Psilocybin pulse regimen reduces cluster headache attack frequency in the blinded extension phase of a randomized controlled trial.

BACKGROUND: In a recent randomized, double-blind, placebo-controlled study, we observed a nonsignificant reduction of attack frequency in cluster headache after pulse administration of psilocybin (10 mg/70 kg, 3 doses, 5 days apart each). We carried out a blinded extension phase to consider the safety and efficacy of repeating the pulse regimen. METHODS: Eligible participants returned to receive a psilocybin pulse at least 6 months after their first round of study participation. Participants kept headache diaries starting two weeks before and continuing through eight weeks after the first drug session. Ten participants completed the extension phase and all ten were included in the final analysis. RESULTS: In the three weeks after the start of the pulse, cluster attack frequency was significantly reduced from baseline (18.4 [95% confidence interval 8.4 to 28.4] to 9.8 [4.3 to 15.2] attacks/week; p = 0.013, d' = 0.97). A reduction of approximately 50% was seen regardless of individual response to psilocybin in the first round. Psilocybin was well-tolerated without any unexpected or serious adverse events. DISCUSSION: This study shows a significant reduction in cluster attack frequency in a repeat round of pulse psilocybin administration and suggests that prior response may not predict the effect of repeated treatment. To gauge the full potential of psilocybin as a viable medicine in cluster headache, future work should investigate the safety and therapeutic efficacy in larger, more representative samples over a longer time period, including repeating the treatment. CLINICAL TRIALS REGISTRATION: NCT02981173.

Conservation and divergence of expression of GA2-oxidase homeologs in apple (Malus x domestica Borkh.).

In domesticated apple (Malus x domestica Borkh.) and other woody perennials, floral initiation can be repressed by gibberellins (GAs). The associated mechanism is a major unanswered question in plant physiology, and understanding organismal aspects of GA signaling in apple has important commercial applications. In plants, the major mechanism for elimination of GAs and resetting of GA signaling is through catabolism by GA2-oxidases (GA2ox). We found that the GA2ox gene family in apple comprises 16 genes representing eight, clearly defined homeologous pairs, which were named as MdGA2ox1A/1B to MdGA2ox8A/8B. Expression of the genes was analyzed in the various structures of the spur, where flowers are initiated, as well as in various structures of seedlings over one diurnal cycle and in response to water-deficit and salt stress. Among the results, we found that MdGA2ox2A/2B dominated expression in the shoot apex and were strongly upregulated in the apex after treatment with exogenous GA3, suggesting potential involvement in repression of flowering. Several MdGA2ox genes also showed preferential expression in the leaf petiole, fruit pedicel, and the seed coat of developing seeds, potentially representing mechanisms to limit diffusion of GAs across these structures. In all contexts studied, we documented both concerted and distinct expression of individual homeologs. This work introduces an accessible woody plant model for studies of GA signaling, GA2ox gene regulation, and conservation/divergence of expression of homeologous genes, and should find application in development of new cultivars of apple and other tree fruits.

Exploratory investigation of a patient-informed low-dose psilocybin pulse regimen in the suppression of cluster headache: Results from a randomized, double-blind, placebo-controlled trial.

OBJECTIVE: Using a patient-informed regimen, we conducted an exploratory randomized, double-blind, placebo-controlled study to systematically investigate the effects of psilocybin in cluster headache. BACKGROUND: Sustained reductions in cluster headache burden after limited quantities of psilocybin-containing mushrooms are anecdotally reported, although to date there are no controlled studies investigating these effects. METHODS: Participants were randomized to receive psilocybin (0.143 mg/kg) or placebo (microcrystalline cellulose) in a pulse of three doses, each ~5 days apart. Participants maintained headache diaries starting 2 weeks before and continuing through 8 weeks after the first drug session. A total of 16 participants were randomized to receive experimental drug and 14 were included in the final analysis. RESULTS: In the 3 weeks after the start of the pulse regimen, the change in cluster attack frequency was 0.03 (95% confidence interval [CI] -2.6 to 2.6) attacks/week with placebo (baseline 8.9 [95% CI 3.8 to 14.0]) and -3.2 (95% CI -8.3 to 1.9) attacks/week with psilocybin (baseline 9.6 [95% CI 5.6 to 13.6]; p = 0.251). Group difference in change from baseline had a moderate effect size (d = 0.69). The effect size was small in episodic participants (d = 0.35) but large in chronic participants (d = 1.25), which remained over the entire 8-week period measured (d = 0.81). Changes in cluster attack frequency were not correlated with the intensity of acute psychotropic effects during psilocybin administration. Psilocybin was well-tolerated without any unexpected or serious adverse events. CONCLUSIONS: Findings from this initial, exploratory study provide valuable information for the development of larger, more definitive studies. Efficacy outcomes were negative, owing in part to the small number of participants. The separation of acute psychotropic effects and lasting therapeutic effects underscores the need for further investigation into the mechanism(s) of action of psilocybin in headache disorders.

First Report of Fusarium avenaceum Causing Postharvest Decay of European Pear in Mid-Atlantic United States.

Fruit losses due to postharvest decay caused by several fungal species is a major challenge for pear production (Sardella et al. 2016). In December 2021, a European pear (Pyrus communis L.) 'Dawn' with brown, circular, watery, and sunken lesions was observed in cold storage at the USDA Appalachian Fruit Research Station in Kearneysville, West Virginia. Only 1 of 14 'Dawn' pears examined in cold storage had the described disease symptoms. The fruit was surface sterilized, and symptomatic tissue was transferred to potato dextrose agar (PDA) and incubated at 25°C under continuous light. The isolate was hyphal tip purified and propagated on PDA plates at 25°C. The colonies grew an average of 8 mm/day and produced fluffy white aerial mycelium and pigmented rings of golden yellow which then darkened to pink with a dark pink on the reverse. The isolate was also cultured in liquid basal medium with carboxymethyl cellulose (Moura et al. 2020) for 7 days at 25°C to promote macroconidia formation. Macroconidia were slightly falcate with a tapering apical cell, usually 2 to 4 septate, and on average 16.8 µm long by 2.8 µm wide. The isolate was identified as Fusarium spp. based on morphology. Identity of the isolate was confirmed through sequencing of the ITS and TEF1 gene region (Stielow et al. 2015). The ITS and TEF1 sequences were deposited in GenBank (OP007197 and OP007198). BLAST analysis of the ITS amplicon identified multiple Fusarium spp. with 100% identity and 100% query coverage including F. avenaceum KJ562378. BLAST analysis of the TEF1 amplicon showed 99% identity and 99-100% query coverage with F. avenaceum isolates KM189442 and MK512754. Organic Bartlett pears were surface sanitized with a 1% aqueous chlorine solution, rinsed with sterile water and dried in a laminar flow hood. Fruit were then wounded with a sterile nail (4 mm diameter x 4 mm depth) and inoculated with a 4 mm mycelial plug taken from a 7- to 10-day old culture on PDA and wrapped with Parafilm. Plugs taken from sterile PDA were used as a control. Inoculated fruit were stored at 25°C in fruit trays in plastic bins for 7 days. Six fruit composed a replicate, and the experiment was repeated for a total of two replications. Lesions developed within 48 hours and expanded to an average of 28.5 mm by day 7. No lesions were observed on control fruit. Symptoms observed on inoculated pears were the same as the decay observed on the original pear obtained from cold storage. Fungal colonies isolated from the lesions and cultured on PDA morphologically resembled the original isolate from the infected pear. In 2014, F. avenaceum was first reported in the United States to cause post-harvest decay of apples in Pennsylvania (Kou et al. 2014). In the Netherlands, F. avenaceum has been reported to cause postharvest decay of 'Conference' pears but was observed at low frequencies (1-5%) in packing-house surveys (Wenneker et al. 2016). Fusarium spp. was also recently found on European pears in Southern Oregon (KC and Rasmussen 2020). F. avenaceum can produce mycotoxins which is a concern for fruit processing (Munkvold et al. 2021). Monitoring for this pathogen to prevent losses and mycotoxin contamination of processed fruit products will be import for consumer safety. To our knowledge, this is the first report of F. avenaceum causing postharvest decay of European pear in the Mid-Atlantic region of the United States.

The Epidemiology of Primary Headache Disorders.

Defining the epidemiology of headache disorders is challenging given the prevalence of stigma and other harmful misconceptions about these diseases. Understanding the widespread impact of these disorders is essential when considering social and policy interventions to mitigate that impact. Tension-type headache is still widely considered the most common primary headache disorder, but population-based estimates of its prevalence vary widely. Migraine remains the most common headache disorder in patients who present for clinical care. Prevalence estimates have remained fairly stable over the last two decades (1-year period prevalence, United States: 18% of women and 6% of men). Recent studies indicate that people who identify as American Indian/Alaskan Native (AI/AN) have the highest migraine prevalence of any ethnic group surveyed, particularly among AI/AN men (15% vs. <10%). Studies in the United States also show an inverse relationship between income level and migraine incidence and prevalence, particularly for chronic migraine; factors mediating this relationship are difficult to define. There are many diseases comorbid with migraine, more so with migraine with aura. The burden of migraine is enormous: the Global Burden of Disease study indicates migraine is the number 1 cause of disability in women younger than 50 years and the number 2 or 3 cause of disability worldwide. Further study is needed into underdiagnosis, undertreatment, and persistent stigma associated with headache disorders, especially in underserved communities. Stakeholders including patients, providers, and governing bodies are affected by the results of epidemiologic studies and should all have a role in crafting and evaluating thoughtful and relevant questions and hypotheses in this field.

The importance of an early onset of migraine prevention: an evidence-based, hypothesis-driven scoping literature review.

Recently approved migraine preventive therapies facilitate rapid control of migraine activity, potentially improving patients' lives and minimizing the societal burden of migraine. This review synthesizes available evidence on rates and timing of early onset of migraine prevention and identifies patient-level outcomes related to early onset prevention. This evidence-based scoping review identified all available clinical trial evidence regarding the early onset of prevention of migraine, under the hypothesis 'Patients with migraine (episodic or chronic) report additional benefits when receiving an approved migraine preventive treatment that demonstrates an early onset of prevention'. Early onset of prevention was defined as migraine preventive benefits within 30 days post-administration. PubMed, EMBASE, and CINAHL were searched for publications between 1988 and 2020. Overall, 16 publications described 18 studies. All studies were conducted in approved treatments [four anti-calcitonin gene-related peptide (CGRP) monoclonal antibodies and one chemodenervation agent] in patients with episodic/chronic migraine; no publications were identified for traditional oral agents for early migraine prevention. Compared to placebo, erenumab (three studies) reduced weekly migraine days within 1 week; fremanezumab (six studies) increased reports of no headache of at least moderate severity on Day 1 and significantly reduced migraine frequency within 1 week; galcanezumab (three studies) significantly reduced the mean number of patients with migraine beginning Day 1 and each day of the first week; eptinezumab (four studies) significantly reduced migraine attack likelihood on Day 1 by > 50% versus baseline; and onabotulinumtoxinA (two studies) reduced headache and migraine days within 1 week. Four publications described function, disability, and quality of life improvements as early as Week 4; none reported cost-benefit. Anti-CGRP monoclonal antibodies (erenumab, fremanezumab, galcanezumab, and eptinezumab) and a chemodenervation agent (onabotulinumtoxinA) provide clinically relevant benefits during the first treatment week. Literature describing clinically relevant benefits regarding early onset of prevention in patients with migraine is limited.

Characterizing the providers of and reimbursement for chronic migraine chemodenervation among the Medicare population.

OBJECTIVE: To characterize reimbursement trends and providers for chronic migraine (CM) chemodenervation treatment within the Medicare population since the introduction of the migraine-specific CPT code in 2013. METHODS: We describe trends in procedure volume and total allowed charge on cross-sectional data obtained from 2013 to 2018 Medicare Part B National Summary files. We also utilized the 2017 Medicare Provider Utilization and Payment Data to analyze higher volume providers (>10 procedures) of this treatment modality. RESULTS: The total number of CM chemodenervation treatments rose from 37,863 in 2013 to 135,023 in 2018 in a near-linear pattern (r = 0.999) and total allowed charges rose from ~$5,217,712 to $19,166,160 (r = 0.999). The majority of high-volume providers were neurologists (78.4%; 1060 of 1352), but a substantial proportion were advanced practice providers (APPs) (10.2%; 138 of 1352). Of the physicians, neurologists performed a higher mean number of procedures per physician compared to non-neurologists (59.6 [95% CI: 56.6-62.6] vs. 45.4 [95% CI: 41.0-50.0], p < 0.001). When comparing physicians and APPs, APPs were paid significantly less ($146.5 [95% CI: $145.6-$147.5] vs. $119.7 [95% CI: $117.6-$121.8], p < 0.001). As a percent of the number of total beneficiaries in each state, the percent of Medicare patients receiving ≥1 CM chemodenervation treatment from a high-volume provider in 2017 ranged from 0.024% (24 patients of 98,033 beneficiaries) in Wyoming to 0.135% (997 of 736,521) in Arizona, with six states falling outside of this range. CONCLUSION: Chemodenervation is an increasingly popular treatment for CM among neurologists and other providers, but the reason for this increase is unclear. There is substantial geographic variation in its use.

Exploratory Controlled Study of the Migraine-Suppressing Effects of Psilocybin.

While anecdotal evidence suggests that select 5-hydroxytryptamine 2A (5-HT2A) receptor ligands, including psilocybin, may have long-lasting therapeutic effects after limited dosing in headache disorders, controlled investigations are lacking. In an exploratory double-blind, placebo-controlled, cross-over study, adults with migraine received oral placebo and psilocybin (0.143 mg/kg) in 2 test sessions spaced 2 weeks apart. Subjects maintained headache diaries starting 2 weeks before the first session until 2 weeks after the second session. Physiological and psychological drug effects were monitored during sessions and several follow-up contacts with subjects were carried out to assure safety of study procedures. Ten subjects were included in the final analysis. Over the 2-week period measured after single administration, the reduction in weekly migraine days from baseline was significantly greater after psilocybin (mean, - 1.65 (95% CI: - 2.53 to - 0.77) days/week) than after placebo (- 0.15 (- 1.13 to 0.83) days/week; p = 0.003, t(9) = 4.11). Changes in migraine frequency in the 2 weeks after psilocybin were not correlated with the intensity of acute psychotropic effects during drug administration. Psilocybin was well-tolerated; there were no unexpected or serious adverse events or withdrawals due to adverse events. This exploratory study suggests there is an enduring therapeutic effect in migraine headache after a single administration of psilocybin. The separation of acute psychotropic effects and lasting therapeutic effects is an important finding, urging further investigation into the mechanism underlying the clinical effects of select 5-HT2A receptor compounds in migraine, as well as other neuropsychiatric conditions. Clinicaltrials.gov : NCT03341689.

Eptinezumab Demonstrated Efficacy in Sustained Prevention of Episodic and Chronic Migraine Beginning on Day 1 After Dosing.

OBJECTIVE: To determine the onset of preventive efficacy with eptinezumab in patients with migraine. BACKGROUND: Eptinezumab is a monoclonal antibody inhibiting calcitonin gene-related peptide approved as an intravenously administered treatment for the prevention of migraine. METHODS: Patients who received eptinezumab 100 mg, eptinezumab 300 mg, or placebo in PROMISE7-1 (episodic migraine; 100 mg, n = 221; 300 mg, n = 222; placebo, n = 222) or PROMISE7-2 (chronic migraine; 100 mg, n = 356; 300 mg, n = 350; placebo, n = 366) were included. Testing of the percentage of patients with a migraine on day 1 after dosing was prespecified and alpha-controlled. In further exploration of this prespecified endpoint, a post hoc closed testing procedure, which controlled the false-positive (type 1) error rate, provided a statistically rigorous evaluation of migraine prevention onset. The procedure involved up to 84 tests of significance, all of which were performed in sequence until the first nonsignificant result. RESULTS: For both studies, all tests for significance for eptinezumab 100 and 300 mg, from days 1-84 through day 1 alone, achieved nominal significance (P < .05), indicating that eptinezumab was fully effective beginning on day 1. Over each interval, the treatment effect was comparable to the effect over weeks 1-12. Mean changes from baseline in monthly migraine days for the primary endpoint period ranged from -3.9 to -4.9, -4.1 to -4.9, and -2.2 to -3.2 for eptinezumab 100, 300 mg, and placebo, respectively, in PROMISE7-1 and from -7.2 to -8.0, -7.9 to -8.2, and -4.3 to -5.6, respectively, in PROMISE7-2. The difference from placebo (95% confidence interval) in day 1 treatment effect was -2.2 (-4.1, -0.3) and -2.5 (-4.4, -0.6) days/month for eptinezumab 100 and 300 mg, respectively, in PROMISE7-1, and was -3.8 (-5.6, -2.0) and -4.0 (-5.8, -2.1) days/month for 100 and 300 mg, respectively, in PROMISE7-2. CONCLUSIONS: The migraine preventive effect of eptinezumab is rapid and sustained in patients with episodic or chronic migraine, with onset of optimal preventive efficacy observed on the day following the initial dose.

Exome Sequencing Implicates Impaired GABA Signaling and Neuronal Ion Transport in Trigeminal Neuralgia.

Trigeminal neuralgia (TN) is a common, debilitating neuropathic face pain syndrome often resistant to therapy. The familial clustering of TN cases suggests that genetic factors play a role in disease pathogenesis. However, no unbiased, large-scale genomic study of TN has been performed to date. Analysis of 290 whole exome-sequenced TN probands, including 20 multiplex kindreds and 70 parent-offspring trios, revealed enrichment of rare, damaging variants in GABA receptor-binding genes in cases. Mice engineered with a TN-associated de novo mutation (p.Cys188Trp) in the GABAA receptor Cl- channel γ-1 subunit (GABRG1) exhibited trigeminal mechanical allodynia and face pain behavior. Other TN probands harbored rare damaging variants in Na+ and Ca+ channels, including a significant variant burden in the α-1H subunit of the voltage-gated Ca2+ channel Cav3.2 (CACNA1H). These results provide exome-level insight into TN and implicate genetically encoded impairment of GABA signaling and neuronal ion transport in TN pathogenesis.

The American Registry for Migraine Research: Research Methods and Baseline Data for an Initial Patient Cohort.

BACKGROUND: The American Registry for Migraine Research (ARMR) is a multicenter, prospective, longitudinal patient registry, biorepository, and neuroimaging repository that collects clinical data, electronic health record (EHR) data, blood samples, and brain imaging data from individuals with migraine or other headache types. In this manuscript, we outline ARMR research methods and report baseline data describing an initial cohort of ARMR participants. METHODS: Adults with any International Classification of Headache Disorders (ICHD) diagnosis were prospectively enrolled from one of the 8 participating headache specialty centers. At baseline, ARMR participants complete web-based questionnaires, clinicians enter the participant's ICHD diagnoses, an optional blood specimen is collected, and neuroimaging data are uploaded to the ARMR neuroimaging repository. Participants maintain the ARMR daily headache diary longitudinally and follow-up questionnaires are completed by participants every 3 months. EHR data are integrated into the ARMR database from a subset of ARMR sites. Herein, we describe the ARMR methodology and report the summary data from ARMR participants who had, from February 2016 to May 2019, completed at least 1 baseline questionnaire from which data are reported in this manuscript. Descriptive statistics are used to provide an overview of patient's sociodemographics, headache diagnoses, headache characteristics, most bothersome symptoms other than headache, headache-related disability, comorbidities, and treatments. RESULTS: Data were available from 996 ARMR participants, enrolled from Mayo Clinic Arizona, Dartmouth-Hitchcock Medical Center, University of Utah, University of Colorado, Thomas Jefferson University, University of Texas Health Science Center at Houston, Georgetown University Medical Center, and DENT Neurological Institute. Among ARMR participants, 86.7% (n = 864) were female and the mean age at the time of enrollment was 48.6 years (±13.9; range 18-84). The most common provider-reported diagnosis was chronic migraine (n = 622), followed by migraine without aura (n = 327), migraine with aura (n = 196), and medication overuse headache (n = 65). Average headache frequency was 19.1 ± 9.2 days per month (n = 751), with 68% reporting at least 15 headache days per month. Sensitivity to light was the most frequent (n = 222) most bothersome symptom overall, other than headache, but when present, cognitive dysfunction was most frequently (n = 157) the most bothersome symptom other than headache. Average migraine disability assessment (MIDAS) score was 52 ± 49 (n = 760), (very severe headache-related disability); however, 17% of the ARMR population had MIDAS scores suggesting "no" or "mild" disability. The most common non-headache health issues were allergies (n = 364), back pain (n = 296), neck pain (n = 296), depression (n = 292), and anxiety (n = 278). Nearly 85% (n = 695) of patients were using preventive medications and 24.7% were using non-medication preventive therapy (eg, vitamins and neuromodulation). The most common preventive medication classes were neurotoxins, anticonvulsants, antidepressants, vitamins/supplements, and anticalcitonin gene-related peptide ligand or receptor-targeted monoclonal antibodies. Nearly 90% (n = 734) of ARMR participants was taking medications to treat migraine attacks, with the most common classes being triptans, non-steroidal anti-inflammatory drugs, antiemetics, acetaminophen, and combination analgesics. CONCLUSIONS: ARMR is a source of real-world patient data, biospecimens, and brain neuroimaging data that provides comprehensive insight into patients with migraine and other headache types being seen in headache specialty clinics in the United States. ARMR data will allow for longitudinal and advanced analytics that are expected to lead to a better characterization of patient heterogeneity, healthcare resource utilization, identification of endophenotypes, factors that predict treatment outcomes and clinical course, and ultimately advance the field toward precision headache medicine.

Cognitive Biases & Errors in Headache Medicine.

PREMISE: In recent years, the importance and prevalence of cognitive biases has gained scholarly attention in medicine as well as management science regarding a wide range of human activities. PROBLEM: The purpose of this review is to illustrate some of the many areas of Headache Medicine that exemplify some of these areas and to highlight the fact that our discipline is, in some cases, apparently more prone to some of these biases than other areas of clinical medicine. POTENTIAL SOLUTION: The lack of prospective studies to identify and address unconscious cognitive processes that skew the process of clinical headache management indicates that this is a field of investigation that is ripe for attention.

Genetic mechanisms in the repression of flowering by gibberellins in apple (Malus x domestica Borkh.).

BACKGROUND: Gibberellins (GAs) can have profound effects on growth and development in higher plants. In contrast to their flowering-promotive role in many well-studied plants, GAs can repress flowering in woody perennial plants such as apple (Malus x domestica Borkh.). Although this effect of GA on flowering is intriguing and has commercial importance, the genetic mechanisms linking GA perception with flowering have not been well described. RESULTS: Application of a mixture of bioactive GAs repressed flower formation without significant effect on node number or shoot elongation. Using Illumina-based transcriptional sequence data and a newly available, high-quality apple genome sequence, we generated transcript models for genes expressed in the shoot apex, and estimated their transcriptional response to GA. GA treatment resulted in downregulation of a diversity of genes participating in GA biosynthesis, and strong upregulation of the GA catabolic GA2 OXIDASE genes, consistent with GA feedback and feedforward regulation, respectively. We also observed strong downregulation of numerous genes encoding potential GA transporters and receptors. Additional GA-responsive genes included potential components of cytokinin (CK), abscisic acid (ABA), brassinosteroid, and auxin signaling pathways. Finally, we observed rapid and strong upregulation of both of two copies of a gene previously observed to inhibit flowering in apple, MdTFL1 (TERMINAL FLOWER 1). CONCLUSION: The rapid and robust upregulation of genes associated with GA catabolism in response to exogenous GA, combined with the decreased expression of GA biosynthetic genes, highlights GA feedforward and feedback regulation in the apple shoot apex. The finding that genes with potential roles in GA metabolism, transport and signaling are responsive to GA suggests GA homeostasis may be mediated at multiple levels in these tissues. The observation that TFL1-like genes are induced quickly in response to GA suggests they may be directly targeted by GA-responsive transcription factors, and offers a potential explanation for the flowering-inhibitory effects of GA in apple. These results provide a context for investigating factors that may transduce the GA signal in apple, and contribute to a preliminary genetic framework for the repression of flowering by GAs in a woody perennial plant.

Update on the diagnostic considerations for neurogenic nasal and sinus symptoms: A current review suggests adding a possible diagnosis of migraine.

BACKGROUND: Treatment of rhinosinusitis (RS) is one of the leading reasons for prescriptions of antibiotics, although they often fail to provide symptomatic relief. Appropriately diagnosing and treating patients presenting with RS for whom antibiotic therapy has failed or who have normal CT findings is a controversial topic. One explanation is that what these patients are experiencing is misinformation from the trigeminal nerve and autonomic nervous system. Midfacial pain and pressure with rhinorrhea and nasal congestion do not represent an infectious, or even inflammatory, condition within the sinus or nasal cavities, but a mirage that is best treated as a migraine variant. Observations Although there is not enough research to definitively prove this alternate etiology, we are reaching a tipping point where the clinical implications, real-world experience, and evolving literature support this possible alternate etiology. Four key factors support a midfacial migraine that mimics RS: 1) Pathophysiology: current pathophysiology literature offers a model of how migraine attacks could replicate clinical presentations of RS; 2) Clinical presentation: patients with infectious RS and midfacial migraine have similar symptomatic presentation, similar demographics, but poorly correlated radiological information; 3) Diagnosis: clinical studies support the proposition that there are alternative diagnostic tools for distinguishing patients with midfacial migraine; and 4) Prognosis: Select RS patients show significant improvement with migraine treatment. CONCLUSIONS: We encourage medical professionals to consider migraine disease as a form of sensory misinformation and as a possible etiology of RS complaints. Clinicians can ask validated questions to determine if possible migraine could be an underlying cause, and there are standard preventative treatments for migraine that could alleviate patient symptoms. Dysfunctional vasomotor activity may be the root of the disturbances, particularly when antibiotic therapy fails and CT findings are discordant with symptoms. Until there is a diagnostic test for migraine, clinicians need to question a patient's self-diagnosis of rhinosinusitis. More research is needed to definitively answer this important question.

Survey Analysis of the Use, Effectiveness, and Patient-Reported Tolerability of Inhaled Oxygen Compared With Injectable Sumatriptan for the Acute Treatment of Cluster Headache.

OBJECTIVE: In this secondary analysis of the Clusterbusters® Medication Use survey, the use, effectiveness, and tolerability of inhaled oxygen were investigated and compared with injectable sumatriptan. We also sought to understand the predictors of medication response. BACKGROUND: Inhaled oxygen is a mainstay abortive intervention in cluster headache but is not approved by the Food and Drug Administration (FDA). Unlike injectable sumatriptan, the only FDA-approved pharmacologic intervention for cluster headache, oxygen can be used multiple times a day, which is highly relevant for a condition with numerous daily attacks. In addition to obstacles in obtaining oxygen therapy, optimal oxygen delivery (ie, mask, flow rate) is not uniformly employed in cluster headache. These factors lead to underuse and imprecise therapeutic response rates. METHODS: A secondary analysis was conducted using deidentified data from the Clusterbusters® Medication Use survey, which was modeled after previously published surveys and available online. Subjects were recruited from headache clinics and cluster headache websites. Most responses were chosen from a list; others were free-texted. The final analysis included responses from 493 adult participants with a validated diagnosis of cluster headache. This analysis of deidentified data from the Clusterbusters® Medication Use survey received institutional approval. RESULTS: The most commonly used delivery system used by subjects was a non-rebreather-type mask. The use of oxygen flow rates >10 L/min was a positive predictor of medication response (OR = 2.36, P = .016). Among those who used flow rates >10 L/min, both inhaled oxygen (81.5%) and injectable sumatriptan (80.5%) were efficacious and did not differ significantly from each other in any specific group examined. At flow rates >10 L/min, positive predictors of oxygen response were male gender (OR = 2.07, P = .031) and cigarette smoking (current or historical; OR = 2.25, P = .017). Among the groups examined, there were no predictors of sumatriptan response. Most comments about side effects and concerns were directed at triptans. CONCLUSION: Therapeutic response to inhaled oxygen at sufficiently high flow rates (>10 L/min) had comparable efficacy to that of injectable sumatriptan for the acute treatment of cluster headache. Other factors in oxygen delivery (ie, flow rate changes) should be explored for optimization of therapy. The reasons for improved oxygen response in males and those with a cigarette smoking history require further exploration. While both oxygen and sumatriptan can be effective in the management of cluster headache, patient-reported side effects and concerns were more commonly directed at triptan medications. Current restrictions on access to inhaled oxygen, which exist at many levels, limit the therapeutic options available for patients with cluster headache, thereby doing a disservice to this patient population and the providers who deliver their care.

A Neurology Clerkship Curriculum Using Video-Based Lectures and Just-in-Time Teaching (JiTT).

Introduction: Just-in-time teaching is an educational strategy that involves tailoring in-session learning activities based on student performance in presession assessments. We implemented this strategy in a third-year neurology clerkship. Methods: Linked to core neurology clerkship lectures, eight brief video-based lectures and knowledge assessments were developed. Students watched videos and completed multiple-choice questions, and results were provided to faculty, who were given the opportunity to adjust the in-person lecture accordingly. Feedback was obtained by surveys of students and faculty lecturers and from student focus groups and faculty. Student performance on the end-of-clerkship examination was analyzed. Results: Between October 2016 and April 2017, 135 students participated in the curriculum, and 56 students (41.5%) responded to the surveys. Most students agreed or strongly agreed that the new curriculum enhanced their learning and promoted their sense of responsibility in learning the content. Faculty agreed that this pedagogy helped prepare students for class. Most students watched the entire video-based lecture, although there was a trend toward decreased audience retention with longer lectures. There were no significant changes in performance on the end-of-clerkship examination after implementation of just-in-time teaching. In focus groups, students emphasized the importance of tying just-in-time teaching activities to the lecture and providing video-based lectures well in advance of the lectures. Discussion: Just-in-time teaching using video-based lectures is an acceptable and feasible method to augment learning during a neurology clinical clerkship. We believe this method could be used in other neurology clerkships with similar success.

Distinguishing Characteristics of Headache in Nontraumatic Subarachnoid Hemorrhage.

INTRODUCTION: Subarachnoid hemorrhage (SAH) is a life-threatening emergency that is frequently missed due to its varied and often subtle presentation. The most common presentation of SAH is with a severe headache. The classical adjective used in SAH is "thunderclap"; however, this has not been well defined in the literature, rendering it a challenge to triage patients in clinical practice presenting with severe headache. METHODS: We undertook a prospective, observational study at a tertiary academic medical center examining the clinical characteristics of the presenting headache in SAH. We enrolled patients through the emergency department and from the neurosciences intensive care unit, and documented clinical features of the headache including the time to peak intensity, location, associated symptoms, and activities that caused worsening. RESULTS: One hundred and fifty-eight subjects were enrolled, of whom 20 patients had SAH and 138 did not. Notable distinguishing features on history included occipital location (55% in the SAH group vs 22% in the non-SAH group, P < .001), "stabbing" quality (35% in the SAH group vs 5% in the non-SAH group, P < .001), presence of prior headache (50% in the SAH group vs 83% in the non-SAH group, P = .002), and associated meningismus (80% in the SAH group and 42% in the non-SAH group, P = .002). Sixty-five percent of patients with SAH reported that their headache peaked within 1 second of onset, compared with only 10% of those without SAH (P < .001). CONCLUSION: This is the first study that has sought to examine in detail the clinical characteristics of the presenting headache in SAH. Our study suggests that the clinical features of headache with SAH are distinct from those associated with other headache syndromes, and that this may prove useful in the acute care setting in triaging patients with a chief complaint of headache.

Public Knowledge and Attitude toward Essential Tremor: A Questionnaire Survey.

BACKGROUND: Public awareness of and attitude toward disease is an important issue for patients. Public awareness of essential tremor (ET) has never been studied. METHODS: We administered a 10-min, 31-item questionnaire to 250 consecutive enrollees. These included three samples carefully chosen to have a potential range of awareness of ET: 100 individuals ascertained from a vascular disease clinic, 100 individuals from a general neurology clinic, and 50 Parkinson's disease (PD) patients. RESULTS: Leaving aside PD patients, only 10-15% of enrollees had ever heard of or read about "ET." Even among PD patients, only 32.7% had ever heard of or read about ET. After providing enrollees with three synonymous terms for ET ("benign tremor," "kinetic tremor," "familial tremor"), ~40% of non-PD enrollees and 51.0% with PD had ever heard or read about the condition. Even among participants who had heard of ET, ~10% did not know what the main symptom was, 1/3 were either unsure or thought ET was the same disease as PD, 1/4 thought that ET was the same condition as frailty- or aging-associated tremor, 2/3 attributed it to odd causes (e.g., trauma or alcohol abuse), only 1/3 knew of the existence of therapeutic brain surgery, fewer than 1/2 knew that children could have ET, and 3/4 did not know of a celebrity or historical figure with ET. Hence, lack of knowledge and misconceptions were common. CONCLUSION: Public knowledge of the existence and features of ET is overall poor. Greater awareness is important for the ET community.