Fibromyalgia syndrome is mainly characterized by pain, fatigue, and sleep disruption. The etiology of fibromyalgia is still unclear: if central sensitization is considered to be the main mechanism involved, then many other factors, genetic, immunological, and hormonal, may play an important role. The diagnosis is typically clinical  and the physician must concentrate on pain and on its features. Additional symptoms  can be associated with this condition. A careful differential diagnosis is mandatory: fibromyalgia is not a diagnosis of exclusion. Since 1990, diagnosis has been principally based on the two major diagnostic criteria defined by the ACR. Recently, new criteria have been proposed. The main goals of the treatment are to alleviate pain, increase restorative sleep, and improve physical function. A multidisciplinary approach is optimal. While most nonsteroidal anti-inflammatory drugs and opioids have limited benefit, an important role is played by antidepressants and neuromodulating antiepileptics: currently duloxetine (NNT for a 30% pain reduction 7.2), milnacipran (NNT 19), and pregabalin (NNT 8.6) are the only drugs approved by the US Food and Drug Administration for the treatment of fibromyalgia. In addition, nonpharmacological treatments should be associated with drug therapy. Fibromyalgia is a syndrome characterized by chronic widespread pain at multiple tender points, joint stiffness, and systemic symptoms  –4 withouWhat today is defined as fibromyalgia had already been described in the nineteenth century. In 1904, Gowers  coined tThis paper is based on a systematic search of the PubMed database to identify articles related to fibromyalgia. The searches were restricted to English language citations from the inception of the database to June 2012. Relevant articles from the bibliographies of selected articles were also identified and used in this paper. All selected articles were published between 1904 and 2012.This paper is primarily intended to assist orthopedic surgeons who find themselves faced with patients' referring musculoskeletal symptoms affected by (often undiagnosed) fibromyalgia. It is very important to know and to remember this syndrome so that the patient can be sent to the correct specialist.The etiology and pathogenesis of fibromyalgia are still not fully understood. Several factors such as dysfunction of the central and autonomic nervous systems, neurotransmitters, hormones, immune system, external stressors, psychiatric aspects, and others seem to be involved.Central sensitization is considered the main mechanism involved and it is defined by the increased response to stimulation mediated by CNS signaling . CentralAnother mechanism supposedly involves the well-known descending inhibitory pain pathways, which modulate spinal cord responses to painful stimuli. They seem to be impaired in patients with fibromyalgia, helping to exacerbate the central sensitization , 22, 23.Apart from augmented neuronal mechanisms, glial cell activation also appears to play an important role in the pathogenesis of fibromyalgia because they help to modulate pain transmission in the spinal cord. Activated by various painful stimuli, they release proinflammatory cytokines, nitric oxide, prostaglandins, and reactive oxygen species that stimulate and prolong spinal cord hyperexcitability –26. Also, various neurotransmitters seem to be involved in the central sensitization. Serotonin (5-HT) has a significant role in the modulation of pain , and sevOther neurotransmitters also play a role. There are data suggesting the involvement of norepinephrine , dopaminFunctional neuroimaging studies support the involvement of the brain in the pathogenesis of this condition.Single-photon-emission computed tomography (SPECT) was one of the first functional neuroimaging techniques to be used for this. After the infusion of a radioactive tracer, this technique provides a measure of regional cerebral blood flow (rCBF) throughout the brain, reflecting neural activity. The thalamus seems to be a region of interest. Mountz et al.  compared18F] fluorodeoxyglucose (FDG) helps to assess variations in glucose metabolism. Yunus et al. [11C] carfentanil, Harris et al. [μ opioid receptor binding potential in patients affected by fibromyalgia. The right and left nucleus accumbens and the left amygdale were the regions most significantly involved and a trend towards reduction was also seen in the right dorsal anterior cingulate cortex. These findings could reflect occupancy by endogenous opioids released in response to the ongoing pain and a receptor downregulation.Positron emission tomography (PET) uses radioactive tracers like SPECT, but it is characterized by increased temporal and spatial resolution. For example, Wik et al.  compareds et al.  did not s et al.  showed as et al.  tried toFunctional magnetic resonance imaging (fMRI) has greater temporal and spatial resolution than either SPECT or PET. In the first fMRI study of fibromyalgia  16 patieThe role of the thalamus has been recently underlined by Foerster et al.  who explFunctional magnetic resonance imaging seems also to be useful to better understand the role of the descending inhibitory pain system. In the study done by Jensen et al.  16 patieAdditional neuroimaging methods have been used to understand central pathogenesis of fibromyalgia.Voxel-based morphometry (VBM) uses MRI images to assess the volume of specific brain regions. Various studies have shown loss of grey matter in fibromyalgic patients involving the amygdala, the cingulate cortex, and the hippocampus –61. The Diffusion tensor imaging (DTI) is based on the movement of water through brain tissue and provides information about the integrity of white matter. Sundgren et al.  showed aMagnetic resonance spectroscopy (MRS) evaluates a signal that reflects the concentration of various molecules  in relation to a standard molecule. Patients affected by fibromyalgia showed a different ratio of choline/creatine within the dorsolateral prefrontal cortex and a different ratio of glutamate/glutamine within the insula and the posterior gyrus –65.Arterial spin labeling (ASL) is similar to fMRI, but uses magnetized blood as contrast agent. The signal of rCBF is mostly from the parenchyma improving the spatial localization. Few authors have used ASL: Owen found abnormal activations in the bilateral insula, the secondary somatosensory cortex, the cingulate cortex, the contralateral primary somatosensory cortex, and the ipsilateral thalamus ; HernandAs fibromyalgia is considered a stress-related disorder, it is easy to understand that the hypothalamic-pituitary-adrenal (HPA) axis is involved . DiffereGrowth hormone (GH) levels tend to be normal during the day, reduced during sleep. It is likely that the explanation is twofold. First, GH is mainly secreted during stage 4 of sleep and this phase is disrupted in patients affected by fibromyalgia. Second, these patients have high levels of somatostatin, a GH inhibitor, induced by ACTH whose levels are high as previously mentioned . ThyroidVarious studies, the most recent of which is based on methodologies such as power spectrum analysis of heart rate variability , 80 and Patients with fibromyalgia often complain of sleep disorders  and thesGenetic predisposition is likely to be an important factor as suggested by several familial studies , 88 and Fibromyalgia is common in patients affected by autoimmune disease –98. DiffPsychiatric problems seem to contribute considerably to the development of fibromyalgia. The prevalence of psychiatric conditions among patients affected by fibromyalgia is higher than among subjects complaining of other rheumatic diseases . The mosPeripheral tissues such as skin, muscles, and microvessels are coming under closer investigation. Vascular dysregulation in muscles , inadequParvovirus [Borrelia [Infections seem to be able to induce fibromyalgia even if a direct causal relationship is not documented . In partrvovirus –124 and Borrelia , 126 couBorrelia –129 and Borrelia , 131.Physical trauma , vaccinaMany cases of fibromyalgia do not precisely align with a standardized set of diagnostic criteria. However, it is not believed to be a diagnosis of exclusion, although some healthcare providers have labeled it as such. Because there is an absence of absolute, definitive diagnostic criteria with universal applicability, providers often settle upon this diagnosis following negative testing for other differentials . Rather than assuming a diagnosis of fibromyalgia, carefully considering a multitude of potential diagnoses shown in  will decDiagnosis is difficult and frequently missed because symptoms are vague and generalized. Despite this, three main symptoms are referred by almost every patient: pain, fatigue, and sleep disturbance , 138. InThe musculoskeletal and neurological examinations are normal in fibromyalgia patients . A detecThey are specific places on the body that are painful when a standard amount of pressure (about 4 kg) is applied. With respect to laboratory tests, they should be limited to a complete blood count, routine serum chemistries, thyroid-stimulating hormone  and erythrocyte sedimentation rate and/or C-reactive protein. Typically there are no laboratory abnormalities specifically associated with this condition. ANA (antinuclear antibody) test is quite often ordered and it may be positive, but the rate of a positive test in fibromyalgia patients is the same as normal controls , 139.As such, diagnosis is principally based on the two major diagnostic criteria defined by the ACR in 1990 : (1) a hhttp://www.ncbi.nlm.nih.gov/pubmed/), 361 English-language original articles with “fibromyalgia” as a keyword were published in the 20 years before the criteria existed, compared with 3844 in the 20-year period after the publication [A proliferation of studies followed publication of the 1990 criteria. According to PubMed , Wolfe et al. retain the 19-site WPI and the self-reported specific symptoms, but eliminate the physician estimation of SS score and replace it with three dichotomous “yes/no” answers regarding the presence of abdominal pain, depression, and headaches in the past 6 months .All these criteria are pooled to give an 0–31 fibromyalgia symptoms (FS) score.The authors report that an FS score of ≥13 correctly classified 93% of patients identified as having fibromyalgia on the basis of the 1990 criteria with a specificity of 96.6% and sensitivity of 91.8% .An implicit aim of the 2010 criteria is to facilitate more rigorous study of fibromyalgia etiology [The 2010 ACR criteria will usefully address the problem, by removing the tender-point examination, and with the publication of modified self-completed criteria that can be included in large scale epidemiological investigations ; consequWolfe et al.  and otheThe goals of fibromyalgia treatment are to alleviate pain, increase restorative sleep, and improve physical function through a reduction in associated symptoms . The ideBecause pain, depression, and other symptoms of fibromyalgia are linked to inherited and environmental causes, a multifaceted treatment approach is often required including both nonpharmacological pain management strategies and medication .The American Pain Society (APS) and the Association of the Scientific Medical Societies in Germany (AWMF) gave the highest level of recommendation to (1) aerobic exercise, (2) cognitive-behavioral therapy (CBT), (3) amitriptyline, and (4) multicomponent therapy. The APS guideline and AWMF guideline were completed prior to the approval of pregabalin and duloxetine for the treatment of fibromyalgia by the United States Food and Drug Administration (FDA). The European League Against Rheumatism (EULAR) gave the highest level of recommendation of “A” to a set of pharmacological treatments , a recommendation strength of “B” to aerobic exercise, and a recommendation strength of only “D” to CBT. EULAR did not give any recommendations for cyclobenzaprine, multicomponent treatment, patient education, hypnotherapy, biofeedback, or other complementary and alternative medicine approaches (CAM), such as acupuncture or homeopathy, whereas EULAR gave a “D” recommendation for CBT, and the APS and AWMF decided on an “A” recommendation. Whereas EULAR and AWMF did not recommend strong opioids (expert opinion), APS recommendation strength was a “C”. APS and AWMF provided the same strength of recommendation (“B”) to tramadol, balneotherapy, hypnotherapy, biofeedback, massage therapy, pregabalin, fluoxetine, and duloxetine. Whereas APS recommended patient education as a single intervention (“B”), acupuncture (“C”), and trigger point injections (“C”), AWMF did not recommend patient education as a single intervention (“A”), acupuncture (“A”) (a minority report recommended acupuncture with a strength of “B”), and trigger point injections (“C”). All three guidelines recommend against the use of NSAIDs (as a single intervention) or corticosteroids .Evaluating the comparative efficacy of interventions for fibromyalgia is difficult because no common definition of response in fibromyalgia exists. At present, the inclusion of assessment domains is inconsistent, and there is wide variation in the use of instruments indexing those domains. Historically, many symptoms have been thought to be associated with fibromyalgia. Because an assessment of all symptoms in each patient is not feasible; consensus was required to identify the key domains that needed to be assessed to determine clinically meaningful improvement. Much of the work in this area has been organized by the Outcome Measures in Rheumatology (OMERACT) Fibromyalgia working group .It was observed that the responder definitions that best favored drug over placebo included improvement in pain and physical function as well as improvement in either sleep or fatigue (at least 30% improvement over placebo in the symptom domains) . Along wIn terms of nonsteroidal anti-inflammatory drugs (NSAIDs), ibuprofen and naproxen have been shown to be no better than placebo , althougThe prevalence of opioid use by fibromyalgia patients is unknown, although Goldenberg et al.  reportedP ≤ 0.05) were observed between the tramadol/acetaminophen and placebo groups for improvements in sleep adequacy (9.3 versus +6.7) and sleep duration (0.4 hours versus 0.2 hours), but not for the other measures of sleep. Its potential for drug abuse is fortunately negligible, but there is a theoretical risk of seizures and serotoninergic syndrome when it is combined with selective serotonin reuptake inhibitors (SSRIs), serotonin-noradrenalin reuptake inhibitors (SNRIs), monoamine oxidase inhibitors (MAOIs), and triptans, although only a few cases have been described [Tramadol has been found to be beneficial in fibromyalgia patients , 162. Itescribed .Both antidepressants and neuromodulating antiepileptics substantially reduce fibromyalgia symptoms. Among antidepressants, serotonin and norepinephrine reuptake inhibitors have been found to provide the best efficacy and tolerability for fibromyalgia , 167. BoDuloxetine should be considered in patients with significant depression symptoms. The maximum dosage for the treatment of fibromyalgia is 60 mg daily, but, due to nausea, 30 mg daily is often started initially .Milnacipran has increased selectivity for norepinephrine than for serotonin. It may be helpful in patients with significant fatigue or cognitive dysfunction. The initial dose is 12.5 mg daily which is increased over several weeks to a maximum daily dose of 100 mg, given in two separate doses. In the milnacipran trials, the composite responder definition for the treatment of fibromyalgia consisted of 3 components: (1) 30% improvement from baseline in pain, (2) a rating of “very much improved” (score 1) or “much improved” (score 2) on the Patient Global Impression of Change (PGIC) scale, and (3) six-point improvement from baseline in physical function  score) .α2-δ  ligand that has analgesic, anxiolytic-like, and anticonvulsant activity in animal models, and biochemical studies have found that the primary binding site for pregabalin and the related gabapentin are  α2-δ  (type 1).  α2-δ  is an auxiliary protein associated with voltage-gated calcium channels, and the potent binding of pregabalin at the  α2-δ  site reduces calcium influx at nerve terminals resulting in reduction of the release of a number of neurochemicals, including glutamate, noradrenaline, and substance P, which may explain the analgesic, anticonvulsant, and anxiolytic-like activity of pregabalin in animal models. It has also been suggested that reducing neurotransmitter release from neurons in the spinal cord and brain may be clinically beneficial for fibromyalgia patients. Pregabalin has significant side effects, including weight gain, dizziness, somnolence, and peripheral edema. When taken with angiotensin-converting-enzyme (ACE) inhibitors it may cause angioedema. The recommended dose is 300–450 mg daily, but many patients respond to lower doses. A single low dose (50–75 mg) at bedtime is frequently employed initially. Pregabalin is an  Crofford et al.  demonstrCurrently duloxetine (DLX), milnacipran (MLN), and pregabalin (PGB) are the only drugs that have been approved by the US Food and Drug Administration (FDA) for the treatment of fibromyalgia. A comparison of the efficacy and harms of these three drugs shows some differences: the NNTs for a 30% pain reduction  were as follows: DLX 7.2 , MLN 19 , and PGB 8.6 . The NNTs for dropout due to lack of efficacy were as follows: DLX −16.5 , MLN −31.1 , and PGB −16.0 . The NNHs for a dropout due to side effects were as follows: DLX 14.9 , MLN 7.6 , and PGB 7.6  .The mechanisms of action of pregabalin, duloxetine, and milnacipran are thought to be related to proposed pathophysiologies of fibromyalgia. However, these therapeutic agents are still not effective for all fibromyalgia patients. A recent study by Katz et al. suggests that the diagnostic criteria for fibromyalgia may be partially responsible, as there is currently no gold standard for fibromyalgia diagnosis .The family of tricyclic antidepressants (TCAs) are effective over the short term in the management of fibromyalgia, specifically the TCA amitriptyline and the biologically similar cyclobenzaprine. By inhibiting the reuptake of both serotonin and norepinephrine, tricyclic compounds enhance norepinephrine and serotonin neurotransmission in the descending inhibitory pain pathways, resulting in a reduction in pain. Four meta-analyses examined the efficacy of tricyclics in fibromyalgia management , 174–176The nonpharmacologic treatments most consistently linked to fibromyalgia improvements are aerobic exercise and strength training. Effective exercise focuses on stretching, with gradual progression to strengthening and reconditioning exercise , 181.Two randomized controlled single blind trials indicate that Tai chi holds potential as a useful modality in the multidimensional treatment of fibromyalgia . Tai chiγ  fibers of muscle spindles and activates the descending pain inhibitory system. According to the “gate theory,” pain relief may be due to the temperature and hydrostatic pressure of water on the skin [Both aquatic exercises and balneotherapy are regarded as nonpharmacological interventions for fibromyalgia. Aquatic exercises  are exercises that are performed in the water. The Chartered Society of Physiotherapists defined aquatic exercises as a therapy program using the properties of water, designed by a suitably qualified physiotherapist, to improve function, ideally in a purpose-built and suitably heated pool . It remathe skin .Spa therapy provokes a series of endocrine reactions, particularly in the release of adrenocorticotropic hormone (ACTH), cortisol, prolactin, and growth hormone (GH), although it does not alter the circadian rhythm of these hormones. A dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, marked by mild hypocortisolemia and glucocorticoid feedback resistance, has been demonstrated in fibromyalgia patients. These findings can explain the beneficial clinical effects of spa therapy in fibromyalgia. The systematic reviews on patients with fibromyalgia concluded, based on 4 RCTs, that there is moderate evidence in favor of the use of balneotherapy . UnfortuPsychological pain management skills have also been reported to be efficacious in patients with fibromyalgia. Cognitive-behavioral therapy (CBT) outperformed other psychological treatments in short-term fibromyalgia pain intensity reduction, reaching a medium effect size. Additionally, CBT and relaxation were significantly more effective than other psychological treatments in reducing sleep problems associated with fibromyalgia. The results indicate that all psychological treatments were equally effective in decreasing depression. For pain intensity and depression, the results also indicate that psychological treatments were more effective than control conditions, with small to medium effect sizes –194.Although not included in the recent evidence-based guidelines, EULAR recommendations additionally support inclusion of warm-water therapy, based on consistently beneficial data reported in numerous studies. Long-term studies found that warm-water exercise for 8 months was cost effective, with improvements of 8% for pain and 20% for physical function in treated patients compared with controls , 195–197F = 0.02; P = 0.007). Pairwise comparisons showed that this effect was significant from day 5 onwards and was maintained until week 25, although the magnitude of the effect tended to decrease during the period of monthly stimulation, from week 16 to 25. Active stimulation significantly improved ; the Brief Pain Inventory (BPI) score reported a marked decrease in the interference of pain with “general activity,” “walking,” “relations with other people,” “enjoyment of life,” and “sleep.” In contrast, the active treatment did not significantly decrease the interference of pain on “work” and “mood.” In addition, active rTMS significantly decreased both the total score  of the Fibromyalgia Impact Questionnaire (FIQ) and the 3 subscores relating to fatigue , stiffness , and morning tiredness .Over the last decade, it has been repeatedly shown that noninvasive repetitive transcranial magnetic stimulation (rTMS) of the primary motor cortex (M1) induces analgesic effects both in experimental pain –202 and F = 5.99, P = 0.02) after active rTMS than after sham treatment. APR, AWMF and EULAR recommendations are summarized in Mean depression and anxiety scores  and the 13-item short form of the Beck Depression Inventory (BDI)) were not significantly affected by active or sham stimulation. Catastrophizing score (PCS) was significantly lower  and nonpharmacological treatment, such as aerobic exercise and strength training, aquatic exercises and balneotherapy, cognitive-behavioral therapy, and also the emerging brain stimulation techniques.


Cow's milk (CM) IgE-mediated allergy is the most common food allergy in children. It affects 2 - 3% of the general population. About 80% of children allergic to CMP reach natural tolerance in the third year of life. It remains difficult to decide when it is time to attempt a controlled food challenge (CFC) to reintroduce CM in their diets. Objectives. To evaluate if the ratio total IgE / CM sIgE or total IgE / casein sIgE can be more useful than the single measurement of sIgE to predict tolerance in our patients, and to determine the highest sensitivity cut-off point.Retrospective, observational study. The medical records of 178 patients allergic to CM with CFC performed between January 2010 and December 2011 were reviewed. Clinical data, skin prick tests (SPT), total IgE, CM sIgE and casein sIgE at baseline and at the time of the CFC were recorded. These measures were compared between groups of tolerant and non-tolerant patients using the nonparametric Mann-Whitney. ROC curves were performed to evaluate predictive values of tolerance for total IgE, CM sIgE, casein sIgE and ratios .178 patients were included. 53% boys, 47% girls; mean age 4 years (range: 5 months - 13 years) at CFC. 107 patients (60%) tolerated, while 71 (40%) continued to be allergic. Of these 71 children, 6 (8%) had moderate anaphylaxis, 30 (42%) mild anaphylaxis, 15 (21%) urticaria and 7 patients (10%) rhinitis. Mean value for CM sIgE 19.12 KU / L (range: 0-727) and for casein sIgE 19.7 KU / L (range: 0-867). CM sIgE < 2.5 KU/L is a good marker for predicting tolerance but the ratio total IgE / CM sIgE ratio ≥ 3.75 allows, with greater reliability, the detection of tolerant patients. If only CM sIgE values < 2.5 kU/L had been used, 22% of our patients wouldn’t have undergone a CFC which has been successful.The use of the ratio total IgE / CM sIgE is useful for predicting tolerance in CM allergic patients, avoiding, thus, unnecessary exclusion diets.None declared.


Glossopharyngeal neuralgia is a rare condition with neuralgic sharp pain in the pharyngeal and auricular region. Classical glossopharyngeal neuralgia is caused by neurovascular compression at the root entry zone of the nerve. Regarding the rare occurrence of glossopharyngeal neuralgia, we report clinical data and magnetic resonance imaging (MRI) findings in a case series of 19 patients, of whom 18 underwent surgery. Two patients additionally suffered from trigeminal neuralgia and three from additional symptomatic vagal nerve compression. In all patients, ipsilateral neurovascular compression syndrome of the IX cranial nerve could be shown by high-resolution MRI and image processing, which was confirmed intraoperatively. Additional neurovascular compression of the V cranial nerve was shown in patients suffering from trigeminal neuralgia. Vagal nerve neurovascular compression could be seen in all patients during surgery. Sixteen patients were completely pain free after surgery without need of anticonvulsant treatment. As a consequence of the operation, two patients suffered from transient cerebrospinal fluid hypersecretion as a reaction to Teflon implants. One patient suffered postoperatively from deep vein thrombosis and pulmonary embolism. Six patients showed transient cranial nerve dysfunctions , but all recovered within 1 week. One patient complained of a gnawing and burning pain in the cervical area. Microvascular decompression is a second-line treatment after failure of standard medical treatment with high success in glossopharyngeal neuralgia. High-resolution MRI and 3D visualization of the brainstem and accompanying vessels as well as the cranial nerves is helpful in identifying neurovascular compression before microvascular decompression procedure. Glossopharyngeal neuralgia is a rare entity with a reported incidence of 0.2–0.7/100,000/year. Epidemiological data are based on the extrapolation of few data from one center and recently from the analysis of a medical record database . The freA coincidence of trigeminal neuralgia and glossopharyngeal neuralgia in the same patient complicates the clinical diagnosis. However, pain attacks do not occur simultaneously in both areas . Due to We report a series of 19 consecutive patients suffering from glossopharyngeal neuralgia referred for surgery due to unsatisfying response to previous medical treatment. The clinical appearance, pain localization, medical treatment and course of the disease were analyzed. The clinical symptoms were classified into pharyngeal, otalgic and vagal manifestation type of glossopharyngeal neuralgia. Data collection was done by retrospective analysis of the patients’ medical records. All patients were treated between 1994 and 2009 in the Department of Neurosurgery of the University of Erlangen-Nuremberg, Germany. Detailed prior history and clinical examination with special attention to cranial nerve function was done in all patients. All patients underwent high-resolution magnetic resonance imaging (MRI) and 3D visualization of the brainstem and accompanying vessels and cranial nerves in this region as described by Naraghi and Hastreiter . Clinicat test analysis.All statistical analyses were performed with PASW Statistics 18.0.0. The demographic data of men and women were compared using Eleven men and eight women were investigated Table . Mean agAll patients underwent high-resolution MRI, and the data were subjected to image processing and 3D visualization (illustrated in patient no 16) Figs. . Data weOf the 18 patients, 16 who underwent microsurgical decompression of the glossopharyngeal nerve were completely pain free after the procedure. They no longer needed any anticonvulsant or other pain medication. One patient (no. 4) improved substantially and medication could be reduced (she currently only takes gabapentin). One patient (no. 5) was pain free for 2 years, and then neuralgia returned. After a second MVD she was sustained pain free.Two patients (nos. 3 and 4) suffered from transient CSF hypersecretion as a reaction to the Teflon implant. CSF examination revealed lymphocytic pleocytosis. No causative bacteria could be found in CSF. Antibiotics were administered while CSF samples were taken repeatedly. Symptoms regressed within a few days. One patient (no. 3) suffered from postoperative deep vein thrombosis and pulmonary embolism, which prompted oral anticoagulation. Six patients showed transient cranial nerve dysfunctions with difficulties in swallowing or vocal cord paresis, but in all cases dysfunction resolved within 1 week. One patient (no. 3) complained of a gnawing and burning pain in the cervical area, but no signs of cranial nerve dysfunction were found on physical examination. Pre-existing disturbance in sensitivity in the trigeminal area of the face subsisted after surgical intervention. No patient suffered any hearing reduction as a result of surgery.This case series focuses on symptomatology and response to medical and surgical treatment in patients suffering from glossopharyngeal neuralgia. Diagnosis should be considered if neuralgic pain occurs in the pharyngeal region or in the auditory canal. The coincidence of trigeminal and glossopharyngeal neuralgia that was found in two patients of our series (9:5%) is comparable to previous reports , 13, 14.The presented data support MVD on the basis of image processing as a safe and promising second-line treatment after failure of standard medical treatment or unacceptable side effects of drug therapy. ICHD-II criteria (13.2.1) for classical glossopharyngeal neuralgia require an inconspicuous neurological examination (criteria D) . More deIn cases of glossopharyngeal neuralgia, MRI  is suggested for the exclusion of symptomatic forms and for a first hint of neurovascular compression. MR-angiography (MRA) can show the anatomical relationship between cranial nerve and vessels (in particular arteries) . In caseOf the 18 patients, 16 who underwent MVD became permanently pain free and the two remaining patients showed pain reduction. In former studies, pain-free rates in 76% of the patients and improvement in an additional 16% of patients were reported . Long-teRisks of surgery consist of the common risk of anesthesiology, bleeding and infection. Special risks are hearing loss, hoarseness and difficulties in swallowing; these symptoms are temporary in the overwhelming majority of the patients. Teflon implant is a suspected cause of CSF hypersecretion, which results in postoperative headache. This was confirmed by a clinical study showing that lumbar puncture with drainage of 20–30 ml CSF results in sufficient headache relief . To imprOf the 19 patients, 6 (32%) in our study suffered from additional arterial hypertension. Autoptic studies and clinical observations show weak evidence of a relationship between hypertension and neurovascular compression of the vagal and glossopharyngeal nerves, especially if left sided with compression of the rostral ventrolateral medulla oblongata –22. MicrPatients suffering from uncommon facial pain syndromes including neuralgias of the cranial nerves should be treated in centers focusing on headaches and facial pain, if first-line medical treatment fails or diagnosis remains unclear. Interdisciplinary workup of cases opens the door to successful treatment even in difficult situations. Modern techniques of imaging such as high-resolution MRI and subsequent image processing with 3D visualization provide precise diagnosis of potential neurovascular compression of various cranial nerves . Microvascular decompression is a safe and successful treatment alternative in patients with failure or several side effects of medical treatment.


The aim of the present study was to compare the pain levels resulting from the use of a silicone ring tourniquet (SRT) to those resulting from the use of a classic pneumatic cuff tourniquet (PT) in patients undergoing carpal tunnel release under local anesthesia.Fifty patients that underwent carpal tunnel release under local anesthesia were randomized using the technique of stratified randomization by minimization. A forearm tourniquet was applied: a standard PT was used in 25 patients, and an SRT was used in the other 25 patients (the model of SRT used was selected according to the standard systolic blood pressure). Patient demographics and complications were recorded. Pain levels were assessed with the visual analogue scale and were recorded (a) just after tourniquet application, (b) 5 min after tourniquet application, and (c) just before tourniquet removal.p = 1.000). The difference between the mean final pain level and the mean initial pain level was statistically significant for the SRT group (p = 0.010) and highly statistically significant for the PT group (p < 0.001). The mean final pain level for the PT group was higher than that for the SRT group (p = 0.043).There was no statistical significant difference in patient demographics between the two groups. The mean tourniquet time was similar for both groups (According to the findings of this study, in patients who underwent carpal tunnel release under local anesthesia, the pain levels at the end of the operation and those just before the removal of the tourniquet were higher in the PT group than in the SRT group of patients. Tourniquet devices are commonly used in orthopedic procedures in order to provide a bloodless operating field during surgical procedures involving the extremities. Pneumatic tourniquets (PTs) are preferred by most surgeons, and modern pneumatic tourniquets are designed to minimize the incidence of complications . NeverthHowever, a new device known as a silicon ring tourniquet (SRT) was introduced into clinical practice relatively recently –6. This The entire device is sterile and comes in different sizes: (a) a small size for pediatric use; (b) a medium size for an upper limb (circumference of the limb at the occlusion site 24–40 cm); (c) a large size for the leg (circumference of the limb at the occlusion site 30–55 cm); and (d) an extra-large size for the leg (circumference of the limb at the occlusion site 50–90 cm and systolic blood pressure ≤160 mmHg). There are three tension models  for the medium and large sizes, and the appropriate model is selected for each patient according to the systolic blood pressure measured in the operating room before the placement of the device.This device has been compared to the pneumatic tourniquet in healthy volunteers , 8, and The aim of this randomized prospective study was to compare the pain levels resulting from the use of the classic pneumatic tourniquet to the pain levels resulting from the use of this new device in patients undergoing carpal tunnel release.Patients who were scheduled for carpal tunnel release under local anesthesia and had no previous fracture or operation in the affected limb as well as no history of anemia, malignancy, or neurological disorder were included in this study. All of the patients gave their informed consent prior to being included into the study. The study was authorized by the local ethical committee , and was performed in accordance with the ethical standards of the 1964 Declaration of Helsinki, as revised in 2000.Fifty patients were randomized using the technique of stratified randomization by minimization , 10. TheA standard pneumatic tourniquet (PT) with an 8 cm wide cuff and the appropriate SRT model (selected according to the standard systolic pressure) were used.The procedure was explained to all participants. They were also instructed how to use the visual analogue scale for discomfort/pain  . The patA forearm tourniquet was used in all patients. A PT with an 8 cm wide cuff was applied over two layers of smoothly applied cast padding. The limb was elevated for 3 min before tourniquet inflation. The PT inflation pressure was 100 mm Hg above the standard systolic blood pressure. The appropriate SRT model was selected according to the standard systolic blood pressure and applied as recommended by the manufacturer.T0), (b) 5 min after the tourniquet application (T5), and (c) just before the tourniquet removal .The VAS levels for pain were recorded (a) just after tourniquet application ; post hoc analysis was performed using Bonferroni’s correction. The interaction between the type of the tourniquet and the change in VAS score over time was established by performing two-way analysis of variance. All tests were two-tailed and statistical significance was considered for p values of less than 0.05.Statistical analysis of the data was performed using the Statistical Package for the Social Sciences (SPSS), version 19.0 . All quantitative variables were expressed as the mean ± SD, while qualitative variables were expressed as frequencies (and percentages). The normality of the quantitative variables was tested with the Kolmogorov–Smirnov test. The p = 0.713), age (p = 0.658), BMI (p = 0.712), smoking status (p = 1.000), occupation (p = 0.758), other illness (p = 0.569), medication (p = 0.569), or the dominant hand (p = 0.208) between the two groups of patients : 10.20 ± 2.78 min  for SRT and 10.20 ± 3.58 min  for PT.The mean tourniquet time was identical in the two groups .One-way repeated-measures ANOVA showed statistically significant changes in the VAS score over time . Overall, SRT application resulted in a statistically significant elevation of the pain score by 26.5 % (p = 0.010) compared to the initial pain score . In the PT group, an initial nonsignificant (p = 0.195) elevation of the VAS score by 24.4 % (from T0 to T5) was followed by a statistically significant elevation of the VAS score by 51.5 % (p < 0.001) . Overall, PT application produced a highly significant elevation of the pain score by 88.5 % (p < 0.001) compared to the initial pain score .Post hoc analysis, using Bonferroni’s adjustment for the number of comparisons, was then performed: SRT application produced a gradual elevation of the VAS score from one measurement to the next by 13.3 and 11.7 %, respectively, but none of these changes reached statistical significance . In this regard, although the initial elevation of the VAS score was similar for the two groups , the pain increased more dramatically in the PT than in the SRT group from the second measurement until tourniquet removal . In addition, the increase in the pain score from tourniquet application until removal was greater in the PT than in the SRT group .The time courses for the pain experienced by the two groups were compared via two-way mixed ANOVA. This analysis revealed a statistically significant interaction between the type of the tourniquet and the change in VAS score over time (p = 0.181) and 5 min after this application (p = 0.294); (2) a significantly higher VAS score for the PT than for the SRT group just before tourniquet removal (p = 0.043).A comparison of the post-application VAS scores of the two groups of patients at each measurement showed that there was: (1) no statistically significant difference between the PT and SRT groups just after tourniquet application (According to the findings of this study, patients that underwent carpal tunnel release under local anesthesia and with the use of a forearm pneumatic tourniquet experienced more pain at the end of the procedure compared to patients for whom the silicone ring tourniquet was used. The pain levels just after the application of the tourniquet were higher in the SRT group and remained higher 5 min later when compared to the PT group. After that, the pain levels in the SRT group continued to gradually increase in the same manner as they did during the first 5 min. However, for the PT group, a more rapid increase in pain levels was observed, and the mean pain levels in the PT group had become higher than those in the SRT group by about 6–7 min after the application of the tourniquet. These fluctuations in pain levels are similar to those seen in a recently reported study of healthy volunteers [A forearm tourniquet was used in our study because, according to previous studies, a forearm tourniquet is tolerated for longer than an upper arm tourniquet , 12.According to previously published studies –6, the STwo recently reported studies of healthy volunteers showed that the SRT performs similarly to the classic PT in terms of tolerance time , and mayThe etiology and the neural pathways of tourniquet pain seem to be multifactorial . The preOn the other hand, a study of human volunteers showed that narrow cuffs resulted in less pain and were tolerated for a longer time than wider cuffs  and, morIn conclusion, according to the findings of this study, in patients who underwent carpal tunnel release under local anesthesia, the pain levels at the end of the operation and those just before the removal of the tourniquet were higher in the PT group than in the SRT group of patients. Therefore, it seems that SRT may be advantageous compared to the classic pneumatic tourniquet from a tourniquet pain perspective in hand operations performed under local anesthesia, such as carpal tunnel release.


Tonsillectomy is a common procedure causing considerable postoperative pain. Postoperative pain intensity of 60 - 70 in the scale of visual analog scale (VAS) has been reported up to 3 - 4 days which could continue until 11 days after the surgery.The current study aimed to compare the analgesic effect of gabapentin and diclofenac on pain after tonsillectomy with the control group.In this double-blind, placebo-controlled clinical trial, 90 patients aged 10-25 years, ASA classes I and II were randomly selected to receive 20 mg/kg oral gabapentin (n = 30), 1.0 mg / kg rectal diclofenac (n = 30) or placebo (n = 30) preoperatively. Pain was evaluated postoperatively on a visual analogue scale at 2, 6, 12 and 24 h. Opioid consumption in the first 24 h after surgery and the side effects were also recorded.There was no significant difference in terms of age, sex, and time of surgery in the three groups. Patients in the gabapentin and diclofenac groups had significantly lower pain scores at all-time intervals than those in the placebo group. The total meperidine consumed in the gabapentin (14.16 ± 6.97 P = 0.001) and diclofenac  groups was significantly less than that of the placebo (33.4 ± 13.97) group. The frequency of side effects such as vomiting, dizziness, and headache was not significantly different among the groups.It can be concluded that gabapentin and diclofenac reduced postoperative pain and opioid consumption without obvious side effects. Postoperative pain is one of the most important and effective factors after surgery. Considering the type of surgery, different methods have been advised to control the pain. One of the most difficult pain management cases is related to larynx, especially tonsillectomy. Postoperative pain intensity of 60 - 70 in the scale of visual analog scale (VAS) has been reported up to 3 - 4 days which could continue until 11 days after the surgery . HoweverThis study aimed to compare the analgesic effect of gabapentin and diclofenac on pain after tonsillectomy with the control group.Ninety patients undergoing tonsillectomy aged 10 - 25 years old admitted to Matini hospital of Kashan University of Medical Sciences (KAUMS) during 2011 were enrolled to this double-blind, placebo-controlled clinical trial study. After obtaining the permission from ethics committee of the university and getting the informed written consent, table of random numbers was used to divide the patients to three groups of 30. The patients with the history of stomach bleeding, coagulation disorders, sensitivity to opioids and diclofenac, kidney diseases, asthma, chronic pains, epilepsy, diabetes, chronic use of analgesic and steroid drugs and drug addiction were excluded from the study. After admitting the patients to the surgery room, intravenous catheter was placed and their heart rate, blood pressure and arterial oxygen saturation were monitored. Thirty patients from the first group received 20 mg/kg gabapentin capsule one hour before the surgery. The second group received 1 mg/kg suppository diclofenac one hour before the surgery and the third group did not receive any medications. All the patients received 10 µg /kg alfentanil and 10 µg /kg atropine as premedication. After 3 - 5 minutes, anesthesia was inducted using thiopental 6 mg/kg, and 0.5 mg/kg atracurium was used to facilitate endotracheal intubation. The patients were ventilated by 100% oxygen and intubation with cuffed tubes was done in appropriate sizes. Anesthesia was continued using a mixture of oxygen and N2O with the ratio of 50% and isofloran. At the end of the surgery, content of the patient’s stomach was suctioned by a G-tube and its relaxant effect was reversed using neostigmine (70 µg /kg) and atropine (40 µg /kg). After extubation and ensuring adequate respiration, the patients were transferred to the recovery and were taken care of for two hours; then, they were transferred to the ward. Postoperative pain intensity was measured by visual analog scale at 2, 6, 12 and 24 h after the surgery and the starting time of feeding, nausea and vomiting, headache and dizziness were recorded. If the patients felt pain in the recovery room or in the ward, and if the pain score was more than 4, they received 25 mg intramuscular meperidine after recording the pain score. A sample size of 30 patients in each group was calculated to detect a significant difference of 15% (as derived from pilot data) in morphine consumption with a power of 85% and a significance level of 5%. SPSS statistical software was employed to analyze the data, student’s t-test and chi-squared test were used to assess significant differences between the two groups. Level of significance was P < 0.05.The results of this study showed that the two groups did not have any significant differences in terms of age, gender and duration of surgery .P > 0.05), patients’ pain in gabapentin group was significantly less than that of the placebo group (P < 0.05). The mean pain intensity in diclofenac group at 2 and 6 h after the surgery was significantly less than that of the placebo group (P < 0.05). This difference was not significant at 12 and 24 h (P > 0.05) (Differences of the mean of pain intensity at different hours between gabapentin and diclofenac groups were not significant ( > 0.05) .P = 0.59) but, it was significant between gabapentin and placebo (P = 0.001) and diclofenac and placebo (P = 0.004). Staring time of feeding after the surgery in gabapentin group  and diclofenac  was significantly less than that of the placebo group (6.26 ± 1.22 h); however, the two groups, Gabapentin and Diclofenac, were not significantly different (Mean meperidine administered after the surgery was 14.16 ± 6.97, 16.66 ± 8.95 and 33.4 ± 13.97 mg in gabapentin, diclofenac and placebo groups, respectively. There was no significant difference in the amount of opioid consumption between the diclofenac and gabapentin groups (ifferent .The results of this study showed no significant difference between vomiting, headache and dizziness. .et al., the effects of gabapentin and diclofenac on pain and opioid consumption after sternotomy were compared (et al. (et al. (et al. administered diclofenac suppository or placebo to the patients before tonsillectomy (et al. (et al. (et al. (The results of this study demonstrated that administration of preoperative gabapentin and diclofenac significantly reduced postoperative pain and reduced the amount of opioid consumption. Thus far, no research has been done to compare the two drugs during tonsillectomy. Only in one study, the effects of these two drugs were compared after a sternotomy . Therefocompared . The res (et al. , the eff (et al. , patientllectomy . In orde (et al. , the eff (et al. -19. Thes (et al. . These s (et al. , 20 on 1 (et al. , similar


Non-specific chronic back pain (CBP) is often accompanied by psychological trauma, but treatment for this associated condition is often insufficient.Nevertheless, despite the common co-occurrence of pain and psychological trauma, a specific trauma-focused approach for treating CBP has been neglected to date. Accordingly, eye movement desensitization and reprocessing (EMDR), originally developed as a treatment approach for posttraumatic stress disorders, is a promising approach for treating CBP in patients who have experienced psychological trauma.Thus, the aim of this study is to determine whether a standardized, short-term EMDR intervention added to treatment as usual (TAU) reduces pain intensity in CBP patients with psychological trauma vs. TAU alone.The study will recruit 40 non-specific CBP patients who have experienced psychological trauma. After a baseline assessment, the patients will be randomized to either an intervention group (n = 20) or a control group (n = 20). Individuals in the EMDR group will receive ten 90-minute sessions of EMDR fortnightly in addition to TAU. The control group will receive TAU alone. The post-treatment assessments will take place two weeks after the last EMDR session and six months later.The primary outcome will be the change in the intensity of CBP within the last four weeks  from the pre-treatment assessment to the post-treatment assessment two weeks after the completion of treatment.In addition, the patients will undergo a thorough assessment of the change in the experience of pain, disability, trauma-associated distress, mental co-morbidities, resilience, and quality of life to explore distinct treatment effects. To explore the mechanisms of action that are involved, changes in pain perception and pain processing  will also be assessed.The statistical analysis of the primary outcome will be performed on an intention-to-treat basis. The secondary outcomes will be analyzed in an explorative, descriptive manner.This study adapts the standard EMDR treatment for traumatized patients to patients with CBP who have experienced psychological trauma. This specific, mechanism-based approach might benefit patients.NCT01850875).This trial has been registered with ClinicalTrials.gov ( Chronic pain conditions of the musculoskeletal system are common and have high socioeconomic relevance -3. This Further, CBP is often complicated by the presence of mental co-morbidities, but treatment for this association remains insufficient. An important comorbidity that has been neglected so far is the role of psychological trauma in the development and maintenance of CBP. Traumatic events have higher prevalence rates in CBP patients as compared to pain-free controls or other diseases ,8.Between 10% and 50% of patients receiving tertiary care treatment for chronic pain have symptoms according to psychological trauma and posttraumatic stress disorder . MoreoveConsidering the association of chronic pain and symptoms of posttraumatic stress disorder a model of shared vulnerability and mutual maintenance is discussed. The model purposes that physiological, affective, and behavioral components of psychological traumatization maintain and exacerbate symptoms of pain and, similarly, that cognitive, affective and behavioral components of chronic musculoskeletal pain maintain or exacerbate symptoms of posttraumatic stress disorder. Some of these factors are expected to constitute a shared vulnerability ,16,17. TConcerning treatment of CBP -24 or psGetting back to the before mentioned specific mechanism-based treatment approach, even if trauma-focused psychotherapy has been shown to be effective in the treatment of psychological trauma, the efficacy of trauma-focused psychotherapy in patients with chronic pain and previous psychological trauma as well as the underlying mechanisms have not yet been investigated in depth so far. However, there are some hints that this might be a promising approach -33. The A psychological first line treatment for psychological trauma, that has been proven to be efficacious, is eye movement desensitization and reprocessing (EMDR) ,28,36-38Several studies report that EMDR is able to reduce pain intensity or even eliminate pain completely in patients with different pain disorders  . FurtherHowever, until now there have predominantly been case-reports and case-series and none of them focused on CBP. Moreover, though there is first evidence that EMDR is effective and useful for the treatment of chronic pain, the underlying mechanisms still remain unclear.Accordingly, we designed a randomized controlled trial on change in pain intensity by EMDR-treatment in patients suffering from chronic non-specific back pain and previous psychological trauma. In addition, our core study is expanded by a comprehensive neurobiological and psychosocial assessment to explore potential underlying mechanisms.Therefore, the purpose of the present study is twofold: 1.) To determine whether a 10-session standardized EMDR short-term intervention in addition to treatment as usual (TAU) reduces pain intensity in CBP patients with experienced psychological trauma vs. TAU alone, and2.) to explore additionally potential underlying mechanisms.This study is part of the consortium ‘Localized and Generalized Musculoskeletal Pain: Psychobiological Mechanisms and Implications for Treatment’  funded bThe study is designed as a randomized controlled trial with two parallel arms  . PatientParticipants that meet all the inclusion criteria will have the trial explained to them in detail and then be asked to provide written informed consent before being enrolled into the trial.All the participants will continue to receive their usual routine care  from their own general practitioners and other healthcare providers in accordance with the guidelines for the treatment of CBP in Germany .In addition to TAU, the participants assigned to the EMDR intervention group will receive a manualized outpatient intervention that is based on the principles of EMDR-trauma therapy ,49 and iBased on the theoretical rationale proposed by Carlson and colleagues  and the Based on the theoretical rationale proposed by Carlson and colleagues , and the0, before randomization), two weeks after the intervention/TAU , and six months after the intervention/TAU . The physical examination and the clinical interviews will only be conducted at baseline. The assessor will be trained at the beginning of the study and will be observed regularly to ensure the reliability and validity of the measures.All the outcome assessments and the EMDR sessions will be conducted at the Department of General Internal Medicine and Psychosomatics, University Hospital Heidelberg, Germany. The outcome assessments will be performed by an independent evaluator who is blinded to the treatment allocation at three time points: baseline . The NRS for pain intensity has proven to be a reliable and valid instrument for assessing treatment effects in pain trials [The primary endpoint with respect to the efficacy of the standardized short-term EMDR intervention for CBP is the change in the intensity of back pain from Tn trials .2), medication intake, health-related quality of life (SF-12), anxiety and depression (HADS), dissociation symptoms (FDS-20), psychological resilience (RS-11), and somatization , will be measured at all assessment points (T1 and T2).The secondary outcomes, which include distinct pain variables  in all the patients to explore the differences in pain processing induced by the EMDR intervention. An overview of the primary and secondary outcomes is shown in Table Moreover, as part of the LOGIN study, all the participants in our study will be assessed for a shared core set of variables, including a comprehensive assessment of neuromodulators  and the functional and structural changes in functional neuroimaging (fMRI), before and after treatment .Serious adverse events (SAEs) will be documented and reported casuistically.1). The expected effect size for our trial is derived from previous evidence about the effect of EMDR therapy for chronic pain patients.The sample size calculation is based on the primary efficacy endpoint: change in the pain intensity  after the intervention  is not appropriate. Therefore, only complete cases will be used in the final analysis. Dropouts, withdrawals and missing values will be analyzed in detail; different techniques will be used to assess them, and these techniques will be compared using sensitivity analyses. Descriptive statistics will be presented as the means and standard deviations for the continuous variables and absolute numbers and percentages for the categorical variables. The questionnaires will be processed in accordance with questionnaire manuals.The differences between the change scores of the patient groups will be analyzed using independent t-tests. Moreover, potential negative effects will be reported descriptively . Preliminary effect sizes will be estimated using Cohen’s d.Pre-processing analyses and statistical analyses of quantitative sensory testing data will be performed according to the protocol used by Rolke et al. . To quanAlthough CBP is often accompanied by psychological trauma and posttraumatic stress symptoms, a specific trauma-focused approach for this subgroup of CBP cases has been a neglected issue to date. Eye movement desensitization and reprocessing, originally developed as a short-duration, high-efficiency treatment approach for posttraumatic stress symptoms, is a promising approach for treating CBP in patients who have experienced psychological trauma. The preliminary evidence suggests that EMDR treatment may benefit patients with medically unexplained somatic symptoms . To dateHowever, most of the research conducted thus far has been preliminary in nature and characterized by small sample sizes, heterogeneous patient groups, the lack of randomization and the absence of adequate control groups. Moreover, to our knowledge, none of these studies have evaluated the efficacy of EMDR in patients suffering CBP. Thus, there is an urgent need for further exploration of the efficacy of EMDR for treating chronic pain patients using well-designed studies with standardized EMDR interventions of sufficient treatment length and adequate control groups. Accordingly, we designed this randomized controlled trial on the effects of EMDR treatment for non-specific chronic back pain patients who have experienced psychological trauma to determine whether a standardized short-term EMDR intervention reduces pain intensity in this subgroup of CBP patients. Because this is the first randomized controlled trial on this topic, the results of this study will encourage a more specific trauma-focused treatment approach, especially for the pain patients who have experienced psychological trauma.However, although there is preliminary evidence that EMDR is effective and useful for the treatment of chronic pain, the underlying mechanisms remain unclear. Therefore, our core study will be supplemented by a comprehensive neurophysiologic and psychosocial assessment to explore these mechanisms of action.Notably, the study is part of the LOGIN consortium study . LOGIN cThe findings of this study might contribute to improvements in the treatment of patients suffering from CBP as well as to better understanding of the mechanisms of action underlying EMDR in chronic pain patients.The authors declare that they have no competing interests.AG and JT have made substantial contributions to conception and design and have been involved in drafting the manuscript. MH and WE have made substantial contributions to conception and design and revised the manuscript critically for important intellectual content. SL, SJ, GHS were involved in data collection and revised the manuscript critically for important intellectual content. All authors read and approved the final version of the manuscript to be published.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2474/14/256/prepub