Spinal Cord In Multiple Sclerosis

Axonal degeneration contributes to the development of Non-Remitting Neurological Deficits and disability in Multiple Sclerosis, but the molecular mechanisms that underlie Axonal Loss in Multiple Sclerosis are not clearly understood.

Studies of White Matter Axonal Injury have demonstrated that Voltage-gated Sodium Channels can provide a route for Sodium influx into Axons that triggers reverse operation of the Na⁺/Ca2⁺ Exchanger (NCX) and subsequent influx of damaging levels of Intra-Axonal Calcium.

The molecular identities of the involved Sodium Channels have, however, not been determined.

We have previously demonstrated extensive regions of diffuse expression of Na(v)1.6 and Na(v)1.2 Sodium Channels along DeMyelinated Axons in Experimental Allergic Encephalomyelitis (EAE).

Based on the hypothesis that the co-localization of Na(v)1.6 and NCX along extensive regions of DeMyelinated Axons may predispose these Axons to injury.

We examined the expression of Myelin Basic Protein, Na(v)1.2, Na(v)1.6, NCX and beta-Amyloid Precursor Protein (ß-APP), a marker of Axonal Injury, in the Spinal Cord Dorsal Columns of mice with EAE.

We demonstrate a significant increase in the number of DeMyelinated Axons demonstrating diffuse Na(v)1.6 and Na(v)1.2 Sodium Channel ImmunoReactivity in EAE (92.2 +/- 2.1% of ß-APP positive Axons were Na(v)1.6-positive).

Only 38.0 +/- 2.9% of ß-APP positive Axons were Na(v)1.2 positive, and 95% of these co-expressed Na(v)1.6 together with Na(v)1.2.

Using triple-labelled fluorescent ImmunoHistoChemistry, we demonstrate that 73.5 +/- 4.3% of ß-APP positive Axons co-express Na(v)1.6 and NCX, compared with 4.4 +/- 1.0% in ß-APP negative Axons.

Our results indicate that co-expression of Na(v)1.6 and NCX is associated with Axonal Injury in the Spinal Cord in EAE.

A set of AntiBodies capable of binding Glial Cells promotes ReMyelination in models of Multiple Sclerosis (MS).

Within this set, the mouse AntiBody, SCH94.03, was ImmunoModulatory implying that Immune System mobilization might be integral to ReMyelination.

We evaluated whether the human ReMyelination-promoting AntiBody rHIgM22 influences Acquired Immunity.

The AntiBody did not bind to Immune Cells, or influence Humoral Immune Responses, Antigen Presentation, T-Cell proliferation or Cytokine production.

Treatment with rHIgM22 had no effect on DeMyelination or Virus infection in two disease models. These results demonstrate that the ReMyelination-promoting activity of AntiBody rHIgM22 is not dependent on ImmunoModulation.

Objective
Voiding Dysfunction is more frequent in Primary/Progressive Multiple Sclerosis (PPMS) than in other subtypes of MS.

We investigated whether Lower Urinary Tract Disorders are reflected in the extent of changes in Brain and Spinal Cord detected by Magnetic Resonance Imaging (MRI).

Methods
Micturition symptoms and specific Urodynamic findings in 24 patients with PPMS were related to MRI abnormalities as analyzed by segmentation and volumetric analysis.

Results
Urgency and urge incontinence were the most frequent Urinary symptoms (83 and 75 %), while Detrusor Sphincter DysSynergia (DSD) (71%), Detrusor HyperReflexia (58%) and Obstruction (58%) were the most common Micturition Dysfunctions.

Comparison between patients with Detrusor HyperReflexia and those with normal Bladder function revealed higher volumes of T₂-weighted plaques in the Brains of former (P = 0.01).

In patients with HypoTonic Bladder the total Brain Volume was smaller (P = 0.02) and the number of Thoracic plaques in T₂-weighted images higher (P = 0.02) compared to patients with normal Bladder function.

Furthermore, DSD was associated with a higher volume of T₂-weighted plaques in the Brain (P = 0.02).

Conclusions
Voiding dysfunction in PPMS is associated with increasing Brain and Spinal Cord abnormalities.

UroDynamic investigation is, however, needed for specific definition of Micturition disturbances and should be made before therapeutic decisions.

Acute Transverse Myelitis (ATM) is a pathogenetically heterogeneous inflammatory disorder of the Spinal Cord. Therefore, the identification of clinical and paraclinical features providing clues of the underlying Etiologies is needed.

The clinical presentation, blood and CerebroSpinal Fluid (CSF) findings as well as Magnetic Resonance Imaging (MRI) and NeuroPhysiological features were retrospectively analyzed in 45 unselected consecutive patients with ATM.

ParaInfectious ATM was diagnosed in 38% of patients. The underlying infectious agent, however, was identified only in a minority of patients.

In 36% of patients, the Etiology remained uncertain ("idiopathic" ATM) and in 22% ATM was the first manifestation of Possible Multiple Sclerosis (ATM-MS) according to recently published diagnostic criteria.

Spinal Cord MRI showed signal alterations in 96% of the patients. In ATM-MS, MonoSegmental involvement of the Spinal Cord was most frequent while Spinal Cord involvement of two or more Segments was more common in ATM of other Etiologies.

Of particular note, NeuroPhysiological Examinations showed evidence of Peripheral Nervous System (PNS) involvement in 27% of patients with ATM but not in patients with ATM-MS.

Therefore, NeuroPhysiological evidence of PNS involvement may provide additional discriminatory features between ATM-MS and ATM of other Etiologies.

Axonal loss is well correlated with functional deficits in Multiple Sclerosis (MS); however, the molecular mechanisms that underlie this Axonal loss are not understood.

In this review we summarize evidence that AntiBodies to Axolemma-Enriched Fractions (AEF) isolated from CNS Myelinated Axons may play a role in Axonal destruction.

AEF contains potent Antigens that elicit high-Titer AntiSera, which destroy Neurites in vitro, prevent Neurite outgrowth, cause reactive changes in the Neuronal Cell Bodies of origin and prevent Myelination.

We propose that these AEF Antigens are cryptic because they are shielded from Immune surveillance in vivo via the tightly sealed ParaNodal loops of Myelin.

AntiBodies to AEF are found in CerebroSpinal Fluid (CSF) and Sera of MS patients at higher levels compared with CSF or Sera derived from patients with Other Neurological Diseases.

The potential identity of these cryptic Antigens and their role in the Axonal destruction characteristic of MS is discussed.

During the last decade, Diffusion-Weighted Imaging (DWI) has matured from an experimental tool to a clinically useful modality.

That has not only significantly impacted the diagnosis of (acute) Cerebral Stroke but has also shown utility in other abnormalities of the Brain.

Although DWI should be equally sensitive to changes in the Spine, it has been used far less frequently in this region of the body.

This is mainly because of the inhomogeneous magnetic environment, the small size of the Spinal Cord, and increased motion in and around the Spine.

However, once these limitations are overcome, a whole range of applications can be envisioned.

Already now, DWI promises to be able to differentiate between benign and malignant Vertebral Compression fractures.

As in the Brain, the immediate reduction of Diffusivity following Ischemic damage in the Spinal Cord may provide an early identification of patients with Infarction.

The study of Diffusion Anisotropy may open new avenues for the detection and better understanding of damage to the long Fiber Tracts.

With important clinical implications for disorders like Multiple Sclerosis and Amyotrophic Lateral Sclerosis.

It may also be possible to address, in a more refined manner, mechanisms of damage such as occur with Spondylotic Myelopathy.

To lay the basis for future research in these areas, we will discuss the most appropriate DWI methods for the Spine.

Following an overview of the basic principles of DWI and associated pitfalls, the most commonly used imaging methods are addressed.

Finally, experimental and clinical applications in the Spinal Cord and the Vertebral Column and their clinical relevance thus far are reviewed.

Background And Aim
Conversion to Multiple Sclerosis (MS) after Optic Neuritis and Myelitis has been thoroughly studied.

However, limited data are available regarding conversion to MS after a Clinically Isolated Syndrome of the BrainStem (CISB).

The aim of this study was to investigate conversion to MS in patients with CISB.

Methods
Fifty-one patients with CISB were prospectively studied.

Cranial Magnetic Resonance Imaging (MRI), determination of OligoClonal Bands (OBs) in the CerebroSpinal Fluid (CSF) and Evoked Potentials (EPs) were performed.

Based on conversion to MS at follow-up, the sensitivity, specificity, accuracy and positive and negative predictive values of these tests were calculated.

Results
1. Clinically Definite MS developed in 18 (35%) patients
   • After a mean follow-up of 37 months
2. Paty's MRI Criteria showed a sensitivity of 89%
   • A specificity of 52% and an accuracy of 65%
3. Fazekas' Criteria showed a sensitivity of 89%,
   • A specificity of 48% and an accuracy of 63%
4. Barkhof's Criteria showed a sensitivity of 78%
   • A specificity of 61% and an accuracy of 67%
5. Presence of OBs in the CSF showed a sensitivity of 100%
   • A specificity of 42% and an accuracy of 63%

No differences for NeuroPhysiological parameters were found between patients who did and those who did not convert to MS.

Conclusion
Fulfilling Paty's, Fazekas' or Barkhof's MRI Criteria and the presence of OBs in the CSF are associated with a higher risk of conversion to MS in patients with CISB.

Determination of OBs in the CSF has the greatest sensitivity of all tests.

Barkhof's MRI Criteria have greater specificity (although less than previously published for mixed cohorts of Clinically Isolated Syndromes) in predicting conversion to MS for CISB than either Paty's or Fazekas' Criteria.

Different MRI techniques are used to investigate Multiple Sclerosis (MS) in vivo. The pathological specificity of these techniques is poorly understood, in particular their relationship to DeMyelination and Axonal Loss.

The aim of this study was to evaluate the pathological substrate of high field MRI in Post-Mortem (PM) Spinal Cord (SC) of patients with MS. MRI was performed in PMSCs of four MS patients and a healthy subject on a 7 Tesla machine.

Quantitative MRI maps (PD; T₂; T₁; Magnetization Transfer Ratio, MTR; Diffusion weighted imaging) were obtained. After scanning, the Myelin content and the Axonal density of the specimens were evaluated NeuroPathologically using quantitative techniques.

Myelin content and Axonal density correlated strongly with MTR, T₁, PD, and Diffusion Anisotropy, but only moderately with T₂ and weakly with the Apparent Diffusion Coefficient.

Quantitative MR measures provide a promising tool to evaluate components of MS pathology that are clinically meaningful.

Further studies are warranted to investigate the potential of new quantitative MR measures to enable a distinction between Axonal Loss and DeMyelination and between DeMyelinated and ReMyelinated lesions.

In Primary/Progressive Multiple Sclerosis (PPMS) abnormalities in Brain Magnetic Resonance Imaging (MRI) differ from abnormalities in other subtypes of Multiple Sclerosis (MS).

It was investigated whether the extent of Brain and Spinal Cord MRI abnormalities is reflected in the Neurological disability in PPMS.

Focal and diffuse changes and Atrophy in Central Nervous System (CNS) in patients with PPMS (n = 28) and healthy controls (n = 20) were assessed by semi-automatic MRI segmentation and volumetric analysis.

The measurements were related to Neurological disability as expressed by the Expanded Disability Status Scale (EDSS), the Regional Functional Scoring System (RFSS), the Arm Index and the Ambulation Index.

Plaques in T₁- and/or T₂-weighted images were seen in all Brains, while Spinal plaques were detected in 23 of 28 patients (82%).

The total volumes of Brain and Spinal Cord were significantly smaller in patients than in controls (P = 0.001 and 0.000, respectively). The volumes of T₁ or T₂ lesions in the Brain correlated to the Ambulation Index (r = 0.51, P = 0.005 and r = 0.53, P = 0.004, respectively).

No correlations were detected between MRI measurements and total EDSS score, but relative Brain Atrophy correlated inversely with the total RFSS scores, poor Arm Index and higher Cerebral disturbances (r = -0.53, P = 0.004; r = -0.53, P = 0.004; and r = -0.52, P = 0.005, respectively).

Although the number of Spinal T₂ lesions correlated with Sensory disturbances (r = 0.60, P = 0.001), no correlations were found between EDSS subscores and Spinal Cord Atrophy.

These findings show that marked Atrophy of Brain and Spinal Cord detected by volumetric quantitation correlates with Neurological disability. This observation indicates the importance of NeuroDegenerative events in PPMS.

Objectives
Brain and Cervical Cord Volume is a potentially valuable index marker of irreversible pathological processes in Multiple Sclerosis (MS).

Volume in both Brain and Cervical Cord regions in the same patients has only been investigated in a small number of subjects.

We aimed at measuring volume in different parts of the Central Nervous System, and its relationship with clinical measures, in Relapsing/Remitting (RR) and Secondary/Progressive (SP) MS patients.

Material And Methods
Conventional Dual Echo and Three-Dimensional (3-D) Magnetization prepared Rapid Acquisition Gradient Echo Imaging was performed on 97 (49 RR and 48 SP) MS patients, and on 31 age- and gender-matched healthy controls.

The volumes of the SupraTentorial Brain, Lateral Ventricles, BrainStem, Cerebellum and Upper Cervical Cord (UCC) were determined on 3-D Magnetic Resonance Imaging.

Results
RR MS patients had significantly smaller SupraTentorial Brain (P=0.002) and larger Lateral Ventricles (P=0.047) compared with controls, but no differences were found for Cerebellum, Brainstem and UCC volumes.

Significantly smaller SupraTentorial Brain (P<0.0001), Cerebellum (P=0.007), BrainStem (P=0.0004) and UCC (P<0.0001) volumes, and larger Lateral Ventricles (P<0.0001) were observed in SP MS patients than in controls.

In RR MS, T₂-lesion volume correlated with SupraTentorial (r=-0.46, P=0.0009), Lateral Ventricular (r=0.65, P<0.0001), Cerebellar (r=-0.42, P=0.003) and BrainStem (r=-0.35, P=0.01) volumes, but not with UCC volume (r=-0.18, P=0.22).

In SP MS, apart from Lateral Ventricular Volume (r=0.52, P=0.0002), none of the estimated structural volumes correlated with T₂-lesion volume. The UCC volume correlated with BrainStem volume in both RR MS (r=0.35, P=0.016) and SP MS (r=0.38, P=0.007).

Multiple regression analysis showed that SupraTentorial Brain Volume in RR group, and UCC volume in SP group, were single significant contributors (P=0.01 and 0.04, respectively) to the Expanded Disability Status Scale of all factors entered into the regression model.

Conclusion
Atrophy is confined to the SupraTentorial compartment early in the disease course corresponding to the RR stage, but becomes more pronounced in the Brain and Cervical Spinal Cord in the SP phase.

The estimate of Cervical Cord Volume for SP MS is relevant to functional disability and may be helpful in monitoring MS evolution in the Progressive form of disease.

Objective
To characterize Central Motor Conduction in relation to the clinical deficits and to the disease duration in 90 patients with acute Relapsing/Remitting MS (RR-MS) and in 51 patients with chronic Primary or Secondary/Progressive MS (P-MS).

Methods
The Triple Stimulation Technique (TST) was used to quantify the Central Motor Conduction Failure (expressed by the TST amplitude ratio) and conventional Motor Evoked Potentials (MEPs) were used to measure the Central Motor Conduction Time (CMCT).

Results
The TST amplitude ratio was reduced in presence of a clinical Motor Deficit (p=0.02 for RR-MS, p<0.01 for P-MS), but did not significantly differ in RR-MS and P-MS (p>0.05) when patients with similar clinical Motor Deficit were compared.

The CMCT was not related to the clinical Motor Deficit in both RR-MS and P-MS. However, the CMCT was markedly prolonged in P-MS, when patients with similar clinical Motor Deficit and with similar disease duration were compared (p<0.01).

The differences were not attributable to differential involvement of the Spinal Cord, which was similar in RR-MS and P-MS.

Conclusions
Our results disclose differences between the Central Motor Conduction in RR-MS and P-MS that are not related to disease severity, Spinal Cord involvement or disease duration.

Objective
To determine whether idiopathic Recurrent Transverse Myelitis (RTM) can be distinguished from Multiple Sclerosis-associated RTM (MSRTM) on the basis of clinical manifestations of Myelopathy, or findings from Magentic Resonance Imaging or CerebroSpinal Fluid examination.

Design
A retrospective analysis of 37 cases was conducted. Patients were classified as having idiopathic RTM on the basis of recurrent Myelitis confirmed by clinical manifestations of Myelopathy and Magnetic Resonance Imaging findings.

On review patients with idiopathic RTM had normal cranial Magnetic Resonance Imagings and did not demonstrate paraclinical evidence of spatial dissemination beyond the Spinal Cord of the disease process.

Patients were classified as having MSRTM on the basis of criteria of Poser et al for Clinically Definite Multiple Sclerosis involving the Central Nervous System. Fifteen patients met study criteria for idiopathic RTM. Twenty-two patients had MSRTM.

Setting
Asan Medical Center, Seoul, South Korea, from January 1, 1992, through December 31, 2001.

Main Outcome Measures
Presenting symptoms and clinical manifestations, relapsing times, Magnetic Resonance Imaging features (involved Spinal Cord Segments in T₂-weighted images and Gadolinium 64-enhanced lesions on T₁-weighted images), IgG index, and OligoClonal Bands in CerebroSpinal Fluid were compared.

Result
Idiopathic RTM occurred preponderantly in male patients and presented more often with acute Transverse Myelitis than did MSRTM. More than 2 relapses occurred in 6 cases (40%) of idiopathic RTM.

The involved Segments of Spinal Cord on T₂-weighted images were not significantly different in idiopathic RTM and MSRTM, with enhancing lesions mostly in the Posterior Columns.

And, the SpinoThalamic and SpinoCerebellar Tracts of White Matter. Additionally, almost all patients with idiopathic RTM had normal CerebroSpinal Fluid indexes.

Conclusion
Idiopathic RTM might be a disease entity distinct from MSRTM, differing in its male preponderance, absence of OligoClonal Bands, frequent multiple relapses, and frequent presentation as acute Transverse Myelitis.