Cortical Reorganisation in Complex Regional Pain Syndrome (CRPS)

Complex Regional Pain Syndrome (CRPS) is a debilitating pain condition of unknown aetiology, usually occurring post-traumatically. Early diagnosis of CRPS remains a challenge with adverse implications on rehabilitation and recovery. The main goals of my research were to help develop clinically useful bedside tests as well as objective biomarkers to improve the early diagnosis of CRPS. The first research project in this thesis, ‘Novel signs in CRPS and their diagnostic clinical utility’ was a prospective observational cohort study which defined the four novel signs (finger misperception, abnormal hand laterality, astereognosis and abnormal body scheme report) in CRPS, examined their prevalence in CRPS and other chronic pain conditions and assessed their diagnostic utility (Sensitivity, Specificity, Predictive values and Likelihood ratios) for identifying patients at risk of CRPS within a Fracture cohort. This study demonstrates that novel signs are present in the majority of CRPS patients and can be reliably detected following simple training. They are practical and have significant clinical utility in diagnosing persistent pain in a fracture group. They can be used to identify patients at high risk of developing chronic pain post-fracture thereby allowing targeted early intervention. Cortical reorganisation, defined as structural and functional changes within the cerebral cortex, is implicated in many chronic pain conditions including CRPS. The second research project in this thesis ‘Cortical reorganisation and finger misperception in CRPS- a high density electroencephalogram study’ was a prospective case control design study which investigated the EEG parameters suggestive of cortical reorganisation in CRPS patients by studying the somatosensory ERPs (Event Related Potentials) elicited on painless finger stimulation. There was no significant difference in the GFP (Global Field Power) latency in the patient group compared to healthy subjects or between affected and unaffected sides of the patient group suggesting there was no impairment of somatosensory conduction from the periphery to the somatosensory cortex. However, GFP amplitude corresponding to P300 was significantly higher in the patient affected side compared to the healthy subjects suggesting cognitive dysfunction possibly related to increased allocation of attentional resources

Altered Neurocognitive Processing of Tactile Stimuli in Patients with Complex Regional Pain Syndrome (CRPS)

Chronic pain in CRPS has been linked to tactile misperceptions and deficits in somatotopic representation of the affected limb. Here, we identify altered cognitive processing of tactile stimuli in CRPS patients that we propose marks heterogeneity in tactile decision-making mechanisms. In a case-control design, we compared middle and late-latency somatosensory-evoked potentials (SEPs) in response to pseudo-randomised mechanical stimulation of the digits of both hands (including CRPS-affected and non-affected sides) between 13 CRPS patients and 13 matched healthy controls. During a task to discriminate the digit simulated, patients (compared to controls) had significantly lower accuracy and slowed response times but with high between-subject variability. At middle latencies (124-132ms), tactile processing in patients relative to controls showed decrements in superior parietal lobe and precuneus (that were independent of task demands) but enhanced activity in superior frontal lobe (that were task-dependent). At late latencies, patients showed an augmented P300-like response under task demands that localised to supplementary motor area (SMA). Source activity in SMA correlated with slowed response times, while its scalp representation intriguingly correlated with better functioning of the affected limb, suggesting a compensatory mechanism. Future research should investigate the clinical utility of these putative markers of tactile decision-making mechanisms in CRPS

Evidence of a genetic background predisposing to complex regional pain syndrome type 1.

BackgroundComplex regional pain syndrome type 1 (CRPS-1) is a rare, disabling and sometimes chronic disorder usually arising after a trauma. This exploratory study examined whether patients with chronic CRPS-1 have a different genetic profile compared with those who do not have the condition.MethodsExome sequencing was performed to seek altered non-synonymous SNP allele frequencies in a discovery cohort of well-characterised patients with chronic CRPS-1 (n=34) compared with population databases. Identified SNP alleles were confirmed by Sanger sequencing and sought in a replication cohort (n=50). Gene expression of peripheral blood macrophages was assessed.ResultsIn the discovery cohort, the rare allele frequencies of four non-synonymous SNPs were statistically increased. The replication cohort confirmed this finding. In a chronic pain cohort, these alleles were not overexpressed. In total, 25 out of 84 (29.8%) patients with CRPS-1 expressed a rare allele. The SNPs were rs41289586 in ANO10, rs28360457 in P2RX7, rs1126930 in PRKAG1 and rs80308281 in SLC12A9. Males were more likely than females to have a rare SNP allele, 8 out of 14 (57.1%) vs 17 out of 70 (24.3%) (Fisher's p=0.023). ANO10, P2RX7, PRKAG1 and SLC12A9 were all expressed in macrophages from healthy human controls.ConclusionA single SNP in each of the genes ANO10, P2RX7, PRKAG1 and SLC12A9 was associated with developing chronic CRPS-1, with more males than females expressing these rare alleles. Our work suggests the possibility that a permissive genetic background is an important factor in the development of CRPS-1

Challenges in the diagnosis and management of immune-mediated necrotising myopathy (IMNM) in a patient on long-term statins.

Immune-mediated necrotising myopathy (IMNM) is a severe and poorly understood complication of statin use. Prompt management with immunosuppressive treatment is often needed to control the condition, which differs from the management of the more commonly recognised statin-induced myopathy. We present a case report and brief review of the literature regarding the pathogenesis, diagnosis, and management of anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) positive IMNM (HMGCR IMNM). There are no randomised clinical trials, but several smaller studies and cases suggest a triple therapy of corticosteroids, IVIG, and a corticosteroid-sparing immunosuppressant appears efficacious in patients with IMNM and proximal weakness. The mechanism of statin-induced IMNM is uncertain, and this is further complicated by the reports of HMGCR IMNM in statin-naïve patients, including children. We present a case of biopsy-confirmed HMGCR IMNM in a woman taking daily statins for treatment of hypercholesterolaemia for 4 years. She presented with symptoms consistent with a urinary tract infection (UTI), including muscle weakness. She was treated as an isolated case of UTI. One month later, she presented again with worsening weakness in her shoulders and hips. Creatine kinase was elevated, and MRI showed increased signal with STIR sequences in both thighs. Anti-HMGCR was positive and leg biopsy-confirmed necrotising changes. Stopping her statin prescription and a short course of prednisolone did not improve her muscle weakness. Adding methotrexate resulted in eventual resolution of her symptoms. IMNM should be considered as a differential in any patient taking statins presenting with muscle weakness, and this case suggests that immunosuppressant therapy in addition to cessation of statins is effective at treating IMNM. Clinical trials are needed to further investigate the efficacy of different combinations of immunosuppressants

Neurocognitive and Neuroplastic Mechanisms of Novel Clinical Signs in CRPS

Complex Regional Pain Syndrome (CRPS) is a chronic, debilitating pain condition that usually arises after trauma to a limb, but its precise etiology remains elusive. Novel clinical signs based on body perceptual disturbances have been reported, but their pathophysiological mechanisms remain poorly understood. Investigators have used functional neuroimaging techniques (including MEG, EEG, fMRI and PET) to study changes mainly within the somatosensory and motor cortices. Here we provide a focused review of the neuroimaging research findings that have generated insights into the potential neurocognitive and neuroplastic mechanisms underlying perceptual disturbances in CRPS. Neuroimaging findings, particularly with regard to somatosensory processing, have been promising but limited by a number of technique-specific factors (such as the complexity of neuroimaging investigations, poor spatial resolution of EEG/MEG, and use of modelling procedures that do not draw causal inferences) and more general factors including small samples sizes and poorly characterized patients. These factors have led to an underappreciation of the potential heterogeneity of pathophysiology that may underlie variable clinical presentation in CRPS. Also, until now, neurological deficits have been predominantly investigated separately from perceptual and cognitive disturbances. Here, we highlight the need to identify neurocognitive phenotypes of patients with CRPS that are underpinned by causal explanations for perceptual disturbances. We suggest that a combination of larger cohorts, patient phenotyping, the use of both high temporal and spatial resolution neuroimaging methods, and the identification of simplified biomarkers is likely to be the most fruitful approach to identifying neurocognitive phenotypes in CRPS. Based on our review, we explain how such phenotypes could be characterized in terms of hierarchical models of perception and corresponding disturbances in recurrent processing involving the somatosensory, salience and executive brain networks. We also draw attention to complementary neurological factors that may explain some CRPS symptoms, including the possibility of central neuroinflammation and neuronal atrophy, and how these phenomena may overlap but be partially separable from neurocognitive deficits.This is the final version of the article. It first appeared from Frontiers via http://dx.doi.org/10.3389/fnhum.2016.0001

Evidence of a genetic background predisposing to Complex Regional Pain Syndrome type 1

Background Complex regional pain syndrome type 1 (CRPS-1) is a rare, disabling, and sometimes chronic disorder usually arising after a trauma. This exploratory study examined whether patients with chronic CRPS-1 have a different genetic profile compared to those who do not have the condition. Methods Exome sequencing was performed to seek altered non-synonymous SNP allele frequencies in a Discovery Cohort of well-characterised patients with chronic CRPS-1 (n=34) compared to population databases. Identified SNP alleles were confirmed by Sanger sequencing and sought in a Replication Cohort (n=50). Gene expression of peripheral blood macrophages was assessed. Results In the Discovery Cohort, the rare allele frequencies of four non-synonymous SNPs were statistically increased. The Replication Cohort confirmed this finding. In a Chronic Pain Cohort these alleles were not overexpressed. In total 25/84 (29.8%) of patients with CRPS-1 expressed a rare allele. The SNPs were; rs41289586 in ANO10, rs28360457 in P2RX7, rs1126930 in PRKAG1, and rs80308281 in SLC12A9. Males were more likely than females to have a rare SNP allele, 8/14 (57.1%) versus 17/70 (24.3%), (Fischer’s p=0.023). ANO10, P2RX7, PRKAG1 and SLC12A9 were all expressed in macrophages from healthy human controls. Conclusion A single SNP in each of the genes ANO10, P2RX7, PRKAG1 and SLC12A9 was associated with developing chronic CRPS-1, with more males than females expressing these rare alleles. Our work suggests the possibility that a permissive genetic background is an important factor in the development of CRPS-1

Evidence of a genetic background predisposing to complex regional pain syndrome type 1

Peer reviewed: TrueAcknowledgements: We thank the CRPS-UK Registry from which we obtained our study cohort and the study individuals for their enthusiastic participation. MCL, MSN and ID were supported by the Wellcome Trust (200183/Z/15/Z). AG was supported by the Pain Relief Foundation, Liverpool. YP was supported by the Indonesian Endowment Fund for Education (LPDP 201908222915477). SSS, NS, DKM, MCHC and CGW; this research was supported by the NIHR Cambridge Biomedical Research Centre (BRC-1215-20014). The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care. SSS, ID, AD and CGW are members of the UKRI Advanced Pain Discovery Platform.Funder: Pain Relief Foundation, LiverpoolBackgroundComplex regional pain syndrome type 1 (CRPS-1) is a rare, disabling and sometimes chronic disorder usually arising after a trauma. This exploratory study examined whether patients with chronic CRPS-1 have a different genetic profile compared with those who do not have the condition.MethodsExome sequencing was performed to seek altered non-synonymous SNP allele frequencies in a discovery cohort of well-characterised patients with chronic CRPS-1 (n=34) compared with population databases. Identified SNP alleles were confirmed by Sanger sequencing and sought in a replication cohort (n=50). Gene expression of peripheral blood macrophages was assessed.ResultsIn the discovery cohort, the rare allele frequencies of four non-synonymous SNPs were statistically increased. The replication cohort confirmed this finding. In a chronic pain cohort, these alleles were not overexpressed. In total, 25 out of 84 (29.8%) patients with CRPS-1 expressed a rare allele. The SNPs were rs41289586 inANO10, rs28360457 inP2RX7, rs1126930 inPRKAG1and rs80308281 inSLC12A9. Males were more likely than females to have a rare SNP allele, 8 out of 14 (57.1%) vs 17 out of 70 (24.3%) (Fisher’s p=0.023).ANO10,P2RX7,PRKAG1andSLC12A9were all expressed in macrophages from healthy human controls.ConclusionA single SNP in each of the genesANO10, P2RX7, PRKAG1andSLC12A9was associated with developing chronic CRPS-1, with more males than females expressing these rare alleles. Our work suggests the possibility that a permissive genetic background is an important factor in the development of CRPS-1.</jats:sec