BackgroundWe demonstrated in the randomised controlled ICON study that 48-week treatment of medically intractable chronic cluster headache (MICCH) with occipital nerve stimulation (ONS) is safe and... Show moreBackgroundWe demonstrated in the randomised controlled ICON study that 48-week treatment of medically intractable chronic cluster headache (MICCH) with occipital nerve stimulation (ONS) is safe and effective. In L-ICON we prospectively evaluate its long-term effectiveness and safety.MethodsICON participants were enrolled in L-ICON immediately after completing ICON. Therefore, earlier ICON participants could be followed longer than later ones. L-ICON inclusion was stopped after the last ICON participant was enrolled in L-ICON and followed for ≥2 years by completing six-monthly questionnaires on attack frequency, side effects, subjective improvement and whether they would recommend ONS to others. Primary outcome was the change in mean weekly attack frequency 2 years after completion of the ICON study compared to baseline. Missing values for log-transformed attack-frequency were imputed for up to 5 years of follow-up. Descriptive analyses are presented as (pooled) geometric or arithmetic means and 95% confidence intervals.FindingsOf 103 eligible participants, 88 (85%) gave informed consent and 73 (83%) were followed for ≥2 year, 61 (69%) ≥ 3 year, 33 (38%) ≥ 5 years and 3 (3%) ≥ 8.5 years. Mean (±SD) follow-up was 4.2 ± 2.2 years for a total of 370 person years (84% of potentially 442 years). The pooled geometric mean (95% CI) weekly attack frequency remained considerably lower after one (4.2; 2.8–6.3), two (5.1; 3.5–7.6) and five years (4.1; 3.0–5.5) compared to baseline (16.2; 14.4–18.3). Of the 49/88 (56%) ICON ≥50% responders, 35/49 (71%) retained this response and 15/39 (38%) ICON non-responders still became a ≥50% responder for at least half the follow-up period. Most participants (69/88; 78% [0.68–0.86]) reported a subjective improvement from baseline at last follow-up and 70/88 (81% [0.70–0.87]) would recommend ONS to others. Hardware-related surgery was required in 44/88 (50%) participants in 112/122 (92%) events (0.35 person-year−1 [0.28–0.41]). We didn't find predictive factors for effectiveness. Show less
Background and ObjectivesFemale-specific factors and psychosocial factors may be important in the prediction of strokebut are not included in prediction models that are currently used. We... Show moreBackground and ObjectivesFemale-specific factors and psychosocial factors may be important in the prediction of strokebut are not included in prediction models that are currently used. We investigated whetheraddition of these factors would improve the performance of prediction models for the risk ofstroke in women younger than 50 years.MethodsWe used data from the Stichting Informatievoorziening voor Zorg en Onderzoek, population-based, primary care database of women aged 20–49 years without a history of cardiovasculardisease. Analyses were stratified by 10-year age intervals at cohort entry. Cox proportionalhazards models to predict stroke risk were developed, including traditional cardiovascularfactors, and compared with models that additionally included female-specific and psychosocialfactors. We compared the risk models using the c-statistic and slope of the calibration curve at afollow-up of 10 years. We developed an age-specific stroke risk prediction tool that may helpcommunicating the risk of stroke in clinical practice.ResultsWe included 409,026 women with a total of 3,990,185 person-years of follow-up. Strokeoccurred in 2,751 women (incidence rate 6.9 [95% CI 6.6–7.2] per 10,000 person-years).Models with only traditional cardiovascular factors performed poorly to moderately in all agegroups: 20–29 years: c-statistic: 0.617 (95% CI 0.592–0.639); 30–39 years: c-statistic: 0.615(95% CI 0.596–0.634); and 40–49 years: c-statistic: 0.585 (95% CI 0.573–0.597). After addingthe female-specific and psychosocial risk factors to the reference models, the model discrimi-nation increased moderately, especially in the age groups 30–39 (Dc-statistic: 0.019) and 40–49years (Dc-statistic: 0.029) compared with the reference models, respectively.DiscussionThe addition of female-specific factors and psychosocial risk factors improves the discrimina-tory performance of prediction models for stroke in women younger than 50 years. Show less
Migraine is associated with altered sensory processing, that may be evident as changes in cortical responsivity due to altered excitability, especially in migraine with aura. Cortical excitability... Show moreMigraine is associated with altered sensory processing, that may be evident as changes in cortical responsivity due to altered excitability, especially in migraine with aura. Cortical excitability can be directly assessed by combining transcranial magnetic stimulation with electroencephalography (TMS-EEG). We measured TMS evoked potential (TEP) amplitude and response consistency as these measures have been linked to cortical excitability but were not yet reported in migraine.We recorded 64-channel EEG during single-pulse TMS on the vertex interictally in 10 people with migraine with aura and 10 healthy controls matched for age, sex and resting motor threshold. On average 160 pulses around resting motor threshold were delivered through a circular coil in clockwise and counterclockwise direction. Trial-averaged TEP responses, frequency spectra and phase clustering (over the entire scalp as well as in frontal, central and occipital midline electrode clusters) were compared between groups, including comparison to sham-stimulation evoked responses.Migraine and control groups had a similar distribution of TEP waveforms over the scalp. In migraine with aura, TEP responses showed reduced amplitude around the frontal and occipital N100 peaks. For the migraine and control groups, responses over the scalp were affected by current direction for the primary motor cortex, somatosensory cortex and sensory association areas, but not for frontal, central or occipital midline clusters.This study provides evidence of altered TEP responses in-between attacks in migraine with aura. Decreased TEP responses around the N100 peak may be indicative of reduced cortical GABA-mediated inhibition and expand observations on enhanced cortical excitability from earlier migraine studies using more indirect measurements. Show less
Objective To evaluate individual and group long-term efficacy and safety of erenumab in individuals with episodic migraine (EM) for whom 2-4 prior preventatives had failed.Methods Participants... Show moreObjective To evaluate individual and group long-term efficacy and safety of erenumab in individuals with episodic migraine (EM) for whom 2-4 prior preventatives had failed.Methods Participants completing the 12-week double-blind treatment phase (DBTP) of the LIBERTY study could continue into an open-label extension phase (OLEP) receiving erenumab 140 mg monthly for up to 3 years. Main outcomes assessed at week 112 were: >= 50%, >= 75% and 100% reduction in monthly migraine days (MMD) as group responder rate and individual responder rates, MMD change from baseline, safety and tolerability.Results Overall 240/246 (97.6%) entered the OLEP (118 continuing erenumab, 122 switching from placebo). In total 181/240 (75.4%) reached 112 weeks, 24.6% discontinued, mainly due to lack of efficacy (44.0%), participant decision (37.0%) and adverse events (AEs; 12.0%). The >= 50% responder rate was 57.2% (99/173) at 112 weeks. Of >= 50% responders at the end of the DBTP, 36/52 (69.2%) remained responders at >= 50% and 22/52 (42.3%) at >80% of visits. Of the non-responders at the end of the DBTP, 60/185 (32.4%) converted to a50% responders in at least half the visits and 24/185 (13.0%) converted to >= 50% responders in >80% of visits. Change from baseline at 112 weeks in mean (SD) MMD was -4.2 (5.0) days. Common AEs (>= 10%) were nasopharyngitis, influenza and back pain.Conclusions Efficacy was sustained over 112 weeks in individuals with difficult-to-treat EM for whom 2-4 prior migraine preventives had failed. Erenumab treatment was safe and well tolerated, in-line with previous studies. Show less
Epidemiological estimates indicate that individuals with epilepsy are more likely to experience headaches, including migraine, than individuals without epilepsy. Headaches can be temporally... Show moreEpidemiological estimates indicate that individuals with epilepsy are more likely to experience headaches, including migraine, than individuals without epilepsy. Headaches can be temporally unrelated to seizures, or can occur before, during or after an episode; seizures and migraine attacks are mostly not temporally linked. The pathophysiological links between headaches (including migraine) and epilepsy are complex and have not yet been fully elucidated. Correct diagnoses and appropriate treatment of headaches in individuals with epilepsy is essential, as headaches can contribute substantially to disease burden. Here, we review the insights that have been made into the associations between headache and epilepsy over the past 5 years, including information on the pathophysiological mechanisms and genetic variants that link the two disorders. We also discuss the current best practice for the management of headaches co-occurring with epilepsy and highlight future challenges for this area of research. Show less
Background Occipital nerve stimulation (ONS) has shown promising results in small uncontrolled trials in patients with medically intractable chronic cluster headache (MICCH). We aimed to establish... Show moreBackground Occipital nerve stimulation (ONS) has shown promising results in small uncontrolled trials in patients with medically intractable chronic cluster headache (MICCH). We aimed to establish whether ONS could serve as an effective treatment for patients with MICCH.Methods The ONS in MICCH (ICON) study is an investigator-initiated, international, multicentre, randomised, double-blind, phase 3, electrical dose-controlled clinical trial. The study took place at four hospitals in the Netherlands, one hospital in Belgium, one in Germany, and one in Hungary. After 12 weeks' baseline observation, patients with MICCH, at least four attacks per week, and history of being non-responsive to at least three standard preventive drugs, were randomly allocated (at a 1:1 ratio using a computer-generated permuted block) to 24 weeks of occipital nerve stimulation at either 100% or 30% of the individually determined range between paraesthesia threshold and neardiscomfort (double-blind study phase). Because ONS causes paraesthesia, preventing masked comparison versus placebo, we compared high-intensity versus low-intensity ONS, which are hypothesised to cause similar paraesthesia, but with different efficacy. In weeks 25-48, participants received individually optimised open-label ONS. The primary outcome was the weekly mean attack frequency in weeks 21-24 compared with baseline across all patients and, if a decrease was shown, to show a group-wise difference. The trial is closed to recruitment (ClinicalTrials.gov NCT01151631).Findings Patients were enrolled between Oct 12, 2010, and Dec 3, 2017. We enrolled 150 patients and randomly assigned 131 (87%) to treatment; 65 (50%) patients to 100% ONS and 66 (50%) to 30% ONS. One of the 66 patients assigned to 30% ONS was not implanted and was therefore excluded from the intention-to-treat analysis. Because the weekly mean attack frequencies at baseline were skewed (median 15.75; IQR 9.44 to 24.75) we used log transformation to analyse the data and medians to present the results. Median weekly mean attack frequencies in the total population decreased from baseline to 7.38 (2.50 to 18.50; p<0.0001) in weeks 21-24, a median change of -5.21 (-11.18 to -0.19; p<0.0001) attacks per week. In the 100% ONS stimulation group, mean attack frequency decreased from 17.58 (9.83 to 29.33) at baseline to 9.50 (3.00 to 21.25) at 21-24 weeks (median change from baseline -4.08, -11.92 to -0.25), and for the 30% ONS stimulation group, mean attack frequency decreased from 15.00 (9.25 to 22.33) to 6.75 (1.50 to 16.50; -6.50, -10.83 to -0.08). The difference in median weekly mean attack frequency between groups at the end of the masked phase in weeks 21-24 was -2.42 (95% CI -5.17 to 3.33). In the masked study phase, 129 adverse events occurred with 100% ONS and 95 occurred with 30% ONS. None of the adverse events was unexpected but 17 with 100% ONS and eight with 30% ONS were labelled as serious, given they required brief hospital admission for minor hardware-related issues. The most common adverse events were local pain, impaired wound healing, neck stiffness, and hardware damage.Interpretation In patients with MICCH, both 100% ONS intensity and 30% ONS intensity substantially reduced attack frequency and were safe and well tolerated. Future research should focus on optimising stimulation protocols and disentangling the underlying mechanism of action. Copyright (C) 2021 Elsevier Ltd. All rights reserved. Show less
Introduction Current prophylactic drugs for cluster headache are associated with limited efficacy, serious side effects and poor tolerability. Greater occipital nerve injection (GON-injection) has... Show moreIntroduction Current prophylactic drugs for cluster headache are associated with limited efficacy, serious side effects and poor tolerability. Greater occipital nerve injection (GON-injection) has been proven effective and safe as a single, one-time injection in episodic (ECH), and to a lesser extent, chronic cluster headache (CCH). We aim to analyse the effectiveness and safety of repeated GON-injections in medically intractable chronic cluster headache (MICCH). Methods Clinical data of all cluster headache patients who had received at least one GON-injection between 2014 and 2018 in our tertiary headache centre were retrieved from patients' medical records. Clinical history was taken as part of routine care shortly before and 6 weeks after GON-injection. Results We identified 47 MICCH patients (79 injections), and compared results with 22 non-MI CCH patients (30 injections) and 50 ECH patients (63 injections). Nineteen MICCH patients received repeated injections (32 in total, range 2-8). Rates of clinical relevant improvement to a first injection were similar in all groups (MICCH: 60%, non-MICCH 73%, ECH 76%; attack freedom: MICCH: 30%, non-MICCH 32%, ECH 43%). Furthermore, no difference in response to the first and second injection was shown between groups (all p > 0.29). Median effect duration in MICCH was 6 weeks (IQR 2.8-12 weeks). Side effects were only mild and local. Conclusion In this retrospective analysis, first and repeated GON-injections were well-tolerated and equally effective in MICCH as in non-MICCH, and ECH. Show less
Goadsby, P.J.; Reuter, U.; Lanteri-Minet, M.; Lima, G.P.D.; Hours-Zesiger, P.; Fernandes, C.; ... ; Klatt, J. 2021
ObjectiveTo report the efficacy and safety of erenumab among patients with episodic migraine (EM) whowere unsuccessful on 2 to 4 preventive treatments observed at week 64 of the open-label... Show moreObjectiveTo report the efficacy and safety of erenumab among patients with episodic migraine (EM) whowere unsuccessful on 2 to 4 preventive treatments observed at week 64 of the open-label extension phase (OLEP) of A Study Evaluating the Effectiveness of AMG 334 Injection in Preventing Migraines in Adults Having Failed Other Therapies (LIBERTY) study (ClinicalTrials.gov NCT03096834).MethodsTheOLEP, evaluatingmonthly erenumab 140 mg for 3 years, enrolled 240 patients who completed the double-blind treatment phase (DBTP) of 12 weeks during which they received placebo or erenumab 140 mg subcutaneous injections every 4 weeks as monotherapy. Efficacy outcomes were evaluated through the initial 52weeks ofOLEP (fromDBTP baseline to total 64weeks) in the overall population, patients receiving erenumab in DBTP, and patients from the DBTP placebo arm who switched to erenumab in OLEP. Endpoints included reduction of >= 50% in monthly migraine days (MMD) from DBTP baseline and change inMMDfrom DBTP baseline, Headache Impact Test score, and Migraine Physical Function Impact Diary score (Physical Impairment and Everyday Activities).ResultsAltogether, the week 52 visit of theOLEP was completed by 204 of 240 (85.0%) patients. Among patients continuing erenumab, the 50% responder rate increased from 29.9% at weeks 9 to 12 to 44.3% at weeks 61 to 64. The 50% responder rate in patientswho initiated erenumab in theOLEP remained higher in the OLEP (50.0% at week 61-64) than during DBTP (14.2% at weeks 9-12) compared to patients in continuous erenumab arm. In the OLEP, the 50% responder rate for the overall population increased from weeks 13 to 16 until weeks 37 to 40 and then remained stable through weeks 61 to 64. Patients treated with erenumab in DBTP showed sustained effects on all efficacy outcomes; those initiating erenumab in theOLEP demonstrated continued improvement from week 13 onward. Adverse events (AEs) were reported, considering both treatment groups, by approximate to 80.8% (serious AEs by 6.7%), 76.3% (5.9%) in the continuing erenumab arm, and 85.2% (7.4%) in those starting erenumab in OLEP. No deaths were reported.ConclusionsIn patients with EM who were unsuccessful on 2 to 4 prior preventive treatments, the LIBERTY study demonstrated sustained efficacy on erenumab monotherapy treatment through 64 weeks in both treatment arms. Safety of erenumab was consistent with that observed in previous clinical trials. Show less
Lanteri-Minet, M.; Goadsby, P.J.; Reuter, U.; Wen, S.H.; Hours-Zesiger, P.; Ferrari, M.D.; Klatt, J. 2021
Objective To evaluate the effect of erenumab on patient-reported, functional outcomes in patients with episodic migraine (EM) in whom 2-4 preventives were not useful from the Phase 3b LIBERTY study... Show moreObjective To evaluate the effect of erenumab on patient-reported, functional outcomes in patients with episodic migraine (EM) in whom 2-4 preventives were not useful from the Phase 3b LIBERTY study.MethodsAs previously reported, 246 patients with EM with 2-4 prior failed preventives were randomised 1:1 to subcutaneous erenumab 140 mg or placebo every 4 weeks for 12 weeks. This analysis evaluated Migraine Physical Function Impact Diary (MPFID), Headache Impact Test (HIT-6) and Work Productivity and Activity Impairment (WPAI) scores at Week 12. P values were nominal without multiplicity adjustment.ResultsErenumab significantly improved MPFID-Physical Impairment (PI) and Everyday Activities (EA) scores versus placebo (treatment difference (TD) (95% CI) MPFID-PI: -3.5 (-5.7 to -1.2) (p=0.003); MPFID-EA: -3.9 (-6.1 to -1.7)) (p<0.001) at 12 weeks. Patients on erenumab were more likely to have a >= 5-point reduction in MPFID score (OR vs placebo (95% CI) MPFID-EA: 2.1 (1.2 to 3.6); MPFID-PI: 2.5 (1.4 to 4.5)). A similar trend was observed for HIT-6 (TD: -3.0; p<0.001); significantly higher proportions of patients on erenumab reported a >= 5-point reduction (OR (95% CI): 2.4 (1.4 to 4.1)). In three out of four WPAI domains, erenumab showed improvement versus placebo.ConclusionAt 12 weeks, erenumab was efficacious on functional outcomes in patients with EM in whom 2-4 preventives were not useful. Show less
Objective We propose a new outcome measure to assess the efficacy of migraine treatments translating the approach of the Global Burden of Disease studies from a societal to an individual level:... Show moreObjective We propose a new outcome measure to assess the efficacy of migraine treatments translating the approach of the Global Burden of Disease studies from a societal to an individual level: Instead of calculating "years lived with disability", we suggest estimating "time lost due to an attack".MethodsTime lost due to an attack is calculated by multiplying the duration and the degree of impaired functioning during an attack.ResultsTime lost due to an attack, different from other outcome measures, does not just focus on the short-term analgesic effects of treatments, but rather on the improvement of all migraine symptoms and restoration of functioning, also considering therapy-related impairment. Importantly, time lost due to an attack measures the entire time patients are not functioning normally, from onset to complete resolution.ConclusionsTime lost due to an attack represents a new paradigm to assess migraine burden in single patients for a patient-centered evaluation of both acute and prophylactic treatments. Show less
Meij, A. van der; Walderveen, M.A.A. van; Kruyt, N.D.; Zwet, E.W. van; Liebler, E.J.; Ferrari, M.D.; Wermer, M.J.H. 2020
BackgroundSecondary damage due to neurochemical and inflammatory changes in the penumbra in the first days after ischemic stroke contributes substantially to poor clinical outcome. In animal models... Show moreBackgroundSecondary damage due to neurochemical and inflammatory changes in the penumbra in the first days after ischemic stroke contributes substantially to poor clinical outcome. In animal models, vagus nerve stimulation (VNS) inhibits these detrimental changes and thereby reduces tissue injury. The aim of this study is to investigate whether non-invasive cervical VNS (nVNS) in addition to the current standard treatment can improve penumbral recovery and limit final infarct volume.MethodsNOVIS is a single-center prospective randomized clinical trial with blinded outcome assessment. One hundred fifty patients will be randomly allocated (1:1) within 12h from clinical stroke onset to nVNS for 5 days in addition to standard treatment versus standard treatment alone. The primary endpoint is the final infarct volume on day 5 assessed with MRI.DiscussionWe hypothesize that nVNS will result in smaller final infarct volumes as compared to standard treatment due to improved penumbral recovery. The results of this study will be used to assess the viability and approach to power a larger trial to more definitively assess the clinical efficacy of nVNS after stroke.Trial registrationClinicalTrials.govNCT04050501. Registered on 8 August 2019 Show less
Mulder, I.A.; Li, M.; Vries, T. de; Qin, T.; Yanagisawa, T.; Sugimoto, K.; ... ; Ayata, C. 2020
Objective Calcitonin gene-related peptide (CGRP) pathway inhibitors are emerging treatments for migraine. CGRP-mediated vasodilation is, however, a critical rescue mechanism in ischemia. We,... Show moreObjective Calcitonin gene-related peptide (CGRP) pathway inhibitors are emerging treatments for migraine. CGRP-mediated vasodilation is, however, a critical rescue mechanism in ischemia. We, therefore, investigated whether gepants, small molecule CGRP receptor antagonists, worsen cerebral ischemia. Methods Middle cerebral artery was occluded for 12 to 60 minutes in mice. We compared infarct risk and volumes, collateral flow, and neurological deficits after pretreatment with olcegepant (single or 10 daily doses of 0.1-1mg/kg) or rimegepant (single doses of 10-100mg/kg) versus vehicle. We also determined their potency on CGRP-induced relaxations in mouse and human vessels, in vitro. Results Olcegepant (1mg/kg, single dose) increased infarct risk after 12- to 20-minute occlusions mimicking transient ischemic attacks (14/19 vs 6/18 with vehicle, relative risk = 2.21,p < 0.022), and doubled infarct volumes (p < 0.001) and worsened neurological deficits (median score = 9 vs 5 with vehicle,p = 0.008) after 60-minute occlusion. Ten daily doses of 0.1 to 1mg/kg olcegepant yielded similar results. Rimegepant 10mg/kg increased infarct volumes by 60% after 20-minute ischemia (p = 0.03); 100mg/kg caused 75% mortality after 60-minute occlusion. In familial hemiplegic migraine type 1 mice, olcegepant 1mg/kg increased infarct size after 30-minute occlusion (1.6-fold,p = 0.017). Both gepants consistently diminished collateral flow and reduced reperfusion success. Olcegepant was 10-fold more potent than rimegepant on CGRP-induced relaxations in mouse aorta. Interpretation Gepants worsened ischemic stroke in mice via collateral dysfunction. CGRP pathway blockers might thus aggravate coincidental cerebral ischemic events. The cerebrovascular safety of these agents must therefore be better delineated, especially in patients at increased risk of ischemic events or on prophylactic CGRP inhibition. ANN NEUROL 2020 Show less
Perenboom, M.J.L.; Ruit, M. van de; Zielman, R.; Maagdenberg, A.M.J.M. van den; Ferrari, M.D.; Carpay, J.A.; Tolner, E.A. 2020
BackgroundMigraine is associated with altered sensory processing and cortical responsivity that may contribute to susceptibility to attacks by changing brain network excitability dynamics. To gain... Show moreBackgroundMigraine is associated with altered sensory processing and cortical responsivity that may contribute to susceptibility to attacks by changing brain network excitability dynamics. To gain better insight into cortical responsivity changes in migraine we subjected patients to a short series of light inputs over a broad frequency range ("chirp" stimulation), designed to uncover dynamic features of visual cortex responsivity.MethodsEEG responses to visual chirp stimulation (10-40 Hz) were measured in controls (n = 24) and patients with migraine with aura (n = 19) or migraine without aura (n = 20). Average EEG responses were assessed at (i) all EEG frequencies between 5 and 125 Hz, (ii) stimulation frequencies, and (iii) harmonic frequencies. We compared average responses in a low (10-18 Hz), medium (19-26 Hz) and high (27-40 Hz) frequency band.ResultsResponses to chirp stimulation were similar in controls and migraine subtypes. Eight measurements (n = 3 migraine with aura; n = 5 without aura) were assigned as "pre-ictal", based on reported headache within 48 hours after investigation. Pre-ictally, an increased harmonic response to 22-32 Hz stimulation (beta band) was observed (p = 0.001), compared to interictal state measurements.ConclusionsWe found chirp responses to be enhanced in the 48 hours prior to migraine headache onset. Visual chirp stimulation proved a simple and reliable technique with potential to detect changes in cortical responsivity associated with the onset of migraine attacks. Show less
The European Position Paper on Rhinosinusitis and Nasal Polyps 2020 is the update of similar evidence based position papers published in 2005 and 2007 and 2012. The core objective of the EPOS2020... Show moreThe European Position Paper on Rhinosinusitis and Nasal Polyps 2020 is the update of similar evidence based position papers published in 2005 and 2007 and 2012. The core objective of the EPOS2020 guideline is to provide revised, up-to-date and clear evidence-based recommendations and integrated care pathways in ARS and CRS. EPOS2020 provides an update on the literature published and studies undertaken in the eight years since the EPOS2012 position paper was published and addresses areas not extensively covered in EPOS2012 such as paediatric CRS and sinus surgery. EPOS2020 also involves new stakeholders, including pharmacists and patients, and addresses new target users who have become more involved in the management and treatment of rhinosinusitis since the publication of the last EPOS document, including pharmacists, nurses, specialised care givers and indeed patients themselves, who employ increasing self-management of their condition using over the counter treatments. The document provides suggestions for future research in this area and offers updated guidance for definitions and outcome measurements in research in different settings.EPOS2020 contains chapters on definitions and classification where we have defined a large number of terms and indicated preferred terms. A new classification of CRS into primary and secondary CRS and further division into localized and diffuse disease, based on anatomic distribution is proposed. There are extensive chapters on epidemiology and predisposing factors, inflammatory mechanisms, (differential) diagnosis of facial pain, allergic rhinitis, genetics, cystic fibrosis, aspirin exacerbated respiratory disease, immunodeficiencies, allergic fungal rhinosinusitis and the relationship between upper and lower airways. The chapters on paediatric acute and chronic rhinosinusitis are totally rewritten. All available evidence for the management of acute rhinosinusitis and chronic rhinosinusitis with or without nasal polyps in adults and children is systematically reviewed and integrated care pathways based on the evidence are proposed. Despite considerable increases in the amount of quality publications in recent years, a large number of practical clinical questions remain. It was agreed that the best way to address these was to conduct a Delphi exercise. The results have been integrated into the respective sections. Last but not least, advice for patients and pharmacists and a new list of research needs are included. Show less
Cluster headache is characterised by attacks of excruciating unilateral headache or facial pain lasting 15 min to 3 h and is seen as one of the most intense forms of pain. Cluster headache attacks... Show moreCluster headache is characterised by attacks of excruciating unilateral headache or facial pain lasting 15 min to 3 h and is seen as one of the most intense forms of pain. Cluster headache attacks are accompanied by ipsilateral autonomic symptoms such as ptosis, miosis, redness or flushing of the face, nasal congestion, rhinorrhoea, peri-orbital swelling and/or restlessness or agitation. Cluster headache treatment entails fast-acting abortive treatment, transitional treatment and preventive treatment. The primary goal of prophylactic and transitional treatment is to achieve attack freedom, although this is not always possible. Subcutaneous sumatriptan and high-flow oxygen are the most proven abortive treatments for cluster headache attacks, but other treatment options such as intranasal triptans may be effective. Verapamil and lithium are the preventive drugs of first choice and the most widely used in first-line preventive treatment. Given its possible cardiac side effects, electrocardiogram (ECG) is recommended before treating with verapamil. Liver and kidney functioning should be evaluated before and during treatment with lithium. If verapamil and lithium are ineffective, contraindicated or discontinued because of side effects, the second choice is topiramate. If all these drugs fail, other options with lower levels of evidence are available (e.g. melatonin, clomiphene, dihydroergotamine, pizotifen). However, since the evidence level is low, we also recommend considering one of several neuromodulatory options in patients with refractory chronic cluster headache. A new addition to the preventive treatment options in episodic cluster headache is galcanezumab, although the long-term effects remain unknown. Since effective preventive treatment can take several weeks to titrate, transitional treatment can be of great importance in the treatment of cluster headache. At present, greater occipital nerve injection is the most proven transitional treatment. Other options are high-dose prednisone or frovatriptan. Show less
Axon pathfinding and synapse formation are essential processes for nervous system development and function. The assembly of myelinated fibres and nodes of Ranvier is mediated by a number of cell... Show moreAxon pathfinding and synapse formation are essential processes for nervous system development and function. The assembly of myelinated fibres and nodes of Ranvier is mediated by a number of cell adhesion molecules of the immunoglobulin superfamily including neurofascin, encoded by the NFASC gene, and its alternative isoforms Nfasc186 and Nfasc140 (located in the axonal membrane at the node of Ranvier) and Nfasc155 (a glial component of the paranodal axoglial junction). We identified 10 individuals from six unrelated families, exhibiting a neurodevelopmental disorder characterized with a spectrum of central (intellectual disability, developmental delay, motor impairment, speech difficulties) and peripheral (early onset demyelinating neuropathy) neurological involvement, who were found by exome or genome sequencing to carry one frameshift and four different homozygous non-synonymous variants in NFASC. Expression studies using immunostaining-based techniques identified absent expression of the Nfasc155 isoform as a consequence of the frameshift variant and a significant reduction of expression was also observed in association with two non-synonymous variants affecting the fibronectin type III domain. Cell aggregation studies revealed a severely impaired Nfasc155-CNTN1/CASPR1 complex interaction as a result of the identified variants. Immunofluorescence staining of myelinated fibres from two affected individuals showed a severe loss of myelinated fibres and abnormalities in the paranodal junction morphology. Our results establish that recessive variants affecting the Nfasc155 isoform can affect the formation of paranodal axoglial junctions at the nodes of Ranvier. The genetic disease caused by biallelic NFASC variants includes neurodevelopmental impairment and a spectrum of central and peripheral demyelination as part of its core clinical phenotype. Our findings support possible overlapping molecular mechanisms of paranodal damage at peripheral nerves in both the immune-mediated and the genetic disease, but the observation of prominent central neurological involvement in NFASC biallelic variant carriers highlights the importance of this gene in human brain development and function. Show less
Ferrari, M.D.; Diener, H.C.; Ning, X.P.; Galic, M.; Cohen, J.M.; Yang, R.H.; ... ; Ashina, M. 2019
