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Objective Motor dysfunction in Complex Regional Pain Syndrome (CRPS) has been associated with bilateral changes in central motor processing, suggesting abnormal coupling between the affected and unaffected limb. We evaluated the occurrence of involuntary muscle activity in a limb during voluntary movements of the contralateral limb (i.e., mirror activity) in unilaterally affected patients to examine disinhibition of contralateral motor activity in CRPS. Methods Mirror activity was examined during unimanual rhythmic flexion–extension movements of the wrist through in-depth analysis of electromyography recordings from the passive arm in 20 CRPS patients and 40 controls. Results The number of mirror-epochs was comparable for both arms in both CRPS patients and controls. Mirror-epochs in the affected arm of patients were comparable to those in controls. Mirror-epochs in the unaffected arm were shorter and showed less resemblance (in terms of rhythm and timing) to activity of the homologous muscle in the moving arm compared to mirror-epochs in controls. Conclusions No evidence for disinhibition of contralateral motor activity was found during unimanual movement. Significance Although motor dysfunction in CRPS has been associated with bilateral changes in cortical motor processing, the present findings argue against disinhibition of interhemispheric projections to homologous muscles in the contralateral limb during unimanual movement.

Patients with complex regional pain syndrome (CRPS) frequently show prominent sensory abnormalities in their affected limb, which may extend proximally and even to unaffected body regions. This study examines whether sensory dysfunction is observed in unaffected body parts of CRPS patients, and investigates whether the extent of dysfunction is similar for the various sensory modalities. Quantitative sensory testing was performed in the unaffected extremities and cheeks of 48 patients with CRPS of the arm (31 with dystonia), and the results were compared with values obtained among healthy controls. The most prominent abnormality was the pressure pain threshold, which showed a consistent pattern of higher sensitivity in unaffected contralateral arms and unaffected legs, as well as the cheek, and demonstrated the largest effect sizes. The cheeks of CRPS patients showed thermal hypoesthesia and hyperalgesia as well as a loss of vibration detection. Except for a lower vibration threshold in the contralateral leg of CRPS patients with dystonia, no differences in sensory modalities were found between CRPS patients with and without dystonia. These results point to a general disturbance in central pain processing in patients with CRPS, which may be attributed to impaired endogenous pain control. Since pressure pain is the most deviant sensory abnormality in both unaffected and affected body regions of CRPS patients, this test may serve as an important outcome parameter in future studies and may be used as a tool to monitor the course of the disease.

At present it is unclear if disturbed sensory processing plays a role in the development of the commonly observed motor impairments in patients with complex regional pain syndrome (CRPS). This study aims to investigate the relation between sensory and motor functioning in CRPS patients with and without dystonia. Patients with CRPS of the arm and controls underwent comprehensive quantitative sensory testing and kinematic analysis of repetitive finger movements. Both CRPS groups showed thermal hypoesthesia to cold and warm stimuli and hyperalgesia to cold stimuli. A decreased pressure pain threshold reflecting muscle hyperalgesia emerged as the most prominent sensory abnormality in both patient groups and was most pronounced in CRPS patients with dystonia. Moreover, the decreased pressure pain threshold was the only nociceptive parameter that related to measures of motor function in both patients and controls. CRPS patients with dystonia had an increased 2-point discrimination as compared to controls and CRPS patients without dystonia. This finding was also reported in other types of dystonia and has been associated to cortical reorganization in response to impaired motor function. We hypothesize that increased sensitivity of the circuitry mediating muscle nociception may play a crucial role in impaired motor control in CRPS.This is the first study linking a sensory dysfunction, ie, muscle hyperalgesia, to motor impairment in CRPS. Circuitries mediating muscle nociception may therefore play an important role in impaired motor control in CRPS.

The aim of this study was to identify risk factors for the development of hallucinations in patients with Parkinson's disease (PD). A broad range of motor and nonmotor features was assessed at baseline and during the following 5 years in 386 PD patients. Cross-sectional analyses of baseline data and longitudinal analyses of follow-up data were performed to identify risk factors for hallucinations in PD. Twenty-one percent of the patients had hallucinations at baseline, whereas 46% of the patients without hallucinations at baseline developed this feature during follow-up. Univariate survival analysis showed that older age, female sex, less education, higher age at onset, and more severe motor and cognitive impairment, depression, daytimes sleepiness, autonomic dysfunction, and motor fluctuations and dyskinesias, as well as higher daily levodopa dose, were associated with the risk of developing hallucinations. This largely corresponds with the features that were associated with the presence of hallucinations at baseline. In a stepwise regression model, older age at onset, female sex, excessive daytime sleepiness, autonomic dysfunction, and dyskinesias emerged as independent risk factors for developing hallucinations. Female sex, autonomic dysfunction, motor fluctuations, and dyskinesias have not been reported as risk factors in previous studies. These findings lend support to the notion that hallucinations in PD are caused by a combination of risk factors that are associated with (the interaction between) older age and more advanced disease. The identification of female sex as a risk factor for developing of hallucinations in PD is a new finding and should be verified in future studies.

BACKGROUND: Studies of genetic association between TOR1A and adult-onset primary torsion dystonia have contradictory results. METHODS: The authors genotyped TOR1A single nucleotide polymorphisms rs1801968, rs2296793, rs1182 and rs3842225 in a cohort of clinically well characterized cervical dystonia patients (n=367) and constructed haplotypes. The authors systematically reviewed the published case-control TOR1A association studies in adult-onset primary torsion dystonia. RESULTS: In this Dutch cervical dystonia cohort, no significant association was found with TOR1A variants. In the meta-analysis (eight studies, 1332 adult-onset primary dystonia patients) no variant reached overall significance. However, in a selection of familial cases the functional variant p.Asp216His (rs1801968) was associated with increased dystonia risk (odds ratio 1.43; 95%CI 1.01-2.02). CONCLUSIONS: Meta-analysis does not show association with common variants in TOR1A in adult-onset primary dystonia, except for the functional variant rs1801968 in familial focal dystonia cases. (c) 2013 Movement Disorder Society.

Genetic disorders causing dystonia show great heterogeneity. Recent studies have suggested that next-generation sequencing techniques such as gene panel analysis can be effective in diagnosing heterogeneous conditions. The objective of this study was to investigate whether dystonia patients with a suspected genetic cause could benefit from the use of gene panel analysis.In this post hoc study, we describe gene panel analysis results of 61 dystonia patients (mean age, 31 years; 72% young onset) in our tertiary referral center. The panel covered 94 dystonia-associated genes. As comparison with a historic cohort was not possible because of the rapidly growing list of dystonia genes, we compared the diagnostic workup with and without gene panel analysis in the same patients. The workup without gene panel analysis (control group) included theoretical diagnostic strategies formulated by independent experts in the field, based on detailed case descriptions. The primary outcome measure was diagnostic yield; secondary measures were cost and duration of diagnostic workup.Workup with gene panel analysis led to a confirmed molecular diagnosis in 14.8%, versus 7.4% in the control group (P = 0.096). In the control group, on average 3 genes/case were requested. The mean costs were lower in the gene panel analysis group (€1822/case) than in the controls (€2660/case). The duration of the workup was considerably shorter with gene panel analysis (28 vs 102 days).Gene panel analysis facilitates molecular diagnosis in complex cases of dystonia, with a good diagnostic yield (14.8%), a quicker diagnostic workup, and lower costs, representing a major improvement for patients and their families. © 2016 International Parkinson and Movement Disorder Society.

Introduction In spite of the multisystem nature of Parkinson's disease (PD), the formal assessment of its impairments is focused on symptoms predominantly reflecting degeneration of dopaminergic neurons. The aim of this study was to develop a valid and reliable rating scale of predominantly non-dopaminergic (PND) symptoms, which can be used as an additional measure of severity and progression of PD. Methods Using data of the PROPARK (N = 396) and ELEP (N = 365) cohorts, three items were selected from each of six selected PND domains (cognitive impairment, depressive symptoms, excessive daytime sleepiness, psychotic symptoms, autonomic dysfunction and Postural-Instability-and-Gait-Difficulty), based on item–total correlations. Hereafter, we evaluated reliability and validity of the resulting scale. Results The 18-item PND scale showed to be reliable and valid. Cronbach's alpha was 0.83. Principal component analysis using the six domain scores resulted in one factor, justifying the calculation of a sum score. Correlation coefficients of the sum score with severity of non-motor symptoms (non-motor part of MDS–UPDRS), motor symptoms (SPES/SCOPA scale), and Hoehn and Yahr stage were 0.63, 0.41 and 0.48, respectively (p Conclusion We developed a short, reliable and valid scale to evaluate severity of PND symptoms in PD. The score is expected to be largely insensitive to dopaminergic effects and may therefore more accurately reflect severity and progression of the underlying disease than currently used dopamine-sensitive measures. In combination with assessment of predominantly dopaminergic (motor) symptoms, a broad yet concise evaluation of PD is obtained, which better captures the widespread clinical consequences of the multisystem disease.

Introduction Excessive daytime sleepiness (EDS) is a common feature of Parkinson's disease (PD) that contributes to the disease burden and increases risk of harm. The aim of this study was to examine persistency, cross-sectional and longitudinal associations, and risk factors for EDS in patients with PD. Methods Analyses were performed on data from the SCOPA–PROPARK cohort, a 5-year hospital-based longitudinal cohort of over 400 PD patients who were examined annually. Cross-sectional analyses were conducted to evaluate differences between patients with and without EDS at baseline, while linear mixed models using data of all patients were used to identify factors associated with longitudinal changes in SCOPA-SLEEP-Daytime Sleepiness (SCOPA-SLEEP-DS) scores. A survival analysis was done using data of patients without EDS at baseline to identify risk factors for future EDS. Results EDS proved a non-persistent symptom, although persistency and the proportion of patients with EDS increased with longer follow-up. At baseline 43% of patients had EDS, while 46% of patients without EDS at baseline developed this symptom during follow-up. Male gender, poorer nighttime sleep, cognitive and autonomic dysfunction, hallucinations, less severe dyskinesias, dose of dopamine agonists and use of antihypertensives were associated with higher EDS scores over time, while use of benzodiazepines was associated with lower scores. Baseline SCOPA-SLEEP-DS score and PIGD phenotype were risk factors for future EDS. Conclusion With longer disease duration a large proportion of patients develop EDS. Some risk factors are modifiable and patients should be monitored to improve quality of life and reduce risk of harm.

Contains fulltext : 95644.pdf (Publisher’s version ) (Closed access) OBJECTIVE: Several studies have suggested an increased frequency of variants in the gene encoding angiogenin (ANG) in patients with amyotrophic lateral sclerosis (ALS). Interestingly, a few ALS patients carrying ANG variants also showed signs of Parkinson disease (PD). Furthermore, relatives of ALS patients have an increased risk to develop PD, and the prevalence of concomitant motor neuron disease in PD is higher than expected based on chance occurrence. We therefore investigated whether ANG variants could predispose to both ALS and PD. METHODS: We reviewed all previous studies on ANG in ALS and performed sequence experiments on additional samples, which allowed us to analyze data from 6,471 ALS patients and 7,668 controls from 15 centers (13 from Europe and 2 from the USA). We sequenced DNA samples from 3,146 PD patients from 6 centers (5 from Europe and 1 from the USA). Statistical analysis was performed using the variable threshold test, and the Mantel-Haenszel procedure was used to estimate odds ratios. RESULTS: Analysis of sequence data from 17,258 individuals demonstrated a significantly higher frequency of ANG variants in both ALS and PD patients compared to control subjects (p = 9.3 x 10(-6) for ALS and p = 4.3 x 10(-5) for PD). The odds ratio for any ANG variant in patients versus controls was 9.2 for ALS and 6.7 for PD. INTERPRETATION: The data from this multicenter study demonstrate that there is a strong association between PD, ALS, and ANG variants. ANG is a genetic link between ALS and PD. ANN NEUROL 2011;70:964-973. 01 december 2011 10 p.

Parkinson's disease (PD) and restless legs syndrome (RLS) have a dopaminergic link. More insight in the clinical profile of RLS in patients with PD may benefit our understanding of this link. The aims of this study were to evaluate the frequency and clinical profile of RLS in a large cohort of PD patients. In 269 nondemented Caucasian PD patients, the four diagnostic criteria for RLS were administered by a RLS trained researcher. In patients with definite RLS, the severity of these symptoms was assessed. Furthermore, in all patients, relevant motor and nonmotor symptoms in PD were evaluated. Definite RLS was present in 11% of the patients. RLS patients were more often female (69% vs. 32%, P < 0.001), but no other significant differences existed between PD patients with and without RLS. Within the PD patients with RLS, severity of RLS correlated positively with PD severity, motor fluctuations, depressive symptoms, daytime sleepiness, cognitive problems, autonomic symptoms, and psychotic symptoms. This study in a large PD cohort shows that prevalence of RLS is similar to that in the general population, which might be caused by underestimation of RLS due to dopaminergic treatment. No relations were found between the presence of RLS and PD symptoms, but the severity of RLS was related to the severity of PD-related, mainly nondopaminergic, symptoms. It is hypothesized that, nondopaminergic systems, such as the noradrenergic system may play a role in the possible link between PD and RLS. (C) 2010 Movement Disorder Society

About 25% of the patients with complex regional pain syndrome (CRPS) suffer movement disorders, including loss of voluntary control, bradykinesia, dystonia, myoclonus, and tremor. These movement disorders are generally difficult to manage and add considerably to the disease burden. Over the last years, interesting findings have emerged that show how tissue or nerve injury may induce spinal plasticity (central sensitization), which alters sensory transmission and sensorimotor processing in the spinal cord and is associated with disinhibition. These changes, in turn, set the stage for the development of movement disorders seen in CRPS. There are no randomized control studies on the treatment of movement disorders in CRPS but findings from fundamental and clinical research suggest that strategies that enhance the central inhibitory state may benefit these patients.

Complex Regional Pain Syndrome (CRPS) is clinically characterized by pain in combination with sensory, autonomic, and motor symptoms that may include weakness, tremor, myoclonus and dystonia of the affected limb(s). The syndrome is multifactorial in origin and mostly attributed to tissue injury. There is some evidence that the human leukocyte antigen (HLA) system plays a role in the pathophysiology of CRPS, but previous studies lacked power. Here we performed the most extensive study investigating the contribution of HLA alleles (i.e. HLA-A, HLA-B, HLA-DRB1, and HLA-DQB1) in 150 CRPS patients who also had fixed dystonia. HLA-B62 (OR=2.05 [95% CI 1.41-2.99], P=0.0005) and HLA-DQ8 (OR=1.75 [95% CI 1.20-2.57], P=0.005) were found significantly associated with CRPS and dystonia. The association remained significant after correction (HLA-B62 P(corrected) [P(c)] = 0.02 and HLA-DQ8 P(c)=0.04). The involvement of HLA-B62 and HLA-DQ8 in CRPS with dystonia may indicate that these HLA loci are implicated in the susceptibility or expression of the disease.

To identify patterns of motor disturbances in Parkinson's disease (PD) and evaluate their relation with other PD domains. A cohort of 399 PD patients was randomly divided into two samples. Factors within the motor section of the SPES/SCOPA were identified by exploratory factor analysis on data from the first sample and next tested by confirmatory factor analysis in the second sample. Relations with other PD domains were evaluated by regression analyses. A four factor model was found to be valid. This included a tremor, a bradykinetic-rigid, and two axial factors. One axial factor ("rise", "gait", "postural instability") was associated with age and cognition, while the other axial factor ("freezing", "speech", "swallowing") was related to dopaminergic medication and complications of therapy. Both other factors showed no relevant associations with demographic and clinical characteristics. The identification of motor factors and their relation with other domains of the disease may help to elucidate the mechanisms responsible for these associations and provide an objective base for further research on subtypes in PD.

Item does not contain fulltext The objective of this study Was to evaluate psychological features in severely affected patients with complex regional pain syndrome type I- (CRPS-I) related dystonia. Personality traits. psychopathology. dissociative experiences. the number of traumatic experiences, and quality of life Were studied in 46 patients. Findings were compared with two historical psychiatric control groups [54 patients with conversion disorder (CD) and 50 patients smith affective disorders (AD)] and normative population data. The CRPS-I patients showed elevated scores on the measures for somatoform dissociation. traumatic experiences. general psychopathology. and lower scores on quality of life compared with general Population data. but had significantly lower total scores on the measures for personality trails, recent life events. and general psychopathology compared with the CD and AD patients. Rates of early traumatic experiences were comparable with the CD and AD patients, and the level of somatoform dissociation was comparable to the CD patients, but was elevated in comparison to the AD patients. Early traumatic experiences were reported in 87% of the CRPS-I patients and were found to be moderately related to somatoform dissociative experiences, indicating that early traumatic experiences might be a predisposing, although not a necessary factor for the development of CRPS-I-related dystonia. Although the psychological profile of the patients with CRPS-I-related dystonia shows some elevations, there dose not scent to be a unique disturbed psychological profile on a group level.

Collins S, van Hilten JJ, Marinus J, Zuurmond WW, de Lange JJ, Perez RS. Development of a symptoms questionnaire for complex regional pain syndrome and potentially related illnesses: the Trauma Related Neuronal Dysfunction Symptoms Inventory. Objective To develop a questionnaire to evaluate symptoms of complex regional pain syndrome type I (CRPS-I), fibromyalgia, and repetitive strain injury to determine the test-retest reliability and investigate concurrence in the clinical manifestations of CRPS-I and fibromyalgia. Design The Trauma Related Neuronal Dysfunction Symptoms Inventory (TSI) was developed by determining the content validity and the practical use of the questionnaire. Furthermore, the test-retest reliability was assessed on 2 identical questionnaires filled out within a 7-day interval by CRPS-I and fibromyalgia patients. Setting Outpatient pain clinic of a Dutch medical center. Participants CRPS-I (n=26; mean age, 54y) and fibromyalgia patients (n=42; mean age, 45.4y). Interventions Not applicable. Main Outcome Measure Test-retest reliability calculated with intraclass correlation (ICC). Results Reliability scores were good for the whole questionnaire, its categories, and domains (ICC>.75) for both CRPS-I and fibromyalgia patients. Sensory complaints (except for change in cold perception), motor complaints, and visceral complaints (diarrhea and incontinence) were reported by both CRPS-I and fibromyalgia patients. A change in cold perception, discoloration, change in skin temperature, change in sweating behavior, change in the severity of edema during exercise, and trophic changes of skin were reported significantly more often by CRPS-I patients, whereas complaints of the (upper and lower) back, constipation, urine retention, and experiencing a dry mouth were reported significantly more often by fibromyalgia patients. Conclusions The TSI is a reliable instrument with good content validity, which can be used in the evaluation of similarities and differences between CRPS-I and fibromyalgia. The systematic evaluation of symptoms of CRPS-I and potentially related illnesses may provide a better basis for future research into the underlying mechanism(s).

The pathogenesis of dystonia in Complex Regional Pain Syndrome type 1 (CRPS-1) is unclear. In primary dystonia, functional magnetic resonance imaging (fMRI) has revealed changes in cerebral networks during execution of movement. The aim of this study was to determine cerebral network function in CRPS-1 patients with dystonic postures. Cerebral processing related to both execution and imagining of hand movements in patients and controls was assessed with fMRI. Eight CRPS-1 patients with dystonic postures of the right upper extremity and 17 age-matched healthy controls were studied. Compared with controls, imaginary movement of the affected hand in patients showed reduced activation ipsilaterally in the premotor and adjacent prefrontal cortex, and in a cluster comprising frontal operculum, the anterior part of the insular cortex and the superior temporal gyrus. Contralaterally, reduced activation was seen in the inferior parietal and adjacent primary sensory cortex. There were no differences between patients and controls when they executed movements, nor when they imagined moving their unaffected hand. The altered cerebral activation pattern in patients with CRPS-I linked dystonia most likely reflects an interface between pain-associated circuitry and higher order motor control, which points at a specific mechanistic pathophysiology of this type of dystonia. (c) 2007 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

Objective: Chronic painful disease is associated with pain on movement, which is presumed to be caused by noxious stimulation. We investigated whether motor imagery, in the absence of movement, increases symptoms in patients with chronic arm pain. Methods: Thirty‐seven subjects performed a motor imagery task. Pain and swelling were measured before, after, and 60 minutes after the task. Electromyography findings verified no muscle activity. Patients with complex regional pain syndrome (CRPS) were compared with those with non‐CRPS pain. Secondary variables from clinical, psychophysical, and cognitive domains were related to change in symptoms using linear regression. Results: Motor imagery increased pain and swelling. For CRPS patients, pain (measured on a 100‐mm visual analog scale) increased by a mean ± SD of 5.3 ± 3.9 mm and swelling by 8% ± 5%. For non‐CRPS patients, pain increased by 1.4 ± 4.1 mm and swelling by 3% ± 4%. There were no differences between groups (P > 0.19 for both). Increased pain and swelling related positively to duration of symptoms and performance on a left/right judgment task that interrogated the body schema, autonomic response, catastrophic thoughts about pain, and fear of movement (r > 0.42, P < 0.03 for all). Conclusion: Motor imagery increased pain and swelling in patients with chronic painful disease of the arm. The effect increased in line with the duration of symptoms and seems to be modulated by autonomic arousal and beliefs about pain and movement. The results highlight the contribution of cortical mechanisms to pain on movement, which has implications for treatment.

Our objective is to evaluate nighttime sleep problems (NSP) and daytime sleepiness (DS) in patients with Parkinson's disease (PD) compared to controls, and to assess relations with demographic, disease-related, and clinical characteristics in patients. NSP and DS were evaluated with the SCOPA-SLEEP questionnaire in PD patients and controls. In patients, other disease-related and clinical characteristics were also evaluated. Four hundred twenty PD patients [mean (SD) age 61.1 (11.5) years] and 150 controls [mean (SD) age 60.9 (9.9) years] participated in the study. Compared to controls, a significantly greater proportion of patients had excessive DS (EDS) (43 vs. 10%), excessive NSP (ENSP) (27 vs. 9%), or used sleep medication (17 vs. 12%). Difficulties with falling asleep were similar in both groups. In both patients and controls, women experienced more NSP than men. In patients, depressive symptoms accounted for 21% of NSP variance and was the major contributor to the total explained variance (30%). Furthermore, NSP were related to dopamine-agonist and levodopa dose, whereas DS was related to age, dopamine-agonist dose, and disease severity. NSP and DS occur frequently in PD, with EDS being reported more commonly than ENSP. No strong relations were found between DS and demographic or clinical variables. The strong relation between NSP and depressive symptoms in PD calls for future studies to explore the nature of this relation.

The origin Of myoclonus ill patients with complex regional pain syndrome (CRPS) is unknown. Eight patients with CRPS related myoclonus were clinically evaluated and Studied with intermuscular and corticomuscular coherence analysis. Jerks were present at test, aggravated during action and were frequently associated with tremulousness or dystonia. Electromyography demonstrated a burst duration ranging from 25 to 240 ins with burst frequencies varying from

Contains fulltext : 167923.pdf (Publisher’s version ) (Open Access) Autosomal-recessive early-onset parkinsonism is clinically and genetically heterogeneous. The genetic causes of approximately 50% of autosomal-recessive early-onset forms of Parkinson disease (PD) remain to be elucidated. Homozygozity mapping and exome sequencing in 62 isolated individuals with early-onset parkinsonism and confirmed consanguinity followed by data mining in the exomes of 1,348 PD-affected individuals identified, in three isolated subjects, homozygous or compound heterozygous truncating mutations in vacuolar protein sorting 13C (VPS13C). VPS13C mutations are associated with a distinct form of early-onset parkinsonism characterized by rapid and severe disease progression and early cognitive decline; the pathological features were striking and reminiscent of diffuse Lewy body disease. In cell models, VPS13C partly localized to the outer membrane of mitochondria. Silencing of VPS13C was associated with lower mitochondrial membrane potential, mitochondrial fragmentation, increased respiration rates, exacerbated PINK1/Parkin-dependent mitophagy, and transcriptional upregulation of PARK2 in response to mitochondrial damage. This work suggests that loss of function of VPS13C is a cause of autosomal-recessive early-onset parkinsonism with a distinctive phenotype of rapid and severe progression.

Introduction The aim of this study was to evaluate odor identification testing as a quick, cheap, and reliable tool to identify PD. Methods Odor identification with the 16‐item Sniffin' Sticks test (SS‐16) was assessed in a total of 646 PD patients and 606 controls from three European centers (A, B, and C), as well as 75 patients with atypical parkinsonism or essential tremor and in a prospective cohort of 24 patients with idiopathic rapid eye movement sleep behavior disorder (center A). Reduced odor sets most discriminative for PD were determined in a discovery cohort derived from a random split of PD patients and controls from center A using L1‐regularized logistic regression. Diagnostic accuracy was assessed in the rest of the patients/controls as validation cohorts. Results Olfactory performance was lower in PD patients compared with controls and non‐PD patients in all cohorts (each P < 0.001). Both the full SS‐16 and a subscore of the top eight discriminating odors (SS‐8) were associated with an excellent discrimination of PD from controls (areas under the curve ≥0.90; sensitivities ≥83.3%; specificities ≥82.0%) and from non‐PD patients (areas under the curve ≥0.91; sensitivities ≥84.1%; specificities ≥84.0%) in all cohorts. This remained unchanged when patients with >3 years of disease duration were excluded from analysis. All 8 incident PD cases among patients with idiopathic rapid eye movement sleep behavior disorder were predicted with the SS‐16 and the SS‐8 (sensitivity, 100%; positive predictive value, 61.5%). Conclusions Odor identification testing provides excellent diagnostic accuracy in the distinction of PD patients from controls and diagnostic mimics. A reduced set of eight odors could be used as a quick tool in the workup of patients presenting with parkinsonism and for PD risk indication. © 2016 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society

Complex regional pain syndrome (CRPS) may lead to movement disorders (MDs) in some patients. Reliable information on the nature, chronology and clinical determinants of MDs in CRPS patients is lacking but could provide better insight in to the underlying pathophysiological mechanism. We retrospectively evaluated the clinical and temporal characteristics of MDs in patients with CRPS. Cox's proportional hazards model was used to evaluate factors influencing the onset of MDs. One-hundred and eighty-five patients suffered CRPS in one or more extremities. MDs occurred in 121 patients, with dystonia (91%) being the most prevalent. Sixty-two percent of these patients displayed dystonia in multiple extremities. Patients with dystonia were on average 11 years younger and more often had CRPS in multiple extremities. The interval between the onset of CRPS and dystonia in the first affected extremity varied from less than 1 week in 26% of the patients to more than 1 year in 27%. The hazard of developing dystonia in subsequent extremities increased with the number of extremities affected by dystonia. We conclude that dystonia in CRPS shows highly variable onset latency and is associated with younger age at onset and increased risk of developing dystonia in other extremities. The delayed onset and progression of dystonia in CRPS may indicate the involvement of a different underlying mechanism, possibly associated with maladaptive neuroplasticity.

Early diagnosis is important for effective disease management. Measurement of biomarkers present at the local level of the skin could be advantageous in facilitating the diagnostic process. The analysis of the proteome of suction blister fluid, representative for the interstitial fluid of the skin, is therefore a desirable first step in the search for potential biomarkers involved in biological pathways of particular diseases. Here, we describe a global analysis of the suction blister fluid proteome as potential body fluid for biomarker proteins. The suction blister fluid proteome was compared with a serum proteome analyzed using identical protocols. By using stringent criteria allowing less than 1% false positive identifications, we were able to detect, using identical experimental conditions and amount of starting material, 401 proteins in suction blister fluid and 240 proteins in serum. As a major result of our analysis we construct a prejudiced list of 34 proteins, relatively highly and uniquely detected in suction blister fluid as compared to serum, with established and putative characteristics as biomarkers. We conclude that suction blister fluid might potentially serve as a good alternative biomarker body fluid for diseases that involve the skin.

The question whether peripheral trauma can cause movement disorders has since long been a subject of debate. In this review we present the pro's and con's of arguments that have been presented in the literature and discuss their plausibility. Additionally, recent developments on the potential mechanisms that underlie dystonia in complex regional pain syndrome are used to illustrate how the relation between peripheral trauma and movement disorders may evolve.

The objective of this study was to develop a clinimetric sound scale that addresses both psychotic and compulsive complications in Parkinson's disease (PD). The SCales for Outcomes in PArkinson's disease-Psychiatric Complications (SCOPA-PC) was developed by modifying the items of the Parkinson Psychosis Rating Scale (PPRS) and including an item on compulsive behavior in PD. To evaluate the validity of the SCOPA-PC, 106 PD patients were assessed. A subsample of 43 patients was assessed for interrater and test-retest reliability. Construct validity was evaluated using the Neuropsychiatric Inventory (NPI) and the South Oaks Gambling Scale (SOGS). Interrater and test-retest reliability for the total score was 0.95 and 0.91 (intraclass correlation coefficient), respectively. For the items, the interrater reliability ranged from 0.62 to 0.96 (weighted kappa) and the test-retest reliability ranged from 0.54 to 0.88 (weighted kappa). Cronbach's alpha was 0.68. The correlation between the SCOPA-PC total score and the NPI was 0.41. The correlation between SCOPA-PC items and NPI items that addressed similar constructs ranged from 0.34 to 0.68, whereas the correlation between the item on compulsive behavior and the SOGS was 0.49. In conclusion, the SCOPA-PC is a reliable, valid, and easily-administered semistructured questionnaire for both psychotic and compulsive complications in PD.

Complex regional pain syndrome (CRPS) is a multifactorial disorder associated with an aberrant host response to tissue injury. About 25% of CRPS patients suffer poorly understood involuntary sustained muscle contractions associated with dysfunctional reflexes that result in abnormal postures (fixed dystonia). A recent modeling study simulated fixed dystonia (FD) caused by aberrant force feedback. The current study aims to validate this hypothesis by experimentally recording the modulation of reflexive force feedback in patients with FD. CRPS patients with and without FD, patients with FD but without CRPS, as well as healthy controls participated in the experiment. Three task instructions and three perturbation characteristics were used to evoke a wide range of responses to force perturbations. During position tasks ('maintain posture'), healthy subjects as well as patients resisted the perturbations, becoming more stiff than when being relaxed (i.e., the relax task). Healthy subjects and CRPS patients without FD were both more compliant during force tasks ('maintain force') than during relax tasks, meaning they actively gave way to the imposed forces. Remarkably, the patients with FD failed to do so. A neuromuscular model was fitted to the experimental data to separate the distinct contributions of position, velocity and force feedback, as well as co-contraction to the motor behavior. The neuromuscular modeling indicated that inhibitory force feedback is deregulated in patients with FD, for both CRPS and non-CRPS patients. From previously published simulation results and the present experimental study, it is concluded that aberrant force feedback plays a role in fixed dystonia.

© 2015 American Academy of Pain Medicine. Objective: Sustained abnormal postures (i.e., fixed dystonia) are the most frequently reported motor abnormalities in complex regional pain syndrome (CRPS), but these symptoms may also develop after peripheral trauma without CRPS. Currently, there is no valid and reliable measurement instrument available to measure the severity and distribution of these postures. The range of motion scale (ROMS) was therefore developed to assess the severity based on the possible active range of motion of all joints (arms, legs, trunk, and neck), and the present study evaluates its reliability and validity. Methods: Inter- and intra-rater reliability of the ROMS was determined in 16 patients with abnormal sustained postures, who were videotaped following a standard video protocol in a university hospital. The recordings were rated by a panel of international experts. In addition, 30 patients were clinically tested with both the Burke-Fahn-Marsden (BFM) scale as well as the ROMS to assess construct validity. Results: Inter-rater reliability for total ROMS scores showed an intra-class correlation coefficient (ICC) of 0.85. The majority of the scores for the separate joints (13 out of 18) demonstrated an almost perfect agreement with ICCs ranging from 0.81 to 0.94; of the other items, one showed fair, one moderate, and three substantial agreement. The ICCs for the intra-rater reliability ranged from moderate to almost perfect (0.68-0.98). Spearman's correlation coefficients between corresponding body areas as measured with the ROMS or BFM were all above 0.82. Conclusion: The ROMS is a reliable and valid instrument to evaluate the severity and distribution of sustained abnormal postures.

To systematically evaluate and compare the clinical manifestations, disease course, risk factors and demographic characteristics of Complex Regional Pain Syndrome type 1 (CRPS), fibromyalgia (FM) and a-specific Repetitive Strain Injury (RSI).A literature search was performed using terms related to the aforementioned topics and diseases. Only original clinical studies that included at least 20 subjects were eligible.Fifty-nine studies on CRPS, 73 on FM and 7 on a-specific RSI were identified. The diseases show similarities in age distribution, male-female ratio, pain characteristics and sensory signs and symptoms. Motor, autonomic and trophic changes are frequently reported in CRPS, but only occasionally in FM and RSI. Systemic symptoms are found in patients with CRPS and FM, and in a subgroup of patients with RSI. In all three disorders, symptoms usually start locally, but may spread to other body regions later, which, in the case of FM, is a prerequisite for diagnosis. Disease onset is always, usually, or occasionally of traumatic origin in RSI, CRPS and FM, respectively. Anxiety and depression are more frequent in patients compared to controls, but probably not very different from patients with other pain conditions or chronic diseases.Apart from some obvious differences between CRPS, FM and RSI, the similarities are conspicuous. The common features of CRPS, FM and a-specific RSI may suggest that a common pathway is involved, but until patients with these type of symptoms are assessed with a uniform assessment procedure, a thorough comparison cannot be made. A systematic evaluation of patients with a suspected diagnosis of CRPS, FM or RSI, may lead to a better appreciation of the differences and similarities in these diseases and help to unravel the underlying mechanisms.

The aim of this study was to assess the accuracy of an interview-based assessment of comorbidity, in patients with Parkinson's disease (PD). The Cumulative Illness Rating Scale-Geriatric (CIRS-G) was completed (1) in an interview with 31 PD patients and their caregivers, and (2) by reviewing the patient's medical charts from their general practitioners. Based on the interview, all patients had some comorbidity, 84% had one or more moderate comorbid diseases. The most frequently affected organ systems were “lower gastrointestinal” and “genitourinary”. The mean ± SD total score of the interview-based (chart-based) CIRS-G was 6.9 ± 3.8 (7.6 ± 3.5) with a mean of 4.3 ± 1.9 (5.0 ± 1.9) affected organ systems and a mean of 2.1 ± 1.7 (2.3 ± 1.6) organ systems with at least moderate comorbidity per patient. The agreement (intraclass correlation coefficients) between the interview-based and chart-based assessments for the six summary scores ranged from 0.69 to 0.81. The agreement for the 14 organ systems ranged from 0.13 to 1.00 (weighted kappa); 12 had a Kw above 0.40 (moderate agreement). The comorbidity summary scores had a moderate correlation with age and disability. The interview-based assessment of the CIRS-G is easy to apply and is an accurate method to assess comorbidity in patients with PD. © 2004 Movement Disorder Society

STUDY OBJECTIVES: To develop a short and practical scale (SCOPA-SLEEP) that evaluates nighttime sleep and daytime sleepiness. The scale is developed for research in Parkinson disease but may be of value for other somatic diseases. DESIGN: Postal survey including 4 instruments, the SCOPA-SLEEP nighttime sleep (5 items) and daytime sleepiness (6 items), the Pittsburgh Sleep Quality Index, and the Epworth Sleepiness Scale. SETTING: Movement Disorders Center, Department of Neurology, Leiden University Medical Center, Leiden, The Netherlands. PARTICIPANTS: 143 patients with Parkinson disease and 104 controls. INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: Reliability of the scale was high: internal consistency of the nighttime sleep and daytime sleepiness scales were 0.88 and 0.91, respectively (Cronbach alpha), and test-retest reliabilities were 0.94 and 0.89, respectively (intraclass correlation coefficient). Scale scores differed significantly between patients and controls (P

Visser M, Marinus J, Bloem BR, Kisjes H, van den Berg BM, van Hilten JJ. Clinical tests for the evaluation of postural instability in patients with Parkinson's disease. Arch Phys Med Rehabil 2003;84:1669–74. Objective To determine which test for postural instability in Parkinson's disease (PD) is reliable, valid, and easy to perform in a clinical setting. Design Cross-sectional reliability and validity study. Setting Academic center for movement disorders. Participants Forty-two patients with PD and 15 controls. Based on the results of a structured interview, the patients were divided in PD-unstable (n=22) and PD-stable (n=20) groups. Interventions Not applicable. Main outcome measures Several variants of the retropulsion test with differences in execution and scoring. Responses were scored on 5 different rating scales (ratings of Nutt, Bloem, Pastor; the Unified Parkinson's Disease Rating Scale [UPDRS]; the Short Parkinson Evaluation Scale). These tests were compared with steady-stance positions. Results The interrater reliability was high for most ratings, with weighted κ ranging from .63 for the UPDRS to .98 for both the Pastor rating and steady-stance positions. Most ratings distinguished between the groups. However, the Nutt rating had the highest overall predictive accuracy, with a sensitivity of .63 and a specificity of .88. Conclusions The most valid test for postural stability in PD was an unexpected shoulder pull, executed once, with taking more than 2 steps backward considered abnormal. This retropulsion test is easy to use in a clinical setting.

The purpose of this study was to develop a short questionnaire for psychosocial functioning in patients with Parkinson's Disease (PD). The SCales for Outcomes in Parkinson's disease-PsychoSocial questionnaire (SCOPA-PS) was tested in a survey and compared with other instruments and with medical information. This survey was sent to 205 patents with idiopathic PD. Eighty-six percent of the questionnaires were returned. Cronbach's alpha was 0.83. Two-week test-retest reliability was 0.85 (intraclass correlation coefficient). Construct validity with other scales (Spearman's rho) was 0.82 for the Parkinson's Disease Questionnaire-39-item version (PDQ-39), 0.76 for the PDQ-8, 0.69 for the Hospital Anxiety and Depression Scale, -0.61 for the Euroqol, and -0.60 for a visual analogue scale evaluating Quality-of-Life. The summary index revealed a significant increase with increasing disease severity. The SCOPA-PS is a new, short psychosocial questionnaire for patients with PD with good clinimetric properties.

Motor dysfunction in complex regional pain syndrome (CRPS) is often considered a func- tional movement disorder. Earlier studies in patients with functional movement disorders found ev- idence of cortical inhibition during explicit but not implicit motor tasks, suggesting active inhibition from other brain areas. In this study, we explored whether active inhibition occurs in CRPS patients. We compared patients with CRPS with 2 control groups: healthy controls matched for age and sex, and patients whose hand was immobilized to treat a scaphoid fracture. We used transcranial mag- netic stimulation to measure corticospinal excitability at rest and during motor imagery (explicit mo- tor task) and motor observation (implicit motor task). Motor corticospinal excitation measured at rest and during implicit and explicit motor tasks was similar for CRPS patients and healthy controls. Pa- tients with an immobilized hand showed an absence of motor cortical excitation of the correspond- ing hemisphere during motor imagery of tasks involving the immobilized hand, but not during motor observation. The normal motor cortical processing during motor imagery and motor observation found in the corresponding hemisphere of CPRS patients suggests that the nature of motor dysfunc- tion in this condition differs from that described in literature for patients with functional paresis or under circumstances of limb immobilization. Perspective: This study shows that the nature of motor dysfunction in CRPS patients differs from that encountered in patients with functional paresis or under circumstances of limb immobilization. This information is important for patients and pain clinicians and could help prevent implementation of therapeutic strategies based on incorrect assumptions.

The objective of this study was to develop a Parkinson's disease diary that evaluates a patient's difficulties in performing activities as a substitute for the amount of "on"- and "off"-time and to assess its clinimetric qualities. In this study, 84 patients with Parkinson's disease kept a diary for 2 or 3 periods of 5 days. Daily, five items were recorded across 11 time periods. Patients simultaneously recorded "on-off" in the traditional way. The diary was easily understood, and median recording time was 5-10 minutes a day. Clinimetric analysis showed that the diary could be reduced successfully to 3 days, in which five items (walking, transfers, manual activities, dyskinesias, and sleep) with four response options (no, slight, moderate, and severe difficulty) were assessed seven times daily. Sumscores of the first three items accurately predicted being "on" or "off" in 93% of the cases, making separate scoring of "on" and "off" unnecessary. The diary was internally consistent and showed good reproducibility. Construct validity with external measures was adequate, and comparisons between patients grouped by disease severity and by degree of fluctuations revealed significant differences in the expected directions. Taken together, this Parkinson's disease diary has a sound clinimetric basis, provides information on the extent of perceived disability, and thereby accurately reflects the severity of "off"-periods and the variability of motor fluctuations.

The purpose of this study was to evaluate the psychometric properties of the Hospital Anxiety and Depression Scale (HADS) in patients with Parkinson's disease (PD) and to assess the prevalence of symptoms of anxiety and depression in this population. The HADS was sent to 205 patients with PD, together with three quality-of-life (QoL) instruments, i.e. the Parkinson's Disease Questionnaire (PDQ-39), the EQ-5D, and a visual analogue scale (VAS). Hospital Anxiety and Depression Scale scores were also compared with Hoehn-Yahr (H&Y) scores. Eighty-six percent of the patients returned the questionnaires. The quality of the data was good. Cronbach alpha for the HADS was 0.88. Test-retest reliability over 2 weeks was 0.84 for the sum score of the HADS (intraclass correlation coefficient) and ranged from 0.42-0.76 for individual items (weighted kappa). Factor analysis revealed two factors, accounting for 51.9% of the variance. One factor represented anxiety, the other depression. Correlations with PDQ-39, EQ-5D, VAS, and H&Y were 0.72, -0.59, -0.59, and 0.32, respectively (p values < 0.001). Depression scores accounted for 52% of the variance in QoL, whereas disease severity explained 24%. Using the cut-off values proposed by the developers indicated that possible and probable anxiety were present in 29.4% and 19.8% of the patients, respectively. Percentages for possible and probable depression were 21.5 and 16.9. The psychometric performance of the HADS in patients with PD is satisfactory. In addition, almost 50% of the patients displayed symptoms of anxiety, whereas nearly 40% showed signs of depression.

Objective Aim of this study was to identify risk factors for the development of dementia in patients with Parkinson's disease (PD). Methods A broad range of motor and non-motor features was assessed at baseline and the following five years in 406 PD patients. Cross-sectional analyses of baseline data and longitudinal analyses of follow-up data were performed to identify risk factors for dementia. Results Thirty-two percent of patients (n = 129) had dementia at baseline, while 26% of patients (n = 68) without dementia at baseline developed dementia during follow-up. Univariate survival analysis showed that higher age, fewer years of education, longer disease duration, higher age-at-onset, higher levodopa dose, higher Hoehn & Yahr stage, presence of dyskinesias, excessive daytime sleepiness (EDS), presence of hallucinations, and more severe autonomic and depressive symptoms were associated with an increased risk of dementia. Higher baseline Postural-Instability-and-Gait-Difficulty scores were also associated with an increased risk of dementia, whereas no effect of tremor severity was found. These findings largely corresponded with the variables that were associated with the presence of dementia at baseline. In a stepwise regression model, higher age at baseline, fewer years of education, higher daily levodopa dose and excessive daytime sleepiness (EDS) emerged as independent risk factors of future dementia. Conclusions In this large prospective cohort study, we identified a combination of potentially interacting risk factors for dementia in PD that are associated with higher age and more advanced disease.

Background: Survival in patients with Parkinson's disease is reduced as compared to the general population. We aimed to identify motor and non-motor features that predict mortality in Parkinson's disease. Methods: A broad range of motor and non-motor features were assessed in a hospital-based cohort of 414 patients with Parkinson's disease, who underwent five annual follow-up examinations including vital status assessment. Multivariable Cox's proportional hazards regression analysis was used to evaluate the association between baseline characteristics and mortality risk. Stepwise regression with backward elimination was carried out to determine the best model to predict mortality in Parkinson's disease. Results: After a mean follow-up period of 4.3 years, 49 (11.8%) patients had died. In the stepwise regression model, predictors of mortality in Parkinson's disease were higher age, male sex, cognitive impairment, higher postural instability gait disorder score, and the presence of psychotic symptoms. Conclusions: Higher age, male sex, cognitive impairment, higher postural instability gait disorder score, and the presence of psychotic symptoms are independent predictors of decreased survival in Parkinson's disease. Mortality in Parkinson's disease thus seems to be affected mainly by non-dopaminergic and non-motor features. (C) 2014 Elsevier Ltd. All rights reserved

Introduction Disease progression in Parkinson's disease is often calculated in data from cross-sectional studies, where a severity score (e.g. UPDRS-motor score) is divided by disease duration. While this intuitively may seem a plausible approach, it is uncertain if these rates are similar to those calculated from longitudinal data. The aim of this study is to examine if progression rates calculated according to both methods yield the same results. Methods We calculated two progression rates in data from the PROPARK study: one where last follow-up SPES/SCOPA motor and activities-of-daily-living scores were divided by disease duration, and one in which baseline motor and activities-of-daily-living scores were subtracted from data collected at last follow-up, and where the difference was divided by the time that passed between both assessments. We subsequently calculated the rank order correlation between both approaches. Results We found that progression rates calculated from cross-sectional data are 1.5–2 times higher than those calculated from longitudinal data, and that the correlation between both methods is Conclusion Progression rates calculated from cross-sectional data not only overestimate actual progression, but also yield a different rank order. We also discuss potential explanations for the discrepancy between both methods and argue that the method of calculating progression rates in data from cross-sectional studies in PD should not be used.

Objective: The aim of this study was to explore the role of predominantly nondopaminergic (PND) features in evaluating disease severity and progression of Parkinson disease (PD). Methods: Principal component analysis was used on the baseline data of 396 patients to explore consistency of interrelations between important PND domains (cognitive impairment, depressive symptoms, excessive daytime sleepiness, psychotic symptoms, autonomic dysfunction, and postural instability and gait difficulty) across different ranges of disease duration. Hereafter, we evaluated the reliability and validity of a composite score of all PND domains and examined reproducibility of the findings in a large independent cohort. Results: Principal component analysis revealed a consistent 1-factor solution across groups with different disease durations. Cronbach α of the total group was 0.75 for the PND composite score, and corrected item-total correlations were all above the criterion value of 0.3. Validity of the PND composite score was confirmed by significant positive correlations with Hoehn and Yahr stage, severity of motor symptoms, disease duration, and age. Findings were replicated in the independent cohort. Conclusions: Our findings show the robustness of a composite score of PND domains as a measure of disease severity across the disease course of PD. Composite measures of PND domains, which largely are insensitive to dopaminergic medication, may provide a more complete and accurate evaluation of disease severity and progression in PD.

In complex regional pain syndrome (CRPS)-related dystonia, compelling evidence points to the involvement of the central nervous system, but the underpinning pathobiology is still unclear. Thus, to enable a hypothesis-free, unbiased view of the problem and to obtain new insight into the pathobiology of dystonia in CRPS, we applied an exploratory metabolomics analysis of cerebrospinal fluid (CSF) of patients with CRPS-related dystonia. 1 H-NMR spectroscopy in combination with multivariate modeling were used to investigate metabolic profiles of a total of 105 CSF samples collected from patients with CRPS-related dystonia and controls. We found a significantly different metabolic profile of CSF in CRPS patients compared to controls. The differences were already reflected in the first two principal components of the principal component analysis model, which is an indication that the variance associated with CRPS is stronger than variance caused by such classical confounders as gender, age, or individual differences. A supervised analysis generated a strong model pinpointing the most important metabolites contributed to the metabolic signature of patients with CRPS-related dystonia. From the set of identified discriminators, the most relevant metabolites were 2-keto-isovalerate, glucose, glutamine, and lactate, which all showed increased concentrations, and urea, which showed decreased concentration in CRPS subjects. Our findings point at a catabolic state in chronic CRPS patients with dystonia that is likely associated with inflammation.

Item does not contain fulltext Fixed dystonia without evidence of basal ganglia lesions or neurodegeneration typically affects young women following minor peripheral trauma. We use eyeblink classical conditioning (EBCC) to study whether cerebellar functioning is abnormal in patients with fixed dystonia, since this is part of the pathophysiology of primary dystonia. An auditory tone (conditioning stimulus) was paired with a supraorbital nerve stimulus (unconditioned stimulus) with a delay of 400 ms in order to yield conditioned responses. We recruited 11 fixed dystonia patients of whom six used medication and seven age-matched healthy controls. Non-medicated patients with fixed dystonia performed as well as healthy controls, while medicated patients showed fewer conditioned responses. We found an influence of medication and possibly extent of dystonic features and/or co-occurrence of complex regional pain syndrome (CRPS) on EBCC performance. Our study argues against abnormal cerebellar function in non-medicated, fixed dystonia patients without CRPS or spread of symptoms. 5 p.

Complex regional pain syndrome (CRPS) is a distressing and difficult-to-treat complication of wrist fracture. Estimates of the incidence of CRPS after wrist fracture vary greatly. It is not currently possible to identify who will go on to develop CRPS after wrist fracture. In this prospective cohort study, a nearly consecutive sample of 1,549 patients presenting with wrist fracture to 1 of 3 hospital-based fracture clinics and managed nonsurgically was assessed within 1 week of fracture and followed up 4 months later. Established criteria were used to diagnose CRPS. The incidence of CRPS in the 4 months after wrist fracture was 3.8% (95% confidence interval = 2.9-4.8%). A prediction model based on 4 clinical assessments (pain, reaction time, dysynchiria, and swelling) discriminated well between patients who would and would not subsequently develop CRPS (c index.99). A simple assessment of pain intensity (0-10 numerical rating scale) provided nearly the same level of discrimination (c index.98). One in 26 patients develops CRPS within 4 months of nonsurgically managed wrist fracture. A pain score of ≥5 in the first week after fracture should be considered a "red flag" for CRPS. Perspective This study shows that excessive baseline pain in the week after wrist fracture greatly elevates the risk of developing CRPS. Clinicians can consider a rating of greater than 5/10 to the question "What is your average pain over the last 2 days?" to be a "red flag" for CRPS. Refereed/Peer-reviewed

The treatment of dystonia related to complex regional pain syndrome (CRPS) remains unsatisfactory, raising the need of alternative targets for intervention. In dystonia, pathologic muscle changes may occur, which contributes to stiffness. Because magnesium sulphate may act as a muscle relaxant through its actions on the neuromuscular junction and muscle, we performed an explanatory study of the muscle relaxant effect and safety of intramuscular magnesium sulphate (IMMG) in CRPS patients with dystonia. In a double-blind randomized placebo-controlled crossover study, 30 patients were assigned to 3-week treatments of IMMG and placebo. Treatments were separated by a 1-week washout period. The daily dose of IMMG was 1,000 mg in week 1, 1,500 mg in week 2, and 2,000 mg in week 3. The primary outcome measure was the difference in change in Burke-Fahn-Marsden scores after 3 weeks of treatment between both interventions. Secondary outcomes involved severity of dystonia, myoclonus, tremor, and pain, and functional activity. Data of 22 patients available for the explanatory analysis revealed no significant differences between IMMG and placebo treatment in any of the outcomes. In conclusion, we found no indication of efficacy of IMMG in a daily dose of 2,000 mg as a muscle relaxant in CRPS-related dystonia. Perspective In this double-blind placebo-controlled crossover study there was no evidence found of a muscle relaxant effect of intramuscular magnesium sulphate in dystonia related to CRPS. Consequently, there is insufficient support for new studies evaluating the efficacy of other routes of MG administration in CRPS-related dystonia.

Our understanding of proprioceptive deficits in complex regional pain syndrome (CRPS) and its potential contribution to impaired motor function is still limited. To gain more insight into these issues, we evaluated accuracy and precision of joint position sense over a range of flexion-extension angles of the wrist of the affected and unaffected sides in 25 chronic CRPS patients and in 50 healthy controls. The results revealed proprioceptive impairment at both the patients' affected and unaffected sides, characterized predominantly by overestimation of wrist extension angles. Precision of the position estimates was more prominently reduced at the affected side. Importantly, group differences in proprioceptive performance were observed not only for tests at identical percentages of each individual's range of wrist motion but also when controls were tested at wrist angles that corresponded to those of the patient's affected side. More severe motor impairment of the affected side was associated with poorer proprioceptive performance. Based on additional sensory tests, variations in proprioceptive performance over the range of wrist angles, and comparisons between active and passive displacements, the disturbances of proprioceptive performance most likely resulted from altered processing of afferent (and not efferent) information and its subsequent interpretation in the context of a distorted "body schema." Perspective The present results point at a significant role for impaired central processing of proprioceptive information in the motor dysfunction of CRPS and suggest that therapeutic strategies aimed at identification of proprioceptive impairments and their restoration may promote the recovery of motor function in CRPS patients. © 2013 by the American Pain Society.

There are indications of motor circuit changes in patients with complex regional pain syndrome (CRPS). Nevertheless, although several studies have analyzed motor behavior in CRPS, a relation with pain could not be detected. This might be explained by the use of cross-sectional designs in these studies, in which pain is considered as a trait- rather than a state-dependent variable. We therefore studied the time-dependent relation between pain and motor function in affected arms of 29 CRPS patients during their participation in a placebo-controlled ketamine study. Movement parameters (velocity, frequency, amplitude, and number of arrests) were assessed during a finger tapping task. Linear mixed model analysis of the effects of pain (numerical rating scale score), treatment (ketamine/placebo), and week (1, 3, 6, and 12 weeks after treatment) on the movement parameters revealed that pain intensity was significantly (inversely) related to motor function, irrespective of whether patients had received ketamine or placebo. Movement parameters changed 3-12% per point numerical rating scale change. Because patients were unaware of possible effects of ketamine on motor function, these findings suggest that motor function changes were mediated by, or occurred simultaneously with, changes in pain intensity. By improving motor function, pain relief may offer a window of opportunity for rehabilitation programs in CRPS.This article provides evidence for a direct relation between pain and motor function in CRPS, which indicates that pain relief may be an important factor in the treatment of motor disturbances in this condition. These findings may help to advance our understanding of the pathways underlying motor disturbances in CRPS.

BACKGROUND: Complex regional pain syndrome (CRPS) is characterized by severe debilitating chronic pain. Patients with CRPS may experience various pain sensations, which likely embody different pathophysiologic mechanisms. In this study, we evaluated the differential effects of central γ-aminobutyric acid (B) receptor stimulation on the different pain qualities in CRPS patients with dystonia. METHODS: The 10 pain qualities of the neuropathic pain scale, dystonia severity, and changes in use of antinociceptive drugs were evaluated every 3 months for a period of 1 year in 42 CRPS patients with dystonia receiving titrated doses of intrathecal baclofen (ITB) treatment in an open design. RESULTS: Using a linear mixed model analysis and controlling for global dystonia severity and the use of supplemental analgesics, we found a significant improvement in global intense pain, sharp pain, dull pain, and deep pain during the first 6 months. After this period, the scores lev - eled off despite further improvement of dystonia and continued ITB dose escalation. CONCLUSIONS: γ-Aminobutyric acid (B) receptor stimulation by ITB exerts differential anti- nociceptive effects on specific pain qualities in CRPS patients with dystonia. (Anesth Analg 2013;116:211-5)

Objectives: We conducted a systematic review of the literature with meta-analysis to determine whether complex regional pain syndrome (CRPS) is associated with a specific inflammatory profile and whether this is dependent on the duration of the condition. Methods: Comprehensive searches of the literature using MEDLINE, Embase, Scopus, Web of Science, and reference lists from published reviews identified articles that measured inflammatory factors in CRPS. Two independent investigators screened titles and abstracts, and performed data extraction and risk of bias assessments. Studies were subgrouped by medium (blood, blister fluid, and CSF) and duration (acute and chronic CRPS). Where possible, meta-analyses of inflammatory factor concentrations were performed and pooled effect sizes were calculated using random-effects models. Results: Twenty-two studies were included in the systematic review and 15 in the meta-analysis. In acute CRPS, the concentrations of interleukin (IL)-8 and soluble tumor necrosis factor receptors I (sTNF-RI) and II (sTNF-RII) were significantly increased in blood. In chronic CRPS, significant increases were found in 1) TNFa, bradykinin, sIL-1RI, IL-1Ra, IL-2, sIL-2Ra, IL-4, IL-7, interferong, monocyte chemoattractant protein-1 (MCP-1), and sRAGE (soluble receptor for advanced glycation end products) in blood; 2) IL-1Ra, MCP-1, MIP-1b, and IL-6 in blister fluid; and 3) IL-1b and IL-6 in CSF. Chronic CRPS was also associated with significantly decreased 1) substance P, sE-selectin, sL-selectin, sP-selectin, and sGP130 in blood; and 2) soluble intercellular adhesion molecule- 1 (sICAM-1) in CSF. Most studies failed to meet 3 or more of our quality criteria. Conclusion: CRPS is associated with the presence of a proinflammatory state in the blood, blister fluid, and CSF. Different inflammatory profiles were found for acute and chronic cases. Refereed/Peer-reviewed

Cervical dystonia, a late onset focal dystonia, has a complex genetic background. Multiple lines of evidence point to a role for aberrant dopamine levels in dystonia. We assessed whether common variation within genes that regulate brain dopamine levels and in key genes of the dopamine metabolic pathway, modulate the risk for cervical dystonia. DNA was collected from 363 Dutch CD patients and a cohort of Dutch control individuals. Haplotype-tagging single nucleotide polymorphisms (SNPs) complemented with selected variants of functional importance in COMT, DAT, TH, MAO-A and -B, DDC and DBH were investigated. We tested the 143 markers in single-SNP, haplotype and epistasis analyses. We did not find an association with any of the selected 143 SNPs in these key dopamine genes. Our data shows that common variations in key genes of the dopamine pathway do not contribute to dystonia risk in the Dutch population. Possibly, risk alleles in this pathway may be rarer than detectable in this study, or might be located in downstream dopamine signaling pathway. Alternatively, found dopamine level changes are secondary to the dystonia disease processes. (C) 2012 Published by Elsevier Ltd

Objective: Motor abnormalities in Complex Regional Pain Syndrome (CRPS) are common and often characterized by a restricted active range of motion (AROM) and an increased resistance to passive movements, whereby the affected body part preferably adopts an abnormal posture. The objective of the present study was to obtain a better understanding of the factors that are associated with these abnormal postures and limitations of the AROM, and to investigate whether these motor impairments reflect dystonia. Methods: We evaluated characteristics of surface EMG of the flexor carpi radialis and extensor carpi radialis muscles during active maintenance of various flexion-extension postures of the wrist of the affected and unaffected side in 15 chronic CRPS patients, and in 15 healthy controls. Results: Deviant joint postures in chronic CRPS - at least in those patients with some range of active movement - were not characterized by sustained muscle contractions, and limitations of the AROM were not attributable to excessive co-contraction. Rather, the agonistic muscle and its antagonist were activated in normal proportions, albeit over a limited range. Conclusions: The AROM limitations and abnormal postures that are often observed in chronic CRPS patients are not associated with excessive muscle activity and hence do not exhibit the characteristics typical of dystonia. Significance: We hypothesize that structural alterations in skeletal muscle tissue and pain-induced adaptations of motor function may contribute to the observed motor impairments. Our findings may have important clinical implications, since commonly prescribed treatments are aimed at reducing excessive muscle contraction. © 2013 International Federation of Clinical Neurophysiology.

We previously showed evidence for a genetic association of the human leukocyte antigen (HLA) system and complex regional pain syndrome (CRPS) with dystonia. Involvement of the HLA system suggests that CRPS has a genetic component with perturbed regulation of inflammation and neuroplasticity as possible disease mechanisms. However, it is at present unclear whether the observed association with HLA-B62 and HLA-DQ8 in CRPS patients with dystonia also holds true for patients without dystonia. Therefore, we tested the possible association with HLA-B62 and HLA-DQ8 in a clinically homogeneous group of 131 CRPS patients without dystonia. In addition, we investigated the possible association with other alleles of the HLA-A, HLA-B, HLA-C, HLA-DR, and HLA-DQ loci. We showed an increased prevalence of HLA-DQ8 (molecularly typed as HLA-DQB1*03:02; OR = 1.65 [95% Cl 1.12-2.421, P = .014) in CRPS without dystonia, whereas no association was observed for HLA-B62 (molecularly typed as HLA-B*15:01; OR = 1.22 [95% Cl .78-1.921, P = .458). Our data suggest that CRPS with and CRPS without dystonia may be genetically different, but overlapping, disease entities because only HLA-DQ8 is associated with both. The findings also indicate that distinct biological pathways may play a role in both CRPS subtypes. Perspective: This study is the first to replicate a specific HLA region conferring genetic risk for the development of CRPS. Moreover, associations of HLA-DQ8 with both CRPS with and CRPS without dystonia, and HLA-B62 only with CRPS with dystonia, suggest that these disease entities may be genetically different, but overlapping. (C) 2012 by the American Pain Society