INTRODUCTION
Through the marvel of modern technology, we are able to keep
updated on the latest research and developments in the CRPS field.
It is encouraging that many more labs around the world are working
on various aspects of CRPS. A recent informal search of PubMed
revealed 2175 recent studies. In Holland, the research on patients
has been ongoing for fifteen years and many new studies are in
the works. One of the hotbeds of research is at the University
Hospital Nijmegen in Nijmegen where Professor R Jan Goris continues
to lead a research team. From this team, many more studies on
CRPS have been completed in the last six years. Dr Veldman and
Dr van der Laan are two doctors who have done outstanding and
ground breaking work with CRPS patients. The following page attempts
to describe and examine some of their research that is having
an impact around the world.
ABOUT THE AUTHOR
Dr van der Laan was born in Roermond, Holland in 1966. He received
his medical degree from Erasmus University in Rotterdam in 1992.
From 1994 to 1999 he was a research fellow at University Hospital
Nijgmegen under the guidance of Dr Prof. RJA Goris. During this
time, he also was in charge of a CRPS clinic and another CRPS
clinic in conjunction with Professor Goris. It is estimated that
he saw over 800 patients. His research topic was the pathophysiological
mechanisms of RSD. Upon presentation of his thesis in 1999 he
received his PhD.
He then began his training as a surgical resident in Nijmegen.
Dr L. van der Laan is presently a surgical resident at St. Elisabeth's
Hospital in Tilburg where he is training to be a vascular surgeon.
Recently, he has been invited to speak in USA, Europe and Canada.
He lectured at the RSD International Conference 2000 held on July
27-29th in Toronto. He presented compelling evidence on the exaggerated
regional inflammatory response theory. He also outlined the Dutch
treatment protocol for RSD patients. He spoke at the World Congress
and 2nd IASP Research Symposium in Cardiff, Wales in October 2000.
His latest article in European Journal of Trauma (2001) is "Reflex
Sympathetic Dystrophy--Another View".
PATHOPHYSIOLOGICAL MECHANISMS OF RSD:
A CLINICAL AND EXPERIMENTAL STUDY
by L van der Laan, MD PhD
Jan. 15, 1999 ISBN 90-9012256-7
SUMMARY
This thesis is written by one of the leading CRPS researchers
in Holland. He recently made some new discoveries about CRPS.
The first chapter includes an introduction to CRPS, the signs
and symptoms. Various theories surrounding the cause of CRPS are
discussed including two inflammatory theories. He proposes that
the exaggerated inflammatory response theory of the involvement
of free radicals is viable due to the mounting scientific evidence
found in his recent studies. However, he also acknowledges that
neuropeptides such as substance P may play a part in the inflammation
of CRPS.
The following chapters are various CRPS studies e.g.. RSD-dystonia,
neurological problems in RSD, histological analysis of skeletal
muscle and nerve tissue, anti-oxidant treatment, and animal models.
To order this book contact:
L.van der Laan MD PhD.
Dept.of Surgery,
St.Elisabeth's Hospital
PO Box 90151,
5000 LC Tilburg, Holland
Tel: 31 135392922
Fax: 31 5363660
PSNS: A Publication on
Pain and the Sympathetic Nervous System
At the recent World Congress on Sympathetic Nervous System and
Pain there was much discussion about the treatment of sympathetically
maintained pain in CRPS. "The Budapest meeting was a wonderful
forum for the presentation by many younger investigators of clinical
pathophysiology that one day may point us in the right direction
for identifying a mechanism of this disease."(1) One of these
young investigators was Dr van der Laan whose research is leading
CRPS studies in a bold, new direction. His well documented studies
support the "exaggerated regional inflammatory response theory"
that free radical damage is responsible for the signs and symptoms
of CRPS type 1 (RSD). A review of Dr van der Laan's work appeared
in the PSNS SIG Newsletter in May 2000.
(1)From the IASP Special Interest Group on Pain and the Sympathetic
Nervous System PSNS SIG Newsletter May 2000, Chairman's Message
page 1)
The Role of Oxygen Derived Free Radical as Mediator in
the Neurological Complaints of Complex Regional Pain Syndrome
(RSD).
Lijckle van der Laan, MD PhD, R Jan Goris, MD PhD, Dept.
of Surgery, University Hospital Nijmegen, Nijmegen and St. Elisabeth's
Hospital, Tilburg, Netherlands
PSNS SIG Newsletter, May 2000 pp.2-4.
In order to be neutral with respect to the various theories of
pathophysiology of reflex sympathetic dystrophy (RSD), this syndrome
has been renamed complex regional pain syndrome (CRPS), subdivided
into type 1 which occurs without a definable nerve lesion and
type II with a definable nerve lesion. Complex regional pain syndrome
(CRPS) is a potentially incapacitating syndrome. occurring in
a extremity usually after a minor injury or operation. In the
acute phase of CRPS (the first two months after onset) the affected
extremity has an alteration in skin colour (red or blue discoloration),
skin temperature (warm or cold), edema, an impaired active range
of motion, and pain sensations which are out of proportion with
respect to injury. These characteristic signs and symptoms of
CRPS appearing an area larger than the area of primary injury
or operation and include the area distal to the primary injury,
Pathognomonic for the disease is that the complaints increase
during and after exercise.
From the onset of the disease various neurological deficits may
appear in the affected limb. The neurological abnormalities observed
most widely in the acute phase are hyperesthesia (typically with
a glove-or stocking-like distribution), hyperpathy (increased
sensitivity to painful stimuli), allodynia (pain from innocuous
stimuli) and paresis. In the chronic phase of CRPS (for one year
or more after onset), the neurological complaints increase in
severity and are more prominently present. Incoordination, tremor,
involuntary movements, muscle spasms, and posture abnormalities
may occur in this phase. The postural abnormalities include dystonia
(a fixed abnormal posture of the extremity such as hyperflexion
of the wrist or fingers, or inversion and plantar flexion or extension
of the foot) and myoclonus (involuntary jerk-like movements produced
by muscle contraction). Sensory disturbances may include anesthesia
dolorosa (severe pain present in the anesthetic area). These neurological
deficits may lead to severe additional disability, untreatable
pain, and a non-functional extremity
Today, there is no consensus as to the pathophysiological mechanisms
leading to neurological problems in CRPS patients. The five main
pathophysiological theories which are currently used to explain
the signs and symptoms of CRPS include psychosocial abnormalities,
inactivity, sympathetic deregulation, causalgia, and an exaggerated
regional inflammatory response. Most of the theories are directed
at the pathophysiology of the pain sensations and seldom explain
the pathophysiological mechanisms of other neurological manifestations.
We suggested that an exaggerated regional inflammatory response
is is involved in the pathophysiology of CRPS. This theory is
supported by various studies performed at our department. The
increased uptake of Indium-111-immunoglobulin G in extremities
affected by acute CRPS as compared to the unaffected extremities,
supports the inflammatory theory (1). This technique is an established
method of recognizing infectious and inflammatory foci. The presence
of the combination of a high oxygen supply with tissue hypoxia
in CRPS extremities (2), seems to be consistently found in varicose
ulcers, malignant tumours, ischemia/reperfusion, and in feet affected
by diabetes mellitius. A diminished oxygen availability to the
skeletal muscle tissue affected by chronic CRPS was also established
by using Phosphorus nuclear magnetic resonance spectroscopy (2).
The positive outcome of treatment of CRPS patients with the free
radical scavengers dimethylsulfoxide (3) as an anti-inflammatory
therapy also supports the hypothesis of the exaggerated regional
inflammatory response.
An animal model based on the chronic ligation of a nerve is currently
used as a representation of human CRPS, especially with regards
to the pain sensations of CRPS. However, it is questionable if
this model may also represent CRPS which develops without a definable
nerve lesion (CRPS: type 1). The aim of my thesis, briefly summarized
below, performed at the Department of Surgery, University Hospital
Nijmegen, the Netherlands, form 1994-99 was to obtain a better
insight into the pathophysiology of CRPS with special attention
to the neurological deficits found by human and experimental investigations.
The thesis started with a retrospective analysis of the prevalence,
predisposing factors and treatment for severe complications of
CRPS such as infection, ulcers, chronic edema, dystonia and/or
myoclonus in a well-documented population of 1006 CRPS patients.
The population of CRPS patients without a severe complication
was compared to the population who developed one or more severe
complications in the CRPS extremity. Within this population of
CRPS patients, mostly young and female, 74 patients developed
severe complications. The main finding of this study was that
in patients in which the CRPS started with a decreased skin temperature
of the affected extremity, severe complications developed significantly
more frequently as compared to CRPS patients with a warm skin
temperature of the extremity at the onset of the disease.
One of the neurological complications of CRPS is dystonia, defined
as a fixed abnormal posture of the affected extremity, such as
hyperflexion of the wrist and fingers, or inversion and plantar
flexion or extension of the foot. This complication is present
in a minority of CRPS patients and may lead do severe disability.
Various pathophysiological mechanism are suggested to generate
dystonia in CRPS patients. One of these theories involves the
role of psychological distress as a main pathophysiological mechanism.
We investigated the involvement of psychological distress in CRPS-dystonia
with the aid of the Symptom-checklist-90 Revised (SCL-90R) questionnaire.
The SCL-90R is a multidimensional self-report inventory covering
various dimensions of psychological distress. Within a population
of 1006 CRPS patients, we analysed the SCL-90R scores of 27 CRPS
patients (23 female and 4 male) with CRPS-dystonia and compared
the scores to sample scores of a control female (n=577) and a
control rehabilitation population (n=56). Insomnia scored significantly
higher in the female CRPS-dystonia population as compared to the
control female population., and in the total CRPS-dystonia population
versus the rehabilitation population. Remarkable was the significantly
higher score of somatization in the rehabilitation population
as compared to the CRPS-dystonia population. For the other dimensions
of psychological distress of the SCL-90R, the corse of the CRPS-dystonia
and control populations were similar. We conclude that a specific
psychological profile is not especially present in CRPS-dystonia
patients, with regard to the SCL-90R scores.
We also investigated the role of the A-delta nerve fibers in
the pathophysiology of CRPS. The neurophysiology of the large
myelinated fibers was studied by analysis of the afferent A-delta
fiber mediated reflexes in lower extremities affected by acute
CRPS during gait. We could determine the involvement of these
fibers by analyzing reflex responses from the tibialis anterior
and biceps femoris muscles after electrical stimulation of the
sural nerve. The reflexes were studied during walking on a treadmill,
in order to investigate whether the abnormalities in gait of these
patients were related either to abnormal amplitudes or deficient
phase-dependent modulation of reflexes. In 5 patients with acute
CRPS of the leg and volunteers, these reflex responses were determined
during the early and late swing phase of the step cycle. No significant
difference was found between CRPS patients and volunteers. From
this finding we argue that in the acute phase of CRPS in the lower
extremity, there is no evidence for abnormal A-delta fiber mediated
reflexes or for defective regulation of such reflexes.
Reports concerning histological analysis of human tissue affected
by CRPS, which would give more insight into the pathophysiology,
are rare. In order to gain more insight into the pathophysiology
of CRPS, we studied the histopathology of skeletal muscle tissue
and peripheral nerves obtained from patients with a chronic stage
of CRPS in a lower extremity. In these chronic CRPS patients (3
female and 5 male), an above the knee amputation was performed
because of a non-functional limb. In all patients the affected
leg showed similar neurological symptoms such as spontaneous pain,
hyperpathy, allodynia, paresis, and anesthesia dolorosa defined
as sensibility to touch absent while severe pain is present in
the anesthetic area. Specimens of sural nerves,tibial nerves,
and common peroneal nerves, gastrocnemius muscles and soleus muscles
were obtained from the amputated legs and analyzed by light and
electron microscopy. The efferent nerve fibers showed no consistent
abnormalities of myelinated fibers. In four patients the C-fibers
showed electron microscopic pathology.
In all patients, the gastrocnemius and soleus muscle specimens
showed a decrease of type I fibers, an increase of lipofuscin
pigment, atrophic fibers and severely thickened basal membrane
layers of the capillaries. Lipofuscin results from oxidation of
unsaturated membrane lipids by free radicals and increases with
age. In diabetes, according to the haemodynamic hypotheses microns
flow and pressure are increase early, giving rise to an injury
response resulting in basal membrane thickening of the capillaries.
The underlying defect may be the increase of oxygen-derived free
radicals in vascular cells caused by an accumulation of advanced
gyration products and resulting in a disturbed autoregulation
of vascular tome. The skeletal muscles consistently showed a variety
of histopathological findings which may be due to oxidative stress
or free radicals
Oxygen-derived free radical are suspected to play an important
role in the pathogenesis of e.g.. inflammation and ischemia/reperfusion
damage. The specific underlying mechanisms are not yet clear.
For this reason, we developed a dynamic animal model which allows
for analysis of soft tissue damage induced by a free radical donor.
In male Wistar rats, retrograde cannulation of the left inferior
epigastric artery was performed, allowing for continuous intra-arterial
infusion into the common femoral artery without inducing ischemia.
The cannula was connected to a flexible tubing system, for the
continuous infusion (1 ml/h) of non-anesthetized rats during 24
h, with the free radical donor terbutyl-hydroperoxide (tert-BuOOH)
25 mmo/l dissolved in saline or saline only (control group). Using
this model, clinical signs and symptoms were measured and observed
such as skin temperature, skin colour, volume and function of
the feet. Spontaneous pain, thermal and mechanical related pain
sensations were scored by methods as used in the evaluation of
the chronic nerve ligation animal model. After 4, 12 and 24 hours
of infusion, the vascular permeability for macro molecules was
assessed by analysis of "Technetium immunoglobulin"
(Tc-IgG) biodistribution. The left and right gastrocnemius muscles
were examined light microscopically for cellular and microvascular
damage
The tert-BuOOH infused food showed increased skin temperature,
increased circumference, redness of the plantar skin, impaired
function and increased pain sensation, while in the contralateral
foot and in rats only perfused with saline, these signs of inflammation
were absent. Histological analysis of the left gastrocnemius muscle
showed edema, muscle cell degeneration with a patchy distribution
pattern and vascular damage. All these features increased in severity
form 4 to 24 h of tertBuOOH infusion. After 24 h of tert-Bu OOH
infusion infiltration of neutrophils in the interstitium was observed.
Vascular permeability, expressed as left to right gastrocnemius
muscle "Tc-IgG uptake ratio, was significantly increased
after 4 h and 12 h of tert-BuOOH infusion compared to saline,
and increased significantly after 24 h. In this animal model,
free radical related soft tissue damage was induced by continuous
infusion of tert-BuOOH followed by increasing necrosis and vascular
permeability in skeletal muscle, coinciding with neutrophilic
infiltration. The observed abnormalities were only present in
the infused hindlimb. In addition, the possible repair capacity
of the hindlimb after 24 h infusion with tert-BuOOH in the free
radical animal model was investigated. After 24 h infusion, the
infusion system was disconnected. During the follow-up period
of 6 weeks, the repair capacity of the left hindlimb was observed
by examination of the clinical signs and symptoms, pain tests,
vascular permeability by Tc-IgG scintigraphy and histology of
the gastrocnemius muscle and sciatic nerve. We also studied the
effect of the antioxidant N-Acetyl-l-cysteine (NAC), in a group
of the tert-BuOOH infused rate. Six of the NAC treated-ted rats
were terminated after 24 h infusion while the remaining 6 rats
were disconnected, reinjected with NAC and observed for one week
Treatment with NAC significantly reduced pain sensations and
by vascular permeability as compared to the untreated tert-BuOOH
infused group, though not to control levels. One week after disconnection,
tissue damage was almost completely repaired in the NAC treated
rats. In the untreated rats, repair took longer but histology
and permeability were completely normalized within the observation
period. Unexpectedly, mechanical pain remained present in the
infused paw during the whole recovery periods, while in the contralateral
control hindlimb an abnormal pain response developed one week
after infusion. Soft tissue damage induced by 24 h infusion of
the free radical donor tert-BuOOH, showed spontaneous repair within
6 weeks. The antioxidant NAC significantly reduced the soft tissue
damage and shortened the repair period.
The main findings of the animal model are that infusion with
tert-BuOOH induced for the left paw an increased skin temperature,
increased volume, redness of the plantar skin, impaired function
and increased pain sensations, while these acute CRPS signs and
symptoms were absent in the saline infused animals. The alterations
in pain sensation (spontaneous, mechanical and thermal pain) were
similar to findings in the chronic ligation of the sciatic nerve
animal model. The clinical observation in CRPS patients, that
unexplained pain regularly develops in the healthy contralateral
extremity has been reproduced in his animal model. Induction of
free radical formation in one hindlimb of awake rats mimics the
acute signs and symptoms of acute human CRPS, with alterations
in pain sensation as found in the classical neuropathic animal
model of CRPS, as well as in acute CRPS patients The main conclusion
of the above mentioned studies performed for this thesis are that,
with the test utilized, no definite psychological factor could
be related to the neurological deficits of CRPS. The histologically
unaffected mixed motor-sensory nerves and the absence of consistent
abnormalities of the C fibers of the sensory nerve of severe CRPS
patients together with the finding of physiologically undisturbed
A-delta fibers, suggest that the large peripheral nerve are not
involved in the neurological complaints of CRPS
On the other hand, the findings of histological abnormalities
in the human skeletal muscle affected by CRPS and by interpretation
of the effect of the free radical donor on soft tissue in the
animal model, supports the theory that oxygen derived free radicals
may be the possible mediator of the pathophysiological mechanism
leading to some of the neurological complaints of CRPS
(reproduced with kind permission of L van der Laan, MD PhD)
NEWEST STUDIES
van der Laan L Goris RJA. Reflex Sympathetic Dystophy--Another
View Eur J Trauma 2001;27:99-103
SUMMARY
This review article summarizes many of the issues surrounding
CRPS type 1:RSD: causation theories, prevention, treatment and
prognosis.
Consider the incidence of RSD. The estimated prevalence of RSD
in Holland is 0.5 per 1,000 or 1 in 2,000 per year.(The population
of Holland is 15.8 million.) It is based on previous studies especially
Veldman et al (1993) who extensively studied 829 patients over
8 years. Women are three times more likely to get RSD than men
and upper extremities are twice as affected as lower limbs. After
a Colles' fracture, the rate is 8%. About diagnosis, van der Laan
states: "no single diagnostic or imaging technique has been
sensitive and specific in establishing the diagnosis" although
bone scans and x-rays are helpful but not conclusive.
The exaggerated regional inflammatory response theory states that
RSD can be caused by an inflammatory response after injury or
surgery of a limb. Inflammation and acute RSD have similar symptoms
e.g. "rubor, calor, dolor, tumor, and functio laesa".
Further studies have revealed mounting evidence to support this
claim which is discussed in detail. He also offers proof of the
involvement of toxic oxygen radicals in inflammation.
The main points of the treatment protocol used in Holland, are
outlined as well as suggestions for prevention of RSD.
This article is highly recommended for doctors.
- van der Laan L Goris RJA. Algodystrophy, in AO Principles
of fracture management In press.
- van der Laan L Goris RJA. Reflex Sympathetic Dystrophy after
a Burn Injury. Burns 1996: 22:303-306
- van der Laan, L.,Veldman PHJM Letter to the Editor.Pain 1997;72;291
- van der Laan, L. ter Laak HJ, Gabreels-Festen, A, Gabreels
F, Goris, RJA Complex Regional Pain Syndrome Type 1: Pathology
of skeletal muscle and peripheral nerve Neurology 1998;51:20-25
- van der Laan, L, Kapitein O, Verhofstad AAJ, Hendriks T, Goris
RJA Clinical signs and symptoms of acute reflex sympathetic
dystrophy in one hindlimb of the rat, induced by infusion of
a free radical donor.Acta Orthop Belg 1998;64:210-217
- van der Laan L, van Spaendonck K, Horstink MWIM, Goris The
symptom checklist-90 revised questionnaire: No psychological
profiles in reflex sympathetic dystrophy-dystonia Journal Pain
Symptom Management 1999:7; 357--362
- van der Laan L, Boks LMH, van Wezel BMH, Goris RJA Duysens
J. Leg muscle reflexes mediated by cutaneous A-beta fibers are
normal during gait in reflex sympathetic dystrophy Clinical
Neurophysiology 2000;111(4): 677-685
- van der Laan L, Kapitein PJC, Oyen WJG, Verhofstad AAJ, HendriksT,
Goris RJA. A novel animal model to evaluate oxygen derived free
radicals in soft tissue. Free Rad Res 1997;4:363-372
- van der Laan L, Oyen WJG, Verhofstad AAJ, Tan ECTH, ter Laak
HJ, Gabreels-Festein A, Hendriks T, Goris RJA Soft tissue repair
capacity after oxygen derived free radical induced damage in
one hindlimb of the rat J Surg Res 1997;72:60-69
- van der Laan L, Oyen WJGm, Tanm ECTH, Verhofstad AAJ, Hendriks
T, Goris, RJAA comparison of free radical induced vascular and
skeletal muscle damage in immunocompetent and neutropenic rats
Surg Res 1999;82:46-52
- van der Laan L. Pathophysiological mechanisms of RSD: A Clinical
and Experimental Study Thesis Nijmegen 1999 ISBN 90-9012256-7
- van der Laan, L Veldman PHJM Goris RJA. Severe complications
of RSD: infection, ulcers, chronic edema, dystonia and myoclonus
Arch Phys Med Rehab 1998: 79;424-9
- van der Laan L Goris RJA. Reflex Sympathetic Dystrophy: An
Exaggerated Inflammatory Response? Hand Clinics Vol 13 No 3
August 1997 p 373-386
- van der Laan L et al Complex Regional Pain Syndrome type 1
(RSD) Pathology of skeletal muscle and peripheral nerveNeurology
1998; 51:20:25
FREE RADICALS (FR)
UPDATE: June 2002
What are free radicals (FR) and how do they work in the
body?
A free radical is an "atom or molecule that contains one
or more unpaired electrons." An unpaired electron can bond
with another atom or molecule. It causes a chemical reaction.
FR can effect dramatic changes in the body and cause a lot of
damage to cells or impair the immune system . Many FR (e.g. superoxide,
hydroxy radicals, various lipid peroxides) play a role in various
diseases in the body such as inflammation, arthritis and pulmonary
diseases.
To counteract FR, the body makes free radical scavengers or antioxidants
which protect against FR by neutralizing them. Examples of free
radical scavengers which are enzymes, are catalase, superoxide
dismutase and glutathione peroxidase. Antioxidants such as Vitamin
A, beta carotene, Vitamin C and selenium also neutralize free
radicals by binding to their free electrons.
If there is excessive FR damage, damage to cells and tissues
can occur. If a large number of free radicals is formed, it stimulates
even more FR to form. This can lead to even more damage.
What do free radicals have to do with CRPS?
DMSO:Dimethylsulfoxide
N-Acetyl-cysteine(NAC) and IV Mannitol Treatments for Early CRPS
In 1942, Sudeck theorized that CRPS could be due to an inflammatory
response in the body after an injury or surgery. The signs and
symptoms of acute inflammation are: redness, warmth, swelling,
pain, and decreased function. These are similar to CRPS's signs
and symptoms. Studies done in Holland to support this theory found
several things:
a) a high oxygen supply with tissue hypoxia in CRPS extremities
b) a diminished oxygen availability to the skeletal muscle tissue
affected by chronic CRPS
Two theories evolved from this inflammatory theory:
One theory involved the role of neuropeptides, chemical messengers
that travel in the body, such as bradykin, substance P(SP) and
calcitonin gene related peptide (CGRP). An analysis of CRPS
patients showed increased levels of bradykin and CGRP. It was
also known that the nerve endings of the C fibers also gave
off substance P. Neuropeptides play a part in CRPS but it is
not yet known how and why. It is thought that substance P may
be involved with the dystonia aspect of CRPS SP and CGRP are
suspected as part of the motor and sensory disturbances in CRPS
Further research is needed in this area.
The other theory supported the fact that free radicals, naturally
occurring in the body, were known to be involved in various
diseases such as inflammation. To test this theory, the researchers
looked for changes in the body brought about by free radicals.They
found several deficiencies in the skeletal muscles of CRPS patients
e.g. disintegration of myofibrils.
Studies in Holland have centered around free radical scavengers
as treatment for CRPS. There are many ongoing studies with DMSO,
NAC in Holland.
In 1985, Dr R Jan Goris at the University of Nijmegen, pioneered
the use of DMSO for CRPS patients, Further studies over the years,
revealed that DMSO was helping and it is now commonly used. Other
free radical scavengers were added. Treatments consisted of DMSO
application to the skin, N acetylcysteine (NAC) in the form of
Fluimucil and IV Mannitol
Patients with acute CRPS for less than one year have greatly
benefited from these treatments e.g.. DMSO is painted on the skin
several times a day to help counteract redness. swelling and pain.
DMSO is now standard treatment for patients in Holland. In addition,
a specific protocol is being used by Dutch doctors.
DMSO/NAC STUDY 2002
In the Dutch literature on CRPS, there has been continuous reference
to the role of free radicals in the inflammation of early CRPS.
Microscopic findings have found evidence of changes brought about
by free radicals in the limbs of CRPS patients. Abnormalities
in the skeletal muscles of chronic CPRS patients have shown. e.g.
"disintegration of myofibrils, swelling and vesiculation
of mitochondria." (van der Laan 1999)
Free radical scavengers such as Dimethylsulfoxide (DMSO), Mannitol
and N-Acetylcysteine (NAC) are used in treatment of early CRPS
in Holland. Recently, a two year double-blind, placebo controlled
study on the free radical scavengers DMSO and NAC studied their
effectiveness. DMSO 50% cream on the skin five times a day vs.
a placebo group and NAC 600 mg. ( 3 times a day) vs. placebo.
None of the groups knew if the treatment was real or not. DMSO
was found to be more effective in "warm" CRPS patients
while NAC was better with "cold" patients. The biggest
improvement was in CRPS 1 (< 90 days) with treatment of DMSO.
The researchers concluded that DMSO and NAC were equally effective
in the treatment of early CRPS.
In a separate study, DMSO was also found to be more cost effective
than NAC for patients.Much of the research in Holland is now based
on the theory that inflammation is the cause of early CRPS. Microscopic
evidence has been found and treatment with free radical scavengers
are proven to be effective.
(Source: Perez R. CRPS 1 A randomized controlled study into the
effects of two free radical scavengers and evaluation of measurement
instruments" Thesis 2002 ISBN #90-9015456-6)
SPECIAL ACKNOWLEDGMENT: Many thanks to Ilona Thomassen, Chairperson
of the Nederlandse Vereniging van PTD Patienten (Dutch RSD Association),
Nijmegen Holland for supplying us with this informative study
by Dr. Perez..
DR. P. VELDMAN
ABOUT THE AUTHOR
Dr Peter Veldman was born and educated in the Netherlands. After
starting university studies in physiotherapy, he switched to medical
studies at the Catholic University in Nijmegen, After obtaining
his medical degree, in 1989, he began creating a database on all
patients with posttraumatic dystrophy (RSD/CRPS) being treated
at the University Hospital in Nijmegen.
From 1990 to 1992, he held a surgical post at the University
Hospital at Alkmaar and in 1992 he began his specialized surgical
postgraduate studies on post-traumatic dystrophy (RSD/CRPS) at
the University Hospital Nijmegen under the supervision of Dr.
R.J.A. Goris.
In 1998 he completed the requirements for a surgical speciality.
He currently practices at Hospital de Tjongerschans in Heerenveen,
Holland.
Dr Peter HJM Veldman recently lectured at the International RSD
Conference in Toronto, Canada held on July 27-29th where he led
a seminar for medical professionals from Canada and USA.
With his thesis, he laid the groundwork for new research being
conducted into RSD/CRPS by Dutch researchers today. His study
of 829 patients revealed some remarkable conclusions.
BIBLIOGRAPHY
Veldman PHJM Clinical Aspects of RSD (Thesis) Koninklijke
Biblioteek, Den Haag 1995 ISBN 90-9007712-X
SUMMARY
This book contains many years of hard work by on various areas
of RSD. He investigates signs and symptoms, surgery, amputation,
multiple RSD and shoulder complaints. The following studies are
some publications that underly the thesis.
- Veldman PHJM Goris RJA Surgery on extremities with reflex sympathetic
dystrophy Unfallchirug 1995; 98: 45-8
- Veldman PHJM Shoulder complaints in patients with RSD of the
upper extremity Arch Phys Med Rehabilitation Vol 76 March 1995
p 239-441
- Veldman PHJM Goris RJA Multiple RSD: Which patients are at risk
for developing a recurrence of RSD in the same or another limb?
Pain 64 1996; 463-66
- Veldman, PHJM et al Signs and symptoms of reflex sympathetic
dystrophy: prospective study of 829 patients Lancet Vol 342 Oct.
23, 1993 p 1012-5
SUMMARY
"The pathogenesis of RSD is not well understood and diagnosing
and treating patients is difficult. We have studied 829 patients
paying close attention to early signs and symptoms. In its early
phase RSD is characterized by regional inflammation which increases
after muscular exercise. Pain was present in 93% of patients
and hypoaesthesia and hyperpathy were present in 69% and 75%
respectively. With time, tissue atrophy may happen and involuntary
movements, muscle spasms, or psuedoparalysis. Muscular incoordination
was found in 54%, and tremor in 49% of patients. Sympathetic
signs of hyperhidrosis are rare and have no diagnostic value.
We found no evidence of the three consecutive phases of the
disease. Early symptoms are those of an inflammatory reaction
and not of a disturbance of the sympathetic system. These data
support the concept of an exaggerated inflammatory response
to injury or operation in RSD."
Editor's Note: The following signs and symptoms were noted
by Dr Veldman in his 829 patients.
- Inflammatory: pain 93%, colour difference
92%, edema 69%, temperature difference 92%, limited movement 88%,
and increase of complaints after exercise 96%.
- Neurological: hyperesthesia 76%, hyperpathy
79%, incoordination 54%, tremor 49%, involuntary movements 36%,
muscle spasm 25%, paresis 95%, and pseudoparalysis 16%.
- Atrophy: skin 40%, nails 27%, muscle 55%, bone
38%.
- Sympathetic: hyperhidrosis 47%, changed hair
growth 55%, and changed nail growth 60%.
EDITOR'S COMMENTS
The CRPS criteria in Dr Veldman's study have been used
as the basis for ongoing Dutch research. Criteria for diagnosis
is
1. 4 or 5 of:
- Unexplained diffuse pain
- Difference in skin color relative to other limb
- Diffuse oedema
- Difference in skin temperature relative to other limb
- Limited active range of motion
2. Occurrence or increase of above signs and symptoms after
use
3. Above signs and symptoms present in area larger than the area
of primary injury and including the area distal to the primary
injury.
FURTHER EVIDENCE
Dr van der Laan has supplied mounting evidence to support that
"an exaggerated inflammatory response" is the how CRPS
begins in the body. Last October, Dr van der Laan presented his
evidence to the Special Interest Group of Pain and the Sympathetic
Nervous System (PSNS SIG)(International Association for the Study
of Pain members) and it was well received. This group is a body
of top CRPS researchers around the world.
The notion that CRPS is caused by the sympathetic nervous system
is unproven, unfounded and outdated. Due to the longstanding belief
in the "sympathetic theory", new treatments for CRPS
have not been forthcoming.
Its time to change!
Based on the inflammatory theory, researchers in Holland have
developed excellent treatments with free radical scavengers which
fight inflammation. DMSO, N-Acetylcysteine and IV Manitol are
standard treatment in Holland. All RSD patients must have DMSO;
it is the law.
The "inflammatory theory" has a scientific basis in
FACT so why is no one here listening? Unfortunately, due to the
narrowmindedness of the Canadian and US doctors and researchers,
these treatments are not available in Canada or USA. Why not?
They have already been proven to work.
Let's bring these treatments to Canada and help patients who so
desperately need it!
TREATMENT PROTOCOL with
DMSO, NAC And IV Mannitol
ATTENTION CANADIAN DOCTORS
It is regrettable that these treatments are not available in Canada.
With the latest DMSO/NAC study for early CRPS, these treatment
have been proven beyond a reasonable doubt, to be effective in
early cases. The protocol used by Dutch doctors for the treatment
of early CRPS cases (up to one year) is available through doctors
in Holland.
Dr. Prof. RJA Goris
Dept. of Surgery
University Hospital Nijmegen
6500 HB Nijmegen, Holland
Tel: 31 24 3-614554
Fax: --540501
UPDATE: Dr. Goris has retired and is available
for consulation with Canadian doctors. Please contact PARC for
his new contact information.
Doctors may also send a request
for information.
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