Multiple Sclerosis Lesions 2

The focus of Multiple Sclerosis (MS) research has been on attempts to identify the specific Pathogenic mechanism responsible for producing the multifocal Central Nervous System inflammatory DeMyelinating lesions.

However, extensive in vitro and in vivo evidence suggests that multiple different Immunological mechanisms may produce the typical DeMyelinated Plaque.

A detailed examination of actively DeMyelinating MS lesions reveals a profound Heterogeneity in the structural and ImmunoPathological patterns of DeMyelination and Oligodendrocyte pathology between different MS patients, suggesting multiple Pathogenic mechanisms may contribute to Oligodendrocyte and Myelin injury in MS.

These observations raise the question whether MS may be a Neurological Syndrome with different ImmunoPathological mechanisms triggering a common pathway rather than a single disease with a uniform mechanism of Myelin destruction.

With the advent of new tools for NeuroBiological and Immunological research applied to actively DeMyelinated MS Lesions, an opportunity exists to reevaluate MS NeuroPathology.

This review highlights the spectrum of the Inflammatory DeMyelinating Diseases, the multitude of effector mechanisms that may produce Myelin destruction, and the pathologic Heterogeneity observed in MS lesions.

A careful evaluation of MS NeuroPathology should provide important clues regarding the induction, target, evolution, and PathoGenesis of this complex disease.

Multiple Sclerosis is an Inflammatory DeMyelinating Disease of the Central Nervous System. The hallmark of its pathology is the DeMyelinated plaque with reactive Glia scar formation.

However, a detailed analysis of the patterns of DeMyelination, Oligodendroglia Cell pathology and the reaction of other tissue components suggests that the PathoGenesis of Myelin destruction in this disease may be heterogeneous.

In this review we present a new classification scheme of lesional activity on the basis of the molecular composition of Myelin degradation products in Macrophages.

When these criteria are used, different patterns of DeMyelination can be distinguished, including DeMyelination with relative preservation of Oligodendrocytes, Myelin destruction with concomitant and complete destruction of Oligodendrocytes or Primary destruction or disturbance of Myelinating cells with secondary DeMyelination.

Furthermore, in some cases a Primary selective DeMyelination may be followed by a secondary Oligodendrocyte loss in the established lesions.

Finally, some extraordinarily severe conditions may result in destructive Lesions with loss of Oligodendrocytes, Myelin, Axons and Astrocytes.

This Heterogeneity of plaque pathology is discussed in the context of recent experimental models of Inflammatory DeMyelination.

Which show that different Immunological pathways may lead to the formation of DeMyelinated Plaques that reveal the diverse structural aspects described above.

Our data indicate, that the DeMyelinated plaques of Multiple Sclerosis may reflect a common pathological end point of a variety of different Immunological mechanisms of Myelin destruction in this disease.

The electron microscopic features of 11 stereotaxic Brain biopsies that demonstrated Inflammatory Primary DeMyelination consistent both morphologically and clinically with Multiple Sclerosis are addressed.

Degeneration of inner Oligodendroglial loops and uniform widening of inner Myelin lamellae antedated complete destruction of Myelin Sheaths.

PeriVascular Lymphocytes, Macrophages, and Plasma Cells were in intimate contact with Myelin sheaths. Astrocytes proliferated even away from DeMyelinated areas.

In areas of chronic, established DeMyelination, Oligodendrocyte numbers were greatly decreased, and fields of completely DeMyelinated Axons were seen among Astrocytic processes.

Axonal injury, evidenced by the formation of Axonal swellings, was apparent in maximally affected areas.

At the edge of acute Lesions with DeMyelinated Axons, Oligodendrocytes were preserved morphologically.

Thinly Myelinated Axons indicative of Central Nervous System-type ReMyelination by Oligodendrocytes were observed primarily at the edges of plaques.

An unusual inclusion observed in presumed Macrophages was "polelike" bodies 0.04- to 0.7-microns thick.

Linearly arrayed, their presumably proteinaceous crystalline substance was moderately electron-dense. Many were membrane-bound and appeared to arise from the Endoplasmic Reticulum.

We conclude that disturbance of the Myelinating function of Oligodendrocytes may be a critical event in the PathoGenesis of Multiple Sclerosis.

The Neurological manifestations of Multiple Sclerosis (MS) have been considered to result from DeMyelination of Axons with relative preservation of Axonal integrity.

This concept has been challenged recently by a landmark pathological study, published in the New England Journal of Medicine, which has demonstrated that Axonal degeneration is also present.

The authors of the study hypothesized that Axonal degeneration is the pathological correlate of the irreversible Neurological impairment in this disease.

However, this hypothesis cannot be reconciled with the clinical results obtained with TransCranial applications of AC pulsed ElectroMagnetic Fields (EMFs) of PicoTesla Flux density.

Without DeMyelinated areas first undergoing ReMyelination or transected Axons undergoing regeneration.

They have shown rapid and sustained improvement of symptoms including normalization of Evoked Potential Responses in patients with Chronic/Progressive or Secondary/Progressive MS.

Biochemical studies have shown that MS patients are Serotonergically depleted with the extent of Cerebral depletion correlating with the degree of Motor disability and a Chronic/Progressive course.

It is believed that Progressive Serotonergic Neuronal Atrophy with Synaptic inactivation, not Axonal degeneration, are the hallmarks of the disease.

And that administration of AC pulsed Magnetic Fields improves symptoms of MS partly through reactivation of Serotonergic Neurons and amplification of Synaptic Serotonergic transmission.

We performed Magnetic Resonance Imaging and Magnetic Resonance Spectroscopic Imaging on 28 patients with Multiple Sclerosis stratified for disability.

And, clinical course (Relapsing with at least partial remissions or Secondary/Progressive disease).

Lesions were segmented on the conventional Proton Density and T₂-weighted Magnetic Resonance Images, and Lesion distribution images were generated for, each patient.

The conventional Magnetic Resonance and Spectroscopic Images were transformed into a standard Brain-based stereotaxic coordinate space, allowing comparison of images from different patients on a Voxel-by-Voxel (volume element) basis.

The spatial distribution of lesions in the transformed Magnetic Resonance Images did not differ significantly between the Relapsing and the Progressive disease groups.

We then generated from the individual data sets, group lesion probability distribution images for the Relapsing and the Progressive disease groups.

The spatial distribution of metabolites was characterized with respect to lesion distribution using the Magnetic Resonance Spectroscopic Images transformed into stereotaxic space and averaged.

The Neuronal marker N-AcetylAspartate was Diffusely lower in the Multiple Sclerosis patients than in normal control subjects.

Comparison of the averaged metabolite and T₂-weighted lesion probability images confirmed loss of N-AcetylAspartate in regions of both high and low lesion probability.

This suggests that diffuse Axonal volume loss or dysfunction extends beyond the Inflammatory lesions of Multiple Sclerosis.

Perhaps due to Microscopic Disease or Wallerian Degeneration along projection pathways of Axons traversing the Lesions.

Multiple Sclerosis (MS) is an Inflammatory DeMyelinating Disease of the Central Nervous System. Its pathological hallmark is the DeMyelinated plaque with reactive Glial scarring.

Recent NeuroPathological and ImmunoPathological data suggest a pronounced pathologic Heterogeneity of MS Plaques.

Although DeMyelination is present in all lesions, the extent of Oligodendroglia loss, ReMyelination and Axonal pathology is highly variable.

In the present review, data are discussed on the fate of Myelin forming cells in MS lesions, which suggest that fundamentally different Immunological mechanisms may be involved in the formation of the lesions in different MS patients.

Possible ImmunoPathoGenetic mechanisms are discussed by comparing the different types of MS lesions with those described in different experimental models of Inflammatory DeMyelinating Disease.

Quantitative measurement of MRI-defined Brain lesions can provide an index of the extent and activity of disease in Multiple Sclerosis patients. However, the relationships between these indices and clinical features are not well-understood.

Heterogeneity of the pathological changes underlying MRI lesions may be an important factor determining the correlation between MRI lesion volumes and clinical measures.

Recent studies have suggested that with Magnetic Resonance Spectroscopy (MRS), it may be possible to define chemical changes that better reflect the pathological changes in Multiple Sclerosis.

Here we report results of combined quantitative Brain T₂-weighted MRI lesion volume and Proton MRS examinations that demonstrate Heterogeneity of the chemical pathology underlying Brain Lesions.

In patients selected on the basis of similar clinical disability but differing with respect to the presence or absence of clinical relapses.

We examined 29 patients with disease characterized by either clear Relapses with at least partial Remissions (RR) or Secondary, chronic progression after an earlier history of a more Relapsing/Remitting course (SP).

Total Hemispheric lesion volume was greater (P < 0.04) in the RR (32.5 +/- 20.9 cm3) than in the SP (16.2 +/- 9.0 cm3) patients, despite the longer duration of disease in the latter group.

Central Brain N-AcetylAspartate: Creatine (NAA:Cr) ratios were reduced relative to normal controls (4.0 +/- 0.3, n = 19) by similar amounts in the two patients groups (RR, 3.1 +/- 0.5; SP, 3.2 +/- 0.4; P < 0.0001).

The ratio lesion volume:(NAA:Cr) was greater for the RR group (11.7 +/- 9.3 cm3) than for the SP group (5.4 +/- 3.3 cm3, P < 0.05).

Implying a greater average degree of Axonal loss per unit lesion volume defined by MRI for subjects in the SP group or, alternatively, a greater proportion of lesions without Axonal Damage or loss in the RR group.

Our results emphasize a limitation of using T₂-weighted MRI lesion volume alone.

And, suggest that combined analysis of MR-based chemical and imaging data might allow improved non-invasive assessment of Lesion pathology in order to better understand its relationship to clinical features of Multiple Sclerosis.

The ultrastructural features of 11 stereotaxic Brain biopsy specimens that demonstrated Inflammatory Primary DeMyelination consistent with acute Multiple Sclerosis were examined.

Uniform widening of inner Myelin lamellae (biphasic Myelinopathy) and degeneration of inner Glial loops ("dying-back" OligodendroGliopathy) were early pathologic abnormalities that antedated complete destruction of Myelin sheaths.

PeriVascular Inflammatory cells (Lymphocytes, Macrophages, and occasional Plasma Cells) were in intimate contact with degenerating Myelin sheaths.

The response of Astrocytes was prominent, even in areas of minimal DeMyelination.

Oligodendrocytes were morphologically preserved in early Lesions but proliferated at the periphery of active lesions.

Thinly Myelinated Axons indicative of Central Nervous System-type ReMyelination by Oligodendrocytes were observed primarily at the edge of Plaques.

Disturbances of the Myelinating function of Oligodendrocytes - unaccompanied by death of these cells - may be among the earliest pathologic features in Multiple Sclerosis.

• Comment in: Mayo Clin Proc 1993 Jul;68(7):711-2

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