Multiple Sclerosis Lesions 3

Background
Multiple Sclerosis is an Inflammatory DeMyelinating Disease of the Central Nervous System and is the most common cause of Neurologic Disability in young adults.

Despite AntiInflammatory or ImmunoSuppressive therapy, most patients have progressive Neurologic deterioration that may reflect Axonal Loss.

We conducted pathological studies of Brain tissues to define the changes in Axons in patients with Multiple Sclerosis.

Methods
Brain tissue was obtained at autopsy from 11 patients with Multiple Sclerosis and 4 subjects without Brain disease.

Fourteen active Multiple Sclerosis lesions, 33 chronic active lesions, and samples of Normal-Appearing White Matter were examined for DeMyelination, Inflammation, and Axonal pathologic changes by ImmunoHistoChemistry and Confocal Microscopy.

Axonal transection, identified by the presence of terminal Axonal ovoids, was detected in all 47 Lesions and quantified in 18 lesions.

Results
Transected Axons were a consistent feature of the lesions of Multiple Sclerosis, and their frequency was related to the degree of Inflammation within the lesion.

The number of Brain transected Axons per cubic millimeter of tissue averaged:

Oligodendrocyte and Axon pathology was studied in 11 autopsy cases of clinically silent Multiple Sclerosis.

A total of 54 Lesion, either DeMyelinated or late ReMyelinated, were distributed through the whole Brain and Spinal Cord with 39% of the lesions located in PeriVentricular areas.

Determination of Axon density revealed an average reduction of 64% and 59% in DeMyelinated and ReMyelinated lesions with an extreme variation between different plaques and cases.

Oligodendrocytes were identified by ImmunoCytoChemistry for Myelin Oligodendrocyte Glycoprotein (MOG) and in situ hybridization for ProteoLipid Protein (PLP) mRNA.

Oligodendrocytes were almost completely lost in DeMyelinated lesions; ReMyelinated lesions revealed preservation of a considerable number of Oligodendrocytes within the lesions.

At the border between plaques and the periplaque White Matter, similar Oligodendrocyte numbers as in ReMyelinated lesions were found.

Different factors including lesion site, Axonal preservation and ReMyelination may thus contribute to the Clinical NonAppearance of Multiple Sclerosis Lesions.

Multiple Sclerosis (MS) is a Chronic Neurologic disease characterized in early phases by a Cellular Immune Response and later by multiple areas of DeMyelination or plaques in the Central Nervous System (CNS) White Matter.

The clinical manifestations of the disease are highly variable, but probably are related to the extent of breakdown of the Blood-Brain Barrier associated with Inflammation in the acute phase, and with the extent of DeMyelination in the chronic phase.

The initiating events of MS are not known, but current hypotheses include Immune Responses to an initiating Viral infection and AutoImmune responses to CNS Myelin Antigens.

Both Inflammatory and CNS resident cells contribute to the ImmunoPathology of the disease. Chronic Lesions are characterized by Glial scarring and depletion of both Oligodendrocytes and Axons.

Patterns of Inflammation, DeMyelination and Oligodendrocyte pathology were studied in acute Multiple Sclerosis and during early and late exacerbations of Chronic Multiple Sclerosis.

Cells within lesions were identified by ImmunoCytoChemistry with markers for T-Lymphocytes, Macrophages, Oligodendrocytes and Astrocytes.

In addition, in situ hybridization for ProteoLipid Protein mRNA was used to identify Myelinating and Myelin supporting Oligodendrocytes.

Degenerating cells in the lesions were detected by DNA fragmentation in cell nuclei. The Inflammatory reaction in all three types of Multiple Sclerosis lesions was shown to be dominated by T-Lymphocytes and Macrophages.

In late Chronic Multiple Sclerosis lesions, a significant increase in the number of ImmunoGlobulin producing Plasma Cells was found in infiltrates as compared with acute and early Multiple Sclerosis Lesions.

In all three types of Multiple Sclerosis, confluent plaques of DeMyelination were found to be present:

1. In acute Multiple Sclerosis, DeMyelination was found to be associated with extensive destruction of other tissue elements, including Oligodendrocytes, Astrocytes and Axons.
• But even in these destructive Lesion, a considerable number of Oligodendrocytes was preserved and at disposal therefore, for rapid ReMyelination.
2. During early exacerbations of Chronic Multiple Sclerosis, selective DeMyelination was associated with almost complete preservation of Oligodendrocytes in the majority of cases.
   • Correspondingly, a high number of ReMyelinating lesions was present at that stage of disease.
3. In lesions developing late after onset of Multiple Sclerosis, DeMyelination generally accompanied extensive destruction and loss of Oligodendrocytes.
• In these lesions, ReMyelination was sparse and restricted to lesional borders.

The observed patterns of cell death suggest that in some cases Oligodendrocytes, in others Myelin Sheaths are the primary target of the destructive process.

Our data indicate that the type and amount of Inflammation, De- and ReMyelination, and of tissue damage vary between different forms of Multiple Sclerosis and between different stages of the disease, possibly reflecting Different Pathogenic Mechanisms in a disease spectrum.

The characteristics of Transverse Magnetization decay of 120 longstanding lesions and 40 regions of Normal-Appearing White Matter have been analyzed in 40 patients with Multiple Sclerosis (MS) and 10 normal controls.

Fifty lesions showed a BiExponential decay in which two water compartments - one probably IntraCellular, the other ExtraCellular - could be defined.

There was a higher frequency of BiExponential lesions in patients with a Primary/Progressive course but no significant difference between Benign and Secondary/Progressive groups.

Seventy lesions showed a MonoExponential decay, of which 31 showed a T₂ of greater than 200 ms, implying that these lesions were predominantly composed of ExtraCellular rather than IntraCellular water.

The results imply that an expanded ExtraCellular space within Chronic MS Brain lesions is a common finding at all levels of disability and disease course.

In so far as an expanded ExtraCellular space implies Axonal loss, the results suggest that the latter occurs commonly in longstanding MS Lesions.

The lack of correlation with Disability suggests a limited role for the technique in therapeutic monitoring.

Recent Magnetic Resonance Imaging (MRI) and Magnetic Resonance Spectroscopic (MRS) techniques have focused the attention of the Multiple Sclerosis (MS) research community on re-analysis of classic pathological approaches that have suggested significant Axonal injury in this DeMyelinating disease.

There now is abundant evidence from animal work that substantial "Innocent Bystander Damage" to Axons can occur with Central Nervous System (CNS) Inflammation.

Given the close interactions between Axons and Glia, it is no surprise that Glial damage leads to secondary Axonal changes.

MRI, MT, and MRS imaging studies have emphasized that Axonal loss or damage in MS can be both substantial and early.

The dynamic observations that are allowed by these noninvasive measures of pathology have demonstrated direct correlations between these Axonal changes and Disability.

Making a compelling case for increased emphasis on finding treatments of MS that may limit damage to CNS Axons or salvage injured Axons.

Multiple Sclerosis lesions are characterized by Inflammation, DeMyelination and a variable degree of Axonal loss

The patterns of Inflammation in MS lesions are compatible with a T-Lymphocyte mediated Immune Reaction. The formation of DeMyelinated plaques, however, seem to require additional Immunological mechanisms.

In this review evidence is discussed for a PathoGenetic role of DeMyelinating AntiBodies, toxic Macrophage products, CytoToxic T-Cells (CD8⁺) as well as metabolic disturbances of Oligodendrocytes.

It is suggested that the pathological Heterogeneity regarding the patterns and extent of DeMyelination, ReMyelination and Axonal Loss may be the outcome of variable dominant ImmunoPathoGenetic mechanisms in different Multiple Sclerosis patients.

Purpose
To investigate the relationship between the enhancement pattern of a Multiple Sclerosis lesion and its Magnetization Transfer effect.

Methods
Fifty-four lesions were chosen from 29 patients with Multiple Sclerosis on the basis of Enhancement Pattern on contrast-enhanced T₁-weighted MR images.

They included 14 Homogeneously Enhancing Lesions, 26 NonEnhancing Lesions, and 14 Ring-Enhancing Lesions.

Magnetization Transfer Ratios (MTR) of the Homogeneously Enhancing Lesions, NonEnhancing Lesions, and central portion of the Ring-Enhancing Lesions were measured. Means were calculated and compared.

Results
The Magnetization Transfer Ratios for Homogeneously Enhancing Lesions were higher (mean, 32.2%; SD, 3.4%) than those for NonEnhancing Lesions (mean 29.4%; SD, 4.3%).

And for the central portion of Ring-Enhancing Lesions (mean, 24.5%; SD, 4.0%).

Significant differences were found between the Ring-Enhancing Lesions and the Homogeneously Enhancing Lesions and between the Ring-Enhancing Lesions and the NonEnhancing Lesions.

Conclusion
We found a relationship between decreased Magnetization Transfer Ratios and those enhancement patterns in which Myelin is known to be decreased HistoPathologically.

Thus, use of the Magnetization Transfer technique may increase the specificity of MR imaging in assessing the extent of residual Myelination in Multiple Sclerosis lesions.

143 autopsy cases of Multiple Sclerosis (19 acute and 124 chronic cases) were analyzed Histologically for the extent of active DeMyelination and the degree of infiltration within and outside the DeMyelinating lesions and in the LeptoMeninges.

The results were compared with the duration of the illness. Infiltrations were found in 60% of all cases but more often (74%) in those with active DeMyelination.

Inflammatory Lesions outside DeMyelinating Foci were observed in 27% of the total, and in 80% of them active DeMyelination was present.

Inflammatory lesions in the Meninges were present in 41% of the total and in 80% of these were accompanied by active DeMyelination.

The duration of illness correlated with decreasing severity of active DeMyelination and of PeriVascular infiltration.

Patients treated with GlucoCorticoSteroids and/or ImmunoSuppressive substances showed no or only moderate Inflammatory lesions.

The duration of illness in both these groups was significantly longer than the average of untreated patients.