Dutch Research and Treatments
 

INTRODUCTION

In the Netherlands, the research on patients has been ongoing for over fifteen years. The TREND consortium in the Netherlands (www.trendconsortium.nl) is composed of seven universities and two companies dedicated to researching CRPS. Nerve centers of research are University Hospitals in Nijmegen, Delft, Groningen, Leiden, Utrecht, Free University of Amsterdam, Rotterdam and Maastricht. From these research teams, there is outstanding and ground breaking work. Heading this consortium is Dr JJ van Hilten, Leiden University Medical Center, noted CRPS researcher and doctor.

For more info see this site:

www.onderzoekinformatie.nl ( click on English version. )

Recently, conclusive evidence that RSD/CRPS starts as "neurogenic inflammation" has been added to the already gigantic stack of previous research on this matter. To explain the "inflammatory theory" see DMSO/NAC and FREE RADICALS section below. Dr Huygen's work on inflammation is irrefutable proof of inflammation as the beginning of RSD/CRPS.

However the exact cause of CRPS is still under investigation.

This is excellent progress.

__________________________

JANUARY 2016:DUTCH TREATMENT GUIDELINES

A huge committee of doctors, researchers and experts in Holland worked tirelessly for 5 years to write the standard treatment protocols for treating CRPS in the Netherlands. Now every Dutch patient can benefit from these very important guidelines. Special thanks to Drs. Ilona Thomassen, of the Dutch Patient Organization (Ned. Ver. van PTD Patienten) for supplying PARC with the Guidelines for Doctors and Patients. She hopes they will help many people.

PARC congratulates the Dutch on their wonderful achievement! Well done!

Dutch Guidelines (ENGLISH version)(there are PATIENT and DOCTOR guidelines)


PAST STUDIES

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

UPDATE April 2004: Dr van der Laan is no longer doing CRPS research. He is taking part in a nationwide Dutch effort by CRPS researchers and doctors to write treatment protocols for RSD/CRPS or PTD (post-traumatic dystrophy) as it is known in Holland.

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)

OLDER 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.

NOTE: Please see link at top of page for latest Dutch Treatment protocols.

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..


INFLAMMATION AND RSD/CRPS

Huygen FJ, Ramdhani N, Van Toorenenbergen A, Klein J, Zijlstra FJ.
Mast cells are involved in inflammatory reactions during Complex Regional Pain Syndrome type 1.
Immunol Lett. 2004 Feb 15;91(2-3):147-154.

Pain Treatment Center, Department of Anesthesiology, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands.

Background: The Complex Regional Pain Syndrome type 1 (CRPS1) is a complication of surgery or trauma but spontaneous development is also described. Although the pathogenesis remains debatable, afferent, efferent and central nervous system mechanisms are proposed. Recently we showed involvement of the pro inflammatory cytokines IL-6 and TNFalpha which is direct evidence for an inflammatory process. Many types of cells, such as activated T lymphocytes, monocytes, macrophages and skin resident cells like mast cells, could contribute to the production of cytokines. Involvement of mast cells is relatively easy to detect by measurement of tryptase. Aim: To establish whether mast cells are involved in the inflammatory reactions during CRPS1. Methods: Twenty patients fulfilling the Bruehl criteria with CRPS1 in one extremity were studied. Impairment was assessed by registration of pain and measurement of differences in temperature, volume and mobility between the involved and uninvolved extremity. Blisters were made with a suction method in order to determine cytokines and mast cell derived tryptase in the involved and uninvolved extremity. Results: In the blister fluid a significant difference range, Wilcox on signed-ranks test was found between the involved and uninvolved extremity in IL-6 {53.5 (17.3-225) versus 6.2 (2-20.3) pg/ml}, TNFalpha {31 (15.5-131.5) versus 8 (4-39) pg/ml}, and tryptase {37 (20.5-62.3) versus 12.5 (6.7-23.5)ng/ml}. There was a significant correlation (0.455) between the intensity of pain and tryptase levels in the involved extremity.

Conclusion: Mast cells are involved in inflammatory reactions during the CRPS-1. Mast cells could play a role in the production of cytokines such as TNFalpha.

RELATED ARTCILE:

Increase in endothelin-1 and diminished nitric oxide levels in blister fluids of patients with Int. cold CRPS 1 BMC Musculoskeletal Disorders 2006 7:91


 

International Dutch RSD Conference:

"PD (Post Traumatic Dystrophy) Beyond Borders."

November 14-15, 2003.

Utrecht, Holland.

 

Read the latest developments from this excellent conference in our March and June 2004 issue of the PARC PEARL. Topics presented were:

  • "Inflammation and RSD" by RJA Goris MD, Dept. of Surgery, Nijmegen
  • "Neurogenic Inflammation in RSD" by F Birklein, Dept. of Neurology, Mainz, Germany
  • "RSD in Childhood" by AA Lebel, Children's Hospital, Boston, MA
  • "Free Radical Scavenger Treatments in CRPS-1" by R. Perez PhD, VUMC, Amsterdam
  • "Dystonia in CRPS-1" by JJ van Hilten MD, Leiden University Medical Center, Dept. of Neurology, Leiden.
  • "Spinal Cord Stimulation in patients with CRPS-1: Long term results" by M van Kleef MD, Dept. of Anesth. and Pain Management, AZ Maastricht
  • "Psychological Aspects of CRPS" by EC Covington MD, Cleveland Clinic Foundation, Pain Rehabilitation Program, Cleveland USA
  • "RSD and the Sympathetic Nervous System" by R Baron MD, Neurology Clinic, University of Kiel, Germany.

WHY IS RESEARCH IMPORTANT?

Significant developments in research point the way for more successful treatments for CRPS. For example, through Dutch research, it was discovered that inflammation in early CRPS is now widely accepted as the cause. As a result, Dutch doctors have a treatment protocol which is used with early CRPS cases (up to one year). This treatment is not yet available in USA or Canada. Why not? There are many closed minds in the medical field in both countries.

It is totally outrageous that a successful treatment for early CRPS is not used when patients could benefit!


 

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.

He is currently a medical advisor for the Dutch RSD patient group and on the medical committee to establish a national Dutch protocol for treating RSD/CRPS. He expects the protocol to be completed in 2006.

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. 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 for CRPS:Dutch Guidelines 2007

ATTENTION DOCTORS
It is regrettable that these treatments are not available in Canada. The 2007 protocol used by Dutch doctors for the treatment of CRPS is available through the NV van PTD Patienten website.

Dutch Guidelines (ENGLISH version) (if link is inoperable contact us.)

Doctors may also send a request for information.

UPDATE: As of November 2003, the best CRPS researchers and doctors in Holland are meeting to create a Dutch protocol which will be used by every doctor in Holland to treat this disease. Estimated time frame is 2 years. Taking part are Drs. Hilten, Veldman, van der Laan, Goris, Zuurmond and many more.We are cheering you on, gentlemen!

UPDATE: 2007 Guidelines completed! Please see the lin above for the latest treatments!

 

 

 
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