MS Abstracts 05a-2g1

  1. Axonal and Neuronal degeneration in Multiple Sclerosis: mechanisms and functional consequences
    Curr Opin Neurol 2001 Jun;14(3):271-8

  2. Magnetization Transfer Imaging in Clinically Isolated Syndromes suggestive of Multiple Sclerosis
    AJNR Am J NeuroRadiol 2001 May;22(5):947-51

  3. The Triple Stimulation Technique to study Central Motor Conduction to the lower limbs
    Clin NeuroPhysiol 2001 May;112(5):938-49

  4. Age-dependent T-Cell tolerance and AutoImmunity to Myelin Basic Protein
    Immunity 2001 Apr;14(4):471-81

  5. ImmunoModulatory drugs for Multiple Sclerosis: a systematic review of clinical and cost effectiveness
    Expert Opin Pharmacother 2001 Apr;2(4):623-39

  6. Human HerpesVirus 6: its impact and influence on infectious diseases and their management
    Expert Opin Pharmacother 2001 Feb;2(2):213-21

  7. Serum and CSF levels of MCP-1 and IP-10 in Multiple Sclerosis with acute and stable disease and undergoing ImmunoModulatory therapies
    J NeuroImmunol 2001 Apr 2;115(1-2):192-8

  8. OpsocClonic-MyoClonic-Ataxic Syndrome
    Rev Neurol 2001 Mar 16;32(5):440-444

  9. Effect of early Interferon treatment on conversion to definite Multiple Sclerosis: a randomized study
    Lancet 2001 May 19;357(9268):1576-1582


Axonal And Neuronal Degeneration In Multiple Sclerosis: Mechanisms And Functional Consequences

Bjartmar C, Trapp BD
Curr Opin Neurol 2001 Jun;14(3):271-8
Lerner Research Institute, Cleveland Clinic Foundation, Dept of NeuroSciences, Cleveland, Ohio, USA
PMID# 11371748; UI# 21264257

Renewed interest in Axonal injury in Multiple Sclerosis has significantly shifted the focus of research into this disease toward NeuroDegeneration.

During the past year MR and Morphologic studies have continued to confirm and extend the concept that Axonal transection begins at disease onset.

And that cumulative Axonal loss provides the pathologic substrate for the progressive Disability that most long-term MS patients experience.

Although inflammation and chronic DeMyelination are probable causes of Axonal transection, little is known about the molecular mechanisms that are involved.

The view that MS can also be considered an Inflammatory NeuroDegenerative Disease has important clinical implications for therapeutic approaches, monitoring of patients, and future treatment strategies.


Magnetization Transfer Imaging In Clinically Isolated Syndromes Suggestive Of Multiple Sclerosis

Brex PA, Leary SM, Plant GT, Thompson AJ, Miller DH
AJNR Am J NeuroRadiol 2001 May;22(5):947-51
Institute of Neurology, Univ, College London, NMR Research Unit, London
PMID# 11337341; UI# 21234673

Background And Purpose
In patients with Multiple Sclerosis (MS), reduced Magnetization Transfer Ratios (MTRs) have been reported in White Matter that appears normal on studies obtained with conventional imaging techniques.

The stage in the disease when this first becomes detectable is unclear.

The purpose of this study was to measure the MTR of Normal-Appearing White Matter (NAWM) and lesions in patients with Clinically Isolated Syndromes (CIS).

Many of whom are at the earliest stages of MS, and to determine the prognostic value of any observed changes.

Twenty-seven CIS patients and 13 matched control subjects were studied. The mean MTR was measured from 10 regions of NAWM and, when present, from lesions.

The patients were followed-up clinically for a median of 12 months.

There was no significant difference in the mean MTR between NAWM in control subjects (38.5% units) and that in CIS patients (38.4% units).

After 12 months' follow-up, MS developed in 26% of the patients. The MTR of NAWM in these patients did not differ from that of the other patients or the control subjects.

The reduced MTR in NAWM, described in established MS, was not detectable in patients with CIS. MTR did not provide prognostic information for this short period of follow-up.


The Triple Stimulation Technique To Study Central Motor Conduction To The Lower Limbs

Buhler R, Magistris MR, Truffert A, Hess CW, Rosler KM
Clin NeuroPhysiol 2001 May;112(5):938-49
Univ of Berne, Dept of Neurology, Inselspital, CH-3010, Berne, Switzerland
PMID# 11336912

To quantify the percentage of motor units of a foot muscle that can be activated by TransCranial Magnetic Stimulation (TMS) in normal subjects and patients.

We adapted the recently described Triple Stimulation Technique (TST) for recordings from abductor hallucis (AH).

Conventional Motor Evoked Potentials (MEPs) of this muscle are usually small and variable in shape, because of an important temporal desynchronization of the TMS induced Spinal Motor Neuron discharges.

The TST allows 'resynchronization' of these discharges and thereby a quantification of the proportion of motor units activated by TMS.

The Lower Limb (LL-) TST was applied to 33 sides of 18 normal subjects and 51 sides of 46 patients with Multiple Sclerosis, Amyotrophic Lateral Sclerosis, or Spinal Cord disorders.

In healthy subjects, the LL-TST demonstrated that TMS achieves activation of virtually all Motor Neurons supplying the AH.

In 33 of 51 patient sides, abnormal LL-TST responses suggested CorticoSpinal Conduction failures of various degrees.

The LL-TST was 2.54 times more sensitive to detect Central Conduction failures than the conventional LL-MEPs.

Combining the LL-TST with TST of the upper limbs further increased the sensitivity to detect a Conduction Failure by 1.50 times.

The LL-TST markedly improves the examination of CorticoSpinal Pathways.


Age-Dependent T-Cell Tolerance And AutoImmunity To Myelin Basic Protein

Huseby ES, Sather B, Huseby PG, Goverman J
Immunity 2001 Apr;14(4):471-81
Univ of Washington, Dept of Immunology, 98195, Seattle, WA, USA
PMID# 11336692

Experimental AutoImmune EncephaloMyelitis (EAE), an animal model for Multiple Sclerosis, is induced by activating a subset of Myelin Basic Protein (MBP)-specific T-Cells that have escaped Tolerance induction.

Here, we define the Tolerance mechanisms that eliminate the majority of MBP-specific T-Cells from the periphery.

We show that MBP-specific T-Cells undergo Central Tolerance mediated by Bone Marrow-derived Antigen-Presenting Cells presenting exogenously derived MBP Epitopes.

The efficiency of Tolerance is age dependent, reflecting the developmentally regulated expression of MBP.

Dependence of Tolerance on the amount of MBP expressed in vivo results in an age window of susceptibility to EAE in mice that peaks during puberty.

These results suggest that factors regulating expression of Self-Antigens in vivo can influence susceptibility to AutoImmunity.


ImmunoModulatory Drugs For Multiple Sclerosis: A Systematic Review Of Clinical And Cost Effectiveness

Clegg A, Bryant J
Expert Opin Pharmacother 2001 Apr;2(4):623-39
Southampton Health Technology Assessments Centre (SHTAC), Wessex Institute for Health Research and Development, Univ of Southampton, Biomedical Sciences Building, Bassett Crescent East, Southampton SO16 7PX, UK
PMID# 11336612

Uncertainties about the clinical and cost effectiveness of ImmunoModulatory drugs for Multiple Sclerosis (MS), as well as concerns about funding treatment, continue to influence their use.

The National Institute for Clinical Excellence (NICE) in England and Wales has been appraising the evidence on the clinical and cost effectiveness of IFN-ß and Glatiramer to provide guidance to the NHS. It has proved a difficult task.

This paper is an update of our systematic review which assesses the evidence on the clinical and cost effectiveness of a range of ImmunoModulatory drugs for MS.

Including Azathioprine, IFN-ß, Cladribine, Cyclophosphamide, Glatiramer, IntraVenous ImmunoGlobulin (IVIg), Methotrexate and Mitoxantrone.

Searches of electronic databases (such as Medline, Embase and the Cochrane Library) and bibliographies of related papers, as well as consultation with experts, for systematic reviews of Randomized Controlled Trials (RCTs).

And direct reports of RCTs revealed 26 studies of clinical effectiveness and eight economic evaluations that met the criteria for inclusion.

The quality of the evidence was often poor, affected by methodological limitations.

Evidence on the clinical effectiveness of ImmunoModulatory drugs showed some clinical effect, with reductions in relapse rates and/or progression to disability for people with MS.

However, benefits from these drugs may be lessened by side effects.

Assessment of cost effectiveness was limited to IFN-ß and Glatiramer, showing that any benefit from these drugs was achieved at very high cost.

The inadequacies in the evidence of clinical and cost effectiveness on some ImmunoModulatory drugs for the treatment of people with MS necessitate further rigorous RCTs and comparative economic evaluations of different alternatives.


Human HerpesVirus 6: Its Impact And Influence On Infectious Diseases And Their Management

Khare MD
Expert Opin Pharmacother 2001 Feb;2(2):213-21
St. George's Hospital Medical School, Cranmer Terrace, London SW17 0RE, UK
PMID# 11336581; UI# 21235126

Human HerpesVirus-6 (HHV-6) was discovered 15 years ago and was then grouped as a member of the family Human HerpesViridae. Its first clinical manifestation was identified 2 years later as the agent responsible for exanthem subitum.

With the advent of newer molecular techniques, its diagnosis is easier and prospective studies have shown that it is the most common pathogen responsible for febrile illness in infants. In some infants, it is associated with febrile convulsions.

Two subtypes, A and B, have been identified, B subtype commonly being responsible for primary infection in infants. Primary infection in healthy adults is rare.

Most of the clinical manifestations are mild, self-limiting and rarely fatal. Reactivation of HHV-6 is frequently found in bone marrow as well as solid organ transplant recipients.

HHV-6 has been shown to be an independent risk factor responsible for recurrence of cytomegalovirus infection, especially in solid organ transplants.

In bone marrow transplant recipients, HHV-6 has been associated with various manifestations like marrow suppression and graft versus host disease, although most infections present as usually mild febrile illness with or without rash.

It has been reported to cause Encephalitis in transplant recipients. Although HHV-6 has been shown to be responsible for upregulation of HIV in vitro studies, its exact role in AIDS is yet to be defined.

In addition to its NeuroTropic manifestation of febrile convulsion in infancy, it has been found in plaques in the Brain of Multiple Sclerosis and Progressive Multifocal Leukoencephalopathy.

Further studies are needed before its role in the PathoGenesis of these Neurological illnesses can be established.

Its Lymphotropic feature was responsible for its discovery and now it has only been detected in some lesions of primary Ocular Mucosa associated Lymphoid tissue Lymphoma.

As HHV-6 is found to be responsible for more and more illnesses, especially causing serious illnesses in the ImmunoCompromized, it is becoming necessary to find effective treatment.

Some agents, like Cidofovir and Phosphonoformic Acid, are effective in in vitro studies and some have shown effectiveness in a clinical setting.

Further studies are needed to identify its role in the PathoGenesis of various Neurological and malignant lesions and AIDS.

Various treatment regimens should be tested in clinical scenario and especially in ImmunoCompromized transplant recipients.


Serum And CSF Levels Of MCP-1 And IP-10 In Multiple Sclerosis With Acute And Stable Disease And Undergoing ImmunoModulatory Therapies

Franciotta D, Martino G, Zardini E, Furlan R, Bergamaschi R, Andreoni L, Cosi V
J NeuroImmunol 2001 Apr 2;115(1-2):192-8
Univ of Pavia, Laboratory of NeuroImmunology, IRCCS, Foundation "Neurological Institute C. Mondino", via Palestro 3, 27100, Pavia, Italy
PMID: 11282170

The two Chemokines, Monocyte Chemoattractant Protein (MCP)-1 and Interferon-gamma Inducible Protein (IP)-10, are thought to be involved in the PathoGenesis of Multiple Sclerosis (MS).

We measured MCP-1 and IP-10 levels in Serum and CSF samples from 38 acute and 25 stable MS patients and from 40 controls.

The latter consisted in patients with Other Inflammatory Neurological Diseases (OIND) or with Non-Inflammatory Neurological Diseases, and healthy controls.

CSF MCP-1 levels exceeded those found in Serum in all the patients studied as well as in healthy controls.

CSF MCP-1 levels were significantly lower in acute MS [468+/-(S.E.M.) 18 pg/ml] than in stable MS (857+/-104 pg/ml).

When detectable, Serum and CSF IP-10 levels were significantly higher in acute MS (serum 331+/-66 pg/ml; CSF 118+/-16 pg/ml) than in stable MS (Serum 69+/-7 pg/ml; CSF 25+/-2 pg/ml).

Among OIND patients, those with HIV-1 associated Dementia showed high Serum and CSF levels of both MCP-1 and IP-10.

Those with Encephalitis showed high Serum and CSF levels of IP-10 and CSF MonoNuclear PleioCytosis.

We also evaluated the effects of 6-MethylPrednisolone or IFN-ß-1a therapy on circulating MCP-1 and IP-10 levels.

Neither MCP-1 nor IP-10 post-therapy levels varied significantly from baseline values.

    Our findings suggest that:
  1. MCP-1 could be constitutively produced within the Brain
  2. MCP-1 and IP-10 CSF levels in acute MS vary significantly from those in stable MS, and these variations are inverse
  3. Current MS therapies do not modify circulating levels of MCP-1 and IP-10


OpsoClonic-MyoClonic-Ataxic Syndrome

Andrade Machado R, Garcia Espinosa A, Barbaro Ramos L
Rev Neurol 2001 Mar 16;32(5):440-444
Hospital Universitario Arnaldo Milian Castro. Hosp. Municipal de Remedios, Santa Clara. Villa Clara, Cuba
PMID# 11346826

The OpsoClonic-MyoClonic-Ataxic Syndrome (OMAS) is that in which there are at least two of the cardinal signs (OpsoClonus, MyoClonus and Ataxia).

To report three cases, their evolution and Etiology, and discuss the main PhysioPathological basis and guidelines for treatment.

Clinical Cases
We present three cases admitted to the Internal Medicine Dept with the diagnosis of OMAS.

The investigations included standard biochemical and haematological tests, a full study of the CerebroSpinal Fluid, Computerized Axial Tomography of the skull and Thorax, and Magnetic Resonance.

We describe the clinical presentation, evolution, Etiology and treatment given. The results of the complementary tests are shown in the form of tables.

Finally we consider the diagnosis of this condition. Three patients, two men and one woman, aged between 43 and 78 were diagnosed as having OMAS.

The causes were: ParaNeoplasia, Acute Diffuse EncephaloMyelitis and Probable Multiple Sclerosis. The patient with Lung Cancer died whilst the other two showed almost complete recovery on the treatment given.

Our cases show that OMAS may be a feature of a diffuse process affecting the BrainStem and Cerebellum.

The commonest causes found are Multiple Sclerosis, Acute Diffuse EncephaloMyelitis and as a ParaNeoplastic feature of a Tumor.

It may improve with treatment, but depending on the Etiology, death may occur. ImmunoModulation treatment is vital even though symptomatic treatment may be given.


Effect Of Early Interferon Treatment On Conversion To Definite Multiple Sclerosis: A Randomized Study

Comi G, Filippi M, Barkhof F, Durelli L, Edan G, Fernandez O, Hartung H, Seeldrayers P, Sorensen PS, Rovaris M, Martinelli V, Hommes OR
Lancet 2001 May 19;357(9268):1576-1582
IRCCS Ospedale S Raffaele, Multiple Sclerosis Centre, Dept of NeuroScience, via Olgettina 60, 20132, Milan, Italy
PMID# 11377645

Interferon-beta reduces activity in Multiple Sclerosis as measured clinically and by Magnetic Resonance Imaging (MRI).

We assessed the effect of Interferon-beta-1a on the occurrence of relapses in patients after first presentation with Neurological events, who are at high risk of conversion to Clinically Definite Multiple Sclerosis.

Eligible patients had had a first episode of Neurological dysfunction suggesting Multiple Sclerosis within the previous 3 months and had strongly suggestive Brain MRI findings.

Patients were randomly assigned Interferon-beta-1a 22 &mgr;g or placebo subcutaneously once weekly for 2 years.

Neurological and clinical assessments were done every 6 months and Brain MRI every 12 months. Analyzes excluded one patient assigned placebo who received no study injections.

241 (78%) of 308 randomized patients received study treatment for 2 years; 278 (90%) remained in the study until termination.

57 (85%) of 67 who stopped therapy did so after conversion to Clinically Definite Multiple Sclerosis.

Fewer patients developed Clinically Definite Multiple Sclerosis in the Interferon group than in the placebo group (52/154 [34%] vs 69/154 [45%]; p=0.047).

The time at which 30% of patients had converted to Clinically Definite Multiple Sclerosis was 569 days in the Interferon group and 252 in the placebo group (p=0.034).

The annual relapse rates were 0.33 and 0.43 (p=0.045).

The number of new T2-weighted MRI lesions and the increase in lesion burden were significantly lower with active treatment.

Interferon-beta-1a treatment at an early stage of Multiple Sclerosis had significant positive effects on clinical and MRI outcomes.

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