MS Abstracts 6a-2g1

Objective

1. To establish whether the Cognitive decline of the early phase of Relapsing/Remitting Multiple Sclerosis depends on the progression of the burden of disease, or on the loss of Brain Parenchyma, or is influenced by both

2. To monitor the loss of Brain Parenchymam in the early phase of the disease

3. To examine its possible relation with the progression of physical disability

Methods
For 2 years 53 patients with Clinically Definite Relapsing/Remitting Multiple Sclerosis with disease duration 1-5 years and Expanded Disability Status Scale </=5.0 at baseline were monitored.

The NeuroPsychological performances, the Psychological functioning, the Neurological impairment, and the disability have been assessed at baseline and after 2 years.

Patients also underwent PD/T₂ and T₁ weighted Brain MRI. T₂ and T₁ lesion volumes were measured by a semiautomatic technique.

Quantification of Brain Parenchymal volumes was obtained using a highly reproducible computerised interactive program.

The relation between Cognitive Impairment and MRI findings has been investigated.

By partial correlation and stepwise multiple regression analyzes excluding the effects of age, Education, Anxiety, Depression, and total days of Steroid use.

Results
In the 2 years of the study the mean change for T₂ and T₁ lesion Volumes and Brain Parenchymal Volumes were:

[Confidence Interval (CI)]
1. +1.7 ml 95% CI 1.3-2.2, p=0.005, (29.8%)
2. +0.2 ml, 95% CI 0.15-0.26, p=0.004, (25%)
3. -32.3 ml, 95% CI 24.2-42.3, p<0.0001, (2.7%)

Overall, 14 patients (26.4%) were judged to be Cognitively impaired at baseline and 28 (52.8%) at the end of the follow up.

Of the 18 NeuroPsychological tests and subtests employed in the study, patients with Multiple Sclerosis failed 5.8 (SD 2.3) tests at the baseline and 8.4 (SD 2.9) (p<0.0001) tests at the end of the study.

When the Cognitive changes were examined in individual patients, five (9.4%) of them were considered Cognitively improved, 33 (62.3%) remained stable, and 15 (28.3%) worsened over 2 years.

T₂ and T₁ volume changes in improved, stable, and worsened patients did not show any significant difference.

Whereas Brain Parenchymal Volume decrease in Cognitively worsened patients was significantly greater (-66 ml (5.4%), 95% CI 37-108.9, p=0.0031).

The Cognitive Impairment was independently predicted over 2 years only by the change of Brain Parenchymal Volumes (R=0.51, p=0.0003).

Ten patients (18.9%), who worsened by one or more points in the EDSS during the follow up period had significant decreases in Brain Parenchymal Volumes (-99 ml (8%), 95% CI 47.6-182.3, p=0.005).

At the end of the study the loss of Brain Parenchyma correlated significantly with change in EDSS (r= 0.59, p<0.0001).

Conclusions
In the early phase of Relapsing/Remitting Multiple Sclerosis the Cognitive deterioration relies more on the development of Brain Parenchymal Volume Atrophy than on the extent of burden of disease in the Brain.

The loss of Brain Parenchymal Volume underlies the progressive accumulation of physical disability from the initial phase of the disease, which becomes more demonstrable only if studied with longer observation periods.

Probably, the main pathological substrate of Brain Atrophy in the early stage of the disease is early Axonal loss.

Which causes the progression of Neurological deficits and the development of Cognitive Impairment.

These data support the debated opinion that disease modifying therapy should be initiated as early as possible.

Objective
Multiple Sclerosis (MS) is a disease characterized by PeriVascular infiltrates and DeMyelination of the White Matter in the Central Nervous System.

Although the precise cause of MS remains unknown, some investigations have been carried out on AntiOxidant mechanisms in these patients.

Methods
In this study, MalonDiAldehyde (MDA), as a Lipid Peroxidation marker, and CeruloPlasmin (Cp) and Transferrin (Trf), as AntiOxidant proteins.

Levels were determined in CerebroSpinal Fluid (CSF) and Serum of 30 MS patients before and after CorticoSteroid therapy and in 20 control subjects.

Transferrin and Cp levels were measured by the Nephelometric method and MDA was measured SpectroPhotometrically.

Results
Mean MDA(Serum) and MDA(CSF) levels were found to be highest in the pretreatment group and lowest in the control group.

Although there was no significant difference in terms of Serum Trf level, Serum Cp was found higher in Pre- and PostTreatment groups than in the control groups.

CeruloPlasmin and Trf levels of CSF were not detectable using the Nephelometric method. A significant correlation was found between MDA(CSF) and MDA(Serum) in the pretreatment group (r=0.58).

Conclusions
These data revealed that Lipid Peroxidation was increased in Serum and particulary in CSF of MS patients and was reduced with CorticoSteroid therapy.

Many patients with upper limb Intention Tremor encounter difficulties in mouse-driven interaction with the personal computer (PC).

An assistive technology system ("the Tremor Control System"), consisting of a motion-filtering software program that supports multiple interfaces.

Was developed and validated with 36 persons with Multiple Sclerosis in a multi-center trial.

PC-tests, requiring basic functions such as cursor placement and click and drag function, were able to differentiate between patients and control subjects (ANOVA: p<0.05).

A significant time improvement on the PC-tests was found when using an optimal alternative interface instead of the standard PC-mouse.

Paired t-tests: p<0.01 for Point & Click test, p<0.05 for Drag & Drop test and p<0.1 for Double Click test.

A significant time improvement was found for the Double Click test (paired t-tests: p<0.05) when the motion-filtering program was implemented.

The number of patients able to perform fully the PC-tests increased with the Tremor Control System. Patients with marked Intention Tremor seemed to profit especially from this assistive technology.

These users reported that working with the Tremor Control System was less fatiguing and more comfortable compared to the use of the standard PC-mouse.

Trigeminal Neuralgia is a very peculiar disease. The pain, also known as "Tic Douloureux", is paroxysmal and very severe.

It can be triggered by a light cutaneous stimulus on a very localized spot on the face (the so-called "trigger zone"). The patient can sometimes benefit from long remissions without any treatment.

With the exception of Multiple Sclerosis and of uncommon cases of Posterior Fossa Tumors or other lesions impinging on the Trigeminal Nerve, Ganglion or Root.

Trigeminal Neuralgia is considered as "idiopathic". Some benign abnormality had for long been suspected. The current opinion is now in favor of a "NeuroVascular conflict".

An artery, most often a loop of the Superior or AnteroInferior Cerebellar Artery, has an offending contact with the Trigeminal Nerve Root. Which results in localized DeMyelination and Ectopic triggering of Neuronal discharges.

This hypothesis is in agreement with the relief provided by AntiEpileptic drugs and is supported by recent NeuroImaging data.

Therapeutic options are reviewed: very efficient drugs are available but fail to provide a significant relief and/or have important side effects in many cases. Surgical alternatives are available, for which guidelines are proposed.

Oligodendrocytes play a significant role in the Central Nervous System, as these cells are responsible for Myelinating Axons and allowing for the efficient Conduction of Nerve Impulses.

Therefore, any understanding we can gain about the functional biology of Oligodendrocytes will give us important insights into DeMyelinating Diseases.

Such as Multiple Sclerosis, where Oligodendrocytes and Myelin are damaged or destroyed. Currently, much attention has focussed on the role of a family of Mitogen-activated protein Kinases in OL.

This Kinase family includes the ExtraCellular signal-regulated protein Kinases (ERKs), the stress-activated c-Jun N-terminal Kinase (JNK), and the 38 kDa high Osmolarity Glycerol response Kinase (p38).

The actions of Mitogen-activated protein Kinases in Oligodendrocytes appear to range from proliferation and cell survival to differentiation and cell death.

In the past, studies on Oligodendrocytes have been hampered by the difficulties inherent in producing large enough quantities of these cells for experimentation.

This problem arises in large part due to the Post-Mitotic nature of mature Oligodendrocytes. Over the years, a cell line known as Central Glia-4 (CG-4) has become a popular Oligodendrocyte model due to its potentially unlimited capacity for self-renewal.

In this review, we will look at the suitability of the Central Glia-4 cell line as an Oligodendrocyte model, specifically in respect to studies on Mitogen-activated protein Kinase signalling in Oligodendrocytes.

VasoSpasm can have many different causes and can occur in a variety of diseases, including Infectious, AutoImmune, and Ophthalmic Diseases, as well as in otherwise healthy subjects.

We distinguish between the primary VasoSpastic Syndrome and secondary VasoSpasm. The term "VasoSpastic Syndrome" summarizes the symptoms of patients having such a diathesis as responding with Spasm to stimuli like cold or emotional stress.

Secondary VasoSpasm can occur in a number of AutoImmune Diseases, such as Multiple Sclerosis, Lupus Erythematosus, AntiPhospholipid Syndrome, Rheumatoid PolyArthritis, Giant Cell Arteritis, Behcet's Disease, Buerger's Disease and PreEclampsia, and also in infectious diseases such as AIDS.

Other potential causes for VasoSpasm are Hemorrhages, Homocysteinemia, Head Injury, Acute Intermittent Porphyria, Sickle Cell Disease, Anorexia Nervosa, Susac Syndrome, Mitochondriopathies, Tumors, Colitis Ulcerosa, Crohn's Disease, ArterioSclerosis and drugs.

Patients with primary VasoSpastic Syndrome tend to suffer from cold hands, low blood pressure, and even Migraine and silent MyoCardial Ischemia.

Valuable diagnostic tools for VasoSpastic Diathesis are nailfold Capillary microscopy and Angiography, but probably the best indicator is an increased Plasma level of Endothelin-1.

The Eye is frequently involved in the VasoSpastic Syndrome, and Ocular manifestations of VasoSpasm include alteration of Conjunctival Vessels, Corneal Edema, Retinal Arterial and Venous Occlusions, Choroidal Ischemia, Amaurosis Fugax, AION, and Glaucoma.

Since the clinical impact of Vascular Dysregulation has only really been appreciated in the last few years, there has been little research in the according therapeutic field.

The role of Calcium Channel Blockers, Magnesium, Endothelin and Glutamate antagonists, and Gene therapy are discussed.

The aim of this study was to further investigate OptoKinetic reflex function in Multiple Sclerosis.

Gaze-holding in darkness, OptoKinetic Nystagmus, OptoKinetic after Nystagmus and latency to circularvection were measured using Electro-Oculography and a rotating OptoKinetic drum.

Gaze-holding was not significantly different between the Multiple Sclerosis and control groups; however, four of 23 Multiple Sclerosis patients exhibited eccentric gaze-evoked Nystagmus.

There were no significant differences in either OptoKinetic Nystagmus frequency or latency to CircularVection.

However, OptoKinetic Nystagmus slow phase velocity during rise time and amplitude during beat time were significantly reduced in the Multiple Sclerosis group (p < 0.05 and p < 0.0001, respectively).

The time constant of OptoKinetic after Nystagmus was also significantly reduced in the Multiple Sclerosis group (p < 0.005).

These results indicate that OptoKinetic Nystagmus and OptoKinetic after Nystagmus are significantly impaired by Multiple Sclerosis.

In normal conditions, Albumin and ImmunoGlobulin (IgG) in the CerebroSpinal Fluid (CSF) originate from the blood, and there is no AntiBody production within the Central Nervous System.

Up to 20% of CSF proteins are Intrathecally synthesized, but the major fraction is blood-derived. The CSF/Serum Albumin quotient (QAlb) is the best marker of the Blood-CSF Barrier function.

The corresponding ImmunoGlobulin quotients (QIGG, QIGA, QIGM) are not linearly related to QAlb and their correlations are defined by an hyperbolic equation.

This equation is used to discriminate between a blood-derived and a locally produced fraction of ImmunoGlobulins in case of an Intrathecal Humoral Immune Response.

The detection of CSF-specific OligoClonal IgG is more sensitive than the quantitative comparison between QIGG and QAlb.

A further step is the determination of AntiBody indices and the detection of specific OligoClonal AntiBodies by Antigen-driven Immunoblots.

CSF analysis remains a cornerstone for the diagnosis of various Neurological Disorders, including Multiple Sclerosis and infectious diseases of the Central Nervous System.

ProInflammatory Cytokines, pathological Iron deposition, and Oxidative Stress have been implicated in the PathoGenesis of Multiple Sclerosis (MS) and Experimental AutoImmune EncephaloMyelitis (EAE).

HO-1 mRNA levels and Mitochondrial uptake of [(55)Fe]Cl(3)-derived Iron were measured in rat Astroglial cultures exposed to InterLeukin-1beta (IL-1ß) or Tumor Necrosis Factor-alpha (TNF-).

Alone or in combination with the Heme Oxygenase-1 (HO-1) Inhibitors, Tin Mesoporphyrin (SnMP) or Dexamthasone (DEX), or Interferon-beta-1b (INF-ß).

HO-1 expression in Astrocytes was evaluated by ImmunoHistoChemical staining of Spinal Cord tissue derived from MS and control subjects.

IL-1ß or TNF- promoted sequestration of Non-Transferrin-derived (55)Fe by Astroglial Mitochondria.

HO-1 inhibitors, Mitochondrial permeability Transition Pore (MTP) Blockers and AntiOxidants significantly attenuated Cytokine-related Mitochondrial Iron sequestration in these cells.

IFN-ß decreased HO-1 expression and Mitochondrial Iron sequestration in IL-1ß- and TNF--challenged Astroglia.

The percentage of Astrocytes coexpressing HO-1 in affected Spinal Cord from MS patients (57.3% +/- 12.8%) was significantly greater (p < 0.05) than in normal Spinal Cord derived from controls subjects (15.4% +/- 8.4%).

HO-1 is over-expressed in MS Spinal Cord Astroglia and may promote Mitochondrial Iron deposition in MS Plaques.

In MS, IFN-ß may attenuate Glial HO-1 Gene induction and aberrant Mitochondrial Iron deposition accruing from exposure to ProInflammatory Cytokines.

Patients with Chronic Fatigue Syndrome (CFS), Multiple Sclerosis (MS), and major Depression were compared with controls and with each other.

On a NeuroPsychological battery that included standard NeuroPsychological tests and a computerized set of tasks that spanned the same areas of ability.

A total of 101 participants were examined, including 29 participants with CFS, 24 with MS, 23 with Major Depressive Disorder, and 25 healthy controls.

There were significant differences among the groups in 3 out of 5 Cognitive Domains: Memory, Language, and Spatial Ability.

Assessment of Psychiatric symptoms indicated that all 3 patient groups had a higher prevalence of Depression than the controls. A total measure of Psychiatric symptomatology also differentiated the patients from the controls.

After covarying the Cognitive test scores by a measure of Depression, the patient groups continued to differ from controls primarily in the area of Memory.

The findings support the view that the Cognitive Deficits found in CFS cannot be attributed solely to the presence of Depressive symptomatology in the patients.