Multiple Sclerosis Abstracts 12a-2g

Object
The purpose of this study was to assess the relationship between the volume of BrainStem that receives 20% or more of the maximum dose (VB20) and the volume of the Trigeminal Nerve that receives 50% or more of the maximum dose (VT50) on clinical outcome following Gamma Knife Radiosurgery (GKS) for Trigeminal Neuralgia (TN).

Methods
Patients with TN were treated with a single 4-mm isocenter with a maximum dose of 75 Gy directed at the Trigeminal Nerve close to where it leaves the BrainStem.

The VB20 and VT50, as determined on dose-volume Histograms, were correlated with clinical outcomes at 6 and 12 months, laterality, presence of Multiple Sclerosis (MS), and each other.

At 6 months excellent pain relief (no pain or required medicine) was achieved in 27 of 48 patients (p = 0.009) when VB20 was greater than or equal to 20 mm3 and in 25 of 78 when VB20 was less than 20 mm3, when all patients are considered.

At 12 months excellent pain relief was achieved in 16 of 32 patients (p = 0.038) when VB20 was greater than or equal to 20 mm3 and in 14 of 52 when VB20 less than 20 mm3, when all patients are considered.

When VB20 was less than 20 mm3 in MS patients, five of 21 had an excellent result at 6 months and two of 13 at 12 months.

The VB20 was 20 mm3 or more in 38 of 64 on the right side and in eight of 41 on the left side (p < 0.001) in patients with TN and without MS.

There is a difference between left and right dose-volume Histograms even when the same isodose is placed on the surface of the BrainStem.

The VB20 was 20 mm3 or more in 45 of 105 patients with TN and without MS but in only three of 21 patients with TN and MS (p = 0.014). There was an inverse relationship between VB20 and VT50 (p = 0.01).

Conclusions
Isocenter proximity to the BrainStem, as reflected in a higher VB20, is associated with a greater chance of excellent outcome at 6 and 12 months. Worse results in patients with TN and MS may be partly explained by a lower VB20.

From a population-based sample of 15,504 patients attending Canadian Multiple Sclerosis (MS) clinics, we have determined the frequency of conjugal MS and have estimated the recurrence risk in offspring of such matings.

Twenty-three MS cases were found among 13,550 spouses of study probands for a crude conjugal rate of 0.17% (95% CI of 0.10%-0.24%).

Despite ascertainment bias that expectedly inflates this number, this is a frequency intermediate between the point prevalence (0.1%) and lifetime risk (0.2%) for the general population and close to an order of magnitude less than reported for half siblings reared apart (1.06%) from the same population.

Six of the 49 offspring of conjugal pairs also had MS, and age conversion gives a rate similar to the concordance rate for Canadian monozygotic twins.

However, this correction may not be appropriate in this special case.

Despite an ascertainment bias in favor of recognizing affected spouses and a large population sample, the common environment in adulthood shared by spousal pairs could not be shown to increase the risk of conjugal MS.

Although the high recurrence rate in offspring is similarly subject to an upward bias, the low risk for MS spouses and the high risk for offspring support other data indicating that familial risk is Genetically determined.

Furthermore, these results imply that susceptibility alleles are shared by unrelated individuals with the disease.

Axonal degeneration has been proposed as a cause of irreversible Neurological disability in Multiple Sclerosis (MS) patients.

The purpose of this study was to quantify Axonal Loss in Spinal Cord lesions from 5 paralyzed (Expanded Disability Status Scale score > or =7.5) MS patients and to determine if Axonal number or volume correlated with levels of the Neuronal marker N-AcetylAspartate (NAA).

Axonal Loss in MS lesions ranged from 45 to 84% and averaged 68%. NAA levels were significantly reduced (>50%) in cross sections of Spinal Cords containing MS lesions.

Reduced NAA correlated with reduced Axonal numbers within lesion areas. In addition, NAA levels per Axonal volume were significantly reduced in DeMyelinated Axons (42%) and in Myelinated Axons in Normal-Appearing White Matter (30%).

The data support Axonal loss as a major cause of irreversible Neurological disability in paralyzed MS patients and indicate that reduced NAA as measured by Magnetic Resonance Spectroscopy can reflect Axonal Loss and reduced NAA levels in DeMyelinated and Myelinated Axons.

Cognitive dysfunction is common in Multiple Sclerosis (MS), yet few studies have examined effects of treatment on NeuroPsychological (NP) performance.

To evaluate the effects of Interferon-beta-1a (IFN-ß-1a, 30 microg administered intramuscularly once weekly [Avonex]) on Cognitive function, a Comprehensive NP Battery was administered at baseline.

And week 104 to Relapsing MS patients in the phase III study, 166 of whom completed both assessments. A Brief NP Battery was also administered at 6-month intervals.

The primary NP outcome measure was 2-year change on the Comprehensive NP Battery, grouped into domains of Information Processing and Learning/Memory (set A), VisuoSpatial Abilities and Problem Solving (set B), and Verbal Abilities and Attention Span (set C).

NP effects were most pronounced in Cognitive Domains vulnerable to MS: IFN-ß-1a had a significant beneficial effect on the set A composite, with a favorable trend evident on set B.

Secondary outcome analyzes revealed significant between-group differences in slopes for Brief NP Battery performance and time to sustained deterioration in a Paced Auditory Serial Addition Test processing rate, favoring the IFN-ß-1a group.

These results support and extend previous observations of significant beneficial effects of IFN-ß-1a for Relapsing MS.

Previous work from this laboratory had demonstrated the presence of endogenous Morphine, Strychnine and Nicotine in the mammalian Brain and human Serum samples.

Morphine is synthesised from Tyrosine and Strychnine and Nicotine from Tryptophan. This study examines the role of Strychnine, Nicotine and Morphine in NeuroPsychiatric disorders.

The blood levels of Tyrosine, Tryptophan, Strychnine, Nicotine and Morphine were studied as also RBC membrane Na⁺-K⁺ ATPase activity.

It was found that Serum Tyrosine levels were reduced and Tryptophan levels elevated in all NeuroPsychiatric disorders studied with a reduction in RBC Na⁺-K⁺ ATPase activity.

Nicotine was present in significant amounts in Serum of patients with Schizophrenia, CNS Glioma and syndrome X with multiple lacunar state.

Morphine was present in significant amounts only in the Serum of patients with Multiple Sclerosis and MDP. Strychnine was present in significant amounts in the Serum of patients with Epilepsy, Parkinson's Disease and MDP.

The presence of Nicotine and Strychnine in significant amounts could be related to elevated Tryptophan levels suggesting the synthesis of these alkaloids from Tryptophan. Morphine was not detected in most of the disorders owing to low Tyrosine levels noted in them.

Na⁺-K⁺ ATPase inhibition noticed in most of the disorders could be related to decreased hyperpolarising Morphinergic transmission and increased depolarising Nicotinergic and Strychinergic transmission.

The role of Morphine, Strychnine and Nicotine in the PathoGenesis of these disorders in the setting of membrane Na⁺-K⁺ ATPase inhibition is discussed.

Inheriting Genetic risk factors for Multiple Sclerosis (MS) is not sufficient to cause this DeMyelinating disease of the Central Nervous System; exposure to environmental risk factors is also required.

MS may be preventable if these unidentified environmental factors can be avoided. MS prevalence increases with decreasing solar radiation, suggesting that sunlight may be protective in MS.

The Vitamin D Endocrine System is exquisitely responsive to sunlight, and MS prevalence is highest where environmental supplies of Vitamin D are lowest.

We have proposed that the Hormone, 1,25-Dihydroxycholecalciferol (1,25-(OH)2D3), may protect Genetically-susceptible individuals from developing MS.

Evidence consistent with this hypothesis comes not only from geographic studies, but also Genetic and biological studies.

Over-representation of the Vitamin D receptor Gene b allele was found in Japanese MS patients, suggesting it may confer MS susceptibility. Fish Oil is an excellent Vitamin D source, and diets rich in fish may lower MS prevalence or severity.

Vitamin D deficiency afflicts most MS patients, as demonstrated by their low bone mass and high fracture rates.

However, the clearest evidence that Vitamin D may be a natural inhibitor of MS comes from experiments with Experimental AutoImmune EncephaloMyelitis (EAE), a model of MS. Treatment of mice with 1,25-(OH)2D3 completely inhibited EAE induction and progression.

The Hormone stimulated the synthesis of two Anti-Encephalitogenic Cytokines, InterLeukin-4 and Transforming Growth Factor-ß-1, and influenced inflammatory cell trafficking or Apoptosis.

If vitamin D is a natural inhibitor of MS, providing supplemental Vitamin D to individuals who are at risk for MS would be advisable.

A role for alpha4 and beta7 Integrins in mediating Leucocyte entry into the Central Nervous System in the Multiple Sclerosis (MS)-like disease Experimental AutoImmune EncephaloMyelitis (EAE) has been demonstrated.

However, the individual contributions of their respective Ligands Mucosal Addressin Cell Adhesion Molecule-1 (MAdCAM-1), Vascular Cell Adhesion Molecule-1 (VCAM-1) and E-Cadherin expressed on the Blood-Brain Barrier has not been determined.

In the present paper, it is shown that an AntiBody directed against MAdCAM-1, the preferential Ligand for 4ß7, effectively prevented the development of a Progressive, Non-Remitting, form of EAE, actively induced by injection of Myelin Oligodendrocyte Glycoprotein peptide (MOG35-55) AutoAntigen.

Combinational treatment with both anti-MAdCAM-1, VCAM-1, and InterCellular Adhesion Molecule-1 (ICAM-1) (Ligand for Integrin Lymphocyte Function-Associated Antigen (LFA)-1) mAbs led to more rapid remission than that obtained with anti-MAdCAM-1 AntiBody alone.

However, neither MAdCAM-1 monotherapy, nor combinational AntiBody blockade was preventative when administered late in the course of disease progression.

In conclusion, MAdCAM-1 plays a major contributory role in the progression of chronic EAE and is a potential therapeutic target for the treatment of MS.

Critically, AntiVascular Addressin therapy must be given early in the course of disease prior to the establishment of irreversible damage if it is to be effective, as a single treatment modality.

The T-helper-1 (Th-1)/T helper-2 (Th-2) paradigm is relevant for the PathoGenesis and therapy of Multiple Sclerosis. In Experimental AutoImmune EncephaloMyelitis, a shift towards a Th-2 Immune Response serves as treatment of the disease.

In the human Immune System, the factors which determine and modulate the differentiation of CD4⁺ T Cells into the Th-1 or Th-2 phenotype have yet to be elucidated completely.

Here, the split-well approach was used to analyze costimulatory requirements for the generation of Myelin Basic Protein-specific T-Cell subsets considered to play a major role in the PathoGenesis of Multiple Sclerosis.

Myelin Basic Protein-specific T-Cell lines were isolated from peripheral blood cells of healthy individuals in the presence or absence of a blockade of the costimulatory molecule B7-1, previously reported to be involved in the development of Th-1 Cells.

T-Helper type was determined by the Interferon/InterLeukin ratio. Blockade of B7-1 did not increase the number of Th2-like Myelin Basic Protein-specific T-Cell lines.

Thus, these data show no evidence for an influence of B7-1 blockade on the development of human Myelin Basic Protein-specific T-Cell subsets.

These results have to be taken into account when discussing whether AntiBody-mediated B7-1 blockade might be a suitable therapy in Multiple Sclerosis, as demonstrated in Experimental AutoImmune EncephaloMyelitis.

To quantify and characterize seasonal variation in Monosymptomatic Optic Neuritis (MON) onsets, Multiple Sclerosis (MS) onsets and MS Exacerbations (MSE), a meta-analysis was performed.

Using established methods and pooling weighted information obtained from nine reports on MON, six reports on MS onsets and nine reports on MSE, which fulfilled specific criteria for report quality and data homogeneity.

The results suggested that MON, MS onsets and MSE in the Northern Hemisphere present a similar pattern with highest frequencies in Spring and lowest in Winter.

These differences were highest for MS onsets, 45% with 95% CI 36-55%, and lowest for MSE, 10% with 95% CI 7-13%, statistically significant and robust, insensitive to an alternative seasonal definition, not unduly influenced by any single primary study, and supported by fail-safe N calculations.

Random variation, misclassification and publication bias were less likely to account for the reported generalized seasonal patterns.

The Myelin Oligodendrocyte Glycoprotein (MOG) is a major target for AutoAntiBody mediated DeMyelination in Experimental AutoImmune EncephaloMyelitis (EAE).

In the current review we discuss the Epitope specificity of this AntiBody response, in particular evidence suggesting that pathogenic Anti-MOG AntiBodies are preferentially directed against conformation-dependent Epitopes present on the ExtraCellular ImmunoGlobulin domain of the protein.

Surprisingly, recent data suggest that this AutoImmune response is in part regulated by polymorphisms in the MOG Gene itself, an observation that may have important implications for the Genetic and Immunological stratification of patients with Multiple Sclerosis.

T-Cell responses to Myelin Basic Protein (MBP) are potentially involved in the PathoGenesis of Multiple Sclerosis (MS).

Immunization with irradiated MBP-reactive T-Cells (T-Cell Vaccination) induces anti-idiotypic T-Cell responses that suppress circulating MBP-reactive T-Cells.

This T-Cell-T-Cell interaction is thought to involve the recognition of TCR expressed on target T-Cells.

The study was undertaken to define the idiotypic determinants responsible for triggering CD8⁺ CytoToxic anti-idiotypic T-Cell responses by T-Cell vaccination in patients with MS.

A panel of 9-mer synthetic TCR Peptides corresponding to Complementarity-determining region 2 (CDR2) and CDR3 of the immunizing MBP-reactive T-Cell clones were used to isolate anti-idiotypic T-Cell lines from immunized MS patients.

The resulting TCR-specific T-Cell lines expressed exclusively the CD8⁺ phenotype and recognized preferentially the CDR3 Peptides. CDR3-specific T-Cell lines were found to Lyze specifically autologous immunizing MBP-reactive T-Cell clones.

The findings suggest that CDR3-specific T-Cells represented anti-idiotypic T-Cell population induced by T-Cell Vaccination.

In contrast, the CDR2 Peptides were less Immunogenic and contained cryptic determinants as the CDR2-specific T-Cell lines did not recognize autologous immunizing T-Cell clones from which the Peptide sequence was derived.

The study has important implications in our understanding of in vivo idiotypic regulation of AutoImmune T-Cells and the regulatory mechanism underlying T-Cell Vaccination.