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J Neurol Neurosurg Psychiatry 1988;51:260-265 doi:10.1136/jnnp.51.2.260

Perivascular iron deposition and other vascular damage in multiple sclerosis.
C W Adams

Division of Histopathology, United Medical School of Guy's Hospital, University of London, UK.

Abstract

Evidence of damage to cerebral vein walls was sought in 70 cases of multiple sclerosis. Seventy control cases were also examined. The multiple sclerosis cases showed venous intramural fibrinoid deposition (7%), recent haemorrhages (17%), old haemorrhages revealed by haemosiderin deposition (30%), thrombosis (6%) and thickened veins (19%). In all, 41% of all multiple sclerosis cases showed some evidence of vein damage. Occasional control cases showed haemosiderin deposition in the brain but, unlike the multiple sclerosis cases, these were diffuse and almost entirely related to coexistent cardiovascular or cerebrovascular disease. Haemosiderin deposition was common in the substantia nigra and other pigmented nuclei in all cases. It is concluded that the cerebral vein wall in multiple sclerosis is subject to chronic inflammatory damage, which promotes haemorrhage and increased permeability, and constitutes a form of vasculitis.

J Clin Pathol 1994;47:129-133 doi:10.1136/jcp.47.2.129

Immunohistochemical study of vascular injury in acute multiple sclerosis.

A J Wakefield, L J More, J Difford, J E McLaughlin

Academic Department of Medicine, Royal Free Hospital, School of Medicine, London.

Abstract
AIMS--To examine the vascular changes occurring in three archival cases of acute multiple sclerosis, and to provide immunohistochemical evidence of early endothelial cell activation and vascular occlusion in this condition.

METHODS--Central nervous system tissues from three cases of acute active multiple sclerosis and six non-inflammatory controls were stained using the following methods: haematoxylin and eosin, Luxol fast blue, cresyl violet, Bielschowsky's silver, and reticulin. Tissues were also immunostained with specific antibodies against collagen type IV, factor XIIIa, class II antigens, glial fibrillary acidic protein, and fibrinogen.

RESULTS--Early vascular endothelial cell activation which may progress to vasculitis and vascular occlusion including class II antigen expression and fibrin deposition were identified. The vascular changes were seen prior to cerebral parenchymal reaction and demyelination, and were not seen in control cerebral tissues.

CONCLUSION--It is proposed that vascular endothelial cell activation may be an early and pivotal event in the evolution of multiple sclerosis, and that demyelination may have an ischaemic basis in this condition. The vascular endothelium may contain an early element in the evolution of multiple sclerosis.

Hypoxia-like tissue injury as a component of multiple sclerosis lesions

Hans Lassmann
Division of Neuroimmunology, Brain Research Institute, University of Vienna, Spitalgasse 4, A-1090 Vienna, Austria

Abstract
Recent data suggest that the mechanisms of demyelination and tissue damage in multiple sclerosis (MS) are heterogenous. In this review, evidence is discussed, which show that in a subset of multiple sclerosis patients the central nervous system (CNS) lesions show profound similarities to tissue alterations found in acute white matter stroke, thus suggesting that a hypoxia-like metabolic injury is a pathogenetic component in a subset of inflammatory brain lesions. Both, vascular pathology as well as metabolic disturbances induced by toxins of activated macrophages and microglia may be responsible for such lesions in multiple sclerosis.

BREAKDOWN OF THE BLOOD-BRAIN BARRIER PRECEDES SYMPTOMS AND OTHER MRI SIGNS OF NEW LESIONS IN MULTIPLE SCLEROSIS
PATHOGENETIC AND CLINICAL IMPLICATIONS

Summary

From an extensive serial magnetic resonance imaging (MRI) study in multiple sclerosis (MS) we have identified 4 cases in which disruption of the blood-brain barrier, as detected by gadolinium-DTPA enhancement, preceded other MRI abnormalities and in 1 case clinical evidence of the new lesion. This supports the view that a defect in the blood-brain barrier, and therefore inflammation, is an early and possibly crucial event in the pathogenesis of the new lesion in MS. These cases showed a marked discrepancy between MRI abnormality and symptoms. The mechanisms contributing to this disparity are discussed, and it is concluded that far from being surprising it is to be expected.

Multiple sclerosis as a vascular disease
Authors: Minagar, Alireza1; Jy, Wenche2; Jimenez, J. J.2; Alexander, J. Steven3
Source: Neurological Research, Volume 28, Number 3, April 2006 , pp. 230-235(6)

Abstract:
Multiple sclerosis (MS) has traditionally been viewed and researched as an immune-mediated disease with principal emphasis on the role of activated inflammatory cells, oligodendrocytes and astrocytes in its pathogenesis. Abnormalities of cerebral endothelial cells (CECs) is an under explored facet of MS pathogenesis and vascular abnormalities play a crucial role in formation of the MS lesions and disease progress, at least in the initial stages of disease. This review will focus on MS as a central nervous system (CNS) disease with a strong vascular constituent and examines abnormalities within CECs in MS and their role in the loss of blood-brain barrier and transendothelial migration of activated leukocytes into the CNS. One goal of this paper is to persuade and promote research on the endothelial abnormalities in pathogenesis of MS and to exploit existing knowledge on endothelial injury. A deeper understanding of endothelial pathophysiology in MS may help develop effective treatments through stabilization of endothelial function, translating into delay or arrest of MS disease onset and disability in MS patients.

Chronic cerebrospinal venous insufficiency in patients with multiple sclerosis

P Zamboni1, R Galeotti1, E Menegatti1, A M Malagoni1, G Tacconi1, S Dall’Ara1, I Bartolomei2, F Salvi2

Abstract
Background: The extracranial venous outflow routes in clinically defined multiple sclerosis (CDMS) have not previously been investigated.

Methods: Sixty-five patients affected by CDMS, and 235 controls composed, respectively, of healthy subjects, healthy subjects older than CDMS patients, patients affected by other neurological diseases and older controls not affected by neurological diseases but scheduled for venography (HAV-C) blindly underwent a combined transcranial and extracranial colour-Doppler high-resolution examination (TCCS-ECD) aimed at detecting at least two of five parameters of anomalous venous outflow. According to the TCCS-ECD screening, patients and HAV-C further underwent selective venography of the azygous and jugular venous system with venous pressure measurement.

Results: CDMS and TCCS-ECD venous outflow anomalies were dramatically associated (OR 43, 95% CI 29 to 65, p<0.0001). Subsequently, venography demonstrated in CDMS, and not in controls, the presence of multiple severe extracranial stenosis, affecting the principal cerebrospinal venous segments; this provides a picture of chronic cerebrospinal venous insufficiency (CCSVI) with four different patterns of distribution of stenosis and substitute circle. Moreover, relapsing-remitting and secondary progressive courses were associated with CCSVI patterns significantly different from those of primary progressive (p<0.0001). Finally, the pressure gradient measured across the venous stenosies was slightly but significantly higher.

Conclusion: CDMS is strongly associated with CCSVI, a scenario that has not previously been described, characterised by abnormal venous haemodynamics determined by extracranial multiple venous strictures of unknown origin. The location of venous obstructions plays a key role in determining the clinical course of the disease.

Expression of immunologically relevant endothelial cell activation antigens on isolated central neurvous system microvessels from patients with multiple sclerosis

Abstract

Activation of the vascular endothelium is thought to be an important facet of inflammation, thrombosis, and vasculitis. Activated endothelial cells express a number of immunologically relevant surface markers not expressed by normal endothelial cells. Many of these surface antigens are thought to augment adhesion reactions and migration. Our results show that endothelial activation may play a central role in the pathogenesis of multiple sclerosis (MS). Normal human central nervous system microvessels isolated from autopsy material do not express endothelial cell activation markers, including the adhesion proteins vascular cell adhesion molecule-1 (VCAM-1) and endothelial cell leukocyte adhesion molecule-1 (E-selectin/ELAM-1). They exhibit little to no constitutive expression of immunoreactive intercellular adhesion molecule-1 (ICAM-1) or the urokinase plasminogen activator receptor. Control microvessels exhibit no major histocompatibility complex (MHC) class II antigen. MS microvessels express significant levels of MHC class II antigens, ICAM-1, VCAM-1, and urokinase plasminogen activator receptor. E-selectin was expressed by 3 of 5 MS brains tested. Histologically unaffected areas of MS brain expressed less VCAM-1, ICAM-1, and E-selectin than did microvessels from periplaque zones. However, MHC class II antigens and urokinase plasminogen activator receptor were increased in areas exhibiting little to no evidence of leukocyte infiltration. When microvessels were examined for dual expression of activation markers, we found that in periplaque areas, 50% of microvessels coexpressed HLA-Dr. and VCAM-1, 28% of microvessels coexpressed HLA-Dr. and urokinase plasminogen activator receptor, and 43% of microvessels coexpressed HLA-Dr. and ICAM-1.

Microvascular Abnormality in Relapsing-Remitting Multiple Sclerosis: Perfusion MR Imaging Findings in Normal-appearing White Matter

Abstract

PURPOSE: To prospectively determine hemodynamic changes in the normal-appearing white matter (NAWM) of patients with relapsing-remitting multiple sclerosis (RR-MS) by using dynamic susceptibility contrast material–enhanced perfusion magnetic resonance (MR) imaging.

MATERIALS AND METHODS: Conventional MR imaging (which included acquisition of pre- and postcontrast transverse T1-weighted, fluid-attenuated inversion recovery, and T2-weighted images) and dynamic susceptibility contrast-enhanced T2*-weighted MR imaging were performed in 17 patients with RR-MS (five men and 12 women; median age, 38.4 years; age range, 27.6–56.9 years) and 17 control patients (seven men and 10 women; median age, 42.0 years; age range, 18.7–62.5 years). Absolute cerebral blood volume (CBV), absolute cerebral blood flow (CBF), and mean transit time (MTT) (referenced to an arterial input function by using an automated method) were determined in periventricular, intermediate, and subcortical regions of NAWM at the level of the lateral ventricles. Least-squares regression analysis (controlled for age and sex) was used to compare perfusion measures in each region between patients with RR-MS and control patients. Repeated-measures analysis of variance and the Tukey honestly significant difference test were used to perform pairwise comparison of brain regions in terms of each perfusion measure.

RESULTS: Each region of NAWM in patients with RR-MS had significantly decreased CBF (P < .005) and prolonged MTT (P < .001) compared with the corresponding region in control patients. No significant differences in CBV were found between patients with RR-MS and control patients in any of the corresponding areas of NAWM examined. In control patients, periventricular NAWM regions had significantly higher CBF (P = .03) and CBV (P = .04) than did intermediate NAWM regions. No significant regional differences in CBF, CBV, or MTT were found in patients with RR-MS.

CONCLUSION: The NAWM of patients with RR-MS shows decreased perfusion compared with that of controls.

THE CERVICAL CORD IN MULTIPLE SCLEROSIS

D. R. OPPENHEIMER

The spinal cords were examined in eighteen cases of multiple sclerosis, with special attention to the cervical enlargement. It was found that (1) lesions in the cervical cord are about twice as common as at lower levels, (2) in this region there is a striking preponderance of fan-shaped lesions in the lateral columns. It is argued that both these findings are explicable on the theory that mechanical stresses play a part in determining the site of lesions; that such stresses are commonly transmitted to the cord via the denticulate ligaments during flexion of the spine; and that many of the lesions are attributable to vascular leakages due to tension in the denticulate ligaments. It is concluded that in patients with multiple sclerosis neck flexion is dangerous–especially in cases where Lhermitte's sign has occurred.

Abnormal Endothelial Tight Junctions in Active Lesions and Normal-appearing White Matter in Multiple Sclerosis

Jonnie Plumb1, Stephen McQuaid1, Meenakshi Mirakhur1, John Kirk2,*
Article first published online: 5 APR 2006

Blood-brain barrier (BBB) breakdown, demonstrable in vivo by enhanced MRI is characteristic of new and expanding inflammatory lesions in relapsing-remitting and chronic progressive multiple sclerosis (MS). Subtle leakage may also occur in primary progressive MS. However, the anatomical route(s) of BBB leakage have not been demonstrated. We investigated the possible involvement of interendothelial tight junctions (TJ) by examining the expression of TJ proteins (occludin and ZO-1) in blood vessels in active MS lesions from 8 cases of MS and in normal-appearing white (NAWM) matter from 6 cases. Blood vessels (10–50 per frozen section) were scanned using confocal laser scanning microscopy to acquire datasets for analysis. TJ abnormalities manifested as beading, interruption, absence or diffuse cytoplasmic localization of fluorescence, or separation of junctions (putative opening) were frequent (affecting 40% of vessels) in oil-red-O-positive active plaques but less frequent in NAWM (15%), and in normal (<2%) and neurological controls (6%). Putatively “open” junctions were seen in vessels in active lesions and in microscopically inflamed vessels in NAWM. Dual fluorescence revealed abnormal TJs in vessels with pre-mortem serum protein leakage. Abnormal or open TJs, associated with inflammation may contribute to BBB leakage in enhancing MRI lesions and may also be involved in subtle leakage in non-enhancing focal and diffuse lesions in NAWM. BBB disruption due to tight junctional pathology should be regarded as a significant form of tissue injury in MS, alongside demyelination and axonopathy.

Increased Endothelin-1 Plasma Levels in Patients With Multiple Sclerosis

Abstract
Objective: We tested the hypothesis that the plasma level of endothelin-1 (ET-1) is increased in patients with multiple sclerosis (MS). The peptide ET-1 is one of the most potent known vasoconstrictors. An increased level of endothelin could explain some of the vascular symptoms of these patients.

Materials and Methods: A specific radioimmunoassay was used to determine ET-1 plasma levels. Twenty patients with MS were compared to 20 age-and sex-pair-matched healthy subjects.

Results: The plasma ET-1 levels were, on average, 224% higher in the patients with MS than in the controls (p < 0.005). The mean ET-1 levels (mean ± standard deviation [SD]) were 3.5 ± 0.83 pg/mL (min 2.13, max 5.37 pg/mL) in patients with MS and 1.56 ± 0.3 pg/mL (min 0.9, max 2.13 pg/mL) in healthy volunteers. Neither the different forms nor stages of MS had an influence on the results. The ET-1 level was also not correlated with the duration of the disease.

Conclusions: The plasma ET-1 level is markedly and significantly increased in patients with MS. Neither the cause of such an increase nor the pathogenetic role is known.

Tissue preconditioning may explain concentric lesions in Baló's type of multiple sclerosis

Summary

Lesions of Baló's concentric sclerosis are characterized by alternating layers of myelinated and demyelinated tissue. The reason for concentric demyelination in this variant of multiple sclerosis is unclear. In the present study we investigated the immunopathology in autopsy tissue of 14 patients with acute multiple sclerosis or fulminant exacerbations of chronic multiple sclerosis with Baló-type lesions in the CNS, focusing on the patterns of tissue injury in actively demyelinating lesions. We found that all active concentric lesions followed a pattern of demyelination that bears resemblances to hypoxia-like tissue injury. This was associated with high expression of inducible nitric oxide synthase in macrophages and microglia. At the edge of active lesions and, less consistently, in the outermost layer of preserved myelin, proteins involved in tissue preconditioning, such as hypoxia-inducible factor 1α and heat-shock protein 70, were expressed mainly in oligodendrocytes and to a lesser degree also in astrocytes and macrophages. Due to their neuroprotective effects, the rim of periplaque tissue, where these proteins are expressed, may be resistant to further damage in an expanding lesion and may therefore remain as a layer of preserved myelinated tissue.