daily life.

First, we review treatment of the main symptoms of MS: Fatigue, Bladder and Bowel Disturbances, Sexual Dysfunction, Cognitive and Affective Disorders, and Spasticity. Even though these symptomatic therapies have benefits, their use is limited by possible side-effects.

Moreover, many common disabling symptoms, such as weakness, are not amenable to drug treatment. However, NeuroRehabilitation has been shown to ease the burden of these symptoms by improving self-performance and independence.

Second, we discuss comprehensive multidisciplinary rehabilitation and specific treatment options.

Even though rehabilitation has no direct influence on disease progression, studies to date have shown that this type of intervention improves personal activities and ability to participate in social activities, thereby improving quality of life.

Treatment should be adapted depending on: the individual patient's needs, demands of their surrounding environment, type and degree of disability, and treatment goals.

Improvement commonly persists for several months beyond the treatment period, mostly as a result of reconditioning and adaptation and appropriate use of medical and social support at home.

These findings suggest that quality of life is determined by disability and handicap more than by functional deficits and disease progression.

Objectives
To study in Relapsing-/Remitting (RR) Multiple Sclerosis (MS) whether exacerbations and Brain activity as measured by Magnetic Resonance Imaging (MRI) are associated with plasma levels of Anti-Epstein Barr (EBV) AntiBodies and EBV DNA.

Methods
This was a prospective study with 73 RR MS patients followed for an average of 1.7 years with frequent Neurological Examination and blood sampling. AntiBodies to various EBV proteins were measured by ELISA and plasma EBV DNA was measured by PCR.

Results
All MS patients had IgG antibodies to EBV (Viral Capsid Antigen (VCA) and/or EBV Nuclear Antigen (EBNA)), irrespective whether samples were taken at stable disease or exacerbation.

A significantly elevated percentage of the patients (48%) had AntiBodies against EBV Antigens (early antigen, EA) that indicate active viral replication, compared with the age matched healthy controls (25%).

AntiBodies against a control herpesvirus, cytomegalovirus, were similar between the two groups. The percentage of EA positive individuals and EA titres did not differ between stable disease or exacerbation.

Anti-VCA IgM was positive in three cases, unrelated to disease activity. Using a highly sensitive PCR on 51 samples taken at exacerbation visits, only three patients were found to have one timepoint with Viraemia, and this viraemia was unrelated to disease activity.

Of special note was the fact that anti-EA seropositive patients remained seropositive during follow up, with stable titres over time.

We hypothesised that these patients may constitute a subgroup With higher disease activity, due to the triggering effect of a chronic attempt of the virus to reactivate.

The EA positive group did not differ from the EA negative with respect to clinical disease activity or other characteristics. However, in the EA positive group, analysis with Gadolinium enhanced MRI indicated more MRI disease activity.

Conclusions
There was no evidence for increased clinical disease activity in the subgroup of MS patients with serological signs of EBV reactivation.

However, the observation that chronic EBV reactivation may be associated with increased inflammatory activity as assessed by Gadolinium enhanced MRI lesions should be reproduced in a larger and independent dataset.

Functional Magnetic Resonance Imaging (fMRI) using Paced Auditory Serial Addition Test (PASAT) as paradigm was used to study the functional connectivity in 18 patients at the very early stage of Multiple Sclerosis (MS).

Compared with 18 controls, to determine the existence of circuitry disturbance inside the Working Memory Network and its relationship with White Matter abnormalities assessed by conventional MRI and Magnetization Transfer Ratio (MTR) imaging.

The left BA Area 45/46 was selected as the seed region to compute correlation maps with other Brain regions. After obtaining the correlation map for each subject, between-group comparisons were performed using random effect procedure.

Compared with controls, patients did not show any greater functional connectivity between left BA 45/46 and other regions during PASAT.

In contrast, decrease in functional connectivity was observed in patients between left BA 45/46 and left BA 9, right BA 3, and the Anterior Cingulate Cortex (BA 24).

In patients, no correlations were found between altered functional connectivity and clinical data.

However, functional connectivity observed between left BA 45/46 and BA 24 in patients was correlated with the MTR of Normal-Appearing White Matter, and with Brain T₂ lesion load.

Altered functional connectivity is present inside the Working Memory Network of patients at the very early stage of MS and is related to the extent of diffuse White Matter changes.

Journal of Cerebral Blood Flow & Metabolism (2005) 25, 1245-1253.

Pain is more common in Multiple Sclerosis (MS) than has previously been recognized. In the present study we have investigated the occurrence of Central Pain (CP) in MS and defined its characteristics.

Questionnaires were sent to all 429 patients with Definite MS in the patient register at our Neurology department. All admitting to pain were interviewed and offered an extended interview and examination.

Three hundred and sixty four patients responded (86%), of whom 57.5% reported Pain during the course of their disease (21% Nociceptive, 2% Peripheral Neuropathic and 1% related to Spasticity).

One hundred patients (27.5%) had CP, including 18 patients (4.9%) with Trigeminal Neuralgia. The Non-Trigeminal CP was, in 87%, located in the lower and in 31% in the upper extremities. It was mostly BiLateral (76%) and constant, with 88% experiencing daily Pain.

Only 2% had Paroxysmal attacks. Aching, burning, pricking were the commonest qualities. The Pain was intense with small to moderate spontaneous variation.

In 5.5% of all patients (20% of the patients with CP), Pain was a presenting symptom, alone or in combination with other symptoms.

The most common Neurological symptoms/signs besides CP were Sensory abnormalities (98%, dominated by abnormal sensibility to painful stimulus and temperature).

Trigeminal Neuralgia in MS started later in life and after longer disease duration than Non-Trigeminal Pain.

Both types of CP existed either chronically or as a feature of relapse. Central Pain is thus an important symptom in MS (around 30%) and causes much suffering.

Aim
In addition to Optic Neuritis (ON), Multiple Sclerosis (MS) may also involve the eye with a typically BiLateral intermediate Uveitis.

The aim of this pilot study was to evaluate the efficacy of type I Interferons (IFN-ß) for the treatment of MS associated Uveitis.

Methods
In this non-randomised, retrospective observational case series 13 patients (eight female, five male) with proved MS and associated Uveitis from five Uveitis centers who were treated with Interferon-ß-1a were included.

Visual Acuity (VA), cell count in the aqueous Humour and Vitreous, as well as the presence of Cystoid Macula Oedema (CMO) were observed.

Results
All except one patient had a BiLateral form of intermediate Uveitis (total of 24 eyes).

Seven patients had documented CMO before IFN treatment (n = 13 eyes). Median duration of treatment was 24.6 months (range 7.9-78.7).

VA improved in 17 eyes (comparing VA before therapy and at last follow up); while 10 eyes (36%) improved >/=3 Snellen lines. Aqueous cell count improved by 1.2 (SD 1.1) grades in all eyes.

Vitreous cell count improved by 1.7 (1.4) in all eyes. Only two patients still had minimal CMO on last follow up angiographically. CMO resolved after or during IFN treatment in nine eyes.

Conclusions
IFN has been shown to have beneficial effects in patients with MS and/or ON.

As shown in the models of Experimental Allergic Encephalomyelitis (EAE) and Uveitis, the Neurological and Ophthalmological manifestations seem to share similar pathogenic mechanisms.

Treatment of MS associated Uveitis with IFN-ßappears to have beneficial effects on VA, IntraOcular inflammation activity, and the presence of CMO.

Objectives
Glatiramer Acetate (GA) is routinely used in Multiple Sclerosis (MS) patients who cannot tolerate or fail to respond to Interferon-beta (IFN-ß).

The aim of this study was to assess the efficacy and tolerability of GA in these patients.

Methods
Fifteen Relapsing/Remitting MS patients who had discontinued IFN-ß therapy due to side effects were included in this open, 1-year prospective study.

Neurologic examinations and laboratory assessments were performed every 3 months. The induction of MxA protein production was also evaluated.

Results
Eleven of fifteen patients (73%) tolerated GA well whereas four patients (27%) discontinued treatment due to side effects.

The relapse rate reduced from 1.86 per year to 0.91 per year. Neither laboratory abnormalities nor MxA protein induction was found.

Conclusion
GA can be considered as a good treatment alternative to IFN-ß-intolerant MS patients.

However, some patients were not able to use available Immunomodulative treatments, which emphasizes the need for new therapeutic options. The lack of MxA protein induction confirms the different mechanisms of action of GA and IFN-ß.

AntiBodies to Myelin components are routinely detected in Multiple Sclerosis patients. However, their presence in some control subjects has made it difficult to determine their contribution to disease pathogenesis.

Immunization of C57BL/6 mice with either rat or human Myelin Oligodendrocyte Glycoprotein (MOG) leads to Experimental Autoimmune Encephalomyelitis (EAE) and comparable Titers of Anti-MOG AntiBodies as detected by ELISA. However, only immunization with human (but not rat) MOG results in a B-Cell-dependent EAE.

In this study, we demonstrate that these pathogenic and nonpathogenic Anti-MOG AntiBodies have a consistent array of differences in their recognition of antigenic determinants and biological effects.

Specifically, substituting Proline at position 42 with Serine in human MOG (as in rat MOG) eliminates the B-Cell requirement for EAE.

All MOG proteins analyzed induced high Titers of Anti-MOG (tested by ELISA), but only AntiSera from mice immunized with unmodified human MOG were Encephalitogenic in primed B-Cell-deficient mice.

Nonpathogenic IgGs bound recombinant mouse MOG and deglycosylated MOG in Myelin (tested by Western blot), but only pathogenic IgGs bound glycosylated MOG.

Only purified IgG to human MOG bound to live rodent Oligodendrocytes in culture and, after cross-linking, induced repartitioning of MOG into lipid rafts, followed by dramatic changes in cell morphology.

The data provide a strong link between in vivo and in vitro observations regarding DeMyelinating Disease, further indicate a biochemical mechanism for Anti-MOG-induced DeMyelination, and suggest in vitro tools for determining Autoimmune AntiBody pathogenicity in Multiple Sclerosis patients.

Defective elimination of AutoReactive Cells is thought to play a role in the development of AutoImmune Diseases including Multiple Sclerosis (MS).

We examined the activation of the ATM-CHK2-p53 pathway in MS patients after subjecting their Peripheral Blood Mononuclear Cells to gamma-irradiation.

We found that peripheral blood mononuclear cells from a subset of MS patients show resistance to cell death induced by irradiation.

This defect is due to impaired constitutive expression and activation of ATM (Ataxia Telangiectasia Mutated), resulting in impaired stabilization of p53.

We predict that these fundamental defects likely alter the regulation of the Immune population of cells in MS and may contribute to the development or progression of the disease.

Ann Neurol 2005;58:577-584.

Objective
To examine Neurological and Magnetic Resonance Imaging (MRI) changes following discontinuation of Interferon-ß-1a (IFN-ß-1a) treatment in Secondary/Progressive Multiple Sclerosis (SPMS).

Methods
The study involved 21 SPMS patients who received subcutaneous (s.c.) IFN-ß-1a 44 microg three times weekly (t.i.w.) for 12 months and were thereafter followed up without treatment for a further 12 months.

The number of relapses, Disability on the Expanded Disability Status Scale (EDSS) and MRI were recorded at baseline, at 12 months of IFN-ß-1a 44 microg t.i.w. and 1 year after discontinuation of treatment.

Results
During the 12-month treatment EDSS score and volumes of Brain T₂- and T₁-weighted lesions remained without significant progression, but at 12 months after treatment discontinuation both EDSS score and the volumes of Cerebral lesions increased significantly.

CerebroSpinal Fluid fraction increased significantly both during the treatment and during follow-up.

Conclusions
Discontinuation of IFN-ß-1a 44 microg t.i.w. in SPMS may be associated with an increase in Neurological Disability and Brain lesions on MRI.

The efficacy of Interferon-ß (IFN-ß) has been shown in several placebo-controlled, parallel-group studies in Relapsing/Remitting Multiple Sclerosis (RRMS).

PRISMS, the largest such study to date, clearly demonstrated the efficacy of IFN-ß-1a on all outcome measures over 2 years during the placebo-controlled, parallel-group phase.

However, this study's placebo-crossover design also provided us with a unique opportunity to conduct a prospective within-group assessment, eliminating the impact of inter-patient variability.

At the start of year 3, patients receiving placebo during years 1-2 were re-randomized in a dose-blinded fashion to receive IFN-ß-1a, 22 or 44 mcg subcutaneously three times weekly, during years 3 and 4.

Clinic visits occurred 3-6 monthly and T₂ MRI scans were obtained after 1 and 2 years on therapy.

Comparison of the mean relapse count per patient over 2 years (the primary outcome measure) during time on placebo (years 1 and 2) with that during active treatment (years 3 and 4) revealed a decrease from 2.6 to 1.2 in both dose groups (54% relative reduction; p< 0.001).

Disability progression, T₂ MRI lesion activity and accumulation of T₂ lesion burden were also significantly improved with therapy (p< 0.01). No new safety issues were noted.

These data provide further support for IFN-ß-1a's efficacy in RRMS. The ability to detect significant treatment effects with reduced patient numbers in this type of before/after analysis, may be due to the reduction in inter-patient variability.