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The TREND Project

The TREND consortium  

Publications and results

TREND objective

TREND funding

Participating institutes  

Societal relevance

Complex Regional Pain Syndrome

Diagnosis of CRPS

TREND research lines  

 

The TREND consortium

TREND (Trauma RElated Neuronal Dysfunction) is a consortium of Dutch medical and technical universities and industrial companies, in which the research on Complex Regional Pain Syndrome type 1 (CRPS-1) is integrated.

Publications and results

 

TREND objective

The consortium aims to develop concepts on disease mechanisms that occur in response to tissue injury and methods for its assessment and treatment. In this project, the study of CRPS-1 takes a central position and serves as a model for other conditions that may be related to CRPS-1 as far as the underlying pathophysiological mechanism is concerned.

 

TREND funding

TREND is supported by a grant of the Dutch Ministry of Economic Affairs (BSIK03016).

 

Participating institutes

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Academic Hospital of Maastricht, department of anesthesiology;

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Delft University of Technology, department of Man-Machine Systems;

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Erasmus Medical Centre Rotterdam, departments of anesthesiology and medical informatics;

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 FCS Control Systems;

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Leiden University Medical Centre, departments of anesthesiology, neurology and human genetics;

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Noldus Information Technology;  

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Utrecht University Medical Centre, department of biochemistry.

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VU University Medical Centre, department of anesthesiology;

 

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Societal relevance

Reliable data are lacking, but crude estimates assume that approximately 20,000 patients in The Netherlands are suffering from the consequences of CRPS. Apart from the impact of a chronic illness upon a patient's personal life, the consequences for society are also considerable. Many patients are unable to work and receive disability compensation. If it proves possible to treat patients more effectively at an early stage of their disease, not only much personal suffering would be avoided, but large societal costs would be saved as well.

In TREND, patient education and public awareness are considered very important. There is a close collaboration with the Dutch Patient Society for Post-traumatic Dystrophy ('Nederlandse Vereniging van Post-traumatische Dystrofie patiŽnten'), who will be informed of relevant findings emerging from the several studies carried out within TREND.

 

Complex Regional Pain Syndrome

Complex Regional Pain Syndrome type 1 (CRPS-1), formerly known as reflex sympathetic dystrophy or posttraumatic dystrophy, is a common, disabling and poorly understood disorder. The syndrome is characterized by pain and various combinations of autonomic, sensory, motor, and trophic changes. In most cases CRPS-1 develops after a trauma, such as an injury or surgery. Reliable epidemiological data are not available. A crude estimate suggests that approximately 8,000 new patients present with CRPS-1 in the Netherlands each year. Reliable information on prevalence, disease duration, and prognostic indicators of CRPS-1 are lacking. The annual costs associated with CRPS-1 for the Netherlands are estimated between Ä 32.5 and 47.3 million.

The aetiology of the disease is unknown, but is likely multifactorial in nature, as indications for both environmental and genetic factors have been found. A generally accepted and undisputed treatment is not available.

 

Diagnosis of CRPS

A diagnostic test or pathognomic sign by which CRPS-1 can be diagnosed is not available and therefore the diagnosis of CRPS-1 is made if a patient fulfils the criteria formulated by the International Association for the Study of Pain (IASP), which state:

  1. Type I is a syndrome that develops after an initiating noxious event.

  2. Spontaneous pain or allodynia/hyperalgesia occurs, is not limited to the territory of a single peripheral nerve, and is disproportionate to the inciting event.

  3. There is or has been evidence of edema, skin blood flow abnormality, or abnormal sudomotor activity in the region of the pain since the inciting event.

  4. This diagnosis is excluded by the existence of conditions that would otherwise account for the degree of pain and dysfunction.

For the diagnosis of CRPS-1, criteria 2-4 must be fulfilled.

 

The presence or absence of major nerve involvement is the discriminating factor between both types of CRPS. CRPS-1 is diagnosed if the above criteria are fulfilled and there is no major nerve involvement, whereas in case of fulfilment of these criteria in the presence of major nerve involvement, the diagnosis of CRPS-2 is made.

 

Recently, the IASP task force on CRPS proposed a modification of these criteria. These so-called Budapest criteria were submitted to the Committee for Classification of Chronic Pain of the IASP for the 3rd taxonomy, but have not yet been accepted. The criteria include:

1.      Continuing pain, which is disproportionate to any inciting event.

2.      Must report at least one symptom in each of the four following categories:

Sensory: reports of hyperesthesia and/or allodynia.

Vasomotor: reports of temperature asymmetry and/or skin color changes and/or skin color asymmetry.

Sudomotor/edema: reports of edema and/or sweating changes and/or sweating asymmetry.

Motor/trophic: reports of decreased range of motion and/or motor dysfunction (weakness, tremor, dystonia) and/or trophic changes (hair, nails, skin).

3.      Must display at least one sign* in two or more of the following categories:

Sensory: evidence of hyperalgesia (to pinprick) and/or allodynia (to light touch and/or deep somatic pressure and/or joint movement).

Vasomotor: evidence of temperature asymmetry and/or skin color changes and/or asymmetry.

Sudomotor/edema: evidence of edema and/or sweating changes and/or sweating asymmetry.

Motor/trophic: evidence of decreased range of motion and/or motor dysfunction (weakness, tremor, dystonia) and/or trophic changes (hair, nails, skin).

4.      There is no other diagnosis that better explains the signs and symptoms.

*      A sign is counted only if observed at the time of diagnosis.

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TREND research lines

The following 5 research lines are discerned:

-               epidemiology

-               assessment technology

-               trials (pharmacotherapeutics and neurostimulation)

-               biomarkers

-               genetics

 

Epidemiology

The aim of this research line is to obtain insight in various relevant epidemiologic parameters, determinants of disease onset and progression, and public health indicators. Much of this information can be retrieved from the Integrated Primary Care Information (IPCI) database, managed by the department of Medical Informatics of the Erasmus Medical Centre. This is a longitudinal observational database with data from electronic patient records of 150 GPs, covering 380,000 patients in the Netherlands. The IPCI database, as well as data obtained from other resources (e.g., patients participating in trials and familial aggregation studies), will be used to study issues dealing with phenotype characterisation, disease course, prognostic factors and cosegregation of other pain syndromes in families of CRPS patients. More specifically, the aims of this research line are:

-         to assess incidence and prevalence of CRPS-1;

-         to evaluate the diagnostic accuracy and validity of diagnostic criteria sets in CRPS;

-         to describe disease course in CRPS-1;

-         to identify determinants associated with disease onset and progression;

-         to assess the role of immunology in CRPS-1;

-         to evaluate drug use in patients with CRPS-1;

-         to evaluate comorbidity among patients with CRPS-1;

-         to calculate costs associated with CRPS-1.

For more information about this research line, please contact epidemiology@crps.nl

 

Assessment technology

This research field will use the conceptual framework on neurogenic inflammation and central sensitisation and aims to develop measures that reflect the aberrant functioning of the different levels along the pathway linking tissue, peripheral nervous system and central nervous system. Thus measures will be developed that reflect C and Ad fibres mediated functions, sensory processing and sensory motor integration at the spinal cord level, and sensor-motor processing along the spinal-cortical pathways. Some of the techniques for these purposes are already available in one or more of the participating centres and measures that can be derived from these techniques are currently evaluated for their reliability, validity and sensitivity to change. The reporting of the applied methodology will be conducted according to the Standards for reporting of Diagnostic Accuracy (STARD-initiative). Other techniques will be developed in the near future.

Several private companies are participating in the TREND consortium for the development of a new line of neurological assessment instruments, recording the sensori-motor and autonomic behaviour. The instruments are aimed for daily use in neurological departments in hospitals, and should be operated by clinical neurophysiological laborants.  More specifically, the following techniques/modalities will be assessed:

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bradykinesia;

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 temperature (static and dynamic thermography);

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proprioceptieve reflexes;

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temperature discrimination and tolerance thresholds (thermosensory assessment);

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bio-impedance;

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audiometry;

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pulse-transit time;

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functional MRI.  

For more information about this research line, please contact assessment@crps.nl

 

Trials

Drug trials will focus their efforts on the micro model of neurogenic inflammation and central sensitisation. As proof-of-concept studies they will strengthen the theoretical and empirical foundations of the model and provide preliminary information on drugs dose and efficacy/safety profile. All trials will be conducted according to Consolidated Standard of Reporting on Trials (CONSORT statement) and will apply a standardised format for trials (powering, trial duration, outcomes, etc) with respect to methodological issues that pertain to CRPS. Standardisation of trials will enhance comparability of the results. Based on the micro model of CRPS, and information available on the potential efficacy of drugs, interventions are planned for neurogenic inflammation (corticosteroids, anti-TNF a, antagonists of NK1, substance P and CGRP) and central sensitisation (intrathecal administration of baclofen, corticosteroids, glycine, magnesium and spinal cord stimulation).

Other studies in this research line involve spinal cord stimulation. Previously it was shown that pain and quality of life in carefully selected chronic CRPS patients may be improved by this intervention.  Future studies will explore whether similar results can be obtained in an earlier phase of the disease.

For more information about this research line, please contact trials@crps.nl

   

Biomarkers

This research field will strongly rely on pharmacotherapeutic studies that focus on neurogenic inflammation and central sensitisation. From patients participating in the acute trials suction-blister fluid will be collected. Suction blister fluid is derived from interstitial fluid of the dermis, the focus of neurogenic inflammation. All studies on intrathecal administration of drugs in the acute and chronic stage of CRPS will collect cerebrospinal fluid. By evaluating fluids from regions of interest, this approach offers a unique opportunity to elucidate the involved pathophysiological mechanisms by quantifying known mediators of the biological pathway and searching for new biomarkers by quantifying and characterising peptides and proteins through a series of innovative technologies including two-dimensional electrophoresis, mass spectrometry, and bio-informatics.  

For more information about this research line, please contact biomarkers@crps.nl

 

Genetics

The aetiology of CRPS-1 is unknown, but there are indications that genetic factors are involved in this disease. Until now, the nature and significance of these genetic mechanisms have not been studied thoroughly. Two pilot studies at the department of Neurology of the Leiden University Medical Center provided evidence of familial clustering of CRPS-1 beyond what might have been expected based on current knowledge of prevalence rates. Although this finding may be partly explained by shared environmental factors, genetic influences are probably involved. The aim of this research line is to evaluate the extent to which genetic factors are involved in the initiation and progression of CRPS-1 and to study the nature of this involvement. Data is collected in three different ways, all of which involve the collection of DNA from both affected and unaffected family members. In the first approach families with at least two CRPS patients are collected. Linkage analysis in extended families and/or affected sib pair analysis in a large number of sibs will be used to determine the approximate chromosomal location of potentially involved disease genes. For the affected sib pair analysis we aim to include at least 160 affected sib pairs. In the second approach our objective is to enrol at least 325 family trios (patient and both parents) or nuclear families (patient and first-degree relatives) to assess association, using the DNA of parents, sibs or children as control samples. (Blood samples collected by the first approach will also be used in the second approach.) In the third approach the relative importance of environmental and genetic factors in the onset and progression of CRPS will be studied, using the data on the prevalence of CRPS and other trauma-induced syndromes (repetitive strain injury, fibromyalgia) from the Netherlands Twin Register.

With this approach we hope to determine the relative importance of genetic factors in CRPS-1 and to identify the loci involved in this disease. Knowledge of the responsible genes may enhance our understanding of the disease pathway, indicate directions for future research, and may ultimately help to identify potentially efficacious pharmatherapeutic interventions or yield targets for drug development.

For more information about this research line, please contact genetics@crps.nl

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