Gynecological malignant tumors refer to malignant tumors of organs and tissues centered on the uterus, ovaries, and fallopian tubes. Among gynecological tumors, endometrial cancer is the most malignant, accounting for more than 80% of malignant tumors in the female reproductive tract. Common symptoms are vaginal bleeding and pain. This article aims to explore the application and analysis of the concept of ERAS (Enhanced Recovery After Surgery) in the clinical care of patients with advanced cancer pain from gynecological malignancies. ERAS aims to reduce complications, shorten hospitalization time, reduce medical costs, and enable patients to recover quickly by adopting a series of perioperative management measures for patients. This article analyzes the pain caused by late-stage cancer, proposes an ERAS multimodal analgesia method, and uses image fusion technology to detect cancer patients. This article finally conducts an experimental exploration of the clinical nursing of the ERAS concept in the treatment of advanced cancer pain in gynecological malignancies. The results of this study showed that in terms of pain impact score, before treatment, the score of group M was 39.07 and the score of group N was 38.92, and the difference was not statistically significant. The score after ERAS concept treatment was 58.14, and the score after traditional treatment was 43.79, with a significant difference. Research shows that the pain impact score after treatment is significantly better than before treatment, and the improvement effect of ERAS concept treatment is more obvious. In the process of disease diagnosis, clinicians usually take the “pain” of patients as an important diagnostic indicator to reduce the pain degree of patients through treatment. Recent studies have shown that chronic pain can be divided into three types: non-specific, physical pain and mental disorders. Advanced cancer pain is a series of chronic and severe pain caused by non-specific malignant tumors. Therefore, effective relief of non-specific cancer pain is of great significance for prolonging the survival of patients with advanced cancer. Cancer pain is different from some chronic pain. It rarely has an intermittent period. Once the cancer progresses, the pain would become more and more severe, and the degree of tissue damage would become more and more serious. Analgesia for advanced cancer has always been the focus of clinicians and nursing staff. With the transformation and progress of medical technology and medical model, ERAS concept has been widely applied and promoted worldwide. The ERAS concept emphasizes the use of evidence-based medical evidence to guide clinical treatment and nursing practice, which can provide personalized pain care programs for cancer patients. The purpose of this article was to explore the application and analysis of ERAS concept in the clinical nursing of patients with advanced cancer pain of gynecological malignant tumors, with a view to making certain contributions to the relief of cancer pain.Based on the existing research results, scholars have carried out relevant research on cancer pain. Pain is a common symptom of cancer patients. Appropriate pain evaluation and treatment is the key to improve the quality of life and health effect of patients. Scarborough Bethann M. reviewed pain control, pain management obstacles, evaluation and management strategies of tumor-related pain, pain management of patients at risk of drug abuse, and problems that should be paid attention to in pain management of patients . Pain waThere are more and more functions of acupuncture and acupoint massage in tumor pain, but the results of these studies are different. He Yihan’s purpose was to determine the relevant evidence of acupuncture and massage for tumor pain relief by evaluating the existing randomized clinical trials . There wSome scholars also have some research on ERAS concept. The concept of ERAS is applied to different surgical fields. Among the patients undergoing radical cystectomy, there is still a lack of prospective data. A prospective randomized study showed that ERAS has more advantages over traditional treatment for these patients. Ziegelmueller Brigitte Katharina aimed to evaluate the long-term follow-up effect of ERAS after radical cystectomy . At presIn order to alleviate cancer pain caused by advanced malignant tumor and cancer pain caused by various reasons, this paper screened out gynecological malignant tumor patients through medical image fusion technology, and analyzed the causes of advanced cancer pain. In this paper, the ERAS multimodal analgesia method was proposed, and based on this, the clinical nursing simulation experiment of gynecological malignant tumor and advanced cancer pain was designed. It can be seen from the experimental results that ERAS concept had a good effect in the nursing of patients with advanced cancer pain of gynecological malignant tumors.22.1Pain is a kind of sensation, and its occurrence and development are mainly regulated by nerves and body fluids. These neurotransmitters or factors participate in central sensitization through corresponding signal transduction pathways. The physiological classification of pain is based on the reasoning of the mechanism of pain, which is divided into injury sensation type and non-injury sensation type. Nociceptive pain can be divided into physical pain and visceral pain. There are two types of non-invasive sensory pain: neuropathic pain and psychological pain. When cancer causes cancerous pain, its mechanism of occurrence and development is as follows: when the body is in a state of stress, factors such as the body’s stress response, sympathetic nerve stimulation, and increased activity of pain receptors would cause corresponding changes in neurotransmitters and inflammatory factors , 9. CancThe basic mechanism of pain is as follows: the sensory nerve roots in the spinal cord and brain are stimulated to produce excitation or inhibition. Neurotransmitters such as dopamine and norepinephrine in the limbic system of the brain are released in varying degrees in the spinal cord and brain. The spinal cord and center would be sensitized, and the neurotransmitter changes (endogenous and exogenous). Central chemical substances act on peripheral organs or systems, inflammatory factors act on peripheral organs or systems, and ion channels or membrane protein abnormalities occur in pain cell membranes. Pain is a subjective feeling of cancer patients. Therefore, patients would have problems in understanding, emotion and behavior of pain. When these problems affect the normal quality of life, they would affect their ability to live and work. The psychological burden of cancer patients mainly includes two aspects. On the one hand, it is anxiety, fear and other emotions caused by various physiological reactions that may occur during the treatment of the disease. On the other hand, it is the physical function damage caused by the physiological function disorder caused by pain. Because of the strong impact of cancer on psychology, the patients’ negative emotions such as depression and despair are generated. During this process, patients may suffer from insomnia, irritability, depression and other psychological abnormalities.2.2The application of multimodal analgesia in postoperative pain management is an important part of ERAS. With the development of ERAS concept, multimodal analgesia technology has gradually been widely used. Multi-modal analgesia refers to the combination of multiple painkillers or different painkillers. It can reduce the amount of single analgesic, reduce the incidence of side effects, and improve the efficacy of surgical analgesia. Multi-mode analgesia includes preemptive analgesia, preventive analgesia, anesthesia and analgesia technology, postoperative analgesia, etc. The preemptive analgesia is to intervene before the nerve center has received the pain information caused by surgical trauma. It includes physical therapy or drug therapy to prevent hyperalgesia in the nerve center. Central hyperalgesia is characterized by hypersensitivity of pain receptors to stimuli. Preventive analgesia can significantly relieve postoperative pain and effectively prevent long-term postoperative pain. Anesthesia analgesia is a method of analgesia, which uses anesthetics to block the pain signals on the nerves. It includes local anesthesia, nerve block, fascial space anesthesia, intraspinal analgesia, etc. The purpose of multimodal analgesia is to effectively control the pain symptoms, reduce the stress response of patients after surgery, and accelerate the recovery of patients. The core principle of ERAS is to reduce the stress response of surgery and reduce the risk of complications through multimodal methods.For cancer patients undergoing chemotherapy, the current mode of analgesia is relatively simple, and opioid analgesics such as morphine are usually used for severe pain. Effective pain management is an important part of ERAS concept, and multimodal analgesia can well control postoperative pain. Multi-modal analgesia can reduce the use of opiates and reduce the adverse reactions related to opiates. ERAS concept is a new perioperative treatment process. It is a new surgical method with the best perioperative treatment. It adopts a new set of technologies to reduce pain, cure patients and recover quickly.ERAS concept is a combination of surgical technology and minimally invasive treatment concept, aiming to reduce the pain of patients, alleviate the physical and psychological pain of patients, and improve the quality of life. Through the application of ERAS concept in the nursing of advanced cancer pain, the analgesic effect is significant. The intervention measures and nursing process implemented by ERAS concept for patients with advanced cancer pain can be implemented, and the traditional surgical technology and minimally invasive technology can be combined to make painkillers and non-pharmaceutical analgesia methods be applied in the treatment of patients with advanced cancer pain. ERAS nursing mode plays an important role in the clinical practice of advanced cancer pain in patients with gynecological malignancies. It can effectively alleviate the adverse symptoms of patients at the physical and psychological levels, and can alleviate or eliminate -the side effects caused by chemotherapy drugs. It can also improve the quality of life and prolong the survival time of patients. ERAS nursing measures are mainly divided into analgesic drugs and non-drug treatment. Analgesics, non-analgesic sedatives, opioid analgesics and physical therapy can be used to relieve the pain of advanced cancer. Psychological counseling and psychotherapy: It can relieve the pain caused by advanced cancer through health education and psychological counseling.2.3In recent years, with the continuous development of computer technology, people pay more and more attention to the diagnosis of cancer, and the research on cancer is also deepening, especially some research related to human health. Cancer cell is a kind of mutant cell, which is the cause of tumor. Unlike ordinary cells, cancer cells have unlimited proliferation, transformation and transplantability. They can proliferate indefinitely and destroy normal cells. Cancer has a certain degree of heredity, and cancer cells have the characteristics of proliferation and spread, so cancer detection and recognition can provide more accurate information for early diagnosis of disease.The process of normal cells developing into tumors is called tumorigenesis. Tumor genesis is a gradual process, involving multi-level reaction and accumulation of mutations. The development of tumor would affect its surrounding normal tissues, and the changes of surrounding tissues are closely related to the metastasis and spread of tumor. Through multimodal medical images, the tissue information around the tumor can be obtained and transmitted to other organs, which is helpful for early detection and diagnosis of cancer. The application of fusion technology in malignant tumors mainly includes single-parameter fusion on magnetic resonance imaging (MRI) and fusion of MRI images using multi-layer convolution neural network. It also includes the layering of tumor, metastasis or normal tissue on electronic computed tomography (CT). The fusion can improve the sensitivity of the tumor edge and its surrounding blood vessels to a certain extent, thus improving the diagnostic accuracy. The fused image can better reflect the difference between malignant tumor cells and surrounding normal tissues in space, which provides better recognition for tumor sites. On the other hand, it can determine the scope of tumor more accurately and objectively, thus providing more accurate basis for tumor resection and follow-up treatment. In some cases, the object of medical image fusion service is people. At this time, the purpose of fusion processing may be to improve the image quality to improve human visual effects. Or, this can increase the amount of information in the fused image or the accuracy and reliability of the information. This can provide richer, more accurate and more reliable image information for people’s decision-making. In other cases, the object of image fusion service is the machine, and the purpose of fusion processing may be to enable the machine or computer to automatically detect, recognize or track the target.Because the target of image fusion is human, the evaluation of image is affected by human visual characteristics, psychological state, knowledge background, value orientation and other factors. Therefore, how to evaluate the effectiveness of image fusion, especially objectively and quantitatively, has very important practical significance.At present, there is no unified and objective fusion image evaluation method. Here are several image fusion evaluation methods: cross entropy, interactive information, WFQI  to make an objective evaluation of the fusion image. The details are as follows:(1) Cross entropy: it is also called correlation entropy, which can be used to measure the difference between two pictures. If the standard reference image is T and the fused image is G, the correlation entropy between the reference image T and the fused image G is:To is the ratio of the number of pixels with a gray value of To to the total number of pixels in the image. The lower the interaction entropy of the image, the better the fusion effect of the fused image and the reference image.A is the gray scale of the entire image, and Q(2) MI : The mutual information MI among images S, N, G is defined as follows:As defined by cross entropy, A is the total gray level of the image. The greater the amount of mutual information MI, the more information the fused image can obtain, so as to achieve better fusion effect.Criteria for evaluation of fusion effect: when the image entropy, average gradient and standard deviation obtained by a certain fusion method are large, the cross entropy is small, and the mutual information is large, the fusion effect is good.(3) WFQIIn WFQI, for the source image s, n, the importance of the fused image s in window e is expressed by d(s|e), which usually depends on the entropy, contrast and variance in window e. Local significant weight γ(e):The global significance V(e) is:Then the global significance weight v(e) is:WFQI emphasizes two aspects: the significance and weighting coefficient of each window e in the fused image. Important areas have better visual effects and richer information. Therefore, different windows cannot be treated equally. It should be the regions with higher significance that have larger weights, and vice versa.With the increase of image quality index, the more information the image contains, the greater the importance of the image, and the better the visual effect.2.4At present, the main applications of multimodal image fusion algorithms include two aspects. The first is to obtain a group of joint information with radiation dose and side effects through multimodal image fusion of image acquisition and information extraction during radiotherapy. In addition, the clinical prediction data obtained from the fusion results of different modes can be used for machine learning training to identify new targets or diseases. The fusion algorithm can be used to build a deep convolution neural network model for multi-source medical images to improve the segmentation, classification and recognition capabilities. This is of great significance for better realization of radiotherapy plan. The fused multimodal image information can be used for radiotherapy plan design, which can help to obtain more accurate treatment dose to achieve the optimal treatment effect. In the field of accurate tumor radiotherapy, accurate registration of multiple tumor parameters and location information and multiple image sequence information can be achieved through multiple image fusion methods to effectively control the tumor area and improve the radiation dose.33.1In recent years, with the promotion and deepening of ERAS concept, more and more research evidence shows that holistic care for cancer patients can reduce the pain of patients. Compared with non-cancer patients, cancer patients are more prone to symptoms such as nausea, vomiting and constipation. This may be caused by the long-term negative emotions of cancer patients. At present, the research on the factors related to cancer pain shows that depression is related to chemotherapy reaction, side effects of chemotherapy, anti-tumor drugs and long treatment time , 15. In In this paper, medical image fusion technology was used to screen patients with gynecological malignant tumors in a third-class A hospital and explore the application of ERAS concept in clinical nursing of advanced cancer pain. A total of 80 patients were divided into two groups, including 40 in the experimental group (M group) and 40 in the control group (N group). Among them, group M adopted ERAS concept for pain management, that is, through prevention, timely and multi-mode analgesia. In group N, pain management was carried out by traditional methods, that is, analgesia on demand. Nine patients were selected from each group for data analysis.The content of pain care in ERAS concept mainly includes: (1) improve the level of mental health: it can reduce patients’ fear of cancer drug treatment and related nursing measures through psychological intervention and other methods, so that they can actively cooperate with treatment. (2) Relieve bad emotions: it can strengthen communication with patients and their families, so that they can understand that cancer pain is not a physiological phenomenon but a pathological phenomenon. (3) Alleviate adverse reactions: it can give active and effective intervention measures to cancer pain. (4) It can provide early intervention for cancer patients. (5) Provide relevant health education: it can encourage patients to participate in health education activities to enhance their awareness of self-care.Inclusion criteria: female patients over 18 years old; All patients were diagnosed as malignant tumors; Patients who have received one course of treatment or longer need further treatment; Have clear perception and the ability to answer questions; Take the initiative to be investigated.Exclusion conditions: unable to cooperate with the investigation; Patients with nerve and digestive tract tumors.Observation method: The NRS  score, KPS score, pain effect and adverse reactions of the patients were recorded truthfully, and the curative effects were compared between the groups.The pain score was evaluated by NRS evaluation method, and the pain of patients was evaluated by professional medical staff according to NRS standards. Among them, 0 indicates no pain, 1-3 indicates mild pain, 4-6 indicates moderate pain, and 7-10 indicates severe pain.Pain impact score: Pain impact includes 7 pain impact shadows of patients’ ability of daily living (A), life enjoyment (B), mood (C), sleep quality (D), walking ability (E), working ability (F), and relationship with others (G). The pain factor scores and total scores are recorded during the test, and the differences between the groups are compared. The score of each item is 0-10, the lowest score is 0, the best score is 10, and the total score of all items is 70.KPS (Karnofsky) score is a comprehensive scoring standard for the physical condition of tumor patients. The total score is 100 points, divided into 10 grades, with 0 point for death and 10 points for dying. 20 points indicates that the patient is seriously ill and needs active hospitalization. A score of 30 indicates that life is extremely hard to take care of. A score of 40 indicates that they cannot take care of themselves and need special care, a score of 50 indicates that they often need care, and a score of 60 indicates that they sometimes need help, but most of the time they can take care of themselves. 70 points refer to self-sufficiency but unable to continue normal life or work. 80 points refers to having certain symptoms or signs, barely able to exercise normally, and 90 points refers to being able to exercise normally, with mild symptoms and signs. A score of 100 indicates that everything is normal without any signs or symptoms. According to the scores of patients’ actual conditions, the differences between the two groups were compared.3.23.33.43.53.6ERAS concept emphasizes the concept of symptomatic treatment according to the individual conditions of patients, and adopts appropriate and effective methods to solve the symptoms caused by various diseases, such as pain, anxiety, etc. This can achieve the purpose of alleviating pain, improving the quality of life and survival probability of patients. Different from the traditional concept, ERAS concept emphasizes the combination of multiple methods in the treatment process. Among them, analgesics are most widely used in gynecological malignant tumors, but they are characterized by large side effects, high price and poor compliance of patients. The analgesic effect of opioid drugs in ERAS concept is significantly better than that of traditional opioid analgesics and local anesthetics, and its side effects are less. Therefore, it can effectively relieve the pain symptoms of patients, improve the quality of life and survival probability of patients.To sum up, ERAS concept can be adopted to have great advantages in clinical nursing of patients with advanced cancer pain of malignant tumors, which can well relieve the pain of patients.4ERAS concept refers to patient-centered, comprehensive and systematic provision of high-quality services for patients. It includes health education, psychological support, related drugs, nursing, and other aspects. At the same time, it also takes into account the participation of patients and their families in the formulation of treatment plans and the whole process of treatment, so as to reduce and eliminate the cancer pain symptoms of patients and improve the quality of life. The application of ERAS nursing intervention in patients with advanced cancer pain has positive significance. First of all, patients with advanced cancer pain need professional guidance, so as to reduce their bad emotions and alleviate their pain. Secondly, pain patients should master the correct medication methods and precautions when using analgesics, which is also an education for patients and their families. ERAS nursing intervention can also relieve patients’ pain symptoms and help patients improve their understanding of cancer pain. Humanized services are provided according to the needs of patients, which can measure blood pressure for patients and provide them with a comfortable rest environment. It is necessary to patiently explain the knowledge about pain to the patient and pass on the correct self-management method of cancer pain. It should inform patients how to prevent adverse reactions of analgesics and guide them to use analgesics reasonably. ERAS nursing intervention can help patients with advanced cancer pain to reduce and eliminate pain stimulation, improve quality of life, prolong survival time, and reduce damage to other organ functions. However, due to the limitations of time and technology, this paper has not carried out a detailed analysis of the problems encountered in the research of cancer pain, which would be further discussed in the future.The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.The studies involving human participants were reviewed and approved by Ethics Committee of Chenzhou First People’s Hospital (AF/SOP-EC-N14-4.0/02). Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.HL: Conceptualization; methodology; software. YL: validation; formal analysis; investigation. Both authors contributed to the article and approved the submitted version.


Patients with FHP often experience neck pain and disability. The aim of this study was to investigate whether treatment programs are effective in the management of neck pain in patients with FHP. (2) Methods: A MEDLINE (PubMed), Embase, Cochrane Library, and Scopus database search was conducted for English language articles on patients with chronic neck pain and FHP published until 12 April 2023. To identify potentially relevant articles, the following key search phrases were combined: ‘forward head posture’ and ‘pain’. After searching, 2516 potentially relevant articles were identified. After reading the titles and abstracts and assessing their eligibility based on full-text articles, 16 articles were included in this review. (3) Results: Among the 16 studies that investigated the efficacy of treatment programs for managing chronic pain in patients with FHP, 11 investigated the effect of exercise programs, and 5 investigated the effect of manual therapy. Patients reported significant improvement in pain and disability after receiving treatment programs such as corrective postural exercises and special manual therapy techniques. (4) Conclusions: Various treatment programs, including postural corrective exercises and manual therapy, are beneficial for improving pain and disability in patients with FHP. Proper posture refers to a state of musculoskeletal balance that imposes a minimum amount of stress and strain on body structures . Many peForward head posture (FHP) is one of the most common cervical postural deviations and is characterized by head protrusion or forward head placement in relation to the shoulder in the sagittal plane . SustainFHP is associated with various disorders, such as trigger points in the suboccipital muscles, temporomandibular disorder, tension-type headache, and dyskinesia . AdditioVarious treatment programs such as exercises, manual therapy, and modalities have been applied to treat neck pain and disability in patients with FHP . HoweverThe protocol was registered on the international platform of registered systematic reviews and meta-analysis protocols (registration number: INPLASY202390061). A MEDLINE (PubMed), Embase, Cochrane Library, and Scopus databases search was conducted for English language articles on patients with chronic neck pain and FHP, published until 12 April 2023. To identify potentially relevant articles, the following key search phrases were combined: ‘forward head posture’ and ‘pain’. The following inclusion criteria were applied for the selection of articles: (1) patients with chronic pain, (2) patients diagnosed with FHP, (3) human studies, and (4) studies written in English. Relevant studies were selected according to the flow diagram shown in Sixteen studies investigated the efficacy of treatment programs in managing chronic pain in patients with FHP. All studies were randomized controlled trials (RCTs) that enrolled patients with FHP who had chronic neck pain or discomfort, mostly for >3 months. The patients were diagnosed with FHP, which is commonly defined as a craniovertebral angle (CVA) of <50° (diagnostic range < 44–53°). Studies have evaluated the efficacy of treatment programs using outcome measures such as pain scales  and numerical rating scale (NRS)), neck disability index (NDI), and CVA.Among the 16 studies included, 11 investigated the effect of exercise programs ,16,17,18Eleven studies compared the effectiveness of exercise programs for managing pain and disability in patients with FHP ,16,17,18Sikka et al. (2020) enrolled 30 adolescents with chronic neck pain, FHP, and neck disability (NDI < 24) who use computers regularly . PatientIn 2021, Kang et al. investigated the effects of a combination of scapular stabilization and thoracic extension exercises . This prThe effect of exercise programs on the management of chronic pain in patients with FHP has been continuously reported in other studies. In 2022, Dareh-Deh et al. conducted an RCT to investigate the effectiveness of exercise in patients with FHP . A totalThe effect of cervical stabilization exercises on chronic neck pain in patients with FHP was also reported by Arif et al. in 2022 . Twenty An RCT by Abd El-Azeim et al. also reported that adding scapular stabilization exercises to corrective postural exercises (30 patients) increased the CVA and pressure pain threshold and decreased disability compared with corrective postural exercises only (30 patients) . The exeMost recently, in 2023, Suwai et al. compared the effect of cervical traction orthotics (DennerollTM) and mirror image exercises  with standardized exercises, which included stretching and strengthening exercises of the cervical muscles  . TreatmeFive studies investigated the effects of manual therapy with or without exercise ,21,22,23The effects of manual therapy were also reported by Kim et al. in 2021 . Joint mIn the same year, Mylonas et al. compared the effects of instrument-assisted soft tissue mobilization (IASTM) (10 patients) and classical massage (10 patients) . The IASThe combined effect of the muscle energy technique (MET) and postural correction exercises was reported in 2022 by Joshi et al. , who enrTo the best of our knowledge, this is the first review to summarize the effectiveness of neck pain treatment programs in patients with FHP. Postural deviation, such as FHP, increases the mechanical loads on the structures around the cervical spine, which may cause pain and increase the risk of degenerative changes and disc herniation. Neck pain associated with FHP is associated with poor posture, workload, and structural disorders that may affect activities of daily living, emotional control, and quality of life . The theCVA is one of the common methods for the assessment of FHP. It is identified at the intersection of a line joining the midpoint of the tragus of the ear to the skin covering the C7 spinous process and a horizontal line passing through the C7 spinous process . SmallerCommon postural corrective exercise programs for FHP are cervical or scapular stabilization exercises, stretching and strengthening exercises , proprioThe mechanism underlying the positive effect of exercise on pain is that, as intrafusal fibers are reset with exercise, the cycle of muscle tension, impaired circulation with metabolite accumulation, and myofascial pain may be reduced . BecauseScapular stabilization exercises help relocate the abnormal position of the scapula, and proper alignment of the scapula induces structural changes and improves the muscle activities of the neck and back muscles . ConsequTreatment programs that include manual therapy, with or without exercise, appear to be effective in managing neck pain and disabilities in patients with FHP. Manual therapies such as joint mobilization and joint manipulation are used to improve joint mobility and adhesion between soft tissues, increase ROM, and enhance the somatosensory system . Manual Special manual therapy techniques are effective for treating neck pain in patients with FHP. Manual therapy can be divided into hands-on therapy techniques, such as soft tissue mobilization and massage, and techniques that use therapeutic equipment, such as IASTM. IASTM is a targeted soft tissue myofascial technique that uses special equipment to improve the mobility of connective tissue and myodynamic adaptations. This technique has been found to be helpful in reducing postural stress and improving neck pain and disability . In addiOverall, correcting improper cervical, thoracic, and scapular kinematics and muscular imbalance via exercise and manual therapy seems beneficial for managing pain and disability in patients with FHP.The first limitation is that the studies did not report long-term effects and are, therefore, unknown. Secondly, many studies had small sample sizes and were limited to patients in the chronic phase. Studies with manual therapy were relatively very few in comparison to stabilization exercises. In addition, the study groups were not matched for age or sex. Further studies should be conducted in different age groups to investigate the activity of specific muscles in patients with neck pain and FHP.Treatment programs seem effective in managing neck pain and disability in patients with FHP. Various treatment programs, including postural corrective exercises and manual therapy, seem beneficial for improving pain and functional status in these patients. Thus, treatment programs are recommended to improve FHP, pain, and disability in these patients.


Pain regimens, particularly for chronic cancer and noncancer pain, must balance the important analgesic benefits against potential risks. Many effective and frequently used pain control regimens are associated with iatrogenic adverse events. Interventional procedures can be associated with nerve injuries, vascular injuries, trauma to the spinal cord, and epidural abscesses. Although rare, these adverse events are potentially catastrophic. Pharmacologic remedies for pain must also consider potential side effects that can occur even at therapeutic doses of over-the-counter remedies such as paracetamol (acetaminophen) or nonsteroidal anti-inflammatory drugs. Opioids are effective pain relievers but are associated with many side effects, some of which can be treatment limiting. A prevalent and distressing side effect of opioid therapy is constipation. Opioid-induced constipation is caused by binding to opioid receptors in the gastrointestinal system, making conventional laxatives ineffective. Peripherally acting mu-opioid receptor antagonists are a new drug class that offers the benefits of preserving opioid analgesia without side effects in the gastrointestinal system. An important safety concern, particularly among geriatric patients is the increasingly prevalent condition of polypharmacy. Many senior patients take five or more medications, including some that may be contraindicated in geriatric patients, duplicative of other drugs, have potential pharmacokinetic drug-drug interactions, or may not be the optimal choice for the patient’s age and condition. Careful assessment of medications in the elderly, including possibly deprescribing with tapering of certain drugs, may be warranted but should be done systematically and under clinical supervision. Pharmacologic therapy and interventional procedures intended to mitigate or eliminate pain may cause treatment-limiting or even potentially life-threatening side effects . PolyphaThe management of iatrogenic effects of pain therapy is an important consideration for pain medicine that must be subjected to both clinical judgment and patient preferences. Clinicians focusing on the medical goal of reducing intractable pain may trivialize side effects that the patient finds diminish his quality of life. Oncologists battling cancer may minimize the suffering of painful chemotherapy-induced neuropathy. Nothing is more personalized in medicine than an individual’s determination of what constitute acceptable risks and tolerable therapy. Clinicians may sometimes be surprised by a patient who opts to discontinue opioids and “live with the pain,” just as they may not understand a patient who seeks strong pain control for what could be considered manageable pain.Physicians must be aware of the risks and benefits of the drugs and interventions they recommend and take steps to educate their patients about such risks and benefits. No analgesics or pain interventions are without risk, and clinicians must become partners rather than patriarchs as they help their patients weighing out risks versus benefits.This article is based on a series of presentations from the “Past, Present and Future in Pain Medicine” held in Tunis, Tunisia on May 11-13, 2023 about iatrogenic side effects of pain-control interventions and drug therapy. It is a short review of various salient topics on the subject of iatrogenic issues in pain management and are based on the current literature and the clinical experiences and academic expertise of the authors.Iatrogenic injuries in interventional pain careIatrogenic injuries related to interventional pain procedures are often multifactorial, tracing back to factors related to procedural techniques, communications among the medical team, and poor clinical judgement . Needle-While the shape of the needle is often discussed in terms of avoiding injury, there is a paucity of evidence supporting the alleged safety advantages of blunt needles . ClinicaSteroids themselves may be associated with adverse events, to the point that the use of epidural steroids in and of itself is coming under question because of the rare but potential risk for stroke, vision loss, paralysis, and fatality . The litThe anatomy of the epidural space is complex, with considerable interpatient variability. Many patients have a ligamentum flavum with midline gaps of about 1 mm which can allow for a small amount of leakage of injectate . Such gaStaphylococcus aureus may be helpful when immunocompromised patients must undergo epidural corticosteroid injections [An epidural abscess with or without meningitis may also occur after corticosteroid injections, such as those for radicular back pain . Paraspijections .Conus medullaris infarction is a rare but potentially catastrophic complication related to interlaminar epidural steroid injections . The conVascular nerve injury caused by injections may be due in part to the anatomical variations of vasculature among patients. Furthermore, tortuous or unusual vessels can make injections challenging. Vessel occlusion can directly injure a nerve. Nerve injury may also be caused by certain steroids, a newly formed thrombus, atherosclerotic plaque, dissection, retrograde flow, and other conditions. The mechanical disruption of the vasculature, such as might be caused by needle transection, can also cause nerve damage. In a 17-year retrospective study of 354 iatrogenic nerve injury cases associated with an injection, the presenting symptoms were pain, paresthesia, and sensory-motor dysfunction. This study reported that 46.3% of nerve-injured patients did not recover .Pharmacologic therapyAnalgesics and Iatrogenic Adverse EventsDrugs remain the mainstay in the armamentarium against pain . NonsterOpioid-induced constipation (OIC) is considered one of the most prevalent and most distressing of all opioid-associated side effects . ResultiOpioids can delay gastric emptying and peristalsis in the gastrointestinal system, resulting in slower absorption of medication and increased absorption of fluid. This increased fluid absorption denies water to the gastrointestinal system, causing hard, dry stools that are difficult to pass. Opioids also increased the tone of the anal sphincter and interfere with the body’s normal reflexes regarding defecation -39. OpioThe incidence of OIC among patients taking opioid therapy ranges from 15% to 81%. In a survey in Japan of patients taking analgesics, constipation was reported by 34% of those taking opioids and 29% of those taking nonopioid pain relievers. However, more respondents in the opioid group fulfilled two or more Rome IV diagnostic criteria for constipation (28% vs. 19%) . This wiIn a study of 25 healthy subjects taking oral oxycodone or placebo over five days in a double-blind crossover study, it was found that oxycodone significantly prolonged the median total gastrointestinal transit time from 22.2 hours to 43.9 hours . OpioidsThe prevalence of constipation symptoms increased with the duration of opioid therapy; health-related quality of life was low in those with chronic abdominal pain . In a suFrom a large multinational European survey, OIC was a bothersome side effect for those taking weak (38%) and strong (40%) opioids, although those using strong opioids reported more intense symptoms . SymptomIn a survey of opioid patients, 41% of respondents said that their prescriber had told them about the possibility of OIC, 29% recommended a high-fiber diet and exercise while taking opioids, and only 20% were prescribed a laxative with their opioid analgesics . Once onThe manner in which OIC is treated appears to vary among specialists. In a survey of 501 various specialists who had occasion to treat patients dealing with OIC, 60% expressed high interest in the topic of OIC, particularly pain specialists and anesthesiologists, while psychiatrists expressed moderate interest. In this survey, oncologists and palliative care specialists were the most likely to treat OIC . DiagnosOIC must be recognized as a prevalent and important adverse effect of opioid treatment and physicians must be prepared to offer meaningful treatment options . In diagWhile a conventional laxative may be a good first-line approach to OIC, if that is not effective, a peripherally acting mu-opioid receptor antagonist (PAMORA) may be considered . A PAMORPatients taking opioids may be advised to start at the outset to commence a bowel regimen, make lifestyle changes in terms of exercise and a high-fiber diet, and take a conventional laxative as needed. The problem with this advice is that it may not address OIC; the mechanisms of action of conventional laxatives, such as osmotic effects, motor effects, lubrication benefits, or effects on the microbiota, are not helpful in reducing OIC. On the other hand, conventional laxatives have several advantages in that they are relatively cheap, available over the counter, and are familiar to most patients. For that reason, conventional laxatives are often recommended as a first-line therapy before OIC symptoms are confirmed. A retrospective multicenter study of 619 hospitalized cancer patients receiving opioid analgesics found a significantly lower incidence of constipation in those patients who were prescribed prophylactic laxatives compared to those were did not receive laxatives  . Over thPolypharmacyPolypharmacy refers to the consistent use of multiple concurrent medications, a condition that is particularly prevalent among geriatric patients. Few disease-specific guidelines address the management of comorbidities; there is little guidance in prescribing for multimorbid patients; and there is a paucity of deprescribing protocols to address the reduction of polypharmacy . Even a Using the definition of taking ≥ 5 concurrently prescribed drugs, irrespective of patient age or duration of therapy, polypharmacy is prevalent and increasing. The potential risks of polypharmacy include drug-drug interactions, drug-food interactions, poor adherence, adverse drug reactions, falls, frailty, increased costs, and patient confusion . Many gePolypharmacy often occurs in patients who have more than one chronic condition, more than one physician, and/or no primary care physician. This is common in older patients who develop degenerative age-related conditions and often suffer from chronic pain. While opioids are effective pain relievers, current guidance suggests that alternatives be tried as first-line therapy and if opioids are needed that they be used at the lowest effective doses for the shortest duration of time possible . Not allThe Beers criteria, the Screening Tool of Older Person’s Prescriptions-Screening Tool to Alert to Right Treatment (STOPP-START) criteria, and the anticholinergic drug scale are important resources in combating potentially dangerous polypharmacy in geriatric patients. The Beers criteria are evidence-based guidance about specific drugs that may cause side effects, be contraindicated, or may have better and/or safe alternatives for geriatric patients. The Beers criteria are endorsed by the American Geriatric Society , 66. AmoThe STOPP-START criteria makes recommendations based on expert consensus and screens for drug-drug interactions, duplicative treatments, and potentially inappropriate medications. STOPP-START guidance is considered particularly appropriate for multimorbid seniors . The antDeprescribing is the systematic evaluation of a patient’s medications with the goal of identifying medications that may be inappropriate for the patient for any number of reasons, such as lack of need for that medication, duplicative prescribing, or medications for which the risk to the patient outweighs the potential benefit . In someClinical considerationsThere are important clinical considerations to help mitigate or prevent iatrogenic effects of pain treatments. While complications in interventional procedures are relatively rare, all spinal procedures should be performed under fluoroscopic guidance. The decision to use injections should be preceded by magnetic resonance imaging (MRI), which will help determine the level of the injection. If arterial blood is encountered during the injection itself, it is prudent to consider aborting the procedure. While clinicians are well advised to take all appropriate and required steps, doing “everything possible” may cause over-management and its own complications.S. aureus. Before administering such an injection, consider the hematological and oncological clearance of the patient and do not inject if there is evidence of any pre-existing systemic infection.Epidural abscesses are rare but potentially life-threatening iatrogenic side effects of epidural injections of corticosteroids. MRI is the preferred imaging mode for diagnosing such abscesses, but computed tomography plus myelography may be used if an MRI is impossible. When conducting imaging studies, it is crucial to note that these abscesses can be multifocal . At greaEducate interventional pain patients to consult with the physician and the dentist before undergoing dental procedures. It has been speculated that individuals at elevated risk for epidural abscesses, such as those with compromised immune systems, be treated with prophylactic antibiotics prior to certain dental procedures, but there is no clear guidance in the literature on that point . EpiduraFor transforaminal epidural injections of steroids into the cervical spine, computed tomography imaging studies or Doppler ultrasound evaluations should be carried out in order to prevent vessel injury. This will allow the visualization of potentially vulnerable vessels . Radial Pharmacologic therapy for painful conditions has proven to be safe and effective for many patients, but sound clinical judgment and periodic re-evaluation are required for optimal results. Particularly for elderly patients and those with impaired renal or hepatic systems, certain drugs may be contraindicated. In all patients who take multiple drugs, there is a potential for pharmacokinetic drug-drug interactions . FurtherOf course, sound clinical judgment is required, particularly for patients with mental health conditions, those at the end of life, or those with extremely complex and life-threatening diseases. Since many patients are prescribed drugs without taking a “big picture” view of their medications and a holistic assessment of their health and function, it is important to review medications on a regular basis . Where mDespite progress in treating painful conditions, interventional procedures and drug therapy to reduce pain may introduce iatrogenic side effects. These adverse events range from those that are merely bothersome to those that reduce the quality of life or even pose threats to life. Pain physicians must be cognizant of the rare but potentially catastrophic iatrogenic events that may occur in interventional pain treatments. Likewise, drug therapy may cause serious side effects, such as opioid-induced constipation which requires judicious management, ideally with a PAMORA product. Geriatric patients and those with complex conditions may require periodical medication reviews to avoid complications associated with polypharmacy, prescribing cascades, and the use of contraindicated or suboptimal drugs. When deprescribing a patient taking polypharmacy, care should be taken to avoid or mitigate withdrawal symptoms, typically using a validated taper plan and a shared decision-making model with the patient.


Recent studies have shown that the mouth–gut–disc axis may play a key role in the process of disc structural failures  and endplate change) in the cervical spine and neck pain. However, the potential mechanisms underlying the mouth–gut–disc axis remain elusive. Therefore, we explored whether periodontal disease is associated with disc structural failures in patients with cervical degeneration disorders and clinical outcomes.Adults (aged > 18 years) who met open surgery criteria for cervical spine were enrolled in this prospective cohort study. Participants were allocated into two groups based on periodontal examinations before surgery: no/mild periodontitis group and moderate/severe periodontitis group. Data were evaluated using an independent t test and Pearson’s correlation analysis.P = 0.005), plaque index (PLI) (P = 0.003), bleeding index (BI) (P = 0.000), and probing depth (PD) (P = 0.000) significantly differed between the two groups. The incidence rate of endplate change (P = 0.005) was higher in the moderate/severe periodontitis group than in the no/mild periodontitis group. A moderate negative association was found between the neck disability index (NDI) score and periodontal parameters .A total of 108 patients were enrolled, including 68 patients in the no/mild periodontitis group and 40 patients in the moderate/severe periodontitis group. The number of common causes of missing teeth (This is the first study to provide evidence that severe periodontitis is associated with a higher occurrence rate of disc structural failures and poor clinical outcomes in patients with cervical degenerative disorders. Chronic neck pain is a significant public health problem, leading to disability and productivity loss worldwide , 2, espeInflammation is thought to be one of the main triggers for developing disc structural failure. Other potential factors for triggering disc structural failure include natural history, aging, smoking, mechanical and genetic factors, obesity, and inadequate metabolite transport. Growing evidence supports that infection of the intervertebral disc by low-virulence organisms may be crucial to the inflammatory response . Our preDiverse microbial communities inhabit the oral cavity, which contains about 50 species with a subset of 1,000 species , 10. TheThe present prospective study investigated the relationships among periodontal disease, IDD, endplate changes, and clinical outcomes in patients with cervical degenerative disorders.This prospective cohort study was approved by the Medical Research Ethics Committee of our institution. All participants agree for their demographic, clinical, and radiological data to be used in this study.Participants aged 18 years or old adults who met the criteria to undergo open cervical spine surgery were enrolled between July 2019 and December 2021. A periodic oral evaluation was performed before surgery at our institution.Participants with a history of spinal deformity, trauma, infection, and tumor in the cervical spine; prior cervical spine surgery; and diagnosed with systemic metabolic, severe organic, and systematic diseases were excluded from this study.Patients’ age, gender, height, weight, body mass index (BMI), duration of neck pain, positive signs, and final diagnosis were obtained during the admission period by surgeons.Periodontal parameters were recorded during the basic periodontal examination by stomatologists (DX and YZ), including the history of periodontal treatment, periodontal maintenance, history of mouthwash, the number of loose teeth, the number of remaining teeth, common causes of missing teeth, plaque index (PLI), gingival recession (GR), bleeding index (BI), and probing depth  , 20. AllThree questionnaires were evaluated before the surgery once written consent was obtained from the participants. The questionnaires included the Visual Analogue Scale (VAS) for evaluating neck pain and/or radicular pain, the neck disability index (NDI) for assessing function and disability, and the Japanese Orthopedic Association score (JOA) for the assessment of cervical myelopathy.Participants’ magnetic resonance images, consisting of sagittal T1-weight fast spin-echo (FSE), sagittal T2-weighted FSE, and axial T2-weighted FSE, were obtained using 3.0 T Trio Tim scanner . The middle slice of T2-weighted FSE images was selected for the measurement. To reduce the potential bias, the same Apple MacBook laptop and DICOM Viewer software  were used for the measurement.The Pfirrmann grade was used to assess the degeneration of IVD , 22. IDDCervical lordosis, range of motion (ROM), and the anterior, middle, and posterior disc height of each cervical IVD level were measured using cervical spine X-rays .t test, and Chi-square test were used to analyze differences in features and clinical scores between no/mild and moderate/severe periodontitis groups. The normality of continuous variables was assessed. Pearson’s correlation analysis was performed to evaluate the relationship between periodontal parameters and radiological and clinical outcomes. The correlation was ranked as very strong, strong, moderate, and weak based on the following values: > 0.7, 0.5–0.7, 0.3–0.5, and < 0.3, respectively. Intra-class correlation coefficient (ICC) and their 95% confidence intervals (95% CI) were used to evaluate intra- and inter-rater reliability [P value of < 0.05 was considered statistically significant.Continuous and dichotomous data were expressed as mean ± standard deviation (SD) and number with percentage, respectively. One-way analysis of variance (ANOVA), independent samples iability . SPSS v22, and 54.88 weeks , respectively. Patients were divided based on the Pfirrmann grading system, with 38 patients in the IDD group and 70 in the non-IDD group. The mean preoperative scores of VAS neck pain, JOA, and NDI were 4.87 ± 1.08, 12.30 ± 1.77, and 25.43 ± 6.97, respectively.A total of 108 consecutive patients with cervical degenerative disorders  who underwent an anterior cervical discectomy and fusion surgery from July 2019 to December 2021 at our institution were enrolled. Of these, 68 subjects were allocated into the no/mild periodontitis group and the remaining 40 subjects were allocated into the moderate/severe periodontitis group. The mean of age, BMI, and duration of pain was 42.52 years , 23.85 kg/mP = 0.005), PLI (P = 0.003), BI (P < 0.001), and PD (P < 0.001) significantly differed between the two groups . No significant differences were found between the two groups regarding VAS neck pain, JOA, and the duration of pain (Table The preoperative NDI was significantly lower in the no/mild periodontitis group than in the moderate/severe periodontitis group (in Table .Table 3CP = 0.005). No significant differences were found between the two groups in terms of the incidence rates of IDD, cervical lordosis, ROM, and disc height of each cervical IVD level  and radiological data  Table .Table 4Ar = − 0.337, P = 0.013; BI: r = − 0.426, P = 0.001; PD: r = − 0.346, r = − 0.010), but no significant differences were observed in terms VAS neck pain and JOA scores. The GR and number of remaining teeth were unrelated to preoperative clinical outcomes, such as VAS neck pain, JOA, and NDI scores  and PD: 0.824 ) and radiological data , disc height: 0.822 , and cervical lordosis: 0.835 ) ranged from good to excellent.This study sought to determine the relationships between the severity of periodontitis and disc structural failures in adults with cervical degenerative disorders. There are two major findings. First, individuals with severe periodontitis had a higher incidence rate of endplate changes. Second, some specific parameters in periodontitis were negatively associated with cervical disability scores. These findings provide a better understanding of the potential mechanisms underlying the mouth–gut–disc axis in the cervical spine.The human microbiome plays a key role in regulating health and diseases. 16S ribosomal RNA sequencing as the most widely used polymerase chain reaction-dependent technique can be used to analyze the microbial diversity and characterize microbiota from IDD patients. A previous review strongly supports the changes in the microbial composition and metabolites, which might emerge as an important player in regulating and managing spinal pain in patients with IDD , 8. DysbThe human oral microbiome—as one of the largest microbial communities with approximately 600 bacterial species—plays a key role in balancing the equilibrium between symbiotic or pathogenic factors and the defense mechanisms of the immune system , 30. MosCutibacterium acnes as the primarily involved pathogen in disc structural failures in the cervical spine [Cutibacterium acnes showed that low-virulence organism infection of cervical IVDs can lead to degenerative changes [Although the cause of IDD is multifactorial, infection with low-virulence organisms has been considered one of the main triggers of inflammation in the degenerative process , 40. Diral spine –29. Rece changes . HoweverRecently, one study provided evidence for the existence of differences in the microbiome composition in healthy, degenerative, and herniated IVD . In addiAlthough oral or gut microbiota is thought to be the essential trigger of inflammation in the degenerative process, the source of the low-virulence organism for the pathogenesis of disc structural failures in the cervical spine is yet to be discovered. Our study provided indirect evidence supporting the concept of the mouth–disc axis in the cervical spine. We found a higher incidence rate of endplate changes in individuals with moderate and/or severe periodontitis. A previous study reported a significant difference in the subgingival microbiome between mild and severe periodontitis groups. The microbial composition was positively correlated with the expression of systemic inflammatory markers . Taken tIn theory, alterations in oral microbiome composition aggravate the severity of PLI, BI, and PD in periodontitis, which may induce local and systemic inflammatory responses for regulating bone development and the involution process. Moreover, the inflammatory state may trigger a change in the internal and external microenvironment of IVD. Furthermore, direct invasion of organisms into the IVDs and dysregulation of local and systemic inflammatory activity can stimulate the expression of inflammatory cytokines and activate immune cells, leading to IDD and endplate changes. Inflammatory cytokines and migration of immune cells can also induce the appearance of nociceptive nerve fibers in IVDs and dorsal root ganglia. Due to these cascade responses, the expression of pain-related channels was elevated for amplifying and transmitting pain signals to the dorsal root ganglia and brain as related spinal pain .Nonetheless, this study has several limitations. First, although this study reports indirect evidence, direct evidence of oral microbial pathogens is missing. Second, although our and previous studies supported the group classification, the group allocation has potential bias. Third, the number of patients with smoking status and diagnosis with diabetes among the study groups were not significant differences. However, the potential bias from the risk factors in the developing disc structural failures still exists. Fourth, the pathological and laboratory tests of tissue samples were not conducted. Future prospective randomized controlled studies with a larger sample size should be performed to investigate the direct relationships between oral microbiome composition and disc structural failures and clinical outcomes.In summary, the present study identified the relationship between severe periodontitis and a high incidence rate of endplate changes and poor clinical outcomes in patients with cervical degenerative disorders. The discovery of these associations provides new insights into a novel mechanism through which the alterations in the composition of the oral microbiome potentially promote disc structural failures and pain in the cervical spine.


This study relates to the LEGATO-HD, multi-centre, double-blinded, Phase 2 clinical trial with laquinimod . Fifteen patients of the UK LEGATO-HD cohort  were treated with laquinimod  or placebo (N = 5) daily. All participants had one 11C-PBR28 PET-CT and one brain MRI scan before laquinimod (or placebo) and at the end of treatment (12 months apart). PET imaging data were quantified to produce 11C-PBR28 distribution volume ratios. These ratios were calculated for the caudate and putamen using the reference Logan plot with the corpus callosum as the reference region. Partial volume effect corrections  were applied. Differences were sought in Unified Huntington’s Disease Rating Scale scores and regional distribution volume ratios between baseline and follow-up and between the two treatment groups (laquinimod versus placebo). No significant change in 11C-PBR28 distribution volume ratios was found post treatment in the caudate and putamen for both those treated with laquinimod (N = 10) and those treated with placebo (N = 5). Over time, the patients treated with laquinimod did not show a significant clinical improvement. Data from the 11C-PBR28 PET-CT study indicate that laquinimod may not have affected regional translocator protein expression and clinical performance over the studied period.Microglia activation, an indicator of central nervous system inflammation, is believed to contribute to the pathology of Huntington’s disease. Laquinimod is capable of regulating microglia. By targeting the translocator protein,  11C-PBR28 PET (specific marker of reactive gliosis). Roussakis and Gennaro report that 12-month long laquinimod treatment (0.5 or 1 mg daily versus placebo) does not affect regional microglia activation.This is a longitudinal study in Huntington’s disease with laquinimod (microglia modulator) and   Indeed, all patients with Huntington’s disease develop a plethora of alterations in the brain at both structural and functional levels, primarily in the striatum, as a result of a CAG repeat expansion on Chromosome 4.5 and Alzheimer’s diseases.7 Microglia activation is considered an indicator of central nervous system inflammation.8 In the context of Huntington’s disease, microglia activation is believed to contribute to the disease pathology. Neurons affected by clusters of abnormal Huntingtin are progressively damaged. It is believed that reactive microglia fail to address regional damage adequately over time. As Huntington’s disease progresses, regional gliosis becomes a toxic environment for the damaged neurons. These points enable microglia as a target for therapeutic intervention in Huntington’s disease and a promising area for research.In the human brain, microglia become ‘activated’ in response to neuronal damage and loss. This process is complicated and can become chronic. Many of the features of reactive gliosis are shared by the most common neurodegenerative disorders including Parkinson’s9–11 To evaluate microglia activation in vivo, we employ 11C-PBR28, a second-generation PET radioligand that is highly specific for the translocator protein (TSPO).12–14The current study concerns the imaging outcomes of a multi-centre, randomized, double-blind, placebo-controlled, parallel-group clinical trial in Huntington’s disease. On 0.5 and 1.0 mg daily, laquinimod has shown favourable CNS kinetics and good tolerability in healthy volunteers and multiple sclerosis patients.15 When the TSPO is in high density within microglia, it is believed to reflect regional gliosis.16–18 The chosen brain regions for this PET study were caudate and putamen, as they are predominantly involved in motor control. The secondary objective of this PET study was to look at a possible relation of striatal 11C-PBR28 binding to the clinical characteristics of Huntington’s disease patients.The TSPO is expressed at various sites in the human CNS, including the mitochondria of microglia.The main clinical trial was organized by Teva Pharmaceuticals in collaboration with the Huntington Study Group and the European Huntington’s Disease Network. The clinical trial details can be found online at the US National Register  and the EU Drug Regulating Authorities Clinical Trials Database (EudraCT: 2014-000418-75). For the UK sites, the study was approved by the Health Research Authority (IRAS: 151325), the South Central Hampshire B research ethics committee (REC Reference: 14/SC/1340), the Medicines and Healthcare Regulatory Agency (MHRA: 34261/0017/001) and the Administration of Radioactive Medicinal Products Committee (ARSAC: 630/3764/32453), UK. Enrolment into the PET-CT imaging study was optional. Written consent was sought in accordance with the Declaration of Helsinki. Dynamic randomization (1:1:1) was performed with interactive response technology to balance the treatment groups at the UK centres. The research team at Imperial College London and the recruiting UK sites as well as the study participants were blinded for the duration of the treatment period.N = 15) who completed the treatment period.Participants enrolled in the LEGATO-HD trial (Sponsor’s reference: TV5600-CNS-20007) were referred to Imperial College London for PET imaging. Nineteen Huntington’s disease patients met the inclusion and exclusion criteria see  of the P20 All healthy volunteers had one PET-CT and one brain MRI scan at the Imanova Imaging Centre under the same protocol of Huntington’s disease patients. Analyses of this data set were performed at outlined below (see relevant section).In addition, we included PET-CT and MRI data from a group of 21 healthy volunteers. Details about this dataset can be found elsewhere.21 UHDRS-Motor and UHDRS-Functional subscores were calculated for each patient from ‘Motor Assessment’ and ‘Functional Capacity’ components of the form. Subjects on high doses of diazepam (20-30 mg/daily) were excluded from the PET-CT imaging study as this may have had central TSPO binding effects,22 thus potentially compromising the quality of the data. At enrolment for the PET study, we excluded those Huntington’s disease patients who were treated with benzodiazepines, tetrabenazine, neuroleptics, or N-methyl-D-aspartate receptor blocking agents. We did not screen for non-steroidal anti-inflammatory drugs.Huntington’s disease patients  were administered laquinimod (0.5 or 1.0 mg) or placebo on a daily basis and were reviewed by Huntington’s disease specialist clinical teams at regular intervals. The severity of Huntington’s disease was assessed using the Unified Huntington’s Disease Rating Scale (UHDRS).rs6971 locus in the TSPO gene has a polymorphism that affects the binding of all known second generation TSPO-specific radioligands.23–25 In the general population, people without the polymorphism have high affinity binding for PBR28, homozygotes have low affinity binding and heterozygotes express both high and low affinity for it (mixed affinity binding). In this study, we recruited high (HAB) and mixed (MAB) affinity binders. For women of childbearing potential, negative urine pregnancy testing was required at the PET imaging facility prior to any procedure involving radiation. These tests were in addition to the standard safety measures taken during the main LEGATO-HD study.The 11C-PBR28 PET-CT imaging took place at the Imanova (currently Invicro Ltd) imaging centre at the Hammersmith Hospital site in London, UK. Specific activity, chemical composition and radiochemical purity of 11C-PBR28 were determined by radioactive high-performance liquid chromatography coupled with a gamma detector. Further details on radioligand synthesis can be found here.27All 11C-PBR28 was injected as an intravenous bolus injection in the PET suite followed by a 90-min dynamic acquisition. The mean 11C-PBR28 injected activity was 323.3 ± 38.5 MBq. PET-CT scanning took place on a Siemens Biograph Hi-Rez 6 PET-CT scanner . PET data were reconstructed using a filtered back projection algorithm (direct inversion Fourier transform) with a 128 matrix, zoom of 2.6, a transaxial Gaussian filter of 5 mm producing images with an isotropic voxel size of 2 × 2 × 2 mm3. Attenuation and scatter correction were applied based on the low-dose CT data. The dynamic images were binned into 26 frames .1-weighted MR sequence at baseline and at follow-up (end of treatment or early termination) within 4 weeks of each PET-CT scan. All healthy volunteers had a volumetric T1-weighted MR sequence. T1-weighted magnetization-prepared rapid acquisition gradient echo (MPRAGE) images were acquired under a standardized protocol across the recruiting sites as described before.28 MPRAGE data were used for the volumetric analyses and for co-registration with the PET images.All patients had a volumetric TThe imaging analysis team was given access to view and electronically download the MRI data in digitized pseudonymized form via the trial-specific online platform. MRI scans of the Huntington’s disease patients were in DICOM  format, without any preprocessing, and labelled with a pseudonymized code identical to that given to each individual patient. Raw MRI data were matched to the PET-CT imaging data, also saved in DICOM format by the imaging analysis team. QC testing was performed at the MR and PET-CT facilities where data had been acquired and at a second level at the PET-CT imaging workstation at Imperial College London.11C-PBR28 PET-CT and MPRAGE MRI data were performed using an in-house integrated pipeline as described before29 with MIAKAT™  software for academic use.30 MIAKAT is implemented in MATLAB® , SPM12  and FSL .Processing and kinetic modelling of the https://surfer.nmr.mgh.harvard.edu) using individual MPRAGE and then customized manually on Analyze  to account for segmentation inaccuracies due to atrophy. Frame-by-frame motion correction was applied to the dynamic PET data. A summed PET image was created and co-registered to ROIs, CC binary masks and the CIC atlas31 using normalized information as the cost function. 11C-PBR28 time activity curves were generated. The distribution volume ratio (DVR) values where calculated employing the Logan reference kinetic plot32 using the CC as a pseudo-reference region. All steps of the above analysis pipeline successfully passed QC testing. MRI volumetric assessment was performed using FreeSurfer with a volume-based subcortical approach as previously reported.33MPRAGE images were rigidly registered to the Montreal Neurological Institute space after brain extraction and segmentation. Binary masks of the caudate and putamen, referred to as region of interest (ROIs), and the corpus callosum (CC) were created on the FreeSurfer images analysis suite  was applied to the PET data, using the PET PVE12 SPM toolbox,α = 0.05. Homogeneity of variances was performed with Bartlett’s test. The Kolmogorov-Smirnov normality test was performed to examine if variables were normally distributed. Graph illustrations were performed using the GraphPad Prism software, Version 6 for Microsoft windows and Microsoft Office Excel.Statistical analyses were performed using the IBM SPSS® Statistics software, Version 25 for Microsoft windows. The significance  level was set at 11C-PBR DVRs and volumes (MRI data) as well as of age between the patients and healthy volunteers were performed with t-test for independent samples. Chi-squared (χ2) test was performed to assess gender differences, followed by Yates’s correction. For the Huntington’s disease group, we sought for correlations of regional 11C-PBR DVRs with CAG repeats, age, disease duration from diagnosis (DDdiagn), disease duration from onset (DDonset) and UHDRS scores using non-parametric Spearman’s rho coefficient (r). Benjamini-Hochberg procedure was applied afterwards.Validation of the Huntington’s disease data set was made through comparisons of means between the Huntington’s disease patients (baseline data) and those from the group of healthy volunteers. Comparisons of caudal and putaminal 11C-PBR28 DVRs and volumes (MRI data) between baseline and follow-up were performed with paired t-tests. Comparisons of 11C-PBR28 DVRs between placebo and laquinimod treatment groups at baseline were performed with non-parametric Mann-Whitney U tests. Comparisons between baseline and follow-up 11C-PBR28 DVRs and UHDRS scores were performed with non-parametric Wilcoxon signed-rank test for related samples. Change over time is shown with 11C-PBR28 ΔDVRs. │Δ│ = │ (Follow-up DVR) – (Baseline DVR)│. Percentage DVR changes were calculated as % DVR change = 100 × │Δ│/(Baseline DVR).Huntington’s disease patients were then divided into two groups: placebo and laquinimod (either 0.5 or 1.0 mg) treatment. Comparisons of caudal and putaminal N = 4), laquinimod 1.0 mg (N = 6) and placebo (N = 5). Imaging (PET and MRI) and clinical data are tabulated below (see Randomization (1:1:1) of Huntington’s disease patients resulted in three groups: laquinimod 0.5 mg  = −0.66, −0.38] and the putamen  in the Huntington’s disease group when compared with healthy volunteers. All patients showed marked striatal volume losses when compared with healthy volunteers at baseline . At enrolment, the healthy volunteers were age-matched to the Huntington’s disease group. However, not matched for gender . See more in Baseline 11C-PBR DVRs correlated with the CAG repeats in 18 Huntington’s disease patients . DVR values also correlated with DDdiagn  and DDonset  from the group treated with laquinimod  was different in the brains of Huntington’s disease participants. This change, however, was not statistically significant for patients treated with either placebo or laquinimod. At the end of the treatment period, Huntington’s disease patients (either on laquinimod or placebo) had no significant change from baseline in their clinical scores, while all maintained marked striatal volume losses , and with disease duration measures (DDdiagn and DDonset). These results are in line with previous work on manifest and pre-manifest Huntington’s disease,38 and add validity to the chosen methods.At first, we would like to acknowledge that there is no consensus in the literature on how to best study neuroinflammation in Huntington’s disease 11C-PBR28 PEC-CT methodology studies,39 we decided to omit arterial cannulation and have a pragmatic approach at enrolment. We acknowledge that this approach may not be adequate for a study on a common disorder.For the purposes of this study, our Huntington’s participants make a representative group of Huntington’s disease patients. Our patients demonstrate variable disease durations and variable number of CAG repeats. Taking into account feasibility aspects , and results from previous 41 By reviewing former research work on PBR28, TSPO expression and Huntington’s disease pathology, we decided to use the CC as the reference region after exploring several brain regions, including the cerebellum.29In the absence of arterial input function from the present design, quantification of TSPO-specific PET-CT data from patients with Huntington’s disease and marked atrophy required extra steps.42 However, the CC has been shown to be least affected by Huntington’s disease when compared with white matter that surrounds the striatum.1 For the purposes of this study, we chose the entire CC as the reference region, as it has (i) reasonably low Huntingtin expression , (ii) comparable TSPO expression with basal ganglia tissue (to assume similar non-specific binding) and (iii) no severe atrophy to allow meaningful analyses. In general terms, the basal ganglia and CC are anatomically and functionally distinct regions. In people with Huntington’s disease, the expression of mutant Huntingtin does not have the same impact on the various types of neurons across the brain. The assumption is that abnormal Huntingtin is a major single factor for regional neuronal damage in this disease. We are making this point to distinguish the basal ganglia from the CC regarding susceptibility to degenerative disease. The latter point refers to evidence from studies in idiopathic Parkinson’s disease.44Issues with TSPO imaging refer to variability in the TSPO affinity status and the integrity of the brain tissue under study. In Huntington’s disease, post-mortem data demonstrate the presence of reactive microglia in the subcortical white matter and internal capsule.45–48 enables the two regions of interest (caudate and putamen) susceptible to a partial volume effect. This phenomenon can introduce a bias in the activity quantification of the PET images,50 and considerably impact the validity of extracted DVRs. Here, we applied PVC to minimize the atrophy bias on our dataset. We also performed statistical testing using the uncorrected values and results remained unchanged  duration of treatment. After considering all available evidence at the set-up of the PET study, we decided to screen for TSPO affinity status and exclude low affinity binders. We acknowledge that HABs and MABs are presented together in this report and that this is a limitation of the current methodology.52 This trend has been recently confirmed by 11C-PBR28 PET-CT data in healthy volunteers.52 However, with current knowledge, epidemiological and genetic sources do not highlight gender as a significant known risk factor for Huntington’s disease.53–55In this study, Huntington’s disease patients and healthy volunteers were age matched but not for gender. Previous work in rodents have shown a greater number of microglia in females.With current evidence, the study of microglia activation in the context of manifest Huntington’s disease is a complex area for research. As neuroinflammation is a chronic process that starts in pre-manifest Huntington’s disease and develops over years, it is possible that the study of microglia activation and the effect CNS modulators (such as laquinimod) have on it require longitudinal study designs, including Huntington’s disease patients as well as pre-manifest cases.11C-PBR28 PET-CT data sets the background for future studies on neuroinflammation in Huntington’s disease.The data from the PET-CT study of the LEGATO-HD trial show that TSPO expression in the caudate and putamen does not change significantly over 1 year in patients with Huntington’s disease. In this cohort, laquinimod treatment did not improve clinical symptoms. The proposed pipeline for analysing fcad084_Supplementary_DataClick here for additional data file.