MS Abstracts 6f-2g1

The Danish Multiple Sclerosis Registry was formally established in 1956 but started operating in 1949 with a nationwide prevalence survey.

Since then, the Registry has continued collecting data on new and old cases of Multiple Sclerosis (MS) or suspected MS from multiple sources.

The Registry reclassifies cases according to standardized diagnostic criteria (currently those of Poser et al).

A total of 14,441 cases fulfilling the diagnostic criteria had been registered at the most recently completed follow-up by 1 January 1997; 10,851 had onset from 1948 to 1996 and 3560 before 1948.

The completeness has formerly been estimated at about 90%, higher for cohorts with older onset and lower for cohorts with onset close to follow-up.

The estimated validity of the diagnosis for autopsy cases classified as Definite MS in the Registry is 94%.

A long-term nationwide Registry has proved to be a valuable instrument for monitoring incidence and prevalence, analyzing survival, performing Genetic analysis.

Providing unselected patient samples for clinical analyzes, performing case-control studies and prospective studies and estimating the need for treatment and care.

We discuss two types of age-associated diseases; aging-dependent such as Alzheimer's Disease and Congestive Heart Failure which increase logarithmically with age.

Versus age-dependent such as Multiple Sclerosis and Amyotrophic Lateral Sclerosis, which occur at proscribed ages, and then occurrence of new cases ceases or diminishes with further aging.

Prevention strategies with both types emphasize postponement or delay of onset.

The non-fatal aging-dependent diseases and conditions are an accumulating burden as we age, and increase overall morbidity in late years.

These include Alzheimer's Disease and other Dementias, Parkinson's Disease, loss of Vision and Hearing, incontinence, Osteoporosis and Hip fracture, OsteoArthritis and Depression.

With mortality postponed, we will be living for many years at old and vulnerable ages. Life's quality will be reasonable for most.

Still, increasing the chance that all will experience this desirable outcome requires pursuing the means to delay the onset of the physical and social events.

Which we categorize as the non-fatal aging-dependent diseases and conditions.

We must recognize that each added year occurs at the tip of an exponential curve where risk is maximal.

A major question in NeuroBiology is whether Myelin repair can restore Neurological function following the course of a severe, progressive CNS DeMyelinating Disease that induces Axonal loss.

In this study we used Theiler's Murine EncephaloMyelitis Virus (TMEV) to induce a Chronic/Progressive CNS DeMyelinating Disease in mice that was Immune-mediated and pathologically similar to human Multiple Sclerosis.

Because ImmunoSuppression of chronically TMEV-infected mice has been shown to enhance Myelin repair, we first addressed the potential roles of CD4⁺ and CD8⁺ T-Cells in the inhibition of CNS ReMyelination during chronic disease.

TMEV infection of susceptible PL/J mice deficient in CD4⁺ but not CD8⁺ T-Cells demonstrated a significant increase in severity of PathoGenesis when compared with wild-type controls.

This was characterized by enhanced DeMyelination, Spinal Cord Atrophy, Neurological deficits, and mortality.

Interestingly, the PL/J CD4^(-/-) mice that survived to the chronic stage of the disease had nearly complete spontaneous Myelin repair mediated by both Oligodendrocytes and infiltrating Schwann Cells.

Therefore, we next addressed whether this spontaneous Myelin repair was associated with improved Neurological function despite the increased pathology.

Of interest, all surviving PL/J CD4^(-/-) mice showed partial restoration of Motor coordination and gait that coincided temporally with spontaneous Myelin repair.

Furthermore, functional recovery of Motor coordination correlated strongly with the percentage of Myelin repair mediated by Schwann Cells.

Whereas restoration of hindlimb Gait correlated with Oligodendrocyte-mediated Myelin repair.

This is the first study to demonstrate that spontaneous ReMyelination correlates with partial restoration of Neurological function during the course of a Progressive, Immune-mediated CNS DeMyelinating Disease.

Of greater importance, functional recovery occurred despite previous severe DeMyelination and Spinal Cord Atrophy.

We reviewed the clinical and laboratorial findings of 200 patients in Curitiba, Southern Brazil (25 degrees 25'40" S; 49 degrees 16'23" W-GR), with Multiple Sclerosis (MS) according to Poser's criteria.

The patients were classified as: Clinically Definite (A1 and A2) - 142 patients (71%); Laboratory-Supported Definite - 42 patients (21%); and Clinically Probable - 16 patients (8%).

Relapsing/Remitting (RR) form was the most common clinical presentation, with 182 (91%), followed by Primary/Progressive (PP)(16 cases, 8%), and only 2 cases with Secondary/Progressive form (SP).

Nine women and 7 men totalized the 16 PP cases. The mean age of onset was 32.0+/-9.9 (median 32 years). The gender ratio was female 1.8:1 male.

All patients, except 3 African-Brazilian, were white. Seven (3.5%) patients developed a clinical history of Devic's Syndrome.

The initial clinical picture included BrainStem/Cerebellar Syndrome in 126 (63%) cases, Sensory findings in 106 (53%)patients, Motor (Pyramidal) Syndrome in 102 (49.5%), and Optic Neuritis in 79 (39.5%) cases.

122 (61%) patients had a final EDSS score < 3.5; 45 (22.5%) a score between 3.5 and 5.5, and 33 (16.5%) a score >/= 6.0.

There was no significant correlation between the number of relapses or duration of disease with EDSS scores (Spearman's test).

Only 14 (7%) of the total number presented the Benign form (EDSS< 3.5 after 10 years of disease).

We observed a later age of onset and initial clinical findings with higher frequency of BrainStem/Cerebellar Syndrome and Optic Neuritis, when compared to other Brazilian and Western series

An international meeting took place in Basel, Switzerland from 5 to 7 October 2000 involving 180 participants from 30 countries.

With the aim of assessing the existing data on autologous Haemopoietic Stem Cell Transplantation (HSCT) in the treatment of severe AutoImmune Disease, and to decide on future trial planning.

Data on 390 patients were presented: 260 from the EBMT/EULAR Basel European/Asian database, 87 from North America (55 from the IBMTR), 39 from Australia, and 4 others.

The major disease categories and number of patients receiving transplant were: Multiple Sclerosis (MS) 127, Systemic Sclerosis (SSc) 72, Rheumatoid Arthritis (RA) 70, Juvenile Idiopathic Arthritis (JIA) 36, Systemic Lupus Erythematosus (SLE) 34, Dermatomyositis/Polymyositis (DM/PM) 5, Idiopathic Thrombocytopenic Purpura (ITP) 7.

Single or several cases of other AutoImmune Diseases were reported.

Clinically significant responses were seen in two thirds of all the cases and in all disease categories, with a more accentuated trend towards relapse in JIA and RA.

Treatment was associated with a significant morbidity and mortality.

In the EULAR/EBMT database (71 centers in 22 countries), a mobilization associated mortality of 1.5% and an overall procedure related mortality (actuarially adjusted at 12 months) of 9% (confidence interval 6 to 12%) were found, with significant variation between diseases.

The North American data showed similar results. Higher mortalities were seen in SSc and systemic JIA, with only one death reported in RA.

After presentation of the data and workshop discussion a consensus was reached on several aspects: prospective randomized phase III trials are now appropriate in SSc, MS, and RA.

A protocol is ready for SSc (ASTIS Trial), concepts are clear for MS and RA. Further phase I and II data are required in SLE, JIA, and Vasculitis.

The need for continuing collection of all cases after mobilization by the standardized EBMT and IBMTR data forms was emphasised.

The effects of the PhotoToxic K⁺- channel blockers 8-MethoxyPsoralen (8-MOP) and 5-MethoxyPsoralen (5-MOP) on Ranvier Nodes were compared to those of 5,8-DiEthoxyPsoralen (5,8-EOP) by means of the Hodgkin-Huxley formalism.

When these test substances were added individually to the bathing solution (8-MOP: 100 micromol/l; 5-MOP: 50 micromol/l; 5,8-EOP: 10 micromol/l) the following completely reversible effects were observed:

1. 8-MOP, caused a nearly potential-independent decrease of the Sodium permeability, P'Na, by ca. 17%. 5-MOP and 5,8-EOP merely decreased the maximal value of P'Na, by ca. 12 and 8% respectively, whereas with weak depolarizations P'Na was unchanged.

2. In the tested potential range the Potassium permeability, P'K, was caused to decrease by ca. 9% by 8-MOP, ca. 21% by 5-MOP and ca. 19% by 5,8-EOP. 3.

The Potassium currents acquired a phasic time course previously described for 8-MOP and 5-MOP.

They reached a relative maximum and approached a lower steady-state value, kinfinity, with a time constant tauk at V = 120 mV of about 16 ms (8-MOP), 20 ms (5-MOP) and 94 ms (5,8-EOP).

To obtain dose-response relations the drug-induced effects on peak P'K and on the steady state value, kinfinity, were measured.

The corresponding apparent dissociation constants (in micromol/l) were 66.6 and 80.1 (for 8-MOP), 87.6 and 25.8 (for 5-MOP), and 13.5 and 6.5 (for 5,8-EOP).

In view of the similarity of the actions of 5-MOP and 5,8-EOP as well as the fact that 5,8-EOP is not PhotoToxic.

In future 5,8-EOP may well prove to be a particularly suitable K⁺-channel blocker for the symptomatic therapy of Multiple Sclerosis and other DeMyelinating Diseases.

Multiple Sclerosis (MS) is one of the most common organic Neurological Diseases of the Central Nervous System.

Because of improved therapies, nurses are confronted with elderly MS patients, but little is known about the specific problems of these patients.

This survey analyzed problems in elderly MS patients. Fifty-three MS patients (44 female, 9 male; average age 73 years, average course of MS 25.3 years).

From the Berlin Section of the German Multiple Sclerosis Association were evaluated by using a standardized questionnaire.

Considering social situation, daily problems, disease course, and disabilities, and by using the Expanded Disability Status Scale (EDSS).

Elderly MS patients reported impaired mobility and inability to use public transportation; about 96% presented EDSS scores above 6.0.

Nearly 50% complained about Spasticity and Pain due to Spasticity. More than 70% suffered from Bladder Dysfunction.

Problems with Sleep and Fatigue were present in less than 20%, but Interrupted Sleep was common.

Selfcare impairments were reported by 50%-75% of the patients, and most of them required professional help.

Depressive moods and thoughts about committing suicide were mentioned by more than 30% of the patients. Elderly MS patients experience physical and PsychoSocial impairments.

Healthcare professionals should consider increasing independence and avoiding nursing home admissions in the management of elderly MS patients.

Objective
Involvement of the Autonomic System in Multiple Sclerosis (MS) may concur with dysfunction of the CardioVascular System.

The introduction of potentially CardioToxic ImmunoSuppressive drugs like Mitoxantrone into the treatment of MS warrants proper assessment of pre-existing Heart Disease.

However, systematic analyzes of functional and metabolic derangements in MS are missing.

Using quantitative 31P-MR-Spectroscopy (MRS) and MR-imaging (MRI) metabolic and functional parameters were analyzed in patients with MS in comparison to healthy volunteers.

Subjects/Methods
14/15 patients with MS could be included in the study, as the MRS examination of one patient had to be excluded from analysis due to movement during the examination.

Using Chemical Shift Imaging (CSI) and AMARES, PhosphoCreatine (PCr) to Adenosine TriPhosphate (ATP) ratios, characterizing MyoCardial high-energy Phosphate metabolism, were determined.

Additionally, absolute concentrations of PCr and ATP were calculated by SLOOP (Spatial Localization with Optimal Pointspread Function).

Analysis of functional changes was performed by Cine-MRI. 14 healthy volunteers matched for age and gender served as control.

Results
A significant decrease of absolute PCr concentration was observed in patients with MS compared to matched volunteers (p < 0.05), whereas ATP concentrations showed no significant changes (p = 0.27).

Metabolite ratios calculated by SLOOP or AMARES showed a tendency to be reduced in patients, however, did not reach significance (p = 0.08, SLOOP; p = 0.47, AMARES).

Using volunteers' mean values +/- 2 x SD as cut off value revealed PCr changes in 5 of 14 patients, whereas only 2 also had pathologic PCr/ATP ratios.

Functional analysis by MRI depicted depressed Left Ventricular ejection fraction in 4 patients.

Conclusions
The reduction in Cardiac high-energy Phosphates in some patients with MS points to a subclinical involvement of the Heart.

This may be important for treatment with potentially CardioToxic drugs. Longitudinal studies are need to understand the clinical relevance of our findings.

There is now evidence that Major Depression is accompanied by activation of the Inflammatory Response System (IRS) as indicated by an increased production of ProInflammatory Cytokines.

There is circumstantial evidence implicating ProInflammatory Cytokines, such as Tumor Necrosis Factor-alpha (TNF-) in the PathoGenesis of Multiple Sclerosis (MS).

The aims of the present study were to examine:

1. The Serum concentrations of InterLeukin-6 (IL-6), IL-8, TNF-, IL-2 Receptor (IL-2R) and CC16 (UteroGlobulin), an endogenous AntiCytokine, in Depressed and MS patients compared to normal controls.

2. The effects of treatment with AntiDepressants on the above IRS variables in Depressed patients.

Serum TNF- was significantly higher in Depressed and MS patients than in normal controls.

Serum IL-8 was significantly higher in Depressed patients than in patients with MS.

Serum CC16 was significantly higher in patients with MS than in normal controls and Depressed patients.

NonResponders to treatment with AntiDepressants had significantly higher Serum IL-2R and lower Serum CC16 concentrations than responders to treatment.

The results show that:

1. Depression is accompanied by activation of the IRS and that this activation is more pronounced in Depression than in MS.

2. IRS activation in Depressed patients is related to a NonResponse to treatment with AntiDepressants.

Objectives
The aim of the present study was to investigate the role of soluble Adhesion Molecules in the PathoGenesis of Multiple Sclerosis (MS) and Systemic Lupus Erythematosus (SLE) with DeMyelinating Syndrome.

Methods
Paired CerebroSpinal Fluid (CSF) and Serum samples were analyzed by an ELISA method to determine the concentrations of sVCAM-1, sICAM-1 and sL-Selectin.

Intrathecal syntheses of the Adhesion Molecules were calculated.

Results
Elevated Serum and CSF concentrations of sVCAM-1 were present in all patient groups.

Intrathecal synthesis of sVCAM-1 was present in the Relapsing/Remitting and Secondary/Progressive forms of MS.

Intrathecal synthesis of sICAM-1 was observed in all clinical forms of MS.

MS patients with Progressive forms of the disease and SLE patients were characterized by Intrathecal synthesis of sL-Selectin.

Conclusions
The data presented suggest that:

1. Blood-Brain Barrier damage can be assumed both in systemic disease and organ-specific disease (sVCAM-1)

2. Clinical forms of MS differ from each other in respect to concentrations of Adhesion Molecules

3. Similar Immunological events in the Central Nervous System of SLE patients with DeMyelinating Syndrome and Progressive forms of MS can be assumed (sL-Selectin)

Copyright 2001 S. Karger AG, Basel.

As part of a large, randomized placebo-controlled trial of inpatients with Multiple Sclerosis (MS), a subsample of 15 underwent Cerebral MRI at baseline and 6-months (eight on Lofepramine and L-Phenylalanine; seven on placebo).

Unlike the placebo group, the active group showed a significant reduction in lesion number visible on T₁-weighted scans (p < 0.05).

The Lateral Ventricular volume increased, on average, by 1020 mm3 in the untreated group and 600 mm3 in the treated group.

In the treated patients the Ventricular size change correlated with both change in Gulick MS-related symptoms scale scores (rs = 0.71, p = 0.07) and Gulick MS-related activities of daily living scale scores (rs = -0.83, p = 0.02).

It is concluded that treatment with Lofepramine and L-Phenylalanine is associated with significant MRI changes.

Objective
To determine whether combination therapy with Lofepramine, L-Phenylalanine, and intramuscular Vitamin B-12 (the "Cari Loder regime") reduces disability in patients with Multiple Sclerosis.

Methods
A placebo controlled, double blind, randomized study carried out in five United Kingdom centers on outpatients with Clinically Definite Multiple Sclerosis, measurable disability on Guy's Neurological Disability Scale (GNDS), no relapse in the preceding six months, and not on AntiDepressant drugs.

Over 24 weeks all patients received Vitamin B-12, 1 mg intramuscularly weekly, and either Lofepramine 70 mg and L-Phenylalanine 500 mg twice daily, or matching placebo tablets.

Outcome was assessed using the GNDS, the Kurtzke Expanded Disability Status Scale; the Beck Depression Inventory, the Chalder Fatigue Scale, and the Gulick MS Specific Symptom Scale.

Results
138 patients were entered, and two were lost from each group. There was no statistically significant difference between the groups at entry or at follow up. Analysis of covariance suggested that treated patients had better outcomes on four of the five scales used.

Both groups showed a reduction of 2 GNDS points within the first two weeks, and when data from all time points were considered, the treated group had a significant improvement of 0.6 GNDS points from two weeks onwards.

Conclusions
Patients with Multiple Sclerosis improved by 2 GNDS points after starting Vitamin B-12 injections. The addition of Lofepramine and L-Phenylalanine added a further 0.6 points benefit.

More research is needed to confirm and explore the significance of this clinically small difference.