MS Abstracts 01b-2g4

Purpose
To correlate quantitative Magnetic Resonance (MR) imaging data (ie, relaxation times and Magnetization Transfer Ratios [MTR]) with histopathologic findings of DeMyelination and Axonal disease in Cervical Spinal Cord specimens from patients with Multiple Sclerosis (MS) and control subjects.

Materials And Methods
Formaldehyde-fixed Cervical Spinal Cord specimens from 11 patients with MS-three men and eight women (mean age at death, 66 years +/- 11.3 [standard deviation])-and two female control subjects without Neurologic Disease (83 and 41 years of age at death) were examined at 4.7 T.

Relaxation time measurements and MTR mapping were performed. Analyses included the Whole Cord Area and region-of-interest measurements.

Histopathologic analyses included semiquantitative Myelin and quantitative Axonal analysis.

Multiple Sclerosis (MS) is a chronic inflammatory disease of the Central Nervous System, associated with primary destruction of Myelin sheaths. Axons are relatively well preserved, although they too are injured in the development of the lesions.

While inflammation and DeMyelination induce Neurological deficit, which is in part reversible, the destruction of Axons, when past the threshold of compensation, is always accompanied by irreversible clinical deficits.

The mechanisms leading to tissue injury in MS are complex and heterogenous. They involve direct CytoToxicity mediated by T-Lymphocytes, specific AntiBodies and Complement as well as toxic products of Macrophages.

In addition, in a small subset of patients a genetically determined increased susceptibility of the Central Nervous System tissue for Immune mediated damage appears to play a role.

Since the pathogenetic pathways of DeMyelination and tissue damage vary between different MS patients, their identification by paraclinical markers is of critical importance for diagnosis and therapeutic management.

Loss of Axons is a major contributor to NonRemitting deficits in the Inflammatory DeMyelinating Disease Multiple Sclerosis (MS). Based on biophysical studies showing that activity of Axonal Sodium Channels can trigger Axonal Degeneration.

Recent studies have tested Sodium Channel-blocking drugs in Experimental Autoimmune Encephalomyelitis (EAE), an animal model of MS, and have demonstrated a protective effect on Axons.

However, it is possible that, in addition to a direct effect on Axons, Sodium Channel Blockers may also interfere with Inflammatory Mechanisms.

We therefore examined the novel hypothesis that Sodium Channels contribute to activation of Microglia and Macrophages in EAE and acute MS lesions. In this study, we demonstrate a robust increase of Sodium Channel Na(v)1.6 expression in activated Microglia and Macrophages in EAE and MS.

We further demonstrate that treatment with the Sodium Channel blocker Phenytoin ameliorates the inflammatory cell infiltrate in EAE by 75%.

Supporting a role for Sodium Channels in Microglial activation, we show that TetrodoToxin, a specific Sodium Channel Blocker, reduces the Phagocytic function of activated rat Microglia by 40%.

To further confirm a role of Na(v)1.6 in Microglial activation, we examined the Phagocytic capacity of Microglia from med mice, which lack Na(v)1.6 channels, and show a 65% reduction in Phagocytic capacity compared with Microglia from wildtype mice.

Our findings indicate that Sodium Channels are important for activation and Phagocytosis of Microglia and Macrophages in EAE and MS and suggest that, in addition to a direct NeuroProtective effect on Axons, Sodium Channel blockade may ameliorate NeuroInflammatory disorders via AntiInflammatory mechanisms.

Copyright 2004 Wiley-Liss, Inc.

Our objective was to investigate whether PolyMorphisms and HaploTypes in the TGFß1 Gene are associated with susceptibility or disease characteristics of Multiple Sclerosis (MS).

In 247 MS patients and 194 controls, Single Nucleotide Polymorphisms (SNPs) at position ⁺869 (Leu10Pro) and position ⁺915 (Arg25Pro) in the signaling sequence of the TGFß1 gene were determined, and the distribution of Alleles, Genotypes, and HaploTypes was related to clinical data.

In addition, Magnetic Resonance Imaging (MRI) data were studied in a subgroup of patients (n = 96). The Allele distribution of the two PolyMorphisms studied was in Hardy-Weinberg Equilibrium in patients and in controls.

No association was found with any of the three HaploTypes found in the Dutch population, denoted as HaploType 1 (TGFß1⁺869T-TGFß1⁺915G), HaploType 2 (TGFß1⁺869C-TGFß1⁺915G), and HaploType 3 (TGFß1⁺869C-TGFß1⁺915C).

However, the TGFß1⁺869 GenoType CC was significantly more frequent in patients (p = 0.031, chi(2) test).

The highest frequency of the TGFß1⁺869 GenoType CC was observed in male patients (25.2% vs. 10.0% in controls, p = 0.004, chi(2) test).

And carriership of TGFß1⁺869 Allele C was correspondingly increased in male patients (74.8% vs. 56.7%, p = 0.008, chi(2) test, OR 2.27, 95% CI 1.23-4.17).

Although there was no association with clinical markers of disease progression, patients homozygous for TGFß1⁺869 Allele C showed a significantly higher annual increase in two MRI parameters: Ventricular Fraction (Central Atrophy) and T₁-HypoIntense Lesion Load (Matrix Destruction).

The TGFß1 T⁺869C (Leu10Pro) Gene PolyMorphism is associated with MS susceptibility, especially in males, and with a more destructive course of the disease as illustrated by MRI.

Objectives/Hypothesis
Auditory BrainStem Response (ABR) testing and magnetic resonance imaging (MRI) are compared for the evaluation of patients with asymmetric sensorineural hearing loss (SNHL).

MRI with Gadolinium administration is the current gold standard for identifying RetroCochlear lesions causing asymmetric SNHL. The study seeks to determine the sensitivity and specificity of ABR in screening for possible RetroCochlear Pathology.

Most important among SNHL etiologies are neoplastic lesions such as Vestibular Schwannomas, CerebelloPontine Angle (CPA) Tumors, as well as Multiple Sclerosis, Stroke, or other rare nonneoplastic causes.

The study results will allow the author to recommend a screening algorithm for patients with asymmetric SNHL.

Study Design
The study is a multi-institutional, institutional review board approved, prospective, nonrandomized comparison of ABR and MRI for the evaluation of patients with asymmetric SNHL.

Methods
Three hundred twelve patients (between the ages of 18 and 87) with asymmetric SNHL completed the study.

Asymmetric SNHL was defined as 15 dB or greater asymmetry in two or more frequencies or 15% or more asymmetry in speech discrimination scores (SDS). These patients prospectively underwent both ABR and MRI.

The ABR and MRI were interpreted independently in a blinded fashion. In addition to the ABR and MRI results, a variety of clinical and demographic data were collected.

Results
Thirty-one (9.94%) patients of the study population of 312 were found on MRI to have lesions causing their SNHL.

Of the 31 patients with causative lesions on MRI there were 24 Vestibular Schwannomas, 2 Glomus Jugulare Tumors, 2 ectatic Basilar Arteries with BrainStem compression, 1 Petrous Apex Cholesterol Granuloma, 1 case of possible DeMyelinating Disease, and 1 parietal lobe mass.

Twenty-two of the 31 patients had abnormal ABRs, whereas 9 patients (7 with small Vestibular Schwannomas) had normal ABRs.

This gives an overall false-negative rate for ABR of 29%. The false-positive rate was found to be 76.84%. Sensitivity of ABR as a screening test was 71%, and specificity was 74%.

Conclusions
Ten percent of patients with asymmetric SNHL (by this study's criteria) are likely to have causative lesions found on MRI.

Although the recently reported annual incidence of Vestibular Schwannoma in the general population is 0.00124%, for patients with asymmetric SNHL in this study, the incidence was 7.7% (nearly 4 orders of magnitude higher).

ABR has been demonstrated to have low sensitivity and specificity in the evaluation of these patients and cannot be relied on as a screening test for patients with asymmetric SNHL.

Keeping the use of MRI conditional on the results of ABR will annually result in missed or delayed diagnosis of causative lesions in 29 patients per 1,000 screened.

The author recommends abandoning ABR as a screening test for asymmetric SNHL and adoption of a focused MRI protocol as the screening test of choice (within certain guidelines).

Multiple sclerosis is characterized by the presence of multiple plaques within the Central Nervous System, manifesting as remission and exacerbation of Neurologic Dysfunction over variable time courses.

We present the case of a 20-year-old woman. Before treatment, her Auditory BrainStem Response (ABR) test revealed bilateral prolongation. A caloric test showed Canal Paresis of the right Ear and a normal response on the left.

A Vestibular Evoked Myogenic Potential (VEMP) test displayed an absent response in the right ear and a delayed response in the left.

A Magnetic Resonance Imaging (MRI) scan demonstrated multiple diffuse high signal lesions in the Hemispheres, BrainStem, and Cerebellum.

Six months after treatment, the DeMyelinating plaques were shown to have resolved spontaneously on MRI. Recovery of caloric responses was anticipated.

Bilateral prolongation of ABRs remained, but the VEMP test disclosed a normal response in the right Ear and a delayed response in the left.

Accordingly, in addition to MRI, caloric tests and ABR and VEMP tests are useful in monitoring the evolution of AudioVestibular function in patients with Multiple Sclerosis.

Introduction
Hyperhidrosis may result from Brain, Spinal Cord or Peripheral Nervous System injuries. We report the case of a 26-year-old patient who presented with Sensorial Disorders and focal Hyperhidrosis of the right hand.

Observation
MRI revealed multiple lesions very suggestive of active DeMyelinization. A lesion in the left ParaMedian posterior portion of the Pons was enhanced after Gadolinium infusion.

The diagnosis of Multiple Sclerosis was suggested by MRI data and OligoClonal IgG Bands on CerebroSpinal Fluid Electrophoresis.

Conclusions
Focal Hyperhidrosis may be due to a lesion of the crossed Sympathetic Inhibitory Tract.

Although autonomic dysfunction is common during the late course of Multiple Sclerosis this case is, to our knowledge, the first report of focal Hyperhidrosis revealing Multiple Sclerosis.

Urination Disorders occur in 80% patients with Multiple Sclerosis (MS). Most common of them is Detrusor-Sphincter Dyssynergia (DSD).

Alpha1-AdrenoBlockers can relax the neck of the Urinary Bladder (UB) and Urethral Sphincters, thus eliminating dynamic obstruction, reducing resistance to urine flow and facilitating voiding.

Our study assessed feasibility of using a selective alpha1A/D-AdrenoBlocker Tamsulosin in MS-associated DSD.

The choice of this alpha-AdrenoBlocker was based on its high safety profile in relation to CardioVascular System. The trial enrolled 28 patients (20 females and 8 males) with verified diagnosis of DSD.

They were given Tamsulosin (omnik) in a dose 0.4 mg/day (1 capsule) for 2 months. To the end of the trial quality of life raised in 96% patients.

Occurrence of Pollakiuria, number of imperative micturate urges diminished, the IPSS score decreased by 54%, QL index improved by 58%.

There was also a decrease in the volume of the residual urine, amplitude of involuntary Detrusor contractions, an increase in maximal volumic speed of urine flow, cystometric volume of the UB, mean urine volume in urination.

Side effects were not registered. Thus, Tamsulosin has a positive effect in voiding disorders in the presence of DSD associated with MS. This considerably improves quality of life of MS patients.

Objective
The concept of Vascular compression of the Trigeminal Root as the main Etiological factor in idiopathic Trigeminal Neuralgia has achieved widespread acceptance, and MicroVascular Decompression (MVD) is a well-established surgical procedure for its treatment.

Multiple Sclerosis (MS) has long been considered to be an absolute contraindication to MVD because of the supposed exclusive causative role of a DeMyelinating lesion affecting the Trigeminal Root Entry Zone.

Magnetic Resonance Imaging preoperative identification of suspicious vessels along the cisternal course of the Trigeminal Nerve in MS patients raises the question of a possible causative role of Vascular Compression in MS patients.

Methods
We describe Magnetic Resonance Imaging findings, surgical findings, and outcomes in 35 MS patients who underwent MVD for medically intractable Trigeminal Neuralgia.

Results were assessed by clinical follow-up and periodic phone surveys. The mean follow-up was 44 months (range, 6-108 mo).

Results
Magnetic Resonance Imaging revealed the presence of DeMyelinating lesions affecting the BrainStem Trigeminal Pathways of the painful side in 26 (74%) of 35 patients.

During surgery, severe NeuroVascular compression at the Trigeminal Root Entry Zone was found in 16 (46%) of 35 patients. The long-term outcome was excellent in 39%, good in 14%, fair in 8%, and poor in 39% of patients.

No statistically significant prognostic factor predicting good outcome could be found. There was no mortality, with a 2.5% long-term morbidity rate (Facial Nerve Palsy in one patient).

Conclusion
Results of MVD in Trigeminal Neuralgia MS patients are much less satisfactory than in the idiopathic group, indicating that central mechanisms play a major role in Pain genesis.

Cortical reorganization has been demonstrated in the Motor Network that mediates performance of a motor task in patients with Multiple Sclerosis. How this network responds to motor training is not known.

This study examined functional MRI (fMRI) activation patterns associated with performance of a motor task, consisting of repetition of directionally specific voluntary thumb movements.

Before and after motor training in a group of Multiple Sclerosis patients with mild motor impairment of the right upper extremity.

Patients and healthy subjects were scanned in one session before, during and after a 30 min training period. fMRI data obtained during rest, thumb flexion (trained movement) and thumb extension (untrained movement) were analyzed using random effects analysis (SPM99).

Motor kinematics of training motions and EMG from the resting hand were monitored with an accelerometer and surface EMG electrodes. Kinematics of thumb movements before, during and after training were comparable in the absence of mirror EMG activity in the resting hand.

Before training, thumb movements elicited more prominent activation of the ContraLateral Dorsal PreMotor Cortex [PMd, Brodmann area (BA) 6] in Multiple Sclerosis patients than in controls.

After training, unlike the control group, Multiple Sclerosis patients did not exhibit task-specific reductions in activation in the ContraLateral Primary Somatosensory (S1), motor (M1) and adjacent Parietal association (BA 40) cortices.

These results indicate that patients engage the ContraLateral PMd more than controls in order to perform directionally specific movements before training.

The absence of training-dependent reductions in activation in S1, M1 and BA 40 is consistent with a decreased capacity to optimize recruitment of the Motor Network with practice.

This study investigates the effect of Nitric Oxide (NO) on both the chemical modifications of CNS proteins and the architecture of the Myelinated InterNode.

Incubation of rat Optic Nerves for 2 h with 1 mM concentration of the NO-donors S-Nitroso-N-Acetyl-Penicillamine (SNAP), Ethyl-2-[Hydroxyimino]-5-Nitro-3-Hexeneamide (NOR-3), and 4-Phenyl-3-Furoxan Carbonitrile (PFC) led to decompaction of Myelin at the level of the IntraPeriod Line (IPL).

In contrast, incubation with 1 mM Sodium Nitroprusside, which slowly releases NO, Sodium Nitrite, and N-NitroSopyrrolidine failed to cause Myelin disassembly.

This suggests that free NO and/or some of its direct oxidation products (e.g., N2O3) are the active molecular species.

NO-induced alterations in Myelin architecture could not be assigned to Protein or Lipid degradation, Lipid peroxidation, ATP depletion, Calcium uptake, Protein Nitration, Protein Carbonylation, and Nerve Depolarization. NO-treatment, however, resulted in the S-Nitrosation of a number of proteins.

In Myelin, one of the major S-Nitrosated substrates was identified as ProteoLipid Protein (PLP), an abundant Cysteine-rich protein that is responsible for IPL stabilization.

Peripheral Nervous System Myelin, whose stability depends on proteins other than PLP, was not decompacted upon incubation of Sciatic Nerves with SNAP.

It is proposed that NO-mediated Nitrosation of Sulfhydryl groups is likely to interfere with the normal function of PLP and other important CNS Myelin proteins leading to the structural demise of this membrane.

These findings are relevant to Multiple Sclerosis and other inflammatory DeMyelinating Disorders where both excessive NO production and Myelin instability are known to occur.

Multiple Sclerosis (MS) develops in young adults with a complex predisposing Genetic trait and probably requires an inciting environmental insult such as a Viral infection to trigger the disease.

The activation of CD4⁺ AutoReactive T-Cells and their differentiation into a Th1 phenotype is a crucial event in the initial steps, and these cells are probably also important players in the long-term evolution of the disease.

Damage of the target tissue, the Central Nervous System, is, however, most likely mediated by other components of the Immune System, such as AntiBodies, Complement, CD8⁺ T-Cells, and factors produced by Innate Immune Cells.

Perturbations in ImmunoModulatory Networks that include Th2 Cells, regulatory CD4⁺ T-Cells, NK Cells, and others may in part be responsible for the Relapsing/Remitting or Chronic/Progressive nature of the disease.

However, an important paradigmatic shift in the study of MS has occurred in the past decade.

It is now clear that MS is not just a disease of the Immune System, but that factors contributed by the Central Nervous System are equally important and must be considered in the future.