Kinetic oscillation stimulation as treatment of acute migraine: a randomized, controlled pilot study.

OBJECTIVE: To assess the relief of migraine pain, especially in the acute phase, by comparing active treatment, ie, kinetic oscillation stimulation (KOS) in the nasal cavity, with placebo. BACKGROUND: Exploratory trials testing the efficacy of KOS on migraine patients indicated that this treatment could be a fast-acting remedy for acute migraine pain. METHOD: Thirty-six patients were randomized 1:1 using a placebo module to active or placebo treatment in this double-blinded parallel design study. Treatment was administered with a minimally invasive inflatable tip oscillating catheter. Symptom scores (0-10 visual analog scale) were obtained before treatment, every 5 minutes during treatment, at 15 minutes, 2, and 24 hours post-treatment, as well as daily (0-3 migraine pain scale) from 30 days pretreatment until Day 60 post. Thirty-five patients were evaluated (active n=18, placebo n=17). The primary end-point was the change in average pain score from before treatment to 15 minutes after treatment. RESULTS: Patients who received active treatment reported reduced pain, eg, average visual analog scale pain scores fell from 5.5 before treatment to 1.2 15 minutes after, while the corresponding scores for recipients of placebo fell from 4.9 to 3.9. The changes in pain scores differed between the 2 treatments by 3.3 points (95% confidence interval: 2.3, 4.4), P<.001. Already 5 minutes into the treatment, the difference (1.9 points) was significant (P=.007). The difference was likewise significant at 2 hours post-treatment (3.7 points, P<.001). One patient experienced an adverse event (a vasovagal reaction with full spontaneous recovery) during placebo treatment. CONCLUSION: KOS is an effective and safe treatment for acute migraine pain.

Achieving symptom relief in patients with myalgic encephalomyelitis by targeting the neuro-immune interface and optimizing disease tolerance.

Myalgic encephalomyelitis (ME) previously also known as chronic fatigue syndrome is a heterogeneous, debilitating syndrome of unknown etiology responsible for long-lasting disability in millions of patients worldwide. The most well-known symptom of ME is post-exertional malaise, but many patients also experience autonomic dysregulation, cranial nerve dysfunction and signs of immune system activation. Many patients also report a sudden onset of disease following an infection. The brainstem is a suspected focal point in ME pathogenesis and patients with structural impairment to the brainstem often show ME-like symptoms. The brainstem is also where the vagus nerve originates, a critical neuro-immune interface and mediator of the inflammatory reflex which regulate systemic inflammation. Here, we report the results of a randomized, placebo-controlled trial using intranasal mechanical stimulation targeting nerve endings in the nasal cavity, likely from the trigeminal nerve, possibly activating additional centers in the brainstem of ME patients and correlating with a ∼30% reduction in overall symptom scores after 8 weeks of treatment. By performing longitudinal, systems-level monitoring of the blood immune system in these patients, we uncover signs of chronic immune activation in ME, as well as immunological correlates of improvement that center around gut-homing immune cells and reduced inflammation. The mechanisms of symptom relief remain to be determined, but transcriptional analyses suggest an upregulation of disease tolerance mechanisms. We believe that these results are suggestive of ME as a condition explained by a maladaptive disease tolerance response following infection.

Tracheobronchial transplantation with a stem-cell-seeded bioartificial nanocomposite: a proof-of-concept study.

BACKGROUND: Tracheal tumours can be surgically resected but most are an inoperable size at the time of diagnosis; therefore, new therapeutic options are needed. We report the clinical transplantation of the tracheobronchial airway with a stem-cell-seeded bioartificial nanocomposite. METHODS: A 36-year-old male patient, previously treated with debulking surgery and radiation therapy, presented with recurrent primary cancer of the distal trachea and main bronchi. After complete tumour resection, the airway was replaced with a tailored bioartificial nanocomposite previously seeded with autologous bone-marrow mononuclear cells via a bioreactor for 36 h. Postoperative granulocyte colony-stimulating factor filgrastim (10 µg/kg) and epoetin beta (40,000 UI) were given over 14 days. We undertook flow cytometry, scanning electron microscopy, confocal microscopy epigenetics, multiplex, miRNA, and gene expression analyses. FINDINGS: We noted an extracellular matrix-like coating and proliferating cells including a CD105+ subpopulation in the scaffold after the reseeding and bioreactor process. There were no major complications, and the patient was asymptomatic and tumour free 5 months after transplantation. The bioartificial nanocomposite has patent anastomoses, lined with a vascularised neomucosa, and was partly covered by nearly healthy epithelium. Postoperatively, we detected a mobilisation of peripheral cells displaying increased mesenchymal stromal cell phenotype, and upregulation of epoetin receptors, antiapoptotic genes, and miR-34 and miR-449 biomarkers. These findings, together with increased levels of regenerative-associated plasma factors, strongly suggest stem-cell homing and cell-mediated wound repair, extracellular matrix remodelling, and neovascularisation of the graft. INTERPRETATION: Tailor-made bioartificial scaffolds can be used to replace complex airway defects. The bioreactor reseeding process and pharmacological-induced site-specific and graft-specific regeneration and tissue protection are key factors for successful clinical outcome. FUNDING: European Commission, Knut and Alice Wallenberg Foundation, Swedish Research Council, StratRegen, Vinnova Foundation, Radiumhemmet, Clinigene EU Network of Excellence, Swedish Cancer Society, Centre for Biosciences (The Live Cell imaging Unit), and UCL Business.

The role of pain-mediating sensory nerves in histamine-induced inflammation of nasal mucosa.

Topical application of histamine on the nasal mucosa causes an inflammatory reaction with increased mucosal swelling and perfusion. In the nasal mucosa histamine receptors are found in the vascular epithelium and at free sensory nerve endings. The aim of this randomized double-blind placebo controlled study was to investigate if this inflammatory reaction to locally administered histamine was dependent upon the stimuli of pain-mediating sensory nerves, or if it mainly was the result of direct stimuli of the vascular epithelium. Eighteen healthy non-allergic subjects were treated with sprays of lidocaine or saline (placebo) in the nose, followed by challenge with histamine. Using a cross-over design the participants later returned and were allocated to the opposite treatment followed by histamine. Nasal congestion, and concentration, velocity and perfusion of erythrocytes were measured with rhinostereometry and laser Doppler flowmetry. Symptoms of blockage, discharge and itching were scored. When comparing the lidocaine group to the placebo group, we found no significant differences in the reaction to histamine concerning any of the measured parameters or subjective symptoms. In conclusion, our results suggest that the stimuli of pain-mediating sensory nerves do not significantly contribute to the inflammatory effect of histamine on human nasal mucosa.

Swine dust exposure is a model for rapid induction of non-allergic neutrophil inflammation in the nasal mucosa of healthy volunteers, and the symptoms as well as the microcirculation are modified by nasal lavage.

BACKGROUND: The pathophysiological mechanism of non-allergic rhinitis is not clear and there is a lack of models in healthy volunteers. It has previously been shown that swine dust exposure is an excellent method for inducing inflammatory changes in the lower airways. We have shown earlier that exposure to swine dust increases the histamine sensitivity of the nasal mucosa as measured by rhinostereometry. In this study the aim was to investigate the effects of swine dust exposure on nasal symptoms as well as the microcirculation. Furthermore, the effect on nasal lavage was investigated. METHOD: Seventeen subjects were exposed to swine dust during a three-hour period of work in a swine house. Nasal symptoms and the nasal mucosal response to histamine before and after exposure to swine dust were evaluated by laser Doppler flowmetry and nasal lavage. RESULTS: Exposure to swine dust increased nasal symptoms and levels of neutrophils, IL-8 and albumin. The increase in nasal symptoms and the microcirculation were modified by nasal lavage. CMBC correlated inversely with an increase in albumin (p = 0.018, R = -0.95). CONCLUSIONS: Swine dust exposure is a useful model for inducing nasal inflammation in healthy volunteers. Furthermore, nasal lavage modifies subjective as well as objective parameters, which should be considered when designing studies. Nasal lavage may be useful in the treatment of workers in a swine dust environment.

Upper-airway inflammation in relation to dust spiked with aldehydes or glucan.

OBJECTIVES: Organic dust is associated with adverse effects on human airways. This study was done to investigate whether the addition of beta-(1,3)-D glucan or aldehydes to office dust causes enhanced inflammation in human airways. METHODS: Thirty-six volunteers were exposed randomly to clean air, office dust, dust spiked with glucan, and dust spiked with aldehydes. The three dust exposures contained between 332 and 379 microg dust/m(3). Spiking with 1 gram of dust was done with 10 milligrams of glucan or 0.1 microliters of aldehydes. Acoustic rhinometry, rhinostereometry, nasal lavage, and lung function tests were applied. RESULTS: After the exposures to dust spiked with the glucan and aldehydes, the nasal volume decreased (-1.33 and -1.39 cm(3) (mean), respectively) when compared with the -0.9 cm(3) after clean air or office dust (P=0.036 for a difference in decrease between exposures). After 2-3 hours the aldehyde-spiked dust caused a 0.6-mm swelling of the inferior turbinate, and glucan-spiked dust produced a 0.7-mm swelling (P=0.039 for a difference in the swelling between the four exposures). The preexposure nasal lavage cleaned off the mucosa, and lower cytokine concentrations were found after all of the exposures. For interleukin-8, this decrease in concentration was smaller after the dust exposures spiked with glucan and aldehydes (-2.9 and -25.8 pg/ml, respectively) than after office dust or clean air (-65.9 and -74.1 pg/ml, respectively) (P=0.042). The nasal eosinophil cell concentration increased after exposure to dust spiked with glucan (P=0.045). CONCLUSIONS: beta-(1,3)-D glucan and aldehydes in office dust enhance the inflammatory effects of dust on the upper airways.

Resting-state fMRI study of acute migraine treatment with kinetic oscillation stimulation in nasal cavity.

Kinetic oscillatory stimulation (KOS) in the nasal cavity is a non-invasive cranial nerve stimulation method with promising efficacy for acute migraine and other inflammatory disorders. For a better understanding of the underlying neurophysiological mechanisms of KOS treatment, we conducted a resting-state functional magnetic resonance imaging (fMRI) study of 10 acute migraine patients and 10 normal control subjects during KOS treatment in a 3 T clinical MRI scanner. The fMRI data were first processed using a group independent component analysis (ICA) method and then further analyzed with a voxel-wise 3-way ANOVA modeling and region of interest (ROI) of functional connectivity metrics. All migraine participants were relieved from their acute migraine symptoms after 10-20 min KOS treatment and remained migraine free for 3-6 months. The resting-state fMRI result indicates that migraine patients have altered intrinsic functional activity in the anterior cingulate, inferior frontal gyrus and middle/superior temporal gyrus. KOS treatment gave rise to up-regulated intrinsic functional activity for migraine patients in a number of brain regions involving the limbic and primary sensory systems, while down regulating temporally the activity for normal controls in a few brain areas, such as the right dorsal posterior insula and inferior frontal gyrus. The result of this study confirms the efficacy of KOS treatment for relieving acute migraine symptoms and reducing attack frequency. Resting-state fMRI measurements demonstrate that migraine is associated with aberrant intrinsic functional activity in the limbic and primary sensory systems. KOS in the nasal cavity gives rise to the adjustment of the intrinsic functional activity in the limbic and primary sensory networks and restores the physiological homeostasis in the autonomic nervous system.

Nasal mucosal histamine reactivity among teachers six years after working in a moisture-damaged school.

OBJECTIVES: The objective of this study was to determine whether verified increased nasal mucosal reactivity among teachers, who had been working in a school with severe moisture problems, still persisted 6 years after remedial measures had been taken. The increased nasal mucosal reactivity, measured as the mucosal swelling reaction upon histamine provocation, had earlier been shown both 1 and 3 years after the renovation. METHODS: Twenty-four teachers in the target school and sixteen teachers in the control school, who participated in all the investigations (1995, 1997 and 2000), answered a standardized questionnaire and underwent a nasal histamine provocation test. In addition to the registration of mucosal swelling, the microcircular reaction to histamine provocation was measured with laser-Doppler flowmetry. RESULTS: The nasal histamine reactivity among the teachers, measured as the mucosal swelling reaction, was no longer increased. However, the laser-Doppler flowmetry showed that the teachers in the target school had significantly divergent microcircular perfusion (P = 0.0022) and a concentration of moving blood cells (P=0.0009) in the histamine provocation when compared with the teachers in the control school; this finding indicates more-pronounced plasma leakage and edema from the nasal mucosa. CONCLUSIONS: Restored nasal histamine reactivity, measured as mucosal swelling reaction, was observed among the teachers 6 years after an obviously successful renovation of the school environment. However, changes in microcirculation indicate a remaining effect on the nasal mucosa.

Kinetic oscillation stimulation as treatment of non-allergic rhinitis: an RCT study.

CONCLUSION: Kinetic oscillation stimulation (KOS) of nasal mucosa at low frequency seems to be a possibly effective and safe short-term treatment of non-allergic nasal stuffiness. OBJECTIVE: To assess the relief of rhinitis symptoms, especially stuffiness, by comparing active treatment, i.e. KOS at low frequency of the nasal mucosa, with placebo. METHODS: Patients were randomized to active or placebo treatment in this double-blinded parallel design study. Treatment with an inflatable oscillating catheter was administered on day 0, and symptom scores (stuffiness, secretion, and itching) were graded daily until day 14. An overall grading of symptoms from 1 week before treatment and during 14 days thereafter was made at day 14. Eighty-six patients (52 with non-allergic perennial rhinitis, NAR; 34 with rhinitis medicamentosa, RM) were randomized, and 71 were evaluated (active treatment, n = 35; placebo, n = 36). RESULTS: Patients with either NAR or RM who received active treatment reported reduced symptom scores by some measures, e.g. median RQSS stuffiness measure fell from 2 to 1 on a scale from 0 to 3 during the week following treatment. No significant effect was observed for patients treated with placebo. Mild side effects were reported.

Non-malignant respiratory tract fistula from the oesophagus. A lethal condition for which novel therapeutic options are emerging.

OBJECTIVES: Fistulas between the oesophagus and the respiratory tract can occur as a complication to anastomotic dehiscence after oesophageal resection, without any signs of local residual tumour growth. Other causes that are, by definition, benign may rarely prevail. The traditional therapeutic approach is to divert the proximal portion of the oesophagus and transpose the conduit into the abdominal cavity. With the introduction and development of self-expandable metal stents (SEMS), new therapeutic options have emerged for these severe complications. We have evaluated our stent-based strategy for managing these life-threatening situations. METHODS: At Karolinska University Hospital, all patients admitted with an oesophago-respiratory fistula during the period 2003-2011 followed a stent-based strategy. On clinical suspicion, a prompt computed tomography scan was performed with contrast ingestion, to visualize the status of the anastomosis and the potential communications. Often an endoscopy was done to assess the oesophagus and the conduit. The respiratory tree was inspected through a concomitant bronchoscopy. The double-stent strategy presently applied meant that covered self-expandable metal stents (SEMS) were applied on the alimentary and airway sides to adequately cover the fistula orifice on both sides. The subsequent clinical course determined the ensuing therapeutic strategy. RESULTS: During the study period, 17 cases with oesophago-respiratory fistulas were treated at our unit, of which 13 exhibited fistulation following an oesophageal resection due to cancer and 4 cases had a benign underlying disease. The cancer patients did not show any obvious demographic profile when it came to the cancer sub-location, histological type of cancer, or treatment with neoadjuvant chemo- and radiochemotherapy. There was an equal distribution between hand-sutured and stapled anastomoses. In 10 of the cases, the anastomoses were located in the upper right chest; the remainder in the neck, and all reconstructions were carried out by a tubulized stomach. The diagnosis of the fistula tract between the anastomotic area and the respiratory tract was attained on the 15th postoperative day (median), with a range from 5 to 24 days. CONCLUSIONS: When an oesophago-respiratory fistula is diagnosed, even in a situation where no neoplastic tissue is prevailing, attempts should be made to close the fistula tract by SEMS from both directions, i.e. from the oesophageal as well as the respiratory side. By this means, a majority of these patients can be initially managed conservatively with prospects of a successful outcome, although virtually all will eventually require a single-stage resection and reconstruction.

New treatment of subglottic stenosis due to Wegener's granulomatosis.

CONCLUSIONS: The presented new endoscopic surgical technique offers a safe and successful approach for treatment of subglottic stenosis due to Wegener's granulomatosis. OBJECTIVE: Subglottic stenosis is a potentially limiting and complex condition among patients with Wegener's granulomatosis. It causes various symptoms and often requires interventional therapy. The purpose of this study was to evaluate a new endoscopic submucosal technique. METHODS: Altogether 13 consecutive patients with subglottic stenosis due to Wegener's granulomatosis were treated with a new endoscopic technique. The procedure was carried out endoscopically, removing the stenotic part submucosally, sealing back the raised mucosal flap, and the bare areas were soaked with mitomycin-C. Follow-up telephone interviews were carried out and hospital records were reviewed. RESULTS: Patients included 3 males and 10 females, with an average age of 37.5 years. A total of 37 procedures were performed, with an average of 2.8 procedures per patient. There was a statistically significant reduction in the all symptoms related to the stenoses (p < 0.05). Mean follow-up period was 3.5 years (range 1.5-6.5 years). Overall success rate was 85%. Only one patient relapsed following adequate medical and surgical treatment. No perioperative mortality was recorded.

Nasal and bronchial histamine responsiveness in pollen-exposed patients with seasonal rhinitis.

In a previous study, we found an increased nasal responsiveness as measured by rhinostereometry and histamine challenge out of season in a sample of 12 patients suffering mainly from hay fever. The aim of the present study was to investigate whether airway responsiveness in these patients was further increased after direct pollen exposure, after a single nasal pollen provocation as well as by repeated exposure during the pollen season. In spite of increased allergic symptoms, the basal degree of nasal mucosal swelling was unchanged before histamine challenge under these circumstances. After histamine challenge, nasal mucosal swelling was increased in the same way over the seasons. Also bronchial responsiveness was unchanged during the pollen season. It correlated to frequent sneezing following nasal histamine challenge during the season (p = 0.0071, r = -0.74). We interpret the results as an indication of a continuos airway inflammation regardless of season in these patients with pollen allergy, with acute symptoms added on direct exposure to the allergen.