Schwannomatosis is the third form of neurofibromatosis and characterized by the occurrence of multiple schwannomas. The most prominent symptom is chronic pain. We aimed to test whether pain in schwannomatosis might be caused by small-fiber neuropathy. Twenty patients with schwannomatosis underwent neurological examination and nerve conduction studies. Levels of pain perception as well as anxiety and depression were assessed by established questionnaires. Quantitative sensory testing (QST) and laser-evoked potentials (LEP) were performed on patients and controls. Whole-body magnetic resonance imaging (wbMRI) and magnetic resonance neurography (MRN) were performed to quantify tumors and fascicular nerve lesions; skin biopsies were performed to determine intra-epidermal nerve fiber density (IENFD). All patients suffered from chronic pain without further neurological deficits. The questionnaires indicated neuropathic symptoms with significant impact on quality of life. Peripheral nerve tumors were detected in all patients by wbMRI. MRN showed additional multiple fascicular nerve lesions in 16/18 patients. LEP showed significant faster latencies compared to normal controls. Finally, IENFD was significantly reduced in 13/14 patients. Our study therefore indicates the presence of small-fiber neuropathy, predominantly of unmyelinated C-fibers. Fascicular nerve lesions are characteristic disease features that are associated with faster LEP latencies and decreased IENFD. Together these methods may facilitate differential diagnosis of schwannomatosis. Schwannomatosis is a newly identified hereditary tumor predisposition disorder  with an SMARCB1 and LZTR1 [The clinical diagnostic criteria for schwannomatosis have changed over time since its first description as separate disease entity besides neurofibromatosis type 2 (NF2) ,4,5. In nd LZTR1 ,7,8,9. Hnd LZTR1 . The most common symptom of schwannomatosis is pain, reported by approximately 70% of patients; either as local, multifocal, or diffuse pain. While most patients remain asymptomatic during childhood and adolescence, adulthood invokes severe and poorly localized pain symptoms, sometimes in combination with pain attacks. Evidently, in the majority of schwannomatosis patients, pain is not associated with macroscopically detectable tumors . The exaAll 20 patients enrolled in this study fulfilled the current clinical diagnostic criteria for schwannomatosis , three oSurgical schwannoma resection had been performed in 19 patients (ranging from one to 16 surgeries per patient), which includes peripheral nerve surgery in 14 patients, thoracic surgery in 11 patients, and cranial surgery in four patients. While pain relief and/or improvement of neurological function was reported by 16 of 18 patients following surgery, six of 18 patients reported new symptoms after surgery, predominantly pain and/or sensory loss or tingling. All patients had used analgesic or co-analgesic drugs in the past for the purpose of pain relief. NSAIDs and/or opioids were used by five of the 20 patients on a regular basis, whereas seven of the 20 patients used them on demand. One patient took gabapentin or pregabalin on a regular basis, one patient took these drugs on demand, and three had stopped the use of these drugs because of side effects or insufficiency of the therapy. Neuroleptics and antidepressants were used by one patient only.We firstly intended to characterize the pain symptoms experienced by schwannomatosis patients by established pain and personality questionnaires. In the painDETECT, six of 20 patients scored in the upper range (19–38 points), which is indicative of a neuropathic pain syndrome. Seven patients had low scores (0–12 points) and, thus, showed no symptoms typically associated with neuropathic pain. The remaining seven patients reached scores in the mid-range (13–18 points), allowing no precise classification. p = 0.004, anxiety U = 126.5, p = 0.046; SCL-90-R depression t(37) = −3.255, p = 0.002, anxiety t(37) = −2.297, p = 0.027). The FPI questionnaire did not detect any association with specific personality traits. Conclusively, the pain syndrome observed in patients with schwannomatosis has neuropathic features. Furthermore, anxiety and depression were over-represented in schwannomatosis patients leading to reduced quality of life in patients affected by schwannomatosis. Schwannomatosis patients showed lower values in all scales of the SF-36 health survey compared to normative data and to the control group indicating a relevant impact on quality of life. Assessment of the HADS and SCL-90-R questionnaires showed a significantly higher vulnerability for anxiety and depression in the schwannomatosis cohort compared to controls (HADS: depression t(38) = −3.063, The painDETECT questionnaire results indicated a neuropathic condition in a subset of schwannomatosis patients. In order to determine the functional integrity of peripheral nerves in schwannomatosis patients we performed standard electrophysiological measurements. In fact, 16 of 20 patients showed normal electrophysiological parameters. Only in four patients could signs of focal or multifocal sensomotoric axonal neuropathy could be detected. In three patients  only one or two nerves were affected and associated with previous surgery in that area or with compressive schwannoma formation. Only one patient (#19) exhibited signs of more generalized neuropathy. t(76) = 0.496, p = 0.621 and t(76) = 0.384, p = 0.702, respectively) as parameters for small fiber function. No differences were observed in the occurrence of pathological paradoxical heat sensations (χ2(1) = 2.646, p = 0.104). Mechanical (t(76) = 1.585, p = 0.117) or vibration detection thresholds  as parameters for large fiber function also showed no differences between patients and controls  was applied as standardized noninvasive method to examine the function of thickly-myelinated Aβ, thinly- and unmyelinated Aδ- and C-fibers as well as their corresponding central pathways. Strikingly, QST did not detect any significant differences between schwannomatosis patients and healthy controls with regard to cold and warm temperature detection thresholds (controls . 2(3) = 3.227, p = 0.358).The number of individuals with signs of small, large, or mixed fiber neuropathy was not higher in the group of patients with schwannomatosis than in the group of healthy controls  investigations were performed in all 20 patients and additional MR neurography (MRN) was conducted in 18 patients . Seven pMRN indicated abnormalities in larger peripheral nerves  in 16 of 18 patients. These abnormalities ranged from small T2-weighted lesions of individual fascicles without caliber increase to large compressive schwannoma formations. Larger intraneural macrolesions or intermediate-sized nerve nodules were detected in MRN scans of 10 of 18 patients . In six p = 0.640; P2: F = 0.110, p = 0.742; N2P2: F = 0.007, p = 0.933). Latencies tended to be faster in the patients group, but did not reach significance in the group comparison  = 1.393, p = 0.247; P2: F = 1.313, p = 0.261). In the individual plotting, 10 of 18 patients showed N2 latencies below the respective 95% confidence interval of the control group, whereas only two2 lay above. The remaining six patients showed latencies within the 95% confidence interval , which can be used to determine the presence of small-fiber neuropathy as it specifically measures the function of A-delta and C-fibers. Regarding LEP amplitudes, no differences were detected in the patient group compared to matched controls  = 0.224, interval . In the To further corroborate our findings that schwannomatosis-related pain might be caused by a loss of C-fiber function, we performed skin biopsies in 14 of 20 patients in order to determine the intraepidermal nerve fiber density (IENFD) as an alternative proxy for the presence of a small-fiber neuropathy in schwannomatosis patients. Strikingly, 13 of 14 patients who underwent skin biopsy exhibited a significant reduction of intraepidermal nerve fiber density (1.85 ± 0.92/mm) in comparison to age-adjusted reference-values (1.7–5.7/mm)  with a m± 10.9 (SD) years; male:female = 1:1) were consecutively included in the study at the Neurofibromatosis outpatient clinic of the University Medical Center Hamburg-Eppendorf. Inclusion criteria were the fulfillment of the clinical diagnostic criteria for schwannomatosis [NF2, SMARCB1, and LZTR1 exons. Sanger sequencing of the PCR products was performed using the BigDye Terminator Cycle Sequencing Kit . Rearrangments involving the NF2 gene were investigated by MLPA .In total, 20 patients  and established reference values . For MRN and IENFD, measurements and analyses were conducted in a blinded manner. For the QST, LEP, and neurophysiological examination blinding the investigators was not possible, however, data analysis was carried out in a blinded fashion.± 11.2 (SD) years; male:female = 1:1) served as a control group. The Hospital Depression and Anxiety Score (HADS) was used to screen for anxiety and depression . Pain pet-tests or Mann–Whitney-U test, as appropriate. p-values < 0.05 were considered statistically significant. Normal distribution was investigated using the Kolmogorov–Smirnov test. Then, questionnaire data was compared between groups using either unpaired Conventional electrodiagnostic testing  of the right peroneal, left tibial, and right ulnar and/or median nerve was performed in the neurophysiology laboratory of the Hamburg-Eppendorf University Hospital using a Nihon Kohden Neuropack X1 .QST is a standardized noninvasive psychophysical method, which examines the function of thickly-myelinated Aβ, thinly- and unmyelinated Aδ-, and C-fibers as well as their corresponding central pathways by the application of thermal and mechanical stimuli on the skin. QST was performed by a certified examiner (ALH) after a pre-defined protocol by the German Network on Neuropathic Pain (DFNS)  in all 2± 11.2 (SD) years; male:female = 1:1) served as control group. QST was assessed on the dorsum of both hands and feet except in one patient (and its matched control) in whom only both hands were assessed. Areas whose innervation could have been compromised by previous surgeries  were avoided. A group of 20 age- and sex-matched healthy controls (mean age 54.8 patient – meancontrols) / SDcontrols [t-tests or the non-parametric Mann–Whitney U-test were used to compare the pooled z-values of hands and feet between patients and controls, as appropriate. Pathological PHS and the number of patients with small, large and mixed fiber neuropathy (according to QST) as categorical variables were compared between groups using the Chi-square test. p-values < 0.05 were regarded as statistically significant.QST statistical analysis was performed using “eQUISTA“ , which calculates a sensory profile by transformation of the absolute measured values into relative data by calculation of z-scores according to the following formula based on the published data of healthy controls: z-value = . Individual pain thresholds were determined using three series of increasing and decreasing stimuli. Beginning at 160 mJ, we used a step-size of 20 mJ. Pain was defined as a feeling of a light pin-prick or burning. LEP are capable to investigate nociceptive pathways, especially A-delta fibers.www.ru.nl/fcdonders/fieldtrip). For detailed artifact rejection see Hauck and colleagues [During the experiment, subjects were comfortably seated in an electrically shielded and sound-attenuated recording chamber with eyes closed. The session consisted of eight blocks and started at the left hand, followed by the right hand, right foot, and left foot. Repetitions of all sites were then performed in the reverse order to minimize confounding of site with habituation effects over time. Each block comprised 30 laser-stimuli with a two-fold pain threshold intensity. The inter-stimulus interval varied between six or seven seconds. Two seconds after the laser stimulus, an acoustic event (2000 Hz tone) prompted a verbal response, scaling pain intensity and ensuring patients attention. EEG was recorded with nose-reference using 64 active channels (EASY CAP) and BrainVision Recorder-software  through two BrainAmp MRplus 32 channel amplifiers with a sampling frequency of 1000 Hz and a band pass filter between 0.1–250 Hz. The electrode impedance was kept below 15 kΩ. The data were analyzed offline using Fieldtrip software  as 4-level dependent variable and group as independent variable. Vestibular schwannomas—the hallmark tumor entity of NF2—were excluded by contrast-enhanced cranial MRI. Patients underwent whole-body magnetic resonance imaging (wbMRI) at 3.0 Tesla according to previously described protocols . PeripheLumbosacral plexus: 3D-isotropic T2-weighted SPACE sequence with fat-saturation by inversion-recovery and TR/TE/TI 3800/267/210, voxel size 0.95 × 0.95 × 1.0 mm, FoV 250 × 245 mm, acquisition time 8:32 min.2, FoV 140 mm, slice thickness 3.0 mm, frequency-selective fat-saturation, acquisition time 7:07 min.Extremities were examined by multiple stacks of 2D T2-weighted turbo-spin-echo sequences  with the following parameters: T2 TSE TR/TE 7552/52, in-plane resolution 0.273 × 0.273 mm(1)Manifest peripheral nerve tumors of more than 5mm in diameter;(2)Intermediate-sized nerve nodules, defined as neural caliber increase between 2 and 5 mm in diameter; and(3)The presence of peripheral nerve microlesions with increased T2-weighted signal but with only minor or no fascicular caliber increase (< 2 mm in diameter as described previously ) Figure.Dedicated surface array coils for plexus imaging and circularly-polarized extremity transmit-receive coils for extremities were used. MR neurography (MRN) scans were evaluated blinded to the patients’ data by two radiologists  with more than eight and 18 years of experience in MRN, respectively, to detect:This quantitative analysis was performed for the right lower extremity, which was examined in all patients except for one whose contralateral leg was examined due to a right hip prosthesis. Manifest peripheral nerve tumors and nerve nodules were counted individually unless they exceeded more than ten. In addition, an overall MRN score for lesion accumulation of peripheral nerves of the right leg was used with regard to the presence of tumors, intermediate lesions, and microlesions on a Likert scale of 0–4 . For MRN statistical analysis, Pearson correlation and unpaired t-test were used to investigate association of MRN lesion load with LEP parameters, IENFD, or tumor load in wbMRI.Skin biopsies were performed in 14 of 20 patients by an expert surgeon for plastic surgery (RF). Six patients refused to have skin biopsies. An 8 mm punch biopsy was taken 10 cm above the lateral malleolus of the distal leg according to the standardized protocol for diagnosis of small fiber neuropathies  . The tisThe study was approved by the ethical board of the Medical Association Hamburg (PV4421), Germany, and performed in accordance with the Declaration of Helsinki. Written informed consent was obtained from all study participantsThe datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.In this study we aimed at investigating the pain characteristics and peripheral nerve abnormalities in patients with schwannomatosis by clinical and genetic examination, psychological testing, detailed electrophysiological measures, wbMRI and MRN, as well as by analyzing the intraepidermal nerve fiber density. We hereby provide evidence that point toward a C-fiber neuropathy as the underlying cause for the pain experienced by most schwannomatosis patients.According to the evaluation of the painDETECT questionnaire, the pain syndrome observed in patients with schwannomatosis has neuropathic features. Anxiety and depression were over-represented in schwannomatosis patients according to the HADS questionnaire and the SCL-90-R. Conclusively, the applied questionnaires indicated a significant pain-burden with a risk of comorbid depression in schwannomatosis. From the SF-36 we conclude that pain reduces the quality of life in patients with schwannomatosis considerably and that the development of effective pain treatment protocols are essential. According to the FPI, the pain perception cannot be referred to specific traits of personality.By standard neurophysiological assessment, a true sensorimotor polyneuropathy was not detectable in our patients except in one. Remarkably, we did not detect signs of neuropathy by means of quantitative sensory testing (QST) either, even though the sensitivity of QST is considered high . In the Importantly, the subjective location of pain symptoms and the extent of pain experienced by the schwannomatosis patients did not correlate with the location of tumors as analyzed by wbMRI. Instead, by using high-resolution MRN we detected generalized fascicular nerve lesions in most patients. These lesions are morphologically comparable to those found in patients with NF2 . HoweverIn performing laser evoked potentials (LEP), we identified that the N2/P2 latencies might be faster in the schwannomatosis patient group compared to matched controls but without reaching significance due to the small sample size. This may contradict the conventional concept of small fiber neuropathy, but may be explained by an exclusive impairment of C-fibers without major affection of the A-delta fibers . Laser sOur assumption that schwannomatosis-related pain might be caused by a loss of C-fiber function and subsequent small-fiber neuropathy is substantiated by the results of intraepidermal nerve fiber density measurements, which are currently considered the gold standard for the diagnosis of small-fiber neuropathies ,24. In oSMARCB1 and LZTR1 germline mutations is negative. Additionally, schwannomas are frequent sporadic tumors [Differential diagnosis of schwannomatosis can be difficult in patients, especially if they are oligosymptomatic and testing for c tumors  and may c tumors ,36,37,38In comparing NF1, NF2, and schwannomatosis with regard to the respective diagnostic features and symptoms, it is reasonable to hypothesize that C-fiber loss is indeed the cause for pain experienced by schwannomatosis patients.Of all three neurofibromatous entities, schwannomatosis is the only one presenting primarily with pain . HoweverConsequently, both the macroscopic tumor burden as well as nerve microlesions are unlikely to be responsible for pain symptoms seen in schwannomatosis patients. The decisive diagnostic feature, which separates schwannomatosis clearly from NF1 and NF2, is the marked reduction of IENFD.Neuropathic pain is defined as pain caused by a lesion or disease of the somatosensory nervous system. Here, we demonstrated this premise for neuropathic pain with the marked loss of epidermal nerve fibers in schwannomatosis patients. The hypothesis that peripheral nerve tumors lead to neuropathic pain has been raised before . There aFurther research on cytokine expression and nerve growth in schwannomas might shed light on this interesting, yet still disregarded topic.The findings presented in our study strongly suggest that reduced intraepidermal small-fiber density and the presence of multiple fascicular nerve lesions are important diagnostic signs indicative of schwannomatosis. Hence, skin biopsies for the analysis of intraepidermal nerve fiber density as well as MR neurography for detection of fascicular nerve lesions might represent powerful diagnostic tools to strengthen the diagnosis of schwannomatosis.In our cohort of 20 schwannomatosis patients we found no significant neurological deficits directly attributable to schwannomatosis. However, the extensive work-up revealed evidence for the existence of a chronic neuropathic pain syndrome in all patients. Larger tumors and disseminated intraneural fascicular nerve lesions shown by wbMRI and MRN, reduced intraepidermal nerve fiber density in the skin biopsy, and possible C-fiber dysfunction in LEP demonstrate affection of nerve fibers, yielding the base for the diagnosis of neuropathic pain. Our study, therefore, indicates that a loss of C-fibers might play a role in the pathogenesis of pain in patients with schwannomatosis. High-resolution microstructural MR neurography and IENFD are potential surrogates to allow differential diagnosis of schwannomatosis in uncertain cases.


This study was to evaluate clinical outcomes using a patient-oriented test that scores health-related quality of life (HRQOL) for patients after minimally invasive surgery using microendoscopic discectomy (MED) for lumbar disc hernia. Few studies regarding MED in terms of disease-specific quality of life measures using Japanese Orthopaedic Association Back Pain Evaluation Questionnaire (JOABPEQ) have been published.Retrospective analysis of the surgical and clinical outcomes with regard to reducing pain and improving the functional status for 31 patients who underwent MED for lumbar disc hernia was conducted. These patients were evaluated at 3-year follow-up. The evaluations were based on a visual analogue scale (VAS), the Japanese Orthopaedic Association (JOA) scoring system, and the JOABPEQ, which is an objective, patient-oriented test that assesses HRQOL in patients with lumbar disorders.A low rate of improvement was seen only in mental health until 1 year, the low rate of improvement in mental health and was independently correlated with body mass index (BMI), pre-operative scores on the Brief Scale for Psychiatric problems in Orthopaedic Patients (BS-POP), and scores on the BS-POP at 12 months post-operatively.All categories of VAS, JOA scores, and all domains of JOABPEQ were significantly higher over 3 years than those obtained pre-operatively. But only mental health domain showed mild improvement until 1 year. Moreover, BMI showed a negative correlation with improvements in the mental health domain post-operatively. As patients may be mentally exhausted from lumbar disc herniation, pre-operative mental health may be improved by surgical treatment. Reducing muscle damage is important, particularly for the multifidus muscle, which helps maintain partial stability . MinimalRetrospective analysis of the surgical and clinical outcomes with regard to reducing pain and improving the functional status (QOL) for patients who underwent MED for lumbar disc hernia, performed by a single experienced spine surgeon at a single centre was conducted. Forty-one patients with lumbar herniated nucleus pulposus were treated with MED from June 2015 through May 2016, among whom, 31  with a minimum of 3-year follow-up were evaluated , and the JOABPEQ. QOL was evaluated using JOABPEQ of a lumbar disease-specific measure. The Brief Scale for Psychiatric problems in Orthopaedic Patients (BS-POP) was also used. Higher scores of BS-POP are thought to indicate a higher probability of associated lower quality of life (QOL) of the psychiatric factors. These items were evaluated pre-operatively, at 3 months, 1 year, and 3 years post-operatively. The VAS scores ranged from 0 to 10, with 0 = no pain or numbness and 10 = the worst pain imaginable or numbness, for assessing current low back pain, buttock–leg pain, and leg numbness. JOA scores were used to evaluate neurological status and clinical results. All patients were examined before and after surgery to assess the neurological findings and examination results. The JOABPEQ is a patient-oriented instrument that measures HRQOL in patients with lumbar disorders. Several studies used the JOABPEQ evaluated in several lumbar diseases , 6, 7. TP < 0.05 were considered statistically significant.Data were presented as the mean and standard deviation (SD). We assumed that three outcomes  were essential measures for lumbar disc hernia, so we compared the pre-operative scores with those at follow-up. Statistical analysis was performed using the Mann–Whitney U test and a stepwise multiple regression analysis. Values of The 3-year follow-up functional outcome analysis was completed for all 31 patients   from 3 months post-operatively, and significant differences were observed from 1 to 3 years post-operatively compared with the pre-operative baseline. Buttock–leg pain and numbness were significantly improved from 3 months post-operatively (P < 0.001) . The mean recovery rates were 92.6% at 3 months post-operatively and 96.8% at 1-year follow-up, and 97.9% at 3 years final follow-up  , BMI , pre-operative BS-POP  and BS-POP scores at 12 months post-operatively  , smoking, prevalence periods, hernia level, operation time, bleeding volume, and VAS, and BS-POP. The analysis showed that the low rate of improvement in mental health was independently correlated with age that scores HRQOL for patients during the early post-operative stage is thought to be important. Moreover, this study was a limited number of the cases, but we had considered to have eliminated bias for clinical outcomes as much as possible by a single experienced spine surgeon technique at a single spine medical center.All categories of VAS and JOA scores over 3 year of follow-up were significantly higher than those obtained pre-operatively, and improvements were significantly seen in the JOABPEQ scores for low back pain, lumbar function, walking ability, social life function, and mental health. However, only mental health had showed mild improvement until 1 year. In such cases, more specialized psychiatric examinations should be considered. Management of these issues is needed to obtain better surgical results in the domain of mental health. These results suggest that confirming patient backgrounds before surgery leads to more accurate assessments of low back pain, neurological condition, and QOL and better outcomes after minimally invasive decompressive surgery using MED.


Intradermal therapy, known as mesotherapy, is a technique used to inject a drug into the surface layer of the skin. In particular, it involves the use of a short needle to deposit the drug in the dermis. The intradermal microdeposit modulates the drug's kinetics, slowing absorption and prolonging the local mechanism of action. It is successfully applied in the treatment of some forms of localized pain syndromes and other local clinical conditions. It could be suggested when a systemic drug-sparing effect is useful, when other therapies have failed (or cannot be used), and when it can synergize with other pharmacological or nonpharmacological therapies. Despite the lack of randomized clinical trials in some fields of application, a general consensus is also reached in nonpharmacological mechanism of action, the technique execution modalities, the scientific rationale to apply it in some indications, and the usefulness of the informed consent. The Italian Mesotherapy Society proposes this position paper to apply intradermal therapy based on scientific evidence and no longer on personal bias. The injections into the skin for therapeutic purposes date back to ancient Chinese and Indian medicine. More recently , Karl BaTo date, LIT is one of the best known and most widely applied microinvasive techniques in many parts of the world for the treatment of various local clinical conditions. Over the past few years, we have noticed that very often patients ask a question: how does mesotherapy work? In order to answer this question, we propose a position paper by the Italian Society of Mesotherapy.Currently, local intradermal therapy  is based on the hypothesis that the drug administered in the superficial layer of the skin allows a longer pharmacological action in the inoculation area and beyond. Preclinical studies have shown that the intradermal inoculation of anti-inflammatory , anestheThe mesotherapeutic technique (LIT) involves the inoculation of a drug with a 4 mm 27 Gouce) or 13 mm (30–32 Gouce) needle appropriately inclined to perform a microdermal deposit. According to some studies, the depth of intradermal injection could be 1 to 1.5 mm , 9 with 7 Gouce oIntradermal therapy has been administered to many patients with different types of localized pain . Nevertheless, the available studies do not allow a standardization of this technique due to the different research methods. Significant clinical benefits such as pain control, improvement of quality of life, systemic dose reduction, and patient satisfaction were reported , 12, 13.Costantino et al. in a randomized study evaluated the effects of LIT compared to a systemic treatment  in patients with acute low back pain . This stHowever, a different efficacy has been reported in response to different analgesic drugs , 20 probWe also underline that the local analgesia is partly due to the effect of the inoculated liquid that causes distension of the dermis and local chemical variations. Three studies have reported that saline-based mesotherapy can reduce pain, although to a lesser extent and for less time, than drug-based mesotherapy –25. It sGenerally, the drugs most commonly used to reduce localized pain in published studies are anesthetics, muscle relaxants, analgesics, and anti-inflammatory, alone or in combination –7, but tMore studies are needed to investigate the role of this technique in various forms of localized pain: acute or chronic, inflammatory or mechanical, nociceptive or neuropathic, and with or without degenerative genesis. Given the complexity of the mechanisms that regulate pain and the individual variability of the response to analgesic therapies, we strongly recommend that LIT must be applied based on the individual patient's condition. Applied for analgesic purposes, it allows three potential advantages: it induces a useful drug-sparing effect specially when a lower possible dose of medication is indicated for the patient ; it is useful when other therapies have failed or cannot be used; it synergize with other pharmacological or nonpharmacological therapies.It is known that the intensity of needle-induced pain and the precision with which the needle is injected into the trigger point are related to the analgesic effect , but we ad hoc clinical studies in order to confirm the clinical rationale and identify tolerability and the best path of care for patients.Intradermal therapy can also synergize with other therapeutic strategies, for example, to reduce dose of systemic opioid  or to imThe slow diffusion, tissue pharmacological action, and interactions between needle-induced microtrauma and tissues may also be useful in other clinical forms. For example, in chronic venous disease, the functional morphological alterations induced by the microcirculatory alteration, chronic edema, and fibrosclerosis could benefit from local treatment. Indeed, improvement of edema, pain control, ultrasound appearance, and satisfaction of patients have been reported in patients with chronic venous disease of the lower limbs treated with LIT , 42. TheMicroinjections induced by mesotherapy cause the formation of a microdrug deposit that disappears within a few minutes. Local reactions of mild and short duration may occur, linked in part to the microtrauma produced by the needle and in part to the chemicophysical and biochemical activity of the drug which may generate transient erythema. Usually, the patient complains of a slight pain following the needle puncture, and even if they disappear within a few moments, the patient should be alerted and prepared for this reaction.In the literature, cutaneous infections are reported mainly after treatments for aesthetic purposes . HoweverSome questions remain open and will guide future clinical research. Many drugs with potential useful mechanism of action have been used, but no comparative studies exist to understand which of them is most effective. The choice of the principles to be injected depends on the clinical-instrumental diagnosis, as well as the modality of application of the technique, and doctors must manage the evaluation of the effects over time. Inoculations of herbs and mixtures of substances are known, sometimes based on the personal conviction of efficacy and sometimes suggested by pharma companies. Taking into account that even with the physiological solution or SWI have obtained therapeutic results, the scientific and ethical problem in the use of substances arises which have not demonstrated their effectiveness in a comparison study. For this reason, we strongly suggest to explain the patient the rationale of the use of each inoculated compound. The treatment of many diseases, including localized pain, involves multimodal treatment. Therefore, intradermal therapy should be considered only one of the pharmacological weapons available and it should be applied when a potential benefit is expected in the individual patient's pathway of care. Since the intradermal route is not without risk, we do not recommend drug mixtures in the same syringe, in particular, when there is not in vitro/in vivo evidence of stability and tolerability of mixtures. There is no evidence that any mixture retains the stability and effectiveness of the individual components, especially when more off-label drugs are mixed , 48. FurMesotherapy is a medical act that can only be practiced by medical personnel; otherwise, it must be assumed  the crime of abusive exercise of the medical profession, provided for and punished by the Penal Code. One of the main responsibilities of the doctor is the informed consent. Informed consent is crucial to establish a proper patient medical partnership, and it must not be interpreted as a bureaucratic act, but an integral part of the care path focused to respect the patient . Some baGiven the complex structure of the LIT, where the doctor is also involved in delicate choices of environment of suitable drugs to be inoculated appropriately, it seems very important that the guidelines are issued as soon as possible, or that, in any case, the good clinical and welfare practices should be proposed by the scientific societies. We also highlight the economic sustainability of the mesotherapy technique in pain therapy. Obtaining the same results on pain using lower doses of drug results in a lower cost for the health system. Therefore, the use of the mesotherapy technique in pain therapy allows increasing the number of patients with the right of pain relief. Health Authorities should consider this ethical aspect.Some authors have recently suggested that routine use of mesotherapy in the emergency department be conducted . It mighFor many years, we have believed that the therapeutic effect obtained depends particularly on the action of the injected drug and that more combined drugs can achieve greater efficacy. However, the data available today suggest that various mechanisms, besides the local pharmacological one, participate in the effect of this technique. So even apparently inert substances can induce short-term and medium-term responses. We suggest that the local spread of the drug and its biological effect, the chemicophysical properties of the inoculated liquids , the needle-induced stimulus, the injection points, and the superficiality of insertion could interact with dermal mechanisms and induce the effects observed in clinical studies.Probably, the intradermal therapy could also become a new experimental method to study interactions between drugs and skin-based mechanisms. Those who practice this technique, by correctly selecting the patients to be treated, with the aim of reducing localized pain and reducing the doses of systemic drugs, discover its therapeutic value. Both the GPs and the specialists could take advantage of this technique to facilitate the treatment path of many patients. The scientific questions still open must represent the goal of the research, not the excuse to discard the hypothesis: if a medicine works, but we do not know why, we should not refuse it.


BackgroundPain is a common complaint among hemodialysis (HD) patients; however, most patients are not assessed for this aspect and are not sufficiently treated. In these patients, pain is reported to be associated with a range of parameters like increased depression and disrupted quality of life (QOL). Previously residual renal function (RRF) was not assessed for associations with pain. The primary aim of the study is to evaluate the pain frequency in the Turkish HD patient population. In addition, the type, origin, and severity of chronic pain, the pain treatment ratio, and the relationship between pain, QOL, and RRF were investigated during the study.MethodsThis study included 328 HD patients. Pain assessment used the McGill Pain Questionnaire and neuropathic pain assessment used the Leeds Assessment of Neuropathic Symptoms and Signs (LANSS) scale. The correlation of pain and quality of life was evaluated with the Short Form 36 (SF-36) quality of life scale.ResultsOf patients, 244 experienced pain (74.4%), and this pain had a neuropathic character in 61.8% of these patients. Patients with pain had a longer dialysis duration than those without pain (4.00 (2.00-8.00), 3.00 (2.00-4.75), p=0.01). The most common site of pain was the lower extremities. Pain was observed more often among females and with increasing age. Only 36.4% of patients used analgesics. The quality of life of patients with pain was found to be lower. The incidence of pain was higher among patients without RRF and had more neuropathic character.ConclusionsPain is a significant problem for the majority of HD patients and is not effectively managed. To increase the quality of life of patients, the care team should regularly question pain symptoms, and it should be treated effectively. In this context, RRF should be regularly monitored and efforts should be made to preserve it. Pain is a commonly observed complaint among hemodialysis (HD) patients -2. ThereResidual renal function (RRF) plays an important role in clearing uremic toxins, prevents excessive volume load and the related complications of left ventricle hypertrophy (LVH) and congestive heart failure (CHF), and is associated with improved metabolic parameters -10. RRF Patient population and demographicsThis prospective cross-sectional study was completed from October 2017-May 2018 and the study included 328 patients with routine hemodialysis treatment for at least three months in three different outpatient hemodialysis units. Patients were dialyzed three times a week with a synthetic membrane, each session lasting four hours with bicarbonate dialysate. Questionnaires were applied only to patients with high cognition. Patients with a cognitive disorder, under the age of 18 years, and who did not volunteer to complete the surveys were excluded from the study. The study was conducted during a four-hour HD session and at one time by a well-trained research assistant who initially explained the study to each patient and invited patients to complete a series of questionnaires about pain and QOL. Three questionnaires were used to evaluate the frequency, origin, severity, neuropathic pain, and the relationship between pain and QOL. To retain the calcium-phosphate metabolism and maintain hemoglobin levels within the target range, patients were using phosphate-binding medications, calcitriol, paricalcitol, cinacalcet, intravenous iron therapy, and an erythropoiesis-stimulating agent. Hypertensive patients were receiving angiotensin-converting enzyme inhibitor, angiotensin receptor blocker, calcium channel blocker, beta-blocker, or combined therapy.Data collectionDemographic data for patients in the study were obtained through patient interviews at the dialysis centers and from laboratory tests within the last three months in the database.Demographic data included history, age, sex, renal disease etiology, dialysis duration, use of analgesics, and vascular access type. Laboratory data included complete blood count (CBC), serum calcium, phosphorus, uric acid, intact parathyroid hormone (iPTH), ferritin, serum albumin, C-reactive protein (CRP), and single pool Kt/V using the Daugirdas formula . RRF wasMeasuresFor an assessment of the patient’s pain, the McGill-Melzack Pain Questionnaire (MPQ) was used and the Leeds Assessment of Neuropathic Symptoms and Signs (LANSS) scale was used for the assessment of neuropathic pain. The correlation of pain with quality of life used the Short Form 36 (SF-36) Quality of Life Scale.The McGill Pain QuestionnaireThe MPQ is the most commonly used survey for the multidimensional assessment of pain . It consLeeds Assessment of Neuropathic Symptoms and Signs (LANSS) ScaleLANSS is the first neuropathic pain assessment scale in the literature. Application of the assessment is easy: there are five items questioning symptoms and two clinical examinations. According to the scoring: >12 points indicates the presence of neuropathic pain, while <12 points indicates no neuropathic pain .Short Form 36 (SF-36) Quality of Life ScaleSF-36 is a self-report scale investigating the eight dimensions of physical function, social function, role limitations due to physical reasons, role limitations due to emotional reasons, mental health, vitality (energy), bodily pain, and general perception of health, with 36 items. Each subdimension has points varying from 0-100, with points directly proportional to quality of life .Statistical analysisData for continuous variables are given as mean ± standard deviation or median (Q1-Q3) and categorical variables are given as frequency and percentage. The compatibility of continuous data with normal distribution was investigated using the Shapiro-Wilk test. Independent samples were compared with the Mann-Whitney test (for two groups) for variables without normal distribution. The relationship between categorical variables was examined using the chi-square test. Data were evaluated using the SPSS version 21 statistical program . P<0.05 was considered significant.The mean age of 328 patients participating in the study was 64±11 years, with 179 males (54.6%) and 149 females (45.4%). The mean HD duration of patients was 7±6 years and the mean K/tV value was 1.52±0.15. Vascular access was an arteriovenous fistula for 216 patients (66%) and a permanent tunnel catheter for 112 patients (34%). While residual urine was present in 91 patients (27.7%), 237 patients (72.3%) had no residual urine. The demographic features of patients can be seen in Tables Of the 328 patients, 244 had pain (74.4%). Of the 244 patients with pain complaints, 181 (74.2%) stated that the pain began to develop after routine HD treatment. Of the 244 patients with pain, 151 (61.8%) had neuropathic character pain while 93 (38.1%) had nociceptive character pain (p<0.001). The mean pain severity score for patients with pain was 67.74±19.8, indicating moderate severity. Pain was present in 81.2% of female patients and 68.7% of male patients, with statistically significantly higher rates of pain among females (p=0.01).When patients with and without pain were compared in terms of age, the mean age of patients with pain was statistically significantly higher . The serum albumin values of patients with pain were significantly lower  and serum calcium values were higher  as compared to pain-free patients. However, serum albumin and calcium values were within normal reference intervals for patients. CRP, ferritin, parathormone, hemoglobin, phosphorus, and k/tV values were similar in both groups (p>0.05). Patients with pain had a longer duration of dialysis as compared to those without pain (4.00 (2.00-8.00), 3.00(2.00-4.75), p=0.01)  had no RRF while 51 (20.9%) were identified to have RRF, and this difference was statistically significant ). Patients with RRF were identified to have less incidence of neuropathic  and non-neuropathic pain  as compared to those without RRF ). The incidence of pain was higher in patients without RRF and more neuropathic character pain was present . Neuropathic pain was present in 87% of patients with diabetes mellitus while 13% had nociceptive pain (p<0.001). Among nondiabetic patients, 47.4% had neuropathic pain and 52.5% had nociceptive pain (p<0.001). The presence of DM was found to significantly affect whether the pain had neuropathic characteristics (p<0.001). The prevalence of neuropathic pain in patients with DM was 6.62 times higher than the prevalence of non-neuropathic pain . Additionally, the HD duration of those with neuropathic pain was found to be longer than those with non-neuropathic pain (5(2-10) and 3(2-5), p<0.001).When the 151 patients who have neuropathic pain were analyzed per their chronic kidney disease (CKD) etiology, 67 had diabetes mellitus (44.4%), 54 had hypertension (35.8%), nine had AA amyloidosis (6%), five had polycystic kidney disease (3.3%), four had urinary tract malignancy (2.6%), three had glomerulonephritis (2%), and one had vesicoureteral reflux (0.7%). The etiology of eight patients (5.3%) out of 151 was unknown.When the 93 patients who had nonneuropathic pain were analyzed per their CKD etiology, 60 had hypertension (64.5%), 10 had diabetes mellitus (10.8%), seven had urinary tract malignancy (7.5%), five had glomerulonephritis (5.4%), two had AA amyloidosis (2.2%), and one had polycystic kidney disease (1.1%). The etiology of eight patients (8.6%) out of 93 was unknown.When patients are assessed in terms of pain localization, 180 patients (69.7%) had pain in the lower extremities, 47 patients (19.3%) had pain in the upper extremities, 15 patients (6.1%) had back pain, and 12 patients (4.9%) had a headache. Vascular access among patients with pain was an arteriovenous fistula (AVF) for 154 patients (63.1%) and tunneled cuffed catheter (TCC) for 90 patients (36.9%). When the correlation between vascular access type and pain localization is assessed, among 47 patients with upper extremity pain, 42 (89.4%) had AVF vascular access (p<0.001). Of the 224 patients with pain, 89 (36.4%) were using analgesics while 155 (63.6%) were not. Of 89 patients using analgesics, 15 (16.84%) were using opioid analgesics , 24 (26.96%) were using tricyclic antidepressants, 35 (39.32%) were using gabapentinoid antiepileptic drugs , and 15 were using paracetamol. All parameters for quality of life of patients with pain were found to be statistically significantly low as compared to those without pain  values were similar in the pain and pain-free groups ,23. We tIn addition to the positive effects of RRF on metabolic parameters and survival in both HD and peritoneal dialysis (PD) patients, it was shown to have a positive effect on the quality of life. The presence of RRF was found to be associated with better physical function, improved vitality, kidney disease symptoms, and fewer sleep disorders -11,13,27In PD patients, the contribution of RRF to total clearance of moderate molecular weight (B-2 microglobulin) and protein-linked materials , was shown to be larger than small solute clearance. Though there is not much definite evidence related to the hypothesis of uremic neuropathy development, it is proposed that it may be related to the retention of neurotoxic moderate molecular weight molecules . The posStrong aspects of our study include the relatively high patient numbers and being the first study to assess the correlation of RRF with pain. The study also has some limitations. The first is that patients were from a single geographic region, the second is that there was no healthy control group, and the third is that there is no information about the use of some medications, which may affect bone mineral metabolism parameters such as the use of phosphate binders , active D3 vitamins , and calcimimetics . Finally, it would be better to use logistic regression analysis to determine factors related to chronic pain among long-term HD patients.In conclusion, pain is a significant problem for the majority of HD patients and is not effectively managed. To increase the quality of life of dialysis patients, it is necessary that the care team, including nephrologists, regularly inquire about pain symptoms and treat them effectively. In this context, RRF should be regularly monitored and efforts should be made to preserve it. The correlation of RRF with pain should be investigated in more studies.Pain is a significant problem for the majority of HD patients and is not effectively managed. To increase the quality of life of patients, the care team should regularly question pain symptoms and the pain should be treated effectively. In this context, RRF should be regularly monitored and efforts should be made to preserve it.


The ways in which locations of ischemia and ischemic pain affect spatiotemporal gait parameters and leg electromyographic activity during walking have never been investigated in patients with peripheral arterial disease presenting intermittent claudication. Two groups were classified according to unilateral location of ischemia . Patients described pain and three gait phases—initial pain-free, onset of pain and maximum pain—were analyzed. Patients with proximo-distal ischemia walked less (230 ± 111 m vs 384 ± 220 m), with increased step length, step time (+ 5.4% and + 5.8%) and reduced cadence (− 8.2%), than patients with distal ischemia. In both, the peaks of vertical ground reaction force were reduced in maximum pain . In the proximo-distal group, tibialis anterior activation peak and time were lower than in the distal group (− 4.5% and − 19.7%). During the maximum pain phase, this peak decreased only in the proximo-distal group (− 13.0%), and gastrocnemius medialis activation peak and time decreased in both groups . Thus, proximo-distal ischemia leads to more adverse consequences in gait than distal ischemia only. Increasing ischemic pain until maximum, but not onset of pain, induced gait adaptations. The most common symptom of lower-limb PAD is intermittent claudication (IC) which manifests as leg muscle ischemic pain progressively occurring during walking. It can cause the patient to stop activity, until pain relief. Pain in IC is based on temporary ischemia due to arterial stenosis or thrombosis, limiting local blood flow2. Ischemia can appear in different locations. Ischemia is classified as “distal” when localized in the calf or “proximo-distal” when localized both in the calf and the thigh and/or buttock. Consequently, depending on the symptom intensity, patients suffering from IC have reduced lower limb mobility, maximum walking distance (distance patients can travel until they have to stop due to ischemic pain) and altered spatiotemporal gait parameters5. Previous studies showed that IC patients have a diminished plantar propulsion force during walking with the prolongation of claudication pain7, compared to a control group. Conversely, one study found no difference between pain-free and painful phases8. Therefore, the relationships between ischemia, claudication and pain development are not fully understood.Peripheral arterial disease (PAD) is a cardiovascular condition caused by atherosclerosis. It affected more than 202 million people in the world in 2010 with an 8 to 12% prevalence after 60 years of age9. Decreased muscle strength, partial denervation of legs muscles and loss in nerve conduction velocity have been described9. Despite this, contradictory results exist concerning the impact of IC on gastrocnemius medialis (GM) activation. One study reported no change in the activation capacity during maximum voluntary contractions10 and one study reported an increase in electromyography amplitudes during walking11. To our knowledge, only one study has described muscle activation modalities in IC patients during walking by using surface electromyography (sEMG)11. These authors showed that tibialis anterior (TA) muscle activity duration decreased during IC, and sEMG amplitudes increased for TA and GM muscles.PAD causes not only muscular but also neuromuscular damageTherefore, the aim of this study was to characterize gait pattern and muscle activation modalities in the ischemic leg of IC patients presenting unilateral lower limb distal (DIS) or proximo-distal (PROXDIS) ischemia during the pain-free, onset of pain and maximum pain periods of a walking-treadmill test. This characterization will help to adapt and optimize rehabilitative care according to ischemia location.Our main hypothesis is that the location of ischemia affects leg muscles and influences the aforementioned parameters differently. Specifically, PROXDIS ischemia is more susceptible to affect the gait pattern than DIS ischemia. Furthermore, despite previous investigations describing the impact of ischemic pain on spatiotemporal gait parameters or neuromuscular activation in IC patients, little is known about the effect of ischemic pain intensity on these parameters. We believe that these alterations appear immediately at the onset of pain and increase with ischemic pain intensity until its maximum.2), ABI of the ischemic leg, smoking status, presence of treated hypertension (number (n)), diabetes (n), hypercholesterolemia (n), distance to onset of pain (m) and maximum walking distance (m). The functional investigation included a treadmill-walking test to confirm the presence and location of ischemia using a transcutaneous oxygen pressure recording with an index indicating ischemia (delta from rest oxygen pressure (DROP) < − 15 mmHg) as previously described32. Patients were included if the test confirmed that they suffered unilateral (one leg) distal or proximo-distal ischemia (DIS and PROXDIS patients), and 22 male patients were finally included .Symptomatic IC patients diagnosed with PAD , and exhibiting claudication, were recruited during an examination from the functional vascular investigations service in Angers university hospital (France). All 59 patients underwent Doppler and/or angiography and/or computed tomography examination Fig. . We reco39. The speed reached 3.2 km/h  in one minute, with a 10% slope. Speed was then stabilized at 3.2 km/h. Patients were instructed to describe pain development in lower limbs (location and intensity) during walking. They were encouraged to perform as long as possible to reproduce claudication symptoms. Exercise was stopped at the patient’s request (pain or other difficulties to maintain the effort) or after 15 min. During this test, we checked the concordance between the description of the pain and DROP values .The treadmill-walking test was a constant load procedure2. We recorded the following parameters:Temporal parameters: step time (s), cadence (step/min), single leg stance and total stance phase in % of the gait cycle,Spatial parameters: step length (m), step width (m), foot progression angle (FPA), defined as the angle (degree) between the longitudinal axis of the foot and the line of progression during walking,Dynamometric parameters: peaks of vertical ground reaction forces (N): first peak corresponding to heel contact and second peak corresponding to toe-off during a gait cycle .Gait parameters in the ischemic leg were recorded at 200 Hz with an instrumented treadmill . This gait analysis system has a recording surface of 108 × 47 cm with 7168 barometric sensors each approximately 0.85 cmThe pain-free phase was the first ten gait cycles at the beginning of the walking test, before the onset of pain.The onset of pain was the first ten gait cycles after the patient reported pain arising during the walking testThe maximum pain was the last ten gait cycles before the patient had to stop the walking test because of the pain.Gait parameters were analyzed on ten successive gait cycles at three different phases in function of pain intensity:To limit anthropometry-based differences, we normalized step length by the height (m) of the patients and peak forces by body weight (N).40. sEMG signals were recorded at 1000 Hz and stored by the Zebris software .sEMG is a non-invasive technique to assess muscle activity during walking. TA and GM muscle activity were investigated in the ischemic leg . These muscles were selected because: (1) they are highly involved in ankle movement during walking, (2) calf (and consequently GM) is the site most often reported by patients when describing pain location during claudication and (3) TA is the GM antagonist muscle. Before placement of the sEMG probes, skin was shaved and cleaned with alcohol. The probes were placed according to “Surface EMG for Non-Invasive Assessment of Muscles” recommendations“peak dynamic method”41. The sEMG process was made with a custom script in Matlab 2016a . An average sEMG profile was obtained from 10 gait cycles for each patient at the phases of the gait studied . A threshold for muscle onset, fixed as recommended at 20% of the peak, was used to detect the time of activation of each muscle (% of gait cycle)41.sEMG signals were band-pass filtered between 15 and 499 Hz with a second-order Butterworth filter and full wave, rectified to create linear sEMG envelopes. sEMG data were normalized to a 100% gait cycle using gait parameters synchronized with sEMG signals. To determine muscle activation level, the Root Mean Square (RMS) was calculated and normalized with respect to the RMS peak values of 10 gait cycles during the pain-free phase, according to the 10.0 . Levene’s test and Fisher’s post-hoc least significant difference (PLSD) analysis were performed to assess variance homogeneity of the series. Prevalence between groups was compared with a Chi-squared test.Data are expressed as mean(SD (standard deviation)). All the statistical procedures were performed using Statistica software VDifferences in anthropometric measurements , gait parameters and EMG signals were studied according to the locations of ischemia (PROXDIS vs DIS), the intensity of pain  and between legs, using a three-way ANOVA procedure; α power was indicated for each test. When normality of the distribution was not assessed, a Kruskal–Wallis test was done. For all tests a significant difference was fixed at P < 0.05.All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee (CPP Ouest II) and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.The procedure, purpose, and risks associated with this study were explained to the subjects, and written informed consent was obtained.A total of 59 PAD patients with IC were recruited. After the treadmill-walking test, 37 were excluded because of inconsistency with our selection criteria Fig. . FinallyThe average distance from which all patients experienced ischemic pain in the lower limbs was 109 ± 75 m. The average maximum claudication distance forcing the patients to stop walking was 306 ± 185 m and the patients with DIS ischemia walked significantly longer than those with PROXDIS ischemia .There was no interaction effect in spatiotemporal gait parameters between location of ischemia and pain effects Table .Table 2GStep length and step time were significantly higher  in the PROXDIS group than in the DIS group, coinciding with a − 8.2% lower cadence at the fixed speed (Table The onset of pain had no impact on gait parameters. Significant differences were found only between the pain-free and maximum pain phases for peak force 1 and 2 in both groups (lower braking and propulsive forces)  and the activation time (DIS activation time was 19.7% higher than PROXDIS) Table .Onset of pain did not induce any change in sEMG parameters compared to the pain-free phase. Between the pain-free and the maximum pain phases, three sEMG parameters were affected Table : the TA To our knowledge, this study is the first to have characterized the influence of ischemia location and ischemic pain intensity on gait parameters and neuromuscular activation in patients presenting IC during walking.Our main finding is that a PROXDIS ischemia location in the lower limbs induces greater gait alterations than DIS ischemia. In addition, ischemic pain affects gait parameters and neuromuscular activation with pain prolongation (and thus increased pain intensity) until maximum pain but not at the onset of pain.13, but none have differentiated between patients suffering from PROXDIS and DIS ischemia. We show that when patients have PROXDIS ischemia, they reduce their walking cadence (− 8.2%) and exhibit longer step length and longer step time than those with DIS ischemia (+ 5.4% and + 5.8% respectively). These latter patients were walking at the classical cadence of healthy old people14. Changes in walking cadence affect the frequency of limb progression and ground contacts leading to a reduction in muscular solicitation. A previous study showed that PAD patients present a more prevalent unsteadiness and history of fallings15. As such, we can assume that a reduced gait cadence in patients with PROXDIS ischemia results from a behavioral adaptation to produce a more stabilizing gait pattern in order to reduce ischemic pain sensation and its development. Such a compensatory phenomenon is observed in other parameters. When studying diabetic patients with peripheral neuropathy and a forefoot ulcer, Hastings et al. showed significantly increased FPA compared to controls (15(9)° vs 9(4)°)16. They hypothesized that this increase in FPA results from a diminished plantar flexion motion to preserve gait stability. We observed FPA in patients with PROXDIS ischemia in the same range as in the aforementioned control population. Many factors could impact FPA values . Nevertheless, the fact that FPA was significantly higher in cases of DIS ischemia (11.8(6.8)° in DIS vs 8.8(4.4)° in PROXDIS) suggests that buttocks-located ischemia affects this compensatory mechanism.Previous studies have investigated the impact of IC on gait parametersThe location of ischemia also impacts sEMG parameters. IC patients with PROXDIS ischemia present a decreased TA activation peak and time (− 4.5% and − 19.7%) compared to DIS ischemia. Indeed, as we previously discussed, these patients adopt a specific gait pattern to reduce muscular solicitation. In the PROXDIS group, ischemia and pain are distributed in two sites in the leg, leading to more extended and global muscular weakness than in the DIS group. This likely explains the lower and shorter neuromuscular activation observed at the TA level and the greater gait alterations in the PROXDIS group.17. When focusing on the influence of pain on neuromuscular activity, previous studies have indicated that muscle activity is not reorganized in a simple systematic redistribution from painful to non-painful muscles and that differences between muscle adaptations to pain might depend on neurophysiological constraints19. It appears that ischemia can be considered as such a neurophysiological constraint and different ischemia locations might explain the different neuromuscular adaptation pattern between groups in our study.The location of ischemia corresponds strongly to the location of pain described by patients. To our knowledge, no study has investigated the relationship between changes in neuromuscular activation in ischemic lower limbs and the location of ischemia when pain occurred during walking. Our results suggest that PROXDIS ischemia induces more noxious alterations in neuromuscular performance during walking than DIS ischemia, as confirmed by a shorter maximum walking distance (-40.1%), which is an indicator of disease progression and of exercise capacity13, while others20 found no difference between the pain-free phase and the pain phase. In our study, when analyzing ground reaction forces, a decrease occurred for the two peak forces (corresponding to braking and propulsive forces) with the increase in ischemic pain intensity until maximum pain. These results corroborate the decrease in the second peak force during the pain phase compared to the pain-free phase in IC patients7. Similarly, it has been demonstrated that the ischemic limb exhibited a decrease in propulsive forces in the forefoot during gait, but without any correlation with the onset of claudication pain6.During the treadmill-walking test, patients suffer ischemia-induced pain and this pain will increase with exercise prolongation (and thus muscular solicitation) until a threshold leading the patients to stop the test. Such a time-effect related to ischemic pain development is likely to affect gait parameters but it has never been investigated before. We observed that the onset of pain did not impact gait parameters directly. Some authors have previously shown that pain during walking affects gait parameters such as step length and cadence22. Between the pain-free and maximum pain phases, sEMG activation amplitude was reduced in TA in patients with PROXDIS ischemia only (− 13.0%) as well as sEMG activation peak and time in GM in both groups (− 3.5% and − 12.3% respectively). Despite the fact that these results fit well with the reduction of plantar peak forces reported, and with lower activation capacity in IC patients10, this will warrant further investigations since on the opposite it has been shown that TA activity duration decreased with IC, and sEMG amplitudes increased for TA and GM muscles11.As revealed by sEMG activity, onset of pain did not affect neuromuscular activation; however, the increasing ischemic pain, with prolongation of exercise, induced modifications in TA and GM activation. When walking, TA ensures support during the early stance (corresponding to the first peak force) and GM plays an important role in propulsion (second peak force)23. Knowing this, defining and characterizing neuromuscular adaptations to ischemic pain in IC patients may allow a better understanding of the motor strategies used to compensate and reduce pain feel in the lower limbs.Many theories about motor adaptations to pain suggest that these adaptations present short-term benefits (reduction of pain and load on painful muscles). However, they can also induce negative long-term consequences such as an increase in the biomechanical constraint at tendon and muscle levels in non-painful areas and then a higher risk of injuries25. Indeed, it has been shown that IC patients can benefit from physical activity programs at various levels: it increased maximum calf muscle blood flow, oxygen extraction levels26, claudication onset distance and total walking distance27, strength, endurance, and coordination of lower-limb muscles28. The results of our study indicate that DIS and PROXDIS ischemia affects walking differently in patients with IC. However, these programs never take into account the location of ischemia and the intensity of ischemic pain as adaptation parameters. Setting up a physical rehabilitation program in patients with IC on the basis of these parameters would therefore be interesting in order to test its effectiveness compared to current protocols and to improve care.Finally, rehabilitation through exercise therapy is well recognized as an effective method to improve gait in IC29. However, we know that:30 and then ischemia that is clinically considered unilateral could be bilateral.Exercise ischemia can occur even in absence of pathological ABI in the asymptomatic leg (non-painful) in a significant proportion (46.7%)32.In proximal ischemia, ABI is frequently non-pathological and iliac arteries could be difficult to visualize, therefore, a great deal of proximal ischemia is not detectedSome studies referred to symptomatic and asymptomatic legs, which is different from ischemic or non-ischemic legs AND we believe that the proof of underlying ischemia as the cause of pain (as reported here) is of major importance in elderly patients when so many co-morbid (mostly osteoarticular) conditions may be painful with exercise.33 were affected differently by claudication pain between symptomatic and asymptomatic legs while others were not34, probably simply because the presence and location of exercise ischemia could not be determined.Some studies find that gait parametersIn our study, we include ten patients with DIS ischemia and 12 with PROXDIS ischemia. This rather small number of patients in our analysis could be perceived as a limitation. On the contrary, we assume that this reveals the quality of our patient’s selection and this is an asset of major importance. Indeed, in most of the studies analyzing gait parameters in PAD-IC, patients were often recruited only on their ABI value and associated symptomsTo avoid any risk of false ischemia classification, we recorded transcutaneous pressure in dioxygen in both limbs all along the procedure to assess the occurrence of ischemia and we studied gait alterations based on this. In addition, concordance between patients’ description of pain (due to ischemia) during walking and the location of ischemia was checked. Consequently, this high level of selectivity leads us to present relatively small populations but with the advantage of being highly specific.35. In addition, age-related changes in neuromuscular activation can also be present during walking35. However, a recent study found that PAD impacts gait parameters more than age36 and our results are consistent with the current literature on PAD. Consequently, we assume that our results stem mainly from PAD and not age.Patients with IC are frequently more than 55 years old ([52–80] years old in our study). Elderly people present gait alterations, similar to those of PAD patients37, there was no change in gait parameters in PAD patients when they were adjusted for diabetes38. Based upon these observations, we deliberately chose not to exclude patients with diabetes.Diabetes could also possibly affect our results. Because of similar risk factors , PAD patients are frequently affected by diabetes. Nevertheless, even if diabetes, with or without neuropathy, can induce gait alterationsPatients with IC present gait parameters and neuromuscular alterations in ischemic lower limbs during walking. Our main finding is that these alterations, leading to specific neuromuscular adaptations, are different according to the location of ischemia and ischemic pain intensity. PROXDIS ischemia leads to lower walking cadence, longer step length and step time, shorter maximum walking distance and decreased TA activation peak and time than DIS ischemia. In addition, the fact that FPA was significantly higher in cases of DIS ischemia suggests that buttocks-located ischemia affects this compensatory mechanism. Therefore, in patients with PROXDIS ischemia, gait parameters and muscular activation are more dramatically impacted than in patients with DIS ischemia. Additionally, while the onset of ischemic pain does not affect gait, its increase, with prolongation of exercise, leads to alterations .Finally, these findings could then be used to adapt rehabilitation programs and improve their specificity and efficiency.


Exoskeletons development arises with a leading role in neurorehabilitation technologies; however, very few prototypes for upper limbs have been tested, contrasted and duly certified in terms of their effectiveness in clinical environments in order to incorporate into the health system. The purpose of this pilot study was to determine if robotic therapy of Hemiplegic Shoulder Pain (HSP) could lead to functional improvement in terms of diminishing of pain, spasticity, subluxation, the increasing of tone and muscle strength, and the satisfaction degree.An experimental study was conducted in 16 patients with painful shoulder post- ischemic stroke in two experimental groups: conventional and robotic therapy. At different stages of its evolution, the robotic therapy effectiveness applied with anti-gravitational movements was evaluated. Clinical trial was developed at the Physical Medicine and Rehabilitation Department of the Surgical Clinical Hospital “Dr. Juan Bruno Zayas Alfonso” in Santiago de Cuba, from September 2016 - March 2018. Among other variables: the presence of humeral scapular subluxation (HSS), pain, spasticity, mobility, tone and muscle strength, and the satisfaction degree were recorded. Results with 95% reliability were compared between admission and third months of treatment. The Mann-Whitney U-Test, Chi-Square and Fisher’s Exact Tests were used as comparison criteria.Robotic therapy positively influenced in the decrease and annulment of pain and the spasticity degree, reaching a range increase of joint movement and the improvement of muscle tone. The World Health Organization (WHO) consider neurorehabilitation as an active process where some individuals, with some injury or neurological disease, could achieve the most optimal integral recovery in order to integrate their activities with the environment in the most appropriate approach. Neurorehabilitation technologies have undergone important changes in the last years due to an exponential increase  of cerebrovascular accidents (CVA) as the third leading cause of death in the world and high rate of disability.In Cuba, the disease incidence is estimated at 22,000 cases per year, where about 9725 patients die , 2. It iExoskeletons with rehabilitation purposes have reached a great media diffusion and their development occupies a significant number of research groups in the world. However, although more than 100 prototypes have been developed in recent years, only 10 have been clinically tested and they are commercial. In clinical rehabilitation tasks, only 2% are used –7. NowadIn the last two decades, some important meta-analyses, including a number of randomized controlled trials, have been performed to investigate the therapeutic effects of upper limb robotic rehabilitation –16. ThesThe main topics discussed in these investigations are linked to the following aspects: improving motor recovery in distal and proximal joints, the effect of robotic therapy in chronic patients and those design parameters such as power/weight ratio actuators, DOF, accurate, compactness, greater range of motion, safe operation, reliability in all operations, relatively low complexity and low engineering and construction cost, simple fitting and removal, comfort in wearing, and easy maintenance. Some research has deeply studied the combination with other neurorehabilitation technologies  in recent years.Although there are well-documented research on the use of exoskeletons in the rehabilitation of the upper limb post-stroke patients, only a few reports have been focused to the treatment of the painful shoulder of the hemiplegic patient using robotic therapy , 12, 13.Hemiplegic Shoulder Pain (HSP) after CVA is a common and debilitating complication. Its incidence varies between 16%, in patients with flaccid paresis and up to 84% in severe paralysis with significant development of spasticity. It may occur in the acute phase (in the first 2 weeks) but more often after two or 3 months, generating greater difficulty in mobilizing the limb, greater disability in transfers, trunk balance and carrying out daily living activities, hindering functional recovery of the upper extremity.Researchers at Robotics Research Laboratory from the Feinstein Institute for Medical Research  conducteIn a randomized controlled trial with 19 patients (eight who received robotic therapy), after 1÷8 weeks post-stroke, researchers from the University of Guelph  analyzedResearchers at Wonkwang University  have conAll these results show the inconsistencies of conventional therapies and the possibilities of using robotic exoskeletons. However, these studies have, as a limitation, not to consider the multifactorial genesis of the HSP syndrome. Therefore, the main purpose of our study is to analyze the influence of changes in abnormal muscle tone like flaccid limb, spasticity  on the evolution of pain as a result of three controlled therapeutic shoulder exercises performed with robotic therapy.An experimental study in patients who survived ischemic stroke with lesion corresponding to the territory irrigated by the middle cerebral artery, who presented HSP syndrome, in order to evaluate the effectiveness of robotic therapy with anti-gravitational movements was performed. The total number of patients with motor deficit who met the selection criteria was included. If the individuals met the inclusion criteria and gave informed consent, they were assessed, then, by an occupational therapist who was blinded to the study and not directly involved with patient care.Voluntariness, age over 40 years, flaccid and spastic stages  of the hemiplegic shoulder and first episode of cerebrovascular disease, body weight and height up to 100 kg and 175 cm respectively, were parameters considered for the inclusion. Some features were excluded: cognitive, sensory, sensitive and communication deficits that made it difficult to understand and follow instructions; pain, motor deficit and/or previous diagnosis of musculoskeletal shoulder disorder, as well as the clinical conditions that contraindicate the rehabilitation treatment. The following were considered as output criteria: voluntary abandonment, appearance of clinical complications that interfered with the study and/or rehabilitation treatment, recurrence of stroke, absence of 3 treatment sessions, and death.Two stages of evolution were observed in the affected upper extremity: flaccid  and spastic . This spastic phase can be complete, initiating a total synergy, or partial and incomplete. The variables related to the clinical-epidemiological characteristics collected were evolution time, affected hemibody and paralysis degree: hemiparesis/hemiplegia. According to the radiological criteria established by Prevost and Arsenault humeral scapular subluxation (HSS) was considered as Absent, Moderate (< 7 mm) or Severe (> 7 mm) .Patients with anthropometric characteristics 168 ± 12 cm of height, and 75.7 ± 15.4 kg of weight concluded 3 months of therapy in the grounded robotic platform of 4 freedom degrees developed by the Mechanical and Industrial Engineering Department , 18  allows aligning the rotational axis of the actuator that ensure the flexion/extension movements of the shoulder, with the anatomical axis of the patient for executing abduction/adduction movements. In this way the therapeutic movements of flexion/extension, internal/external rotation and abduction/adduction are performed during the shoulder rehabilitation.No other kinds of therapy  were programmed for the experimental group.Exoskeleton is able to permit a physiological range of mobility for selected movements, and the displacement angles were controlled by physiotherapist trough an interface designed for this purpose. Initial values for every patient in each session of the selected routines were fixed considering the maximum pain-tolerable range of motion of the shoulder joint.Patients of conventional therapy group  first received superficial thermotherapy –22. The Assisted Passives by the physiotherapist, for those patients unable to execute the indicated movement.Self-assisted passives by the patient himselfAssisted actives by the physiotherapist, for those patients with certain mobility but unable to complete the movement.Resisted (actives), for those patients capable of completing the movement, and who, as part of their muscular recovery during the performance of the movements receive a resistive force from the physiotherapist.These exercises incorporated the nature of the movements selected for the study  and were indicated in correspondence with muscle tone, assessed for all patients according to their classification in the MRC scale and their evolution.In both experimental and control group, each set of repetitive movement will be divided into 3 time sessions with 10 repetitions each.Omalgia assessment: instruments were applied, which allowed weighting the clinical variables indicating their evolution . All of them were recorded at the beginning, every 10 sessions of treatment, with a monthly summary and after 3 months of robotic therapy. Radiological and neurophysiological studies were also performed at the beginning and the end of the treatment.Pain assessment: The severity degree of the painful shoulder was defined . This result has a great importance in this study since the HSP reduces participation in functional activities and in the rehabilitation process. For conventional treatments, after hospital discharge it predicts a poor functional recovery of the arm, a longer duration of admission and the percentage of patients who are discharged to their home is lower [In all patients of robotic therapy group, the pain disappeared between 22.5 ± 4.5 treatment sessions, result that remained during the following evaluations, while for patients with conventional therapy the pain ceases after 63.7 ± 19.7 sessions. One patients of this last group remained at discharge with persisted pain [is lower , 30–32.Although there were few analyzed cases, another interesting result, was related to subluxation as one of the etiologies of the painful shoulder of the hemiplegic patient. Figure On the other hand, robotic therapy caused a decrease in the magnitude of subluxated shoulder of 10 mm after 3 months Fig. .Fig. 5HThis patient (S5), arrived to admission in a hemiparetic condition, with a time of evolution of 14 months after the stroke, spasticity degree MAS = 1and a large scapula-humeral subluxation. This is a clear example of how much the HSP delays the rehabilitation of the patient, given that 14 months before entering the study group she showed a very discreet rehabilitation degree. The results obtained in this chronic patient denoted the advantages of robotic rehabilitation even in these cases.p < 0.45).Regarding the treatment of spasticity, the results of the conventional treatment were discrete, which meant that there was an improvement in two of the patients, precisely these two patients, showing an enhancement in the treatment of their spasticity, (moderate to mild hypertonia), they presented successively a recovery of muscle tone and range of mobility. The rest kept their level of spasticity, and one of them worsened (p < 0.02). Between both groups MAS scores improved significantly (p < 0.003).The systematic anti-gravity training in the exoskeleton caused, however, a reduction and control of spasticity in all cases . This patient who experienced an important recovery did not develop spasticity. The same happened with those patients with normal muscle tone during admission.Other important results are related with the improvement of the range of articular movement (ROM) and muscular tone.Ranges of joint mobility below those functional, spasticity and absence of muscle tone characterized both groups during admission. As it is known, in the stroke population involved in this kind of experimental studies, there are differences between in general characteristics according to spasticity degree, muscular strength and joint mobility. In this heterogeneity groups exoskeletons can be more helpful and appropriate treatment option for a customized therapy.In this sense, from Table The increase in joint mobility experienced by patients in the robotic therapy group significantly exceeded those achieved by patients in the control group, in which only one of the patients meets the functionality criteria established in this work. The continuous and significant gradual increase in active joint movement (ROM) of these patients from the admission is the result largely of the control and reduction of spasticity that limits, as it is known the active flexion, abduction and external rotation patterns and the consequent early elimination of pain. These aspects, which however have little or no change during conventional therapy delayed pain elimination, that take place in a period of time that undermines the prediction for better rehabilitation rates , 34–36.From Fig. Table In this regard, it is worth highlighting those cases of the experimental group whose indicators during admission were comparable to those of the conventional group and nonetheless reach recovery rates on par with the rest of the experimental group, for example the patient with a flaccid limb and the chronic patient S5, who receiving prior conventional therapy entered the experimental group with severe subluxation, spasticity, even with pain and very discrete degrees of joint mobility.This effect could be explained in how the decrease in spasticity and pain allow a gradual increase in the arcs of articular mobility of the shoulder in patients from the experimental group.p < 0.002) in muscle tone patients did not show an important recovery as robotic therapy (Tables p < 0.0014).Another important outcome is referred to the recovery of motor capacity expressed in the evaluation of muscle strength from admission and during treatment. From Tables y Tables  and 6. TIt can be concluded that robotic therapy in general prompted an increase in muscle strength in the patients . Only patient S5, who showed since admission to 3 months a value of muscular strength MRC = 2 was the exception, coincidentally being the patient with an evolution time of 14 months and a great subluxation in the left arm, aspects that seem to have influenced in the recovery of the muscle tone.In general, a greater muscular strength can be observed associated with those patients who achieve greater active ranges of joint movement with robotic therapy, as it has been suggested by other authors , 35, 37.Considering the nature of such pathologies, it is noteworthy the motivation and enthusiasm of the patients during the treatment with robotic therapy. A great satisfaction degree of the people being treated Table , constitFinally, all the functional and motor achievements reached by the patients from experimental group were sustained over time, showing in this way, the potential of such treatment in the early recovery of the hemiplegic shoulder.Although it was not the object of this study, significant results were reported in the rehabilitation of the different indicators in the elbow joint and to a lesser extent of the wrist , in addiThe outcomes of this study favored robotic therapy over conventional therapy in an early elimination of pain in a significant way (20÷30 sessions), which enables the obtaining of better rehabilitation indicators. It means that it is possible to control pain through reducing shoulder spasticity using a proper upper limb exoskeleton therapy.As it has been reported in the scarce literature on shoulder subluxation in the hemiplegic patient, a rapid and significant decrease in the magnitude of subluxation even in chronic patients (evolution times greater than 6 months) was obtained. In this sense, it is worth mentioning the attainment rehabilitation indices in patients with different evolution times for different etiologies of the painful shoulder of the hemiplegic patient.Our findings and outcome results were adjusted for the data for this study, even when small sample size was used. A large number of patients would allow more conclusive results than those presented here.These findings suggest that the lack of mobility that follows the stroke is the main cause of the development of spasticity, muscle contractures, flaccidity and subluxations as multifactorial causes of shoulder pain. Indeed the performance of precise routines and gradually controlled movements, lead to the decrease of these abnormal muscle tones, the disappearance of pain and the greater recovery of joint movement with the use of robotic therapy.


Evaluation of the safety and efficacy of a topical lidocaine gel 2% (LG) during scaling and root planing (SRP) and professional mechanical plaque removal (PMPR).The anesthetic effects as well as unwanted effects of LG prior to or during SRP and PMPR were evaluated in an observational, non-randomized, non-interventional study design. A total of 385 treatments were recorded in 68 study centers all over Germany. Rating of the anesthetic effect of LG by treating personnel and patients using a four-item verbal rating scale (VRS), tolerability, safety (adverse effects), and need for additional local injection anesthesia (ALI).In SRP as well as in PMPR, application of LG allowed a sufficiently pain-free therapy in more than 90% of the patients as stated on the VRS . Overall, ALI was needed in only 4.23% of the patients treated . One adverse effect occurred within the observation.Application of LG may offer a safe and effective way to achieve pain-free therapy in periodontal patients.Patient compliance is key to the success of periodontal maintenance therapy. Effective and safe pain control during various kinds of periodontal therapy might increase patient compliance and therefore contribute to the long-term treatment success, among other factors. With regard to the patients observed in this study, 47% had previously received periodontal maintenance therapy and were therefore familiar with the treatment and the associated pain. Severe periodontitis was the sixth most prevalent disease condition in the world in 2010, affecting 743 million people worldwide . The sucAlthough there is usually no anesthesia given for PMPR, many patients prefer some kind of anesthesia even during supragingival tooth cleaning. Up to 30% of the patients undergoing PMPR require pain control . InjectiVarious studies have demonstrated that topical anesthetic gels are a well-accepted possible alternative to either injection anesthetics , 11 or pTherefore, the aim of this non-interventional observational study was to collect data, under real-life practice circumstances, about the use of lidocaine gel 2%  as a topical anesthetic for non-surgical treatment of periodontal disease and for PMPR in dental practices all over Germany.This non-interventional observational study was conducted according to the recommendations from the German Health authorities   and accoThe Ethical Committee of the University of Muenster, Germany, was consulted (2015-385-f-S). All subjects gave informed written consent (data privacy statement) before taking part in this study.A total of 385 subjects were enrolled in 68 participating study centers. The subjects had to be at least 18 years old and requiring scaling and root planing, professional mechanical plaque removal, or a different treatment where LG could be applied as anesthetic. Exclusion criteria were pregnancy and lactation as well as the presence of any contraindications for treatment with LG such as allergy.Lidocaine gel 2% as used in this observational study is a white topical anesthetic gel that has been commercially available as a medicinal product in Germany  in tubes and cylindrical carpoules as an anesthetic for temporary, symptomatic treatment of pain at the oral mucosa, gingiva, and lips since 1976. For each participating patient, one treatment session was observed and documented. Prior to the treatment patient demographics, periodontal screening and recording codes (PSR) and the indication were recorded. LG was applied into periodontal pockets or to the sulcus with a blunt cannula. Whether LG was applied into all periodontal pockets at once prior to treatment or sequentially for each quadrant to be treated was recorded. The maximum anesthetic effect occurs approximately 45 to 60 s after application. Therefore, no explicit rules for retention time before starting any therapeutic intervention were given. Re-application in cases of insufficient pain control was explicitly possible and had to be documented. If sufficient pain control could not be achieved, an additional local injection anesthesia (ALI) could be given. The evaluations were performed immediately after completion of treatment. The treating personnel were asked to evaluate the anesthetic efficiency as well as the handling using grades from 1 to 6 . The subjects were asked to evaluate the pain during treatment using a verbal rating scale (VRS) with four categories: no pain, mostly pain free, sufficiently pain free, not sufficiently pain free. The subjects were also questioned about unwanted effects and whether they would choose LG for a similar future treatment.Since the study was designed as an observational trial, no ex-ante calculations of power and sample size were possible. Standard descriptive methods were used to summarize the parameters studied. Statistical analysis was performed using SAS® Version 9.4.A total of 385 subjects were enrolled into this observational trial study between September 2015 and July 2016, among them 229 female (59.95%) and 153 (40.05%) male patients. The average age was 53.79 (± 14.21) years, the youngest patient was 20, the oldest 86 years old. The majority of the patients were between 50 and 70 years old (48.81%). Within the cohort, 29.21% of the patients were active smokers and 6.04% were diabetics.Out of 382 patients, 179 individuals (46.86%) had previously received periodontal maintenance therapy (PMT), many of those (31.13%) over 2–5 years or longer.n = 198, 55.15%) and scaling and root planing . Other indications given for at least five patients were measuring of pocket depth , PMT , cleaning of dental implants , and calculus removal .The most frequent indications for the application of LG were professional mechanical plaque removal . The patient evaluation and the preference concerning anesthesia for future treatment were compared for the overall study population versus the patients who had not taken analgesics.Twelve patients had taken oral analgesics on the day of treatment, primarily Ibuprofen (For 187 patients (53.28%), the anesthetic gel was applied to all periodontal pockets prior to treatment, whereas 164 patients (46.72%) were sequentially anesthetized in the quadrant that was about to be treated.The periodontal screening and recording (PSR) code  was deteSeventy-seven patients 20.42%) required a re-application of LG for single dental pockets or sulcus areas. The need for re-application was similar for patients who received full-mouth anesthesia prior to treatment (18.68%) and for patients who received sequential anesthesia per quadrant (23.31%). The values for SRP and PMPR patients differ as depicted in Fig. 2% requirThe treating personnel were asked to evaluate the following categories by using grades from 1 to 6 : handling/application, onset of anesthetic effect, duration of anesthetic effect, and patient treatability/compliance. The ratings for all four categories were predominantly “very good” or “good”. On average, handling/application was rated 1.58 (± 0.75), onset 1.69 (± 0.90), duration 1.78 (± 0.96), and treatability/compliance 1.69 (± 0.87)  compared to the PMPR group , but the number of patients who were not sufficiently pain free was higher in the PMPR group (6.21%) compared to the SRP group (2.21%). A total of 350 (92.35%) of 379 patients would choose LG for a similar future treatment, whereas 29 (7.65%) patients would refuse a repeated LG application. The decision is the same for the 373 patients who had not taken analgesics on the treatment day (92.64% yes and 7.36% no). The preference for LG for a fictive future treatment was even stronger in the SRP group  as opposed to the PMPR group .A total of 146 (38.02%) of 384 patients did not perceive any pain during the treatment, 179 (46.61%) were mostly pain free, and 40 (10.42%) were sufficiently pain free. Nineteen (4.95%) patients indicated that they were not sufficiently pain free. The average score was 1.82 (2 = mostly pain free). The evaluations by the sub-population of patients who had not taken any analgesics were comparable . Figure Only one adverse effect was observed during this non-interventional study: one patient experienced an oral hypoesthesia (numb tongue) for about 15 min. No serious adverse effects were reported.A major problem of studies assessing pain or pain levels is the fact that pain perception is subjective and may vary considerably between individuals. Aches and pains are considered complex products of a variety of physical, cognitive, and emotional factors. In a clinical setting as the one assessed here, the operator is an additional important factor, which may act as confounder, since dexterity and operation skills are important factors influencing the pain level perceived by the patient. Data indicates that correct communication and explanation about the topic of pain prior to therapy may lower the need for anesthetics . These hIf the choice for LG in a future treatment is regarded separately, the preference among the patients who received SRP is even higher with 97% than for the patients who received PMPR with 92%. The need for re-application seems to have no influence on the acceptance by the patients. This is consistent with studies comparing topical anesthetic gels with injection anesthesia which show a high preference for anesthetic gels by up to 80% of the patients , 23. In The anesthetic depth that can be achieved with LG is sufficient for most patients, which can also be seen from the small percentage of patients, 5% for SRP versus 3% for PMPR, who actually needed “rescue anesthesia”. The evaluation of LG by the treating personnel with regard to the efficacy (onset and duration), handling, and patient treatability resulted in mostly “very good” and “good” grades, also demonstrating a very high acceptance. Whether freedom of pain is achieved by the use of LG or may simply be explained by the fact that the patient is less sensitive to pain cannot be assessed in an observational study. In addition, it can be assumed that subgingival debridement is perceived as being more unpleasant than supragingival cleaning. Another point to discuss is the impact of the method of instrumentation on perceived pain. Data indicates that patients may perceive hand instrumentation as being more painful than ultrasonic scaling even when topical anesthetics are applied . HoweverOnly one adverse effect was observed in this non-interventional study, demonstrating a high degree of safety for LG. One patient suffered from a transitional numb tongue. It can only be speculated whether some gel was accidentally applied to the tongue or the patient moved his tongue to the gel applied to the sulcus. According to the PSR values recorded, 79% of the PMPR patients suffered from moderate or severe periodontitis, indicating that the PMPR performed could rather be classified as periodontal maintenance therapy.Lidocaine gel 2% offers a safe, effective, and highly accepted method of achieving a pain-free treatment for periodontal and maintenance patients.