The multiple sclerosis lesion: initiated by a localized hypoperfusion in a central nervous system where mechanisms allowing leukocyte infiltration are readily upregulated?

doi:10.1016/S0306-9877(98)90052-4

Medical Hypotheses

Volume 51, Issue 4, October 1998, Pages 299-303

https://doi.org/10.1016/S0306-9877(98)90052-4 Get rights and content

Abstract

A mechanism is proposed that may explain the factors that initiate a multiple sclerosis (MS) lesion. It is based upon the following two hypotheses: (i) there is a lower stimulus threshold for upregulating the mechanisms that result in leukocyte infiltration in individuals predisposed to developing MS; (ii) the MS lesion is initiated as a reduction in blood flow to a localized region of white matter. This reduction in blood flow leads to: (a) degenerative white matter changes affecting oligodendrocytes; (b) upregulation of chemokines in the endothelial cells and/or glial cells; and (c) upregulation of cell adhesion molecules on endothelial cells. Signals from the hypoxemic and hypoglycemic glial cells, likely involving myelin molecules and cytokines, result in an inflammatory immune response that results in rampant demyelination. Evidence supporting the proposed mechanism is presented, as well as suggestions on how to test the validity of the proposal.

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Cited by (14)

Retinal microvascular and neuronal function in patients with multiple sclerosis: 2-year follow-up
2021, Multiple Sclerosis and Related Disorders
Citation Excerpt :
Sufficient blood supply is required to maintain adequate tissue perfusion, which is essential to supply nutrition and oxygen for the organ's functionality. Low blood supplies and tissue perfusion (i.e., hypoperfusion) occurred in patients with MS in the retina (Jiang et al., 2016; Liu et al., 2019) and brain (De Keyser et al., 2008; Juurlink, 1998; Wuerfel et al., 2007). In our previous cross-sectional study of RBF and RTP in patients with RRMS, we found ∼40% lower than healthy controls (Liu et al., 2019).
Objective: To determine the longitudinal changes in retinal microstructure, microvasculature, microcirculation, and axonal and neuronal functions in patients with relapsing-remitting multiple sclerosis (RRMS) over the time course of about two years.
Methods: A total of 30 patients (60 eyes) with RRMS were followed for a period of 27 ± 6 months and evaluated with a battery of clinical tests including low contrast letter acuity (LCLA), intraretinal layer thicknesses by optical coherence tomography (OCT), ganglion cell function by steady-state pattern electroretinography (PERG), axonal function by polarization-sensitive OCT, volumetric vessel density (VVD) by OCT angiography, and retinal tissue perfusion (RTP) by retinal function imager.
Results: Axonal function measured as retinal nerve fiber layer birefringence in the temporal quadrant and vessel density in the deep vascular plexus were significantly decreased at 2-year follow-up (P < 0.05). Subgroup analyses showed that the increased retinal blood flow volume occurred in patients with no evidence of disease activity (NEDA), and with stable or improved visual function (P < 0.05). There was no significant difference in the expanded disability state scale, LCLA, RTP, VVD, or PERG measures between the two visits (P > 0.05).
Conclusion: To our best knowledge, this is the first 2-year prospective comprehensive study with a detailed assessment of retinal microstructure and neuronal functions in patients with RRMS. The recovery of retinal microcirculation occurred in patients with NEDA, and stable or improved visual function, suggesting these measurements as potential imaging biomarkers for monitoring disease progression.
Visual Function and Disability Are Associated with Increased Retinal Volumetric Vessel Density in Patients with Multiple Sclerosis
2020, American Journal of Ophthalmology
Citation Excerpt :
In addition to inflammation, the increased VVD could be due to a compensatory response to retinal tissue hypoperfusion.19 Tissue hypoperfusion can impair tissue oxygenation38 and induce hypoxia-like changes.7–9 Such hypoxia can form increased microvascular density39 through the increased release of vascular endothelial growth factor and production of several other angiogenic molecules.
The goal of this study was to determine the volumetric vessel density (VVD) in the intraretinal layers and its relationship with visual function and disability in patients with multiple sclerosis (MS).
Cross-sectional study.
A total of 80 patients with relapsing-remitting MS and 99 age- and sex-matched healthy controls (HC) were recruited. The retinal microvascular network in the macular area was imaged using optical coherence tomography angiography in 123 eyes without a history of optic neuritis (ON) (MSNON) and 36 eyes with a history of ON (MSON). The VVD was calculated as the vessel densities in the retinal vascular network (RVN), superficial vascular plexus (SVP), or deep vascular plexus (DVP) of an annulus (0.6-2.5 mm in diameter), divided by the corresponding tissue volume of the intraretinal layers respectively.
The VVD of RVN and DVP in MSNON were significantly higher than in HC (P < .05). The VVD of RVN, SVP, and DVP in MSON were significantly higher than in MSNON and HC (P < .05). The VVD in both RVN and SVP were positively related to EDSS and disease duration, but negatively related to low-contrast letter acuity (P < .05). The VVD measurements were also negatively and strongly related to the corresponding tissue volumes (P < .05).
This is the first study to reveal increased retinal VVD in patients with relapsing-remitting MS. The measurements of VVD in the RVN and SVP were related to disability and visual function, which may be developed as image markers for tracking disease progression.
Prevalence of extracranial venous narrowing on catheter venography in people with multiple sclerosis, their siblings, and unrelated healthy controls: A blinded, case-control study
2014, The Lancet
Citation Excerpt :
Multiple sclerosis is a leading cause of neurological disability and is estimated to affect more than 2 million people worldwide.1 The cause of the disease remains uncertain and a vascular mechanism has long been suggested to have a possible role.2,3 Zamboni and colleagues4 reported that the presence of multiple stenoses of the extracranial venous drainage system—a disorder they called chronic cerebrospinal venous insufficiency—was significantly associated with multiple sclerosis.
Chronic cerebrospinal venous insufficiency has been proposed as a unique combination of extracranial venous blockages and haemodynamic flow abnormalities that occurs only in patients with multiple sclerosis and not in healthy people. Initial reports indicated that all patients with multiple sclerosis had chronic cerebrospinal venous insufficiency. We aimed to establish the prevalence of venous narrowing in people with multiple sclerosis, unaffected full siblings, and unrelated healthy volunteers.
We did an assessor-blinded, case-control, multicentre study of people with multiple sclerosis, unaffected siblings, and unrelated healthy volunteers. We enrolled the study participants between January, 2011 and March, 2012, and they comprised 177 adults: 79 with multiple sclerosis, 55 siblings, and 43 unrelated controls, from three centres in Canada. We assessed narrowing of the internal jugular and azygous veins with catheter venography and ultrasound criteria for chronic cerebrospinal venous insufficiency proposed by Zamboni and colleagues. Catheter venography data were available for 149 participants and ultrasound data for 171 participants.
Catheter venography criteria for chronic cerebrospinal venous insufficiency were positive for one of 65 (2%) people with multiple sclerosis, one of 46 (2%) siblings, and one of 32 (3%) unrelated controls (p=1·0 for all comparisons). Greater than 50% narrowing of any major vein was present in 48 of 65 (74%) people with multiple sclerosis, 31 of 47 (66%) siblings (p=0·41 for comparison with patients with multiple sclerosis), and 26 of 37 (70%) unrelated controls (p=0·82). The ultrasound criteria for chronic cerebrospinal venous insufficiency were fulfilled in 35 of 79 (44%) participants with multiple sclerosis, 17 of 54 (31%) siblings (p=0·15 for comparison with patients with multiple sclerosis) and 17 of 38 (45%) unrelated controls (p=0·98). The sensitivity of the ultrasound criteria for detection of greater than 50% narrowing on catheter venography was 0·406 (95% CI 0·311–0·508), and specificity was 0·643 (0·480–0·780).
This study shows that chronic cerebrospinal venous insufficiency occurs rarely in both patients with multiple sclerosis and in healthy people. Extracranial venous narrowing of greater than 50% is a frequent finding in patients with multiple sclerosis, unaffected siblings, and unrelated controls. The ultrasound criteria are neither sensitive nor specific for narrowing on catheter venography. The significance of venous narrowing to multiple sclerosis symptomatology remains unknown.
MS Society of Canada, Saskatoon City Hospital Foundation, Lotte and John Hecht Memorial Foundation, Vancouver Coastal Health Foundation, and the Wolridge Foundation.
Age-dependent VEGF expression and intraneural neovascularization during regeneration of peripheral nerves
2004, Neurobiology of Aging
The physiologic ability of peripheral nerves to regenerate after injury is impaired with aging. However, the mechanisms responsible for this phenomenon are still incompletely characterized. In this study, we investigated whether aging influences the intraneural angiogenic response that occurs after injury and during regeneration of peripheral nerves. We performed a crush injury of the sciatic nerve in old and senescence accelerated mice and found that the peripheral nerves of these animals are unable to locally upregulate vascular endothelial growth factor (VEGF), a prototypical angiogenic cytokine, after injury and have substantial deficits in mounting an appropriate intraneural angiogenic response during nerve regeneration.
Our findings provide new evidence of possible interdependent relationships between aging, VEGF, angiogenesis, and nerve regeneration and suggest that vascular abnormalities might play a role in aging-associated neurological dysfunction, with potentially important fundamental and clinical implications.
Peripheral nerve ischemia: Apolipoprotein E deficiency results in impaired functional recovery and reduction of associated intraneural angiogenic response
2003, Experimental Neurology
Apolipoprotein E-knockout (apoE KO) mice have peripheral sensory nerve defects, reduced and delayed response to noxious thermal stimuli, abnormal morphology of unmyelinated fibers, and impaired blood-nerve and blood-brain barriers. In this study, we show that, compared to wild-type mice, peripheral nerves of apoE KO mice have impaired ability to respond to ischemia, as demonstrated by measurement of motor and sensory conduction velocity. In addition, mice lacking apoE exhibit a deficit of reinnervation of ischemic epidermis, evaluated by immunofluorescent staining for the pan-neuronal marker PGP 9.5. Also regional nerve blood flow, measured by laser Doppler, and intraneural angiogenesis after ischemia are significantly compromised in apoE-deficient mice. Finally, upregulation of the angiogenic cytokine vascular endothelial growth factor (VEGF), which physiologically occurs after ischemia in the peripheral nerve of wild-type mice, is severely impaired in apoE KO mice. Among the several neural defects that have already been described in mice lacking apoE, this is the first demonstration that functional recovery to ischemia is impaired in the peripheral nerves of these animals. This deficit is mirrored by the inability of upregulating VEGF and mounting an appropriate intraneural angiogenic response following injury. These findings provide new evidence of possible interdependent relationships between VEGF, angiogenesis, and nerve function and regeneration and may provide new important information on the role of apoE in the nervous system.
Retinal Tissue Perfusion in Patients with Multiple Sclerosis
2019, Current Eye Research

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The multiple sclerosis lesion: initiated by a localized hypoperfusion in a central nervous system where mechanisms allowing leukocyte infiltration are readily upregulated?

Abstract

Brain Res

Brain Res

Neurosci Biobehav Rev

Brain Res

Neurosci Lett

J Neurol Sci

Med Hypotheses

J Biol Chem

Type-2 astrocytes have much greater susceptibility to heat stress than type-1 astrocytes

J Neurosci Res

Low glutathione and high iron govern the susceptibility of oligodendroglial precursors to oxidative stress

J Neurochem

Update on Raynaud's phenomenon [editorial]

Br J Hosp Med

Cerebral white matter is highly vulnerable to ischemia

Stroke

Cumulative white matter changes in the gerbil brain under chronic cerebral hypoperfusion

Acta Neuropathol Berl

Glial activation and white matter changes in the rat brain induced by chronic cerebral hypoperfusion: an immunohistochemical study

Acta Neuropathol Berl

Protective effect of cyclosporin A on white matter changes in the rat brain after chronic hypoperfusion

Stroke

Hypoxicischemic leukoencephalopathy in man

Arch Neurol

Delayed neurological deterioration following hypoxia

Adv Neurol

A white matter disorder in dementia of the Alzheimer type: a pathoanatomical study

Ann Neuro

Binswanger's disease: a review

Stroke