CRPS: Inflammatory, Neuropathic and Immunologic?

Researchers Continue To Look for Basic Understanding of CRPS Causes

Toronto—Researchers tasked with developing a rudimentary understanding of complex regional pain syndrome (CRPS) are dividing their attention in several different directions. According to several experts who spoke at the 2013 International Congress on Neuropathic Pain, there is evidence for inflammatory, neuropathic and immunologic roots to the enigmatic syndrome, and further investigation into these three aspects of the syndrome is necessary for the development of more effective treatments.

“These different contributing factors all influence each other, so we need to address all of them so that patients don’t get onto a downward spiral where each factor worsens another,” Anne Louise Oaklander, MD, PhD, associate neurologist at Massachusetts General Hospital and associate professor at Harvard Medical School, both in Boston, told Pain Medicine News after attending the panel discussion.

Not a Perfect Fit

Ralf Baron, MD, vice chair of the Department of Neurology and head of the Division of Neurological Pain Research and Therapy at the University Hospital Schleswig-Holstein in Kiel, Germany, told attendees that until recently, CRPS was understood to be clearly a neuropathic pain disorder. However, CRPS does not fit with the 2008 redefinition of neuropathic pain, defined as “pain arising as a direct consequence of a lesion or disease affecting the somatosensory system” (Neurology 2008;70:1630-1635).

“CRPS is neuropathic in that there are characteristic neuropathic sensory abnormalities, but it also shows signs of central sensitization, inflammation, and autonomic and motor abnormalities,” Dr. Baron told attendees.

One way of grouping CRPS patients is by looking at their distinct somatosensory dysfunctions, Dr. Baron suggested. Individuals with deficits in temperature detection but no allodynia, and with loss of small nerve fibers, innervation and nerve degeneration, can be classified as having a neuropathic disorder. A second cluster of patients can be seen as having central sensitization, with normal temperature sensitivity but severe mechanical and thermal hyperalgesia. A third patient cluster may have inflammatory CRPS, with deep hyperalgesia and heat hyperalgesia but no hyperalgesia to prick testing, Dr. Baron explained.

An Autoimmune Disease?

Another way of understanding CRPS, proposed by Andreas Goebel, MD, PhD, senior lecturer and honorary consultant at the University of Liverpool and Walton Centre National Health Service Foundation Trust in Liverpool, United Kingdom, is that a subset of CRPS patients have an autoimmune disorder–related condition.

“It is possible that a regional immune response is triggered following stress, inflammation and trauma,” he posited.

Dr. Goebel believes some of the 15% of CRPS patients with refractory symptoms lasting longer than six to 12 months may fall into this group (Pain 2009;142:218-224). He noted that several studies support the autoimmune paradigm, with results showing that a subset of CRPS patients have elevated levels of serum antibodies to several bacterial pathogens.

“Furthermore, there is evidence for CRPS serum immunoglobulin binding to peripheral nerves,” he said (Neurology 2004;9:1734-1736).

Indeed, several small case series, including his own, have demonstrated the efficacy of intravenous immunoglobulin G (IgG) in subsets of patients with long-standing, refractory CRPS, Dr. Goebel said (Pain Med 2002;3:119-127). Additionally, a randomized controlled trial of 12 patients with long-standing CRPS who received the agent found that 25% had pain relief at least 50% relative to baseline and 17% had improvements in pain between 30% and 50% (Ann Intern Med 2010;152:152-158).

Although IgG has anti-inflammatory effects in addition to being an immunomodulator, Dr. Goebel believes IgG’s efficacy is likely not explained by its anti-inflammatory effect.

“All of the investigations which we have done, both in the lab and clinically, have been leaning more and more toward confirming there is an autoimmune aspect to CRPS,” Dr. Goebel concluded. “However, since we do not know which structures the autoimmune response is targeting, our current evidence remains somewhat indirect.”

According to Dr. Goebel, if some patients in fact have CRPS of autoimmune origin, “a range of potential therapies, such as therapeutic plasma exchange and B-cell modulating therapies, can be at our disposal.

“These have all been tried and tested in other autoimmune disorders, and we can have access to an armamentarium that we did not have before,” he said.

An “Ultralocal” Inflammatory Response?

Frank Huygen, MD, PhD, professor of anesthesiology at Erasmus Medical Center in Rotterdam, the Netherlands, argued the inflammatory component to CRPS could be the most clinically meaningful element of the syndrome in some patients. However, rather than looking for systemic inflammation, he believes researchers need to consider an “ultra-local” inflammatory response.

“There are inflammatory mediators that are increased in the blister fluid of an involved extremity in CRPS,” Dr. Huygen said.

His own research has documented increased levels of interleukin-6 and tumor necrosis factor (TNF)-alpha in some patients (Eur J Pain 2008;12:716-721).

In a small, placebo-controlled, randomized trial, Dr. Huygen and his colleagues showed that the anti-TNF drug infliximab (Remicade, Janssen) exacerbated symptoms in some CRPS patients, leading to discontinuation of the trial (Pain Pract 2013; May 22: doi: 10.1111/papr.12078). The researcher still believes there could be a role for infliximab and other biologics in the treatment of CRPS.

“Although the sponsor stopped the study early, preliminary data showed enormous reductions in TNF-alpha levels in blister fluid with infliximab treatment, but these did not correlate with clinical changes,” he said.

Summarizing the challenge of understanding and treating a complex syndrome, Dr. Baron suggested CRPS should no longer be seen monolithically as a neuropathic disorder.

“As long as we do not have a clearer pathophysiological picture of CRPS patients, and because of the obvious heterogeneity of the signs, symptoms and mechanisms of the syndrome,” he said, “it would be wise to look at the condition separately from other classical neuropathic pain syndromes.”

—David Wild

THE SUPPRESSED SPEECH OF WAMSUTTA (FRANK B.) JAMES, WAMPANOAG

THE SUPPRESSED SPEECH OF

WAMSUTTA (FRANK B.) JAMES, WAMPANOAG

To have been delivered at Plymouth, Massachusetts, 1970

ABOUT THE DOCUMENT:
Three hundred fifty years after the Pilgrims began their invasion of the land of the Wampanoag, their "American" descendants planned an anniversary celebration. Still clinging to the white schoolbook myth of friendly relations between their forefathers and the Wampanoag, the anniversary planners thought it would be nice to have an Indian make an appreciative and complimentary speech at their state dinner. Frank James was asked to speak at the celebration. He accepted. The planners, however , asked to see his speech in advance of the occasion, and it turned out that Frank James' views — based on history rather than mythology — were not what the Pilgrims' descendants wanted to hear. Frank James refused to deliver a speech written by a public relations person. Frank James did not speak at the anniversary celebration. If he had spoken, this is what he would have said:

I speak to you as a man -- a Wampanoag Man. I am a proud man, proud of my ancestry, my accomplishments won by a strict parental direction ("You must succeed - your face is a different color in this small Cape Cod community!"). I am a product of poverty and discrimination from these two social and economic diseases. I, and my brothers and sisters, have painfully overcome, and to some extent we have earned the respect of our community. We are Indians first - but we are termed "good citizens." Sometimes we are arrogant but only because society has pressured us to be so.
It is with mixed emotion that I stand here to share my thoughts. This is a time of celebration for you - celebrating an anniversary of a beginning for the white man in America. A time of looking back, of reflection. It is with a heavy heart that I look back upon what happened to my People.
Even before the Pilgrims landed it was common practice for explorers to capture Indians, take them to Europe and sell them as slaves for 220 shillings apiece. The Pilgrims had hardly explored the shores of Cape Cod for four days before they had robbed the graves of my ancestors and stolen their corn and beans. Mourt's Relation describes a searching party of sixteen men. Mourt goes on to say that this party took as much of the Indians' winter provisions as they were able to carry.
Massasoit, the great Sachem of the Wampanoag, knew these facts, yet he and his People welcomed and befriended the settlers of the Plymouth Plantation. Perhaps he did this because his Tribe had been depleted by an epidemic. Or his knowledge of the harsh oncoming winter was the reason for his peaceful acceptance of these acts. This action by Massasoit was perhaps our biggest mistake. We, the Wampanoag, welcomed you, the white man, with open arms, little knowing that it was the beginning of the end; that before 50 years were to pass, the Wampanoag would no longer be a free people.
What happened in those short 50 years? What has happened in the last 300 years? History gives us facts and there were atrocities; there were broken promises - and most of these centered around land ownership. Among ourselves we understood that there were boundaries, but never before had we had to deal with fences and stone walls. But the white man had a need to prove his worth by the amount of land that he owned. Only ten years later, when the Puritans came, they treated the Wampanoag with even less kindness in converting the souls of the so-called "savages." Although the Puritans were harsh to members of their own society, the Indian was pressed between stone slabs and hanged as quickly as any other "witch."
And so down through the years there is record after record of Indian lands taken and, in token, reservations set up for him upon which to live. The Indian, having been stripped of his power, could only stand by and watch while the white man took his land and used it for his personal gain. This the Indian could not understand; for to him, land was survival, to farm, to hunt, to be enjoyed. It was not to be abused. We see incident after incident, where the white man sought to tame the "savage" and convert him to the Christian ways of life. The early Pilgrim settlers led the Indian to believe that if he did not behave, they would dig up the ground and unleash the great epidemic again.
The white man used the Indian's nautical skills and abilities. They let him be only a seaman -- but never a captain. Time and time again, in the white man's society, we Indians have been termed "low man on the totem pole."
Has the Wampanoag really disappeared? There is still an aura of mystery. We know there was an epidemic that took many Indian lives - some Wampanoags moved west and joined the Cherokee and Cheyenne. They were forced to move. Some even went north to Canada! Many Wampanoag put aside their Indian heritage and accepted the white man's way for their own survival. There are some Wampanoag who do not wish it known they are Indian for social or economic reasons.
What happened to those Wampanoags who chose to remain and live among the early settlers? What kind of existence did they live as "civilized" people? True, living was not as complex as life today, but they dealt with the confusion and the change. Honesty, trust, concern, pride, and politics wove themselves in and out of their [the Wampanoags'] daily living. Hence, he was termed crafty, cunning, rapacious, and dirty.
History wants us to believe that the Indian was a savage, illiterate, uncivilized animal. A history that was written by an organized, disciplined people, to expose us as an unorganized and undisciplined entity. Two distinctly different cultures met. One thought they must control life; the other believed life was to be enjoyed, because nature decreed it. Let us remember, the Indian is and was just as human as the white man. The Indian feels pain, gets hurt, and becomes defensive, has dreams, bears tragedy and failure, suffers from loneliness, needs to cry as well as laugh. He, too, is often misunderstood.
The white man in the presence of the Indian is still mystified by his uncanny ability to make him feel uncomfortable. This may be the image the white man has created of the Indian; his "savageness" has boomeranged and isn't a mystery; it is fear; fear of the Indian's temperament!
High on a hill, overlooking the famed Plymouth Rock, stands the statue of our great Sachem, Massasoit. Massasoit has stood there many years in silence. We the descendants of this great Sachem have been a silent people. The necessity of making a living in this materialistic society of the white man caused us to be silent. Today, I and many of my people are choosing to face the truth. We ARE Indians!
Although time has drained our culture, and our language is almost extinct, we the Wampanoags still walk the lands of Massachusetts. We may be fragmented, we may be confused. Many years have passed since we have been a people together. Our lands were invaded. We fought as hard to keep our land as you the whites did to take our land away from us. We were conquered, we became the American prisoners of war in many cases, and wards of the United States Government, until only recently.
Our spirit refuses to die. Yesterday we walked the woodland paths and sandy trails. Today we must walk the macadam highways and roads. We are uniting We're standing not in our wigwams but in your concrete tent. We stand tall and proud, and before too many moons pass we'll right the wrongs we have allowed to happen to us.
We forfeited our country. Our lands have fallen into the hands of the aggressor. We have allowed the white man to keep us on our knees. What has happened cannot be changed, but today we must work towards a more humane America, a more Indian America, where men and nature once again are important; where the Indian values of honor, truth, and brotherhood prevail.
You the white man are celebrating an anniversary. We the Wampanoags will help you celebrate in the concept of a beginning. It was the beginning of a new life for the Pilgrims. Now, 350 years later it is a beginning of a new determination for the original American: the American Indian.
There are some factors concerning the Wampanoags and other Indians across this vast nation. We now have 350 years of experience living amongst the white man. We can now speak his language. We can now think as a white man thinks. We can now compete with him for the top jobs. We're being heard; we are now being listened to. The important point is that along with these necessities of everyday living, we still have the spirit, we still have the unique culture, we still have the will and, most important of all, the determination to remain as Indians. We are determined, and our presence here this evening is living testimony that this is only the beginning of the American Indian, particularly the Wampanoag, to regain the position in this country that is rightfully ours.
Wamsutta
September 10, 1970

Merwinism

Thanks
by W. S. Merwin


Listen
with the night falling we are saying thank you
we are stopping on the bridges to bow from the railings
we are running out of the glass rooms
with our mouths full of food to look at the sky
and say thank you
we are standing by the water thanking it
smiling by the windows looking out
in our directions

back from a series of hospitals back from a mugging
after funerals we are saying thank you
after the news of the dead
whether or not we knew them we are saying thank you

over telephones we are saying thank you
in doorways and in the backs of cars and in elevators
remembering wars and the police at the door
and the beatings on stairs we are saying thank you
in the banks we are saying thank you
in the faces of the officials and the rich
and of all who will never change
we go on saying thank you thank you

with the animals dying around us
our lost feelings we are saying thank you
with the forests falling faster than the minutes
of our lives we are saying thank you
with the words going out like cells of a brain
with the cities growing over us
we are saying thank you faster and faster
with nobody listening we are saying thank you
we are saying thank you and waving
dark though it is

I Flushed the Toilet [Now updated by photojournalism...]

MONDAY PHOTO UPDATE:  my friend diana broke her foot (a much more serious injury, i think) -- also on saturday. and it was her birthday! i'm thinking conspiracy, i'm thinking international plots, espionage, some sort of orthopedic movement of oppression! so we toddled to the doc, who was more obsessed with my right foot than my broken wrist.  "it's gangrenous," he whispered, adding the observant:  "it's PURPLE!"  by the time we got there, ulnar nerve palsy had set in, which is the reason for the attempt to splint my last two fingers straight out.  you can see that they are defiantly curling under toward the palm, snickering at the pathetic attempt.  still, diana got the raw deal.  send either one of us a crate of nicely aged single malt, and a spirit of thanksgiving might yet survive.

SUNDAY EVENING:
I've always longed for great stories to go along with my broken bones.

"It was that double-back ziparoo round-off into a triple-toed handspring spring roll that broke my big toe, a small price to pay for Olympic Gold..."

That sort of thing.

A few weeks back, I cracked the crapola out of my left lower shin.  I got my leg trapped between my speeding wheelchair and a mop.

Last night...

Oh, you don't need to know.

It's not like there is any snow or ice here.
No deeds of derring-do.
Not even any house-cleaning.
Haven't been wrestling Buddy the Outrageosly Large Maine Coon for his weird Mr. Potato Head, made of cheap felt.  Well, I have, but without injury.
There've been no intrepid home invaders trying to leap into the house through a broken window over the washer.  That was last year, and this year, I have Bear Repellent.

But last night...

I flushed the toilet and may have fractured my ulna/wrist.

I went to bed straight away, with a handful of candy and my music playing very, very loudly in my oddly shaped earbuds.  Woke myself several times yelling as I pushed off on that hand in an effort to hoist the heft into a more comfortable position.  Then this morning, CRPS decided it was offended to have another of its territories maltreated, and the hand has gone ice cold. No swelling, no redness, no wrist at a right angle to its forearm.  It may be a tendon, a sprain, a nerve issue, a small fracture.  Like Honey Badger, CRPS don't care.

Icy CRPS?  It burns.  It hurts.  I cry.  I'm the portrait of immaturity.  I EMBODY immaturity.

And that place on my leg?  The swelling is almost all gone.  The bruise is still ugly but the pain much better. And... that precise area is hot.  Which may mean infection, though that's a hell of a stretch, especially since there is no hardware there.  Still.

So, baby that I am, I called go-to-guy doctor, wimpering and whining.  Was I partly driven because Fred called to say, "Oh, by the way, someone had an extra ticket to The Nutcracker... I will be a while."  Of course not.  Who gives a hoot, really?  I mean, I saw Baryshnikov in The Nutcracker in San Francisco. And everyone knows the music sucks, and, well, you know.  Ho ho ho.

The doctor said to apply ice, and I just have to politely ignore that.  He still knows nothing of basic CRPS care.  That got to me.  Elevate it.

Luckily, I didn't scream:  "If anyone gave a good goddamn they'd chop these appendages off, or slap two-dozen plus three (to die on) 100 mcg Fentanyl patches all over moi.  If anyone gave a good goddamn they'd shoot me between the eyes."

Good thing I decided to cook Fred, Bianca, Sven and a petulant Cabana Boy one kickass stir fry before going to the bathroom and FLUSHING THE TOILET.

Tomorrow, off we'll trot to get x-rays, and they'll be normal except for hairline nonsense and an alarmed radiologist who'll cry "osteoporosis out the wazoo," and run screaming down lead-lined hallways.

That's right.  I flushed the toilet.
Wanna make something of it?

Fred is hanging in there, by the way.  He's taking the high road and trying not to worry about his hearing. And WTF, he's at the freaking ballet.  One non-hearing ear, the other with tinnitus.  On his way home, he's picking up a wrist immobilizer.  That's the one piece of orthopedic equipment we are lacking.

© 2013 L. Ryan

"The undiscover'd country...": Sunday's bit of Shakespeare

Hamlet, Act III, Scene I [To be, or not to be]

  by William Shakespeare

To be, or not to be: that is the question:
Whether 'tis nobler in the mind to suffer
The slings and arrows of outrageous fortune,
Or to take arms against a sea of troubles,
And by opposing end them? To die: to sleep;
No more; and by a sleep to say we end
The heart-ache and the thousand natural shocks
That flesh is heir to, 'tis a consummation
Devoutly to be wish'd. To die, to sleep;
To sleep: perchance to dream: ay, there's the rub;
For in that sleep of death what dreams may come
When we have shuffled off this mortal coil,
Must give us pause: there's the respect
That makes calamity of so long life;
For who would bear the whips and scorns of time,
The oppressor's wrong, the proud man's contumely,
The pangs of despised love, the law's delay,
The insolence of office and the spurns
That patient merit of the unworthy takes,
When he himself might his quietus make
With a bare bodkin? who would fardels bear,
To grunt and sweat under a weary life,
But that the dread of something after death,
The undiscover'd country from whose bourn
No traveller returns, puzzles the will
And makes us rather bear those ills we have
Than fly to others that we know not of?
Thus conscience does make cowards of us all;
And thus the native hue of resolution
Is sicklied o'er with the pale cast of thought,
And enterprises of great pith and moment
With this regard their currents turn awry,
And lose the name of action.--Soft you now!
The fair Ophelia! Nymph, in thy orisons
Be all my sins remember'd.