Multiple Sclerosis Lesions 1

  1. Axonal dystrophy as a consequence of long-term DeMyelination
    Lab Invest 1989 May;60(5):714-25

  2. The ovoid lesion: a new MR observation in patients with Multiple Sclerosis
    AJNR Am J Neuroradiol 1989 Mar-Apr;10(2):303-5

  3. Increased diameter of DeMyelinated Axons in Chronic Multiple Sclerosis of the Spinal Cord
    NeuroPathol Appl NeuroBiol 1988 Nov-Dec;14(6):505-10

  4. HistoPathologic correlate of HypoIntense lesions on T1-weighted Spin-Echo MRI in Multiple Sclerosis
    Neurology 1998 May;50(5):1282-8

  5. Oligodendrocytes in the early course of Multiple Sclerosis
    Ann Neurol 1994 Jan;35(1):65-73

  6. Association between Tumor Necrosis Factor-alpha and disease progression in Multiple Sclerosis
    N Engl J Med 1991 Aug 15;325(7):467-72

  7. The Benign form of Multiple Sclerosis. Anatomo-clinical aspects
    Acta Neurol Scand 1977 Apr;55(4):289-98

  8. Are there any body fluid markers of Brain atrophy in Multiple Sclerosis?
    Mult Scler 1998 Jun;4(3):138-42

  9. Bcl-2 expressing T-Lymphocytes in Multiple Sclerosis lesions
    NeuroPathol Appl NeuroBiol 1998 Jun;24(3):202-8

  10. HistoPathology and the Blood-CerebroSpinal Fluid Barrier in Multiple Sclerosis
    Ann Neurol 1994;36 Suppl:S42-6


#1

Axonal Dystrophy As A Consequence Of
Long-Term DeMyelination

Raine CS, Cross AH
Lab Invest 1989 May;60(5):714-25
Albert Einstein College of Medicine, Rose F. Kennedy Center for Research, in Mental Retardation and Human Development, Dept of Pathology, Bronx, New York
PMID# 2716284; UI# 89237118
Abstract

Central Nervous System Lesions in guinea pigs sensitized for Chronic/Relapsing Experimental Allergic EncephaloMyelitis for between 18 and 36 months have been found to possess a small but probably significant degree of Axonal involvement.

Axonal identity was established by light and Electron Microscopy and ImmunoCytoChemistry. Axonal changes were restricted to White Matter and consisted of:

  1. Massive (up to 95 microns) scattered Axonal Spheroids
    • which displayed lateral branches and Vacuoles
  2. Small groups of Spheroids filled with a wide assortment of AxoPlasmic Organelles
  3. Deeper, more extensive collections of affected DeMyelinated Axons and Spheroids
    • which frequently displayed abortive Axonal regeneration into the Virchow-Robin space

Although accumulations of most AxoPlasmic Organelles occurred in the Spheroids and reactive Axons, MicroTubules were relatively rare.

These formations were never seen in adjacent unaffected White Matter and Spinal Cord tissue from normal aged animals contained only the occasional Spheroid.

It is hypothesized that the disease process in EAE may be more dynamic than previously described.

And that prolonged interruption in normal Axon-Glial relationships in Chronically DeMyelinated (sometimes ReMyelinated) Gliotic lesions might lead to a block in AxoPlasmic transport and a disruption of the Axonal CytoSkeleton.

Although most affected Axons appeared intact, some of the Spheroids probably represented proximal stumps from which sprouting occurred, leading to neuroma-like formations.

The implications of the findings are discussed in reference to long-term DeMyelination and Multiple Sclerosis where almost identical profiles have been documented.
#2

The Ovoid Lesion: A New MR Observation In Patients With Multiple Sclerosis

Horowitz AL, Kaplan RD, Grewe G, White RT, Salberg LM
AJNR Am J Neuroradiol 1989 Mar-Apr;10(2):303-5
Resurrection Hospital, Dept of Magnetic Resonance Imaging, Chicago, IL
PMID# 2494849; UI# 89190296
Abstract

We investigated the frequency of oval-shaped, high-signal-intensity lesions oriented perpendicular to the AnteroPosterior Axis of the Brain on abnormal, axial T2-weighted MR Brain scans in 59 patients with clinically documented Multiple Sclerosis.

This finding, not heretofore described in patients with Multiple Sclerosis, was observed in 86% of patients, and correlates with the NeuroPathologic description of DeMyelination in Multiple Sclerosis.
#3

Increased Diameter Of DeMyelinated Axons In Chronic Multiple Sclerosis Of The Spinal Cord

Shintaku M, Hirano A, Llena JF
NeuroPathol Appl NeuroBiol 1988 Nov-Dec;14(6):505-10
Montefiore Medical Center, Bluestone Laboratory of the Division of NeuroPathology, Bronx, NY 10467
PMID# 3226507; UI# 89143950
Abstract

In an autopsied case of Chronic Multiple Sclerosis, many Axons in some DeMyelinated plaques of the Spinal Cord had remarkably increased diameters and reduced Argentophilia.

The increase in Axonal diameter extended for some distance and was restricted to the DeMyelinated areas. A review of 22 autopsy cases of Chronic Multiple Sclerosis revealed similar findings in the plaques of the Spinal Cord in seven cases.

They were also noted in the Brain but much less frequently.

On electron microscopy, the NeuroFilaments in these enlarged DeMyelinated Axons were not closely packed but were separated by an increased amount of Electron-lucent AxoPlasma.

It is thought that this finding may be a manifestation of increased water content in the AxoPlasma secondary to increased permeability of the DeMyelinated AxoLemma.
#4

HistoPathologic Correlate Of HypoIntense Lesions On T1-Weighted Spin-Echo MRI In Multiple Sclerosis

van Walderveen MA, Kamphorst W, Scheltens P, van Waesberghe JH, Ravid R, Valk J, Polman CH, Barkhof F
Neurology 1998 May;50(5):1282-8
Academic Hospital Vrije Universiteit, MR Center for MS Research, Dept of Radiology, Amsterdam, The Netherlands
PMID# 9595975; UI# 98255414
Abstract

Postmortem unfixed whole Brains from five Multiple Sclerosis (MS) patients were examined by MRI using a T2- and T1-weighted Spin-Echo (SE) sequence and Histology to investigate the HistoPathologic characteristics of HypoIntense lesions on T1-weighted SE MR images.

The degree of HypoIntensity was scored semiquantitatively by two blinded observers in reference to Normal-Appearing White Matter. Signal intensities of the Lesions and the Normal-Appearing White Matter were measured to obtain contrast ratios.

Hematoxylin-Eosin stain was used to assess degree of Matrix destruction (decrease of density of the Neuropil) and cellularity of a lesion.

Kluver-Barrera stain for degree of DeMyelination, Bodian stain for Axonal density, and ImmunoStaining of Glial Fibrillary Acid Protein for reactive Astrocytes and fibrillary Gliosis.

Nineteen lesions were selected for analysis. Nearly all lesions were compatible with the chronic MS Plaque: HypoCellularity, absence of Myelinated Axons, in the presence of reactive Astrocytes.

Contrast ratios of the Lesions were highly correlated (R = -0.90; p < 0.01), with degree of HypoIntensity scored semiquantitatively.

Degree of HypoIntensity on T1-weighted SE images did not correlate with degree of DeMyelination or number of reactive Astrocytes, but was associated with Axonal density (R = -0.71; p = 0.001).

A trend was found with degree of Matrix destruction (R = 0.45; p = 0.052).

We conclude that, in our limited sample, HypoIntense lesions seen on T1-weighted SE MR images are associated HistoPathologically with severe tissue destruction, including Axonal Loss.

Our results need to be substantiated in a larger study on more varied patient material to evaluate the use of HypoIntense lesions as a surrogate marker of persistent deficit in MS patients.
#5

Oligodendrocytes In Early Multiple Sclerosis

Bruck W, Schmied M, Suchanek G, Bruck Y, Breitschopf H, Poser S, Piddlesden S, Lassmann H
Ann Neurol 1994 Jan;35(1):65-73
Univ of Gottingen, Institute of NeuroPathology, Germany
PMID# 8285595; UI# 94113596
Abstract

The NeuroPathology of DeMyelinating lesions in Multiple Sclerosis was studied in specimens obtained by diagnostic needle biopsy during early stages of the disease.

The lesions were characterized by a Chronic Inflammatory reaction dominated by Lymphocytes and Macrophages, plaque-like DeMyelination, and Astroglial Sclerosis.

Oligodendrocytes within the Lesions were studied by ImmunoCytoChemistry using AntiBodies against various Myelin and Oigodendroglia components.

The expression of messenger RNA for ProteoLipid Protein was determined by in situ hybridization.

Our studies revealed that Myelin-Oigodendrocyte GlycoProtein is a sensitive and reliable marker for identification of Oligodendrocytes in DeMyelinated plaques.

The results suggest that in the early course of the disease in some patients, Oigodendrocytes may largely be preserved, whereas in others OigodendroGlial loss is pronounced.

Loss of Oigodendrocytes was only marginally related to the stage of DeMyelinating activity within the Lesions.

These findings indicate that the PathoGenesis of DeMyelination may vary within different Multiple Sclerosis patients.
#6

Association Between Tumor Necrosis Factor-alpha And Disease Progression In Multiple Sclerosis

Sharief MK, Hentges R
N Engl J Med 1991 Aug 15;325(7):467-72
National Hospital for Neurology and NeuroSurgery, Dept of Clinical NeuroChemistry, London, United Kingdom
PMID# 1852181; UI# 91304530
Abstract

Background
Cachectin, or Tumor Necrosis Factor-alpha (TNF-alpha), is a principal mediator of the Inflammatory response.

And may be important in the PathoGenesis and progression of Multiple Sclerosis, an Inflammatory disease of the Central Nervous System.

Methods
In a 24-month prospective study, we used a sensitive enzyme-linked Immunosorbent assay to determine levels of TNF-alpha.

In CerebroSpinal Fluid and Serum in 32 patients with Chronic/Progressive Multiple Sclerosis and in 20 with stable Multiple Sclerosis and 85 with Other Neurologic Diseases.

An attempt was made to relate TNF-alpha levels with the degree of disability of the patients with Multiple Sclerosis and with their Neurologic deterioration during the 24 months of observation.

Results
High levels of TNF-alpha were found in the CerebroSpinal Fluid of 53 percent of the patients with Chronic/Progressive Multiple Sclerosis.

And in none of those with stable Multiple Sclerosis (P less than 0.001).

TNF-alpha was detected in the CerebroSpinal Fluid of 7 percent of the controls (P less than 0.01) with other Neurologic disease.

In patients with Chronic/Progressive Multiple Sclerosis, mean TNF-alpha levels were significantly higher in the CerebroSpinal Fluid than in corresponding Serum samples (52.41 vs. 11.88 U per milliliter; range, 2 to 178 vs. 2 to 39; P less than 0.001).

In these patients, CerebroSpinal Fluid levels of TNF-alpha correlated with the degree of disability (r = 0.834, P less than 0.001) and the rate of Neurologic deterioration (r = 0.741, P less than 0.001) before the start of the study.

CerebroSpinal Fluid levels also correlated with the increase in Neurologic disability after 24 months of observation (r = 0.873, P less than 0.001).

Conclusions
These data provide evidence of Intrathecal synthesis of TNF-alpha in Multiple Sclerosis.

And suggest that the level of TNF-alpha in CerebroSpinal Fluid correlates with the severity and progression of the disease.

Our results suggest that TNF-alpha may reflect histologic disease activity in Multiple Sclerosis and could be used to monitor outcomes or responses to therapy.

  • Comment in: N Engl J Med 1992 Jan 23;326(4):272-3
#7

The Benign Form Of Multiple Sclerosis. Anatomo-Clinical Aspects

Vuia O
Acta Neurol Scand 1977 Apr;55(4):289-98
PMID# 857573; UI# 77178303
Abstract

The present paper is a study of three cases presenting the pathological aspect of Chronic, non-evolutive Multiple Sclerosis, corresponding to a clinical picture of Benign Multiple Sclerosis.

The first case was discovered at autopsy, the second patient had two subclinical attacks of Multiple Sclerosis, with a twenty-year evolution (forme fruste), and in the third case the course of the Chronic Multiple Sclerosis ran parallel to that of a Cerebral and Visceral Arteriopathy.

Anatomic study of the DeMyelinating lesions revealed their non-evolutive aspect and the presence within the plaques of lesions of the walls of small vessels with the PeriVascular adventitial fibrosis.

The Vascular changes appear to play a primordial role in the lack of evolution of the DeMyelinating areas, manifested clinically by a stationary, Benign picture.
#8

Are There Any Body Fluid Markers Of Brain Atrophy In Multiple Sclerosis?

Giovannoni G, Green AJ, Thompson EJ
Mult Scler 1998 Jun;4(3):138-42
Institute of Neurology, Dept of Clinical Neurology, London, UK
PMID# 9762663; UI# 98435411
Abstract

The weak correlation between Inflammatory activity and disease progression in patients with Multiple Sclerosis has shifted the emphasis from Inflammatory monitoring to the investigation of the pathological processes of DeMyelination, Axonal loss, and Gliosis.

New Magnetic Resonance Imaging (MRI) techniques that have been developed to measure these processes appear very promising.

This paper will briefly discuss potential body fluid markers of Axonal loss, Gliosis and DeMyelination, as the pathological substrates of Brain Atrophy, their function and the principles behind their future study in patients with Multiple Sclerosis.
#9

Bcl-2 Expressing T-Lymphocytes
In Multiple Sclerosis Lesions

Zettl UK, Kuhlmann T, Bruck W
NeuroPathol Appl NeuroBiol 1998 Jun;24(3):202-8
Univ of Rostock, Dept of Neurology, Germany
PMID# 9717185; UI# 98382913
Abstract

Multiple Sclerosis (MS) is a chromatic Inflammatory disease of the Central Nervous System, T-Lymphocytes play a major role in the PathoGenesis of the disease.

The exact mechanisms by which the Inflammation is regulated in MS have not yet been defined.

Studies in animal models of MS suggest that Apoptosis (Suicide) of T-Cells is the main factor terminating Inflammation.

The process of Apoptosis itself is regulated by a range of Pro- and Anti-Apoptotic proteins. The Bcl-2 Gene family is an important member of these proteins.

The present study investigated the expression of the Anti-Apoptotic protein Bcl-2 in 11 Chronic MS cases including five Relapsing/Remitting and six Chronic/Progressive MS patients.

A total of 35 lesions containing all stages of DeMyelinating activity were studied.

The number of CD 3-positive T-Cells and the absolute and relative numbers of T-Cell expressing Bcl-2 were determined by double ImmunoCytoChemistry.

Bcl-2 is expressed by T-Lymphocytes in MS plaques.

Patients with Chronic/Progressive MS have a higher proportion of Bcl-2 expressing T-Cells than patients with Relapsing/Remitting disease.

Highest numbers of Bcl-2-positive T-Lymphocytes were found in ReMyelinating and DeMyelinated lesions, whereas active DeMyelinating lesions revealed lower numbers.

These data indicate that cell-death-related proteins such as the Anti-Apoptotic protein Bcl-2 are expressed in MS lesions.

And that they might have important effects on the regulation of elimination or persistence of Inflammatory cells in the Central Nervous System.
#10

HistoPathology And The Blood-CerebroSpinal Fluid Barrier In Multiple Sclerosis

Lassmann H, Suchanek G, Ozawa K
Ann Neurol 1994;36 Suppl:S42-6
Austrian Academy of Sciences, Research Unit for Experimental NeuroPathology, Vienna, Austria
PMID# 8017888; UI# 94288572
Abstract

HistoPathology of Multiple Sclerosis is defined by a chronic Inflammatory process and the presence of large confluent plaques of DeMyelination.

Ongoing disease activity is due to an active Inflammatory process, mainly mediated by T-Lymphocytes and Macrophages, and is associated with Blood-Brain Barrier damage.

B-Lymphocytes and Plasma Cells are present especially in the lesions that occur during the late chronic stage of the disease.

Although all plaques are characterized by DeMyelination, the patterns of Oigodendroglia destruction and of damage to other tissue elements, such as Axons and Astrocytes, are variable in different cases.

Oligodendrocytes are less affected by plaques that develop during the first bouts of the disease than by those plaques arising after several years of disease duration.

Our data indicate that mechanisms of plaque formation may vary in different Multiple Sclerosis patients and in different stages of the disease process.

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