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BACKGROUND Women with dysmenorrhoea plus symptomatic urinary calculosis experience enhanced pain and referred muscle hyperalgesia from both conditions than women with one condition only (viscero-visceral hyperalgesia). The study aimed at verifying if enhanced dysmenorrhoea persists after urinary stone elimination in comorbid women and if local anaesthetic inactivation of myofascial trigger points (TrPs) in the lumbar area (of urinary pain referral) also relieves dysmenorrhoea. METHODS Thirty-one women with dysmenorrhoea plus previous urinary calculosis (Dys+PrCal) and lumbar TrPs, and 33 women with dysmenorrhoea without calculosis (Dys) underwent a 1-year assessment of menstrual pain and muscle hyperalgesia in the uterus-referred area (electrical pain threshold measurement in rectus abdominis, compared with thresholds of 33 healthy controls). At the end of the year, 16 comorbid patients underwent inactivation of TrPs through anaesthetic injections, whereas the remaining 12 received no TrP treatment. Both groups were monitored for another year at the end of which thresholds were re-measured. RESULTS In year1, Dys+PrCal presented significantly more painful menstrual cycles and lower abdominal thresholds than Dys, thresholds of both groups being significantly lower than normal (p

Headache is a significant reason for access to Emergency Departments (ED) worldwide. Though primary forms represent the vast majority, the life-threatening potential of secondary forms, such as subarachnoid hemorrage or meningitis, makes it imperative for the ED physician to rule out secondary headaches as first step, based on clinical history, careful physical (especially neurological) examination and, if appropriate, hematochemical analyses, neuroimaging or lumbar puncture. Once secondary forms are excluded, distinction among primary forms should be performed, based on the international headache classification criteria. Most frequent primary forms motivating ED observation are acute migraine attacks, particularly status migrainous, and cluster headache. Though universally accepted guidelines do not exist for headache management in an emergency setting, pharmacological parenteral treatment remains the principal approach worldwide, with NSAIDs, neuroleptic antinauseants, triptans and corticosteroids, tailored to the specific headache type. Opioids should be avoided, for their scarce effectiveness in the acute phase, while IV hydration should be limited in cases of ascertained dehydration. Referral of the patient to a Headache Center should subsequently be an integral part of the ED approach to the headache patients, being ascertained that lack of this referral involves a high rate of relapse and new accesses to the ED. More controlled studies are needed to establish specific protocols of management for the headache patient in the ED.

Background ATP-binding cassette A1 (ABCA1) and G1 (ABCG1) mediate cholesterol efflux from lipid-laden macrophages, thus promoting anti-atherosclerotic outcomes. The mechanism(s) linking treatment with statins and ABCA1/ABCG1 in human atherosclerosis are not fully understood and require further investigation. Therefore, we studied whether short-term treatment with low- or high-dose rosuvastatin may affect ABCA1 and ABCG1 expression in human atherosclerotic plaques. Methods Seventy patients with severe stenosis of the internal carotid artery were randomized to receive low (10 mg/day) or high (40 mg/day) dose rosuvastatin for 12 weeks before elective endarterectomy. As controls, we analyzed a reference group of 10 plaques from subjects with hypercholesterolemia but not receiving statin treatment and an additional set of 11 plaques collected from normocholesterolemic patients. On atherosclerotic plaques, ABCA1 and ABCG1 expression was evaluated at RNA level by qPCR and at protein level by immunoblotting and immunohistochemistry. Results Both rosuvastatin doses were associated with lower plaque ABCA1 mRNA levels and with a trend toward reduction for ABCG1. However, ABCA1 protein was paradoxically higher in patients treated with high-dose rosuvastatin and was associated with lower levels of miR-33b-5p, a microRNA known as a regulator of ABCA1. Multivariate analyses showed that the effect is cholesterol-independent. Finally, no effects were found for ABCG1 protein. Conclusions High-dose rosuvastatin increases macrophage ABCA1 protein levels in human atherosclerotic plaque despite mRNA reduction in a mechanism unrelated to plasma cholesterol reduction and potentially involving miR-33b-5p. This pathway may reflect an additional feature contributing to the anti-atherosclerotic effect for high-dose rosuvastatin. Trial registration: ISRCTN16590640

Since it has been recognized that sarcoidosis (SA) is not an exclusive disorder of the lungs but can also affect other organs such as the liver and spleen, efforts have been made to define specific imaging criteria for the diagnosis of the single organ involvement, and the concept has been reinforced that the exclusion of alternative causes is important to achieve the correct diagnosis. Ultrasound (US) is a useful tool to evaluate patients with suspected abdominal SA, such as of the liver, spleen, kidney, pancreas and other organs, showing findings such as organomegaly, focal lesions and lymphadenopathy. While the diagnosis of abdominal SA is more predictable in the case of involvement of other organs (e.g., lungs), the problem is more complex in the case of isolated abdominal SA. The recent use of contrast-enhanced ultrasound and endoscopic ultrasound elastography has provided additional information about the enhancement patterns and tissue rigidity in abdominal SA. Here we critically review the role of US in abdominal SA, reporting typical findings and limitations of current evidence and by discussing future perspectives of study.

Background: Point-of-care lung ultrasound (LUS) score is a semiquantitative score of lung damage severity. High-resolution computed tomography (HRCT) is the gold standard method to evaluate the severity of lung involvement from the novel coronavirus disease (COVID-19). Few studies have investigated the clinical significance of LUS and HRCT scores in patients with COVID-19. Therefore, the aim of this study was to evaluate the prognostic yield of LUS and of HRCT in COVID-19 patients. Methods: We carried out a multicenter, retrospective study aimed at evaluating the prognostic yield of LUS and HRCT by exploring the survival curve of COVID-19 inpatients. LUS and chest CT scores were calculated retrospectively by 2 radiologists with >10 years of experience in chest imaging, and the decisions were reached in consensus. LUS score was calculated on the basis of the presence or not of pleural line abnormalities, B-lines, and lung consolidations. The total score (range 0–36) was obtained from the sum of the highest scores obtained in each region. CT score was calculated for each of the 5 lobes considering the anatomical extension according to the percentage parenchymal involvement. The resulting overall global semiquantitative CT score was the sum of each single lobar score and ranged from 0 (no involvement) to 25 (maximum involvement). Results: One hundred fifty-three COVID-19 inpatients (mean age 65 ± 15 years; 65% M), including 23 (15%) in-hospital deaths for any cause over a mean follow-up of 14 days were included. Mean LUS and CT scores were 19 ± 12 and 10 ± 7, respectively. A strong positive linear correlation between LUS and CT scores (Pearson correlation r = 0.754; R2 = 0.568; p < 0.001) was observed. By ROC curve analysis, the optimal cut-point for mortality prediction was 20 for LUS score and 4.5 for chest CT score. According to Kaplan-Meier survival analysis, in-hospital mortality significantly increased among COVID-19 patients presenting with an LUS score ≥20 (log-rank 0.003; HR 9.87, 95% CI: 2.22–43.83) or a chest CT score ≥4.5 (HR 4.34, 95% CI: 0.97–19.41). At multivariate Cox regression analysis, LUS score was the sole independent predictor of in-hospital mortality yielding an adjusted HR of 7.42 (95% CI: 1.59–34.5). Conclusion: LUS score is useful to stratify the risk in COVID-19 patients, predicting those that are at high risk of mortality.

Background Triptans and erenumab are both migraine-specific agents acting on the calcitonin gene-related peptide pathway. Therefore, response to triptans might be associated with response to erenumab. Main body In our study, consecutive patients referring to the Headache Centers of the Abruzzo region from January 2019 to March 2020 and treated with erenumab were interviewed about past use and efficacy of triptans. Triptan users were classified as ‘triptan responders’ if they were headache-free 2 h after treating ≥3 migraine attacks with ≥1 triptan. We considered patients as ‘erenumab responders’, if they had a ≥ 50% mean reduction in monthly migraine days between the 4th and the 6th month from treatment start compared with baseline. Of 91 triptan users, 73 (80.2%) were triptan responders and 58 (63.7%) were erenumab responders. The odds ratio of being erenumab responder was 3.64 (95% CI, 1.25–10.64) for triptan users as compared to non-users. (P = 0.014). Besides, starting erenumab improved triptan response in both erenumab responders and non-responders. Conclusions Our data of an association between response to triptans and response to erenumab can be useful for patient advice and to improve the understanding of migraine pathophysiology and treatment.

Sarcoidosis is a granulomatous disorder of unknown etiology characterized by noncaseating granulomas virtually in every organ and tissue. This finding represents the most important diagnostic clue to reach a correct definition of sarcoidosis, although the biopsy is invasive and has several risk procedures. Several efforts are made to suspect the diagnosis of sarcoidosis by combining noninvasive elements, in particular from imaging, though these findings are often nonspecific and reflect the wide multifactorial pathogenesis. Every effort should be made to obtain a detailed radiological picture that, if associated with a suggestive clinical picture, could avoid the need of biopsy in some specific cases. In this narrative review, we aim to describe main computed tomography (CT) features of pulmonary and abdominal sarcoidosis, by reporting strengths and limits of this technique, in particular for the identification of extrapulmonary, isolated disease.

BackgroundMost patients treated with erenumab in clinical practice have chronic migraine (CM). We assessed the rate and possible predictors of conversion from CM to episodic migraine (EM) in a real-life study.Main bodyWe performed a subgroup analysis of patients treated with erenumab from January 2019 to February 2020 in the Abruzzo region, central Italy. Treatment was provided according to current clinical practice. For the purpose of the present study, we included patients fulfilling the definition of CM for the three months preceding erenumab treatment and with at least 6 months of follow-up after treatment. We assessed the rate of conversion to EM from baseline to Months 4–6 of treatment and during each month of treatment. To test the clinical validity of conversion to EM, we also assessed the decrease in monthly headache days (MHDs), acute medication days, and median headache intensity on a Numerical Rating Scale (NRS). We included in our study 91 patients with CM. At Months 4–6, 62 patients (68.1%) converted from CM to EM; the proportion of converters increased from Month 1 to Month 5. In the overall group of patients, median MHDs decreased from 26.5 (IQR 20–30) to 7.5 (IQR 5–16;P P P ConclusionsIn our study, two thirds of patients with CM converted to EM during 6 months of treatment with erenumab. MHDs, acute medication use, and headache intensity decreased regardless of conversion from CM to EM.

Background We aimed to assess the efficacy and safety of erenumab, a fully human monoclonal antibody inhibiting the calcitonin gene-related peptide receptor (CGRPr), for the prevention of migraine in a real-life setting. Main body We included in our observational study all patients with episodic or chronic migraine treated with erenumab during the year 2019 in the Abruzzo region, central Italy, and with a 6-month follow-up. We included 89 patients; 76 (85.4%) received 6 doses of erenumab, 11 (12.4%) autonomously withdrew the drug due to perceived inefficacy, and 2 (2.2%) due to adverse events. Seventy-eight patients (87.6%) were female, with a mean age of 46.8 ± 11.2 years; 84 (94.4%) had chronic migraine, and 64 (71.9%) medication overuse. All patients had ≥2 prior preventive treatment failures. Fifty-three patients (69.7%) had a 50% decrease in monthly migraine days (MMDs) within the first three doses; 46 (71.9%) of 64 patients withdrew medication overuse. In the 76 patients who completed a 6-dose treatment, erenumab decreased median MMDs from 19 (interquartile range [IQR] 12–27.5) to 4 (IQR 2–9.5; P Conclusions Our real-life data confirm the efficacy and tolerability of erenumab for the prevention of migraine in a difficult-to-treat population of patients with a high prevalence of chronic migraine and medication overuse.

Hyperuricemia and gout represent important issues in the obese patients. Considering the epidemic trend of overweight and obesity in developed countries, the impact of these conditions is likely to increase. At present, bariatric surgery represents the most effective treatment for the management of severe obesity for reducing weight and the impact of associated comorbidities, but its effects on hyperuricemia and gout have not been fully elucidated.In this narrative review, we discuss the current knowledge about hyperuricemia and gout in obese patients undergoing bariatric surgery. We also suggest a useful approach to prevent gouty attacks in the perioperative period.Weight loss seems to reduce hyperuricemia in the long-term follow-up, but there is evidence also of a high frequency of acute attacks early after surgery in patients with a diagnosis of gout.Bariatric surgery has a high impact on hyperuricemia and gout. A perioperative approach is suggested, based on appropriate hydration, early physical resumption, urate lowering drugs and nonsteroidal anti-inflammatory drugs (NSAIDs), or colchicine and corticosteroids if NSAIDs are ineffective or not tolerated.

Background and aims: Individuals with non-acute pain are challenged with variable pain responses following surgery as well as psychological challenges, particularly depression and catastrophizing. The purpose of this study was to compare pre- and postoperative psychosocial tests and the associated presence of sensitization on a cohort of women undergoing elective laparoscopic surgery for non-acute pain defined as pain sufficient for surgical investigation without persistent of chronic pain. Methods: The study was a secondary analysis of a previous report (Am J Obstet Gynecol 2014 Oct;211(4):360–8.). The study was a prospective cohort trial of 77 women; 61 with non-acute pain and 16 women for a tubal ligation. The women had the following tests: Pain Disability Index, Pain Catastrophizing Scale, CES-D (Center for Epidemiologic Studies Depression Scale) depression scale and the McGill Pain Scale (short form) as well as their average pain score and the presence of pain sensitization. All test scores were correlated together and comparisons were done using paired t-test. Results: There were reductions in pain and psychosocial test scores that were significantly correlated. Pre-operative sensitization indicated greater changes in psychosocial tests. Conclusions: There was a close association of tests of psychosocial status with average pain among women having surgery on visceral tissues. Incorporation of these tests in the pre- and postoperative evaluation of women having laparoscopic surgery appears to provide a means to a broader understanding of the woman’s pain experience.

Migraine is a highly disabling neurological condition, and preventative treatment still remains problematic, due to aspecificity of the majority of the currently available prophylactic drugs. Calcitonin-gene-related peptide (CGRP) plays a crucial role in migraine pathophysiology; agents aimed at blocking its activity have, therefore, been developed in recent years, among which are monoclonal antibodies (mAbs) against CGRP, to prevent migraine. Erenumab is the only mAb that targets the CGRP receptor instead of the ligand, with high specificity and affinity of binding. This review will report on the most recent data on erenumab characteristics and on the results of clinical trials on its employment in the prevention of episodic migraine (4-14 monthly migraine days): one Phase II and two Phase III trials (completed) and one Phase III trial (ongoing). Monthly subcutaneous administration (70 mg or 140 mg) of erenumab vs placebo for 3-6 months showed significantly higher efficacy in reducing the mean monthly number of migraine days and the use of migraine-specific medication, and in decreasing physical impairment and impact of migraine on everyday activities (P

Many pain conditions in patients tend to co-occur, influencing the clinical expressions of each other in various ways. This paper summarizes the main concurrent pain conditions by analyzing the major interactions observed. In particular, co-occurrence will be examined in: visceral pain (especially ischemic heart disease, irritable bowel syndrome, dysmenorrhea/endometriosis and urinary pain), fibromyalgia, musculoskeletal pain and headache. Two concurrent visceral pains from internal organs sharing at least part of their central sensory projection can give rise to viscero-visceral hyperalgesia, i.e., enhancement of typical pain symptoms from both districts. Visceral pain, headache and musculoskeletal pains (myofascial pain from trigger points, joint pain) can enhance pain and hyperalgesia from fibromyalgia. Myofascial pain from trigger points can perpetuate pain symptoms from visceral pain conditions and trigger migraine attacks when located in the referred pain area from an internal organ or in cervico-facial areas, respectively. The pathophysiology of these pain associations is complex and probably multifactorial; among the possible processes underlying the mutual influence of symptoms recorded in the associations is modulation of central sensitization phenomena by nociceptive inputs from one or the other condition. A strong message in these pain syndrome co-occurrence is that effective treatment of one of the conditions can also improve symptoms from the other, thus suggesting a systematic and thorough evaluation of the pain patient for a global effective management of his/her suffering.

New evidence suggests that non-alcoholic fatty liver disease (NAFLD) has a strong multifaceted relationship with diabetes and metabolic syndrome, and is associated with increased risk of cardiovascular events, regardless of traditional risk factors, such as hypertension, diabetes, dyslipidemia, and obesity. Given the pandemic-level rise of NAFLD—in parallel with the increasing prevalence of obesity and other components of the metabolic syndrome—and its association with poor cardiovascular outcomes, the question of how to manage NAFLD properly, in order to reduce the burden of associated incident cardiovascular events, is both timely and highly relevant. This review aims to summarize the current knowledge of the association between NAFLD and cardiovascular disease, and also to discuss possible clinical strategies for cardiovascular risk assessment, as well as the spectrum of available therapeutic strategies for the prevention and treatment of NAFLD and its downstream events.

The upcoming 11th revision of the International Statistical Classification of Diseases and Related Health Problems (ICD) of the World Health Organization (WHO) offers a unique opportunity to improve the representation of painful disorders. For this purpose, the International Association for the Study of Pain (IASP) has convened an interdisciplinary task force of pain specialists. Here, we present the case for a reclassification of nervous system lesions or diseases associated with persistent or recurrent pain for $3 months. The new classification lists the most common conditions of peripheral neuropathic pain: trigeminal neuralgia, peripheral nerve injury, painful polyneuropathy, postherpetic neuralgia, and painful radiculopathy. Conditions of central neuropathic pain include pain caused by spinal cord or brain injury, poststroke pain, and pain associated with multiple sclerosis. Diseases not explicitly mentioned in the classification are captured in residual categories of ICD-11. Conditions of chronic neuropathic pain are either insufficiently defined or missing in the current version of the ICD, despite their prevalence and clinical importance. We provide the short definitions of diagnostic entities for which we submitted more detailed content models to the WHO. Definitions and content models were established in collaboration with the Classification Committee of the IASP’s Neuropathic Pain Special Interest Group (NeuPSIG). Up to 10% of the general population experience neuropathic pain. The majority of these patients do not receive satisfactory relief with existing treatments. A precise classification of chronic neuropathic pain in ICD-11 is necessary to document this public health need and the therapeutic challenges related to chronic neuropathic pain. ispartof: PAIN vol:160 issue:1 pages:53-59 ispartof: location:United States status: published

Chronic pain is a major source of suffering. It interferes with daily functioning and often is accompanied by distress. Yet, in the International Classification of Diseases, chronic pain diagnoses are not represented systematically. The lack of appropriate codes renders accurate epidemiological investigations difficult and impedes health policy decisions regarding chronic pain such as adequate financing of access to multimodal pain management. In cooperationwith theWHO,an IASP Working Group has developed a classification system that is applicable in awide range of contexts, including pain medicine, primary care, and low-resource environments. Chronic pain is defined as pain that persists or recurs formore than 3months. In chronic pain syndromes, pain can be the sole or a leading complaint and requires special treatment and care. In conditions such as fibromyalgia or nonspecific low-back pain, chronic pain may be conceived as a disease in itsownright; in our proposal,we call this subgroup “chronic primary pain.” In 6 other subgroups, pain is secondary to an underlying disease: chronic cancer-related pain, chronic neuropathic pain, chronic secondary visceral pain, chronic posttraumatic and postsurgical pain, chronic secondary headache and orofacial pain, and chronic secondary musculoskeletal pain. These conditions are summarized as “chronic secondary pain” where pain may at least initially be conceived as a symptom. Implementation of these codes in the upcoming 11th edition of International Classification of Diseases will lead to improved classification and diagnostic coding, thereby advancing the recognition of chronic pain as a health condition in its own right. ispartof: PAIN vol:160 issue:1 pages:19-27 ispartof: location:United States status: published

Chronic visceral pain is a frequent and disabling condition. Despite high prevalence and impact, chronic visceral pain is not represented in ICD-10 in a systematic manner. Chronic secondary visceral pain is chronic pain secondary to an underlying condition originating from internal organs of the head or neck region or of the thoracic, abdominal, or pelvic regions. It can be caused by persistent inflammation, by vascular mechanisms or by mechanical factors. The pain intensity is not necessarily fully correlated with the disease process, and the chronic visceral pain may persist beyond successful treatment of the underlying cause. This article describes how a new classification of chronic secondary visceral pain is intended to facilitate the diagnostic process and to enable the collection of accurate epidemiological data. Furthermore, it is hoped that the new classification will improve the tailoring of patient-centered pain treatment of chronic secondary visceral pain and stimulate research. Chronic secondary visceral pain should be distinguished from chronic primary visceral pain states that are considered diseases in their own right.

The recent COVID-19 pandemic has dramatically changed the world in the last months, leading to a serious global emergency related to a novel coronavirus infection that affects both sexes of all ages ubiquitously. Advanced age, cardiovascular comorbidity, and viral load have been hypothesized as some of the risk factors for severity, but their role in patients affected with other diseases, in particular immune disorders, such as sarcoidosis, and the specific interaction between these two diseases remains unclear. The two conditions might share similar imaging findings but have distinctive features that are here described. The recent development of complex imaging softwares, called deep learning techniques, opens new scenarios for the diagnosis and management.

Migraine is a highly disabling neurological pain disorder in which management is frequently problematic. Most abortive and preventative treatments employed are classically non-specific, and their efficacy and safety and tolerability are often unsatisfactory. Mechanism-based therapies are, therefore, needed. Calcitonin gene-related peptide (CGRP) is recognized as crucial in the pathophysiology of migraine, and new compounds that target the peptide have been increasingly explored in recent years. First tested were CGRP receptor antagonists; they proved effective in acute migraine treatment in several trials, but were discontinued due to liver toxicity in long-term administration. Monoclonal antibodies against CGRP (LY2951742, ALD-403, and LBR-101/TEV-48125) or its receptor (AMG334) were subsequently developed. As reviewed in this study, numerous phase 1 and 2 trials and preliminary results of phase 3 trials have shown a good safety/tolerability profile and efficacy in migraine prevention, especially in high frequent episodic and chronic forms. Being macromolecules, these mAbs are not suitable for oral administration; however, their intravenous or subcutaneous delivery can be performed at relatively low frequency-every month or even quarterly-which enhances patients' compliance. Although not all migraineurs respond to this treatment, and longer administration periods will be needed to assess long-term effects, the results so far obtained are extraordinarily promising. The future introduction of mAbs on the market will probably represent a turning point for prevention similar to that represented by triptans for abortive treatment in migraine.

Migraine is a common and highly disabling neurological disorder whose acute treatment remains problematic and unsatisfactory in a high percentage of cases. Consequently, there remains a need for new symptomatic therapies that can be easily handled by patients (i.e. by oral administration).This review reports on compounds currently under development for the oral treatment of acute migraine attacks, focusing on Calcitonin-Gene-Related-Peptide receptor antagonists, specifically ubrogepant and rimegepant. This article is based on literature obtained from PubMed and publicly available clinical trial data.Both reviewed compounds meet the need for rapid and effective pain control, combined with the control of associated bothersome symptoms while also lacking significant adverse events and safety concerns. Though further studies should assess the profile of these compounds comparatively with existing and available treatments (namely triptans), the currently available data points to these new therapies as being very promising new symptomatic oral treatments of migraines.

Background In migraine patients with cervical myofascial trigger points whose target areas coincide with migraine sites (M + cTrPs), TrP anesthetic injection reduces migraine symptoms, but the procedure often causes discomfort. This study evaluated if a topical TrP treatment with 3% nimesulide gel has similar efficacy as the injection but produces lesser discomfort with higher acceptability by the patients. Methods Retrospective analysis of medical charts of M + cTrPs patients in the period January 2012–December 2016 at a single Headache Center. Three groups of 25 patients each were included, all receiving migraine prophylaxis (flunarizine 5 mg/day) for 3 months and symptomatic treatment on demand. Group 1 received no TrP treatment, group 2 received TrP injections (bupivacaine 5 mg/ml at basis, 3rd, 10th, 30th and 60th day), group 3 received daily TrP topical treatment with 1.5 g of 3% nimesulide gel for 15 consecutive days, 15 days interruption and again 15 consecutive days. The following were evaluated: monthly number of migraine attacks and rescue medications, migraine intensity; pain thresholds to skin electrical stimulation (EPTs) and muscle pressure stimulation (PPTs) in TrP and target (basis, 30th, 60th and 180th days); discomfort from, acceptability of and willingness to repeat treatment (end of study). ANOVA for repeated measures and 1-way ANOVA were used to assess temporal trends in each group and comparisons among groups, respectively. Significance level was set at p

Objective : To investigate enzymatic reactive aldehyde-scavenging enzyme capacity together with lipid peroxidation as expression of oxidative stress in atherosclerotic plaques of cigarette smokers and nonsmokers. Methods : We have assessed specific enzymatic activities of class 1, 2, and 3 aldehyde dehydrogenase (ALDH1, ALDH2, and ALDH3, respectively), glutathione S -transferase (isozyme A4-4, GSTA4-4), and aldose reductase (AR), namely the major reactive aldehyde-scavenging enzymes, together with lipid peroxidation, i.e., fluorescent damage products of lipid peroxidation (FDPL), in carotid atherosclerotic plaques surgically removed from 17 cigarette smokers and 17 nonsmokers. Results : The enzymatic activities of ALDH1 plus ALDH2, ALDH3, GSTA4-4, and AR were significantly lower in the atherosclerotic plaques of smokers than in those of nonsmokers, while plaque FDPL levels were significantly higher in the smokers than in the nonsmokers. The amount of cigarette smoking was correlated inversely with the aforementioned plaque enzymatic activities and directly with plaque FDPL content. Plaque FDPL levels were inversely correlated with plaque enzymatic activities in smokers and nonsmokers. The degree of carotid atherosclerotic stenosis, as expression of atherosclerosis severity, was correlated inversely with plaque enzymatic activities and directly with plaque FDPL levels in smokers and nonsmokers; moreover, the degree of carotid stenosis was directly correlated with the amount of cigarette smoking. Conclusion : atherosclerotic lesions of cigarette smokers are endowed with a depressed enzymatic reactive aldehyde-scavenging capacity eventually favoring oxidative stress and the severity of atherosclerosis.

In the "proton pump inhibitors era", a penetrating peptic ulcer (PPU) represents an exceptional cause of abdominal pain, and was more frequently observed in the past where there was not an effective antacid treatment. Ulcer-induced pancreatitis is very rare, too, and manifests with persistent, intense pain radiating to the back. A mild to severe pancreatitis with peripancreatic fluid collection can be observed at imaging. However, only a few cases of association between PPU and emphysematous pancreatitis (EP) have been published in the literature. EP is a rare but potentially fatal form of acute necrotizing pancreatitis in which gas grows in and outside the pancreas, and typically involves the whole parenchyma in diabetic individuals. Here we report an extremely rare case of a duodenal ulcer penetrating the pancreas and complicated with EP. Unlike the classic form of EP, which involves the whole parenchyma and has a poor prognosis, we found that the emphysematous involvement of the pancreas by PPU has a benign course if a conservative therapy is promptly established. Gas is confined to the site of penetration, usually the pancreatic head, and ulcers most often involve the duodenum.

The spontaneous isolated celiac artery dissection (siCAD) represents a challenging cause of abdominal pain and complete information regarding incidence, etiology and risk factors in the young is still lacking. In this study, we report a case of siCAD occurred in a young woman and we systematically searched for information on siCADs in literature databases.PubMed/Embase and Cochrane were searched for, using the following terms: Isolated celiac trunk dissection, isolated celiac artery dissection, celiac artery dissection, celiac trunk dissection, spontaneous isolated visceral artery dissection, spontaneous isolated dissection of visceral arteries, isolated celiac artery dissection in the young, isolated celiac trunk dissection in the young. Patients were included if they were younger than 50 years, if they had a spontaneous etiology and a selective involvement of the celiac artery (with or without involvement of its branches).180 studies were found, and 18 remained after screening. Twenty-one patients (male = 19, female = 2) with siCADs were included. Mean age was 44.71 ± 3.61 years. Hypertension was the most prevalent comorbidity. All patients presented with abdominal pain, more often located in the epigastrium (n = 11). Almost all patients underwent CT to confirm the diagnosis. A conservative treatment was adopted in 13 patients while an invasive approach was adopted in 8 patients (endovascular approach in 7).siCADs represent a rare but important cause of vascular dissection in the young. Uncomplicated cases can be safely treated with conservative strategies. The surgical or endovascular repair is indicated when dissections complicate or symptoms persist despite an adequate conservative treatment.

Fibromyalgia syndrome (FMS) is a central sensitization syndrome; however, peripheral pain sources potentially exacerbate its symptoms of chronic diffuse musculoskeletal pain and hyperalgesia. This prospective study evaluated visceral pain as a possible triggering factor for FMS pain and hyperalgesia in comorbid patients. Women with (1) FMS + irritable bowel syndrome (IBS); (2) FMS + primary dysmenorrhea (Dys); (3) FMS + Dys secondary to endometriosis (Endo); (4) FMS + colon diverticulosis (Div) were compared with FMS-only women, for fibromyalgia pain (number and intensity of episodes and analgesic consumption) over comparable periods and for somatic hyperalgesia (electrical and pressure pain thresholds) in painful (tender points) and control areas (trapezius, deltoid, quadriceps muscles, and overlying subcutis and skin). In comorbid subgroups, FMS symptoms were also reassessed after treatment of the visceral condition or no treatment. All comorbid groups vs FMS-only had significantly higher FMS pain (number/intensity of episodes and analgesic consumption) and hyperalgesia in deep somatic tissues (subcutis and muscle) at all sites (0.05 < P < 0.0001). Visceral pain (number of IBS days, painful menstrual cycles, and abdominal pain episodes from diverticulitis) correlated directly with all parameters of FMS pain and inversely with muscle pain thresholds at all sites (0.03 < P < 0.0001). Fibromyalgia syndrome pain and hyperalgesia in all tissues and all sites significantly decreased in patients after visceral comorbidity treatment (dietary for 6 months [IBS], hormonal for 6 months [dysmenorrhea], laser [endometriosis], and surgery [diverticulosis]) (0.05 < P < 0.0001) vs no change in untreated patients. Visceral pain enhances FMS symptoms, probably augmenting the level of central sensitization typical of the syndrome. Systematic assessment and treatment of visceral pain comorbidities should be a part of FMS management strategy.

Bilirubin has protective effects against atherosclerotic cardiovascular diseases hypothetically due to its antioxidant–antilipoperoxidative properties. Thus, we investigated whether serum bilirubin is associated with oxidant damage, namely lipid peroxidation, of human atherosclerotic plaques and the severity of atherosclerosis. In this regard, we correlated the levels of serum total bilirubin (STB), direct (conjugated) bilirubin (SDB) and indirect (unconjugated) bilirubin (SIB) with those of fluorescent damage products of lipid peroxidation (FDPL) and lipid hydroperoxides (LOOH) of 32 endarterectomy-derived carotid atherosclerotic plaques. Moreover, we compared the levels of serum bilirubin and plaque lipoperoxides between two groups of patients of the study population with different severity of atherosclerosis as judged by the carotid stenosis degree, i.e.

To update on the latest developments in sensory changes of female patients with chronic pelvic pain (CPP). CPP is very common, but its pathophysiology is still controversial. Evaluation of pain sensitivity in painful and nonpainful areas is key to understanding the underlying peripheral vs. central contributions to the symptom. This in turn is fundamental to improving the treatment strategies.We reviewed the experimental studies published over the last year on pain thresholds to different stimuli measured at both the somatic and visceral level in women with different forms of recurrent or CPP. The majority of the studies indicate a pain threshold decrease to most stimuli in skin, subcutis and muscle in painful pelvic areas, the site of referred pain from pelvic viscera, as well as a decreased pain threshold in most viscera (colon and urinary bladder). A significant threshold decrease is also found in deep somatic tissues (subcutis and muscle) outside the painful zone in the most severe cases, indicating a state of central sensitization.These findings have important implications for clinical practice: pain threshold measurement in both painful and nonpainful sites could have important predictive value of the clinical evolution and response to therapy of CPP.

Objective To evaluate whether a diclofenac epolamine + heparin topical (plaster) is more effective than diclofenac plaster alone in reducing deep somatic hyperalgesia in subjects without spontaneous pain and whether the effect is linked to or independent of the anti-edematous action of heparin. Design Prospective, double-blind, randomized and controlled, four-arm parallel design trial. Subjects One hundred and four patients (84 women, 20 men, mean age 42.2 ± 13.3 years), with deep somatic hyperalgesia in one thigh, randomly assigned to one of 4 groups of 26 each. Intervention Each group underwent one of the following plaster treatments on one thigh: diclofenac+heparin; diclofenac; heparin; placebo, for 7 days, renewing the plaster every 24 hours. Outcome Measures Before treatment (day 1), at day 4 and day 8, assessment of (a) pressure and electrical pain thresholds of vastus lateralis and overlying subcutis and skin; and (b) structure/thickness of subcutis and muscle with ultrasounds at the same level. Results During treatment, in placebo and heparin, no significant threshold changes, except subcutis thresholds which increased slightly (P

The effects of tramadol versus placebo administration on behavioral indicators of ureteral pain, pelvic pain and referred lumbar muscle hyperalgesia were investigated in a rat model of viscero-visceral hyperalgesia from endometriosis plus ureteral calculosis (endo + stone). Fifty female Sprague-Dawley rats underwent surgical induction of endometriosis and, 2 weeks later, were randomly assigned to five groups (10 each), to be treated i.p., twice a day, with tramadol (0.625, 1.25, 2.5, or 5 mg/kg) or saline for 5 days (14-18th day postendometriosis; prestone treatment). On the 21st day, they underwent laparotomy for stone formation in the upper left ureter (dental cement injection). All were video-taped 24 h nonstop for 7 days before and 4 days after stone formation (14-25th day postendometriosis) to record ureteral and pelvic pain behaviors. Lumbar sensitivity (L1) was tested bilaterally, daily over the same period, by verifying presence/absence of vocalization upon muscle pinching at a predefined pressure (calibrated forceps). Additional fifty endo + stone rats underwent the same protocol, except that treatment was performed on 21st-25th day (poststone treatment). Tramadol vs. saline significantly reduced number and duration of ureteral crises, duration of pelvic behavior, and incidence of muscle hyperalgesia (P0.0001), with a dose-dependent effect. Prestone treatment was significantly more effective than poststone treatment for the 1.25 dose for all parameters and 2.5 dose for pelvic and muscle parameters (0.003P0.02). Tramadol, even at low doses, is thus highly protective against pain from 'viscero-visceral hyperalgesia' in endometriosis plus ureteral calculosis; it can represent a valid therapeutic approach in women with these comorbidities.

The hypothesis of a relationship between sarcoidosis and malignancy was firstly formulated in 1972 by Brincker. He documented an association of sarcoid reactions or sarcoidosis with 19 lymphomas and associated malignancies. Based on various epidemiological studies, for more than 20 years sarcoidosis has been considered as a condition at increased risk for cancer, particularly lymphoproliferative disorders. The existence of a sarcoidosis-lymphoma syndrome was therefore proposed, highlighting, as a potential mechanism, the uncontrolled lymphocyte proliferation and mitotic activity. A reduced ability to eliminate an antigen and chronic inflammation have been suggested as triggering events. Leading to a reduced tumor immune surveillance, a diminished myeloid dendritic cells (mDC) function, despite up-regulated co-stimulatory and maturation markers, was also raised as potential mechanism. However, some subsequent studies have questioned the presence of a close association between the two entities and have explained those previously published as the result of selection bias and misclassification. Recently, a Swedish population-based cohort study documented a significant overall excess incidence of cancer among sarcoidosis patients, especially those with multiple hospitalizations or admission in older age, emphasizing again a potential neoplastic risk. Therefore, currently, whether these patients have an increased risk of developing malignant lesions is still debated. Larger and unbiased studies are needed before drawing definite conclusions.

Primary headaches and visceral pain are both very frequent medical conditions in the general population. Epidemiologic studies indicate that they very often coexist. Particularly frequent is the comorbidity between migraine and cardiac ischemic pain and between migraine/tension-type headache and functional gastrointestinal disorders, particularly irritable bowel syndrome (IBS). In women, overlap exists between migraine, dysmenorrhea, primary or secondary to endometriosis and interstitial cystitis/painful bladder syndrome (IC/PBS). The pathophysiology of these frequent associations remains elusive. Comorbidity between cardiac pain and migraine is probably based on an endothelial dysfunction common to both migraine and atherosclerosis, the major cause of ischemic cardiac pain. For IBS, dysmenorrhea and IC/PBS, a common likely mechanism is that of central sensitization, present in all conditions, as testified clinically by a generalized increase in pain sensitivity not only in painful but also non-painful areas. This chapter addresses the general epidemiology of visceral pain-headache comorbidities focusing on the clinical characteristics and therapeutic challenges posed by the most frequently encountered associations.

Introduction: WHO ranks migraine as the 6th highest cause of disability worldwide when considered alone, and the 3rd highest when medication overuse headache (MOH) is included. Migraine is an episodic disorder but in its natural course, its frequency could progressively increase and evolve to a chronic form. More than 50% of chronic migraine patients show acute pain medications overuse which is linked to the development of MOH.Areas covered: Our goal is to review the existing data on OnabotulinoumtoxinA and CGRP-targeting drugs such as anti-CGRP monoclonal antibodies, one of the most promising migraine drugs under development. The research of bibliographic databases has included only published peer-reviewed articles from indexed journals.Expert commentary: To date, real-life studies are supporting OnabotulinumtoxinA in the treatment of chronic migraine. Additionally, anti-CGRP mAbs showed good efficacy and safety in recent RCTs and may soon contribute to improve the quality of life of patients suf...

Fibromyalgia, a chronic syndrome of diffuse musculoskeletal pain and somatic hyperalgesia from central sensitization, is very often comorbid with visceral pain conditions. In fibromyalgia patients with gallbladder calculosis, this study assessed the short and long-term impact of laparoscopic cholecystectomy on fibromyalgia pain symptoms. Fibromyalgia pain (VAS scale) and pain thresholds in tender points and control areas (skin, subcutis and muscle) were evaluated 1week before (basis) and 1week, 1,3,6 and 12months after laparoscopic cholecystectomy in fibromyalgia patients with symptomatic calculosis (n = 31) vs calculosis patients without fibromyalgia (n. 26) and at comparable time points in fibromyalgia patients not undergoing cholecystectomy, with symptomatic (n = 27) and asymptomatic (n = 28) calculosis, and no calculosis (n = 30). At basis, fibromyalgia+symptomatic calculosis patients presented a significant linear correlation between the number of previously experienced biliary colics and fibromyalgia pain (direct) and muscle thresholds (inverse)(p

Aims This article reports current evidence on the association between Lp(a) and cardiovascular (CV) disease and on pathophysiological mechanisms. The available information on therapy for reduction of lipoprotein(a) is also discussed. Data synthesis Although some evidence is conflicting, Lp(a) seems to increase CV risk through stimulation of platelet aggregation, inhibition of tissue factor pathway inhibitor, alteration of fibrin clot structure and promotion of endothelial dysfunction and phospholipid oxidation. Lp(a) 3.5-fold higher than normal increases the risk of coronary heart disease and general CV events, particularly in those with LDL cholesterol ≥ 130 mg/dl. High Lp(a) values represent also an independent risk factor for ischemic stroke (more relevant in young stroke patients), peripheral artery disease (PAD) and aortic and mitral stenosis. Furthermore, high Lp(a) levels seem to be associated with increased risk of cardiovascular events in patients with chronic kidney disease, particularly in those undergoing percutaneous coronary intervention. Conclusions Lipoprotein (a) (Lp[a]) seems to significantly influence the risk of cardiovascular events. The effects of statins and fibrates on Lp(a) are limited and extremely variable. Nicotinic acid was shown effective in reducing Lp(a) but, due to its side effects and serious adverse events during clinical trials, it is no longer considered a possible option for treatment. To date, the treatment of choice for high levels of Lp(a) in high CV risk patients is represented by LDL-Apheresis. Thanks to innovative technologies, new selectively inhibiting LPA drugs are being developed and tested.

Background Fibromyalgia (FMS) and high frequency episodic/chronic migraine (M) very frequently co-occur, suggesting common pathophysiological mechanisms; both conditions display generalized somatic hyperalgesia. In FMS-M comorbidity we assessed if: a different level of hyperalgesia is present compared to one condition only; hyperalgesia is a function of migraine frequency; migraine attacks trigger FMS symptoms. Methods Female patients with fibromyalgia (FMS)(n.40), high frequency episodic migraine (M1)(n.41), chronic migraine (M2)(n.40), FMS + M1 (n.42) and FMS + M2 (n.40) underwent recording of: −electrical pain thresholds in skin, subcutis and muscle and pressure pain thresholds in control sites, −pressure pain thresholds in tender points (TePs), −number of monthly migraine attacks and fibromyalgia flares (3-month diary). Migraine and FMS parameters were evaluated before and after migraine prophylaxis, or no prophylaxis, for 3 months with calcium-channel blockers, in two further FMS + H1 groups (n.49, n.39). 1-way ANOVA was applied to test trends among groups, Student’s t-test for paired samples was used to compare pre and post-treatment values. Results The lowest electrical and pressure thresholds at all sites and tissues were found in FMS + M2, followed by FMS + H1, FMS, M2 and M1 (trend: p

Sigmoid colon gallstone ileus is a mechanical large bowel obstruction caused by a biliary stone which migrates into the colon through a cholecysto-enteric fistula and gets impacted in the sigma. It is a very rare complication of gallbladder calculosis in the general population, but its frequency increases with age, with elderly people being the most frequently affected. Diagnosis is often delayed because of the prevalent symptom aspecificity, and the choice of the optimal surgical treatment is still debated, especially as the elderly have increased operative risk also due to multiple comorbidities. The most frequently employed procedures are: the enterolithotomy alone, aimed at just removing the obstacle and solving the occlusion; the one-stage procedure, where enterolithotomy, cholecystectomy and fistula repair are performed in the same operation, and the two-stage procedure, where enterolithotomy is performed first and cholecystectomy at a later stage. We report the case of a sigmoid colon gallstone ileus in an 81 year-old female patient with multiple comorbidities, who was treated with enterolithotomy alone-with residual gallbladder stone-to minimize the operating time and risk. A successful outcome of the intervention performed in our case is reported at a 1-year follow-up, the patient was in a good clinical status at the medical checks performed and had experienced no recurrences of ileus and no new pain symptoms from the gallbladder. The case and its outcome are discussed in the light of the background literature on pathogenesis, symptomatology, diagnosis and treatment of sigmoid colon gallstone ileus.

The effects of ultramicronized palmitoylethanolamide were evaluated on pain behaviours and markers of mast cell (MC) activity in a rat model of endometriosis plus ureteral calculosis (ENDO+STONE)-induced viscerovisceral hyperalgesia (VVH). Female Sprague-Dawley rats that underwent surgical induction of endometriosis were randomly assigned to receive active (ultramicronized palmitoylethanolamide 10 mg·kg(-1)·d(-1), orally) or placebo treatment for 25 days. At day 21, they underwent ureteral stone formation and were video-recorded till day 25 to evaluate ureteral and uterine pain behaviours. At autopsy (day 25), ureteral condition and number and diameter of endometrial cysts were evaluated. The following were then measured: number and percentage of degranulating MCs, number of vessels, chymase, nerve growth factor (NGF), vascular endothelial growth factor (VEGF), and Flk-1 (VEGF receptor) in cysts, and NGF in dorsal root ganglia (DRG). Ultramicronized palmitoylethanolamide-treated vs placebo-treated rats showed significantly lower number, duration and complexity of ureteral crises, shorter duration of uterine pain, and smaller cyst diameter (0.0001 < P < 0.004); a significantly higher percentage of expelled stones (P < 0.0001); significantly lower MC number (P < 0.01), vessel number (P < 0.01), chymase (P < 0.05), NGF (P < 0.05), VEGF (P < 0.01), and Flk-1 (P < 0.01) expression in cysts and NGF expression in DRG (P < 0.01). In all animals, the global duration of ureteral crises correlated linearly and directly with cyst diameter, MC number and chymase in cysts, and NGF in cysts and DRG (0.02 < P < 0.0002). Ultramicronized palmitoylethanolamide significantly reduces VVH from ENDO+STONE, probably by modulating MC expression/activity in cysts, thus reducing central sensitization due to noxious signals from endometriotic lesions. The results suggest potential utility of the compound for VVH in clinics.

Myofascial pain syndromes (MPSs) from trigger points (TrPs) and fibromyalgia syndrome (FMS) are common musculoskeletal pain conditions that frequently coexist in the same patients. In recent decades, it has become evident that these entities greatly influence each other's clinical expression. FMS is mainly rooted in the central nervous system, while TrPs have a peripheral origin. However, the nociceptive impulses from TrPs may have significant impact on symptoms of FMS, probably by enhancing the level of central sensitization typical of this condition. Several attempts have been made to assess the effects of treatment of co-occurring TrPs in FMS. We report the outcomes of these studies showing that local extinction of TrPs in patients with fibromyalgia produces significant relief of FMS pain. Though further studies are needed, these findings suggest that assessment and treatment of concurrent TrPs in FMS should be systematically performed before any specific fibromyalgia therapy is undertaken.

Objectives: The perception of pain in regions other than the affected organ is the rule in visceral nociception. This paper reviews the current knowledge about modalities of clinical presentation and pathophysiological mechanisms of visceral referred pain, based on the results of clinical and experimental studies.Findings: Visceral referred pain occurs in somatic areas neuromerically connected with the affected organs where secondary hyperalgesia takes place mostly in deep body wall tissues, extending to superficial layers in repetead/prolonged visceral processes. When two internal organs sharing part of their central sensory projection are affected, visceral pain and referred hyperalgesia from each organ are significantly enhanced [“viscero-visceral hyperalgesia”]. In this case, treatment of one visceral condition significantly improves symptoms from the other. Referred phenomena are mainly sustained by central sensitization processes, involving viscero-somatic or viscero-visceral-somatic converg...

This study evaluated the contribution of myofascial trigger points (TrPs) to migraine pain. Seventy-eight migraine patients with cervical active TrPs whose referred areas (RAs) coincided with migraine sites (frontal/temporal) underwent electrical pain threshold measurement in skin, subcutis, and muscle in TrPs and RAs at baseline and after 3, 10, 30, and 60 days; migraine pain assessment (number and intensity of attacks) for 60 days before and 60 days after study start. Fifty-four patients (group 1) underwent TrP anesthetic infiltration on the 3rd, 10th, 30th, and 60th day (after threshold measurement); 24 (group 2) received no treatment. Twenty normal subjects underwent threshold measurements in the same sites and time points as patients. At baseline, all patients showed lower than normal thresholds in TrPs and RAs in all tissues (P < .001). During treatment in group 1, all thresholds increased progressively in TrPs and RAs (P < .0001), with sensory normalization of skin/subcutis in RAs at the end of treatment; migraine pain decreased (P < .001). Threshold increase in RAs and migraine reduction correlated linearly (.0001 < P < .006). In group 2 and normal subjects, no changes occurred. Cervical TrPs with referred areas in migraine sites thus contribute substantially to migraine symptoms, the peripheral nociceptive input from TrPs probably enhancing the sensitiza- tion level of central sensory neurons. Perspective: This article shows the beneficial effects of local therapy of active myofascial trigger points(TrPs)onmigrainesymptomsinpatientsinwhommigrainesitescoincidewiththereferredareas of the TrPs. These results suggest that migraine pain is often contributed to by myofascial inputs that enhance the level of central neuronal excitability.

This study evaluated sensory and biomechanical assets in 2 heel pain conditions with similar symptoms, entrapment syndrome of the nerve to abductor digiti quinti and myofascial syndrome of abductor hallucis. Thirty-three patients with unilateral heel pain and 20 asymptomatic subjects underwent pressure pain threshold measurement in the painful area in site A (medial process of calcaneal tuberosity, trigger point site of abductor hallucis) and site B (1 cm posteriorly to site A, where the nerve to abductor digiti quinti becomes most superficial) and contralaterally; electroneu- rography of posterior tibial nerve; evaluation of ground-foot reaction on a dynamic platform. Eighteen patients had electric shock-type pain (entrapment syndrome, Group 1), 15 had cramp-like pain (myofascial syndrome, Group 2). Pain thresholds on the affected side versus contralaterally were significantly lower in site B in Group 1 and in site A in Group 2 (P < .001). Nerve conduction velocity was slightly reduced in Group 1 (P.05). Ground-foot reaction was significantly altered on the affected side in all patients versus asymptomatic subjects; a significant difference between the 2 sides was found for peak of force (F1) in Group 1 and for all parameters except temporal phase of peak of force (TF3) (P.05) for Group 2 (P < .0001). The different sensory and biomechanical patterns of the 2 examined syndromes help the differential diagnosis and consequent therapeutic approach. Perspective: This study shows different sensory and biomechanical patterns in 2 algogenic condi- tions of the heel with similar pain location. These distinct patterns reflect different pathophysiologic mechanisms in the 2 cases, which has a potential significant impact on treatment.

Introduction Primary headaches have high epidemiologic impact but their symptomatic treatment often remains problematic. Nonsteroidal anti-inflammatory drugs (NSAIDs) are frequently used, but their modality of employment and efficacy/differential efficacy are highly variable. This study investigated current NSAID use for episodic headache at an Italian headache center (January 2000 to February 2013). Methods A retrospective evaluation was performed on 6,443 patient records: migraine (n = 2,330), tension-type headache (TTH; n = 807), and migraine plus TTH (n = 3,306). Results Among migraine patients, 80% had used NSAIDs in the past year. Preferences were: nimesulide (57%), ketoprofen (25%), and ibuprofen (24%); complete efficacy was significantly higher than incomplete/absent efficacy (P < 0.0001). NSAIDs were replaced with triptans in 53% of patients at first visit; after 1 year there was a spontaneous significant return to NSAIDs (56%; P < 0.0005). Among TTH patients, 90% were NSAID users; preferences were: nimesulide (48%), ketoprofen (47%), and diclofenac (19%), with significantly higher complete vs. incomplete/absent efficacy (nimesulide and ketoprofen, P < 0.02). Replacement with analgesics was performed in 24% of patients; after 1 year, there was a 29% return to NSAIDs. Among migraine plus TTH patients, 89% were NSAID users. Preferences were: nimesulide (44%), ibuprofen (42%), and ketoprofen (38%), with significantly higher complete vs. incomplete/absent efficacy (0.001 < P < 0.0001). Replacement with analgesics was performed in 31% of patients; after 1 year, there was a 37% return to NSAIDs. Conclusions Nonsteroidal anti-inflammatory drug use in headache was higher than could be hypothesized based on guidelines, with NSAID preferences not entirely coinciding with international recommendations. This outcome suggests the need for greater awareness of all treatment options in headache by both patients and physicians.

The diagnosis and treatment of neurosarcoidosis can be very challenging for several reasons. It affects clinically 5%-10% of sarcoidosis patients, but can be found in up to 25% of autopsies. These data reveal that a high percentage of asymptomatic or misdiagnosed cases can be missed at an initial diagnostic approach. Clinical and imaging findings are often non-specific since they can be found in a large number of neurological disorders. Histopathology can also be confounding if not performed by an expert pathologist and not placed in an appropriate clinical context. In this review, we discuss clinical features, laboratory findings, imaging, and histology of neurosarcoidosis, and we report current evidence regarding drug therapy. We conclude that a correct diagnostic approach should include a multidisciplinary evaluation involving clinicians, radiologists, and pathologists and that future studies should evaluate the genetic signature of neurosarcoidosis as they could be helpful in the assessment of this uncommon disease. With head-to-head comparisons of medical treatment for neurosarcoidosis still lacking due to the rarity of the disease and an increasing number of immunomodulating therapies at hand, novel therapeutic approaches are to be expected within the next few years.

Medication-overuse headache—i.e., a too-frequent consumption of acute headache medications leading to increased headache frequency and reduced effectiveness of acute and preventive treatments—is a serious medical condition whose pathophysiology still remains incompletely known, which is reflected into a lack of mechanism-based treatments. The first mandatory step in the therapeutic strategy remains withdrawal of the abused drug, preferably abrupt, in concomitance with a detoxification pharmacological regimen to lessen withdrawal symptoms. Intravenous hydration, antiemetics, corticosteroids (prednisone), tranquilizers (benzodiazepine), neuroleptics, and rescue medication (another analgesic than the overused) should be delivered in various combinations, on an inpatient (hospitalization and day hospital) basis or outpatient basis, depending on the characteristics of the specific patient and type of overuse. Inpatient withdrawal should be preferred in barbiturate and opioid overuse, in concomitant depression, or, in general, in patients who have difficulty in stopping the overused medication as outpatients. In contrast, in overuse limited to simple analgesics in highly motivated patients, without high levels of depression and/or anxiety, home detoxification should be chosen. Re-prophylaxis should immediately follow detoxification, ideally with local injections of onabotulinumtoxinA every 3 months or topiramate orally for at least 3 months. Adequate information to patients about the risks of a too-frequent consumption of symptomatic headache medications is essential and should constantly parallel treatment to help preventing relapse after detoxification and re-prophylaxis.