June 25, 2012 at 1:47pm
I wanted to put together the research I've compiled considering multiple sclerosis as a disease of primary neurodegeneration due to hypoperfusion, with secondary reperfusion injuries. I felt it was important to document and organize the scientific research. I also want your input and thoughts.
The reason why MS relapses and remits during the onset of the disease has been difficult to understand, and impossible to replicate in animal models of MS. EAE, the current animal model for MS, is not like MS. EAE is more akin to ADEM, in that it does not relapse and remit. EAE is an ongoing immune reaction. https://www.msard-journal.com/article/S2211-0348(14)00063-7/fulltext
I believe stroke and cardiovascular researchers may be better able to create models of MS using perfusion--or blood flow. Stroke specialists, like Dr. Peter Stys, have been questioning the autoimmune theory of MS, and suggesting that the immune reaction may be secondary. link
Most of us have heard the word hypoperfusion in relation to multiple sclerosis. The slowed perfusion or less than normal blood flow we see in the MS brain has been documented. Researchers have shown how people with MS have less cerebral blood flow than normal people, which creates an ongoing low level ischemic environment.
The relatively new concept of neurovascular unit (NVU) helps to clarify the hemodynamic changes due to the intricate interplay between cerebral blood flow (CBF) and vasoactive factors. Several studies have demonstrated the importance of endothelial factors, their neurovascular interaction, and that vascular changes are also highly conducive to neurodegenerative changes and clinical impairment.10–13 Cerebral hypoperfusion and vascular factors are strictly involved in neurovascular dysfunction, vascular oxidative stress, and relative tissue hypoxia, well in advance of any demyelinating lesions. Changes in capillary resistance and neurovascular function may, in fact, represent important common denominators for conditions that increase the risk of developing both demyelinating lesions and progressive MS forms. https://journals.sagepub.com/doi/full/10.1177/1177271918774800
Stroke researchers understand the process of ongoing cerebral ischemic stress causing white matter damage.
Compared with gray matter, white matter of the brain is more sensitive and susceptible to ischemic stress because of its relatively limited blood supply.73 In addition, DM can induce white matter damage, as well as aggravate white matter injury after stroke.73 DM stroke patients are prone to developing earlier and exacerbated white matter hyperintensities compared with non-DM patients.74 Vascular dysfunction including BBB disruption that leads to leakage of serum components into the white matter can also induce white matter damage.75The white matter in the brain is also highly sensitive to inflammatory responses, which can injure the white matter directly as well as indirectly by damaging the BBB and/or creating an inhospitable environment for axonal/myelin regeneration.76 https://www.ahajournals.org/doi/pdf/10.1161/JAHA.117.005819
It was a published theory of Dr. Bernhard Juurlink which first prompted my exploration into hypoperfusion and MS. I read his 1998 hypothesis paper in 2007, after Jeff returned from a trip to high altitude with dozens of lesions and an MS diagnosis.
http://www.ncbi.nlm.nih.gov/pubmed/9824835
After ischmic events, the brain is reperfused. Reperfusion simply means to redeliver blood. Reperfusion is a good thing and a bad thing. Reperfusion can be a natural occurrence; it returns blood to tissue after there is an event which slows blood flow, like a stroke or ischemia. Reperfusion brings essential O2 and glucose to cells after such an event, but it also brings inflammation and the immune system with it. Blood returns to the area of tissue where it had been absent, at a cost.
http://www.ajnr.org/content/25/8/1342After ischmic events, the brain is reperfused. Reperfusion simply means to redeliver blood. Reperfusion is a good thing and a bad thing. Reperfusion can be a natural occurrence; it returns blood to tissue after there is an event which slows blood flow, like a stroke or ischemia. Reperfusion brings essential O2 and glucose to cells after such an event, but it also brings inflammation and the immune system with it. Blood returns to the area of tissue where it had been absent, at a cost.
Dr. Michael Dake mentioned in a presentation at International Society for Neurovascular Disease (ISNVD) how "hyperperfusion" (otherwise known as reperfusion injury) occurs BEFORE an MS lesion forms. He referenced this paper, which discusses how this perfusion change happens before the break in the blood brain barrier, before the immune system entry, before demyelination. The very first step is a change in perfusion. I wanted to know--why?
I believe reperfusion injury explains the relapsing remitting course of early MS and ties together research into collateral circulation and hypoperfusion in the MS brain. There will be an explanation as to how this theory functions in progressive MS at the end of this note.
We are learning more and more that gray matter loss, or brain atrophy, is a reliable method for monitoring the neurodegenerative process in MS. Gray matter loss and death of neurons begins from the inception of the disease and continues with increasing disability. It is linked, only modestly, with white matter lesions. This is why the current medications which suppress the immune system do not stop MS, and are not effective in progressive MS.
http://www.neurology.org/content/68/24/2161
https://www.ncbi.nlm.nih.gov/pubmed/29741648
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0209326
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4706325/
https://www.ncbi.nlm.nih.gov/pubmed/29741648
https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0209326
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4706325/
We already know that pwMS have lower levels of glucose and O2 being delivered to their brain and spinal tissue, due to hypoperfusion, which can cause neurodegeneration and mitochondrial dysfunction.
Right now, the debate as to whether this hypoperfusion is primary, or hypoperfusion is simply a result of an unknown disease process we call "MS". On that note, here is research stating the hypoperfusion seen in the MS brains looks like primary ischemia, or low oxygen.
Lower levels of O2 and glucose delivery can be correlated to hypoperfusion caused by venous insufficiency.
I think that on top of this ongoing process of neurodegeneration, there are intermittent ischemic events which take these glucose and O2 levels dipping even lower-- events like an illness, a trip to high altitude, stress, an injury, giving birth, a bacterial infection--and when the event is over, the reperfusion cycle begins--this is what we call an exacerbation or "MS flare."
I believe this is why many pwMS can directly tie their relapses to times after viruses, stress, lack of sleep, etc. These events become the straw that break the camel's back. And once these events end, reperfusion injury happens. It's a damaging one/two punch.
Reperfusion injury is NOT the complete disease. It is a reaction to an event. MS relapses are not MS. Relapses are a reaction to an event. The MS neurodegenerative process continues underneath. Let's look at how an MS relapse is like reperfusion injury.
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Reperfusion Injury and Multiple Sclerosis relapses share:
1. Demyelination -- Loss of myelin occurs after nerves have blocked blood flow, low O2 and glucose, and then a return of blood flow. Reperfusion causes demyelination of nerves.
Perivascular demyelination and intramyelinic oedema in reperfusion nerve injury.
Acute inflammatory demyelination in reperfusion nerve injury
2. Blood brain barrier disruption--the blood brain barrier becomes permeable, and endothelial tight junctions are altered in reperfusion injury.
Reperfusion-induced injury to the blood-brain barrier after middle cerebral artery occlusion in rats.
Blood-brain barrier disruption and matrix metalloproteinase-9 expression during reperfusion injury: mechanical versus embolic focal ischemia in spontaneously hypertensive rats.
3. An excessive innate immune response--immune cells are called in
Association of immune responses and ischemic brain infarction in rat.
Naturally Occurring Autoantibodies Mediate Ischemia/Reperfusion-Induced Tissue Injury
http://www.landesbioscience.com/curie/chapter/5117/
4. An excess of free radicals, oxidative stress and partially reduced oxygen species are found in both reperfusion injury and Multiple Sclerosis
Oxidative Stress in Multiple Sclerosis
http://www.ncbi.nlm.nih.gov/pubmed/20120717
Mechanisms of Oxidative Damage in Multiple Sclerosis
The role of oxidants and free radicals in reperfusion injury
5. Endothelial Dysfunction as evidenced by elevated levels of endothelin-1 in plasma
Increased endothelin-1 plasma levels in patients with multiple sclerosis.
Extraocular blood flow and endothelin-1 plasma levels in patients with multiple sclerosis.
Endothelin-1 is involved in the pathogenesis of ischemia/reperfusion liver injury
6. NEW RESEARCH 2019 which considers newly discovered CNS lymphatic vessels. Impaired cerebrospinal fluid (CSF) drainage in the central nervous system, due to malfunction of neurovascular unit (NVU) after ischemia, may lead to neuronal cell death and reperfusion injury.
In the adverse event of ischemia, pericytes around capillaries constrict, eventually leading to pericyte death in rigor and could cause neutrophil trapping in the arterioles. These findings suggest reconsideration of neutrophil involvement in ischemia and reperfusion. Rather than acting neurotoxic, neutrophil accumulation in arterioles may have an impact on the vascular function including CSF drainage recently shown to occur along these pathways.15,116 In fact, cerebral ischemia results in impaired fluid clearance along the perivascular spaces in the affected cortex117 underscoring a neutrophil-induced malfunction of the NVU in I/R.
Functional impairment of lymphatic drainage from the CNS after ischemic stroke may lead to rapid neuronal cell death due to the accumulation of toxic metabolites in the brain parenchyma.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6111395/
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Reperfusion has been studied extensively on the arterial side. However, the all important lymphatic drainage mentioned in the paper linked above, occurs on the venous side. Like most medical research, the study of the veins and venous return is lacking, and stroke researchers admit this is a problem in understanding the full impact of reperfusion injury.
I did find one animal study which looked at venous hypertension as a complicating factor in reperfusion injury
Although most experimental studies target arterial aspects of recirculation in stroke, a few have focused on the venous side.49 In contrast to studies of cerebral artery occlusion, which are methodologically more consistent among different laboratories, studies of venous thrombosis models are at an early stage of development and lack standardization, which greatly complicates comparison of results from different laboratories. Furthermore, most published studies have focused either on arterial or venous components, and very few have examined both arterial and venous components in studies of recirculation. Therefore, a goal of the present commentary is to emphasize that both arterial and venous components should be considered in studies of acute ischemic and hemorrhagic stroke.
Overall, the “recirculation” concept strongly suggests that stroke treatment paradigms need to address venous outflow from the brain in relation to arterial inflow. Therefore, to minimize potential brain swelling and reperfusion injury for severe stroke patients, we need to consider carefully venous pressure and outflow, potential arterial smooth muscle and venous endothelial phenotype changes, possible pre-existing venous sinus hypoplasia, and in particular, if nimodipine will be used.I did find one animal study which looked at venous hypertension as a complicating factor in reperfusion injury
Elevated venous pressure can be associated with severe tissue injury. Few links, however, between venous hypertension and tissue damage have been established. We examined here the effects of micropressure elevation on the outcome of venular occlusion/reperfusion in the mesenteric microvasculature of male Wistar rats. One hour of venular occlusion (diameter approximately 50 microm) by micropipette occlusion followed by reperfusion were carried out with sham surgery without occlusion as control. Leukocyte rolling, adhesion, and migration, oxygen radicals detected by dichlorofluorescein (DCF), and parenchymal cell death detected by propidium iodide (PI) were recorded simultaneously in the same vessel at a location upstream of the occlusion site with elevated micropressure and at a downstream location with low micropressure.
The number of rolling, adhering, and migrating leukocytes increased on the upstream side of the occlusion to a higher level than downstream of the occlusion site.
Microhemorrhages of blood cells into the mesentery interstitium were observed only on the upstream side of the occlusion. These results indicate that an elevation of the venular blood pressure during occlusion/reperfusion exacerbates the inflammatory cascade and tissue injury. Venous occlusion may constitute an important mechanism for tissue injury.
(note the upstream microhemorrhages caused by venous hypertension in this study. These tiny, pinpoint spots of blood escaping into tissue might be linked to the iron deposition and hemosiderin we find in the MS brain.)
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This theory continues--when MS becomes progressive and relapses no longer occur, it is because the body has been conditioned--- trained from years of hypoxia and low levels of O2 and the recurrent reperfusion. Eventually, as the body ages, this reperfusion response no longer happens. It burns out. There is no more white matter damage---but the low levels of O2 and glucose are still causing mitochondrial dysfunction, neuronal and axonal death.
Hypoperfusion becomes worse, as the body ages and becomes more inactive. MS continues to progress, even without the reperfusion injury seen during the RRMS days. Gray matter continues to atrophy- even if there is no demyelination, inflammation or damage to white matter.
The underlying disease process---low levels of O2 and glucose to CNS tissue, causing neurodegeneration--has remained the same. MS progresses. Gray matter atrophies. But the period of reperfusion injury eventually stops happening, due to conditioning. There are no more relapses. The disease moves into the progressive phase.
In the past, MS has largely been considered a chronic inflammatory and demyelinating disease, driving most of the research and treatment development towards targeting the immune system. As of now, disease modifying therapies for MS are limited to various anti-inflammatory agents that reduce acute inflammatory lesions, clinical relapses and disability progression in RRMS. These anti-inflammatory agents, however, do not completely prevent axonal injury and are largely ineffective in treating progressive MS.
The recent resurgence of MS research focused on axonal degeneration mechanisms has resulted in convincing experimental evidence and potential treatment targets. As reviewed above, mitochondrial function is crucial in preserving axonal integrity in both acute inflammatory and progressive stages of MS. Therefore, therapies that protect mitochondria and enhance their functioning warrant investigation.
The current drugs are treating the body's natural response of reperfusion, and the resultant immune activation. But they do not address the diffuse cerebral hypoxia and lowered glucose transport which remain. And that's why MS continues to progress.
Dr. Zamboni sought to treat this hypoperfusion caused by venous malformations and collateral circulation. He used venoplasty to increase perfusion and blood flow by allowing the body to use the jugular veins, rather than less efficient collaterals. It's worked for many people, but not all---we obviously need more research.
This hypoperfusion/reperfusion theory also explains why HBOT treatment, nutrition, antioxidants, smoking cessation, exercise, stress reduction and vascular approaches help those with MS to receive stability and remission. These measures provide balance to the body, enable more energy and O2 to be delivered to the central nervous system and help the body avoid these ischemic events which call in the reperfusion response. These treatments directly address cardiovascular health and the heart-brain connection.
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A brief recap:
Venous insufficiency, arterial issues, or cardiovascular problems cause primary hypoperfusion of the MS brain. This leads to lowered glucose and O2 delivery to the CNS. During the RRMS stage of the disease, the body responds to events which lower levels of O2 with reperfusion. This creates venous hypertension and reperfusion injury. The immune system is activated. Lesions form. MS progresses. As the body slows down with increasing disability and age, hypoperfusion worsens, axons and neurons continue to die. Gray matter atrophies. It's a vicious cycle.
How to stop the cycle? Addressing venous insufficiency or cardiovascular issues. Oxygen therapy. A whole food diet full of nutrients and plant-derived antioxidents. Regular exercise to improve cardivascular health. Lifestyle modifications including stress reduction, meditation, smoking cessation. Potential immuno therapy to avoid reperfusion injury during RRMS stage.
But, as you all know by now---I'm not a doctor. I just hate MS. And I want more answers.
Please, let me know your thoughts, and please share with medical people and researchers you may know, what part of this theory is lacking? Does this make any sense? How should research move forward?
Joan
Thank you always Joan from me here in ENGLAND UK
ReplyDeleteAs I was reading your synopsis of complicated topics, you made it all quite understandable to my cog-fog brain. And I thought your posts should earn you a Phd! AND our deepest thanks.
ReplyDeleteThanks, Saskia! My husband has said that I make medicalese understandable...I hope so! The research is being generated, but the disconnect between medical research teams is real, and problematic. All I do is read and translate, and hopefully help lay people make connections that can help them live healthier lives. Groups like the ISNVD www.isnvd.org are where the real developments will happen. We're getting there!
DeleteMy overwhelmed brain always appreciates your translations Joan. Thank you, always. 💖
ReplyDeleteMy overwhelmed brain always appreciates your translations Joan. Thank you, always. 💖
ReplyDelete