Information on RSD spreading

By Dr. Schwartzman!

Note: This article explains some theories about how RSD works. This is a current working definition based on the best animal research that has been done to date. Nobody can say that this is definitely the way RSD works but it is the best that many researchers know. This is a very technical and difficult article. If you get lost, please read each sections called Remember and you will get a general idea about what is being discussed.

The information for this article comes from a tape of Dr. Schwartzman's presentation at the RSDS Association of America's first conference in October of 1995. Chapters by Dr. Schwartzman in 1) Vascular Medicine, 1995 2) Handbook of Clinical Neurology: Vol.17 (61), Chapter 7 pg.121-136 Spinal Cord Trauma, and information obtained from previous articles including studies that have been done with RSD patients throughout the years.

*<^>*<^>*<^>*<^>*<^>*<^>*<^>*<^>*<^>*<^>*
Reflex Sympathetic Dystrophy (RSD) is a agonizingly painful condition which causes edema, difficulty with motor function, changes in the way the nervous system functions and in the late stages affecting the immune system. The pain of RSD consists of a variety of different pain. The most common and consistent pain is a severe burning. This burning is the neuropathic pain that has become the landmark of RSD. The other pain has been described as: stabbing, tearing, crushing, bursting, or throbbing pain felt deep in the affected part. Many describe the pain as exhausting and causing the patient to feel wretched and miserable. The autonomic nervous system affects blood vessels, endocrine system, and the functioning of all of the organs in the body. The motor function problems can be divided into two major areas 1) spasms or myoclonic jerks and 2) problems with initiating movement. (RSD doesn't cause paralysis.)

Not much is known about how RSD affects the immune system but in the late stages (stage 3 & 4) RSD, resistance is decreased and the ability to recover from infection is severely limited. Most of the research on RSD's affect on the immune system is being done in Europe. Dr. Steven Felton at the University of Rochester, Medical School has been studying these effects. He was a presenter at the "Living With RSD" conference on Oct. 22 1996. (See article)

The Spinal Cord is where it all occurs. Pain is carried through the spinal cord, and the animal research on RSD has shown that many chemical reactions change the cells in the spinal cord. These causing the pain of RSD to become Sympathetically Independent (SIP) rather than being dependent on the sympathetic nervous system (Sympathetically Maintained; SM). Because of all of these changes we know that the spinal cord is where interference with this process can occur. For years we have known that spinal cord simulators and intrathecal pumps with morphine can lessen the pain and halt the changes in the cells that RSD pain can precipitate.

The amount and type of pain is directly related to the type of nerve fibers that fire, and the frequency with which they fire. Nerve fibers in layer 1 and 2 of the dorsal horn section in the spinal cord cross with nerve fibers in the 5 and 6 layers (rexus layer) of the spinal cord forming the spinothalamic track. These fibers include the neurons that carry pain messages. When these fibers cross, the chemical reaction that allows the pain stimuli to travel the rest of the way to and from the brain occurs. We know that cells in the rexus layer of the spinal cord (5th & 6th layers) have connections to cells both above and below them. When the pain becomes severe enough, it spreads to these connections and out of the segment of the spinal cord in which it was concentrated. This spread does not follow the classic dermatomes (routes that somatic nerves travel), instead causes an abnormal spread of inflammation to cells surrounding the segments of the spinal cord that is carrying the pain. This is the “exquisiteness" of RSD pain, it's ability to spread. This also explains why many physicians who have not studied RSD are stumped by the fact that the pain does not follow a dermatome.

Spinal nerves run in pairs. There are 31 pairs that enter the spinal cord from the rest of the body. Each pair has a dorsal root (controlling sensory and/or pain perception) and a ventral root (controlling motor function). These come together to form the spinothalamatic tract and here the messages can be shared between pain neurons and neurons that control the function of movement. The Dorsal Root Ganglion (DRG) is where all of the individual sensory nerves are gathered, just outside of the spinal cord. It sits in the exit area for all of the peripheral nerves. The Ventral root ganglion is where the motor nerves come together. In the ganglion, nerve fibers receive instructions before the nerve impulses travel to the brain or to other parts of the body carrying messages that make us move, feel or think.


*<>**<>*<>*<>*<>*<>*<>*<>*<>*<>*
REMEMBER:

1) Fibers from layers 1 & 2 of the spinal cord cross with fibers from layers 5 & 6 forming the spinothalamic tract. The crossing of these fibers allows the pain signals to be carried to the brain.

2) The amount of pain the frequency that the pain projecting neurons fire.

3) The type of pain that is felt is controlled by the type nerve fibers that are firing. (C-nociceptor Fibers carry burning pain, the A nerve fibers carry the dull aching pains.

There are many ways to get RSD. Theses precipitating events may be: an accident; illness; or iatrogenic event (when injury is caused by medical treatment). Fifty percent of all RSD cases are caused by a minor, soft tissue injury such as sprains, that also injure c-nociceptor and/or A nerves fibers. When these nerve fibers are injured, the pain is immediately more severe than that level of injury should cause. We know that the injury of these peripheral nerve fibers somehow causes the sympathetic nervous system to carry pain, which it normally does not. Some physicians believe that the C or A nerve fibers are firing so hard and fast that they mechanically cause the sympathetic nerves, which lie very close to the C or A fibers, to fire. This is known as Sympathetically Maintained pain (SM). Later, as the chemical reactions occur, the sympathetic nervous system no longer carries the pain. It is said to become “Sympathetically Independent Pain” (SIP). RSD is caused by the injury of peripheral nerve fibers and the fact that the pain becomes chronic. Peripheral nerve fibers carry the pain stimulus into the Dorsal Horn, (DH) which then stimulates the Dorsal Root Ganglion (DRG). Dr. Bennet has shown that if you block the c-nociceptor fibers that carry the pain into the DH, you can change the physiology of the pain cycle. This prevents the switching of these pain signals when lamina 1 & 2 fibers cross with lamina 5 & 6 nerve fibers. These changes result in an end to the pain. RSD becomes an irreversible condition when the pain stimulation in the DH and DRG cause the release of neuropeptides. The neuropeptides change the genetic makeup of the cells in the spinal cord and central nervous system. Pain triggers this process and the release of the neuropeptides is the catalyst. Once these chemical reactions actually change the genetic character of areas of the spinal cord, the pain becomes SIP.

1) Allodynia is pain due to a stimulus that does not usually cause pain. Allodynia takes a stimulus that should not cause pain and changes it to a painful one. A shirt sitting on your arm should not cause pain, but for those with allodynia, it is very painful.

2) Hyperalgesia occurs when there are too much pain impulses from a stimulus. The pain is magnified. This is different than allodynia, in that these are stimuli that normally cause pain, but the stimuli cause the C-nociceptor nerve fibers to fire too easily, causing increased pain.

3) Hyperpatheia occurs when difficult to feel stimuli occurs, and once the threshold is passed, the pain reaches a maximum intensity quickly. The pain is overwhelming and does not stop when the stimulus is removed. A repetitive stimuli, such as the stroking of an arm, increases the hyperpatheia. This is a most horrific pain that usually comes in late stage RSD and is generated from the central nervous system. Most people with RSD have all three types of pain. We need to know how these types of pain work so we can control them. Most of the information that follows has been discovered recently through research that has been conducted on the animal models of RSD. Dr. Bennet of the NIH (National Institute of Health) discovered how to induce RSD in rats about 7 years ago. Since this discovery, research of RSD and neuropathic pain has taken off. The results of this research, may lead to a cure or control of these overwhelming painful conditions.

When there is an injury, inflammatory substances such as bradykynins and prostaglandin are released in the area of the injury. These chemicals are synthesized by activity between the tissues and white blood cells that come to heal the injury. There are large lists of chemicals, (seritonin, hydrogen ions, potassium) which are released in the area of an injury. Sensitizations of c-nociceptor nerve fibers cause the threshold to be lowered. The lowered threshold make these nerve fibers fire more frequently causing more intense pain. The cycle just described and is shown in Chart #1. These chemical reactions start the vicious pain cycle that runs RSD. It is this chronicity of pain that causes RSD to develop from a minor injury to an injury with sensitized nerve fibers and permanent changes in the cells of the dorsal root in the spinal cord. Constant noxious peripheral stimulation (from damaged c-fibers) in the spinal cord can cause the neurophysical phenomena of sensitization that is when the pain fibers fire too easily. The spinal cord around the sensitized nerve fibers changes. This sensitized area touches areas around it causing the nerve fibers adjacent to the sensitized area to fire more easily thus causing a larger sensitized area and the spread of the pain to new areas of the spinal cord and body. This spread causes "the wind-up" phenomena, which occurs when the c-nerve fibers are sensitized in the dorsal horn. This causing them to fire many times for each pain stimuli that are received. The wind-up phenomenon is responsible for the constant pain of RSD and explains how hyperpathia occurs. This is one of the areas researchers are trying to interfere with the cell firings. Damaged nerves in the area of injury and in the peripheral nervous system try to regenerate by growing nerve sprouts. These new sprouts fire too easily and allow too much sodium to enter the nerve sprouts. The excess sodium increases the sensitivity of these sprouts lowering the threshold. This causes multiple nerve firings for each stimulus received. These sensitive nerve sprouts give off alpha-adrogenic receptors, which stimulate the sympathetic nerves to fire and carry pain. This sympathetic stimulation drives RSD in the early stages. The development of the nerve sprouts is the body trying to heal itself. Instead the new nerve sprouts actually cause more problems. In a normal state the sympathetic nerves do not carry pain stimuli but the sensitization of these nerves by the alpha adrogenic receptors and the chemical reactions caused by chronic pain (explained above) cause the up regulation of the sympathetic system and allows it to carry pain stimulus.

*<>*<>*<>*<>*<>*<>*<>*<>*<>*<>*
REMEMBER: The sympathetic nervous system is trying to heal by releasing white cells and helping the injured nerve regenerate with new nerve sprouts. The intensity and chronicity of the pain causes chemical reactions that change the nature of the sympathetic nervous system that allows it to carry pain during the early stages of RSD. One of the medications effectively used to stop RSD during the very early stages are Steroids. They reduce the inflammation and take away the inflammatory chemicals that begin the whole process of RSD. Dr. Franklin Kozin studied the benefits of early steroid therapy in the 1980's. Take an injury scenario: A twisted ankle causes the C fibers to send pain signals. If they go through a normal process the pain stops, which is acute pain. A twisted ankle causes swelling with all of the inflammatory mediators (bradykins, postaglandins, etc.) If C-nociceptor or A nerve fibers are also injured the inflammatory chemicals react with the white blood cells causing the injured nerve fibers to fire more easily. Nerve sprouts that are trying to replace the injured nerve fibers become sensitized and fire too easily. These pain fibers release substance P (neuropeptide). This causing the partial depolarization of the pain nerve fibers in the spinal cord, making them easier to fire. These nerve fibers do not fire completely which allows other neurotransmitters (which normally cannot fire a pain nerve) to fire the pain nerve fibers.

Calcium occurs outside the neuron until the partially depolarized neurons allows excess sodium to enter the cell lifting the magnesium block in the neuron. Lifting this block activates the NMDA receptors that allow the endogenic calcium into the cell turning on chemical cascades. Part of this cascade turns on the phosphokinase C cascade which turns on the immediate cell response. This causes release of proteins, which change the genetics of the spinal cord cells. This genetic change causes RSD to be irreversible. During these chemical and genetic changes, the part of the neuron known as the amper receptor. (Amper receptors accept the pain stimulus and normally turn it off. This keeps the pain from becoming chronic because each stimuli is actually turned off.) These receptors are destroyed. Now the "wind up" phenomenon can occurs, allowing each stimuli to cause repeated pain responses.

This all sounds very technical, though it is important to realize the complexities of the chemical responses. At any one of these junctures a medication can stop the process and not allow the pain impulse to travel up the spinal cord to the brain (i.e. NMDA receptor antagonists prevent the "wind up" phenomenon in the spinal cord).

*<>*<>*<>*<>*<>*<>*<>*<>*<>*<>*

REMEMBER: Chronic pain turns on cascades of deleterious chemical reactions within the neuron (nerve cell). These chemical reactions then turn on an immediate cell response that causes production of proteins and these proteins change the genetic makeup of the cells. This destroys the amper receptors that stop the transmission of some pain fibers and allowing the pain fibers to fire many times for each stimulus. Said in the simplest of terms: Chronic pain turns on the production of new genes in the cells which is how RSD becomes an irreversible disease.

There are plenty of places to stop the process and keep the damaging calcium out of the neurons. Every chemical reaction has to have a stimuli and a receptor site. The reactions can be blocked at either site. Many chemicals such as 1-Zinc glycene, PCP receptors, Ketamine and other drugs will most probably work. Ketamine, an NMDA inhibitor is the most promising but when it was brought out into clinical trials, the Ketamine also activates natural PCP receptors, which causes hallucinations. Dextromethorphan (decks-tro-meth-OR-fan) is another NMDA inhibitor that has been released as a cough suppressant. It is not strong enough to stop pain though it can cause hallucinations. Some researchers think that it may also be withdrawn from the market, as some persons are abusing the cough syrup to get high. This can cause other damage. If Ketamine or another NMDA inhibitor can be modified it may stop the NMDA receptor from accepting the calcium in the neuron. This could effectively stop the deleterious chemical cascade and the amper receptors would remain active.

Centralized pain may be caused by a two-step process:

1) Chronic pain can turn on genetic material in the cells of the pain carrying neurons. These cells are sensitized and send multiple pain stimuli for each firing of the pain carrying neuron. These cells may also signal pain when it should not. (allodynia)

2) These chemical reactions can kill the inhibitory neurons in the spinal cord by killing the amper receptors and blocking the chemical reactions that bring out natural endorphins. A graphic way to understand this is use this image: There are umbrellas (amper cells) in your spinal cord. When the umbrellas are open, many of the pain signals that your peripheral nerves send are caught in the umbrellas and never reach the brain. Close the umbrellas (kill the amper cells) and every pain spinal will get through allowing you to feel more pain than the average person.

Dr. Hooshmand and many other physicians are against the use of narcotics for RSD patients. They feel that the narcotics kill the body’s natural defense against pain. Maybe they do but it looks like those natural pain-killing factors (amper receptors and endorphin) may be being destroyed in the development of the centralized or SI pain that characterizes the late stages of RSD. Oral narcotics help to lessen the severity of not only the pain but also the other effects of the RSD. A growing body of evidence indicates that selected patients may obtain enhancement of physical and psychological function simultaneously with the long-term use of narcotics. Eight percent of the patients in these studies suffer from neuropathic pain and their results were the same as the patients with lower back pain and headaches.

We know that Intrathecal morphine pumps stop the pain and actually help reverse the other symptoms of RSD. Animal studies have shown that the opioids actually inhibit the calcium from entering the cells in the DRG. The opioids work even at very high voltages and when the nerve fires the opiates bring the nerve back to its normal resting voltage, and help maintain it there for a period of time. Studies have also shown that morphine limits the amount of plasma that leaks into the tissues thus lessening the edema. Naloxone, the antidote for morphine reverses this effect. Oral delivery of opiates uses up much of the drugs potential effects before it gets to the spinal cord and the DRG but some of the medication does get there. It is believed that the spinal cord stimulators help increase the natural inhibitors of the cells in the spinal cord. We have discussed the mechanism of the most prevalent symptom of RSD-PAIN- but we need to look at where the other symptoms come from.

EDEMA- A major component of RSD especially early in the disease is edema. This swelling can be seen at the injury site, distal to it and over major portions of the body. Often the edema has a ligature mark: a definite line above which there is no swelling and below which is often massive edema. RSD is the only disease that has a definite ligature sign. Physicians who aren't familiar with RSD often point to the ligature mark to prove that RSD is a psychological condition. It actually may look as if the patent has tied something very tight on the limb to cause the swelling. Even Dr. Schwartzmam admits that he accused the first RSD patient that he saw with a ligature make of causing her own swelling. Reflex Neurogenic Inflammation (edema of RSD) is believe to be caused because the DRG releases SP which goes to the peripheral and central nerve terminals and areas of the spinal cord. A stimulus from the nerve causes the SP to be released. SP causes the capillaries to be permeable and leak. When SP is release, histamines and the Calcium Gene Related Peptide (CGRP) are also released. Histamines potentates (enhances) the effect of the SP and causes more plasma to leak. CGRP inhibits the smooth muscles, preventing the uptake of the fluid so you are left with fluid leaking from the arteries and no way of pumping the fluid out. Lack of the ability to walk, wear compression stockings and a compromised lymph system contribute to this problem. When a small amount of saline was injected into the hind paw of a rat for three consecutive days, swelling is seen in the ipsilaterally (other limb on the same side) as well as in the contralateral hind limb. Sympathectomy and destruction of the c-nociceptor fibers in the sciatic nerve of either hind paw will lessen the contralateral response. The process that causes the edema in different areas of the body seems to be mediated at the spinal cord level and by the sympathetic nervous system during the early stages of RSD. Remember the edema of RSD is present because Substance P causes the blood vessels to leak and Calicatonin G Related Peptides (CGRP) prevent the smooth muscles from pumping the fluid out of the extremity.

MOVEMENT DISORDER

The movement disorders of RSD have been well described within the past few years. These disorders consist of: an inability to initiate movement; weakness; tremor; muscle spasms; dystonia, and increased reflexes. They may come before the pain and they are frequently seen on the contralateral side of the body. Even as early as the Civil War, Dr. J. Mitchell Weir saw that there was an apparent spread of the pain and motor disturbance to the "mirror image" limb.

Sympathetic blockade will alleviate these motor manifestations. If not treated early, they may become permanent because the motor disorders as well as the pain become independent of the sympathetic nervous system.

1) Dystonia is a term used to describe a neurologic disorder characterized by sustained involuntary muscle contractions and spasms that result in abnormal postures and movements. In the dystonia caused by RSD, you will often find a contracted or hyperextended hand, foot, finger or toe. These contractures remain in sleep. Even the facial muscles have become dystonic in some patients.

What causes the dystonia of RSD? To move any part of the body, you need two muscles that work in opposition to each other. One causes the wrist to bend the other straightens it out. When one muscle gets strong and the opposite one weak a contracture or extension will happen. *The sympathetic innervation during the early stages of RSD causes the release of too much norephedrine causing type I or aerobic muscle to get weak. Type 2 (anaerobic) muscles get hyperactive. This is called the Orbelli effect.

Dystonia can often be treated by injections of Botox, which is a very minute amount of the botulism toxin. It weakens the muscle that is too strong by actually causing a very localized nerve block that permanently destroys some of the over tight muscle fibers.

2) RSD does not cause paralysis. The nerve impulses that cause movement do get to the limb even though there may be a delay in the order to begin the movement This may become apparent when a person is walking. Each foot moves forward so quickly when the brain sends the proper signal that we move without a thought. If there is a delay between the brain and movement of the leg, a person will fall because the forward movement of the body will continue without a leg to take the weight. I found that I was falling often and didn't know why until a friend was watching me walk when he observed the delay in action and my fall.

3) Increased tone/spasms occurs when the sympathetic system is activated and it secrets neuropeptides. The sympathetic nerves innervate the muscles and these chemicals cause the muscle spindles to shorten thus increasing the tone in muscles. Some RSD’ers have muscle wasting in their affected limb and for some of us the increased tone actually causes the muscle to be bulkier even though it is weak.

AUTONATIC DYSFUNCTION is evident throughout the course of RSD. Early in the disease the involved limb is usually warm, red and dry but with time it becomes cool, pale, sweaty and cyanotic. Often the discoloration, and mottling of the skin may be seen in the contralateral limb. These symptoms appear to be caused by the peripheral nerve injury, chronic pain and chemical reaction that occur in the injured limb but no one is exactly sure how this happens. Early in the disease vasoconstriction of the blood vessels may be caused by a hyperactive sympathetic system. Vasoconstriction causes a cold limb. When the RSD becomes SI, the vasoconstriction may be caused by the chemical reactions that we discussed earlier, namely an increase of epinephrine. SP still causes blood vessels dilate.

There have been many studies done that show that there is a central reorganization of the sympathetic nervous system. Normally throughout each day the blood vessels dilate and constrict in a rhythmic fashion causing the small vessels to go up and down spontaneously. This helps regulate the temperature of the skin. After this reorganization the rhythmic dilation and constriction stop and other things control the dilation and constriction of the blood vessels. The release of epinephrine as mention above is one.

Many people that who have RSD state the environmental temperature changes the temperature of the affected limb. When the temperature is over 85, many times the skin in the affected side becomes hot and red. There is a test that will show whether the reorganization has taken place. Put one limb in a bucket of ice. The normal sympathetic system will allow only the limb in the ice to vasoconstrict, the rest of the limbs stay warm. If the sympathetic nervous system has already reorganized, a person with RSD will find that all of his/her limbs constrict. This is because the central mechanisms of the Sympathetic

Nervous System have been damaged. Dr. Schwartzman believes that when the limbs change temperature, what we are actually seeing as a warfare between the neuropeptides such as Substance P which causes vasodilation and the sympathetic system adrenergic receptors which let off epinephrine which causes vasodilation. There are time when a person with the ABC syndrome of RSD with cross temperature modulation can have one finger hot and the next cold.

AUTOIMMUNE DISORDERS

The autoimmune response of RSD has not been very well researched but we see the symptoms of a compromised system in the late stages of RSD. Most of this research is happening in Europe. The symptoms that show that the Autoimmune system has been compromised are:

1) Gardner Diamond syndrome- This appears as large discolored areas that look like a raised welt. It is caused by a reaction to your own blood when some of the blood leaks into the tissue

2) Chronic Infections: too many infections and the ability to fight the infections become compromised.

3) Tissue Necrosis Factor is an autoimmune attack on your own skin. Collagen doesn't work and the skin sloughs off in the areas affected.

4) Fever of unknown origin is caused by the lymphocytes that go to the hypothalamus (area of the brain that controls many of our body’s functions & emotions) and affect the temperature. Remember: that RSD causes movement disorders, changes in the autonomic nervous system and the autoimmune system in people who suffer from this syndrome. Many of these symptoms seem impossible to physicians who are not familiar with RSD and the odd symptoms may cause many doctors to feel that you are faking it. Research will continue to bring us answers that will convince most physicians that we really do suffer as we say we do. It will just take time. RSD DOES SPREAD: Besides the sensitization and spread of the pain in the spinal cord that we discussed earlier, most of these ideas about how RSD spreads have not been researched. There seems to be an overall sensitization of the sympathetic system so that new injuries can cause the spread of RSD. Injuries as slight as an IV being put into a healthy limb or using crutches, which stretches the brachial plexus, can cause this spread of RSD.

Dr. Schwartzman believes that the spread of RSD can be prevented by: 1) Blocking the nociceptor pain. (2) Actually correcting when possible but definitely blocking the pain source so active physical therapy can be started. (3) This physical therapy is not just for mobility. What it will do is change the molecular genetics and prevents the firing of the pain nerve fibers from going through other nerve fibers through retrograde transport to carry the pain fibers.

Dr Schwartzman believes that even many cases of severe RSD can be corrected if the pain can be controlled so that movement and active Physical Therapy can be done.

Remember: So much has been learned about how pain in general and RSD works. This is very promising because the more we know the closer we are to finding a medication to stop the transmission of the pain. The best hope is with the NMDA receptors. The only problem is that the NMDA receptors are needed to think, feel and do all the functions of life and the medication needs to target only the specific NMDA receptor sites that carries pain or it can cause all types of problems such as hallucinations.