Genetic and epidemiological aspect of Complex Regional Pain Syndrome
Rooij, A.M. de
Citation
Rooij, A. M. de. (2010, April 27). Genetic and epidemiological aspect of Complex Regional Pain Syndrome. Retrieved from https://hdl.handle.net/1887/15335
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1
Introduction
Clinical characteristics
Complex Regional Pain Syndrome (CRPS) is a painful disorder affecting one or more extremities. CRPS is characterized by various combinations of sensory, autonomic and motor disturbances.1 Within the sensory domain chronic pain predominates and is frequently associated with positive sensory phenomena, including allodynia (i.e., non- painful stimuli are experienced as painful) and hyperalgesia (i.e., painful stimuli are experienced as extremely painful).2 It is also not uncommon that patients display negative sensory phenomena, including hypoalgesia (i.e., reduced perception of painful stimuli) and hypoesthesia (i.e., reduced perception of subtle touch), or combinations of positive and negative sensory symptoms and signs. The autonomic domain is characterized by changes in skin color, temperature and perspiration, trophic disturbances and edema.3 The motor domain includes muscle weakness and movement disorders.3 Dystonia is the most frequently encountered movement disorder in CRPS 3,4,5 and is characterized by involuntary muscle contractions causing sustained postures.6
Diagnosis of CRPS
The diagnosis of CRPS is made on the basis of clinical criteria. Several different diagnostic criteria sets are used, like those developed by Harden and Bruehl 5,7 and Veldman et al.3 The most commonly used diagnostic criteria, however, are the criteria endorsed by the International Association for the Study of Pain (IASP). These criteria are:
(1) CRPS is a syndrome that develops after an initiating noxious event;
(2) Spontaneous pain, allodynia or 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, changes in color and temperature, or abnormal perspiration in the region of the pain since the inciting event; and (4) The diagnosis is excluded by the existence of conditions that would otherwise
account for the degree of pain and dysfunction.
For the diagnosis of CRPS, criteria 2,3 and 4 must be fulfilled.1
In this thesis, the IASP criteria will be used.
Although the existence of diagnostic criteria may suggest that CRPS is a homogeneous condition, it is important to realize that there is a conspicuous heterogeneity in the
clinical picture, which may point at the existence of subtypes. Indeed, over the years subtypes like ‘CRPS with dystonia’ or ‘warm-type’ and ‘cold-type CRPS’ - dependent on the predominant skin temperature - have been proposed.4,8
Epidemiology
The reported incidence of CRPS ranges from 5.5 to 26.2 per 100,000 person years.9,10 CRPS predominantly affects women (~75%) and may occur at all ages although the highest incidence is found between 50 and 70 years.9 In the majority of patients, CRPS is preceded by a trauma including a fracture, an operation or a soft tissue injury, although spontaneous onsets have been described in about 10% of cases.3 A medical history of asthma, migraine, osteoporosis, menstrual cycle related problems and preexisting neuropathies are associated with CRPS.11 These associations hint towards shared pathogenic or etiologic factors between these diseases and CRPS.11 For instance, neurogenic inflammation is suggested to play a role in asthma and migraine,12,13 a disease mechanism also linked to CRPS.14
Possible disease mechanisms CRPS
Over the years, different pathophysiological mechanisms have been suggested in CRPS, namely disturbances of the autonomic and somatic nervous system, aberrant inflammation, vasomotor dysfunction and psychological factors.15,16
The autonomic nervous system (ANS) is the part of the peripheral nervous system that controls different body functions, like heart rate, body temperature, and transpiration. The ANS can roughly be divided in a parasympathetic (rest and digest) and sympathetic (fight or flight) nervous system. For many years, hyperactivity of the sympathetic nervous system was held responsible for CRPS features, like pain, increased sweating, trophic changes and disturbed vasomotor regulation.17,18
The somatic nervous system (SNS) is the part of the peripheral nervous system that controls voluntary body movement and the processing of sensory information.
Disturbances of the sensory SNS may result in hyperalgesia and allodynia.19 Disturbances of the motor SNS may show itself as weakness, loss of voluntary control, and dystonia.20,21,22
Inflammation is a normal response of the body to tissue injury and is the start of the healing process. A local inflammatory response is characterized by an increase in blood flow to the site of injury, enhanced vascular permeability and an influx of cells of the immune system which help the body to return to its normal state. Since edema,
skin temperature and color changes are prominent symptoms and signs of CRPS, several investigators have suggested that perturbed regulation of inflammation is an important mechanism in CRPS.23,24,25 In support of this view, it was shown that in patients with CRPS levels of pro-inflammatory cytokines (immunomodulating agents) were increased in blister fluid from the affected extremities 24,26 as well as in venous blood.27,28 Additionally, it was shown that neurogenic inflammation played a role in CRPS.15 In neurogenic inflammation nociceptive C-fibers secrete the neuropeptides substance P (SP) and calcitonin-gene-related protein (CGRP), which leads to a vasoactive and immunologic reaction.15,29 This view is supported by the observation that SP causes CRPS-like symptoms in rats30 and by the finding that SP and CGRP levels are elevated in blood of CRPS patients.31
Patients with CRPS may develop cold extremities and cyanotic discoloration of the skin. Contrary to former belief that sympathetic hyperactivity was a major mechanism of disease in CRPS, it was shown that vasomotor dysfunction is associated with a decreased sympathetic activity.32 Later, it became clear that in CRPS, impaired microcirculation of the skin could also result from endothelial dysfunction.33,34 As a result of endothelial dysfunction, tissue is deprived of adequate oxygen supply (i.e., hypoxia).35
In the absence of a clear and generally accepted somatic cause for any disease, psychological factors are often put forward as potential predisposing mechanisms.36,37 However, studies on psychological risk factors, which included a proper control group and where reliable information regarding the period before onset was available, failed to show evidence of premorbid psychopathology in CRPS.38
Finally, it is possible that in CRPS combinations of various disease mechanisms contribute to the heterogeneity of the clinical profile and that different mechanisms may play a role in different patients.16
CRPS is a multifactorial disease
Although the etiology of CRPS is incompletely understood, there are convincing arguments that the syndrome has a multifactorial origin. In a multifactorial disease, environmental and genetic factors both play a role in the development of the disease.
A role for environmental factors in the onset of CRPS is clearly established, given that a physical injury precedes the onset of the syndrome in approximately 90% of the cases.3 Injury thus seems to be an important trigger factor in CRPS. However, an injury is not required as the syndrome may also develop spontaneously.3,39,40,41,42,43 A wide range of eliciting factors have been described, such as fractures, operative
procedures, soft tissue injuries, tumors and infections.44 Environmental factors may also modulate the probability of developing CRPS, as was shown in a recent Dutch study that found a dose- and duration-dependent association between the use of Angiotensin-Converting Enzyme (ACE) inhibitors and the risk of developing this condition.45 ACE is involved in the inactivation of the pro-inflammatory peptides SP and bradykinin,46,47 both well-known mediators of inflammation and peripheral sensitization. Hence, it was hypothesized that inhibition of ACE increases the levels of these peptides thereby contributing to an increased inflammatory response in CRPS.45 In contrast to the environmental factors in CRPS, the role of genetic factors has not been studied thoroughly.
Evidence for a role of genetic factors in disease
In almost every human disease genetic factors contribute to the etiology. Even in infectious diseases, such as bacterial diarrhea, genetics is implicated in either the susceptibility to infection or the severity of the disease.48,49 Understanding the role of genetics in disease etiology will: (i) provide insight into the pathogenesis of the disease;
(ii) assist in providing a more accurate diagnosis; (iii) yield direct targets for potential therapeutic interventions; and (iv) control for known genetic susceptibility to improve the ability to identify other risk factors and additional genes.50 It is generally easier to detect the responsible genetic mechanisms in Mendelian diseases than in complex diseases. In Mendelian disorders a single mutation in a gene causes the disease and the inheritance pattern in families generally is clear.50 Mutations are called high-penetrant, because individuals that carry the mutation have a very high risk of developing the disorder. In complex disorders, such as cardiovascular disease and psychiatric disorders, however, the inheritance pattern is not so clear. Complex diseases are caused by an interplay of environmental and genetic factors. The different genetic factors each confer a relative small risk (i.e., they are low-penetrant) to develop the disease.
There are several different methods to explore the contribution of genetic factors in a disease.
Twin studies: In this type of study, disease concordance in monozygotic twins, whose DNA is virtually 100% identical, is compared with that in dizygotic twins, who share on average 50 % of their DNA. Disease concordance is present, if both twins are affected with the same disease. A greater disease concordance among monozygotic twins compared with dizygotic twins is a strong indication that the disease has a genetic basis. If disease concordance is below 100% this indicates that environmental factors also play a role.
Family studies: If genetic factors play a role in a disease one may expect that the disease aggregates in families. Inheritance patterns are often not straightforward because of reduced penetrance and phenocopies. Reduced penetrance means that the disease does not become manifest in all mutation carriers. Phenocopies define patients that have the disease, but because of a non-genetic cause. For family-based studies, large extended families, large numbers of affected sibpairs, or large numbers of affected relative pairs are needed. These families can be used for linkage or family-based association
studies. In a linkage study, the co-segregation of a chromosomal locus with disease is investigated by testing several hundreds of genetic, multi-allelic, markers evenly spread over all chromsomes using molecular and statistical methodologies. Additional genetic research is aimed to narrow down the locus and identify the disease gene. In an association study, the association between a gene variant and disease is investigated by testing, depending on the whether candidate genes or whole genome is tested, a few to several hundred thousands of so-called single nucleotide polymorphisms, respectively.
In family-based association studies, information on the segregation of associated polymorphisms is used in the statistical analysis.
Recurrence Risk in relatives: If genetic factors are involved in disease etiology, a greater risk of disease is expected in family members compared to the risk of an individual of the general population. This risk depends on the strength of the genetic influence.
Functional studies: If a potential disease gene has been discovered, the ultimate proof that this particular gene indeed is responsible for causing the disease, can be provided by functional studies. In a functional study, evidence is gathered from cellular and/or animal studies that an identified disease mutation or variant affects a readout of the gene (e.g., a difference in enzyme activity, growth advantage of cells, or properties to transport ions or neurotransmitters over the plasma membrane), and can be considered disease-causing or at least involved in the disease.50
Genetic factors in CRPS?
Indications for genetic factors in CRPS
There are several indications that genetic factors may play a role in CRPS. First, CRPS patients with a more severe phenotype, for instance those with multiple affected extremities or CRPS in combination with fixed dystonia, have a substantially younger age at onset compared to patients in whom the disease remits or stabilizes.20,43 The idea is that early-onset forms of a disease are more likely genetic in origin, as opposed to being merely a result of aging or exposure to environmental stimuli.51 Second, the syndrome can develop without a noxious event. Up to 11% of CRPS patients have a spontaneous onset.3,39,40,41,42,43 An increased genetic predisposition could explain why these patients develop the syndrome without an eliciting event. However, some researchers argue that CRPS can not be diagnosed in situations where no clear eliciting event can be identified and the diagnosis of spontaneous CRPS is subject of debate.
Third, CRPS may show familial occurrence. There have been a few case reports of CRPS families with two or three affected members.3,52,53,54,55,56 Although these reports provide some indication of genetic predisposition in these families, it should be realized that this finding may also reflect chance occurrence.
Prior to starting time-consuming and expensive gene identification studies, it is important to be knowledgeable of the potential genetic basis of CRPS. If genetic factors indeed play a role in the onset of CRPS, it is interesting to know how much the risk is increased for direct relatives of patients. This information is not only important from a clinical point of view, because patients typically want to know whether their own diagnosis of CRPS translates to an increased risk of the syndrome in their closest relatives, but also for the design of genetic studies in which knowledge of the magnitude of the genetic effect is essential. If in the general CRPS population, the effect of genetic factors is small, it may be wise to focus on homogeneous subtypes of the syndrome, such as CRPS patients with fixed dystonia. Homogeneous groups likely reflect stronger clinical, pathological, and genetic coherence, which, in turn, may facilitate the understanding of the involved biological pathways. Currently, information on the familial risk of CRPS is not available.
Previous genetic studies in CRPS
A few, mostly small, genetic studies have been performed in CRPS. The first suggestion of a link between CRPS and a possible genetic factor was provided by Mailis and Wade.57 Their study suggested that possible susceptibility genes reside in the Human Leukocyte Antigen (HLA) complex on the short arm of chromosome 6.
The HLA complex comprises a gene family that has important immunologic functions and is very polymorphic. In most situations an association between HLA alleles and disease indicates that this association is a predisposing factor, slightly increasing the risk, and not a high-penetrant mutation.58,59 The role of HLA genes in CRPS was studied by different groups and yielded contradictory results, possibly as a consequence of small patient numbers and broad inclusion criteria of patients. Kemler and coworkers found a significant association between CRPS and HLA-DQ1 in 52 CRPS patients.60 Van Hilten and coworkers found a significant association with HLA- DR13 in 26 CRPS patients with fixed dystonia.61 Vaneker and coworkers did not find any significant results in their total patient population of 161 patients, but a subgroup analysis showed a significant association with HLA-DR6 and HLA-DQ1 in 82 patients with primary cold type CRPS.62 They also found a significant association with a polymorphism of the tumor necrosis factor alpha gene promoter, a gene in the HLA region, in 63 CRPS patients with primary warm-type CRPS.62
Finally, Kimura and coworkers found an association between CRPS and a polymorphism in the ACE gene, that is located on the long arm of chromosome 17,63 but this result was not replicated in an underpowered German study of twelve CRPS patients from six families.55
Possible candidate genes
As an alternative for (relatively) common complex diseases, there is the possibility to study rare monogenic subtypes of the diseases. Unfortunately, at this stage there are no monogenic subtypes known for CRPS. However, there are several familial pain syndromes that show clear overlap in clinical symptoms with CRPS. One such syndrome is primary erythromelalgia (PE), a disease that is characterized by attacks of symmetrical burning pain, as well as red discoloration, edema and increased temperature of the skin of certain extremities.64,65,66 Another related familial pain syndrome is paroxysmal extreme pain disorder (PEPD) that is primarily characterized by attacks of burning pain in the rectal, ocular and mandibular areas which may spread over the whole body. The pain is accompanied by autonomic symptoms such as color changes and edema of the skin.67,68 In both syndromes different mutations have been found in the same gene: the SCN9A gene.65,69 SCN9A encodes for the α 1 subunit of voltage-gated NaV1.7 Na+ channels.70 This channel is predominantly expressed within nociceptors and is able to amplify subtreshold stimuli so they can reach the threshold, thereby setting the gain on nociceptors.71,72,73,74,75 Both the clinical overlap of these syndromes as the function of NaV1.7 Na+ in pain transmission makes SCN9A a good candidate gene.
There are a number of known monogenic forms of dystonia, which could be considered since dystonia is the most frequently encountered movement disorder in CRPS.3,4,5 A role for genetic factors is especially suggested in CRPS patients with fixed dystonia, because this more severe phenotype is associated with a much younger age at onset compared to patients in whom the disease remits or stabilizes. This is also reflected in the increased risk of developing dystonia in other extremities.20 Furthermore, an association with the HLA complex was found in a group of CRPS patients with fixed dystonia.61 At present, at least 17 subtypes of dystonia can be distinguished on a genetic basis.76 In ten of these subtypes, the causative gene has been identified (Table 1).77,78,79,80,81,82,83,84,85,86 Since tissue injury has been identified as a trigger for the onset of some of these genetically established dystonias, these genes may also play a role in the susceptibility for CRPS patients to develop dystonia. In conclusion, genes that have been identified in the disorders that have relevance to CRPS and have been described above may be potentially interesting candidates to test in CRPS.
Table 1 Identified dystonia genes
Dyt Chromosome Gene symbol Name gene
Dyt1 Chr.9 TOR1A Torsin A
Dyt3 Chr.X TAF1 Dystonia 3
Dyt5a Chr.14 GCH1 GTP-cyclohydrolase 1
Dyt5b Chr.11 TH Tyrosine hydroxylase
Dyt6 Chr.8 THAP1 THAP domain containing, apoptosis associated protein 1 Dyt8 Chr.2 PNKD myofibrillogenesis regulator 1 Dyt11 Chr.7 SGCE epsilon-Sarcoglycan
Dyt12 Chr.19 ATP1A3 NA/K ATPase alfa 3 subunit
Dyt16 Chr.2 PRKRA protein kinase, interferon-inducible double stranded RNA dependent activator Dyt18 Chr. 1 SLC2A1 Solute carrier family 2, member 1 Dyt = Dystonia gene; Chr. = Chromosome
Aims of this thesis
The first aim of this thesis was to obtain information on the contribution of genetic factors in the onset and progression of CRPS. It is hypothesized that genetic factors play a larger role in patients who develop CRPS without a clear identifiable trauma, yet some researchers and clinicians argue against the diagnosis of CRPS in situations where no clear eliciting event can be identified. To evaluate whether spontaneous CRPS differs in any respect from CRPS that develops after a clear inciting event, we compared the phenotypic characteristics of CRPS patients with a spontaneous onset with those of patients with a trauma-induced onset in chapter 2. To further examine the potential role of genetic factors in CRPS, we evaluated the familial occurrence of CRPS in the Netherlands in chapter 3.
The second aim was to obtain insight in the size of the contribution of genetic factors in the etiology of CRPS. A possible parameter to assess this is the sibling recurrence risk.
In chapter 4 we calculated this parameter by comparing the risk of CRPS for a person given that his or her sibling is affected to the risk to develop the disease in the general population.87,88 Values higher than one are indicative of familial aggregation.
The third aim was to identify possible susceptibility and causative genes of CRPS. To increase the chance of success we attempted to reduce heterogeneity by using patients from specific CRPS subgroups. In chapter 5 we investigated the contribution of HLA alleles in 150 CRPS patients with fixed dystonia. A link between CRPS-related dystonia and the HLA system has been suggested by a small previous study,61 but would be further supported if this result could be replicated in a large independent population.
In a group of 44 young onset CRPS patients with fixed dystonia we evaluated whether DYT genes play a role in CRPS-related dystonia. To enhance our chance of success we selected DYT genes that showed resemblance to disease characteristics of CRPS or have a known function in pathways suggested to play a role in CRPS. For this reason we sequenced DYT1 (TorsinA), DYT5a (GTP cyclohydrolase 1), DYT5b (Tyrosine Hydroxylase), DYT11 (epsilon-sarcoglycan), DYT12 (NA/K ATPase alfa 3 subunit) and DYT16 (protein kinase, interferon-inducible double stranded RNA dependent activator). The findings are discussed in chapter 6.
Because of the clinical overlap of CRPS with two familial painful disorders with a gain-of-function mutation in the SCN9A gene; i.e. inherited erythromelalgia 65 and paroxysmal extreme pain disorder69 probands of four CRPS families were systematically scanned for mutations in this gene in chapter 7.
A general discussion of the results of this thesis and suggestions for further genetic research are provided in Chapter 8.
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