RSD Pain

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Vic's Articles, starting with article #1.



There is a word that is rarely, if ever, mentioned in the context of CRPS.  That word is hypoxia; a deficiency of oxygen reaching the cells of the body.  One would think that it would draw significant interest, since cyanosis is the sign that cells aren’t getting enough oxygen, and our bluish to purplish skin color is cyanosis.

Hypoxia is not something doctors ignore, except when it involves CRPS.  When we die, our skin becomes hypoxic; that is because the cells don’t die until all of the oxygen has been consumed.  Diabetic cyanosis is a major sign; this is because diabetes usually affects the major artery.  In a short while, the hypoxia is darker, and without intervention, there will be gangrene, leading to death.

So why isn’t it important in CRPS?  It is, but doctors have learned that it only rarely develops into gangrene.  We can be hypoxic for years, and many have, without seeing it worsen at all.

That blue to purplish skin color is made up of surface microvascular systems (MVS); the arterioles, capillaries and venules that bring arterial blood, pass it to the cells, then collect carbon dioxide and return it to the veins and thence to the lungs.  What you see is only a tiny percentage of the number of hypoxic cells below the skin.

When our cells don’t get adequate oxygen and nutrients they can’t function properly.  Chronic hypoxia weakens muscle; partly from disuse, but actually from pain after little exercise.  Without oxygen, subcutaneous cells cut back on their functions as the minimal amount of nutrients and oxygen just barely sustain cell life.

Not every cell in the CRPS area is deprived of oxygen, and our cells were created to signal distress to nearby cells.  Eventually some oxygen is provided.  Visually, you could perceive this as a bucket brigade at a fire.

All of the cells in the hypoxic area are affected; in the “bucket brigade” just mentioned, cells that receive adequate arterial blood must pass most of it to hypoxic cells.  If this didn’t happen, many cells would start to die (called necrosis), and like rotten apples in a barrel, the cells next to them are killed.  The circle of necrotic cells just grows wider.

Bone cells are severely affected, as the bone constantly reshapes itself so it is thicker where it is needed.  Other parts of the bone are pared down when the extra cells are not needed.  Without this paring down of bone cells, the bone would get larger and heavier.  More bone weight in the legs means muscle has to work harder to lift your feet when you walk.

Bone cells die, just as skin cells do.  During hypoxia, the cells die and there is no calcium to replace them.  Bone weakens and osteoporosis develops.

Ligaments and muscle are affected and contracture (clawed hands and curled in soles of the feet, then wrists, and movement is restricted by this affect; not only by pain during movement.

Our nerve cells need oxygen and nutrients.  As oxygen supplies dwindle, these nerve cells will do one of three things: completely shut down, sending no more (or much fewer) signals to the spinal cord and brain; they could continue to act normally, apparently unaffected by the loss of oxygen and nutrients, or; they can signal the brain that something is wrong.

There are several different kinds of sensory nerves.  Thermal nerves give the brain information about both external and external temperatures.  If these nerves either send few signals or act normally, there wouldn’t be anything more to talk about.

There is more, of course.  There is the fact that thermal sensory cells are virtually screaming that they burn.  They most likely suspect is hypoxia.  This justifies heroic efforts to restore circulation.  If the burning continues after circulation is restored, something else is the problem.  This certainly wouldn’t mean restoration of circulation failed.  Our cells can begin functioning again.

We can never know whether impaired circulation is causing the burning and the hypersensitive skin of allodynia and the deep, bone-chilling cold, deep inside, are caused by hypoxia unless circulation is restored.

There is no way to know whether the sympathetic nervous system is somehow constricting blood flow unless the damaged or defective nerve is identified.  In other disorders, there are different ways to measure nerve activity, but there hasn’t been any published research showing that any defective nerves or signals are acting abnormally in CRPS.

Dr Rene LeRiche thought he had identified the problem 90 years ago.  We might have to wait to find which nerves are affected, but it was obvious that sympathetic nerves were causing the smooth muscle of an artery to contract to the point where only a small amount of blood could pass.

His answer was the sympathectomy, which made sense, because when you sever the nerves, the pain stops.  There is no question but that this surgical severing of nerves relieves symptoms, but not in the way LeRiche envisioned.  It has since been shown that arterial blood flow remains normal, or even increases in CRPS.

There are other theories of how the sympathectomy works.  I am not aware of any research had been done on sympathectomized nerves, but sympathetic nerve blocks sometimes bring pain relief (at least temporarily).

There has been research into how blocks work, and one of the most interesting of them shows that if nor-epinephrine is injected below the site of the block, symptoms return.  The SNS controls adrenalin, epinephrine, nor-epinephrine, and other neurotransmitters and hormones.  The research I just mentioned indicates that sympathetic blocks prevent normal SNS activity.

However blocks affect CRPS a symptom, the relief is not always provided, not always complete, but is always temporary.

The next article will begin discussion of one way that research has proved causes hypoxia.

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In the 1990’s, a small number of researchers began investigating a possible link between the immune system and CRPS. Their research came about as a result of earlier research into unexplained inflammation and high patient mortality following apparently successful heart surgeries.

Those earlier researchers discovered large numbers of white blood cells (WBCs) in the tissue of the heart. These WBCs, called polymorphonuclear leukocytes (PMNLs), are our first line of defense when a pathogen enters our body.


PMNLs make up more than 50% of the WBCs in our body. Their role is to “patrol” the circulatory system, always on the lookout for anything foreign in the blood. If they don’t recognize something as belonging, it is a threat to be destroyed.

Their primary function takes place in the microvascular systems (MVS); the arterioles, capillaries and venules that deliver arterial blood to the cells and return used carbon dioxide saturated blood to the veins.

When a pathogen is discovered in the MVS there are sure to be up to millions more just on the other side of the MVS wall. A pathogen in the MVS means that it entered at the capillary, during the exchange of oxygen and nutrients for carbon monoxide.

If one pathogen enters the capillary, there will be hundreds of thousands, or even millions more in the interstitial space on the other side of the MVS wall.

Interstitial space (IS) is membrane that surrounds groups of cells. It also contains a liquid that lubricates the cells so they don’t damage one another by friction as the body moves.

When a PMNL encounters foreign matter it raises the alarm by releasing chemical messages that can be read by messenger cells and other WBCs.

It then releases chemicals to force the cells that line the circulatory system to retract, leaving gaps that the PMNL can pass through.

Once inside the IS, the PMNL again releases chemicals; everything within is a target. The skeletal muscle cells in the IS are not as strong as those that line the MVS wall, and are easily destroyed along with the pathogens that could threaten the body.

Viruses can be deadly, and can spread through the body in very little time. It is likely that some viruses will have already passed through the MVS, entered the blood and invaded other cells before the body knows they are there.

They only do two things; eat and multiply. A single virus burrowing into a cell can result in millions of viruses in only four to five hours.

In two more hours their numbers can increase into the billions; each one destroying a cell while making hundreds of copies each hour.

PMNLs destroy as many viruses as they can, limiting their numbers until a messenger cell reaches the one cell in the body that can destroy them all; an antibody left over from a previous viral infection by a similar virus.

That one antibody multiplies faster than viruses, and these antibodies spread throughout the body searching out every virus and destroying it. One missed virus is all that is necessary to start the infestation anew.

During the initial stages of the immune response, inflammation from the chemicals released by PMNLs and other WBCs cause pain. Edema adds to the pain. It is caused by the release of fluids from the cells and by fluid passing from the MVS into the IS through the gaps in the MVS wall.

The common cold is an excellent example of inflammatory pain. The symptoms you experience don’t come from the virus, but from the chemicals released in the fight to destroy them.

Infectious material acts much differently than viruses. It spreads cell by cell in an ever-widening area. Here, when white blood cells die they remain concentrated around the infection. The pus from infection is mostly made up of dead PMNLs.

Instead of a system-wide response that leads to fever and general weakness, a relatively small area affected, and many more WBCs are concentrated in that area. This means more chemicals are released, causing more intense pain and swelling. Skin temperature can exceed that of most fevers.

Despite heavier concentrations of WBCs, infectious matter is better able to withstand the assault and continue to spread, ultimately to the veins, where inflammation is manifested by the red streaks that denote damage to the veins.

As the infection spreads, dead tissue in the affected area rots. Since the infection isn’t limited to a single IS there may be hundreds of thousands of dead cells. They must be removed otherwise gangrene could develop.

Our immune system is programmed to deal with this. After releasing their chemicals, PMNLs take on the role of phagocyte; cells that engulf and consume foreign material and debris.

A rough analogy of this change in roles is viewing the PMNL/phagocyte as unfurling the cell body, making a larger surface that can more easily capture the material, surround and then dissolve it.

The phagocyte becomes adhesive, making it easier to capture and hold the material. As you will see, this fact is key to understanding how hypoxia develops.

As the immune response draws to an end, phagocytes are programmed to die. This mass suicide is called apoptosis, something that serves many important functions, such as maintaining a healthy cell population.

When apoptosis doesn’t happen…..

This will be the focus of the next article

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There is a disorder that begins with trauma followed by the immune response; but the immune response doesn’t end with phagocyte programmed cell death (apoptosis). Instead, phagocytes remain alive and adhesive.

The reason why they don’t die hasn’t been answered yet, but the fact that phagocytes are found in the venules of the microvascular systems (MVS), and that they are attached to the endothelial cells that line the inside of venules, leaves no doubt that they were alive and adhesive when they reached that point.

The interior diameter of the MVS is so tiny that red blood cells can only pass through in single file. PMNL/phagocytes are larger than red blood cells, so living, adhesive phagocytes, attached to the venule wall would quickly and permanently plug it.

With circulation through the MVS permanently stopped, the cells that get their oxygen and nutrients from that MVS are left without a source for these life-sustaining products. They soon show the effects of hypoxia, shutting down one activity after another until all they can do are the minimal functions necessary to stay alive.

The blood in the plugged MVS is quickly depleted of oxygen and nutrients. Red blood cells change to the blue to purplish color of cyanosis. This disorder involves more than a few plugged MVS. Thousands are plugged and millions of cells slowly starve.

This disorder is called ischemia-reperfusion injury (IRI). It is the disease described in the first paragraph in article 2. In IRI, the starved cells are part of a heart or other internal organ, and when they stop functioning, the organ dies. If the organ is necessary to sustain life, the patient dies.

There is another disorder that begins with trauma, followed by immune-inflammation and then cell hypoxia; made evident by the blue to purplish skin color indicating cyanosis. That disorder is called complex regional pain syndrome (CRPS).

In both disorders, the immune system is clearly the cause of the plugged MVS and the ensuing hypoxia. IRI and CRPS are the only disorders in which pathogens are not the cause of the non-specific immune response. There are no pathogens; just cell debris resulting from trauma.

All traumas, no matter how minor, damages and destroy cells, leaving cell debris in its wake. In the vast majority of traumas, however, there is no evidence of immune system involvement.

Even when the trauma results in immune-inflammation, only a tiny fraction will go on to become IRI or CRPS.

No one can tell us why the immune response sometimes leads to these two disorders, but that isn’t unusual. Medical science can’t tell us why some people can be sunburned time and again without developing skin cancer, while others who may even spend less time in the sun don't develop this disease. The same is true of smokers and lung cancer.

Knowing how something goes wrong can lead to precautions that can prevent a disease from developing, and this it true of IRI. Researchers learned that by simply applying vitamin E to the surgical wound, IRI rarely develops; patients recover from the surgery, go home, and lead normal lives.

It isn’t known whether the same precaution will protect from CRPS, because no one has tried using vitamin E at the first sign of inflammation after a traumatic injury. Even if this were tried and proved to be effective in preventing CRPS, it wouldn’t help us.

We need medical science to find a way to cure or at lease stop the disease from further retrogression after it has begun.

There is a therapy that has been tried by people suffering from CRPS, but the results have been mixed. Some people live symptom-free following this therapy; others may need to return when symptoms reappear, and some show almost instant improvement, closely followed by catastrophic relapse.

The therapy is hyperbaric oxygen (HBO) and is often called hyperbaric oxygen therapy (HBOT). In this and future articles I will use HBOT, since that is the common usage.

HBOT is frequently used to treat patients diagnosed with IRI. Not everyone with this diagnosis dies, since some internal organs aren’t absolutely essential in order to live. The pancreas is an example; and sometimes organs are damaged but not destroyed, such as the liver, lungs and even the brain.

The results of HBOT in treating these patients have also been mixed.

I will go into much more detail about the reasons why HBOT sometimes works and sometimes fails in an upcoming article, but before any discussion of how it may be possible to improve HBOT outcomes, we need to learn more about IRI.

Since the facts are identical when describing IRI or CRPS, I will use IRI/CRPS when I mention this disorder. The reasons for this will become even more evident as you read on.

As you have already seen, IRI represents ischemia-reperfusion injury.

Ischemia is local anemia resulting from blocking the inflow of arterial blood. During surgery, tourniquets and hemostats block blood flow, but even here ischemia is also caused by inflammatory edema. In CRPS ischemia is almost always the result inflammatory edema.

During the immune response, chemicals released by PMNLs cause pain and swelling. More swelling comes from fluids of destroyed healthy cells and by fluids passing from the MVS into the interstitial space (IS). Added to the fluids already found in the IS, the result is edema from expanded IS’.

The IS presses against nearby small arteries, veins and MVS, compressing them until little, if any blood can pass through them.

Edema eventually subsides, however, and circulation through these arteries, veins and MVS is restored. Scientists call this reperfusion. Sometimes reperfusion can cause more damage than ischemia. This damage is called ischemia-reperfusion injury.

IRI will be the subject of the next article.

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The first step toward Ischemia-reperfusion injury begins when a PMNL encounters cell debris in a microvascular system, activates the non-specific immune response,  and other PMNLs arrive and invade interstitial spaces but encounter only cell debris instead of the pathogens they are programmed to fight.                                                                                                                                      

Exactly why cell debris leads to IRI isn’t clear yet, but a likely explanation is that when they don’t encounter pathogens (whose numbers can run into the millions), their release of chemicals destroys a much larger number of healthy cells and causes additional damage to the interstitial spaces (IS’) membrane.

The addition of more fluids into the IS’ from so many destroyed cells, along with increased inflammation to the IS’ membranes could cause a more rapid onset of inflammation and edema.  This would mean that ischemia would also begin sooner.

What is known is that ischemia blocks many PMNLs from reaching the target area.  When reperfusion begins, many PMNLs reach areas already damaged by the first wave; there they release their chemicals just as programmed, causing even more severe damage to the microvascular systems (MVS’) and IS.

Research has also shown that in IRI, MVS’ are so permeable that migration back and forth between them and the IS’ is easily done.  Evidence of this includes the discovery of large accumulations of PMNLs and PMNL/phagocytes in both the MVS’ and the IS’.

This migration back into MVS’ is the point when IRI begins; adhesive phagocytes entering the capillaries then move on to the venules, where they adhere to the venule walls, permanently plugging them.  

Premature ischemia would also result in trapped PMNLs following blood flow into smaller branch arteries and into MVS they might not have reached as quickly if circulation had been normal (unobstructed).  

Research has also shown that in IRI, phagocyte apoptosis (programmed suicide) does not kill all of them.  Many stay alive until for long periods.

One explanation for this is that phagocyte apoptosis may be activated by the act of capturing and consuming debris.  If so, the absence of millions of bits of pathogens may mean there is not enough debris to go around.

Whatever the reason, some adhesive phagocytes just drift in the IS fluid until a few eventually pass back into the MVS, and then pass into the venules where plugging becomes inevitable.  

It doesn’t take many phagocytes to plug a venule; the MVS are so small that red blood cells can only pass through in single file, and PMNLs are larger than red blood cells.  Even as few as three or four PMNLs are all that are needed.

IRI is not a single event; it has been shown that secondary rounds of IRI can and do take place.  Research in this aspect is limited, most likely because researchers have been interested in how tissue damage extends beyond the original ischemic area, and not in long-term effects of this disorder.

At first glance, there appears to be a major flaw in this explanation; that is the fact that the body heals itself.  Our MVS are constantly being damaged and destroyed.  Each bruise and cut involves the damage and destruction of MVS, but those areas don’t become hypoxic.

Something prevents the normal process of replacing MVS that we know takes place all of the time.  That “something” is oxygen free radicals (OFRs).

OFRs are oxygen molecules that are missing an electron in their outer ring.  This missing electron causes problems beyond the scope of this series; for example, molecules are made up of atoms that bond with one another by their electrons.  All we really need to understand is that this missing electron must be replaced.

The OFR does this by stealing an electron from another molecule, and it does it in .0001 second.  This solution may be good for the OFR but harmful for us.  When the OFR steals an electron its victim must replace it.  The first electron theft starts a chain reaction of 10,000 thefts and replacements per second within the cell.  

OFRs are the chemicals released by PMNLs, and when thousands of OFRS hit a pathogen or soft tissue cell, thousands of chain reactions destroy it instantly.  Not all of the cell matter is destroyed however, and the chain reactions continue in the bits of debris.

These chain reactions continue indefinitely.  When these bits of debris come into contact with other matter, such as new or previously undamaged cells, electrons are stolen and chain reactions begin in the new cells; but not with the destructive power that follows the release of thousands of OFRs at once.  

The material needed to repair the body is mostly carried in the blood.  The cell DNA is found amongst the surviving healthy cells, but that is only a blueprint; the material to build new cells must be brought in.

Even when MVS replacements begin, the constant stop and go of blood flow, as ischemia and reperfusion alternate in an ever-widening area means that FRs damage some repairs that began but were interrupted during these intervals.

Some new MVS are created, but many of them are eventually destroyed.  Still, if free radical damage was complete, all MVS and IS’ in the area would be destroyed and no blood would reach any cells in the area, nor could dead cells be removed.  The result would be cell necrosis and gangrene.

Also, PMNL invasions of MVS are random; there is no programmed pattern of dispersal, so the activated PMNLs don’t enter every MVS.  Some MVS will be invaded by too few PMNLs to cause the gaps necessary to enter the IS.  A minimal amount of blood flow continues, otherwise there would be complete hypoxia.

Ischemia-reperfusion injury appears to be the best explanation for hypoxia in CRPS, but what about symptom migration and trophic changes?  Any explanation of CRPS that doesn’t explain every aspect of this disease is no explanation at all.

The next article will show how OFRs mediate symptom migration, and how hypoxia affects the peripheral nerves responsible for trophic changes.

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Some call it symptom migration, others call it “spread”, but whatever it’s called, no one has published an explanation or description of the mechanism through which CRPS symptoms begin to appear in diverse parts of the body; often several times during the course of this disease.

You may or may not be surprised to read that there is no published research showing any neurological explanation of symptom migration.  In fact, symptom migration is nearly as taboo as cyanosis/hypoxia in SNS literature.

No matter; medical science already knows enough about the behavior of one molecule to explain how CRPS symptoms can emerge spontaneously.  That molecule is the oxygen free radical, and it doesn’t have to go anyplace in order to cause us problems; it’s already there.

In the last article you read about white blood cells, called PMNLs, release thousands of oxygen free radicals (OFRs) against pathogens and cells during the non-specific immune response.   How these huge numbers of OFRs caused thousands of chain reactions within these cells and pathogens, instantly destroying their targets by literally tearing them apart.

And you are about to see that all of the OFRs released during an immune response don’t even come close to the billions of these chain reactions that take place in our bodies every day of our lives.

The vast majority of OFRs are not produced by PMNLs and other white blood cells, but by every cell in our body.  They are the by-products of cell metabolism; whenever the cell needs energy, a mitochondria (the power plant of the cells) combines one molecule of nutrient with one oxygen electron, transforming matter into energy.

Most of our cells need several mitochondria in order to keep up with their energy needs, and each one can produce several OFRs per day.  Some of that energy is needed in order to repair the damage from chain reactions caused by these OFRs.  In CRPS, the energy demands become too great.

I wrote that chain reactions can continue indefinitely, and they appear to do that in ischemia-reperfusion injury, but in our cells, most chain reactions are ended in one of two ways:

Two free radicals (FRs) can meet in the cell, in which case one loses an electron while the other gains one; but both are now in balance again, or;  A free radical will encounter a molecule that can lose an electron without becoming a FR.  

This new molecule is called an antioxidant, and under normal circumstances the body produces enough of them to limit OFRs to the number the body needs (and they are needed for several purposes), but not enough wreak havoc in our cells

CRPS, however, isn’t normal.  Millions of chain reactions are still going on in CRPS (hypoxia) affected areas; some are destroying the MVS’ the body creates in order to heal itself, while many others are on the borderline between hypoxic and healthy cells.

This second group of OFRs constantly attack cells outside the hypoxic area as they come into contact with them, causing new cell damage and expanding the damaged area.  Extra antioxidants are needed there to prevent or at least limit this spread.

Since our bodies can’t produce unlimited numbers of antioxidants, those diverted to the border of hypoxic areas leave less protection for other parts of the body.

Muscle cells consume large amounts of oxygen and nutrients, but unlike internal organs, they aren’t essential to sustain life; they are near the bottom of the list in terms of antioxidant protection.  

With less antioxidant protection, the soft tissue muscles cells must expend more energy to repair oxidative damage.  This, of course, increases the cell’s energy needs, leading to increased OFR production.

At some point in time, at some part of the body, oxidative stress begins to destroy these cells.  The chain reactions, however, continue.  Some continue in the bits of cell debris, and some move to nearby cells.  

Over time, enough cells will be destroyed to produce significant cell debris, and this cell debris will accumulate where the cells are; in the interstitial spaces.  

Eventually, small bits of cell debris will pass into the microvascular system (MVS), and inevitably a PMNL will discover one of these bits and begin a new immune response.  Those who have read the previous articles know what happens next.

Symptom migration is the result of inadequate antioxidant protection.  The reason for this lack of antioxidant protection is the need for extra antioxidants to protect against extensive oxidative damage at already existing CRPS sites.

Up to this point I have talked about research that is easily available on the Internet.  You can go to nearly every search engine, type “non-specific immune response”, and find much more detail than I described in these articles; but you will read that white blood cells, mainly PMNLs, release OFRs that destroy pathogens and cells.

You can find more research involving ischemia-reperfusion injury at Medscape than you will ever want to read.  You will need to learn some new words, of course, but anything that can point you toward a way to stop this disease is worth any effort.

Research about the immune response to trauma, ischemia-reperfusion injury and OFR behavior can be found in many places on the Internet, so I haven’t cited any of it here.  (I will be happy to provide research abstracts about any aspect of the immune response or IRI to anyone who requests them).

Actual research into CRPS is more difficult to find.  The difficulty involves wading through countless abstracts that can best be described as part of the “publish or perish” syndrome of academia; most offer opinions, not research.

In addition to explaining trophic changes in CRPS, the next article will highlight some of this research into CRPS; much of it linking this disease to IRI and OFRs.


Trophic changes are actually called trophoneurotic atrophy (TA) and defined as;  “Abnormalities of the skin, hair, nails, subcutaneous tissues and bone, caused by peripheral nerve lesions”

In CRPS, the first problem is to learn which changes are caused by oxidative damage to the cells vs changes caused by abnormalities of the specific peripheral nerves that affect hair growth/loss and changes structure of bones, nails and skin.  This is not an easy task.

Many diagnosed with CRPS suffer hair loss or report differences in hair structure (thicker, coarser hair).  When the diagnosis is CRPS of the foot, and scalp hair is changed, it is difficult to imagine how nerve damage (whether peripheral or sympathetic), could be involved.

The same can be said of nails, bone, hair and skin of limbs not directly affected by CRPS.  It seems much more likely that these changes outside hypoxic areas are the result of oxidative damage.

Changes in peripheral nerve function within hypoxic areas are easily explained by abnormal nerve responses due to the hypoxia.

These explanations may seem simplistic and need much more detail, but neurotrophic atrophy is almost incidental when compared to the major signs and symptoms of this disease, and even though too brief, they are the only explanations you will find.  

Like symptom migration, research-based explanations of trophic changes by those who hold to the SNS view can’t be found.  A much more detailed discussion of the role of research in the SNS view of this disease will appear in a future article.

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Because they play the most important role the non-specific immune response, I limited my discussion on that topic to OFRs and PMNLs, but other variables are also involved, including antigens such as HLA-DQs.  

In a study of 52 CRPS patients, Kemler found “significantly increased” frequency of these antigens when compared with a control group.  He stated;  “This association provides an indication for an organic basis of RSD”.  The SNS view of this disease denies any organic source.

Mast cells are white blood cells, and they too play a role in the immune response; their presence is fairly easy to detect.  Huygen compared mast cell levels between affected and unaffected limbs of 20 CRPS patients and not only found increased numbers in affected limbs, but the numbers were correlated with reported pain levels [2].

Using 5-phase bone scintography, Leitha found positive correlations between five signs of inflammation (including PMNLs) among CRPS patients.  The author concluded:  “…increased micro vascular permeability and bone metabolism…and blood cell counts are suggestive of a sub acute inflammatory process, even in patients with no overt signs of inflammation” [3].                

Damage to microvascular systems is associated with the immune inflammatory response.  In study using 24 CRPS patients and 25 healthy controls, Schurmann tested arterial, venous and MVS changes.  

In the unaffected limbs of CRPS patients and healthy controls, there were no differences.

All measures were significantly higher among CRPS patients, and Schurman noted that the high CFC contributes to edema formation.  He reports that his findings are in agreement with the hypothesis of an inflammatory origin of CRPS. [4]

Van der Laan, the most prolific researcher into the role of OFRs and IRI in CRPS, injected specific OFRs into the left hind limbs of rats and after killing them, compared them with the right hind limbs of infused rats and both hind limbs of healthy rats.

He noted that the OFRs mediated the immune response, as shown by increased PMNLs in the interstitium (IS); and edema; vascular, and; skeletal muscle damage in the OFR infused left hind limbs.  

There were no changes in the contralateral limbs or in the limbs of the control animals. [5].

Bailey, et al, tested the hypothesis that acute mountain sickness among hikers at high altitude, was caused by OFR damage and hypoxia of skeletal muscle.  Blood samples were collected from hikers at various intervals during the ascent.  Results showed increasing OFR mediated vascular damage of the blood- brain barrier and also systemic tissue damage. [6]

In another rat study, van der Laan again infused the left hind limbs of test rats while infusing saline in the left hind limb of controls; The test animals showed increased temperature and redness of the paw, impaired function and increased pain reactivity in the OFR infused limbs, with no change in controls or contralateral limbs.  Once again, muscle damage in OFR infused hind limbs was visible. [7]

In perhaps his most significant research into microvascular damage in CRPS, van der Laan, et al, examined the above the knee amputated limbs of eight CRPS patients.  Nerves, muscle and MVS were examined by light and electron microscopy.

This research showed histopathological findings of muscle similar to that found in muscle in patients with diabetes, atrophic muscle fiber and severely thickened basal membrane layers of the capillaries (MVS destruction).  

Efferent (away from the brain) nerve fibers showed no changes, while C afferent (toward the brain) fibers showed abnormalities in four patients [8].

Further evidence of OFR involvement is explicit in five studies showing improvement in early stage CRPS with the application of the anti-inflammatory/antioxidant DMSO [9], [10], [11], [12], [13].

Tissue hypoxia (frequently evidenced by cyanotic skin color) is [should be] the most critical sign of CRPS, despite the profound silence from those who cling to the view that this disease is caused by some lesion involving sympathetic nerves.

Sudarim reports;  “Atrophy has been considered to be the most common manifestation of the disease [CRPS].  We catalogued the abnormal skin conditions in RSD by means of chart review.  

“Vascular problems were the most common, followed by inflammatory diseases, infections and atrophic diseases.  Atrophic disease accounts for a minority of skin problems seen in RSD” [14].

In an important study involving perfusion and the sympathetic nervous system, Goldstein, et al, tested 30 patients with single limb CRPS, comparing and contrasting the CRPS affected limb with the other, unaffected side. 14 of these patients had undergone sympathectomies with later resurgence of pain.

Using PET scanning after administration of specific ammonia to assess local perfusion, (blood flow) this team found that patients with chronic CRPS have decreased perfusion of the affected limb.

Fleurodopamine was used to assess sympathetic innervation, and no difference was found between affected and unaffected limbs.  Norepinephrine, a hormone and neurotransmitter released by sympathetic nerves - and its metabolites - were symmetrical in both limbs.

This team, made up of researchers from the National Institute of Neurological Disorders and Stroke (NINDS), concluded:  “These findings suggest augmented vasoconstriction, intact sympathetic nerve terminal innervation, possibly impaired sympathetic neurotransmission, and pain usually independent of sympathetic neurocirculatory outflows” [15].

In investigating tissue pH, Heerschap, et al, compared CRPS affected lower leg muscles of 11 patients with unaffected contralateral limbs and found “A significant increase was observed for the average pH of the muscles of the affected side…”

The team concluded that:  “The impairment of high energy phosphate metabolism, as deduced by the NMR (nuclear magnetic resonance spectroscopy) date, may be caused by cellular hypoxia or diminished oxygen utilization, which would agree with previous findings that oxygen extraction is reduced in extremities affected by reflex sympathetic dystrophy” [16].

All of this combines to provide powerful evidence of OFR involvement and severely diminished blood flow in CRPS.

The next article will discuss research that supports the SNS view of this disease.

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The last six articles presented a great deal of scientific research showing an organic explanation of the symptoms of CRPS.  I didn’t cite sources for the non-specific immune response or ischemia-reperfusion injury (IRI), because this information is available from numerous sources.

Research confirming IRI in skeletal muscle is more difficult to find, and research involving any potential cause for CRPS requires hundreds of hours of reading and rejecting 90% of the published material because it presents only opinions.  Sources for this research information were cited.

Now it is time to look at the science behind the sympathetic nervous system (SNS) view of CRPS.  Just as in the last article, only published research will be used.  Speculation has no place here.

As you will soon see, the difference between this article and the last is that this time I didn’t have a difficult time selecting what to use and what to painfully put aside because there wasn’t space.  

Nearly everyone reading this believes that the sympathetic nervous system (SNS) view of CRPS is scientifically based.  Some, possibly most who read this might believe I deliberately omitted research involving the SNS and CRPS.  It will, I know, be difficult to accept that there isn’t any.

There is research that attempts to link the SNS and CRPS, but this mostly involves changes in some SNS functions in minor areas; none of it even attempting to identify any abnormal SNS activity that could cause this disease.

This sort of research will be included in appendices, which will allow enough space to present the entire abstract and to contrast it with other research and common sense.

It is possible to confirm the absence of research into how the SNS could cause CRPS.  All you need to do is go to Medscape or another medical research source, read each abstract listed, and keep only those that represent actual research.

After reading hundreds of abstracts, you will be forced to concede that there is no research showing that it is even possible, much less proved, that the SNS can cause CRPS.

If such research existed, you would not read these quotes; found in the Clinical Practice Guidelines for the treatment of RSD, published by the Reflex sympathetic Dystrophy Syndrome association of America (RSDSA):


”For reasons we don’t understand, the sympathetic nervous system seems to assume an abnormal function after injury”  or

“Current research suggests that the mechanism by which injury triggers RSD/CRPS is unclear”  (emphasis added)

The National Institute for Neurological Disorders and Stroke (NINDS) puts it more directly:

“The cause of RSDS is unknown... The disorder is unique in that it simultaneously affects the nerves, skin, muscles, blood vessels, and bones”  (emphasis added).

Since I don’t have documentation, I will limit myself to pointing out the fact that the International Association for the Study of Pain (IASP) replaced “reflex sympathetic dystrophy” with “complex regional pain syndrome, type I”

It may be that like the RSDSA and NINDS, the membership of the IASP was forced to take note of the fact that there is no research linking the SNS to CRPS.  

On the other hand, it may not always be possible to track down the precise action that explains the entire constellation of signs and symptoms of a disorder, but it may still be possible to reach a conclusion by a preponderance of evidence.

This requires reviewing the medical literature for research into specific signs and symptoms of CRPS.

Pain is the single most important symptom of CRPS in the minds of those of us who suffer from this disease.  You can find a lot of material that tries to explain CRPS pain, but nothing to explain how the SNS could cause it.  

In fact, all of the pain research you will find involves the peripheral nervous system, not the SNS.

Published research intended to explain how the SNS acts on the body so that that peripheral nerves are activated and send pain messages to the brain just doesn’t exist.

OK, pain is subjective; maybe they can do better with objective signs.

Cyanosis is an objective sign of CRPS.  That blue to purplish skin color means the tissue is not getting adequate arterial blood, or at least not the oxygen and nutrients arterial blood supplies.  

Cyanosis is the most obvious sign of hypoxia.

If research into the role of the SNS in CRPS were to be found, it would be here.  The SNS exerts almost total control over the circulatory system.  If any research has been done in this area, however, it hasn’t been published.

Symptom migration is one of the truly terrifying signs in CRPS.  It means more pain, more disability and less hope.  There is no evidence that anyone has ever researched a potential role for the SNS in symptom migration.

It could be argued, I guess, that “sympathetically maintained pain” (SMP) confirms a role for the SNS in CRPS, but no one has researched it.  In fact, there is no evidence that SMP is real.

The entire argument for SMP is based upon the fact that sympathetic blocks either don’t work on some patients or that they lose effectiveness over time.  When blocks stop working, you no longer have SMP.  That is speculation, not science.

The bottom line, in my mind at least, is that no one has bothered to research these things.  Medical technology has advanced to the point where single nerve impulses can be tracked, yet no one has tested the SNS.  Or if they did, they didn’t publish it.

The next article will return to science, as I present research showing how hyperbaric oxygen therapy (HBOT) is used to treat ischemia-reperfusion injury, and how IRI explains why some CRPS benefit from HBOT, while for others it is a disaster.                                                                                  

I dont have the next article, not sure if he completed it.  

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Vic!

Ya know, this would be enough in any major college to earn a doctorate. I mean you researched this, then wrote a paper that could have earned you your degree it is that good.

 :giggle