Prevalence of restless legs syndrome in migraine patients with and without aura: a cross-sectional,case-controlled study

Background

Although the comorbidity of migraine and restless legs syndrome (RLS) has been well-documented, the association between RLS and migraine frequency has yet to be elucidated. The present study aims to evaluate the prevalence of RLS among individuals who experience low-frequency, high-frequency, or chronic migraine presenting with and without aura.

Methods

We conducted a cross-sectional, case-controlled study involving 505 participants receiving outpatient headache treatment. Standardized questionnaires were administered to collect information on experiences of migraine, RLS, sleep quality, anxiety, depression, and demographics. Participants were categorized into low-frequency (1–8/month), high-frequency (9–14/month), and chronic (≥15/month) headache groups. RLS was diagnosed according to the criteria outlined by the International RLS Study Group (IRLSSG). The Pittsburgh Sleep Quality Index (PSQI) and Hospital Anxiety and Depression Scale (HADS) were used to assess sleep quality and identify symptoms of anxiety and depression. Associations between migraine frequency and RLS prevalence were investigated using multivariate linear and logistic regression.

Results

Univariate analysis revealed an effect of migraine frequency on RLS prevalence (p?=?0.026), though this effect did not persist following adjustment for baseline characteristics (p?=?0.256). The trend was robust in patients whose migraines presented with auras (p _univariate?=?0.002; p _multivariate?=?0.043) but not in those without auras (p _univariate and p _multivariate?>?0.05). Higher anxiety [odds ratio (OR)?=?1.18, p?=?0.019] and sleep disturbance (OR?=?1.17, p?=?0.023) scores were associated with higher RLS prevalence.

Conclusions

Higher migraine frequency correlates with a higher prevalence of RLS, particularly among patients with auras.

     

Migraine induction with calcitonin gene-related peptide in patients from erenumab trials

Background

Migraine prevention with erenumab and migraine induction by calcitonin gene-related peptide (CGRP) both carry notable individual variance. We wanted to explore a possible association between individual efficacy of anti-CGRP treatment and susceptibility to migraine induction by CGRP.

Methods

Thirteen migraine patients, previously enrolled in erenumab anti-CGRP receptor monoclonal antibody trials, received CGRP in a double-blind, placebo-controlled, randomized cross-over design to investigate their susceptibility to migraine induction. A standardized questionnaire was used to assess the efficacy of previous antibody treatment. The patients were stratified into groups of high responders and poor responders. Primary outcomes were incidence of migraine-like attacks and area under the curve of headache intensity after infusion of CGRP and placebo. All interviews and experiments were performed in laboratories at the Danish Headache Center, Copenhagen, Denmark.

Results

Ten high responders and three poor responders were included. CGRP induced migraine-like attacks in ten (77%) patients, whereof two were poor responders, compared to none after placebo (p?=?0.002). The area under the curve for headache intensity was greater after CGRP, compared to placebo, at 0–90 min (p?=?0.009), and 2–12 h (p?=?0.014). The median peak headache intensity score was 5 (5–9) after CGRP, compared to 2 (0–4) after placebo (p?=?0.004).

Conclusions

Patients with an excellent effect of erenumab are highly susceptible to CGRP provocation. If an association is evident, CGRP provocation could prove a biomarker for predicting antibody treatment efficacy.

Trial registration

Retrospectively registered at clinicaltrials.gov with identifier: NCT03481400.

     

Long-term Efficacy of Safinamide on Parkinson’s Disease Chronic Pain

Introduction

Chronic pain is an important yet overlooked non-motor symptom of Parkinson’s disease (PD), caused by an imbalance of the dopaminergic and glutamatergic systems. Safinamide has a multimodal mechanism of action, dopaminergic (reversible MAO-B inhibition) and non-dopaminergic (modulation of the abnormal glutamate release), that might be beneficial for both motor and non-motor symptoms.

Objectives

To investigate the long-term (2-year) efficacy of safinamide on PD chronic pain and to confirm the positive effects observed after 6 months of treatment.

Methods

This is a post hoc analysis of the data from the 2-year study 018, focused on the reduction of concomitant pain treatments and on the scores of pain-related items of the Parkinson’s disease quality of life questionnaire (PDQ-39).

Results

Safinamide, compared with placebo, significantly improved the PDQ-39 items 37 (“painful cramps or spasm,” p?=?0.0074) and 39 (“unpleasantly hot or cold,” p?=?0.0209) and significantly reduced the number of concomitant pain treatments by 26.2% (p?=?0.005). A significantly greater proportion of patients in the safinamide group was not using pain drugs after 2 years of treatment (p?=?0.0478).

Conclusions

The positive effects of safinamide on PD chronic pain were maintained in the long term. Further investigations are desirable to confirm their clinical relevance.

Funding

Zambon SpA.

     

Nonspecific periaqueductal gray lesions on T2WI in episodic migraine

Background

The specific periaqueductal gray (PAG) lesions with migraine-like headache were easily identified on conventional MR images in clinical practice, and the aim of this study is to investigate the nonspecific periaqueductal gray (PAG) lesions in episodic migraine (EM) patients based on T2 weighted imaging (T2WI).

Methods

T2WI images were obtained from 18 EM patients and 18 normal controls (NC) on 3.0 T MR system. The images were observed by two experienced radiologists, and the lesions were identified on T2WI by consensus by 2 experienced neuroradiologists blinded to the patient identity. Chi-Square test was performed for the significance test.

Results

Ring-like hyperintensity lesions (HILs) around the PAG region were observed in 14 EM patients and in 5 NCs on T2WI. Four EM patients and 13 NCs were normal in PAG region. The significance was revealed by Chi-Square test (P?=?0.003).

Conclusion

HIL of PAG may be the direct evidence of the EM genesis, and the further structural and functional study should be performed to elucidate the neuromechanism of migraine pathogenesis.

     

Impact of migraine on the clinical presentation of insomnia: a population-based study

Background

Insomnia and migraine are closely related; insomnia aggravates migraine symptoms. This study was conducted to investigate the impact of migraine on the clinical presentation of insomnia symptoms.

Methods

The data of the Korean Headache-Sleep Study (KHSS) were used in the present study. The KHSS is a nation-wide cross-sectional population-based survey regarding headache and sleep in Korean adults aged 19 to 69 years. If a participant’s Insomnia Severity Index (ISI) score?≥?10, she/he was classified as having insomnia. The clinical presentation of insomnia symptoms was assessed using total and subcomponent scores of the ISI.

Results

Of 2695 participants, 290 (10.8%) and 143 (5.3%) individuals were assigned as having insomnia and migraine, respectively. The proportions of migraine (12.8% vs. 4.4%, p?<? 0.001) and non-migraine headache (59.0% vs. 39.9%, p?<? 0.001) were higher among individuals with insomnia compared to those without insomnia. Among participants with insomnia, total ISI scores were not significantly different among participants with migraine, non-migraine, and non-headache [median and interquartile range: 13.0 (11.0–17.5) vs. 13.0 (11.0–17.5) vs. 12.0 (11.0–16.0), p?=?0.245]. ISI scores for noticeability of sleep problems to others were significantly higher among participants with migraine [3.0 (2.0–4.0) vs. 2.0 (2.0–3.0), p?=?0.011] and non-migraine headache [3.0 (2.0–4.0) vs. 2.0 (2.0–3.0), p?=?0.001] compared to those without headache history. Other ISI subcomponent scores did not significantly differ between headache status groups.

Conclusions

Participants with insomnia had an increased risk of migraine and non-migraine headache compared to those without insomnia. Among participants with insomnia, overall insomnia severity was not significantly influenced by the headache status.

     

The prevalence of primary headache disorders in Ethiopia

Background

Knowledge of the epidemiology of primary headache disorders in sub-Saharan Africa (SSA) remains very limited. We performed a population-based survey in rural and urban areas of Ethiopia, using methods similar to those of an earlier study in Zambia and tested in multiple other countries by Lifting The Burden.

Methods

In a cross-sectional survey we visited households unannounced in four regions of Ethiopia: the mostly urban populations in Addis Ababa and its environs and rural populations of selected districts in Oromia, Amhara and South Nations Nationalities and People’s Regions States (SNNPRS). We used cluster-randomized sampling: within clusters we randomly selected households, and one adult member (18–65 years old) of each household. The HARDSHIP structured questionnaire, translated into the local languages, was administered face-to-face by trained interviewers. Demographic enquiry was followed by diagnostic questions based on ICHD-II criteria.

Results

From 2,528 households approached, 2,385 of 2,391 eligible members (1,064 [44.7%] male, 596 [25.0%] urban) consented to interview (participating proportion 99.8%). Headache in the preceding year was reported by 1,071 participants (44.9% [95% CI: 42.4–46.3]; males 37.7%, females 49.9%), and headache yesterday by 170 (7.1% [6.2–8.2]; males 45 [4.1%], females 125 [9.2%]). Adjusted for gender, age and habitation (urban/rural), 1-year prevalence of migraine was 17.7%, of tension-type headache (TTH) 20.6%, of all headache on ≥15 days/month 3.2%, and of probable medication-overuse headache (pMOH) 0.7%. The adjusted prevalence of headache yesterday was 6.4%. Very few cases (1.6%) were unclassifiable. All headache disorders were more common in females. TTH was less common in urban areas (OR: 0.3; p?<?0.0001), but pMOH was very strongly associated (OR: 6.1; p?<?0.0001) with urban dwelling. Education was negatively associated with migraine (OR: 0.5–0.7; p?<?0.05) but (at university level) positively with pMOH (OR: 2.9; p?=?0.067). Income above ETB 500/month showed similar associations: negatively with migraine (OR: 0.8; p?=?0.035), positively with pMOH (OR: 2.1; p?=?0.164).

Conclusions

Findings for migraine and TTH in Ethiopia were quite similar to those from Zambia, another SSA country; pMOH was much less prevalent but, as in Zambia, essentially an urban problem. Primary headache disorders are at least as prevalent in SSA as in high-income western countries.

     

Increased nitroglycerin-mediated vasodilation in migraineurs without aura in the interictal period

Purpose

Migraine is associated with vascular disorders, but the underlying mechanism is unknown. Nitric oxide (NO) sensitivity is believed to play a major role in migraine pathophysiology. We investigated flow-mediated vasodilatation (FMD) and nitroglycerin-mediated vasodilatation (NMD) of the brachial artery by means of a key molecular mediator, NO, in patients with migraine without aura in the interictal period whether the abnormality is found.

Methods

A total of 12 patients with migraine without aura and 12 matched healthy controls were enrolled in this study. FMD and NMD were measured in all patients and controls using brachial artery ultrasonography.

Results

There was no significant difference in brachial artery diameter between migraineurs and nonmigraineurs (3.39?±?0.68 vs 3.89?±?0.67 mm, respectively; p?=?0.083). A significant difference in FMD was not found between migraineurs and nonmigraineurs (6.94?±?5.72 vs 6.08?±?2.98%, respectively; p?=?0.651). However, NMD in migraineurs was significant higher than that in nonmigraineurs (21.56?±?7.36 vs 14.23?±?7.41%, respectively; p?=?0.024).

Conclusion

We think that patients with migraine without aura in the interictal period have selective sensitivity in dilator response to nitroglycerin and may have systemic NO sensitivity.

     

Headache disorder and the risk of dementia: a systematic review and meta-analysis of cohort studies

Background

Until now, headache disorders have not been established as a risk factor for dementia. The aim of this study was to determine whether headache was associated with an increased risk of dementia.

Methods

We systematically searched electronic databases, including PubMed, Embase, and Web of Science, for studies investigating the association between headache and dementia. We then conducted a meta-analysis to determine a pooled-effect estimate of the association.

Results

We identified 6 studies (covering 291,549 individuals) to investigate the association between headache and the risk of all-cause dementia or Alzheimer’s disease (AD). Pooled analyses showed that any headache was associated with a 24% greater risk of all-cause dementia (relative risk [RR]?=?1.24; 95% confidential interval [CI]: 1.09–1.41; P?=?0.001), and that any headache was not statistically significantly associated with an increased risk of AD (RR?=?1.47; 95% CI: 0.82–2.63; P?=?0.192).

Conclusions

Our results indicated that any headache was associated with an increased risk of all-cause dementia. However, additional studies are warranted to further confirm and understand the association.

     

Early onset of efficacy with erenumab in patients with episodic and chronic migraine

Background

Subcutaneous erenumab reduced monthly migraine days and increased the likelihood of achieving a?≥?50% reduction at all monthly assessment points tested in 2 pivotal trials in episodic migraine (EM) and chronic migraine (CM). Early efficacy of migraine preventive medications is an important treatment characteristic to patients. Delays in achievement of efficacy can result in failed adherence. The objective of these post-hoc analyses were to evaluate efficacy in the first 4 weeks after initial subcutaneous administration of erenumab 70 mg, erenumab 140 mg, or placebo.

Methods

There is no generally accepted methodology to measure onset of action for migraine preventive medications. We used a comprehensive approach with data from both studies to evaluate change from baseline in weekly migraine days (WMD), achievement of ≥?50% reduction in WMD, and proportion of patients experiencing migraine measured on a daily basis. The 7-day moving averages were overlaid with observed data.

Results

In both studies (EM: N?=?955; CM: N?=?667), there was evidence of onset of efficacy of erenumab vs. placebo during the first week of treatment, which in some cases reached nominal significance. For EM the changes in WMD were (least squares mean [LSM] [95% CI]): placebo, ??0.1 (??0.3, 0.0); erenumab 70 mg, ??0.3 (??0.5, ??0.2) p?=?0.130; erenumab 140 mg, ??0.6 (??0.7, ??0.4) p?<?0.001. For CM the changes were: placebo, ??0.5 (??0.8, ??0.3); erenumab 70 mg, ??0.9 (??1.2, ??0.7) p?=?0.047; erenumab 140 mg, ??0.8 (??1.1, ??0.5) p?=?0.18. Achievement of ≥?50% reduction in WMD was observed as early as Week 1 (adjusted OR [95% CI] erenumab vs placebo) in EM: erenumab 70 mg, 1.3 (1.0, 1.9) p?=?0.097; erenumab 140 mg, 2.0 (1.4, 2.7) p?<?0.001. A similar outcome was observed for CM: erenumab 70 mg, 1.8 (1.1, 2.8) p?=?0.011; erenumab 140 mg, 1.9 (1.2, 2.9) p?=?0.009. Seven-day moving averages of observed data showed each treatment arm differed from placebo by Week 1 (OR [95% CI]): in EM Day 3 for erenumab 140 mg, 0.7 (0.5, 1.0) p?=?0.031 and at Day 7 for 70 mg, 0.6 (0.4, 0.8) p?=?0.002; in CM: Day 6 for erenumab 70 mg, 0.6 (0.4, 0.9) p?=?0.022 and at Day 7 for 140 mg, 0.7 (0.4, 1.0); p?=?0.038.

Conclusion

Erenumab showed early onset of efficacy with separation from placebo within the first week of treatment in both chronic and episodic migraine patients.

     

Effects of a self-managed home-based walking intervention on psychosocial health outcomes for breast cancer patients receiving chemotherapy: a randomised controlled trial

Purpose

This study evaluated the effectiveness of a self-managed home-based moderate intensity walking intervention on psychosocial health outcomes among breast cancer patients undergoing chemotherapy.

Methods

The randomised controlled trial compared a self-managed, home-based walking intervention to usual care alone among breast cancer patients receiving chemotherapy. Outcome measures included changes in self-report measures of anxiety, depression, fatigue, self-esteem, mood and physical activity. Fifty participants were randomised to either the intervention group (n?=?25), who received 12 weeks of moderate intensity walking, or the control group (n?=?25) mid-way through chemotherapy. Participants in the intervention group were provided with a pedometer and were asked to set goals and keep weekly diaries outlining the duration, intensity and exertion of their walking. Levels of psychosocial functioning and physical activity were assessed pre- and post-intervention in both groups.

Results

The intervention had positive effects on fatigue (F?=?5.77, p?=?0.02), self-esteem (F?=?8.93, p?≤?0.001), mood (F?=?4.73, p?=?0.03) and levels of physical activity (x ²?=?17.15, p?=?0.0011) but not anxiety (F?=?0.90, p?=?0.35) and depression (F?=?0.26, p?=?0.60) as assessed using the HADS. We found an 80 % adherence rate to completing the 12-week intervention and recording weekly logs.

Conclusion

This self-managed, home-based intervention was beneficial for improving psychosocial well-being and levels of physical activity among breast cancer patients treated with chemotherapy.

Trial registration

Current Controlled Trials ISRCTN50709297.

     

Chronic Temporomandibular Disorders: disability,pain intensity and fear of movement

Background

The objective was to compare and correlate disability, pain intensity, the impact of headache on daily life and the fear of movement between subgroups of patients with chronic temporomandibular disorder (TMD).

Methods

A cross-sectional study was conducted in patients diagnosed with chronic painful TMD. Patients were divided into: 1) joint pain (JP); 2) muscle pain (MP); and 3) mixed pain. The following measures were included: Craniomandibular pain and disability (Craniofacial pain and disability inventory), neck disability (Neck Dsiability Index), pain intensity (Visual Analogue Scale), impact of headache (Headache Impact Test 6) and kinesiophobia (Tampa Scale of Kinesiophobia-11).

Results

A total of 154 patients were recruited. The mixed pain group showed significant differences compared with the JP group or MP group in neck disability (p?<?0.001, d?=?1.99; and p?<?0.001, d?=?1.17), craniomandibular pain and disability (p?<?0.001, d?=?1.34; and p?<?0.001, d?=?0.9, respectively), and impact of headache (p?<?0.001, d?=?1.91; and p?<?0.001, d?=?0.91, respectively). In addition, significant differences were observed between JP group and MP group for impact of headache (p?<?0.001, d?=?1.08). Neck disability was a significant covariate (37 % of variance) of craniomandibular pain and disability for the MP group (β?=?0.62; p?<?0.001). In the mixed chronic pain group, neck disability (β?=?0.40; p?<?0.001) and kinesiophobia (β?=?0.30; p?=?0.03) were significant covariate (33 % of variance) of craniomandibular pain and disability.

Conclusion

Mixed chronic pain patients show greater craniomandibular and neck disability than patients diagnosed with chronic JP or MP. Neck disability predicted the variance of craniofacial pain and disability for patients with MP. Neck disability and kinesiophobia predicted the variance of craniofacial pain and disability for those with chronic mixed pain.

     

A genome-wide analysis in cluster headache points to neprilysin and PACAP receptor gene variants

Background

Cluster Headache (CH) is a severe primary headache, with a poorly understood pathophysiology. Complex genetic factors are likely to play a role in CH etiology; however, no confirmed gene associations have been identified. The aim of this study is to identify genetic variants influencing risk to CH and to explore the potential pathogenic mechanisms.

Methods

We have performed a genome-wide association study (GWAS) in a clinically well-defined cohort of 99 Italian patients with CH and in a control sample of 360 age-matched sigarette smoking healthy individuals, using the Infinium PsychArray (Illumina), which combines common highly-informative genome-wide tag SNPs and exonic SNPs. Genotype data were used to carry out a genome-wide single marker case-control association analysis using common SNPs, and a gene-based association analysis focussing on rare protein altering variants in 745 candidate genes with a putative role in CH.

Results

Although no single variant showed statistically significant association at the genome-wide threshold, we identified an interesting suggestive association (P?=?9.1?×?10^?6) with a common variant of the PACAP receptor gene (ADCYAP1R1). Furthermore, gene-based analysis provided significant evidence of association (P?=?2.5?×?10^?5) for a rare potentially damaging missense variant in the MME gene, encoding for the membrane metallo-endopeptidase neprilysin.

Conclusions

Our study represents the first genome-wide association study of common SNPs and rare exonic variants influencing risk for CH. The most interesting results implicate ADCYAP1R1 and MME gene variants in CH susceptibility and point to a role for genes involved in pain processing. These findings provide new insights into the pathogenesis of CH that need further investigation and replication in larger CH samples.

     

Non-invasive Neuromodulation in Primary Headaches

Purpose of Review

There is growing interest in neuromodulation for primary headache conditions. Invasive modalities such as occipital nerve stimulation, deep brain stimulation and sphenopalatine ganglion stimulation are reserved for the most severe and intractable patients. Non-invasive options such as vagal nerve stimulation (nVNS), supraorbital nerve stimulation (nSONS) and transcranial magnetic nerve stimulation (TMS) have all emerged as potentially useful headache treatments. This review examines the evidence base for non-invasive neuromodulation in trigeminal autonomic cephalalgias and migraine.

Recent Findings

Although a number of open-label series of non-invasive neuromodulation devices have been published, there is very little controlled evidence for their use in any headache condition. Open-label evidence suggests that nVNS may have a role in the prophylactic treatment of cluster headache and there is limited evidence to suggest it may be useful in the acute treatment of cluster and potentially migraine attacks. There is limited controlled evidence to suggest a role for nSONS in the prophylactic treatment of episodic migraine but there is no evidence to support its use in cluster headache. TMS may be efficacious in the acute treatment of episodic migraine has no controlled evidence to support its use as a preventative in any headache condition.

Summary

Non-invasive neuromodulation techniques are an attractive treatment option with excellent safety profiles but their use is not yet supported by high-quality randomised controlled trials.

     

Relationships between markers of neurologic and endothelial injury during critical illness and long-term cognitive impairment and disability

Purpose

Neurologic and endothelial injury biomarkers are associated with prolonged delirium during critical illness and may reflect injury pathways that lead to poor long-term outcomes. We hypothesized that blood–brain barrier (BBB), neuronal, and endothelial injury biomarkers measured during critical illness are associated with cognitive impairment and disability after discharge.

Methods

We enrolled adults with respiratory failure and/or shock and measured plasma concentrations of BBB (S100B), neuronal (UCHL1, BDNF), and endothelial (E-selectin, PAI-1) injury markers within 72 h of ICU admission. At 3 and 12 months post-discharge, we assessed participants’ global cognition, executive function, and activities of daily living (ADL). We used multivariable regression to determine whether biomarkers were associated with outcomes after adjusting for relevant demographic and acute illness covariates.

Results

Our study included 419 survivors of critical illness with median age 59 years and APACHE II score 25. Higher S100B was associated with worse global cognition at 3 and 12 months (P?=?0.008; P?=?0.01). UCHL1 was nonlinearly associated with global cognition at 3 months (P?=?0.02). Higher E-selectin was associated with worse global cognition (P?=?0.006 at 3 months; P?=?0.06 at 12 months). BDNF and PAI-1 were not associated with global cognition. No biomarkers were associated with executive function. Higher S100B (P?=?0.05) and E-selectin (P?=?0.02) were associated with increased disability in ADLs at 3 months.

Conclusions

S100B, a marker of BBB and/or astrocyte injury, and E-selectin, an adhesion molecule and marker of endothelial injury, are associated with long-term cognitive impairment after critical illness, findings that may reflect mechanisms of critical illness brain injury.

     

Cerebrolysin for the Treatment of Aneurysmal Subarachnoid Hemorrhage in Adults: A Retrospective Chart Review

Introduction

Cerebrolysin is a neuroprotective drug used in the treatment of acute ischemic stroke. To our knowledge, this drug has never been evaluated in patients with aneurysmal subarachnoid hemorrhage (SAH). The aim of this study was to evaluate the effect of Cerebrolysin in patients with aneurysmal SAH.

Methods

Aneurysmal SAH patients who had their aneurysm obliterated at our institution from 2007 to 2016 were retrospectively studied. Patients received Cerebrolysin treatment or standard care only (control group). Subgroup analyses were performed according to Hunt and Hess grade (good grade?≤?2, N?=?216; poor grade?≥?3, N?=?246) and treatment procedure (clip or coil).

Results

In good-grade patients (N?=?216), clinical outcomes and mortality did not differ significantly between the control and Cerebrolysin groups. In poor-grade patients (N?=?246), the mortality rate was significantly lower in the Cerebrolysin group (8.7%) than in the control group (25.4%, p?=?0.006). In patients who received microsurgical clipping (N?=?328), the mortality rate was significantly lower in the Cerebrolysin group (7.3%) than in the control group (18.5%, p?=?0.016).

Conclusion

Cerebrolysin injection during the acute period of SAH appeared to reduce the mortality rate, especially in poor-grade patients. This study suggests the potential of Cerebrolysin for treating aneurysmal SAH. Further studies are needed to confirm our results.

     

Clinical Efficacy and Safety of Current Interventions for Choroidal Neovascularization Associated with Rare Diseases: A Systematic Literature Review

Introduction

The aim of this systematic literature review was to evaluate the efficacy and safety of interventions for the treatment of choroidal neovascularization (CNV) secondary to etiologies other than age-related macular degeneration and pathologic myopia.

Methods

Relevant randomized controlled trials (RCTs) and prospective observational studies were identified by searching MEDLINE, MEDLINE In-Process, EMBASE, and CENTRAL.

Results

The search identified 5 RCTs; no relevant observational studies were identified. The studies differed in terms of underlying cause of CNV, patient numbers (n?=?9–178), follow-up time (2–36 months) and quality assessment. In the largest RCT (n?=?178 across a range of rare CNV etiologies), intravitreal ranibizumab showed superior efficacy versus sham from baseline to month 2 [mean best-corrected visual acuity (BCVA): +?9.5 vs. ??0.4 letters; p?<?0.001]; the gain was maintained up to month 12. In the treatment of CNV secondary to presumed ocular histoplasmosis syndrome (POHS), both intravitreal ranibizumab and photodynamic therapy (PDT) showed significant improvement from baseline BCVA over the 12-month period (n?=?9); however, all patients in the PDT group required rescue ranibizumab therapy. Unlicensed intravitreal bevacizumab was associated with a statistically significant improvement in BCVA compared to PDT at 12 months (p?<?0.001) in patients with CNV secondary to multifocal choroiditis (n?=?27). The use of steroids before PDT showed better BCVA outcomes than PDT alone (p?<?0.05) in patients with idiopathic CNV (n?=?20). Argon green laser therapy showed limited efficacy in patients with CNV secondary to OHS (n?=?134).

Conclusion

There is evidence from a relatively large, good-quality study to support the use of intravitreal ranibizumab for the treatment of CNV secondary to rare diseases. However, the limited number of RCTs for this indication and differences in study characteristics between RCTs mean that there is uncertainty regarding comparative clinical effectiveness of interventions. RCTs with an active comparator are required to fully establish the comparative effectiveness of treatments for CNV secondary to rare diseases.

Funding

Novartis Pharmaceuticals UK Ltd, Surrey, UK.

     

Subtypes of pediatric acute respiratory distress syndrome have different predictors of mortality

Purpose

Acute respiratory distress syndrome (ARDS) is heterogeneous in etiology, which may affect outcomes. Stratification into biologically-defined subtypes may reduce heterogeneity. However, it is unknown whether pediatric ARDS has clinically relevant subtypes. We aimed to determine whether clinical characteristics and predictors of mortality differed between direct and indirect ARDS, and separately between infectious and non-infectious ARDS.

Methods

This was a single center, prospective cohort study of 544 children with ARDS (Berlin) between July 2011 and June 2017, stratified into direct versus indirect ARDS, and separately into infectious versus non-infectious ARDS. Multiple logistic regression was used to test for predictors of mortality in the entire cohort, and separately within subtypes. Effect modification by subtype was assessed using interaction tests.

Results

Direct ARDS had lower severity of illness (p?<?0.001) but worse oxygenation (p?<?0.001), relative to indirect. Predictors of mortality were similar for direct and indirect ARDS. When comparing infectious and non-infectious ARDS, infectious ARDS had lower severity of illness (p?<?0.001), worse oxygenation (p?=?0.014), and lower mortality (p?=?0.013). In multivariable analysis, immunocompromised status demonstrated effect modification between infectious and non-infectious ARDS (p?=?0.005 for interaction), with no association with mortality in non-infectious ARDS.

Conclusions

In children, direct and indirect ARDS have distinct clinical characteristics, but similar outcomes and similar predictors of mortality. In contrast, infectious and non-infectious ARDS demonstrate heterogeneity of clinical characteristics, mortality, and predictors of mortality, with traditional predictors of ARDS mortality only applicable to infectious ARDS.

     

Cancer Patient–Derived Circulating Microparticles Enhance Lung Metastasis in a Rat Model: Dual-Source CT,Cellular, and Molecular Studies

Purpose

This study aimed to test the hypothesis that lung cancer patient–derived circulating microparticles (LCC-MPs) enhance metastatic lung tumors in a rat model.

Procedures

The controls (n?=?6) and LCC-MP-treated rats (n?=?6) with N1S1-induced pulmonary metastatic hepatocellular carcinoma (HCC) underwent dual-source CT (DSCT) on days 10, 15, and 20. Cellular and molecular studies were performed subsequently.

Results

DSCT revealed slow progression of metastatic lung tumors in the controls. Compared with the controls, the LCC-MP-treated rats exhibited significantly more and larger metastatic tumors on days 15 and 20 on DSCT, enhanced angiogenesis with higher microvessel count (CD34+), more CXCR4+ and VEGF+ cells in immunohistofluorescence studies, and higher protein expression levels of eNOS, angiopoietin, vascular endothelial growth factor, and CD31 on western blotting (Mann–Whitney test, all P?<?0.05).

Conclusions

LCC-MPs can elicit oncogenic stimulation and accelerate metastatic HCC growth in rat lung as demonstrated on DSCT and enhanced tumoral angiogenesis as confirmed in cellular and molecular studies.

     

Influence of cancer treatment on the <Emphasis Type="Italic">Candida albicans</Emphasis> isolated from the oral cavities of cancer patients

Purpose

Cancer treatment causes mucositis and the manifestation of oral candidiasis. This study investigated the virulence properties and antifungal susceptibilities of Candida albicans isolated from cancer patients undergoing therapy.

Methods

C. albicans were isolated from 49 patients on cancer treatment and 21 healthy individuals and their virulence attributes measured. A correlation was determined between the length of treatment and the fungal counts and their virulence factors.

Results

Although Candida carriage was similar in all the study groups, high quantities of C. albicans and variety of Candida were found in cancer patients. Germ tubes were produced by all the strains. Significantly high number of yeast isolated from radiotherapy and chemotherapy produced large quantities of phospholipase compared to healthy individuals (p?<?0.01). The length of chemotherapy was associated with an increase in the phospholipase production (p?=?0.03) by the C. albicans. Proteinase production was seen in a significant number of isolates from the radiotherapy group (p?<?0.01). Type of cancer treatment had no effect. Resistance to antifungal agents was low.

Conclusions

High quantities of phospholipase were produced by C. albicans in cancer patients on therapy which also increased with the length of chemotherapy suggesting enhanced risk of oral and systemic infection. Therefore, during treatment, prophylactic topical antifungal therapy may be considered.

     

Consistent effects of non-invasive vagus nerve stimulation (nVNS) for the acute treatment of migraine: additional findings from the randomized,sham-controlled,double-blind PRESTO trial

Background

Non-invasive vagus nerve stimulation (nVNS) has been shown to be practical, safe, and well tolerated for treating primary headache disorders. The recent multicenter, randomized, double-blind, sham-controlled PRESTO trial provided Class I evidence that for patients with episodic migraine, nVNS significantly increases the probability of having mild pain or being pain-free 2 h post stimulation. We report additional pre-defined secondary and other end points from PRESTO that demonstrate the consistency and durability of nVNS efficacy across a broad range of outcomes.

Methods

After a 4-week observation period, 248 patients with episodic migraine with/without aura were randomly assigned to acute treatment of migraine attacks with nVNS (n =?122) or a sham device (n =?126) during a double-blind period lasting 4 weeks (or until the patient had treated 5 attacks). All patients received nVNS therapy during the subsequent 4-week/5-attack open-label period.

Results

The intent-to-treat population consisted of 243 patients. The nVNS group (n =?120) had a significantly greater percentage of attacks treated during the double-blind period that were pain-free at 60 (P =?0.005) and 120 min (P =?0.026) than the sham group (n =?123) did. Similar results were seen for attacks with pain relief at 60 (P =?0.025) and 120 min (P =?0.018). For the first attack and all attacks, the nVNS group had significantly greater decreases (vs sham) in pain score from baseline to 60 min (P?= 0.029); the decrease was also significantly greater for nVNS at 120 min for the first attack (P =?0.011). Results during the open-label period were consistent with those of the nVNS group during the double-blind period. The incidence of adverse events (AEs) and adverse device effects was low across all study periods, and no serious AEs occurred.

Conclusions

These results further demonstrate that nVNS is an effective and reliable acute treatment for multiple migraine attacks, which can be used safely while preserving the patient’s option to use traditional acute medications as rescue therapy, possibly decreasing the risk of medication overuse. Together with its practicality and optimal tolerability profile, these findings suggest nVNS has value as a front-line option for acute treatment of migraine.

Trial registration

ClinicalTrials.gov identifier: NCT02686034.