Neuropathic pain (NeuP) is a complex, debilitating condition of the somatosensory system, where dysregulation between pro- and anti-inflammatory cytokines and chemokines are believed to play a pivotal role. As of date, there is no ubiquitously accepted diagnostic test for NeuP and current therapeutic interventions are lacking in efficacy. The aim of this study was to investigate the ability of three biofluids - saliva, plasma, and cerebrospinal fluid (CSF), to discriminate an inflammatory profile at a central, systemic, and peripheral level in NeuP patients compared to healthy controls.The concentrations of 71 cytokines, chemokines and growth factors in saliva, plasma, and CSF samples from 13 patients with peripheral NeuP and 13 healthy controls were analyzed using a multiplex-immunoassay based on an electrochemiluminescent detection method. The NeuP patients were recruited from a clinical trial of intrathecal bolus injection of ziconotide . Multivariate data analysis  was used to identify proteins significant for group discrimination and protein correlation to pain intensity. Proteins with variable influence of projection (VIP) value higher than 1  were considered significant.We found 17 cytokines/chemokines that were significantly up- or down-regulated in NeuP patients compared to healthy controls. Of these 17 proteins, 8 were from saliva, 7 from plasma, and 2 from CSF samples. The correlation analysis showed that the most important proteins that correlated to pain intensity were found in plasma (VIP > 1).Investigation of the inflammatory profile of NeuP showed that most of the significant proteins for group separation were found in the less invasive biofluids of saliva and plasma. Within the NeuP patient group it was also seen that proteins in plasma had the highest correlation to pain intensity. These preliminary results indicate a potential for further biomarker research in the more easily accessible biofluids of saliva and plasma for chronic peripheral neuropathic pain where a combination of YKL-40 and MIP-1α in saliva might be of special interest for future studies that also include other non-neuropathic pain states. Neuropathic pain (NeuP) is a complex chronic secondary pain condition characterized, according to ICD11, by spontaneous pain, allodynia, and hyperalgesia. It affects approximately 6.9–10% of the global population and represent a significant burden for patients and their families as well as society and healthcare systems .The current definition of NeuP is pain caused by a lesion or disease of the somatosensory system, either centrally or peripherally . MultiplAccordingly, the underlying molecular mechanisms of NeuP may vary between patients, which subsequently exemplifies the challenges associated with attaining accurate diagnosis and thus pharmacological interventions . ConsequGenerally, chronic NeuP pain is mainly thought of as a disorder of the nervous system, including intricate mechanisms of neuronal excitability, ectopic discharge, central and peripheral sensitization. However, immune cells and their mediators have also been shown to act as key contributors to the instigation of various pain states; including NeuP , 11. TheCytokines belongs to a class of small molecules that are derived from immune cells and glial cells, which acts as pro- or anti-inflammatory mediators at picomolar and nanomolar concentrations to regulate synaptic activity as well as pain sensitivity , 16. ForHence, knowledge of the involvement of cytokines and chemokines in the neuro- immunological interaction in NeuP patients, occurring at different biofluid compartments, may aid in development of more effective pharmacological therapies. Accordingly, the aim of this study was to investigate the suitability of plasma, saliva, and CSF for studies of an inflammatory signature of cytokines and chemokines at a central, systemic, and peripheral level, collected concurrently from NeuP patients and healthy controls. To further explore the inflammatory profile of NeuP we also investigated if altered levels of inflammatory markers were correlated to pain intensity in neuropathic pain and if physiological quotients of cytokines in [saliva]/[plasma] and [plasma]/[CSF] differed between the groups.The cohort of neuropathic pain patients have been extensively described in a previous paper by Bäckryd et al. . In shorIn brief, healthy controls were recruited by local advertisement at the Faculty of Medicine and Health Sciences, Linköping University Sweden, and by contacting healthy subjects from previous studies. Once, informed consent was obtained, absence of any significant medical condition was ensured by conducting a structured interview. Detailed information regarding healthy controls has been described previously and will not be discussed here .The study was conducted in accordance with the Helsinki Declaration and Good Clinical Practice. The Ethical Review Board Regional Ethics Committee in Linköping approved the study (Dnr M136-06 and Dnr 2012/94 − 32). All participants received verbal and written information about the study, and after that, written informed consent was obtained from all the participants in this study.Intrathecal access was obtained by lumbar puncture with a 27 GA pencil-point Whitacre needle  as described previously . BrieflyVenous blood sample (10 ml) was collected in a EDTA tube.Whole saliva was collected using Salivette (Sarstedt). Subjects were not allowed to eat within 30 min of saliva collection. Subjects rinsed their mouth with water, and saliva sampling was collected after 10 min by putting a swab in the mouth for 3 min.The samples were immediately cooled on ice and transported to Painomics® laboratory, Linköping University Hospital. Each sample was then centrifuged, divided into aliquots, and stored in − 70 °C awaiting analysis.The concentrations of 71 cytokines, chemokines and growth factors in saliva, plasma and CSF samples from patients and healthy controls was analyzed using a U-PLEX assay based on an electrochemiluminescent detection method  according to the manufacturer’s recommendations. Data were collected and analyzed using MESO QUICKPLEX SQ 120 instrument equipped with DISCOVERY WORKBENCH® data analysis software . The precision based on both intra and inter-assays variations were < 10 % within the detection limits provided by the manufacturer. Samples were thawed on the day of analysis, blinded to the clinical groupings and were randomly mixed. In short, 96-well plates were coated with linker-coupled capture antibodies (provided by the manufacturer) for one hour and then aspirated and washed with washing buffer (PBS/ 0.05 % Tween-20) 3 times. Standards and plasma samples (25 µl) were added to appropriate wells and incubated for one hour at room temperature with shaking. The fluid was then removed, and the wells were washed 3 times with washing buffer. Detection antibodies were added to each well, and incubated for 1 h at room temperature, followed by washing 3 times. After washing, 150 µl of reading buffer was added to each well. The plate was analyzed on the MSD instrument immediately. Standard curves were formed by fitting electrochemiluminescence signal from calibrators to a weighted 4-parameter logistic model. For the purposes of statistical analyses, any value that was below the lowest limit of detection (LLOD) for the assay was replaced with half of LLOD of the assay.P ≤ 0.05 was used as level of significance in all analyses. For descriptive statistics, all analyses were performed using IBM SPSS and the results were given as mean values. Mann-Whitney U test was used to compare groups. When calculating physiological quotients between saliva and plasma concentrations and plasma and CSF concentrations, all calculations were based on [saliva value]/[plasma value] and [plasma value]/[CSF value] respectively.Statistical analyses were made using IBM SPSS  and SIMCA-P+  and 2, Q2, and CV-ANOVA were presented in the results. The tables also present p(corr) for each significant molecule: the loading of each variable scaled as a correlation coefficient and thus standardizing the range from − 1 to + 1; p(corr) is stable during iterative variable selection and comparable between models. An absolute p(corr) > 0.4–0.5 is generally considered significant. R2 describes the goodness of fit – the fraction of sum of squares of all the variables explained by a principal component. Q2 describes the goodness of prediction – the fraction of the total variation of the variables that can be predicted by a principal component using cross validation methods. R2 should not be considerably greater than Q2; if R2 is substantially greater than Q2 (a difference > 0.3) [Traditional univariate statistical methods can quantify level changes of individual substances but disregard interrelationships and thereby ignore system-wide aspects. Moreover, traditional statistical methods  are not designed to handle data sets with more variables than subjects . Therefore, we used advanced multivariate data analysis by projection (MVDA) using SIMCA-P+. When applying MVDA, we followed the recommendations presented by Wheelock and Wheelock . Variable > 0.3)  the robue > 0.3) . Moreove2 = 0.25, Q2 = 0.02). Subsequently, an OPLS-DA regression model was computed to discriminate between patients and healthy controls , R2 = 0.503, Q2 = 0.413, P = 0.002 by CV-ANOVA).The inflammatory signature, at a central, systemic, and peripheral level, was investigated in 13 NeuP patients and 13 healthy controls. The data was initially controlled by conducting an unsupervised PCA to probe for potential multivariate outliers. No strong outliers were identified by Hotelling’s T2, and no serious moderate outliers by DModX  > 0.5 and VIP > 1 as cut-offs, a total of 17 cytokines/chemokines were identified as significant for group separation Fig. . ThirteeFrom Table 2 = 0.961, Q2 = 0.675, and p = 0.041 by CV-ANOVA). VASPI ranged from 40 to 94 mm among the 13 NeuP patients, as shown in Table To explore the inflammatory signature in respect to pain intensity in NeuP, an OPLS regression model was computed on the 13 NeuP patients to examine the association between VASPI (the Y-variable), and the 71 analyzed cytokines and chemokines in three biofluids . MIP-1α in plasma did not differ between groups. This result support previous studies where low to moderate associations between cytokine concentrations in plasma and saliva has been demonstrated, which is believed to depend on the restrictive pathway of cytokines into the salivary glands , 28. ConNotably, whole saliva is not a single fluid, but rather a mixture of salivary gland secretions with different glands having varying contributions . SalivarAlthough there is limited literature on the involvement of MIP-1α in the pathogenesis of human neuropathic pain, there is evidence from animal models highlighting its putative implication. For instance, in the partial sciatic nerve ligation (PSL) model, long-lasting tactile allodynia and thermal hyperalgesia was associated with dramatic up-regulation of MIP-1α and its receptors (CCR1 and CCR5) on macrophages and Schwann cells of the injured sciatic nerve in mice . ConversHowever, interpretations based on assumed analogies between animals and humans are fundamentally problematic and susceptible to incorrect assumptions when it comes to deciphering the complexity of human disease states . For insInterestingly, the extent of copy number variation of CCL3-L1 in a cohort of Caucasians have been described by Townson et al. where they also showed that LPS-stimulated monocyte-induced increase of CCL3-L1 copy number was related to an increased ratio of CCL3-L1-mRNA to CCL3-mRNA and hence functional protein . NotablyFollowing MIP-1α, the pro-inflammatory cytokine IL-6 showed the second highest discriminatory power between groups, where it was found to be selectively up-regulated in plasma samples from patients Table . This suNonetheless, mounting evidence from animal studies indicate that pro-inflammatory cytokines, such as IL-6, are involved in both peripheral and central mechanisms of pain hypersensitivity. . For insIL-1β is another pro-inflammatory cytokine that has been extensively implicated in the pathogenesis of neuropathic pain . For insChitinase 3-like protein 1 (YKL-40) was the only protein, to be significantly up-regulated in two biofluids; its concentration was shown to be higher in both plasma samples and saliva samples taken from patients compared to healthy controls Table .YKL-40 is primarily secreted by chondrocytes, but it is also synthesized by macrophages, neutrophils, synoviocytes, cancer cells, vascular smooth muscle cells, and liver cells among others –51. Not In contrast to YKL-40, the growth factor GRO-1α was the only protein to be significantly up- and downregulated in two separate biofluids. In saliva, GRO-1α was significantly upregulated whereas in plasma GRO-1α was significantly downregulated in patients compared to healthy controls Table . LikewisUnexpectedly, none of the 17 significant cytokines/chemokines detected for group separation was found to be significantly up-regulated in the cerebrospinal fluid among patients. However, 2 proteins, CTACK and IL-13, where elevated in CSF samples taken from healthy controls. Interestingly, peripheral IL-13 has been shown in animal models of neuropathic pain to reduce PLS-induced hyperalgesia by down-regulating IL-1β as well as reversing inflammatory macrophages and tactile allodynia , 59. ThuThere are several limitations in this study. One limitation was the relatively low number of included subjects (n = 26), which depended on the fact that this was an additional study conducted prior to a ziconotide trial and the number of patients were calculated with respect to outcomes in that trial. Another constraint concerned CSF sampling which is an invasive procedure that limited the inclusion of both gender and age matched healthy controls. Although the differences in age and gender were not statistically significant (p > 0.05) between the groups, it is worth mentioning that this might be due to the relatively low sample size. To be able to clarify if there are any association between the identified proteins and gender/age a larger cohort including only healthy controls without any diseases or NeuP are warranted. Furthermore, many of the significant cytokines in this study are known to be involved in a variety of different pathologies and the inflammatory profile may therefore not be specific for NeuP. It is possible that the cytokine profile presented indicates a state of chronic disease rather than a state of chronic neuropathic pain. Inclusion of patients with non-neuropathic chronic pain would have been an option to explore this specificity but then another potential confounding effect would have been introduced.There is much evidence from animal studies supporting a pivotal role of cytokines and chemokines in the crosstalk between neural and immunological systems associated with neuropathic pain. In this pilot study we investigated the inflammatory profile of patients with chronic peripheral NeuP in three separate biofluids, where 15 out of 17 proteins that were significant for group separation came from saliva and plasma samples. It was also shown that proteins in plasma samples had the highest correlation to pain intensity among the NeuP patients. These preliminary results indicate a potential for further biomarker research in the less invasive biofluids of saliva and plasma for chronic neuropathic pain, where a combination of YKL-40 and MIP-1α in saliva might be of special interest for future studies that also include other non-neuropathic pain states.


Gliomas are widely considered to be related to the altered topological organization of functional networks before operations. Tumors are usually thought to cause multimodal cognitive impairments. The structure is thought to form the basics of function, and the aim of this study was to reveal the rich-club organization and topological patterns of white matter (WM) structural networks associated with cognitive impairments in patients with frontal and temporal gliomas.Graph theory approaches were utilized to reveal the global and regional topological organization and rich-club organization of WM structural networks of 14 controls (CN), 13 frontal tumors (FTumor), and 18 temporal tumors (TTumor). Linear regression was used to assess the relationship between cognitive performances and altered topological parameters.When compared with CN, both FTumor and TTumor showed no alterations in small-world properties and global network efficiency, but instead showed altered local network efficiency. Second, FTumor and TTumor patients showed similar deficits in the nodal shortest path in the left rolandic operculum and degree centrality (DC) of the right dorsolateral and medial superior frontal gyrus (SFGmed). Third, compared to FTumor patients, TTumor patients showed a significantly higher DC in the right dorsolateral and SFGmed, a higher level of betweenness in the right SFGmed, and higher nodal efficiency in the left middle frontal gyrus and right SFGmed. Finally, rich-club organization was disrupted, with increased structural connectivity among rich-club nodes and reduced structural connectivity among peripheral nodes in FTumor and TTumor patients. Altered local efficiency in TTumor correlated with memory function, while altered local efficiency in FTumor correlated with the information processing speed.Both FTumor and TTumor presented an intact global topology and altered regional topology related to cognitive impairment and may also share the convergent and divergent regional topological organization of WM structural networks. This suggested that a compensatory mechanism plays a key role in global topology formation in both FTumor and TTumor patients, and as such, development of a structural connectome for patients with brain tumors would be an invaluable medical resource and allow clinicians to make comprehensive preoperative planning. Gliomas are the most frequently occurring type of primary brain tumors , and wheThe development of complex network analysis using graph theory  in the brain offers the potential to identify the impacts of focal and diffuse pathologies in glioma patients , such asRecent studies using magnetoencephalography (MEG)  and funcThe aim of this study was to compare the structural topological organization in frontal and temporal gliomas and healthy controls using graph-theory analysis. As per the existing literature , we woulA total of 13 patients with frontal tumors (6 left hemisphere tumors and 7 right hemisphere tumors), 18 patients with temporal tumors (7 left hemisphere tumors and 11 right hemisphere tumors), and 14 age- and gender-matched healthy control (CN) subjects were included in this study. Written informed consent was obtained from all participants, and the study was approved by the responsible Human Participants Ethics Committee of the Affiliated Brain Hospital of Nanjing Medical University .Inclusion criteria for the patient groups were as follows:  tumor paAll subjects underwent comprehensive neuropsychological assessments performed by two experienced neuropsychologists, including digit span, memory, visuospatial, and digital symbol substitution tests, mapping, and similarity. Similarity – the similarity test includes 13 pairs of nouns, each of which represented something in common. Subjects were asked to summarize where the two were similar. This test was mainly performed to measure the ability of logical thinking, abstract thinking ability, and generalization ability. Mapping – picture completion test, includes 20 pictures, each of which was deliberately missing a part. Subjects were asked to identify the missing part. This test was mainly performed to investigate visual memory, visual recognition, and the ability to distinguish between the main characteristics and unimportant details. Information processing speed, memory, visuospatial function, executive function, and perceptual speed were evaluated.MRI images were acquired before surgery using a 3.0-T Verio Siemens scanner  in the Department of Radiology, Nanjing Brain Hospital. T1-weighted MR images were obtained by a 3D magnetization-prepared rapid gradient echo (MPRAGE) with the following parameters: repeat time (TR) = 1,900 ms, echo time (TE) = 2.49 ms, time inversion (TI) = 900 ms, matrix = 256 × 256, flip angle (FA) = 90°, thickness = 1 mm, gap = 0.5 mm, slices = 176.b value = 1,000 s/mm2 and one additional image with no diffusion weighting (b = 0), slices = 62, TR = 6,500 ms, TE = 95 ms, gap = 3 mm, FA = 90°, field of view (FOV) = 120 mm × 120 mm, acquisition matrix = 128 × 128, and thickness = 3 mm.Diffusion tensor imaging (DTI) data were collected using an echo planar imaging (EPI) sequence, three times, with the following parameters: in 32 independent, non-collinear directions of a The preprocessing steps used were as previously described  and wereStructural connectivity networks were modeled as a weighted network comprising a total of 90 nodes see , definedIn this study, we defined the mean fractional anisotropy (FA) of the connected fibers between two regions as the weights of the network edges. For each participant, the FA-weighted structural network was constructed, which was represented by a symmetric 90 × 90 matrix . FinallyTo characterize the topological organization of WM structural networks at a sparsity threshold, we calculated multiple network metrics of regional nodal characteristics and global network properties.Eglob), local efficiency (Eloc), shortest path length (Lp), clustering coefficient (Cp), nodal betweenness (Bnod), nodal degree , nodal efficiency , nodal path length (NLp), small worldness (Sigma)  , and ric (Sigma) . In refe (Sigma) , the intAccording to previous brain network studies , each neAnalysis of variance (ANOVA) and chi-square tests (only applied in the comparisons of gender) were employed to compare the differences in demographic data and neuropsychological performances among control, FTumor, and TTumor groups.t-test was used to perform a post hoc comparison for each two pairs of groups. For analyses of regional nodal characteristics, the FDR correction for multiple comparisons was performed at a significance level of p < 0.05.ANOVA was employed to compare the group differences on the AUC value of each network metric in global network measures and regional nodal characteristics, rich-club coefficients, and connectivity strength among the control, FTumor, and TTumor groups after controlling for age, sex, and education level. The Student’s Linear regression model was used to assess the relationship between cognitive performances and the altered topological parameters after controlling the effects of age, sex, and education level.p > 0.05). Compared with CN subjects, both Ftumors and TTumors showed significantly lower memory test, visuospatial test, Digital Symbol Substitution Test (DSST), mapping, and similarity scores , and global efficiency (Eglob) (Eloc)  and almost identical characteristic path lengths (λ≈ 1). The small-worldness scalar was σ > 1 for all three groups . However (Eglob) , 4. Ther) (Eloc) . Post hoo the CN .Brain regions were further localized for significant group effects in at least one nodal property, i.e., nodal shortest path (NLP), degree centrality (DC), betweenness centrality (BC), and nodal efficiency (NE), in the FTumor and TTumor patients. ANOVA analysis showed significant group differences on NLP in the left rolandic operculum, DC in the right dorsolateral and medial superior frontal gyrus, BC in the right medial superior frontal gyrus, and NE in left middle frontal gyrus and the right medial superior frontal gyrus .Post hoc comparisons showed that (wed that  comparedwed that  (Raysi Dwed that . Comparewed that  (Fornitowed that . Comparewed that  Comparedwed that .The top 13 (15%) highest-degree nodes were selected as rich-club members based on the averaged nodal degree across CN and both FTumor and TTumor patients . Rich-clCompared with controls, both FTumor and TTumor showed a lower rich-club coefficient  after cor = 0.503, p < 0.001), while the altered local efficiency in FTumor correlated with information processing speed  after controlling the effects of age, sex, and education level. In addition, no any significant correlations were found between disrupted topological parameters, and rich-club parameters and cognitive functions in FTumor and TTumor patients.Linear regression analysis showed that the altered local efficiency in TTumor correlated with memory function  compared to the CN group, FTumor and TTumor showed alterations in local efficiency; (ii) FTumor and TTumor patients showed similar deficits of the nodal shortest path in left rolandic operculum, and degree centrality in right dorsolateral superior frontal gyrus and SFGmed; and (iii) compared with FTumor patients, TTumor patients showed significantly higher DC in right dorsolateral and SFGmed, higher BC in right SFGmed, and higher NE in left MFG and right SFGmed. Third, compared to FTumor patients, TTumor patients showed a significantly higher DC in the right dorsolateral and SFGmed, a higher level of betweenness in the right SFGmed, and higher nodal efficiency in the left middle frontal gyrus and right SFGmed. Finally, rich-club organization was disrupted, with increased structural connectivity among rich-club nodes, and reduced structural connectivity among peripheral nodes, in FTumor and TTumor patients. The altered local efficiency in TTumor patients correlated with memory function, while the altered local efficiency in FTumor patients correlated with information processing speed. Therefore, it is reasonable that FTumor and TTumor may share convergent and divergent altered regional topological organization of WM structural networks, which is linked to specific cognitive impairment.In this study, we showed a clear decline in multidomains of cognitive function, including memory, information processing speed (DSST test), visuospatial function, and executive function (DST and similarity tests) in patients with brain tumors. The present observation corroborated the previously described deficit in patients with brain tumors , these cThere were no alterations in small-world properties and global efficiency; however, an altered local efficiency was observed in both FTumor and TTumor patients, which was inconsistent with previous similar functional network studies on graph-theory analysis . PreviouAnother interesting finding was that FTumor and TTumor patients showed similar deficits of the nodal shortest path in the left rolandic operculum. The nodal shortest path of a network quantifies the ability for information to propagate in parallel; therefore, our results suggested that FTumor and TTumor presented with an aberrant ability for information to propagate in parallel in the left rolandic operculum. Previous studies have indicated a tractography functional pathway between Rolandic region and temporal lobe . TherefoOur findings also showed that FTumors may present with a reduced degree centrality in the right dorsolateral superior frontal gyrus and SFGmed and reduced network efficiency in the left MFG and right SFGmed. Degree centrality represents the connectivity of a node with the rest of nodes in a network, and the nodal efficiency shows how efficient the communication is among the first neighbors of one node when it is removed. Therefore, our findings suggested that these regions displayed reduced connectivity and efficiency of the communication with other regions. Our findings are consistent with previous studies in which functional networks were investigated , which iIn our study, we also showed that, compared with FTumor patients, TTumor patients showed significantly higher degree centrality in the right dorsolateral and medial superior frontal gyrus, higher nodal betweenness in right SFGmed, and higher nodal efficiency in left MFG and right SFGmed. These findings suggested divergent topological organization between frontal and temporal gliomas. Betweenness of a node captures the influence of the node over information flow between all the other nodes in the network. Therefore, we proposed that frontal and temporal gliomas have different effects on nodal properties in the network. These altered regions in terms of nodal properties were located in the default mode network   and cognOur findings also showed that rich-club organization was disrupted, with increased structural connectivity among rich-club nodes and reduced structural connectivity among peripheral nodes, in FTumor and TTumor patients. Together, these findings indicated that rich-club regions in FTumor and TTumor were closer when peripheral regions became isolated. This might further reflect that both FTumor and TTumor patients have mainly disrupted structural connectivity among peripheral regions when a compensatory mechanism in the structural connectivity among rich-club regions is employed . WhetherEspecially important, this study showed that the altered local efficiency in TTumor correlated with memory function while the altered local efficiency in FTumor correlated with information processing speed. Moreover, our findings suggested that the tumor affected cognitive function in terms of local network efficiency. Furthermore, several studies have shown that the temporal lobe is involved in memory processes of the memory system/network , and theThis study has some limitations: (i) the sample sizes in this study are relatively small to better demonstrate the core locations and pathologies, and (ii) our results did not distinguish low- and high-grade glioma network features. This means that future studies with a larger sample size containing a variety of lesions are needed to confirm our results. Previous studies have indicated that distinct connectivity disturbances have been found within the low- and high-grade glioma patient groups , but theThis study provides novel information on the structural connectome disruptions in glioma patients. Our findings also suggested that FTumor and TTumor may share convergent and divergent regional topological organization of WM structural networks, which is associated with specific cognitive impairment. Both suggested that providing information on the structural connectome in patients with brain tumors to clinicians would provide greater insights into the precise location to aid surgical planning of cognitive function protection in glioma patients. In summary, by combining structural topological organization techniques, it would be expected to help improve the survival and the quality of life of brain tumor patients .The datasets generated for this study are available on request to the corresponding author.The studies involving human participants were reviewed and approved by the responsible Human Participants Ethics Committee of the Affiliated Brain Hospital of Nanjing Medical University. The patients/participants provided their written informed consent to participate in this study.JC and HL contributed to the study concept and design. YL, XH, KY, CX, JR, ZL, DL, YZ, and JC acquired, analyzed or interpreted the data. YL, XH, and KY drafted and revised the manuscript. All authors approved the final version of the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Minimally invasive procedures have been increasingly used for the treatment of herniated discs. Nonsurgical interventions minimize the secondary damage to other tissues and shorten the length of hospital stay by avoiding general anesthesia. Possible complications are thermal injuries, root injury, discitis, endplate damage, dural injury, meningitis, infection, increase in pain, and muscle spasm. We aimed to evaluate the efficacy of percutaneous decompression therapy by using intradiscal navigable electrodes on pain and functional movement index in patients with herniated nucleus pulposus (HNP).A total of 209 patients with protrusive lumbar disc herniation underwent percutaneous ablation decompression treatment using an intradiscal routable electrode (L-Disq) in our pain clinic. Visual analog scale (VAS) and Oswestry Disability Index (ODI) scores were recorded at the beginning and at the 1st, 3rd, 6th, and 12th months after treatment. Patient satisfaction was evaluated at the 12th month by a patient satisfaction scale (PSS).When compared to initial values, VAS and ODI scores showed statistically significant improvement at the 1st, 3rd, 6th, and 12th months (P < 0.001). Mean VAS scores were 7.28 and 3.03 points (P < 0.001) while mean ODI scores were 32.46 and 20.48 points (P < 0.001) at the beginning and at the 12th month, respectively. Satisfaction rate of all patients was 81%. We also attempted to treat the existing annular fissure using an ablation method and we believe that treating the herniated disc together with the fissure in the same session increased our success rate.With clinical evidence, we suggest that L-Disq may be considered as an appropriate option with a low risk of complications in pain management in cases of lumbar disc herniation that are resistant to conservative methods. Lumbar radiculopathy due to herniated nucleus pulposus (HNP) is associated with severe morbidity (1). A lumbar HNP compresses the nerve roots and mechanical and inflammatory mechanisms cause pain (2). The outcome after a microdiscectomy is worse in patients with small hernias than in those with sequestrated hernias (3), and this has led to a rise in the popularity of minimally invasive procedures for the treatment of herniated discs. Recently, with the increasing knowledge of spinal anatomy and the evidence that conventional procedures have not always been useful, there has been a tendency to carry out minimally invasive procedures for the treatment of disc herniation (4), which can be advantageous in terms of early recovery, early return to daily life, short operational times, relatively fewer surgical traumas, and less pain. Percutaneous disc decompression (PDD) methods are based on the principle that the removal of small amounts of discoid tissue will result in significant pain relief by reducing intradiscal pressure (5), as pressure on the nerve will be decreased and radicular findings will be reduced. There is also evidence that PDD can lead to a reduction in patients’ disability and increased safety (6–8).Possible complications are thermal injuries, root injury, discitis, endplate damage, dural injury, meningitis, infection, increase in pain, and muscle spasm . All patients are given antibiotics for 7 days for prophylaxis of infection. So as to minimize direct nerve root irritation or damage during the procedure, our patients are kept awake and conscious, being in communication with the surgeon. Dural ruptures may sometimes occur and the treatment is hydration, rest, and medication. An epidural blood patching was planned for patients with remaining complaints of dural rupture. In this study, we evaluate the efficiency of PDD therapy using an intradiscal navigable electrode (L-Disq) on the pain and functional movement index in patients with HNP.After the approval of the ethics committee, clinical data from 209 patients with back/leg pain due to HNP who underwent ablation decompression treatment using L-Disq in our pain clinic between January 2013 and January 2017 were reviewed retrospectively.Patients with disc herniation with a sagittal diameter greater than 33% of the spinal canal, narrowing of the discal space greater than 50%, previous lumbar spine surgery, sequestrated disc, vertebral fracture, spinal canal stenosis or spondylolisthesis, psychological problems detected during the examination, systemic or localized infection, history of tumor or coagulopathy, pregnancy, osteoarthritis, or a body mass index of ≥35 kg/m2 were excluded from the study. Patients were included if they were aged >18 years old and in the ASA I–II risk group; had no response to conservative treatments such as muscle relaxants, antiinflammatory agents, facet joint blockade, or epidural steroid injections for at least 3 months; and had waist and/or hip pain or secondary pain in the lower extremities associated with disc herniation. For the analysis, we used an L-Disq navigable percutaneous decompression device  that can reach the outer ring of a herniated and/or degenerated disc (11). All the decompression procedures were performed by a single experienced practitioner. The patients’ blood pressure, heart rate, electrocardiogram, oxygen saturation, and respiratory rate were monitored, and an aseptic technique was used throughout the whole procedure. Prior to the procedure, all patients were given 1 g of cefazolin for prophylaxis and 2 mg of midazolam to minimize anxiety and discomfort. In the case of pain, 0.5 µg/kg fentanyl was planned to be injected intravenously. The patients were calm, but alert and conscious, and could inform the practitioner in the event of unusual pain.The patients were placed on the operating table in prone position and fluoroscopic images of the lumbar spine were obtained to confirm and determine the intervertebral disc levels and the appropriate level for needle entry. We used a standard posterolateral approach (12) to reach the L1–L4 intervertebral disc segments. The lumbar intervertebral level was marked 8–10 cm laterally from the midline on the interventional side under fluoroscopy. In the oblique position, we rotated the C-arm 90° from the front-rear position to a 30–35° lateral and 15° cephalic direction and then inserted the needle into the skin at a 30° angle. The most important procedural challenge during the intradiscal entry at the L5–S1 level was to overcome the positional and anatomical difficulty. Entry to the L5–S1 level at this angle is very difficult, and is even impossible in some patients. For this reason, while entering the L5–S1 segments, we inserted the needle 14–15 cm away from the vertebrae at an angle of 45° and by angling the scope 30° in the cephalic direction. The intervention through the L5–S1 level by changing the angle and site of the needle insertion and the scope angle greatly reduced the difficulties encountered due to anatomic location and contributed to the success of the procedure.After injecting a local anesthetic agent, 2–3 mL (20 mg/mL) of prilocaine, into the cutaneous and subcutaneous tissues, the C-arm was placed to obtain a lateral view of the surgical field and an 18-gauge spinal needle of 8.9 cm was entered and pushed forward into the middle of the disc under fluoroscopy. Both anteroposterior (AP) and lateral views of the L-Disq electrode were obtained and the position within the disc was checked. The safety of the procedure was confirmed through negative motor nerve stimulations with short bursts in order to test the proximity of the electrode to the nerve root within the disc. Close monitoring of pain is necessary to prevent injuries from heat. In addition, if the electrical activity causes lower extremity stimulation, the rod must be straightened and moved into an open position. In all procedures, the bar was repeatedly rotated and moved back and forth in order to increase the ablated volume. If findings of disc degeneration (annular fissure) with disc protrusion were detected on MRI images, the fissure line was ablated by placing the tip of the electrode. The procedures lasted between 20 and 30 min.If needed, patients with pain were given an antiinflammatory drug or paracetamol during the follow-up period. All patients were prescribed antibiotics to use for 7 days and instructed to take an antiinflammatory drug or paracetamol in case of pain. No patient required additional pain intervention after the procedure. After the procedure, patients were informed not to drive for at least 48 h, to start limited walking for 10–20 min after a few days, to obey the lifting limit of 5–10 kg for the first 2 weeks, not to bend or twist their waists, to avoid compulsive movements, to perform chiropractic manipulation for the first 12 weeks, to avoid massage or traction, to perform gentle flexion and extension movements at home for the first 2–3 weeks, and to perform specific physiotherapy for the first 3–5 weeks. If the patient had no contraindication, MRI images were taken at routine controls after the procedure. MRI findings were evaluated by the radiology clinic but the rate of change was not determined. All patients were evaluated using the Oswestry Disability Index (ODI) and a visual analog scale (VAS) according to the clinical data and the patient’s answers before and after treatment at the 1st, 3rd, 6th, and 12th months, and using a patient satisfaction scale (PSS) at the 12th month following treatment.Statistical analyses were carried out using the SPSS 15 for Windows . Descriptive statistics were expressed as mean ± standard deviation for variables with normal distribution, as median (min–max) for variables with abnormal distribution, and as number of cases and percentage (%) for nominal variables. Within the groups, the significance of the differences in median values and median values between times were assessed by the Friedman test. If present, multiple intertime comparisons of the differences were evaluated using appropriate post hoc tests.Between the groups, the significance of the difference in terms of average values was evaluated by a two-related-samples test, and in terms of median values by the Wilcoxon test. P < 0.05 was considered significant.Of the 209 patients in the ASA I–II risk groups, 41% were men and 59% were female with mean age of 50.57 ± 12.49 years, mean height of 168.27 ± 8.35 cm, and mean weight of 74.54 ± 11.1 kg. Of our patients, 99 were treated with L-Disq decompression at a single level while 110 procedures were performed at two levels. Single-level procedures were performed at L4–L5 level in 43 patients and L5–S1 level in 56 patients. On the other hand, two-level procedures were performed at L4–L5 + L5–S1 levels in 97 patients, L3–L4 + L4–L5 levels in 9 patients, and L3–L4 + L5–S1 levels in 4 patients. The demographic data are summarized in the Table. None of the patients had previously undergone lumbar surgery at the spinal levels of the procedure.All patients were also evaluated by PSS 12 months after the procedure, and 43 patients (20.6%) rated their satisfaction as very good, 126 patients (60.3%) as good, and 40 patients (19.1%) as moderate. The overall satisfaction rate was 80.9%. When compared to the initial values, VAS scores were found to be statistically significant for each treatment method at the 1st, 3rd, 6th, and 12th months (P = 0.001). When VAS scores were compared in binary between months, all differences were statistically significant (P = 0.001) aside from the difference between the 6th and 12th months (P = 0.394). A decrease in time-dependent VAS scores was detected although VAS scores increased between the 6th and 12th months after the procedure in some patients, but not to a significant level. When compared to the initial values, ODI scores were found to be statistically significant for each treatment method at the 1st, 3rd, 6th, and 12th months (P = 0.001). When the ODI scores were compared in binary between months, the differences were statistically significant (P = 0.001), aside from the differences between the 3rd and 6th and the 6th and 12th months . We concluded that the procedure had a significant effect in reducing ODI scores. Comparisons of VAS scores and ODI indexes are shown in Figure 1.PDD methods are based on the principle that removal of the small amounts of discoid tissue will result in significant pain relief by reducing intradiscal pressure (5). Therefore, pressure on the nerve will be decreased and radicular findings will be reduced. There is evidence of clinically significant pain reduction, reduced disability of the patients, and safety of PDD (6–8).In all procedures of our study, the therapeutic effect was significantly related to patient selection and the experience of the practitioner. The statistically significant reductions in VAS and ODI scores can be attributed to the long-term efficacy of the treatment with a follow-up of 12 months, as well as to the larger patient population in the present study when compared to previous studies. In the present study, the mean VAS scores reduced by 51.24%, 52.89%, 57.70%, and 58.38% at the 1st, 3rd, 6th, and 12th months, respectively, while the mean ODI score reduced from 32.46 points at the beginning to 20.48 points at the 12th month. A precise approach to the target region is crucial for a successful outcome and this may be achieved through the proper control of the navigable tip of the electrode. The electrode of L-Disq including the tip can be monitored under fluoroscopy (11). In our study, following the tip of the electrode by fluoroscopy made it easier to navigate towards the protruded disc. We believe that long-term continuity also contributed to the favorable results of our study. The target region for the insertion of the electrode was determined according to the current pathology of the herniated disc on MRI images. The interventional area is very close to the neural tissues at the posterior and vascular tissues at the anterior. Though the temperature rises significantly around the tip of the electrode, nerves or other structures outside the disc do not carry the risk of thermal damage if the tip remains intradiscal (13). We think that this will increase the success rate and safety of the procedure. The practitioner must be careful in order to prevent serious damage to neural and surrounding tissues. It is a great advantage that the tip of the electrode is visible during ablation and it should be prevented from moving out of the disc (11). Placing the tip of the electrode within the disc approximately 5–6 mm away from the border of the neural tissue provides an optimal benefit for safety (14).Chen et al. (10) concluded that the volumetric removal of target discal tissue can be achieved without damage to the neighboring nuclei, rings, end plates, spinal cord, or nerve roots. The method of targeted ablation within the disc minimizes the amount of ablated discal tissue and fibrous damage to the outer ring, meaning that an adequate amount of nucleus pulposus is preserved and excessive reduction in discal height is prevented (5). Application of the L-Disq and an image of the L-Disq electrode under fluoroscopy are shown in Figures 2 and 3.Lee et al. analyzed the data from 20 patients with discogenic waist pain who underwent ablation decompression using the L-Disq. When compared to the baseline values, the mean VAS score reduced from 7.55 to 3.60 points, and the mean ODI score reduced from 48.04 to 27.8 points. The authors concluded that significant pain relief and reductions in disability index could be achieved following ablation in patients with discogenic lower back pain (5). In addition to disc herniation detected by MRI, we also ablated the area of annular fissure in degenerated discs, if present. We suppose that treating the herniated disc together with the fissure in the same session may have increased our success rate.In another study, Lee et al. reported their results of lumbar disc decompression using an L-Disq device in 25 patients with acute pain and extruded or protruded discs. The mean VAS score was 7.08 points at the beginning and reduced to 1.84 points at the 12th month, while the mean ODI score was 41.88 points at the beginning and reduced to 16.66 points at the 12th month (15). The results of our study were parallel to those of the two previous studies mentioned above.Grönemeyer et al. reported the success rate of percutaneous laser discectomies (PLDDs) as 74% in 20 patients with HNP after a follow-up of 4 years (16). Although the results were similar to those of our present study, it has been shown that percutaneous laser nucleolysis offers an insufficient level of temperature control, which may lead to injury of adjacent tissues (17–19). This procedure comes with some disadvantages, such as moderate to severe intraoperative pain, thermal effects of the laser, postoperative back pain, spasm, and lack of visualization of the laser tip under fluoroscopy (20). Our patients experienced no muscular pain or burning during or after the procedure, and suffered no muscular spasms after the procedure. Accordingly, we believe that L-Disq is a more preferable technique in terms of patient comfort when compared to PLDD. The overall satisfaction rate from the L-Disq procedure was 80.9%. We also observed that our recommendations related to postprocedure lifestyle for the first 7–14 days helped our patients to reduce the spasms and inflammatory responses that may occur in this period, and no complications were seen in any of the patients discharged within 24 h after the procedure. Some authors in previous studies (21–23) did not observe a significant correlation between MRI findings and pain or various clinical signs. In our study, we did not perform MRI routinely for follow-up after the procedure. The pain and functional status was determined by clinical anamnesis and physical examination.Although not statistically significant, our patients recorded increased VAS scores in their later follow-up appointments, but to evaluate this result more accurately, it would have been necessary to have noted the patient’s occupational status, social life, and living conditions, and to have followed their physical activities when recording the changes in VAS scores. This would have allowed us to classify the discal degeneration and healing rates more accurately, based on daily activities. The presence of such causal factors as vertebral instability, lifting heavy loads, and hard working conditions may lead to the recurrence or incomplete relief of discogenic pain. In conclusion, all of our patients benefited from the procedure. We believe that the most important factors playing a role in these promising results were performance of the procedure by the same experienced physician, giving weight to appropriate patient selection, the advantage of the access technique especially at the L5–S1 level, the navigable feature of the device, repairing the annular fissure together with the protruding disc, performing the procedure on a second level if detected on MRI, and performing regular follow-up after the procedure. We think that L-Disq is a safe and efficient procedure in patients with HNP when applied by an experienced practitioner because of its short duration, its own moving probe, the mechanical safety of the tip of the probe, and the opportunity to visualize the inside of the disc.


Opiates are addicting and have a high potential for dependency. In the past decades, opiates remained the first-line pharmaceutical option of prehospital treatment for acute traumatic pain in the civilian population. Ketamine is an N-methyl-d-aspartate (NMDA) receptor antagonist that has analgesic properties and may serve as an alternative agent for the treatment of acute traumatic pain in prehospital settings. This study aims to assess the safety and efficacy of ketamine administration by paramedics in civilian prehospital settings for the treatment of acute traumatic pain.This was a prospective observational study in San Bernardino, Riverside and Stanislaus counties. Patients were included if they were > 15 years of age with complaints of traumatic or burn-related pain. Patients were excluded if they received opiates up to six hours prior to or concurrently with ketamine administration. The dose administered was 0.3 mg/kg intravenously over five minutes with a maximum dose of 30 mg. The option to administer a second dose was available to paramedics if the patient continued to have pain after 15 minutes following the first administration. Paired-T tests were conducted to assess the change in the primary outcome (pain score) and secondary outcomes . P-value<0.05 was considered to be statistically significant.A total of 368 patients were included in the final analysis. The average age was 52.9 ± 23.1 years, and the average weight was 80.4 ± 22.2 kg. There was a statistically significant reduction in the pain score . Additionally, there was a statistically significant change in systolic blood pressure , pulse , and respiratory rate .The current study suggested that paramedics are capable of safely identifying the appropriate patients for the administration of sub-dissociative doses of ketamine in the prehospital setting. Furthermore, the current study suggested that ketamine may be an effective analgesic in a select group of adult trauma patients. The medicinal effects of opium have been exploited for centuries, long before the synthesis of the first opiate drug. However, the extent of its addictive properties were not evident until the last several decades. Currently, 11.4 million people misuse prescription opiates in the United States, with an estimated 130 people dying every day from opioid-related drug overdoses . The ecoKetamine may be a non-opioid alternative used for pain management. In 1982, Lodge et al. conclusively demonstrated that ketamine acts as an N-methyl-d-aspartate (NMDA) receptor antagonist . HoweverTo date, there were limited data on the use of ketamine in the civilian prehospital environment as an analgesic. This study aimed to evaluate the safety and efficacy of paramedic administration of ketamine as a prehospital analgesic in traumatically injured civilian patients. We hypothesize that the administration of ketamine in the prehospital setting by paramedics is safe and effective in reducing pain.A prospective observational study was conducted by paramedics representing 30 advanced life support (ALS) transport providers in three California counties . Prior authorization was obtained from Local Emergency Medical Services Agencies. Additionally, the protocol was approved by the Institutional Review Board at Arrowhead Regional Medical Center . An oversight committee in each participating county regularly reviewed the data and addressed any discrepancies during the study period. The paramedics participating in the study were trained by their respective participating agencies regarding the ketamine administration inclusion and exclusion criteria and appropriate documentation. Patients were included in the study if they: were at least 15 years of age; had experienced an acute traumatic or burn injury; had a Glasgow Coma Scale (GCS) score of 15; would normally receive analgesia during routine care and/or transport, and had a pain score of at least “5” on a scale of 0 - 10, with 0 meaning “no pain” and 10 meaning “extremely severe pain”. The exclusion criteria were: GCS 14 or less; known or suspected pregnancy; known allergy to ketamine; known or suspected alcohol or drug intoxication; having received narcotic analgesia in any form within six hours of planned ketamine administration; and pain score less than "5" prior to the first dose of ketamine. Paramedics assessed each patient for the source of the pain to determine whether the pain was somatic or visceral. Paramedics were taught that visceral pain or chronic pain is less likely to respond to ketamine, and they should choose a different analgesic in those circumstances. However, if the patient met the inclusion criteria, then ketamine was preferred. Pain was assessed on a visual analogue pain scale ranging from 0 (no pain) to 10 (most severe pain). Pain assessment was performed by a paramedic prior to administration of ketamine. Reassessment of pain was performed every five minutes following administration. The pain scale measured at 15 minutes was used as the final pain scale. EMS personnel were instructed to document age, weight, chief complaint, initial vital signs (including systolic blood pressure), Glasgow coma scale, as well as past medical history, allergies and home medications used by the patient.Paramedics were instructed to administer 0.3 mg/kg (max dose 30 mg) of ketamine as slow intravenous push over five minutes. An additional dose of 0.3 mg/kg (max dose 30 mg) was permitted if pain severity remained greater than five on the pain scale, 15 minutes following first administration. The time of ketamine administration and total dose were documented in the electronic patient care report, as well as any observed adverse effects.All statistical analyses were conducted using the SAS software for Windows version 9.3 . Descriptive statistics were presented as means and standard deviations for continuous variables, along with frequencies and proportions for categorical variables. Change in the pain scale and vital signs were analyzed using the paired T-test. Change in the pain scale was also compared between those who received one vs two doses of ketamine using independent T-test. All statistical analyses were two-sided. P-value<0.05 was considered to be statistically significant.Among the original 429 patients, 368 patients were included in the final analysis. Figure The change of pain score and vital signs were compared using a paired T-test. The analysis results were presented in Table A total of 58 (15.8%) patients received a second dose of ketamine. A subgroup analysis of change in pain score and vital signs was compared between cohorts who received one vs two doses of ketamine. The analysis results were presented in Table The complications associated with ketamine were reported in Table The current study suggested the effective reduction of acute pain with the use of sub-dissociative doses of ketamine in the prehospital setting. Furthermore, the treatment of pain was not associated with clinically significant adverse effects. While dysphoria was described in a small percentage of patients, hemodynamic instability or respiratory depression were not witnessed. In contrast, opiates, while effective in reducing pain, have a known side effect profile of respiratory depression and hypotension. Similar findings were reported in the literature. One systematic review and meta-analysis, including six trials and 438 patients, suggested that ketamine’s analgesic effects to be similar or superior to placebo or opiates, and while ketamine potentially had increased risk of neurological and psychological adverse effects, the opioid group had a higher risk of major cardiopulmonary events .Other studies have evaluated the use of ketamine in conjunction with opiates to treat acute pain in the emergency department. These studies aim to determine if co-administration reduces the overall use of opiates, and consequentially, the associated adverse effects. The results demonstrate a clinically significant reduction in pain, comparable to opiate alone, with less need for rescue analgesia and decreased incidence of clinically deleterious adverse effects .The opioid epidemic has increased the demand for a less-addictive alternative pharmacologic means of treating acute pain. Several studies demonstrated anti-depressant and anti-addiction properties of ketamine. One study suggested that ketamine may be used to treat addiction by decreasing the incentive-motivational value of reward-related cues . Other sThis study has several limitations. First, this study focused on the prehospital setting, and was therefore limited in its capacity to assess whether the use of ketamine may lead to dependence or addiction. However, research has reported the anti-addiction property of ketamine -22. A prhttps://escholarship.org/uc/item/40k6b3fx.The current research was presented as a podium presentation at the 10th Mediterranean Emergency Medicine Congress in Dubrovnik, Croatia in September 2019. The abstract was published in Western Journal of Emergency Medicine Volume 20 Supplement (5.1). The web address for the published abstract was There is sufficient support for the use of ketamine as a safe alternative to opiates for the treatment of acute pain. Ketamine’s use as an analgesic is well documented in the emergency department, perioperative and inpatient settings. Limited studies in combat demonstrate its efficacy in the prehospital setting. As this study suggests, its use as an analgesic may be expanded to include prehospital administration for civilian populations. Our assessment via the NRS, demonstrated an absolute reduction of pain following the administration of ketamine. Ketamine is safe to administer as slow intravenous push. The trial did not demonstrate severe adverse effects, including hemodynamic instability or respiratory failure. Ketamine appears to be a suitable alternative to opiates for analgesia in the prehospital setting.Future studies are needed to evaluate for the potential of dependence and abuse, determining the safety and efficacy of ketamine use in the pediatric population, and alternative routes of administration, including intranasal and intramuscular.


The medical history, clinical parameters, and OPAS scores were compared between groups. Results: The incidence of systemic comorbidities was higher in group 2 than in other groups. The corneal staining scores were lower in groups 2 and 3 than in group 1. Among the treatment response groups, group 2 showed improvements in OPAS scores of ocular pain severity, pain other than eyes, and quality of life, while group 1 showed improved OPAS scores of ocular pain severity and ocular associated factors. Group 2 exhibited lower scores of pains aggravated by mechanical and chemical stimuli than group 3. Conclusions: Gabapentin could be effective in patients who have systemic comorbidity and less pain evoked by mechanical and chemical stimuli for the treatment of DE patients with NOP, which is refractory to topical treatment.Purpose: To investigate the response to gabapentin treatment in patients with dry eye (DE) accompanied by features of neuropathic ocular pain (NOP), and to analyze the differences between clinical manifestations of the groups according to treatment response. Methods: We retrospectively reviewed the records of 35 patients with DE accompanied by NOP features and obtained information on their medical history and previous ocular history. The patients underwent clinical examinations of the tear film, ocular surface, and meibomian gland and completed the Ocular Pain Assessment Survey (OPAS). One month after treatment with topical eye drops, add-on of gabapentin treatment was determined according to the Wong–Baker FACES Pain Rating Scale (WBFPS). A reduction of 2 points or more on the WBFPS was considered a positive treatment response. Enrolled patients were divided into three groups according to the treatment response: topical treatment response group (group 1,  Dry eye (DE) is a multifactorial disease of the ocular surface characterized by a loss of homeostasis of the tear film and accompanied by ocular symptoms . The preThe classification of pain is based on the underlying etiology: nociceptive, neuropathic, and mixed . The priDE and neuropathic pain share several common features, including frequent discordance between the symptoms and signs, abnormal somatosensory testing, accompanying comorbidity, and anatomic nerve injury or somatosensory nerve sensitization ,13. OculOral gabapentin is the first-line agent for the treatment of chronic systemic neuropathic pain . EspeciaEthical approval was obtained from the Chonnam National University Hospital Institutional Review Board, and the study protocol adhered to the guidelines of the Declaration of Helsinki. Data were collected by retrospective review of the patients’ medical charts and recorded using electronic case report forms.Patients with DE accompanied by NOP features, who underwent evaluation between January 2018 and February 2020, were included in the analysis. DE was diagnosed at the first visit, based on an ocular surface disease index (OSDI) score ≥ 13 and tear break-up time (TBUT) ≤ 10 s. The inclusion criteria were as follows: (1) chronic ocular pain lasting for more than 3 months, which was unresponsive to topical lubricants ; (2) discordance between the painful DE symptoms and signs; (3) specific descriptors, including spontaneous burning, stinging, photosensitivity, and allodynia; and (4) Wong–Baker FACES Pain Rating Scale (WBFPS) score ≥ 6. The exclusion criteria were as follows: (1) topical anti-inflammatory drug use, including steroids and cyclosporin; (2) use of systemic medications that alter the pain and mood status, including analgesics, antidepressants, and antiepileptics; (3) systemic comorbidities that contraindicate the use of gabapentin, including chronic kidney disease; and (4) follow-up duration of less than 2 months.The OSDI score, TBUT, Schirmer score, corneal stain score (CSS), and meibomian gland (MG) parameters were evaluated by the same investigator (K.C.Y.). Only the “worse” eye was assessed as follows: (1) eyes with severe CSS, or (2) the right eye if the CSS was the same in both eyes.The OSDI questionnaire was used to quantify the vision-related QoL and included the following subscales: (1) ocular symptoms (OSDI symptoms); (2) vision-related activities of daily living ; and (3) environmental triggers (OSDI trigger). The total OSDI score and each subscale score, which ranged from 0 to 100, were analyzed .TBUT was assessed using a moistened fluorescein strip , and the time interval between the last complete blink and the first appearance of a dry spot or disruption of the tear film was recorded in seconds. This examination was performed thrice, and the mean TBUT value was used for the analysis. CSSs were obtained through a white light and cobalt blue filter, using the area-density index, scoring area and density of the superficial punctate corneal lesion and multiplying the area and density score . SchirmeThe MG quality score was graded using a scale ranging from 0 to 3 as follows: grade 0, normal, clear oil expressed; grade 1, opaque, diffusely turbid, normal viscosity; grade 2, opaque, increased viscosity; and grade 3, inspissated  meibum or non-expressible glands. The MG expressibility score was graded by counting the central eight expressed MG orifices of the lower lid as follows: grade 0, all glands are expressible; grade 1, 3–4 glands are expressible; grade 2, 1–2 glands are expressible; and grade 3, no gland is expressible .The WBFPS was chosen to screen pain severity in patients with DE. We explained to the patients that each face represented a person who had no pain, had some pain, or had severe pain. Patients chose the face that best depicts the pain they were experiencing at that moment .All patients completed the OPAS, which is a validated questionnaire for neuropathic pain that combines patient responses regarding ocular and non-ocular pain intensity, impact on QoL, aggravating factors, associated factors, and symptomatic relief . The que®, Taejoon Pharmaceutical Co., Ltd., Seoul, Korea) 6 times a day, and loteprednol 0.5%  and cyclosporin A ophthalmic nanoemulsion 0.05%  twice a day. After 1 month of treatment, an add-on of gabapentin 600 to 1200 mg/day  was determined according to the WBFPS score. The topical treatment was continued without gabapentin if the WBFPS score decreased by more than 2 points. If not, the add-on gabapentin treatment was administered for 1 month.At the first visit, all patients were instructed to instill preservative-free sodium hyaluronate 0.15% ; group 2 comprised patients who experienced symptomatic relief after the administration of gabapentin ; and group 3 comprised patients who were unresponsive to both treatments . The normality of distribution for all variables was assessed using the Shapiro–Wilk test. Fisher’s exact test was used for categorical data. Variables satisfying normal distribution were analyzed using the one-way analysis of variance and independent t-test, and those with non-normal distribution were analyzed with the Mann–Whitney U test. Post hoc analysis was performed after multiple comparison analysis using Tukey’s honestly significant difference test and Bonferroni adjustment. The symptom scores obtained before and after treatment were compared using the Wilcoxon signed-rank test, with differences corrected using the Benjamini–Hochberg procedure using false discovery rates of 0.25. This study included 35 patients with DE accompanying NOP features. The mean age was 55.6 ± 11.7 years, and 27 patients (77.1%) were women. There were no differences in baseline characteristics according to sex (data not shown). Only 1 of the 24 patients treated with gabapentin experienced a side-effect (mild tremor).p = 0.034). No differences were observed between the previous ocular histories of groups 2 and 3.p = 0.048 and p = 0.033). There were no differences between the CSS and other clinical parameters of groups 2 and 3.p = 0.026). Group 2 exhibited improved OPAS scores of ocular pain severity, pain other than eyes, and QoL .p = 0.019, p = 0.003, and p = 0.004, respectively).The comparisons of the OPAS scores between groups 2 and 3 are presented in Pain is an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described with respect to such damage, and can be classified into nociceptive and neuropathic pain . NocicepDE is a multifactorial disease of the ocular surface, which is accompanied by ocular symptoms . At timeHowever, limited data are available to support the use of systemic neuropathic pain medication for NOP associated with DE. A prospective, placebo-controlled study demonstrated that gabapentin reduced postoperative pain after photorefractive keratectomy . HoweverOur results showed that the frequency of other comorbidities such as rheumatologic, neurologic, and psychological disorders was higher in the gabapentin response group. Gabapentin has pharmacologic characteristics, binding to voltage-sensitive calcium channels at the α2δ subunit, affecting their function as well as influencing receptor trafficking . It can In contrast, the topical treatment response group had no ocular history including surgery and trauma, with more severe CSS compared to the other groups. The sensory neurons of the ocular surface and nociceptors could actually be injured in patients who had ocular surgery and trauma leading to neuroinflammation associated with peripheral and central sensitization ,8,13. ToThe evoked pain in response to chemical and mechanical stimulation tended to be greater in the gabapentin non-response group than in the gabapentin response group. Evoked pain, including allodynia and hyperalgesia, is provoked or increased pain in response to stimulation . These mDieckmann et al.  suggesteOur study had some limitations. First, it was designed retrospectively and the sample size was small. Patients were recruited from a single tertiary center; thus, the findings may not be representative of the general DE population. Further prospective and longitudinal studies with a large sample size are required in the future. Second, the threshold value for determining the group classification may not have been a representative value. We classified patients with an improvement of 2 or more points on the WBFPS as the treatment response group; however, this might be not a standardized cut-off value. Moreover, we did not analyze the results of the proparacaine challenge test. It was difficult to classify the enrolled patients based on the central or peripheral phenotype of pain, since the majority of participants showed a mixed phenotype. Third, the extent of actual nerve damage was not measured using in vivo confocal microscopy. However, to the best of our knowledge, this was the first study to analyze the differences in the clinical manifestations between groups according to treatment response in DE patients with NOP features.In conclusion, gabapentin could be successful for the treatment of DE patients with NOP features who have systemic comorbidities including rheumatological, neurological, and psychological disorders, and less evoked pain in response to mechanical and chemical stimuli. Topical treatment for DE with NOP features could be successful for patients who have a corneal staining and no ocular history including surgery and trauma.


With respect to symmetry a statistically significant difference was noted in the case of the sternocleidomastoid muscles (p = 0.00729). In conclusion, soft tissue mobilization seems to be effective in the relaxation of masticatory muscles in patients with temporomandibular disorders. Our findings proved that soft tissue mobilization does not improve the symmetry and synergy of the masticatory muscles limited by dental occlusion.The aim of the study was functional evaluation of soft tissue mobilization in patients with temporomandibular disorder-myofascial pain with referral. The study group consisted of 50 individuals—37 females and 13 males. The average age was 23.36 ± 2.14 years. All subjects were diagnosed with myofascial pain with referral (diagnostic criteria for temporomandibular disorders). Soft tissue mobilization was applied three times. Electromyography of selected masticatory muscles was performed six times—before and after the treatment. After each mobilization, a decreasing tendency of muscular activity was observed in the entire study group. The Friedman test indicated that mobilization altered the activity of the right temporal muscle ( Myofascial pain was first described in 1952 by Travell and Rinzler ,4. They According to Jafri, myofascial pain is a combination of sensory experiences, motor reactions and autonomic symptoms, including local and projected pain. Its typical manifestations include a limited range of movement, impaired coordination and muscle weakness . Mood diThe cause of myofascial pain may include micro and macrotraumas, overloads leading to chronic muscle fatigue, improper posture, poor work ergonomics, degenerative changes accompanying the process of ageing and the resulting loss of myofascial elasticity and nerve root compression that enhances sensitization of spinal cord structures . AttentiMyofascial pain probably results from hypothyroidism, parasitic diseases, babesiosis, Lyme disease, recurrent fungal infections, deficiency of vitamins D and B12, low levels of iron and hormonal disorders in both sexes ,10,11.The main causes of myofascial pain are: chronic emotional stress, impaired functioning of the descending inhibitory system, sleep deprivation, specific unhealthy behavior and depression . These fIn numerous cases the elimination of the above-mentioned factors may lead to the deactivation of trigger points and reduction of the pain. Their early diagnosis and subsequent exclusion determine therapy success in patients with chronic pain .Considering that soft tissue mobilization is associated with changes of myofascial balance it was hypothesized that there is at least one significant difference between pre- and post-treatment activity of selected muscles of the stomatognathic system in patients with temporomandibular joint disorder-myofascial pain with referral.The aim of our study was functional evaluation of soft tissue mobilization in patients with temporomandibular joint disorder-myofascial pain with referral.The study was approved by the Ethics Committee of the Medical University of Bialystok, Poland (permission number: R-I-002/322/2016). The research was conducted in accordance with the principles of the Declaration of Helsinki of the World Medical Association and the Guidelines for Good Clinical Practice. Participation in the study was voluntary. All the patients obtained comprehensive information about the nature, scope of clinical activities and the course of the proceedings. At each stage, the subjects had the right to refuse to participate in the research without any resulting consequences. Participation in the study had been preceded by a written consent by every patient.The research was conducted in the Department of Prosthodontics at the Medical University of Bialystok, Poland, on a group of 50 generally healthy individuals. Participating in the study were 37 females and 13 males. The average age of the subjects was 23.36 ± 2.14 years. The range of age was 18–25 years. All participants underwent a clinical examination with respect to the diagnostic criteria for temporomandibular disorders and were diagnosed as patients with myofascial pain with referral (axes I and II) . The. The3]. The therapy of trigger points involved initiating a slow pressure increase over the active trigger point until the tissue barrier was reached . One finMyofascial relaxation was used to functionally release fascia. The physiotherapist placed one hand over the temporal muscle and took up the slack by applying upward traction  3]. The. The3]. Statistical analysis was performed using the Statistica 13.1 software , IBM SPSS Statistics 26.0  and PQStat Software v.1.6.8 . All the studied parameters  were assessed in 6 periods—directly before and immediately after all three soft tissue mobilizations.r), degrees of freedom (df), p-value and Kendall’s coefficient of concordance (W) were presented. The results for the test probability level of p < 0.05 were considered statistically significant. Kendall’s coefficient of concordance (W) at the level of 0.1 indicated a small effect size, 0.3—moderate effect and results above 0.5—strong effect size. A Dunn–Bonferroni post hoc test was used to subsequently compare the different treatments following the Friedman test.Central tendency measures, including arithmetic mean and median and measures of differentiation, i.e., standard deviation, were presented. The Friedman test was used for repeated measures to determine whether soft tissue mobilization has an effect on the activity, symmetry and synergy of selected muscles of the stomatognathic system. Friedman statistic , and thus the muscle engrams conditioning a specific pattern of muscular activation . AccordiIn females, statistically significant differences in the muscle activity may indicate the main source of dysfunction, pointing to the subtle neuromuscular discoordination. The general direction of changes was similar to that observed in the entire study group . Among tIn the entire study group, high values of symmetry of muscular activity (>80%) were observed in the case of the temporal and masseter muscles, both before and after the treatment cycle . The resp < 0.05) [Ries et al. observed that in patients with temporomandibular disorders the symmetry of the temporal muscle at maximum intercuspation was 95.03% ± 0.58% . The ave < 0.05) . These a < 0.05) . These a < 0.05) . Therefo < 0.05) . These o < 0.05) .Ries et al. observed the highest asymmetry of the temporal and masseter muscles in the resting position of the mandible, when the feeling of proprioception is weakened due to the lack of dental contacts , and lowTartaglia et al. showed that in the group of patients with temporomandibular joint disorders the most appropriate symmetry of the temporal and masseter muscles  was noted in individuals with a myogenic component . In the It should be emphasized that the dysfunction of temporomandibular joints is the second cause of pain in the craniofacial area after tooth derangement . Only 3%In the presented study, soft tissues mobilization probably contributed to the reduction of sympathetic nervous system activation and lowering of muscle hypertonia, thus leading to changes in the EMG registration and reduction of pain . DiffereThe DC/TMD protocol enables the qualification of patients for the study in relation to strictly defined research criteria. It allows for better communication between scientists conducting research in similar fields and also enables comparison of the results of similar studies regarding their subject. The clear DC/TMD protocol and the clinical standards of BioEMG registration ensure research repeatability. As an extension of the DC/TMD concept, this study additionally included instrumental analysis, clinical intervention (soft tissue mobilization) and reassessment. The observed research findings could be referred to patients with temporomandibular disorders, including myofascial pain with referral. The main goal of our clinical intervention was to help patients reduce their pain, and this goal was achieved.However, it should be borne in mind that DC/TMD protocol and instrumental analysis are time-consuming. Moreover, answers of self-reported questionnaires (DC/TMD) could be exaggerated. Sometimes patients are too embarrassed to reveal their emotions, social relations and other details. DC/TMD protocol contains an abundance of information, which makes it difficult to present all data in one publication. Extending the protocol by the inclusion of instrumental analysis and clinical intervention requires the generation of even more data. The aim of using the DC/TMD protocol in scientific research is usually to establish a diagnosis that could provide a more homogeneous study group.The advantage of BioEMG is the fact that surface electromyography is a widely used, repeatable and non-invasive method. The registration requires unchanged testing conditions . The weakness of our research is the fact that both the DC/TMD protocol and EMG do not include the functions of all of the muscles affecting jaw mobility. Sixty eight pairs of muscles above and below the mandible could be examined during head, cervical, shoulder and jaw positioning . FurtherSoft tissue mobilization appears to be effective in the relaxation of the masticatory muscles in patients with temporomandibular disorders-myofascial pain with referral. Despite the small group of subjects, our findings provide some evidence confirming that in patients with myofascial pain with referral, soft tissue mobilization does not improve the symmetry and synergy of the masticatory muscles limited by dental occlusion. Further studies on a larger number of samples should be conducted.


EFA resulted in a six-factor model. The findings demonstrate that the CSI was successfully trans-culturally adapted into a simplified Korean version (CSI-K) that was reliable and valid for Korean-speaking patients who awaiting TKA for knee OA.The purpose of this study was to establish a Korean version of the Central Sensitization Inventory (CSI-K) for Korean-speaking patients facing total knee arthroplasty (TKA) for knee osteoarthritis (OA) and to investigate the psychometric characteristics of the CSI-K. We recruited a total of 269 patients with knee OA who were scheduled to undergo TKA for the study. CSI-K and pain-related outcomes, including the pain visual analog scale (VAS) and the Western Ontario and McMaster Universities OA Index (WOMAC) pain sub-scores, were measured. Since central sensitization (CS) is closely related to the quality of life (QOL) and limited functionality as well as pain, the patient’s function was measured using the WOMAC function sub-scores, and QOL was measured using the EuroQol five-dimension test (EQ-5D). Reliability and validity were evaluated. Exploratory factor analysis (EFA) was conducted to begin the data reduction to validate the existing questionnaire translation. The internal consistency was excellent, with a Cronbach's alpha of 0.941. The test-retest reliability was acceptable-to-excellent with an ICC of 0.888. As expected, the CSI scores correlated strongly with the WOMAC pain scores ( Total knee arthroplasty (TKA) is the most effective surgical method for treating the pain caused by chronic knee osteoarthritis (OA) , 2. A grCS is defined as an abnormal and intense increase in pain caused by mechanisms in the central nervous system (CNS) . CS-relaCS-related research has been actively carried out on TKA as well as on knee OA , 12, 14.All procedures performed in the studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. This study was approved by the Institutional Review Board of our institution . Study number was KC19RISI0894. All patients provided informed consent.The Korean translation was performed according to the instructions provided by Guillemin et al.  using thThe first 282 TKA candidates with end-stage knee OA were asked to participate in this study. The exclusion criteria included patients diagnosed with primary neuropathic pain , congenital deformity, history of previous knee infection, history of surgery on the ipsilateral or contralateral leg, cancer, dementia, poor Korean-language comprehension, and those who declined to participate in the study. Thirteen patients were excluded, including two with primary neuropathic pain, one with a congenital deformity, three with previous surgery history, five with cancer, and two with dementia. Finally, 269 patients facing TKA due to primary knee OA were enrolled in the final analyses. All patients underwent TKA at our hospital from March to October 2019.All patient demographics including age, sex, operation side, height, weight, and body mass index (BMI) were recorded. Prospectively, the preoperative CSI-K and pain-related outcomes, including the pain visual analog scale (VAS) and the Western Ontario and McMaster Universities OA Index (WOMAC)  pain subThe CSI is a newly developed and validated self-reported inventory to assess patients with central sensitivity syndrome (CSS) , 24. TheScores were not measured in part B, which was used to determine the presence of one or more specific disorders, such as restless leg syndrome, chronic fatigue syndrome, fibromyalgia, temporomandibular joint disorder, migraine or tension headaches, irritable bowel syndrome, multiple chemical sensitivities, or neck injuries. Each item was rated on a 5-point Likert scale from 0 to 4 . The CSI scale ranged from 0–100, with 0 being the worst score and 100 being the best score , 24. TheThe WOMAC has been widely used as an indicator for evaluating knee OA and TKA patients  and has The EQ-5D is a measurement tool commonly used for health-related quality of life. It was developed by the Euro Quality of Life (EuroQol) Group , 39. It Reliability was evaluated by internal consistency and test-retest reliability. Internal consistency was measured using Cronbach’s alpha. A Cronbach’s alpha of 0.5–0.6 was evaluated as poor, one between 0.60 and 0.70 was considered acceptable, between 0.70 and 0.90 was considered good, and higher than 0.90 was excellent . The tesTo find the concurrent validity, we assessed the domains of the CSI-K by comparing them to the appropriate subscales of the Korean WOMAC and the Korean EQ-5D using Spearman’s coefficients. The correlation was considered strong if the value was greater than 0.5, moderate if the value was between 0.5 and 0.35, and weak if the value was less than 0.35 .Exploratory factor analysis (EFA) was conducted to begin data reduction to validate the existing questionnaire translations using the maximum-likelihood method with Promax rotation. In the EFA, the number of dimensions was measured as eigenvalues, which should be 1.0. In addition, the correlation and contribution of a single item in a dimension can be evaluated using the loading factor, and to contribute enough to the dimension, the cutoff for loading should be set at 0.4 , 30.p < 0.05 or less was taken to indicate significance.Statistical analyses were performed using SPSS ver. 21.0 . The mean values are shown with the standard deviation (SD), and a The internal consistency was excellent, with a Cronbach's alpha of 0.941. The Cronbach’s alphas for the individual CSI items ranged from 0.739 to 0.920. The test-retest reliability was acceptable-to-excellent with ICCs of 0.888 . Sixteen of the 25 items of the CSI had an excellent ICC greater than 0.75, and nine of the 25 items showed good reliability, with a range from 0.586 to 0.748 .r = 0.524, p < 0.001) and moderately with the pain VAS , the WOMAC function , and the EQ-5D scores .As expected, the CSI scores strongly correlated with the WOMAC pain scores (p < 0.001) indicated that factor analysis was appropriate for this sample. EFA resulted in a six-factor model. Four factors showed behavior similar to that of the original English version items, including physical symptoms, emotional distress, urological symptoms, and headache/jaw symptoms. Items 12 to 17 were loaded on factor 1, which was named “Emotional Distress.” Factor 2 consisted of items 1, 2, 3, 6, 9, 22, and 23, and was named “Physical Symptoms.” Factor 3 consisted of items 1, 7, 10, and 19, and was named “Headache and Jaw Symptoms.” Factor 4 consisted of items 5, 8, 18, 21, and 25, and was named “Urological Symptoms.” Factor 5 consisted of items 4, 14, and 20, and was named “High Central Sensitivity” and items 6 and 24 were loaded on factor 6, which was named “Psychiatric Problems.” Factor 1, Emotional Distress, contained four items  relating to emotional distress in the original article [We used EFA to evaluate whether the original English CSI study dimensionality and factor-loading patterns were like the Korean subject sample. The contributing factors with item loadings higher than 0.4 are shown in  article . Factor  article . Factor  article . In fact article  and headn = 97); mild ; moderate ; severe ; and extreme . Eighty-eight patients (32.7%) had a CSI score of over 40, indicating CS . The proportion of patients with different CSI severities and the number of patients in each subgroup were: subclinical , 0.91 in the Brazilian version (two weeks), 0.88 in the Dutch version   [The CSI-K demonstrated adequate construct validity when compared to the Korean pain VAS, the Korean WOMAC, and the Korean EQ-5D. The correlation tests showed strong a correlation with the pain subscales of the Korean WOMAC and moderate correlation with its function subscales. Pain and functional limitations caused by CS also had a significant effect on the QOL of the patients. Therefore, it would be very important to understand the relationship between the CSI and QOL in patients with TKA for knee OA. In the current study, the CSI-K showed a moderate positive correlation with QOL measured by the EQ-5D (< 0.001) , 33. Our< 0.001) , perhapsThe average score of the CSI-K was 33 points in this study. The average Japanese score was 21.9 points , the AmeThere were numerous limitations to this study that should be acknowledged. First, our subjects were recruited from one hospital, which could limit generalization elsewhere in Korea. Second, the majority of the patients were elderly women, which should be taken into account as a demographic feature of TKAs in Korea –47. BecaThe CSI-K was successfully trans-culturally adapted into a simplified Korean version that was demonstrated to be reliable and valid in Korean-speaking patients who awaiting TKA for knee OA. In addition, we found evidence for the convergent validity of the CSI-K by its association with pain, function, and the QOL in patients with TKA for knee OA. This scale is a reliable instrument for evaluating the CS of Korean patients with knee OA and is useful for psychometric measurements in clinical research.