Ischemic Cascade as May Explain ME/CFS

The intention of the following article provide a theory that maysimplify the pathophysiology of CFS/ME symptoms by classifying it under an already-established medical condition called Ischemic Cascade. Ischemic Cascade (IC) is a 16 stage cascade of body reactions aimed at restoring homeostasis in one region of the body, most often the brain being discussed, in response to a local condition of hypoxia.

Hypoxia appears to be the key issue in lack of exertion endurance in both skeletal muscle, and in the cognitive brain. Anecdotal reports have added that lowered emotional tolerance can precede or follow fatigue and "brain fog" in CFS/ME; that any one of the 3 areas of function can bring down either or both of the other two in a situation of exertion intolerance. This is evidence that CFS/ME is not about a single pathogen, and is not about a single tissue. RATHER, as shown in the 2019 SARS-COV2 pandemic and sequelae, this condition can arise from various types of insults to the human body but with the same types of results in the same body systems as seen in CFS/ME and in other autoimmune syndromes.

Leading theory on the subject of Long-Covid sequelae indicates that blood vessel dysfunction, specifically endothelial cell dysfunction, is the key weak link in the otherwise healthy body system. But the blood vessels: capillary, vein, artery, become compromised by systemic infection and SYSTEM-WIDE deficiency. What is NOT much discussed is the possible cause of MODS, multiple organ dsyfunction syndrome which is resulting often in Long-Covid. The possible cause postulated in this theory is attack of all smooth muscle organs, not limited to blood vessels, since common receptors preferred by some viruses exist in both areas.

The reason for the scrutiny of this article on the condition "Ischemic Cascade" in context of Chronic Fatigue Syndrome/ Myalgic Encephalomyelitis/ SEID is that this Cascade of responses appears to have been delineated as a local condition in mainstream medicine, and most often as a brain condition... but a system-wide predominance of this condition has not been widely considered as an explanation or definition of CFS/ME/SEID and may well aptly explain the syndrome which as yet has no explained pathology.

Since SEID is a system-wide intolerance to exertion, and since the IC phases closely resemble its symptoms, it appears prudent to consider that system-wide blood vessel damage and system-wide organ damage caused by Covid19 or by previous Influenza pandemics, and even triggered by patient-specific bacterial infections and weakened immune system function, may already have been defined in the definition of Ischemic Cascade, and could quite potentially explain the following definitive symptoms of CFS/ME/SEID, and lately, Long-Covid sequelae. If so, the definition of Ischemic Cascade may lead to the most direct intervention in ceasing the ME/CFS/SEID/Long-Covid obstacle to health.

The following standards are known to the author of this article: the Canadian Consensus criteria and the Fukuda criteria for diagnosing an ailment as Chronic Fatigue Syndrome.

The appellation SEID or Systemic Exertion Intolerance Disease was established and adopted AFTER the previously mentioned disease monikers for the same condition.

This article seeks to bring to light an already-medically established phenomenon which seems to have been overlooked in the CFS/ME/SEID studies and furthermore overlooked in research as to their mitigation. The key clue that repeating IC may be the condition observed in CFS/ME/SEID is that there is non-restorative sleep with an as-yet unknown cause. The component in IC which can account for hyper-arousal during sleep and prevention of adequate delta phase sleep is an initial Glutamate Excitotoxicity and some amount of feedback sometimes leading to additional Glutamate release outside affected cells.

Chronic Fatigue Syndrome as a medical appellation seems to indicate the obvious, that the symptoms have lasted past the 3-month appellation time limit for a disease being considered to be in the ACUTE stage of up to 3 months. It indicates a chronic state of feelings of physical fatigue, coupled with bouts of Post Exertional Malaise and also Unrefreshing sleep, as the 3 indisputable symptoms. This leaves two other symptoms of which one or the other must be present in order for the condition to qualify or be diagnosed as CFS/ME/SEID:

Either cognitive impairment

or

Orthostatic intolerance.

or both.

These 5 current criteria have been redacted by the medical community from the original mandatory 10 symptoms

POTS, or Postural Orthostatic Tachycardia Syndrome is the official name for such orthostatic intolerance.

What do ME/CFS/SEID/Long-Covid/POTS have in common?

INTOLERANCE.

And intolerance is a breach of homeostatic recovery.

NOTABLY: the key causative problem in MECFSSEIDLONGCOVID is:

a continued inflammation from a continued pathogen insult, long after the main infection has ceased.

Lastly, before describling the ISCHEMIC CASCADE stages, it is fitting to make a plausible reference

to latent viruses which can be reactivated in cells throughout the course of one's life,

putatatively because they evaded the patient's immune reaction and also eradication by

novel antibodies.

THE ISCHEMIC CASCADE of EVENTS in response to Hypoxia:

NOTE: You are free to attempt to read the PubMed explanation of Ischemic Cascade, at your own personal cost.

However, the following is quoted from Wikipedia Ischemic cascade - Wikipedia

"Mechanism

A cascade is a series of events in which one event triggers the next, in a linear fashion. Thus "ischemic cascade" is actually a misnomer, since the events are not always linear: in some cases they are circular, and sometimes one event can cause or be caused by multiple events. In addition, cells receiving different amounts of blood may go through different chemical processes. Despite these facts, the ischemic cascade can be generally characterized as follows:^{[citation needed]}

1. Low blood supply decreases amount of oxygen that reaches tissues, leading to hypoxia
2. Deficiency of oxygen causes the neuron's normal process for making ATP for energy to fail.
3. The cell switches to anaerobic metabolism, producing lactic acid.
4. ATP-reliant ion transport pumps fail, causing the cell to become depolarized, allowing ions, including calcium (Ca²⁺), to flow into the cell.
5. The ion pumps can no longer transport calcium out of the cell, and intracellular calcium levels get too high.
6. The presence of calcium triggers the release of the excitatory amino acid neurotransmitter glutamate.
7. Glutamate stimulates AMPA receptors and Ca²⁺-permeable NMDA receptors, which open to allow more calcium into cells.
8. Excess calcium entry overexcites cells and causes the generation of harmful chemicals like free radicals, reactive oxygen species and calcium-dependent enzymes such as calpain, endonucleases, ATPases, and phospholipases in a process called excitotoxicity. Calcium can also cause the release of more glutamate.
9. As the cell's membrane is broken down by phospholipases, it becomes more permeable, and more ions and harmful chemicals flow into the cell.
10. Mitochondria break down, releasing toxins and apoptotic factors into the cell.
11. The caspase-dependent apoptosis cascade is initiated, causing cells to "commit suicide."
12. If the cell dies through necrosis, it releases glutamate and toxic chemicals into the environment around it. Toxins poison nearby neurons, and glutamate can overexcite them.
13. If and when the brain is reperfused, a number of factors lead to reperfusion injury.
14. An inflammatory response is mounted, and phagocytic cells engulf damaged but still viable tissue.
15. Harmful chemicals damage the blood–brain barrier.
16. Cerebral edema (swelling of the brain) occurs due to leakage of large molecules like albumins from blood vessels through the damaged blood brain barrier. These large molecules pull water into the brain tissue after them by osmosis. This "vasogenic edema" causes compression of and damage to brain tissue (Freye 2011; Acquired Mitochondropathy-A New Paradigm in Western Medicine Explaining Chronic Diseases)."" (Ischemic cascade - Wikipedia)

The CRUCIAL elements of Ischemic Cascade are:

1. this was only considered to be local, such as in the brain or a damaged area: conside this as as SYSTEM-WIDE reaction to system-wide hypoxia and endothelial cell damage as result of Influenza infection via Sialic Acid receptors, and also coronavirus infection by Covid19 via ACE2 receptors.
2. NOTE: ACE2 receptor means: Angitension Converting Enzyme receptor with the purpose of converting Angiotensin II vasoconstrictor to Angiotensions 1-7 of which one is a vasodilator, and a trigger of NADPH antioxidant flourishing in the Krebs Cycle.
   

See ME/CFS.

the maintenance of stable internal biological conditions (e.g. body temperature) in a changable environmen

homeostasis the maintenance of stable internal biological conditions (e.g. body temperature) in a changable environmen

cognition Thought processes, including attention, reasoning, and memory.

myalgic encephalomyelitis (M.E.) - A disease often marked by neurological symptoms, but fatigue is sometimes a symptom as well. Some diagnostic criteria distinguish it from chronic fatigue syndrome, while other diagnostic criteria consider it to be a synonym for chronic fatigue syndrome. A defining characteristic of ME is post-exertional malaise (PEM), or post-exertional neuroimmune exhaustion (PENE), which is a notable exacerbation of symptoms brought on by small exertions. PEM can last for days or weeks. Symptoms can include cognitive impairments, muscle pain (myalgia), trouble remaining upright (orthostatic intolerance), sleep abnormalities, and gastro-intestinal impairments, among others. An estimated 25% of those suffering from ME are housebound or bedbound. The World Health Organization (WHO) classifies ME as a neurological disease.

systemic exertion intolerance disease (SEID) - A term for ME/CFS that aims to avoid the stigma associated with the term "chronic fatigue syndrome", while emphasizing the defining characteristic of post-exertional malaise (PEM). SEID was defined as part of the diagnostic criteria put together by the Institute of Medicine (IOM) report of 10 February 2015.

See systemic exertion intolerance disease.

See myalgic encephalomyelitis.

See chronic fatigue syndrome.

systemic exertion intolerance disease (SEID) - A term for ME/CFS that aims to avoid the stigma associated with the term "chronic fatigue syndrome", while emphasizing the defining characteristic of post-exertional malaise (PEM). SEID was defined as part of the diagnostic criteria put together by the Institute of Medicine (IOM) report of 10 February 2015.

glutamate (Glu) - Glutamate is one of the amino acids used by the body to make proteins. It is a salt or ester of glutamic acid, and the terms glutamate and glutamic acid are often used interchangeably. It also functions as the principal excitatory neurotransmitter in the brain.

post-exertional malaise (PEM) - A notable exacerbation of symptoms brought on by small physical or cognitive exertions. PEM may be referred to as a "crash" or "collapse" and can last for days or weeks. Symptoms can include cognitive impairments, muscle pain, trouble remaining upright (orthostatic intolerance), sleep abnormalities, and gastro-intestinal impairments, and others.

orthostatic intolerance (OI) - The development of symptoms when standing upright, where symptoms are relieved upon reclining. Patients with orthostatic intolerance have trouble remaining upright for more than a few seconds or a few minutes, depending upon severity. In severe orthostatic intolerance, patients may not be able to sit upright in bed. Orthostatic intolerance is often a sign of dysautonomia. There are different types of orthostatic intolerance, including postural orthostatic tachycardia syndrome (POTS).

See postural orthostatic tachycardia syndrome.

postural orthostatic tachycardia syndrome (POTS) - A form of orthostatic intolerance where the cardinal symptom is excessive tachycardia due to changing position (e.g. from lying down to sitting up).

postural orthostatic tachycardia syndrome (POTS) - A form of orthostatic intolerance where the cardinal symptom is excessive tachycardia due to changing position (e.g. from lying down to sitting up).

antibodies Antibody/immunoglobulin refers to any of a large number of specific proteins produced by B cells that act against an antigen in an immune response.

antibodies Antibody/immunoglobulin refers to any of a large number of specific proteins produced by B cells that act against an antigen in an immune response.

The word "membrane" can have different meanings in different fields of biology. In cell biology, a membrane is a layer of molecules that surround its contents. Examples of cell-biology membranes include the "cell membrane" that surrounds a cell, the "mitochondrial membranes" that form the outer layers of mitochondria, and the "viral envelope" that surrounds enveloped viruses. In anatomy or tissue biology, a membrane is a barrier formed by a layer of cells. Examples of anatomical membranes include the pleural membranes that surrounds the lungs, the pericardium which surrounds the heart, and some of the layers within the blood-brain barrier.

membrane The word "membrane" can have different meanings in different fields of biology. In cell biology, a membrane is a layer of molecules that surround its contents. Examples of cell-biology membranes include the "cell membrane" that surrounds a cell, the "mitochondrial membranes" that form the outer layers of mitochondria, and the "viral envelope" that surrounds enveloped viruses. In anatomy or tissue biology, a membrane is a barrier formed by a layer of cells. Examples of anatomical membranes include the pleural membranes that surrounds the lungs, the pericardium which surrounds the heart, and some of the layers within the blood-brain barrier.

chronic disease a disease or condition that usually lasts for 3 months or longer and may get worse over time. Chronic diseases are long-term (typically incurable and requiring long-term management) but are not necessarily severe.

enzyme a substance produced by a living organism which acts as a catalyst to bring about a specific biochemical reaction.