MS Abstracts 01d-2g6

High dose CorticoSteroid (CS) administration is a common mode of therapy in treatment of acute relapses in Multiple Sclerosis (MS) but the effects of CS on ReMyelination and the cellular mechanisms mediating this repair process are controversial.

We have examined CS effects on repair of toxin-induced DeMyelinating lesions in the adult rat Spinal Cord.

CorticoSteroids reduced the extent of Oligodendrocyte ReMyelination at 1 month post lesion (whereas Schwann-Cell mediated repair was unaffected).

However, CS did not cause permanent impairment of ReMyelination as lesions were fully ReMyelinated at 2 months after cessation of treatment.

The delay in Oligodendrocyte mediated repair could be attributed to inhibition of differentiation of Oligodendrocyte Progenitor Cells (OPCs) into Oligodendrocytes, with no effect of CS treatment observed on OPC colonization of the lesions.

No differences were observed in animals treated with MethylPrednisolone Succinate alone or with a subsequent Prednisone taper indicating that CS effects occur at an early stage of repair.

The potential consequences of delayed ReMyelination in inflammatory lesions are discussed.

(c) 2006 Wiley-Liss, Inc.

Evoked Potentials (EP) have a role in making the diagnosis of Multiple Sclerosis (MS) but their implication for predicting the future disease course in MS is under debate.

EP data of 94 MS patients examined at first presentation, and after five and ten years were retrospectively analysed.

Patients were divided into two groups in relation to the prior duration of disease at the time point of first examination: group 1 patients (n=44) were first examined within two years after disease onset, and group 2 patients (n=50) at later time points.

As primary measures sum scores were calculated for abnormalities of single and combined EP (Visual (VEP), SomatoSensory (SEP), magnetic Motor Evoked Potentials (MEP)).

In patients examined early after disease onset (group 1), a significant predictive value for abnormal EP was found with MEP and SEP sum scores at first presentation correlating significantly with Expanded Disability Status Scale (EDSS) values after five years, while the VEP sum score was not.

The cumulative number of abnormal MEP, SEP and VEP results also indicated higher degrees of disability (EDSS > or = 3.5) after five years. Combined pathological SEP and MEP findings at first presentation best predicted clinical disability (EDSS > or = 3.5) after five years (odds ratio 11.0).

EP data and EDSS at first presentation were not significantly linked suggesting that EP abnormalities at least in part represented clinically silent lesions not mirrored by EDSS.

For patients in later disease phases (group 2), no significant associations between EP data at first presentation and EDSS at five and ten years were detected.

Together with clinical findings and MR imaging, combined EP data may help to identify patients at high risk of long-term clinical deterioration and guide decisions as to ImmunoModulatory treatment.

Ring-enhancing lesions seen on MR images can occur with a variety of etiologies. Some ring-enhancing lesions have HypoIntense rims peripherally on T₂-weighted MR images.

In this study, we examined whether T₂ HypoIntense rims were associated with specific pathologies.

A search for ring-enhancing lesions on MR images obtained from 1996 to 2004 was performed, and revealed 221 patients with MRI findings of ring enhancement.

The pattern of T₂ HypoIntensity (arc or rim) corresponding with ring enhancement was recorded.

In addition, we analyzed other imaging characteristics, including signal on Diffusion-weighted images, central homogeneity on T₂ and multiplicity of lesions.

We then reviewed clinical data on the patients to ascertain the diagnosis for each examination. The most common associated pathologies in our study were Gliomas (40%), Metastases (30%), Abscesses (8%) and Multiple Sclerosis (MS; 6%).

HypoIntense borders on T₂-weighted images were present in 67% of lesions in the form of a rim in 40% and an arc in 60%. Abscesses had the highest percentage of HypoIntense rims.

Metastases and Gliomas more commonly had arcs, and MS lesions were divided between rims and arcs.

Abscesses and MS lesions were more commonly homogeneous centrally, compared to Gliomas and Metastases. Additionally, abscesses were more often bright on Diffusion imaging than the other pathologies.

As expected, Abscesses and MS lesions were usually multiple, whereas Metastases were typically multiple in approximately 50% of the patients; Gliomas were generally solitary.

Trends in T₂ HypoIntensity may aid in distinguishing among etiologies of ring-enhancing lesions, although there is overlap between the MR appearance of these various pathologies.

Objectives
To evaluate the association between Callosal or PeriVentricular lesions, and the presence of OligoClonal IgG Bands (OB) or the IgG index in Japanese patients with Multiple Sclerosis (MS).

Materials And Methods
Brain Magnetic Resonance Imaging (MRI) was studied in 34 Japanese clinically definite MS cases.

Sagittal 2-mm fast Fluid-Attenuated Inversion-Recovery (FLAIR) imaging was added to the routine MRI studies.

Results
Among the 34 patients, 20 (59%) were OB positive. Among the 20 patients with OB-positive MS, 17 (85%) had Callosal lesions, although only two (14%) of 14 OB-negative MS patients had Callosal lesions.

The PeriVentricular lesion area was significantly larger in the OB-positive patients compared with the OB-negative patients.

Conclusions
The present study clearly demonstrated a strong association between the PeriVentricular lesions and OB in Japanese MS.

Certain OB-related Immune mechanisms may contribute to the development of Callosal and PeriVentricular lesions in MS. OB may be an important factor to understand the pathomechanisms of MS lesions.

Background
The Controlled High Risk Subjects Avonex Multiple Sclerosis Prevention Study (CHAMPS) showed that IM Interferon-beta-1a (IFN-ß-1a) significantly slows the rate of development of clinically definite Multiple Sclerosis (CDMS).

Over 2 years, in high-risk patients who experience a first clinical DeMyelinating event.

This report highlights the primary results of a 5-year, open-label extension of CHAMPS (the Controlled High Risk Avonex Multiple Sclerosis Prevention Study in Ongoing Neurologic Surveillance [CHAMPIONS Study]).

Objective
To determine if the benefits of IFN-ß-1a observed in CHAMPS are sustained for up to 5 years.

Methods
CHAMPS patients at participating CHAMPIONS sites were enrolled in the study.

All patients were offered, but not required to take, IFN-ß-1a 30 microg IM once weekly for up to 5 years (from CHAMPS randomization).

Patients who received placebo in CHAMPS were considered the Delayed Treatment (DT) group, and patients who received IFN-ß-1a in CHAMPS were considered the Immediate Treatment (IT) group.

The primary outcome measure was the rate of development of CDMS. Additional outcomes included disease state classification at 5 years, annualized relapse rates, disability level at 5 years (Expanded Disability Status Scale), and MRI measures at 5 years.

Results
Fifty-three percent (203/383) of patients enrolled in CHAMPIONS (n = 100, IT group; n = 103, DT group) and 64% (32/50) of CHAMPS study sites participated in CHAMPIONS.

The median time to initiation of IFN-ß-1a therapy in the DT group was 29 months.

The cumulative probability of development of CDMS was significantly lower in the IT group compared with the DT group (5-year incidence 36 +/- 9 vs 49 +/- 10%; p = 0.03).

Multivariate analysis suggested that the only factors independently associated with an increased rate of development of CDMS were randomization to the DT group and younger age at onset of Neurologic symptoms.

Few patients in either group developed major disability within 5 years.

Conclusions
These results support the use of IM Interferon-ß-1a after a first clinical DeMyelinating event and indicate that there may be modest beneficial effects of immediate treatment compared with delayed initiation of treatment.

Objective
To investigate disease progression and risk factors in a large geographically based population with Multiple Sclerosis (MS), using two different inception points--clinical onset and date of birth.

Methods
The authors reviewed a database of subjects with definite MS and symptom onset prior to July 1988.

The main outcome was sustained progression to Expanded Disability Status Scale (EDSS) 6 (requires a cane), using the date of birth and date of MS onset as inception points in separate analyses.

Risk factors examined were sex, Relapsing vs Primary/Progressive course, onset age, and onset symptoms.

Results
The study included 2,837 patients, followed prospectively for 22,723 patient years.

The median time to EDSS 6 was 27.9 years, 15 years after onset; only 21% reached EDSS 6, and by age 50, 28% required a cane.

Men progressed 38% more quickly than women from onset (p < 0.0005), yet both required canes at similar ages: 58.8 years for men and 60.1 for women (p = 0.082).

A younger onset age predicted a slower progression, but those older at onset were consistently older when reaching EDSS 6.

A Primary/Progressive course predicted a more rapid progression from both onset (p < 0.0005) and birth (hazard ratio = 2.7 [95% CI: 2.2 to 3.3]). No onset symptom consistently predicted progression.

Conclusion
Disability progression in Multiple Sclerosis (MS) accrued more slowly than found in earlier longitudinal studies.

The authors also challenged two fundamental concepts in MS, demonstrating that neither male sex nor older onset age was associated with worse disease outcome.

Many efforts have been devoted to the description of the prognosis of Multiple Sclerosis and its possible influential factors in terms of time to reach disability milestones.

By contrast, the age at which patients with Multiple Sclerosis reach these milestones has not yet stirred much interest.

We have tested the hypothesis whether the prognosis of Multiple Sclerosis depends on the current age of patients and the initial course of the disease.

We have assessed disease onset and course, and assignment of scores of irreversible disability in 1844 patients with Multiple Sclerosis.

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

We used Kaplan-Meier analyses to estimate the age of the patients at assignment of disability milestones.

The possible influence of the initial course of Multiple Sclerosis and of other clinical variables early assessable in the disease on these outcome measures was also studied, using the Kaplan-Meier curves for univariate analyses and Cox models for multivariate analyses.

For the 1844 patients, median ages at time of assignment of irreversible disability were 44.3 years (95% CI 43.3-45.2) for a score of DSS 4, 54.7 years (95% CI 53.5-55.8) for DSS 6 and 63.1 years (95% CI 61.0-65.1) for DSS 7.

These results were essentially similar whether the initial course of Multiple Sclerosis was Exacerbating/Remitting or Progressive, and whatever the initial symptomatology. Females reached disability milestones at an older age than males.

The most influential clinical factor was age at clinical onset of Multiple Sclerosis: the younger the onset, the younger the age at assignment of disability milestones.

Therefore, prognosis in Multiple Sclerosis appears, at least to some extent, as age-dependent and not substantially affected by the initial course, be it Exacerbating/Remitting or Progressive.

Aside acute focal recurrent inflammation and diffuse chronic NeuroDegeneration, accelerated ageing-related mechanisms may operate in the Central Nervous System of Multiple Sclerosis patients.

There is convincing evidence that Neurological relapses in Multiple Sclerosis (MS) are the clinical counterpart of acute focal inflammation of the Central Nervous System (CNS) whereas Neurological progression is that of chronic diffuse NeuroDegeneration.

The classical view is to consider that MS is an organ-specific Autoimmune Disease, i.e. that inflammation is the cause of the NeuroDegeneration.

The succession of relapses eventually leads to accumulation of disability and clinical progression results from subclinical relapses.

A series of recent observations tends to challenge this classical concept. Important observations have come from the study of the natural history of MS.

In the Lyon MS cohort, accumulation of irreversible disability appeared not to be affected by clinically detectable Neurological relapses.

This has also been shown to be "amnesic" for the early clinical characteristics of the disease, and essentially age-dependent.

Suppressing relapses by disease-modifying agents does not dramatically influence the progression of irreversible disability.

Interferons-beta reduce the relapse rate by 30% and conventional MRI activity by more than 50%. In spite of this effect on inflammation, the effect on disability is only marginal and possibly relapse-reduction-dependent.

Administration of Campath-1H to patients with very active disease in terms of frequency of relapses, accumulation of disability and MRI activity, results in a profound, prolonged Lymphopenia and the suppression of clinical and MRI activity, but in spite of this, clinical disability and Cerebral Atrophy still progress.

The same experience has been reported with Cladribine and Autologous Haematopoietic Stem Cell Transplantation. All these observations give support to the fact that relapses do not essentially influence irreversible disability in the long term in MS.

They are consistent with what has been shown at the individual level in the 1970s by performing serial quantitative Neurological Examinations over several years, and with what is currently emerging from early and serial structural brain MRI studies.

These breakthroughs have immediate implications for the counselling of patients with MS.

They suggest that MS is as much NeuroDegenerative as inflammatory, and should cause the modification of disease-modifying therapeutic strategies by focussing on the protection and repair of the Nervous System and not only on the control of inflammation.

Objective
To compare the effects of IntraVenous MethylPrednisolone (IVMP) in patients with Relapsing/Remitting (RR-MS), Secondary/Progressive (SP-MS), and Primary/Progressive Multiple Sclerosis (PP-MS).

Methods
Clinical and NeuroPhysiological follow up was undertaken in 24 RR-MS, eight SP-MS, and nine PP-MS patients receiving Solu-Medrol 500 mg/d over five days for exacerbations involving the motor system.

Motor Evoked Potentials (MEPs) were used to measure Central Motor Conduction Time (CMCT) and the Triple Stimulation Technique (TST) was applied to assess conduction deficits.

The TST allows accurate quantification of the number of conducting Central Motor Neurons, expressed by the TST amplitude ratio.

Results
There was a significant increase in TST amplitude ratio in RR-MS (p < 0.001) and SP-MS patients (p < 0.02) at day 5, paralleling an increase in muscle force. TST amplitude ratio and muscle force remained stable at two months.

In PP-MS, TST amplitude ratio and muscle force did not change. CMCT did not change significantly in any of the three groups.

Conclusions
In RR-MS and SP-MS, IVMP is followed by a prompt increase in conducting Central Motor Neurons paralleled by improvement in muscle force, which most probably reflects partial resolution of Central Conduction Block.

The lack of similar clinical and NeuroPhysiological changes in PP-MS corroborates previous clinical reports on limited IVMP efficacy in this patient group and points to PathoPhysiological differences underlying exacerbations in PP-MS.

Background
The relationship of Gray and White Matter Atrophy in Multiple Sclerosis (MS) to NeuroPsychological and NeuroPsychiatric impairment has not been examined.

Methods
In 40 patients with MS and 15 age-/sex-matched normal controls, the authors used SPM99 to obtain Whole Brain normalized volumes of Gray and White Matter, as well as measured conventional lesion burden (total T₁ HypoIntense and FLAIR HyperIntense lesion volume).

The whole Brain segmentation was corrected for misclassification related to MS Brain lesions.

To compare the effects of Gray Matter, White Matter, and lesion volumes with respect to Brain-behavior relationships, the MS group (disease duration = 11.2 +/- 8.8 years;

EDSS score = 3.3 +/- 1.9) underwent NeuroPsychological assessment, and was compared to a separate, larger group of age-/sex-matched normal controls (n = 83).

Results
The MS group had smaller Gray (p = 0.009) and White Matter Volume (p = 0.018), impaired Cognitive performance (Verbal Memory, Visual Memory, Processing Speed, and Working Memory) (all p < 0.0001), and greater NeuroPsychiatric symptoms (Depression, p < 0.0001;

Dysphoria, p < 0.0001; Irritability, p < 0.0001; Anxiety, p < 0.0001; Euphoria, p = 0.006;

Agitation, p = 0.02; Apathy, p = 0.02; and Disinhibition, p = 0.11) vs controls.

Hierarchical stepwise regression analysis revealed that Whole Gray and White Matter Volumes accounted for greater variance than lesion burden in explaining Cognitive performance and NeuroPsychiatric symptoms.

White Matter Volume was the best predictor of mental processing speed and Working Memory, whereas Gray Matter Volume predicted Verbal Memory, Euphoria, and Disinhibition.

Conclusion
Both Gray and White Brain Matter Atrophy contribute to NeuroPsychological deficits in Multiple Sclerosis.

Background
The possibility that head injury may influence the development of Multiple Sclerosis (MS) has been studied inconclusively in the past.

Objective
To determine whether head injury is associated with an increased risk of MS.

Method
Analysis of database of linked hospital and death records, comparing the occurrence of MS in a cohort of people admitted to hospital with head injury and a reference cohort.

Results
The rate ratio for MS after head injury, compared with the reference cohort, was 1.1 (95% confidence interval, 0.88 to 1.36). There was no significant increase in the risk of MS at either short or long time periods after head injury.

Using length of hospital stay as a proxy for severity of injury, there was no significant increase in the rate ratio for MS after head injuries with hospital stays of less than two days (rate ratio = 1.1 (0.71 to 1.57)), two or more days (rate ratio = 1.0 (0.68 to 1.45)), or seven or more days (rate ratio = 1.3 (0.64 to 2.34)).

Conclusions
The method used, record linkage, ensures that patients' recollection of injury, or any tendency to attribute MS to injury, cannot have influenced the results.

Injuries to the head were not associated with either the Etiological initiation or the clinical precipitation of onset of Multiple Sclerosis.

Background And Objective
Fatigue is one of the most frequent symptoms in Multiple Sclerosis (MS) but there is a lack of knowledge about its behavior over time.

The aim of our study was to investigate changes in Fatigue in a large cohort of MS patients and to determine the relationship between changes in disability and Depression with changes in Fatigue severity.

Methods
We studied Fatigue in 227 MS consecutive patients and again after one year. During the clinical interview, we recorded the patient's degree of disability using the Expanded Disability Status Scale and relapses.

Fatigue was measured by means of the Modified Fatigue Impact Scale (MFIS) and Fatigue Severity Scale (FSS) and Depression was measured by the Beck Depression Inventory (BDI).

Results
After a mean follow-up of 18 months, 86.8% of patients who were fatigued at study onset remained in a fatigued status, whereas 25% of those without Fatigue at onset had become fatigued at the end of follow-up.

We observed that only variations on BDI scores positively correlate with variations on Fatigue scales, mainly with MFIS (r = 0.49, p < 0.0001).

An increase of BDI score was the factor that best predicted the increase of Fatigue over time.

No differences in the increase of Fatigue were found between patients with and without progression of disability during the follow-up period, or between patients with or without relapses.

Conclusions
Fatigue in MS persists over time. Changes in mood status but not in disability are related to changes in Fatigue in MS patients.