Earlier studies suggest that lumbar radicular pain following disc herniation may be associated with a local or systemic inflammatory process. In the present study, we investigated the serum inflammatory protein profile of such patients. All 45 patients were recruited from Oslo University Hospital, Ullevål, Norway, during the period 2007–2009. The new multiplex proximity extension assay (PEA) technology was used to analyze the levels of 92 proteins. Interestingly, the present data showed that patients with radicular pain 12 months after disc herniation may be different from other patients with regard to many measurable serum cytokines. Given a false discovery rate (FDR) of 0.10 and 0.05, we identified 41 and 13 proteins, respectively, which were significantly upregulated in the patients with severe pain one year after disc herniation. On the top of the list ranked by estimated increase we found C-X-C motif chemokine 5 , epidermal growth factor , and monocyte chemotactic protein 4 . Moreover, a clear overall difference in the serum cytokine profile between the chronic and the recovered patients was demonstrated. Thus, the present results may be important for future protein serum profiling of lumbar radicular pain patients with regard to prognosis and choice of treatment. We conclude that serum proteins may be measurable molecular markers of persistent pain after disc herniation. Lumbar radicular pain, also referred to as “sciatica,” is characterized by radiating pain that typically follows the dermatome of the affected nerve-root. When strict criteria are used, the prevalence rate is approximately 2% , 2. RougEarlier studies suggest that leakage of nucleus pulposus into the spinal canal after disc herniation may initiate immunological and inflammatory responses close to the nerve-roots , 6 that In addition, recent data point to increased levels of circulating cytokines in patients with chronic pain. For example, higher systemic IL-2 and TNF levels have been observed in patients with painful neuropathies compared to painless neuropathies . MoreoveIn the present study, in contrast, we take advantage of the new multiplex proximity extension assay (PEA) technology to simultaneously analyze the levels of 92 inflammatory proteins . To adjuPatients with lumbar radicular pain were recruited from the outpatient clinic at Oslo University Hospital, Ullevål, Norway, during the period 2007–2009. The inclusion criteria were age between 18 and 60 years, lumbar disc herniation confirmed by magnetic resonance imaging (MRI) with corresponding radicular pain, and positive Straight Leg Raising (SLR). The exclusion criteria were lumbar spinal stenosis, previous surgery for herniated disc at the same level or fusion at any level in lumbar spine, generalized musculoskeletal pain, inflammatory rheumatic disease, diabetic polyneuropathy, cardiovascular disease (NYHA III and IV), cancer, psychiatric disease, cauda equine syndrome, alcohol or drug abuse, recent surgery (within one month), pregnancy, poor Norwegian language, or non-European-Caucasian ethnicity. In total, 122 patients (82%) of the 148 patients who met the eligibility requirement were included in the intended follow-up assessment.Surgical treatment was given to patients with persistent radicular pain lasting for more than 8 weeks, neurological deficits , and corresponding magnetic resonance imaging findings in the anticipated location. Patients who did not clearly fulfill these criteria were managed conservatively by a treatment comprised of a brief cognitive intervention, activity guidance during the acute phase of disc herniation, and, for the majority of patients, physiotherapy.At inclusion, at 6 weeks and at 12-month follow-up, the patients were asked to rate their pain intensity in activity during the last week on a 10 cm visual analog scale (VAS) with endpoints “no pain” and “worst possible pain.” Hopkins symptom checklist (HSCL), a 25-item questionnaire, was used to register psychological distress, that is, anxiety and depression. The drop-out rate was 8% and ultimately, 112 patients were assessed at 12-month follow-up.n = 23). Moreover, a gender and age matched sample from the same 112 patients with VAS < 1 at 12-month follow-up was defined as a low pain group (n = 22). The serum levels in inflammatory-related proteins in the high pain group versus the low pain group were analyzed. All participants received written information and signed an informed consent form. The study was approved by the Norwegian Regional Committee for Medical Research Ethics and the Norwegian Social Science Data Services.Among these 112 patients, patients with VAS > 6 at 12-month follow-up were defined as a high pain group  is simultaneously analyzed [μL incubation mix containing two PEA probes, that is, antibodies equipped with single strand DNA oligonucleotide, against each protein was mixed with 1 μL serum and the mixture was incubated at 8°C overnight. The mixture was then mixed with 96 μL extension mix containing PEA enzyme and PCR reagents and incubated for 5 min at room temperature before the plate was transferred to a thermal cycler for 17 cycles of DNA amplification. A 96.96 Dynamic Array IFC  was prepared and primed according to the manufacturer's instructions. 2.8 μL of sample mixture was mixed with 7.2 μL detection mix in a new 96-well plate and 5 μL was loaded into the right side of the primed 96.96 Dynamic Array IFC. The unique primer pairs for each cytokine were loaded into the left side of the 96.96 Dynamic Array IFC, and the protein expression program was run in Fluidigm Biomark reader according to the instructions for Proseek.In the present study we took advantage of the multiplex proximity extension assay (PEA) technology in which a panel of 92 proteins . Therefore, we used a multiple linear regression model with LoD imputed values in place of below-LoD values to test the differences between the groups.Because of the difficulties associated with analyzing data with a high proportion of below-LoD values –22, onlyxij denote the vector of protein measurements of patient j in group i (with i = 1 corresponding to high pain and i = 2 corresponding to low pain), i, and ni denote the number of patients in group i, the discriminant score for each individual was computed asThe linear discriminant analysis , 24 was The weighted protein score was visualized in a simple dot plot where each patient was represented by one dot. A positive score indicated a high inflammatory activity, whereas a negative score indicated a low inflammatory activity.The high pain group had more pain when they arrived at the hospital, at 6 weeks and 12-month follow-up, than the low pain group . More smThe analyses of the levels of 92 proteins showed 76 proteins for which at most 20% of the patients had expression levels below the LoD. Among these 76 proteins, we identified 41 with FDR < 0.10 and 13 with FDR < 0.05, which were considered upregulated in the patients with severe pain one year after disc herniation . The anaOn the top of the list ranked by estimated increase we found C-X-C motif chemokine 5 , epidermal growth factor , and monocyte chemotactic protein 4 .For each patient, an inflammation score, that is, weighted average of the 41 protein levels, was also constructed. Notably, the two groups were completely separated; all high pain patients had positive scores, whereas all low pain patients had negative scores . Thus, aIn the present study, we examined the serum levels of 92 inflammatory proteins in patients one year after lumbar disc herniation. Among these, 41 proteins with FDR < 0.10, including IL-6 and IL-8, seemed to be upregulated in the chronic pain patients compared to the patients that fully recovered within one year. Hence, in accordance with our earlier ELISA findings from the same cohort where IL-6 and IL-8 in almost all patients were increased the first weeks after disc herniation , 25, theMany of the upregulated proteins with FDR < 0.05 were chemokines and other molecules associated with inflammation, activation of macrophages, and/or immune responses including regulators of glial cells. For example, C-X-C motif chemokine 5 (CXCL5) is a neutrophil chemoattractant which increases the expression of several proinflammatory mediators . Moreoveβ [α (IL-15Rα) is expressed in monocytes, NK cells, and T-cells [Several of the upregulated proteins with FDR < 0.05 have also previously been linked to healing and tissue regeneration. C-C motif chemokine 4 (CCL4) that reduces the expression of TNF and IL-1β  may be iβ . Vasculaβ –35 and fβ . Interle T-cells .β (TGFβ) has important immune-regulative role and may reverse inflammation [In addition, some of the upregulated proteins with FDR < 0.05 may induce cell differentiation, apoptosis, and neuronal loss and influence cell cycle regulation. Epidermal growth factor (EGF) stimulates cell growth, proliferation, and differentiation . Moreoveammation , whereasammation , 41 and ammation .In PEA, each target molecule is recognized by a pair of affinity binders in which both have to bind the same target molecule prior to signal amplification via qPCR. Similar to other proximity assays , 44, theStill, as some of the protein expressions were below the LoD, the actual expression levels of these proteins remain unknown. As high proportions of below-LoD measurements lead to tests with low power, we opted to only analyze the proteins for which the proportion of below-LoD measurements was at most 20%. Moreover, the two groups were balanced in terms of age, sex, and treatment but differed in smoking habits and HSCL scores . Our linIn the present study, we examined 92 serum proteins. Thus, the analyses of the data include multiple testing, that is, associated with many challenges. Clearly, we cannot control the family wise error rate by Bonferroni correction as such corrections tend to be far too conservative, resulting in statistical procedures with very low power. However, since this is a study where the focus is on evaluation of the methodology (proof of concept), a limited rate of false positives is acceptable. We therefore controlled the false discovery rate using the procedure of Benjamini and Hochberg .Given a FDR of 0.10 and 0.05, up to 1/10 and 1/20 of our findings are likely to be false positives. Importantly, however, almost all inflammatory markers moved in the same direction. Moreover, although a few false positive markers may be present, our study clearly demonstrated that inflammatory profiling can be used to characterize chronic sciatica patients. The present data also showed that the PEA is a reliable and sensitive method to study proteins in serum associated with clinical measures.Despite the above mentioned challenges, the linear discriminant analysis demonstrated a clear difference between the high pain group and the low pain group. A weighted average of the differentially expressed proteins with FDR < 0.10 was used . This alAlthough the present study had a prospective design when it comes to the pain ratings, the serum protein levels of the patients were only measured at one time point, that is, 12 months after disc herniation. Thus, it is hard to tell whether the observed differences in serum proteins are a trait or a state of the patients that develop chronic pain. Moreover, medication and other life style factors may also influence the serum protein levels. However, the analgesics and anti-inflammatory-drugs taken by the patients were higher in the high pain group than in the low pain group. Therefore, it seems likely that the effect of medication reduces rather than increases the difference in inflammatory serum proteins. Nevertheless, the results demonstrated that it is possible to detect differences between persistent and nonpersistent pain patients. The fact that this protein pattern can be detected in serum suggests that the PEA technology may have a clinical potential.In summary, the present data demonstrated that sciatica patients with a chronic outcome have increased levels of inflammatory proteins in serum one year after disc herniation. This is to our knowledge the first protein serum profiling study of patients with chronic lumbar radicular pain. An inflammatory PEA-based fingerprint of these persistent pain patients was demonstrated. We conclude that serum proteins may be measurable molecular markers of patients that develop persistent pain after disc herniation. The pathophysiological relevance of these proteins, however, remains to be investigated.In the Proximity Extension Assay (PEA) each of the 92 human protein biomarkers were addressed by a pair of oligonucleotide-labeled antibodies. The amount of the proteins was measured by quantitative real-time PCR. The dual recognition DNA-coupled method excluded cross-reactivity in the detection process.


Complex Regional Pain Syndrome (CRPS) is a disabling disease that is sometimes difficult to treat. Although spinal cord stimulation (SCS) can reduce pain in most patients with CRPS, some do not achieve the desired reduction in pain. Moreover, the pain reduction can diminish over time even after an initially successful period of SCS. Pain reduction can be regained by increasing the SCS frequency, but this has not been investigated in a prospective trial. This study compares pain reduction using five SCS frequencies  in patients with CRPS to determine which of the modalities is most effective.All patients with a confirmed CRPS diagnosis that have unsuccessfully tried all other therapies and are eligible for SCS, can enroll in this trial (primary implantation group). CRPS patients that already receive SCS therapy, or those previously treated with SCS but with loss of therapeutic effect over time, can also participate (re-implantation group). Once all inclusion criteria are met and written informed consent obtained, patients will undergo a baseline assessment (T0). A 2-week trial with SCS is performed and, if successful, a rechargeable internal pulse generator (IPG) is implanted. For the following 3 months the patient will have standard 40 Hz stimulation therapy before a follow-up assessment (T1) is performed. Those who have completed the T1 assessment will enroll in a 10-week crossover period in which the five SCS frequencies are tested in five periods, each frequency lasting for 2 weeks. At the end of the crossover period, the patient will choose which frequency is to be used for stimulation for an additional 3 months, until the T2 assessment.Currently no trials are available that systematically investigate the importance of variation in frequency during SCS in patients with CRPS. Data from this trial will provide better insight as to whether SCS with a higher frequency, or with burst stimulation, results in more effective pain relief.ISRCTN36655259Current Controlled Trials  Complex Regional Pain Syndrome (CRPS) is defined as a collection of locally appearing painful conditions following a trauma, which mainly occurs distally and exceeds in severity and duration the expected clinical course of the original trauma; this often results in considerably restricted motor function and is characterised by a variable progression over time . The diaThe natural course of the disease is not always favourable, even with a multidisciplinary approach and the use of evidence-based guideline-supported treatment algorithms. CRPS has an estimated incidence of 5.46–26.2 per 100,000 person years (95 % CI: 23.0–29.7) [Although the pathophysiology of CRPS is incompletely understood, several mechanisms are proposed to contribute to this disease such as inflammation, vasomotor dysfunction, and involvement of the central nervous system with features of central sensitisation and neuroplasticity .Some patients with diagnosed CRPS are unresponsive to any conventional therapy, such as physical therapy, medication and invasive interventions such as sympathetic blockade. In these cases there is a clear indication for spinal cord stimulation (SCS) as a last resort therapy to reduce pain. SCS has been performed in many CRPS patients and has shown an evident and clinically relevant pain reduction that can be maintained for a prolonged period of time –12.The exact mechanism of action that occurs during SCS, which results in pain relief, has not been fully elucidated. However, it is known that for neuropathic pain in general, SCS decreases the hyperexcitability of the multimodal wide dynamic range neurons (WDR), increases the release of gamma-aminobutyric acid (GABA) in the dorsal horn and, subsequently, decreases the release of glutamate. Other mechanisms proposed to be involved are activation of an inhibitory descending pathway and involvement of the cholinergic system. Several CRPS-specific mechanisms of SCS are considered to play a pivotal role, such as inhibiting the hyperexcitable central neural circuitry, a decrease in the efferent-sympathetic output and by antidromic activation which, in turn, causes the release of several vasoactive substances, such as nitric oxide, substance P and calcitonin gene-related peptide –15.However, despite these successes some CRPS patients are not responsive or, in others, the pain-reducing effect diminishes over time due to tolerance –12. It iThis study aims to compare the effects of five different SCS modalities in patients with CRPS and determine which frequency is most effective in terms of pain reduction; these frequencies are standard stimulation with 40 Hz , 500 Hz, 1200 Hz, burst and placebo stimulation.This is a prospective randomised, double-blind and placebo-controlled crossover trial. The study is a multi-centre trial including one university hospital and four regional hospitals located throughout the Netherlands. Figure Patients considered for enrollment in this trial must be diagnosed with CRPS that is in accordance with the endorsed IASP criteria at the time of disease onset. We defined two groups of patients that can take part in this trial. The first group (primary implantation group) consists of patients with chronic CRPS who are unresponsive to conventional therapies . The second group (re-implantation group) consists of patients who already have SCS therapy, or were treated with SCS in the past but with loss of therapeutic effect over time. In the re-implantation group it is imperative that the paresthesia, that is or was felt under SCS therapy, has adequate overlap with the painful area.Eligibility for SCS is in accordance with the Dutch CRPS and Neuromodulation Guidelines. These guidelines state that patients must have a mean pain intensity of a least 5, as measured on a visual analogue scale , a CRPS duration of at least 12 months, and no lasting success or complications with conventional therapy. An additional requirement for this study is that the CRPS is located in one extremity only. Exclusion criteria are: anticoagulant drug therapy or disturbed coagulation, age < 18 years, pregnancy, ICD or pacemaker, life expectancy < 1 year, lack of cooperation of the patient, drugs, medication or alcohol addiction, and immune-compromised patients.Approval from the Medical Ethics Committee of Erasmus Medical Center Rotterdam was obtained in August 2011 (Registration number: MEC-201 1-012). The trial was subsequently registered in the Current Controlled Trials register (ISRCTN 36655259). Written informed consent is obtained from all patients before enrollment into the trial.The main study parameters are pain reduction and patient satisfaction. The pain scores are measured with the McGill Pain Questionnaire-Dutch Language Version (MPQ-DLV) , 19 and Secondary outcomes consist of detecting temperature asymmetry by using video thermography imaging –27, and A MicroFet Dynamometer® is used to measure muscle strength of the flexors and extensors of the elbow in case of the upper extremity, and of the knee and the foot in case of CRPS in the lower extremity. The grip strength and the pinch strength is determined by means of a Jamar Hydraulic Hand Dynamometer® and a Jamar Hydraulic Pinch Gauge®, respectively. The pinch strength is measured in two ways: thumb tip to index fingertip, and thumb pad to lateral aspect of middle phalanx of index finger; the biceps and the triceps. In addition, a walking test is performed only in patients that have lower extremity CRPS. This test records how long it takes to cover a 10 m distance when walking at a comfortable and maximum walking pace. Furthermore, the maximum walking distance is assessed during a 2-min walk where the patient is instructed to cover as much distance as possible within these 2 min –40.The types of activity and physical activity level (PAL) of a patient is continuously measured with the VitaMove system  for multiple days (2–3 day), providing a detailed and continuous report on the patient’s energy expenditure, motions and postures over the course of several days –46. ThisArtificial skin blisters are created to measure whether local inflammation is still present in these patients before SCS and the effects stimulation therapy might elicit on the inflammatory profile –56. A blpsychological and social evaluation: Inventory for Social Support (ISS) [Physical activity: the Disabilities of Arm Shoulder and Hand Questionnaire (DASH) [Economic evaluations: The cost analysis is performed from a societal viewpoint in collaboration with the Institute for Medical Technology Assessment of Erasmus University Rotterdam. Three categories of costs are distinguished: 1) Direct costs within the healthcare system, 2) Direct costs outside the healthcare system, and 3) indirect costs outside the healthcare system. These data are collected using diaries and the Trimbos/iMTA questionnaire for Costs associated with Psychiatric Illness (TiC-p) and health consumption, simultaneously with the clinical data and quality of life data. The costs are valued using the Dutch guidelines for cost analysis in healthcare .Multiple questionnaires are filled in by the patient throughout the course of the study to monitor the various dimensions Table . These irt (ISS) , Pain Cart (ISS) –63, RANDrt (ISS) –66, the rt (ISS) , 68 and rt (ISS) , 70. Phye (DASH) , 71, 72 e (DASH) –75. EconProductivity costs: The productivity costs are defined as the costs of absence from paid work due to CRPS, including the impact of compensation mechanisms, the cost of efficiency losses (productivity costs while working at a slower pace) and the costs of hindrance at unpaid work. For this, the three modules of the PRODISQ questionnaire for measuring and valuing productivity costs for unpaid work are used , 77. ForMedication consumption is assessed by taking an inventory of all (pain)medication and dosing the patients use at the time of the T0, T1 and T1 assessment. The pain medication will be stratified into the various medication groups and a the sum dosage of the various pain medication groups will be calculated.By means of MANOVA for repeated measurements within factors, the potential differences in effect of the five different stimulation modalities will be assessed. A minimal detectable effect size (f) of 0.15 on the main primary outcome parameter pain intensity (VAS) was chosen. The required minimum number of participating patients is negatively associated with the correlation between measurements during the cross-over. Unfortunately, no data of previous research on this correlation were available at the time of setting up this study. Therefore, we made an conservative guess and a correlation of 0.6 was chosen. Thus, assuming a power of 0.8 and a significance level (σ) of 0.05 , an a priori sample size of 48 is required.Randomization was performed with a computer based program at the beginning of the trial and no blocks were used since this is not viable in our study design. In our study design all patients in the crossover will be subjected to all five stimulation modalities in random order, resulting in 5! (120) different orders in which the stimulation modalities can be programmed. Only 48 (the required sample size) of these 120 potential different orders are selected at random by the computer to be used.The specific order of the programming for an individual patient is revealed to the local SCS programmer only during each of the five crossover periods. The patient is blinded for the intervention by means of a mask that cannot be seen through. The outcome assessments at the end of each 2-week period are done by means of questionnaires. The statistician who performs the analysis of the measurements and questionnaires is blinded for the allocation key for the treatments for each patient.Data are analyzed using the latest version of IBM SPSS Statistics. Descriptive statistics are used to determine the frequencies of the demographic and secondary outcome parameters, and to describe measures of central tendency and of dispersion, dependent on the shape of their distribution. The Kolmogorov-Smirnov test is used to analyze whether or not the scores on the these parameters are normally distributed. The outcome parameters are analyzed using Mixed Linear Models for repeated measurements within factors model. These Mixed Linear Models model require normality of residuals. These models are however relatively robust against violations of this assumption . TherefoPatients with an indication for neuromodulation are referred by their physicians to the SCS nurses for further evaluation, and to provide them with additional information about the procedure and lifestyle limitations. Also, a psychologist will screen the patient to rule out any psychological contraindication that might influence the outcome of the SCS trial. The patients are contacted by the researcher for trial information and enrollment once all the clinical inclusion criteria for SCS treatment have been met. After obtaining written obtained consent from the patient, the next phase in the trial can commence. It is noteworthy that patients who decline to participate in the trial will still be treated with regular SCS therapy.The patient is invited to our medical centre to participate in various test that are conducted as well as medical history and physical examination. All questionnaires must be filled in by the patient prior to this visit. Table The trial stimulation is conducted at the various hospitals attended by the patients and lasts for 2 weeks. Only experienced physicians are allowed to perform implantation. During the test stimulation the patient is positioned in the prone position and spinal column landmarks are identified with fluoroscopy. Local anaesthetics are used during this procedure; however, a mild sedative or short-acting opioid can be used without compromising the patient’s ability to cooperate during the intra-operative testing. The surgical procedure used is left to the discretion of the physician in charge.The cylindrical percutaneous Octrode™ lead  is primarily used in all patients to gain unilateral stimulation and is positioned under fluoroscopic guidance. The correct position is determined by means of intra-operative stimulation and is deemed successful if the induced paresthesia has an adequate overlap with the painful area. The lead is sutured to the fascia using an anchor. An extension cable is attached to the lead and is tunneled under the skin towards a suitable exit site. A temporary battery is attached to the external part of this extension cable during the trial period.The parameters used for stimulation is up to the SCS nurse in charge, except for the mandatory frequency setting of 40 Hz. All other parameters  are the result of the individual clinical paresthesia mapping. The trial period will generally last for 1 or 2 weeks and is considered successful if a patient has >50 % pain reduction on a VAS and/or has stated that the symptoms are much improved. All patients with a successful trial receive a permanent rechargeable internal pulse generator (IPG) from the Eon family line  under general anaesthesia. The trial extension cable is removed and replaced with a new extension cable that is connected to the IPG. In some instances, a direct connection with the lead and IPG can be made if the length of the lead is sufficient. The pocket location for the IPG is free of choice and can either be in the lower abdomen or in the gluteal are. All materials are removed if a trial is unsuccessful and the patient is then excluded from further follow-up during this trial. The standard stimulation setting is further optimised during the regular checkups in the subsequent weeks. Antibiotic prophylaxis is given during both the trial and implantation in accordance with the local hospital antimicrobial guidelines.Three months after the IPG implantation and therapy with normal tonic 40 Hz SCS, another assessment T1) takes place. This serves as an evaluation of the effects of regular SCS on the previously described tests (Table  takes plThe crossover period consists of five periods (each lasting for 2 weeks) in which the 5 different frequencies are tested. After each period, a small assessment (S1-S5) is done to evaluate the stimulation effects on pain and GPE. A 2-day wash-out period, during which the stimulation is switched off, is incorporated at the beginning of the first 2-week period (S1) and at the end of each period. The purpose of a wash-out period is to objectively determine the baseline pain levels and symptoms of CRPS when they are not masked by SCS, and to minimise the carryover effects of the previous period into the next period. The small assessments (S1-S5) comprise a stimulation evaluation, a pain diary, the McGill Pain Questionnaire and the Global Perceived Effect. Stimulation evaluation requires a patient to keep a stimulation diary in which they must answers four questions; (1) the effect(s) of stimulation on pain in the CRPS effected area, (2) if they feel paresthesia and if so where do they feel it and how is the stimulation described, (3) how they would rate the ease of use of the stimulation, (4) the advantages and (5) the disadvantages per stimulation modality. A detailed overview of the crossover period is provided in Fig. During the final evaluation (S6) a decision is made by the patient regarding which stimulation modality is to be used for the subsequent 3 months at the end of these 5 periods. This decision is mainly based on pain reduction, but also on other CRPS-related symptoms and practical matters related to the stimulation. The patient continues with their stimulation of choice for another 3 months. A switch of stimulation within these 3 months is possible in certain cases.The five stimulation modalities are all programmed in such a way the maximum effect pain be obtained. Standard 40 Hz stimulation will be performed above threshold which generates paresthesia in the affected area and is in accordance with normal practice. Both 500 Hz and 1200 Hz will be above threshold stimulation and will also generate paresthesia. At the time this study protocol was postulated there were no other reports available on how best to program 500 and 1200 Hz SCS based on mechanisms of action. Thus, in absence of evidence stating the contrary, we decided to program 500 and 1200 Hz SCS like standard 40 Hz stimulation with the intention to induce paresthesia and thus being an above threshold stimulation. Placebo stimulation is performed with the IPG switched off and thus does not generate paresthesia. The rationale is to evaluate how big a part of the pain relief could be attributed to the placebo effect. Burst stimulation is performed with fixed stimulation parameters and the intensity of the stimulation will be sub-threshold and therefore is does not generate paresthesia. The fixed parameters of burst stimulation are: an overall frequency of 40 Hz per burst complex. Each burst complex delivers 5 spikes with a frequency of 500 Hz and a pulse width per spike of 1 ms and an inter-spike interval of 1 ms. The charge is balanced during the 15 ms pause between the burst complexes.The T2 assessment is performed when a patient has completed the 3-month period with the frequency of choice. This T2 evaluation enables us to compare all the primary and secondary outcomes parameters with the T1 assessment with standard SCS and the baseline T0 assessment prior to SCS therapy. The patient is actively asked whether they want to continue with the SCS program they have chosen, or want to switch to another one based on the crossover results.After completion of this trial the patient will continue with the chosen stimulation and a clinical follow-up is performed once a year by the physicians and nurses.Data obtained from this trial will provide better insight as to whether SCS, as it is currently applied, is the best available therapy modality, or whether stimulation with a higher frequency or with burst stimulation results in better pain relief. Another result might be that these new modalities of stimulation are equally preferred by the patients. Irrespective of the outcomes, this trial will provide new insights into the mechanisms of action involved in SCS treatment and, particularly, in patients with CRPS.For this trial, standard SCS was defined as stimulation with 40 Hz and corresponds with the normal stimulation setting used in our daily practice. The choice to select 500 Hz was based on studies reporting that blood flow and endogenous opioid release are at their maximum while applying SCS at this frequency , 59, 81.High-frequency SCS (HF-SCS) with 10,000 Hz is also available and multiple studies have shown its effect in pain patients and its ability to reduce pain over a longer period of time , 86. OurBurst stimulation is a new concept which requires a totally different programming algorithm in daily practice. The stimulation must be programmed to a sub-threshold current output level so that a patient will not experience paresthesia. This paresthesia free ‘side-effect’ can be used to incorporate a placebo element into the trial where paresthesia cannot be felt because the stimulation is switched off.The question remains if a 2 week test period per frequency along with a 2 day wash-out to counteract the possible carryover effects of the various frequencies are enough. In clinical practice a patient can conclude whether the SCS is beneficial to him/her within a two week period during trial SCS. We choose to maintain the 2 week per period analogy in the crossover period which should provide the patient with enough time to decide if one of the test frequencies is beneficial or not. Moreover, by increasing the crossover period to 3 weeks or even longer the possibility of patient withdrawal from the study increases in case one of the test stimulations does not provide (sufficient) pain relief. This is further supported by what clinicians hear from patients that the pain returns when the stimulation is switched off. Some experience an instantaneous increase in pain while others report that it takes a few minutes or a few hours before the pain has fully returned, but never longer than 24 h. On these arguments we decided on a wash-out period of 2 days between the various stimulation modalities to be tested –90.A potential pitfall in the design of the present trial that might influence the patient’s choice, is that the patients are preconditioned with standard stimulation for the first 3 months. On the other hand, if they do choose a SCS setting other than the standard one, it is a choice they make despite the odds being in favour of the standard stimulation.Bias and in particular attrition bias is a serious problem that could affect the results of the trial. In our trial attrition bias will be handled by describing all patients that have dropped out of the trial before its completion and the reasons for dropping out/trial exit will be documented and provided in a flowchart in a separate manuscript with the results of this trial. The flowchart will adhere to the requirements of the CONSORT statement for transparent reporting of trials. Furthermore, data will be analysed using linear mixed models. Hence we can use all of the data, i.e., if a score is missing, it has no effect on other scores from that same patient.With the results obtained from this study, that focuses solely on patients with CRPS, we aim to increase knowledge on the effects of SCS in this patient group. However, caution is advised when extrapolating these results to other neuropathic pain states because of the single-disease inclusion approach.Patient recruitment and inclusion started in August 2011 and the trial is currently ongoing. Completion of the first part of the study  is expected in early 2015. The completion of T2 and long-term data collection is expected towards the end of 2015.


This article evaluates the long-term outcomes of computed tomography (CT)-guided percutaneous radiofrequency thermocoagulation (PRT) for patients with recurrent trigeminal neuralgia (TN) after microvascular decompression (MVD).This is a retrospective study of 41 patients with intractable TN who after MVD underwent CT-guided PRT procedures between 2002 and 2012.The mean length of follow-up after PRT was 44.4 months. Immediate pain relief was in 37 patients (90.2%); the percentage of patients who remained in “excellent” or “good” pain relief condition after CT-guided PRT procedure was 85% at 1 year, 80% at 2 years, 51% at 5 years, and 41% at 10 years. Six patients received the second PRT and all achieved “excellent” or “good” pain relief. In total, 34 of these patients (82.9%) received multi-PRT procedure and remained satisfied with their pain relief during the follow-up period. Postoperative complications included facial numbness in 36 patients, limited eyes opening in 1 patient, ear paresthesia in 1 patient, no tears in 1 patient, and taste hypesthesia in 1 patient; these symptoms were all improved in the process of follow-up and their life had not severely affected. No mortality was observed during and after CT-guided PRT procedures.CT-guided PRT should be considered as an alternative treatment for patients with recurrent TN after MVD. The biggest advantage of MVD, which remove the vascular compression of root entrance of the trigeminal nerve, was maintaining the normal facial sense with long-term effective pain relief and avoiding the appearance of the facial numbness and discomfort after procedure. However, some patients can only get partial pain remission or even be invalid, the reported annual recurrence rate range from 1% to 5%.7 How to cure these refractory TN patients is challenging for TN treatment.Trigeminal neuralgia (TN) is a severe syndrome characterized by facial pain that is described as excruciating and causes serious impairments of the quality of life. Since Jannetta8 and now PRT is the most commonly performed ablative procedure at the level of the gasserian ganglion for TN patients.9 The advantage of PRT is that it is safely used for multirepeated procedure. Repeated PRT provides long-term pain relief benefits to patients with recurrent TN after single PRT has been reported11; however, little is known regarding clinical outcome analysis solely for patients with recurrent TN following MVD procedures.CT-guided percutaneous radiofrequency thermocoagulation (PRT) of the trigeminal gasserian ganglion, an effective and less-invasive treatment, has gained wide acceptance in the treatment of TN patients who are refractory to medical therapy. This technique has been popularized since 197412 The present study aimed to evaluate the clinical outcomes of CT-guided PRT procedure in patients with TN after MVD.In our unit, CT-guided PRT has become the treatment of choice for refractory TN since 2002, and there were several studies focused on evaluating the long-term outcomes of PRT for the patients with TN.From January 2002 to December 2012, 996 patients underwent CT-guided PRT procedure for classic TN at the Department of Pain Management in Xuanwu Hospital, Beijing, China; 41 patients of them who had received MVD previously were included in the final analysis.13 Follow-up was conducted via telephone interview and medical records.This study was approved by the Ethical Committee of the Xuanwu Hospital. Prior to the CT-guided PRT procedure, all patients were informed about the procedure and its possible complications, and written informed consent was obtained. Classic TN was diagnosed according to the International Classification of Headache Disorders II (2004) criteria.14 The patient was taken to our disinfected CT examination room and was placed in a supine position with their head overhanging on the CT scanner bed. Each patient's vital signs were monitored during the entire procedure. The puncture of gasserian ganglion was according to Hartel anterior route. The best puncture approach to the oval foreman and the corresponding skin insertion point was determined by CT scanning. After sterilization, the insertion point was anesthesized with 1% lidocaine. Then, a 22-gauge radiofrequency-insulated needle with a 5-mm active tip was inserted. The insertion angle and the advanced depth to the foramen ovale of the needle were according to the best puncture approach. While piercing the needle into the foramen ovale, repeated CT scan was used to reconfirm the position of the needle tip. After verification, motor  and sensory  were performed to confirm or readjust the needle tip position to confirm the accuracy. After certifying the proper location, the patient was administered intravenous anesthesia with propofol (1–2 mg/kg) and supplemented with facemask oxygen. No tracheal intubation was performed. The gasserian ganglion was thermally coagulated with radiofrequency at 75°C for 120 seconds.CT-guided PRT procedure was performed according to our previously reported studies.15 The outcomes were classified as follows: “excellent” results were defined as BNI grade I (no pain and no medicine), “good” results were defined as BNI grade II  or BNI grade III , and “poor” results were accomplished when the pain remained at an intensity BNI ≥ grade IV  after treatment; CT-guided PRT were repeated in cases of BNI grade IV or V after the first PRT procedure.Pain degree was evaluated at the baseline and postoperative follow-up, using the Barrow Neurological Institute (BNI) grading score.The data were analyzed using the statistical package for the social sciences version 17.0 . Kaplan–Meier curves were calculated to determine the percentage of patients that were in the “excellent” and “good” outcome category after first CT-guided PRT. Patient follow-up was censored at last contact (n = 20) and time of subsequent surgery (n = 6).Table After the first PRT, 37 patients (90.2%) achieved immediate pain relief and 4 patients (9.8%) experienced recalcitrant symptoms. The Kaplan–Meier curve for “excellent” or “good” outcomes of 41 patients after first CT-guided PRT procedures are shown in Figure Of the 37 patients with immediate pain relief, 23 patients (62.2%) maintained pain relief with “excellent” results for the duration of their follow-up  and their medication were tapered off a period of several weeks; 5 patients (13.5%) achieved “good” results and got effective pain control with drugs . The remaining 9 patients (24.3%) experienced pain recurrence with “poor” results ; 4 of them underwent stereotactic radiosurgery including 2 patients who achieved “excellent” pain relief with a follow-up of 12 and 27 months, respectively. Another 2 patients did not achieve pain relief; 5 of 9 patients with “poor ” results after first PRT underwent second procedure. After the second PRT, “excellent” pain relief was obtained in 1 patient when checked at 15 months of follow-up; 2 patients had “good” pain relief result switched to drug treatments, which resulted in an effective pain control when assessed 17 months later; 2 patients were with “poor” results after the second procedure at 10 months, 1 received a third PRT procedure and the other underwent stereotactic radiosurgery and did not achieve pain relief.Of 4 patients whose pain had no relief after first PRT, 2 of them experienced second PRT, and his pain had relieved completely and maintained with follow-up of 18 and 27 months, respectively. The other 2 patients both underwent stereotactic radiosurgery, 1 of them got partial pain relief and needed drug to control pain attack with follow-up of 31 months, and the other patient was not still relieved and he died in myocardial infarction  24 months after stereotactic radiosurgery.Thirty-six of all patients (87.8%) had a mild-to-moderate degree of facial numbness after PRT. This sense gradually alleviated in follow-up. No painful dysesthesia occurred after PRT. Additional postoperative complications included limited eyes opening in 1 patient, paresthesia of ipsilateral ear in 1 patient, no tears in 1 patient, and taste hypesthesia in 1 patient; these symptoms were improved in the process of postoperative follow-up and their life had not been affected. There was no mortality and no permanent cranial nerve deficit except dysesthesia observed in these 41 patients.16 Devor et al17 believed that compression and demyelination of sensory nerve is generally associated with tough numbness or vibration sense, and not pain. Additionally, MVD procedure has certain recurrence rates. Cho et al18 reported that in the first year, the recurrence rate was 14% with 2% to 3.5% growth per year, and >25% after 5 years. Some studies revealed that the pain did not ease completely after MVD; insufficient decompression, without significant vascular compression, or vascular compressed the nerve again might be reasons, but they were not verified,20 at the same time long history (>8 years) is also a negative factor.21 There were lots of report about reoperation after MVD,26 but recurrent TN after first MVD poses a management challenge because of arachnoid adhesions and abnormal anatomical relationships,22 and complications are relatively higher than first MVD.27 A large-scale MVD study reported that the morbidity rate of MVD is about 0.3%.28 The effectiveness of MVD in the unobvious vessel compression group was worse than those in the obvious group.29 Meanwhile, patients would become elder when it recurred that lead to higher risks of operation and endotracheal anesthesia. More minimally invasive procedures are needed for these patients.Given that most cases of TN are believed to be caused by “neurovascular compression,” MVD was thought to be the preferred method for TN treatment. But approximately 15% of patients may not have a significant vascular compression, or adequate decompression may not be achieved safely in them.30 However, PRT and MVD have similar initial success rate and recurrence rate; a lower rate of adverse events makes it more acceptable, so neurosurgeons should be familiar with both the techniques to select the best treatment for each patient.31No need for endotracheal anesthesia and short hospitalization make PRT one of the most common procedures for TN. This procedure is especially suitable for elderly, and patients with poor fitness or who refuse to perform MVD. A nationwide study of 3 invasive treatments for TN found that after MVD, most patients had a PRT as second procedure.32 Our results suggest that PRT is a safe and effective therapy for the patients with recurrent TN after MVD. PRT management of TN is based on interrupting the pain by partial damage to the trigeminal nerve fiber; the destruction of the surrounding tissue is very limited and repeated PRT could be safe and effective.11In our study, 41 patients who had “poor” outcomes after MVD received CT-guided PRT procedure, 37 (90.2%) patients achieved immediate pain relief, and 34 (82.9%) received multi-PRT procedure and remained satisfied with their pain relief during the follow-up period. Neither mortality nor life-threatening complications was observed, and the rate of adverse events conformed to the previous reports.The success rates of initial MVD, repeated MVD, repeated PRT, and PRT after MVD are shown in Table 12 Fortunately, facial numbness of all patients after PRT is mild, limited, and well tolerated by most patients; no painful dysesthesia occurred.The most common complication is facial numbness; in our study, 36 patients (87.8%) experienced significant facial numbness. Achievement of numbness is a prerequisite for prolonged pain cessation of PRT procedure.Four patients who underwent MVD, PRT, and stereotactic radiosurgery did not achieve successful pain relief, as we inferred in the previous study; there might be a subpopulation of TN patients resistant to all currently available treatment modalities and this remains unclear which patient might fail to benefit from PRT. Neural plasticity up to the gasserian ganglion may be dominant for this refractory pain, and these patients might benefit from motor cortex stimulation or deep brain stimulation. These refractory patients should be further studied in future.In the present study, data from 41 patients with recurrent TN after MVD who underwent CT-guided PRT procedure are presented. PRT procedure may achieve long-term pain relief with minimal rate of complications in patients with recurrent TN after MVD. Given that CT-guided PRT is a safe and effective treatment procedure to perform with a minimal complication rate, it should be considered a practical treatment option in treating recurrent TN after MVD, especially for patients with poor fitness or who refuse to receive craniotomy surgery again.


The associations between a higher number of comorbidities and worse outcomes were stronger in THA than in TKA. In multivariate analyses including all comorbidities with a prevalence of >5 %, in THA dizziness in combination with falling and severe back pain, and in TKA dizziness in combination with falling, vision impairments, and elbow, wrist or hand pain was associated with worse outcomes in most of the analyses. A broad range of specific comorbidities needs to be taken into account with the interpretation of patients’ health status after THA and TKA. More research including the ascertainment of comorbidities preoperatively is needed, but it is conceivable that in particular, the presence of dizziness with falling, pain in other joints, and vision impairments should be assessed and treated in order to decrease the chance of an unfavorable outcome.The aim of the study was to examine the relationship between comorbidities and pain, physical function and health-related quality of life (HRQoL) after total hip arthroplasty (THA) and total knee arthroplasty (TKA). A cross-sectional retrospective survey was conducted including 19 specific comorbidities, administered in patients who underwent THA or TKA in the previous 7–22 months in one of 4 hospitals. Outcome measures included pain, physical functioning, and HRQoL. Of the 521 patients (281 THA and 240 TKA) included, 449 (86 %) had ≥1 comorbidities. The most frequently reported comorbidities (>15 %) were severe back pain; neck/shoulder pain; elbow, wrist or hand pain; hypertension; incontinence of urine; hearing impairment; vision impairment; and cancer. Only the prevalence of cancer was significantly different between THA ( Total joint replacement surgery is a very effective treatment option in the end stages of hip and knee osteoarthritis (OA) . By 2009One of the factors being associated with a poor outcome after THA and TKA concerns the presence of comorbidity . In patiWith respect to the association of the number of comorbidities and the outcomes of THA and TKA, it was found that an increasing number of affected joints was associated with worse postsurgical pain, physical function, and mental health , 18 as wSo far, the literature on the associations of comorbidity with outcome in patients with hip or knee OA undergoing THA or TKA often focused on one or a limited number of comorbidities , 20, 23.In daily practice, orthopedic surgeons take the presence of comorbidity into account in their decision for surgery, in part by using the ASA (American Society of Anesthesiologists) classification to identify patients with an increased risk of death or surgical complications. This use of this classification is, however, not aiming to identify patients with an increased risk of a worse functional outcome . In 2012Given the lack of knowledge on the incidence and associations of a wide range of specific comorbidities and health status after THA and TKA, the aim of this study was to determine the burden of comorbidities among patients who underwent THA and TKA and to evaluate the association between comorbidities and pain, physical function and HRQoL one year after surgery.http://www.wma.net/en/30publications/10policies/b3/].This study had a cross-sectional design. It was a part of multicenter survey concerning the use of physical therapy  among coPatients diagnosed with hip or knee OA were eligible for the study if they were 18 years or older and underwent primary THA or TKA between January 1 and December 31, 2011.Exclusion criteria were surgery for diagnoses other than OA and revision surgery.We aimed to obtain total number of 400 completed questionnaires (200 THA and 200 TKA). Anticipating a response rate of 40 %, we planned to invite 1,000 patients from 4 different hospitals. Selection was done by means of hospital registries. All patients in whom the diagnosis primary THA or TKA was made between January 1 and December 31, 2011 were first selected, subsequently, all patients with a diagnosis of hip or knee OA, and age 18 years or older were identified. In hospital 1, all eligible persons were invited. In hospital 2, the survey was sent to all persons who were already participating in a prospective study and underwent surgery in 2011, whereas in hospitals 3 and 4, all consecutive patients who underwent surgery were invited, until the total number of 1,000 invited patients was reached.In all 4 hospitals, the treating orthopedic surgeon sent a letter explaining the study and requesting the patient to participate, together with an information leaflet, an informed consent form, the survey and a pre-stamped, pre-addressed envelope to all selected patients. After patients signed the informed consent form, they were included in the study. Because the questionnaires were completed anonymously, no information was obtained on the patients who did not respond.Sociodemographic characteristics included age (years), sex, level of education , and marital status . In addition, patient’s height (cm) and weight (kg) were recorded , as well as their smoking status (current smoker yes/no).Information on comorbidities was gathered with two questionnaires:Musculoskeletal comorbidities: severe back pain (including slipped disc); severe neck or shoulder pain; severe elbow, wrist or hand pain; other chronic rheumatic diseases; Non-musculoskeletal comorbidities: asthma or COPD (Chronic Obstructive Pulmonary Disease); (severe) cardiac disorder or coronary disease; arteriosclerosis (abdomen or legs); hypertension; (consequences of) stroke; severe bowel disorder; diabetes mellitus; migraine; psoriasis; chronic eczema; cancer; incontinence of urine; Sensory impairments: hearing impairments (group and face-to-face conversation); vision impairments (short and long distance); dizziness in combination with falling.First, a comorbidity questionnaire developed by the Dutch Central Bureau of Statistics (CBS)  was usedSecondly, we used the self-reported Charnley Classification , 27, whiInformation on current postoperative physical functioning was collected by means of the pain and physical functioning subscales of the Hip disability Osteoarthritis Outcome Score (HOOS)  and the Health-related quality of life (HRQoL) was measured with the Short Form-36 questionnaire (SF36) . The SF3t test or Chi-square tests, where appropriate.Patients’ characteristics, the presence of different specific comorbidities, pain, physical functioning, and HRQoL were analyzed by using descriptive statistics. Differences between the characteristics of patients undergoing THA and TKA were examined by means of unpaired Students’ To study the relationship between the number of comorbidities and the four outcomes, multivariate regression models were employed. For this purpose, the number of comorbidities was categorized into four groups: 1–2 comorbidities, 3–4 comorbidities, and 5 or more comorbidities, with 0 comorbidities being the reference group.Then, all comorbidities (which occured in ≥5 of the patients) and potential confounders which were significantly associated with the outcomes were included in final multivariate regression models.All the analyses were corrected for BMI, whereas the analyses with pain and physical functioning as dependent variables were also adjusted for sex and age .p < 0.05 for all analyses.All data were analyzed using the SPSS statistical package . The level of statistical significance was set at In total 1,005 patients were requested to complete the survey in the 4 participating hospitals. Of these patients, 539 (53.6 %) underwent THA and 466 (46.4 %) TKA. The response to the survey was 521 out of 1,005 (51.8 %) for the total group, with 281 out of 539 (52.1 %) patients responding in the THA and 240 out of 466 (51.5 %) in the TKA groups.p < 0.001)). There were significantly more obese (BMI 30–40) patients in the TKA group than in the THA group , while no difference regarding the frequency of morbid obesity (BMI > 40) was seen between THA and TKA.Table p = 0.010 and p = 0.014, respectively), whereas the SF36 mental and physical component summary scales did not differ between THA and TKA.The average pain and physical functioning scores as measured by the HOOS and KOOS, respectively, were significantly higher in the THA group than in the TKA group .In the group of patients who underwent THA, statistically significantly more patients were classified as Charnley Class A and significantly less patients classified as Charnley Class C as compared to TKA . Severe back pain; severe neck/shoulder pain; severe elbow, wrist or hand pain; cancer; incontinence of urine; and vision impairment short distances were reported by 15–25 % of the patients in the total group (Table p = 0.01)]. Regarding all other specific comorbidities, there were no differences between THA and TKA (Table The occurrence of cancer was significantly lower in the THA group than in the TKA group .Table Table Table The presence of all the 19 specific comorbidities, except hypertension, was associated with one or more of the outcomes in both THA and TKA (results not shown).Table In Table This study in patients who underwent THA or TKA showed the presence of considerable amount of comorbidities in patients after surgery. Hypertension and hearing impairments in a group conversation had the highest occurrence rates (>25 %), while severe back pain; neck/shoulder pain; elbow, wrist or hand pain; cancer; and vision impairments regarding short distances were also relatively frequent, as they were reported by 15–20 % of the patients.Some of the present frequencies of the occurrence of specific comorbidities in this study were comparable with earlier studies, i.e., hypertension  were associated with 2 out of 4 outcomes.The presence of dizziness in combination with falling is difficult to compare with other studies, as these studies did not include this comorbidity. Dizziness has, however, been previously identified as one of the main reasons for a longer stay in hospital after surgery  and can In our study, obesity was not considered as a specific comorbidity, but rather as an influential factor. Therefore, BMI was included in all analyses. The literature shows conflicting evidence regarding the association of obesity with complications after surgery . RegardiThis study has a number of limitations. First, only 4 hospitals in a specific area in the Netherlands were involved, the sample size was limited and varied between sites, the response rate was moderate (52 %), and no comparison of the characteristics of the participants and non-responders could be made. Therefore, results cannot be generalized to all patients undergoing THA or TKA. However, based on baseline characteristics, it seems to be a representative sample of this patient group. Furthermore, the study is cross-sectional and not longitudinal, which makes that only associations can be determined, and no predictions can be made. Preferably, data on the presence of comorbidity should be gathered preoperatively. Moreover, the assessments only included self-reported questionnaires. Examination of the medical records could probably have given more reliable and additional information; however, this very time-consuming method could not be used in the framework of this study.Despite these limitations, this study taking a large number of comorbidities into consideration and analyzing THA and TKA patients separately found that not only the number of comorbidities but also their nature are related to the outcomes. In particular, dizziness in combination with falling plays a consistent role in both THA and TKA, and severe low back pain in THA. Although a prospective study including the presence of a wide range of comorbidities preoperatively is needed, the results of the present study suggest that a large number of specific comorbidities have an impact on patients’ health status after surgery. As many comorbidities are chronic by nature and therefore likely to have been present before surgery as well, their presence should probably be ascertained before surgery and treated if possible, since the predictive value is confirmed in earlier studies . AlthougCurrently, the ASA classification  is used


Fibromyalgia, a chronic syndrome of diffuse musculoskeletal pain and somatic hyperalgesia from central sensitization, is very often comorbid with visceral pain conditions. In fibromyalgia patients with gallbladder calculosis, this study assessed the short and long-term impact of laparoscopic cholecystectomy on fibromyalgia pain symptoms. Fibromyalgia pain  and pain thresholds in tender points and control areas  were evaluated 1week before (basis) and 1week, 1,3,6 and 12months after laparoscopic cholecystectomy in fibromyalgia patients with symptomatic calculosis (n = 31) vs calculosis patients without fibromyalgia (n. 26) and at comparable time points in fibromyalgia patients not undergoing cholecystectomy, with symptomatic (n = 27) and asymptomatic (n = 28) calculosis, and no calculosis (n = 30). At basis, fibromyalgia+symptomatic calculosis patients presented a significant linear correlation between the number of previously experienced biliary colics and fibromyalgia pain (direct) and muscle thresholds (inverse)(p<0.0001). After cholecystectomy, fibromyalgia pain significantly increased and all thresholds significantly decreased at 1week and 1month , the decrease in muscle thresholds correlating linearly with the peak postoperative pain at surgery site (p<0.003-p<0.0001). Fibromyalgia pain and thresholds returned to preoperative values at 3months, then pain significantly decreased and thresholds significantly increased at 6 and 12months (p<0.05-p<0.0001). Over the same 12-month period: in non-fibromyalgia patients undergoing cholecystectomy thresholds did not change; in all other fibromyalgia groups not undergoing cholecystectomy fibromyalgia pain and thresholds remained stable, except in fibromyalgia+symptomatic calculosis at 12months when pain significantly increased and muscle thresholds significantly decreased (p<0.05-p<0.0001). The results of the study show that biliary colics from gallbladder calculosis represent an exacerbating factor for fibromyalgia symptoms and that laparoscopic cholecystectomy produces only a transitory worsening of these symptoms, largely compensated by the long-term improvement/desensitization due to gallbladder removal. This study provides new insights into the role of visceral pain comorbidities and the effects of their treatment on fibromyalgia pain/hypersensitivity. Fibromyalgia is a chronic pain syndrome affecting 4–7% of the general population, prevalently women . Its diaSurgery is a powerful source of peripheral impulses, leading to possible sensitization, and fibromyalgia patients have indeed been shown to be at increased risk of experiencing enhanced pain subsequent to various surgical procedures –18. No rPatients affected with fibromyalgia primarily diagnosed according to the ACR criteria (1990), with confirmation of the diagnosis based on the 2010 revised preliminary criteria, with and without concurrent gallbladder calculosis, were considered . ConfirmFor fibromyalgia, the following groups were considered:[FMS+sGb+Cholec]: patients with fibromyalgia + symptomatic gallbladder calculosis, scheduled to undergo laparoscopic cholecystectomy in the forthcoming month;[FMS+aGb]: patients with fibromyalgia + asymptomatic gallbladder calculosis, not scheduled for cholecystectomy;[FMS]: patients with fibromyalgia without gallbladder calculosis;[FMS+sGb]: patients with fibromyalgia + symptomatic gallbladder calculosis, not willing to undergo laparoscopic cholecystectomy in the immediate future.A further group was considered:[sGb+Cholec]: non-fibromyalgic patients + symptomatic gallbladder calculosis scheduled for laparoscopic cholecystectomy in the forthcoming month.In patients to be subjected to laparoscopic cholecystectomy surgery was performed either at the Institute of Surgical Pathology of the “G. D’Annunzio” University of Chieti or in other Surgery Units of their choice throughout Italy.Inclusion criteria for [FMS+sGb+Cholec] were: female sex; age 18–70 years; a diagnosis of FMS performed by a specialist 2–5 years previously, with the start of symptoms not earlier than 6 years before, average intensity of diffuse pain ≥50 mm of VAS, on a stable dose of amitriptyline (10 mg/day)–in the preceding 3 months; gallbladder stone diagnosed at least 1 year previously, longest stone diameter 10–40 mm documented at abdominal ultrasounds (AUs), symptomatic for biliary pain episodes (first and last episodes maximum 5 years and 1 month before), respectively; laparoscopic cholecystectomy scheduled in the next month; a negative clinical history for other recurrent/chronic pain conditions  over the past 5 years and for any medical condition known to influence general sensitivity to pain ; exclusion of previous and current conditions known to represent a preoperative risk factor for conversion in laparoscopic cholecystectomy ; exclusion of major psychiatric disorders at specialistic psychiatric examination; informed, written consent to participate in the study ,22–25.Inclusion criteria for [FMS+aGb] were the same as for [FMS+sGb+Cholec], except that the gallbladder calculosis had to be asymptomatic with respect to colic pain  and no cholecystectomy was scheduled in the immediate future.Inclusion criteria for FMS were the same as for [FMS+sGb+Cholec], except that patients had to be free from gallbladder calculosis as documented by AUs performed no more than 6 months previously.Inclusion criteria for [FMS+sGb] were the same as for [FMS+sGb+Cholec], except that patients had to be unwilling to undergo cholecystectomy in the immediate future.Inclusion criteria for [sGb+Cholec] were the same as for [FMS+sGb+Cholec], except that a diagnosis of fibromyalgia had to be excluded at a specialistic evaluation.The study was carried out in two phases of 1-year duration each. The first phase was conducted in all groups. The second phase was conducted only in patients with fibromyalgia + symptomatic gallbladder calculosis not undergoing cholecystectomy during the first year. All evaluations were carried out at the Fibromyalgia and Musculoskeletal Pain Center of Chieti University.In patients scheduled for laparoscopic cholecystectomy, evaluations were carried out at six time points: in basal conditions (1 week before surgery) and 1 week, 1 month, 3, 6 and 12 months after the operation. Patients not undergoing cholecystectomy underwent the same evaluations at comparable time points as those subjected to surgery.In all FMS patients, the recorded parameters were:average intensity of diffuse musculoskeletal pain from FMS on a Visual Analogue Scale (VAS) (self-described average in a single measurement);pain sensitivity at the 18 TePs through measurement of pressure pain thresholds (PPTs) via Fischer’s algometer ;pain sensitivity in areas outside the TePs (control areas), i.e., in 3 body sites: trapezius, deltoid and quadriceps of one side, through measurement of electrical (EPTs) and pressure pain thresholds in muscle and of electrical pain thresholds in overlying subcutis and skin ;number of previously experienced biliary colics  .In non-FMS patients, in basal conditions evaluations c-d were performed.Patients subjected to laparoscopic cholecystectomy were also requested to note, in an ad-hoc diary, the intensity of the pain  perceived at the site of the intervention on a daily basis, during the first post-operative week . DiariesA total of 116 FMS patients meeting the inclusion criteria were included in the study: n = 31 for [FMS+sGb+Cholec] (mean age: 42.3 ± 5.2 SD years), n = .28 for [FMS+aGb] (41.1 ± 5.9 yrs); n = 30 for [FMS](41.5 ± 6.2 yrs) and n = 27 for [FMS+sGb](40 ± 7.6 yrs). A total of 26 non-FMS patients with symptomatic gallbladder calculosis [sGb+Cholec] (39.3 ± 4.8 yrs) meeting the inclusion criteria were included in the study. All groups of patients did not differ in mean age. [FMS+sGb] patients were informed that they were free to interrupt the study protocol should they decide to undergo cholecystectomy at any time during the first year of evaluation.This phase was designed only for the 27 patients [FMS+sGb] who had been unwilling to undergo cholecystectomy at the beginning of the first year. None of them interrupted the study during this period. At the start of the second year, 20 decided to be scheduled for the intervention within the next month [FMS+sGb with delayed Cholec](41.3±7.5 yrs) while 7 of them continued to refuse to undergo cholecystectomy [FMS+sGb without delayed Cholec](38.7±8.2 yrs). All of them accepted to continue to be monitored for their FMS symptoms for a further year, according to the same protocol as for the first year of evaluation.A pressure dynamometer was used . The devsee  and clinical condition  for each evaluated parameter during the 1The linear regression analysis was employed to evaluate:in patients with symptomatic gallbladder calculosis, the possible correlation between the number of previously experienced biliary colics and FMS parameters in basal conditions ;in patients undergoing cholecystectomy, the possible correlation between extent of postoperative pain  and the change in FMS parameters postoperatively . The level of significance was set at P<0.05.The softwares used for the statistics were GraphPad InStat and GraphPad Prism. Raw data of the evaluated parameters are reported in st year study, in particular:At 2-way ANOVA, a significant effect was found of time  and clinical condition  for all the evaluated parameters during the 1for VAS, time  and clinical condition ;for PPTs in TePs, time  and clinical condition ;for EPTs in skin, time  and clinical condition ;for EPTs in subcutis, time  and clinical condition ;for EPTs in muscle, time  and clinical condition ;for PPTs in muscle, time  and clinical condition .Biliary symptoms. Patients of the three groups with symptomatic gallbladder calculosis, [FMS+sGb+Cholec], [FMS+sGb] and [sGb+Cholec], did not differ for the number of previously experienced biliary colics .Fibromyalgia symptoms. Spontaneous fibromyalgia pain (VAS of FMS pain) and pressure pain thresholds at tender point sites (PPTs in TePs) were similar between [FMS+sGb+Cholec] and [FMS+sGb] and between [FMS+aGb] and [FMS], respectively. In fibromyalgia patients with symptomatic gallbladder calculosis with respect to fibromyalgia patients with asymptomatic gallbladder calculosis and without gallbladder pathology: VAS of FMS pain was significantly higher and PPTs in TePs were lower, the difference being significant for FMS+sGb+Cholec and FMS+sGb vs FMS .Pain sensitivity in control sites. All thresholds were similar between [FMS+sGb+Cholec] and [FMS+sGb] and between [FMS+aGb] and [FMS]. They were lower in the two fibromyalgia groups with symptomatic gallbladder calculosis, [FMS+sGb+Cholec] and [FMS+sGb], than in the two other fibomyalgia groups, [FMS+aGb] and [FMS]. Differences were significant: for electrical subcutis and muscle thresholds (lower in [FMS+sGb] than in FMS), for pressure muscle thresholds (lower in [FMS+sGb+Cholec] than [FMS+aGb]). All thresholds in the four fibromyalgia groups were significantly lower than those in the non-fibromyalgia group with symptomatic gallbladder calculosis .Biliary symptoms vs fibromyalgia symptoms / pain sensitivity. In [FMS+sGb+Cholec], a significant direct linear correlation was present between the number of previously experienced colics and the VAS for FMS pain  and a significant inverse linear correlation was found between the number of colics and pressure pain thresholds in TePs , electrical muscle pain thresholds  and pressure muscle pain thresholds  in control areas .There was no significant correlation between number of previously experienced colics and electrical pain thresholds in skin  and subcutis .In [FMS+sGb], the number of previously experienced colics had a significant direct linear correlation with the VAS of fibromyalgia pain  and an inverse linear correlation with pressure pain thresholds in TePs , electrical muscle pain thresholds  and pressure muscle pain thresholds  in control areas .There was no significant correlation between the number of previously experienced colics and electrical thresholds in skin .All patients scheduled for cholecystectomy underwent surgery without complications. The laparoscopic procedure was carried out as planned in all of them, with no need for conversion.VAS scores for pain perceived at abdominal surgery site in the postoperative period (1 week after surgery) are reported in Biliary symptoms. In patients subjected to cholecystectomy, both fibromyalgic and non-fibromyalgic ([FMS+sGb+Cholec] and [sGb+Cholec]), biliary pain was no longer experienced over the whole year of evaluation after surgery. In fibromyalgia patients with asymptomatic gallbladder calculosis not undergoing cholecystectomy [FMS+aGb], calculosis continued to remain silent with respect to biliary pain throughout the same period. In most fibromyalgia patients with symptomatic gallbladder calculosis who had refused to undergo surgery during the first year, further biliary colics instead occurred over this period .Fibromyalgia symptoms and pain sensitivity in control areas. In fibromyalgia pain subjected to cholecystectomy, [FMS+sGb+Cholec], the evolution of FMS symptoms and pain sensitivity in control areas over the first year of evaluation is reported in A significant trend for variation was present for all parameters. FMS pain intensity significantly increased with respect to basal values at 1 week and 1 month after the intervention, to return to pre-intervention values at 3 months; it then significantly decreased at 6 and 12 months (A). All thresholds (B-F) significantly decreased at 1 week and 1 month compared to basal values, returned to basal values at 3 months and then significantly and progressively increased at 6 and 12 months.A significant direct linear correlation was found between the peak values of postoperative pain and the change (decrease) in electrical pain thresholds in muscles at 1 week  and 1 month  .All other correlations were not significant, as reported below.Postoperative pain vs change in FMS pain: at 1 week  = 0.01880), at 1 month  = 0.1369), at 3 months  = 0.1640), at 6 months  = 0.1775), at 12 months  = 0.03948).Postoperative pain vs change in PPTs in TePs: at 1 week  = -0.02687), at 1 month  = -0.03473), at 3 months  = 0.05924), at 6 months  = 0.1101), at 12 months  = -0.02272).Postoperative pain vs change in skin EPTs: at 1 week  = -0.1583), at 1 month  = 0.1770), at 3 months  = 0.2971), at 6 months  = 0.1932), at 12 months  = 0.1732).Postoperative pain vs change in subcutis EPTs: at 1 week  = -0.3478, at 1 month  = -0.1666), at 3 months  = -0.07961), at 6 months  = -0.07713), at 12 months  = -0.2816).Postoperative pain vs change in muscle EPTs: at 3 months  = 0.2523), at 6 months  = -0.04394), at 12 months  = 0.06947).Postoperative pain vs change in muscle PPTs: at 1 week  = 0.07531), at 1 month  = -0.09566), at 3 months  = 0.03377), at 6 months  = 0.1737), at 12 months  = -0.01051).In fibromyalgia patients with asymptomatic gallbladder calculosis not subjected to cholecystectomy [FMS+aGb] and fibromyalgia patients without gallbladder calculosis [FMS] the 1st-year evolution of FMS symptoms and pain sensitivity in control areas (at time points comparable to patients undergoing surgery) is reported in Figs In fibromyalgia patients with symptomatic gallbladder calculosis not undergoing cholecystectomy during the first year [FMS+sGb], the evolution in time of FMS symptoms and pain sensitivity in control areas over the same period is reported in In non-fibromyalgic patients with symptomatic gallbladder calculosis undergoing cholecystectomy [sGb+Cholec] the evolution in time of pain thresholds in control areas during the whole year of study is reported in The comparison among different groups at each time point subsequent to basal evaluation, performed via 1-way ANOVA, is reported in st year [FMS+sGb+Cholec] and fibromyalgia patients with comorbid symptomatic calculosis who did not undergo the intervention in this 1-year period [FMS+sGb]. Values of FMS pain were significantly lower and those of all thresholds significantly higher in the former vs the latter suggesting that an earlier intervention on the gallbladder more effectively improved FMS spontaneous and evoked symptoms.Of particular note is the comparison at 12 month between fibromyalgia patients with comorbid symptomatic calculosis subjected to cholecystectomy during the 1Biliary symptoms. In basal conditions at the beginning of the second year of evaluation, the number of previously experienced colics in the 20 patients who decided to undergo cholecystectomy [FMS+sGb with delayed Cholec] had passed from 3.25 ± 1.80 to 3.65 ± 1.75 (significant increase: P<0.02), while in the 7 patients who continued to refuse cholecystectomy [FMS+sGb without delayed Cholec] it had passed from 2.57 ± 1.51 to 2.86 ± 1.68 .Fibromyalgia symptoms and pain sensitivity in control areas. Since the second year of evaluation initiated immediately after completion of the first year study, values of FMS symptoms and of pain thresholds recorded at 12 months of the first year were used as basal values for the second year.In [FMS+sGb with delayed Cholec], VAS scores had passed from 75.9 ± 4.1 to 80.4 ± 4.2 mm (P<0.0007), PPTs in TePs from 1.32 ± 0.32 to 1.09 ± 0.33 kg-f (P<0.05), EPTs in skin from 1.05 ± 0.34 to 0.80± 0.34 mA (P<0.03), EPTs in subcutis from 0.87± 0.34 to 0.92± 0.28 mA , EPTs in muscle from 1.45±0.36 to 1.22 ± 0.39 mA , PPTs in muscle from 1.69 ±0.41 to 1.46 ± 0.41 kg-f (P<0.009).In [FMS+sGb without delayed Cholec] VAS scores had passed from 77.86 ± 5.7 to 81.43 ± 5.1 mm  PPTs in TePs from 1.21 ± 0.31 to 0.86 ± 0.18 kg-f (P<0.02), EPTs in skin from 1.08 ± 0.39 to 0.84 ± 0.26 mA , EPTs in subcutis from 0.58 ± 0.13 to 0.98 to 0.31 mA (P<0.02), EPTs in muscle from 1.57± 0.22 to 1.13± 0.18 mA (P<0.02), PPTs in muscle from 1.78 ± 0.25 to 1.5 to 0.33 kg-f st year showed: for VAS, P = 0.33; for PPTs in TePs, P = 0.44; for EPTs in skin, P = 0.82; for EPTs in subcutis, P<0.05; for EPTs in muscle, P = 0.44; for PPTs in muscle, P = 0.57.The comparison between the two groups in basal conditions of the 1nd year showed: for VAS, P = 0.60; for PPTs in TePs, P = 0.08; for EPTs in skin, P = 0.44; for EPTs in subcutis, P = 0.61; for EPTs in muscle, P = 0.54; for PPTs in muscle, P = 0.82.The comparison between the two groups in basal conditions of the 2No complications occurred with surgery in the 20 patients scheduled for cholecystectomy; laparoscopy was successfully carried out in all of them.VAS scores for pain perceived at abdominal surgery site in the postoperative period are reported in In [FMS+sGb with delayed Cholec] the evolution of FMS parameters and pain sensitivity in control areas during this second year is reported in A significant trend for variation was present for all parameters. FMS pain intensity significantly increased 1 week after cholecystectomy, to return to preoperative values at 1 and 3 months and then significantly decrease at 6 and 12 months (A). All thresholds significantly decreased 1 week and 1 month after cholecystectomy, to return to pre-operative values at 3 months and then significantly increase at 6 and 12 months (B-F).A significant inverse linear correlation was found between the peak postoperative pain experienced at the operation site during the first week after laparoscopy and the change (decrease) in electrical pain thresholds at control sites 1 week after surgery  = -0.8731; p<0.0001) .All other explored correlations were not significant, as follows:Postoperative pain vs change in FMS pain: at 1 week  = 0.08494), at 1 month  = -0.1167), at 3 months  = 0.2504), at 6 months  = 0.1826), at 12 months  = 0.1034);Postoperative pain vs change in PPTs in TePs: at 1 week  = -0.04277), at 1 month  = -0.03965), at 3 months  = -0.09983), at 6 months  = -0.2065), at 12 months  = 0.2001);Postoperative pain vs change in skin EPTs: at 1 week  = -0.1156), at 1 month  = 0.3238), at 3 months  = -0.2245), at 6 months  = -0.2516), at 12 months  = 0.002855);Postoperative pain vs change in subcutis EPTs: at 1 week  = -0.2736), at 1 month  = -0.2763), at 3 months  = -0.2470), at 6 months  = -0.3501), at 12 months  = -0.1156);Postoperative pain vs change in muscle EPTs: at 1 month  = 0.4324), at 3 months  = 0.4417), at 6 months  = 0.2131), at 12 months  = 0.2785);Postoperative pain vs change in muscle PPTs: at 1 week  = -0.05825), at 1 month  = -0.1584), at 3 months  = -0.2099), at 6 months  = 0.08075), at 12 months  = 0.1440).In [FMS+sGb without delayed Cholec] the profile of FMS symptoms and pain sensitivity in control areas during this second year, evaluated at the same time points as patients subjected to cholecystectomy, is reported in This study on fibromyalgia patients with and without gallbladder calculosis comorbidity, subjected or not to laparoscopic cholecystectomy, has highlighted a number of outcomes in relation to spontaneous FMS pain and pain sensitivity at somatic level.Firstly, all fibromyalgia patients are confirmed as presenting generalized hypersensitivity to pain stimuli in all three tissues of the body wall, as shown by significantly decreased pain thresholds to more than one modality of stimulus  with respect to non-fibromyalgia patients ,10. SecoThis outcome of enhanced FMS pain/hypersensitivity due to the biliary colics is very similar to what was previously observed for other peripheral pain comorbidities in FMS patients, such as myofascial pain syndromes (from trigger points) or painful joints, which were also shown to worsen FMS symptoms, and whose effective local treatment significantly improved them ,12,30. TLaparoscopic cholecystectomy in all of our patients produced a complete and longlasting resolution of biliary symptoms. This outcome differs from a number of previous studies showing several persisting pain and non-pain consequences of the intervention, including symptoms from gastroparesis, significantly more frequent in patients with cholecystectomy than in those without, i.e., early satiety, postprandial fullness, nausea, vomiting, and abdominal pain . HoweverA third outcome of our study is that laparoscopic cholecystectomy in FMS plus symptomatic gallbladder calculosis, while producing a complete and longlasting resolution of biliary symptoms, instead determined a relatively transient worsening of FMS symptoms and hypersensitivity, at 1 week and 1 month, compared to preoperative levels. At 3 months, all FMS symptoms had returned to pre-surgery values and then significantly improved in the long term, at 6 and 12 months.This time evolution of FMS symptoms was substantially different from that of FMS patients with or without gallbladder calculosis, who, although not undergoing cholecystectomy, were assessed at comparable time points over a period of 1 year. These patients, in fact, showed a substantial stable pattern of all parameters over time, with only a slight worsening at the end of the year for the group with FMS plus symptomatic calculosis. The post-cholecystectomy time evolution of general pain sensitivity in FMS+symptomatic calculosis also differed from that of patients with gallbladder calculosis without fibromyalgia. In the latter group, in fact, thresholds in all somatic tissues did not change significantly from preoperative values, confirming results of previous studies showing no impact of this intervention in non-fibromyalgic patients on pain sensitivity in areas outside that of pain referral from the gallbladder (quadriceps).A further aspect of our study regards pain at the surgery site during the first week after laparoscopy. The levels of this pain in non-fibromyalgia patients were of relatively moderate intensity and comparable in extent and time evolution to those already reported in previous studies . HoweverThe effects of cholecystectomy on central sensitization have been explored in non-fibromyalgic subjects in previous studies. Stawowy et al  applied In conclusion, our results show that laparoscopic cholecystectomy for gallbladder calculosis in fibromyalgia produces only a transitory worsening of FMS symptoms in the postoperative period, which is largely compensated by the long-term outcome of desensitization due to gallbladder removal. This study provides new insights into the role of visceral pain comorbidities for central pain in FMS, helping the planning of adequate therapy of these comorbidities as a tool to also control FMS symptoms.S1 TableNumber of biliary colics experienced by patients with symptomatic gallbladder calculosis. Raw data.(ISD)Click here for additional data file.S2 TableIntensity of fibromyalgia pain in FMS+sGb+Cholec, FMS+aGb, FMS and FMS+sGb patients. Raw data.(ISD)Click here for additional data file.S3 TableIntensity of fibromyalgia pain in FMS+sGb with delayed Cholec and FMS+sGb without delayed Cholec patients. Raw data.(ISD)Click here for additional data file.S4 TablePressure pain thresholds in tender points in FMS+sGb+Cholec, FMS+aGb, FMS and FMS+sGb patients. Raw data.(ISD)Click here for additional data file.S5 TablePressure pain thresholds in tender points in FMS+sGb with delayed Cholec and FMS+sGb without delayed Cholec patients. Raw data.(ISD)Click here for additional data file.S6 TableElectrical skin and subcutis pain thresholds in FMS+sGb+Cholec and FMS patients. Raw data.(ISD)Click here for additional data file.S7 TableElectrical skin and subcutis pain thresholds in FMS+aGb and FMS+sGb patients. Raw data.(ISD)Click here for additional data file.S8 TableElectrical skin and subcutis pain thresholds in FMS+sGb with delayed Cholec and FMS+sGb without delayed Cholec patients. Raw data.(ISD)Click here for additional data file.S9 TableElectrical muscle pain thresholds in FMS+sGb+Cholec, FMS+aGb, FMS and FMS+sGb patients. Raw data.(ISD)Click here for additional data file.S10 TablePressure pain thresholds in muscle in FMS+sGb+Cholec, FMS+aGb, FMS and FMS+sGb patients. Raw data.(ISD)Click here for additional data file.S11 TableElectrical and pressure pain thresholds in muscle in FMS+sGb with delayed Cholec and FMS+sGb without delayed Cholec patients. Raw data.(ISD)Click here for additional data file.S12 TableElectrical and pressure pain thresholds in the three tissues of the body wall in sGb+Cholec patients. Raw data.(ISD)Click here for additional data file.S13 TableIntensity of pain at the surgical site experienced by patients subjected to laparoscopic cholecystectomy (during 1 week after surgery). Raw data.(ISD)Click here for additional data file.


Weights assigned to comorbidities to predict mortality may vary based on the type of index disease and advances in the management of comorbidities. We aimed to develop a modified Charlson comorbidity index (CCI) in incident hemodialysis patients (mCCI-IHD), thereby improving risk stratification for mortality.Data on 24,738 Koreans who received their first hemodialysis treatment between 2005 and 2008 were obtained from the Korean Health Insurance dataset. The mCCI-IHD score were calculated by summing up the weights which were assigned to individual comorbidities according to their relative prognostic significance determined by multivariate Cox proportional hazards model. The modified index was validated in an independent nationwide prospective cohort .c statistics compared with the CCI at 6 months and 1 year. The analyses using continuous net reclassification improvement revealed that the mCCI-IHD improved net mortality risk reclassification by 24.6% , 26.2%  and 42.8%  with respect to the CCI at 6 months and 1 and 2 years, respectively.The Cox proportional hazards model revealed that all comorbidities in the CCI except ulcers significantly predicted mortality. Thus, the mCCI-IHD included 14 comorbidities with re-assigned severity weights. In the validation cohort, both the CCI and the mCCI-IHD were correlated with mortality. However, the mCCI-IHD showed modest but significant increases in The mCCI-IHD facilitates better risk stratification for mortality in incident hemodialysis patients compared with the CCI, suggesting that it may be a preferred index for use in clinical practice and the statistical analysis of epidemiological studies. Although the prognosis of dialysis patients has improved significantly in recent years, mortality rates for these patients remain several times higher than those for individuals in the general population . ComorbiAmong the current indices, the Charlson comorbidity index (CCI) which was developed in 1987, is the most popular and simple. It has been successfully validated in diverse chronic disease populations, including dialysis patients . NeverthIn the present study, we aimed to modify the CCI by recalibrating the weights of comorbidities in the CCI using a Korean national population-based registry database, to validate the index in a separate nationwide prospective end-stage renal disease (ESRD) cohort, and to compare its performance with the CCI.Deidentified data on all Koreans aged ≥18 years who received hemodialysis (HD) as their first modality of renal replacement therapy between January 2005 and December 2008 were obtained from the Korean Health Insurance database . Data on all Korean HD patients could be reviewed because Koreans are obligated to register with the national insurance system, which consists of health insurance and medical aid. Subjects who died , changed their modality of renal replacement (n = 229), or underwent kidney transplantation (n = 314) within 3 months after starting HD were excluded. Therefore, a total of 24,738 patients were included in the analysis to develop a modified CCI for incident HD patients (mCCI-IHD).All patients aged ≥18 years who started HD as their first modality of renal replacement therapy between August 2008 and December 2012 in 31 centers of the Clinical Research Center (CRC) for ESRD and remained on HD for more than 3 months were initially screened for the validation cohort . The CRC for ESRD is a nationwide multicenter prospective cohort of patients with ESRD in Korea (NCT00931970). Patients who died within 3 months of the commencement of hemodialysis (n = 65) were excluded from the analyses. A total of 1,100 incident HD patients were included to externally validate the mCCI-IHD.th Revision (ICD-10)   16]. Fo. Foth Reβ coefficients while accounting for age, sex, and all 15 comorbidities simultaneously. We excluded an unnecessary item of severe renal disease given its presence in all of the study subjects. Prognostic weights were derived by dividing each β coefficient by the lowest one with statistical significance and rounding to the nearest integer , and all patients provided their written informed consent.Baseline characteristics of the development cohort are listed in β coefficients and weights for each comorbidity. All comorbidities except ulcers significantly predicted mortality. The relative weights of comorbidities were calculated by their ratios with the lowest β coefficient of chronic pulmonary disease. As expected, metastatic solid tumors were the strongest predictor of mortality among comorbidities; accordingly, the weight assigned to this condition was the highest. Moderate to severe liver disease, any tumor (including leukemia and lymphoma), diabetes with end-organ damage, dementia, and cerebrovascular disease followed consecutively.P<0.0001) and 1.72 , respectively. Based on the CCI and mCCI-IHD scores, the subjects were further collapsed into 4 risk groups according to the following criteria: no comorbidity, ≤50th percentile, 50th-90th percentile, and >90th percentile. To determine the cutoff values of the comorbidity scores for each risk group, we examined the distributions of the scores using a histogram .The summed scores of the original and recalibrated weights were applied to each patient in the development cohort. In the Cox proportional hazards model adjusted for age and sex, the HRs of the CCI and mCCI-IHD scores for mortality were 1.42 , 26.2%  and 42.8%  relative to the CCI at 6 months and 1 and 2 years, respectively, after adjustment for the above-mentioned confounders. This finding indicates that the mCCI-IHD may provide better risk stratification for mortality in incident HD patients than the CCI. Additionally, the mCCI-IHD also improved the predictability for mortality compared with the age-adjusted CCI  and the mCCI  after adjusting the confounding factors.As detailed in In the present study, we modified the CCI using population-based registry data that included nearly all Korean patients who began HD between 2005 and 2008 to develop a comorbidity index that provides better risk stratification in incident HD patients. In addition, we validated the usefulness of the modified index in an independent prospective cohort by comparing its performance with the original index. To our knowledge, this is the first study to recalibrate the CCI using a large sample of incident HD patients and to validate the index using an independent nationwide prospective observational cohort of ESRD patients.et al. [Despite highly prevalent comorbidities and their influence on mortality rates in ESRD patients, it has not yet been determined which comorbidities significantly affect mortality and what weight each comorbidity carries when predicting mortality. Therefore, many previous studies have examined the influence of comorbidity on survival in patients with ESRD –25, and et al.  Click here for additional data file.