MS Abstracts 02c-2g4

The use of Low Doses of Naltrexone for the treatment of Multiple Sclerosis (MS) enjoys a worldwide following amongst MS patients.

There is overwhelming anecdotal evidence, that in Low Doses Naltrexone not only prevents relapses in MS but also reduces the progression of the disease.

It is proposed that Naltrexone acts by reducing Apoptosis of Oligodendrocytes. It does this by reducing inducible Nitric Oxide Synthase activity.

This results in a decrease in the formation of Peroxynitrites, which in turn prevent the inhibition of the Glutamate transporters.

Thus, the Excitatory NeuroToxicity of Glutamate on Neuronal Cells and Oligodendrocytes via activation of the alpha-Amino-3-Hydroxy-5-Methyl-Isoxazole-4-Propionic Acid class of Glutamate Receptor is prevented.

It is crucial that the medical community respond to patient needs and investigate this drug in a clinical trial.

Background
Measuring Perfusion provides a potential indication of metabolic activity in Brain Tissue.

Studies in Multiple Sclerosis (MS) have identified areas of decreased Perfusion in Gray Matter (GM) and White Matter (WM), but the pattern in clinical subgroups is unclear.

Objectives
This study investigated Perfusion changes in differing MS clinical subgroups on or off Interferon-beta therapy using a non-invasive MRI technique (continuous arterial spin labelling).

To investigate whether different clinical MS subtypes displayed Perfusion changes and whether this could give a further insight into the pathological mechanisms involved.

Methods
Sixty patients (21 Relapsing/Remitting, 14 Secondary/Progressive, 12 Primary/Progressive, 13 Benign) and 34 healthy controls were compared.

Statistical Parametric Mapping (SPM '99) was used to investigate regional variations in Perfusion in both GM and WM.

Global WM Perfusion was derived by segmenting WM from images using T₁ relaxation times.

Results
Regions of lower Perfusion in predominantly GM were observed in the Primary and Secondary/Progressive cohorts, particularly in the Thalamus.

Increased WM Perfusion was seen in Relapsing/Remitting and Secondary/Progressive cohorts.

Conclusions
Low GM Perfusion could reflect decreased metabolism secondary to Neuronal and Axonal Loss or dysfunction with a predilection for Progressive forms of MS.

Increased WM Perfusion may indicate increased metabolic activity possibly due to increased cellularity and inflammation.

Improved methodology and longitudinal studies may enable further investigation of regional and temporal changes, and their relationship with physical and Cognitive Impairment.

In the absence of pathognomonic clinical features or a definitive laboratory test, Multiple Sclerosis (MS) remains ultimately a diagnosis of exclusion.

Accurate diagnosis is increasingly important with available disease modifying therapy.

Unfortunately the rate of misdiagnosis remains around 5%-10%, indicating that 1 in 20 patients thought to have MS has, instead, a condition resembling MS.

In this review we describe conditions that may be confused with MS because they can present as lesions disseminated in time, space, or both.

Conditions often confused with MS may be:
1. Inflammatory Disease
   Systemic Lupus Erythematosus, Sjogren's Syndrome, Vasculitis, Sarcoidosis, Behcet's
2. Infectious Disease
   Progressive Multifocal Leukoencephalopathy, HTLV-1 infection, Herpes Zoster, Lyme, Syphilis
3. Genetic
   Lysosomal Disorders, Adrenoleukodystrophy, Mitochondrial Disorders, CADASIL
4. Metabolic
   Vitamin B12 deficiency
5. Neoplastic
   CNS Lymphoma
6. Spinal Diseases
   Degenerative and Vascular malformations

The key to the accurate diagnosis of MS is vigilance for atypical features, suggesting the possibility of an alternative diagnosis.

The study describes the clinical and pathological findings in 12 patients with Relapsing and Remitting Multiple Sclerosis, who died during or shortly after the onset of a relapse.

Pathological changes not previously associated with the formation of new symptomatic lesions were observed in seven cases.

Namely, extensive Oligodendrocyte Apoptosis and Microglial activation in Myelinated tissue containing few or no Lymphocytes or Myelin Phagocytes.

No current laboratory model of Multiple Sclerosis, in particular, Experimental Allergic Encephalomyelitis, is known with these features, which raises the possibility of some novel process underlying new lesion formation in Multiple Sclerosis.

Neurological manifestations of GastroIntestinal disorders are described, with particular reference to those resembling Multiple Sclerosis (MS) on clinical or MRI grounds.

Patients with Celiac Disease can present Cerebellar Ataxia, Progressive MyoClonic Ataxia, Myelopathy, or Cerebral, BrainStem and Peripheral Nerve involvement.

AntiGliadin AntiBodies can be found in subjects with Neurological dysfunction of unknown cause, particularly in Sporadic Cerebellar Ataxia ("Gluten Ataxia").

Patients with Whipple's Disease can develop mental and psychiatric changes, Supranuclear Gaze Palsy, Upper MotoNeuron Signs, HypoThalamic Dysfunction, Cranial Nerve abnormalities, Seizures, Ataxia, Myorhythmia and Sensory deficits.

Neurological manifestations can complicate Inflammatory Bowel Disease (e.g. Ulcerative Colitis and Crohn's Disease) due to Vascular or Vasculitic mechanisms. Cases with both Crohn's Disease and MS or Cerebral Vasculitis are described.

Epilepsy, Chronic Inflammatory PolyNeuropathy, muscle involvement and Myasthenia Gravis are also reported.

The Central Nervous System can be affected in patients with Hepatitis C Virus (HCV) infection because of Vasculitis associated with HCV-related CryoGlobulinemia.

Mitochondrial NeuroGastroIntestinal Encephalopathy (MNGIE) is a disease caused by multiple deletions of Mitochondrial DNA.

It is characterized by Peripheral Neuropathy, Ophthalmoplegia, Deafness, LeukoEncephalopathy, and GastroIntestinal symptoms due to Visceral Neuropathy.

Neurological manifestations can be the consequence of Vitamin B1, Nicotinamide, Vitamin B12, Vitamin D, or Vitamin E deficiency and from nutritional deficiency states following Gastric surgery.

Background And Purpose
In Multiple Sclerosis (MS) lesions appear both in Brain and Cervical Cord.

The aim of this study was to estimate the presence of MRI changes in Cervical Cord depending on the course, duration of the disease and a disability.

Material And Methods
Clinical measures included 66 patients suffering from MS, the diagnosis was made according to McDonald's Criteria. Patients were aged from 18 to 62 (41 women and 25 men).

Results
In patients with Relapsing/Remitting form (EDSS 1-4) single lesions were seen.

Whereas, Secondary/Progressive patients (EDSS 3-7) had diffuse DeMyelinating lesions and Primary/Progressive patients (EDSS 4-8) - both kinds of changes.

It has been shown that the lesions occurred as the disease proceeds. Patients without DeMyelinating lesions in Cervical Cord had EDSS from 1 to 3 and the duration of their disease was longer than 10 years (Benign MS).

Conclusions
The duration of the disease depends on the presence and character of DeMyelinating lesions in Cervical Cord to a large extent.

That dependence was not noticed in a Primary/Progressive form. In Benign MS there were no lesions in Cervical Cord.

Clinical, imaging, and pathological studies in Multiple Sclerosis have generally emphasized the relative preservation of Axons in comparison with Myelin.

Recent evidence, however, demonstrates that Axonal Loss is also significant, affects long Tracts such as the CorticoSpinal and Sensory Tracts and relates closely to functional disability.

Accordingly, the distribution and extent of this Axonal Loss is the focus of the current investigation.

Post-mortem material of 55 Multiple Sclerosis patients and 32 matched controls was used to examine quantitatively.

The population of Axons in the CorticoSpinal Tracts from the Medulla to the Lumbar Spinal Cord and the Sensory Tracts from the Lumbar to the Upper Cervical Spinal Cord.

Myelin- and Axon-stained sections have been prepared to estimate the notional area and Axon Density, respectively of both Tracts.

Our results indicate that in the CorticoSpinal Tracts there is a significant reduction of the area and Axon density at all levels investigated in Multiple Sclerosis cases when compared with controls.

In contrast, the Sensory Tracts in Multiple Sclerosis cases showed a significant reduction in area and Axon density only in the upper regions of the Spinal Cord.

As has been found with MRI plaque load and T₂ burden, correlations of Axonal Loss with duration of disease were not strong.

Of the Fibers lost in Multiple Sclerosis, we have found that small Fibers (<3 microm²) seem to be particularly affected, with large Fibers remaining relatively preserved in both the CorticoSpinal and Sensory Tracts.

In Multiple Sclerosis, Axonal Loss is widespread, and its extent is Tract specific and size selective.

Following diffuse traumatic Brain Injury, there may be persistent Functional or Psychological deficits despite the presence of normal conventional MR images.

Previous experimental animal and human studies have shown Diffusion abnormalities following focal Brain Injury.

Our aim was to quantify changes in Apparent Diffusion Coefficient (ADC) and absolute relaxation times of Normal-Appearing White Matter (NAWM) in humans following traumatic Brain Injury.

Twenty-three patients admitted with a diagnosis of head injury (nine mild, eight moderate, and six severe) were scanned an average of 7.6 days after injury using a quantitative Echo Planar Imaging acquisition to obtain co-registered T₁, T₂, and ADC parametric maps.

Mean NAWM values were compared with a control group (n = 13).

The patient group showed a small but significant increase in ADC in NAWM, with no significant change in T₁ or T₂ relaxation times.

There was a correlation between injury severity and increasing ADC (p = 0.03) but no correlation with either T₁ or T₂.

Suggesting that ADC is a sensitive and independent marker of diffuse White Matter tissue damage following traumatic insult. None of the patients had a reduced ADC, making Ischemia unlikely in this cohort.

PathoPhysiological mechanisms that may explain diffusely raised ADC include Vasogenic Edema, chronic Ischemic phenomena, or changes in tissue CytoArchitecture or NeuroFilament alignment.

Magnetic Resonance Imaging (MRI) has significantly extended the understanding of Multiple Sclerosis (MS), owing to its ability to sensitively depict the dynamics of the disease process in vivo.

The subject of this review is the use of MRI in the post-mortem setting, with emphasis on how it may be used to improve the specimen selection process at autopsy.

Lesions with active DeMyelination are highly interesting in the study of MS PathoGenesis, but are rare in a typical autopsy material of chronic MS.

The yield of MS lesions in autopsy specimen selection can be increased by the use of MRI-guided tissue sampling, as a significant proportion of abnormalities detected by post-mortem MRI are not macroscopically visible/palpable.

The majority of these MRI abnormalities have been found to represent either discrete areas of Microglial activation with no DeMyelination (so-called (p)reactive lesions), or active DeMyelinating MS lesions by further HistoPathological examination.

The presence and extent of MS pathology outside of the focal DeMyelinated lesions is more readily appreciated by MRI-guided specimen sampling, as has been shown in the study of extensive areas of partial Myelin loss in the Spinal Cord.

A further advantage of MRI-guided specimen sampling is the ability to use three-dimensional and quantitative measures.

The potential of correlating these with HistoPathological data may be further exploited in the future. The technical procedure for MRI-guided tissue sampling at autopsy is presented, and the limitations of the technique are discussed.

Background
Early-onset Multiple Sclerosis (MS) typically has a more favorable course than adult-onset disease.

Objective
To assess the extent of microscopic tissue damage in the Brain and Cervical Cord of patients with early-onset MS.

Design
During a single Magnetic Resonance Imaging session, images of the Brain and Spinal Cord were obtained using Diffusion Tensor and Magnetization Transfer Magnetic Resonance Imaging.

Patients
We studied 13 patients with early-onset MS and 10 healthy volunteers.

Results
Compared with control subjects, patients with early-onset MS showed only a slight increase of the average Mean Diffusivity of the Normal-Appearing Brain Tissue.

Conclusion
The relatively modest Central Nervous System damage detected in these patients might explain why early-onset MS typically has a more favorable clinical course than adult-onset MS.

Glatiramer Acetate (GA, Copaxone, Copolymer-1) is an approved drug for the treatment of Multiple Sclerosis and is highly effective in the suppression of Experimental Autoimmune Encephalomyelitis in various species.

The mode of action of GA is by initial strong promiscuous binding to MHC molecules and consequent competition with various Myelin Antigens for their presentation to T-Cells.

A further aspect of its action is potent induction of specific Suppressor Cells of the T-Helper 2 (Th2) type that migrate to the Brain and lead to in situ Bystander Suppression.

Furthermore, the GA-specific cells in the Brain express the AntiInflammatory Cytokines IL-10 and Transforming Growth Factor-ß.

In addition to Brain-Derived NeuroTrophic Factor, whereas they do not express IFN-γ.

Based on this ImmunoModulatory mode of action, we explored the potential of GA for two other applications: prevention of graft rejection and amelioration of Inflammatory Bowel Diseases.

GA was effective in amelioration of graft rejection in two systems by prolongation of skin graft survival and inhibition of functional deterioration of Thyroid grafts, across Minor and Major Histocompatibility barriers.

In all transplantation systems GA treatment inhibited the detrimental secretion of Th1 inflammatory Cytokines and induced beneficial Th2/3 AntiInflammatory response.

GA was effective also in combination with low-dose ImmunoSuppressive drugs.

Inflammatory Bowel Diseases are characterized by detrimental imbalanced ProInflammatory Immune reactivity in the gut.

GA significantly suppressed the various manifestations of Trinitrobenzene Sulfonic Acid-induced Colitis, including mortality, weight loss, and macroscopic and microscopic Colonic damage.

GA suppressed local Lymphocyte proliferations and Tumor Necrosis Factor-alpha detrimental secretion but induced Transforming Growth Factor-ß, thus confirming the involvement of Th1 to Th2 shift in GA mode of action.

Our purpose was to evaluate the role of Magnetization Transfer and image subtraction in detecting more enhancing lesions in Brain MR imaging of patients with Multiple Sclerosis (MS).

Thirty-one MS patients underwent MR imaging of the Brain with T₁-weighted Spin Echo sequences without and with Magnetization Transfer (MT) using a 1.5 Tesla imager.

Both sequences were acquired before and after intravenous injection of a paramagnetic contrast agent. Subtraction images in T₁-weighted sequences were obtained by subtracting the pre-contrast images from the post-contrast ones.

A significant difference was found between the numbers of enhanced areas in post-Gadolinium T₁-weighted images without and with MT ( p=0.020).

The post-Gadolinium T₁-weighted images with MT allowed the detection of an increased (13) number of enhancing lesions compared with post-Gadolinium T₁-weighted images without MT.

A significant difference was also found between the numbers of enhanced areas in post-Gadolinium T₁-weighted images without MT and subtraction images without MT ( p=0.020).

The subtraction images without MT allowed the detection of an increased (10) number of enhancing lesions compared with post-Gadolinium T₁-weighted images without MT.

Magnetization Transfer contrast and subtraction techniques appear to be the simplest and least time-consuming applications to improve the conspicuity and detection of contrast-enhancing lesions in patients with MS.