INPP5K controls the dynamic structure and signaling of wild-type and mutated, leukemia-associated IL-7 receptors.

The downstream signaling of the interleukin-7 (IL-7) receptor (IL-7R) plays important physiological and pathological roles, including the differentiation of lymphoid cells and proliferation of acute lymphoblastic leukemia cells. Gain-of-function mutations in the IL-7Rα chain, the specific component of the receptor for IL-7, result in constitutive, IL-7-independent signaling and trigger acute lymphoblastic leukemia. Here, we show that the loss of the phosphoinositide 5-phosphatase INPP5K is associated with increased levels of the INPP5K substrate phosphatidylinositol 4,5-bisphosphate (PtdIns[4,5]P2) and causes an altered dynamic structure of the IL-7 receptor. We discovered that the IL-7Rα chain contains a very conserved positively charged polybasic amino acid sequence in its cytoplasmic juxtamembrane region; this region establish stronger ionic interactions with negatively charged PtdIns(4,5)P2 in the absence of INPP5K, freezing the IL-7Rα chain structure. This dynamic structural alteration causes defects in IL-7R signaling, culminating in decreased expressions of EBF1 and PAX5 transcription factors, in microdomain formation, cytoskeletal reorganization, and bone marrow B-cell differentiation. Similar alterations after the reduced INPP5K expression also affected mutated, constitutively activated IL-7Rα chains that trigger leukemia development, leading to reduced cell proliferation. Altogether, our results indicate that the lipid 5-phosphatase INPP5K hydrolyzes PtdIns(4,5)P2, allowing the requisite conformational changes of the IL-7Rα chain for optimal signaling.

The role of caffeine in headache disorders.

PURPOSE OF REVIEW: Caffeine is known to have both beneficial and adverse effects in individuals with headache disorders. This review describes recent findings regarding caffeine that are relevant to headache disorders and puts these findings into the context of clinical management. RECENT FINDINGS: Preclinical studies show that caffeine has complex effects on sleep, brain blood flow, and intracranial pressure that may depend on the timing of caffeine intake relative to the sleep-wake cycle. Caffeine metabolism may have significant inter-individual variation that influences its therapeutic and/or adverse effects. Caffeine has acute therapeutic benefit for some primary headache disorders. For migraine, this benefit is predominantly in milder headache without cutaneous allodynia. High levels of caffeine intake may contribute to progression of headache disorders. Caffeine-containing combination analgesics commonly cause medication overuse headache. Abrupt reduction in caffeine consumption is a trigger for migraine that may be important in situations including the hospital setting, religious and cultural fasting, and pregnancy. SUMMARY: There is not sufficient evidence to support universal guidelines for the use of dietary and medicinal caffeine in headache disorders. A sensible approach based upon available evidence is to limit dietary caffeine intake to moderate amounts with consistent timing before noon, and to use caffeine-containing combination analgesics infrequently for milder headache.

Reduction in retinal microvascular perfusion during migraine attacks.

OBJECTIVE: To determine if there are changes in structure and function of the retinal vasculature during and between migraine attacks using optical coherence tomography angiography (OCTA). BACKGROUND: Migraine attacks commonly include visual symptoms, but the potential role of the retina in these symptoms is not well understood. OCTA is a rapid, non-invasive imaging technique that is used to visualize the retinal microvasculature with high spatial resolution in a clinical setting. In this study we used OCTA to quantify different features of the retinal vasculature in patients with migraine during and between attacks, as well as in healthy controls (HCs). METHODS: We performed a prospective cohort study of 37 patients with migraine with aura (MA) (median [interquartile range, IQR] age of 37 [14] years, 86% female) and 30 with migraine without aura (MO) (median [IQR] age of 37 [17] years, 77% female) and 20 HCs (median [IQR] age of 35 [7] years, 50% female). Macular OCTA scans were obtained for all participants for the interictal analysis. In 12 MA and eight MO, scans were captured both during and outside of migraine attacks and five HCs had initial and repeat scans. In addition to analyzing the morphology of the foveal avascular zone, we calculated the vessel flux index (VFI), which is an indicator of retinal perfusion and conventional metrics (such as vessel area density) in the foveal and parafoveal regions. RESULTS: There was a significant difference in the parafoveal VFI in the ictal state between the groups (p = 0.009). During migraine attacks there was a significant reduction in the parafoveal region VFI in MA (-7%, 95% confidence interval [CI] -10% to -4%; p = 0.006) and MO (-7%, 95% CI -10% to -3%; p = 0.016) from their interictal baseline as compared to the change between repeat scans in HCs (2%, 95% CI -3% to 7%). Interictally, there was a mean (standard deviation [SD]) 13% (10%) (p = 0.003) lower blood perfusion in the MA group as compared to the MO group in the foveal region (mean [SD] 0.093 [0.023] vs. 0.107 [0.021], p = 0.003). Interictal analysis also revealed higher circularity in the superficial foveal avascular zone in the MA group compared with the MO group (mean [SD] 0.686 [0.088] vs. 0.629 [0.120], p = 0.004). In addition, interictal analysis of the patients with MA or MO and unilateral headache showed increased retinal vascular parameters consistent with greater perfusion in the eye ipsilateral to the side of the pain as compared with the contralateral eye. CONCLUSIONS: These results indicate that perfusion is reduced in MA and MO in the parafoveal retina during the ictal period. Interictally, the foveal retina in MA has reduced perfusion when compared to the foveal retina in MO. Patients with unilateral headache showed interictal asymmetry of retinal perfusion between eyes. These results indicate that changes in retinal perfusion could be a part of migraine pathophysiology, and that distinct retinal vascular signatures identified with OCTA could represent biomarkers for migraine.

Calcitonin gene-related peptide-targeting therapies are a first-line option for the prevention of migraine: An American Headache Society position statement update.

OBJECTIVE: To provide a position statement update from The American Headache Society specifically regarding therapies targeting calcitonin gene-related peptide (CGRP) for the prevention of migraine. BACKGROUND: All migraine preventive therapies previously considered to be first-line treatments were developed for other indications and adopted later for migraine. Adherence to these therapies is often poor due to issues with efficacy and tolerability. Multiple new migraine-specific therapies have been developed based on a broad foundation of pre-clinical and clinical evidence showing that CGRP plays a key role in the pathogenesis of migraine. These CGRP-targeting therapies have had a transformational impact on the management of migraine but are still not widely considered to be first-line approaches. METHODS: Evidence regarding migraine preventive therapies including primary and secondary endpoints from randomized placebo-controlled clinical trials, post hoc analyses and open-label extensions of these trials, and prospective and retrospective observational studies were collected from a variety of sources including PubMed, Google Scholar, and ClinicalTrials.gov. The results and conclusions based upon these results were reviewed and discussed by the Board of Directors of The American Headache Society to confirm consistency with clinical experience and to achieve consensus. RESULTS: The evidence for the efficacy, tolerability, and safety of CGRP-targeting migraine preventive therapies (the monoclonal antibodies: erenumab, fremanezumab, galcanezumab, and eptinezumab, and the gepants: rimegepant and atogepant) is substantial, and vastly exceeds that for any other preventive treatment approach. The evidence remains consistent across different individual CGRP-targeting treatments and is corroborated by extensive "real-world" clinical experience. The data indicates that the efficacy and tolerability of CGRP-targeting therapies are equal to or greater than those of previous first-line therapies and that serious adverse events associated with CGRP-targeting therapies are rare. CONCLUSION: The CGRP-targeting therapies should be considered as a first-line approach for migraine prevention along with previous first-line treatments without a requirement for prior failure of other classes of migraine preventive treatment.

The headache research priorities: Research goals from the American Headache Society and an international multistakeholder expert group.

OBJECTIVE: To identify and disseminate research priorities for the headache field that should be areas of research focus during the next 10 years. BACKGROUND: Establishing research priorities helps focus and synergize the work of headache investigators, allowing them to reach the most important research goals more efficiently and completely. METHODS: The Headache Research Priorities organizing and executive committees and working group chairs led a multistakeholder and international group of experts to develop headache research priorities. The research priorities were developed and reviewed by clinicians, scientists, people with headache, representatives from headache organizations, health-care industry representatives, and the public. Priorities were revised and finalized after receiving feedback from members of the research priorities working groups and after a public comment period. RESULTS: Twenty-five research priorities across eight categories were identified: human models, animal models, pathophysiology, diagnosis and management, treatment, inequities and disparities, research workforce development, and quality of life. The priorities address research models and methods, development and optimization of outcome measures and endpoints, pain and non-pain symptoms of primary and secondary headaches, investigations into mechanisms underlying headache attacks and chronification of headache disorders, treatment optimization, research workforce recruitment, development, expansion, and support, and inequities and disparities in the headache field. The priorities are focused enough that they help to guide headache research and broad enough that they are widely applicable to multiple headache types and various research methods. CONCLUSIONS: These research priorities serve as guidance for headache investigators when planning their research studies and as benchmarks by which the headache field can measure its progress over time. These priorities will need updating as research goals are met and new priorities arise.

Collective Identity: Making the Case for a Stage Model Approach to Addressing Water Quality in the Chesapeake Bay Watershed.

The Chesapeake Bay watershed encompasses six states and the District of Columbia. Consequently, the people within it display great diversity in terms of values, allegiances, and experiences. That diversity may help to explain an apparent inability to coordinate actions aimed at redressing the dismal water quality throughout the watershed. In this paper, we bridge theory to an applied scenario to examine the importance of developing a collective identity within the watershed to bring about changes in individual behavior and policies. We present the current conditions of the Chesapeake Bay watershed, propose a stage model for the development of a collective watershed identity, outline theoretically grounded determinants of each stage, and discuss the challenges in developing a collective identity. We further suggest several guiding questions for future research.

Maternal migraine and risk of pediatric cancers.

BACKGROUND: Maternal migraine has been linked to adverse birth outcomes including low birth weight and preterm birth, as well as congenital anomalies in offspring. It has been speculated that this may be due to the use of medications in pregnancy, but lifestyle, genetic, hormonal, and neurochemical factors could also play a role. There is evidence for varying cancer incidences among adults with migraine. Here, we utilized data from national registries in Denmark to examine associations between maternal diagnoses of migraine and risk for cancer in offspring. METHODS: We linked several national registries in Denmark to identify cases from the Cancer Registry among children less than 20 years (diagnoses 1996-2016) and controls from the Central Population Register, matched to cases by birth year and sex (25:1 matching rate). Migraine diagnoses were identified from the National Patient Register using International Classification of Diseases, versions 8 and 10 codes and migraine-specific acute or prophylactic treatment recorded in the National Pharmaceutical Register. We used logistic regression to estimate the risk of childhood cancers associated with maternal migraine. RESULTS: Maternal migraine was positively associated with risk for non-Hodgkin lymphoma (odds ratio [OR] = 1.70, 95% confidence interval [CI]: 1.01-2.86), central nervous system tumors ([OR = 1.31, 95% CI: 1.02-1.68], particularly glioma [OR = 1.64, 95% CI: 1.12-2.40]), neuroblastoma (OR = 1.75, 95% CI: 1.00-3.08), and osteosarcoma (OR = 2.60, 95% CI: 1.18-5.76). CONCLUSIONS: Associations with maternal migraine were observed for several childhood cancers, including neuronal tumors. Our findings raise questions about the role of lifestyle factors, sex hormones, genetic, and neurochemical factors in the relationship between migraine and childhood cancers.

Different characteristics of cortical spreading depression in the sleep and wake states.

OBJECTIVE: The objective of this study is to characterize the effects of the sleep-wake cycle on neurovascular and behavioral characteristics of cortical spreading depression (CSD). BACKGROUND: There is an important bi-directional relationship between migraine and the sleep-wake cycle, but the basic mechanisms of this relationship are poorly understood. METHODS: We have developed a minimally invasive microchip system to continuously monitor cerebral blood volume (CBV) with optical intrinsic signal (OIS), head movement, and multiple other physiological and behavioral parameters in freely behaving mice over weeks. Behavior is also monitored with simultaneous video recording. This system can also be used to intermittently trigger and record CSD and accompanying neurovascular and behavioral responses. CSD was triggered optically in different stages of the sleep-wake cycle. RESULTS: The optical stimulus threshold to trigger CSD was significantly higher in the wake state compared to sleep (stimulation duration = 16.4 ± 9.7 s vs. 10.8 ± 5.8 s, p = 0.037, n = 6 mice). CSD evoked in the wake versus sleep state produced changes in CBV that were smaller (largest relative change -4.5 ± 5.0% ∆OIS vs. -14.3 ± 8.5% ∆OIS, p = 0.001) and shorter in duration (33:22 ± 6:37 vs. 49:42 ± 8:05 min:s, p = 0.012, n = 6 mice). The threshold for CSD and kinetics of associated CBV changes were correlated with the time since falling asleep or awakening (n = 47 CSDs in 6 mice). CSD triggered in the wake state was associated with a transient freezing behavior. CSD triggered during sleep typically caused a transient awakening and behavioral response. This was followed by a return to sleep until recovery from the sustained phase of decreased CBV that occurred 30-60 min later, at which time there was consistent awakening with behaviors similar to those that occurred at CSD onset. CSD triggered in the wake state evoked a transient decrease in heart rate (from 11.9 ± 0.8 to 9.6 ± 0.8 Hz, p = 0.002, n = 5), whereas when triggered in the sleep state there was a transient increase in HR (from 7.5 ± 0.4 Hz to 9.3 ± 1.1 Hz, p = 0.016, n = 5). CONCLUSIONS: The sleep-wake cycle has significant effects on CSD that may have relevance to the clinical presentations of migraine and brain injury.

Media Contributions to a Chesapeake Bay Watershed Collective Identity? A Tale of Three Cities.

Although collective action is needed to address many environmental challenges, it cannot proceed in the absence of collective identity, that is, evidence of group belongingness expressed in or via communicative behavior. This study looked for evidence of a collective identity in newspaper articles that referenced the Chesapeake Bay Watershed. The data were drawn from local papers published in municipalities located at the headwaters of the Susquehanna River, midway down the Susquehanna, and where the river meets the Bay. Computerized content analysis assessed the frequency with which the Chesapeake Bay and watershed were mentioned alongside a set of keywords thought to represent different facets of identity (e.g., agriculture, fishing, swimming). The results showed substantial variation in frequency across time and place but low absolute levels of coverage of the Bay and the watershed. Multidimensional scaling revealed different structures to collective identity as a function of place. These differences in content may be attributable to varying demographic and environmental characteristics along with proximity to the Bay. But, to the extent that media contribute to collective identity among residents of the watershed at all, they do so in a complex and heterogeneous manner.

Pain Following Endoscopic Foreheadplasty Surgery in Women.

BACKGROUND: Endoscopic foreheadplasty surgery (EFS) is a common procedure; however, little has been reported about the nature or treatment of postoperative headache pain and associated symptoms. OBJECTIVES: The objective of this study was to describe the intensity, quality, location, and duration of headache pain in women following EFS. We also compared post-EFS symptoms with migraine, described medication use and efficacy, and measured emotional and functional outcomes. METHODS: This descriptive study used an observational repeated-measures design. Forty-two women (mean [standard deviation] age, 59.0 [7.9] years) undergoing EFS were prospectively recruited from 12 private cosmetic practices in 3 California counties. Telephone interviews with the Acute Short-Form 12v2 and the Headache Pain Questionnaire were conducted on postoperative days (POD) 1, 3, 7, and 30. RESULTS: On POD 1, 93% reported at least moderate pain and 64% severe pain. Severe pain was characterized as throbbing (71%), sharp (53%), dull (76%), exploding (41%), imploding (53%), continuous (53%), or intermittent (41%) on POD 1. Moderate pain was most frequent on POD 3 (21%) compared to POD 1 (19%), 7 (12%) and 30 (12%). Mild pain predominated on POD 3 (40%) and 7 (40%), with 20% remaining on POD 30. The majority (79%) of post-EFS symptoms included light sensitivity and nausea, and therefore met most International Classification of Headache Disorders criteria for migraine. Analgesic use provided inconsistent relief. Functional and emotional status did not return to baseline throughout the 30-day postoperative period. CONCLUSIONS: Immediately following EFS, most women experience moderate to severe headache pain, despite use of medications. Pain persists in many patients for up to 1 month. Headache is associated with migraine symptoms, including light sensitivity and nausea.

Continuous long-term recording and triggering of brain neurovascular activity and behaviour in freely moving rodents.

A minimally invasive, microchip-based approach enables continuous long-term recording of brain neurovascular activity, heart rate, and head movement in freely behaving rodents. This approach can also be used for transcranial optical triggering of cortical activity in mice expressing channelrhodopsin. The system uses optical intrinsic signal recording to measure cerebral blood volume, which under baseline conditions is correlated with spontaneous neuronal activity. The arterial pulse and breathing can be quantified as a component of the optical intrinsic signal. Multi-directional head movement is measured simultaneously with a movement sensor. A separate movement tracking element through a camera enables precise mapping of overall movement within an enclosure. Data is processed by a dedicated single board computer, and streamed from multiple enclosures to a central server, enabling simultaneous remote monitoring and triggering in many subjects. One application of this system described here is the characterization of changes in of cerebral blood volume, heart rate and behaviour that occur with the sleep-wake cycle over weeks. Another application is optical triggering and recording of cortical spreading depression (CSD), the slowly propagated wave of neurovascular activity that occurs in the setting of brain injury and migraine aura. The neurovascular features of CSD are remarkably different in the awake vs. anaesthetized state in the same mouse. With its capacity to continuously and synchronously record multiple types of physiological and behavioural data over extended time periods in combination with intermittent triggering of brain activity, this inexpensive method has the potential for widespread practical application in rodent research. KEY POINTS: Recording and triggering of brain activity in mice and rats has typically required breaching the skull, and experiments are often performed under anaesthesia A minimally invasive microchip system enables continuous recording and triggering of neurovascular activity, and analysis of heart rate and behaviour in freely behaving rodents over weeks This system can be used to characterize physiological and behavioural changes associated with the sleep-wake cycle over extended time periods This approach can also be used with mice expressing channelrhodopsin to trigger and record cortical spreading depression (CSD) in freely behaving subjects. The neurovascular responses to CSD are remarkably different under anaesthesia compared with the awake state. The method is inexpensive and straightforward to employ at a relatively large scale. It enables translational investigation of a wide range of physiological and pathological conditions in rodent models of neurological and systemic diseases.

Fifty years of EPA science for air quality management and control.

Research and development has been a key part of the foundation for improvements in US air quality since the establishment of the Environmental Protection Agency (EPA) 50 years ago. Although the scientific accomplishments and advances over the course of EPA's history are often overshadowed by policy debates, much of the air pollution science and engineering we now consider to be routine did not exist when EPA was established. Many of the advances in air pollutant measurement, monitoring, modeling, and control were developed by EPA researchers or supported by EPA programs. The technical foundation built during EPA's early years has since given the Agency the scientific ability to respond quickly and effectively to unexpected and emerging issues. Equally important, EPA also developed approaches to conducting and presenting science in policy settings to ensure that the science was as objective and complete as possible and was communicated effectively. A look back at some of the accomplishments of EPA scientists and engineers provides a reminder that the cumulative effect of continual, incremental advances can result in large and lasting benefits to society.

Targeting calcitonin gene-related peptide: a new era in migraine therapy.

Migraine is one of the most prevalent and disabling diseases worldwide, but until recently, few migraine-specific therapies had been developed. Extensive basic and clinical scientific investigation has provided strong evidence that the neuropeptide calcitonin gene-related peptide (CGRP) has a key role in migraine. This evidence led to the development of small molecule CGRP receptor antagonists and monoclonal antibodies targeting either CGRP or its receptor. Clinical trials investigating these therapies have consistently shown statistically significant efficacy for either the acute or preventive treatment of migraine. No serious safety or tolerability issues have been identified in the trials of the monoclonal antibody therapies. Although the appropriate place of these new migraine-specific therapies relative to other available acute and preventive treatments remains to be determined, a growing body of evidence shows that therapeutic approaches targeting CGRP have the potential to transform the clinical management of migraine.

Is the Vectra 3D Imaging System a Reliable Tool for Predicting Breast Mass?

BACKGROUND: In selecting breast implants for breast reconstruction, current preoperative planning largely relies on 2-dimensional measurements, which are often limited in suboptimal accuracy and objectivity. Although the introduction of 3-dimensional imaging modalities has further improved preoperative planning, they require in-depth analysis of accuracy if they are to be considered as a standardized part of preoperative planning. Thus, the present study analyzes the reliability of the Vectra 3D Imaging System in predicting breast mass and explores potential confounding variables that may limit its accuracy. METHODS: A retrospective review of 202 breasts that received direct-to-implant reconstruction by a single surgeon between February 2015 and February 2019 was conducted. Variables recorded included Vectra predicted mass (VPM; in grams), mastectomy mass (MM; in grams), ptosis grade, and body mass index (BMI). Body mass index was classified as follows: underweight (BMI < 20 kg/m), normal (20 kg/m ≤ BMI < 25 kg/m), overweight (25 kg/m ≤ BMI < 30 kg/m), and obese (BMI ≥ 30 kg/m). Cup size was approximated as follows: A and smaller (MM ≤250 g), B (250 g < MM ≤ 450 g), C (450 g < MM ≤ 600 g), and D and larger (MM ≥ 600 g). Correlation between MM and VPM was evaluated using 2-tailed Pearson correlation coefficients (r), and associated formula was derived from a linear model. Equality of variances was assessed with the Bartlett test. Correlation coefficients calculated for ptosis and BMI categories were then compared with the overall correlation coefficient. Significance was set at α = 0.05, and analyses were conducted in R 3.6.0, version 1.70. RESULTS: There was a strong correlation between MM and VPM (R = 0.90, P < 0.0001). The following equation was derived to predict MM: [MM] = 0.8 × [VPM] + 32 (adjusted r = 0.81). The Bartlett test indicated that VPM varies significantly across cup sizes (P < 0.0001). Comparison of correlation coefficients for ptosis and BMI categories revealed a significantly reduced correlation coefficient for pseudoptosis (0.90 vs 0.75, P = 0.0425). CONCLUSIONS: The present study suggests that the reliability of Vectra in predicting breast mass varies across cup sizes and that there exists a significantly decreased association between VPM and MM among pseudoptotic breasts. These are important considerations when using this technology in surgical planning.

Cortical spreading depression as a site of origin for migraine: Role of CGRP.

PREMISE: Migraine is a complex neurologic disorder that leads to significant disability, yet remains poorly understood. PROBLEM: One potential triggering mechanism in migraine with aura is cortical spreading depression, which can activate the trigeminal nociceptive system both peripherally and centrally in animal models. A primary neuropeptide of the trigeminal system is calcitonin gene-related peptide, which is a potent vasodilatory peptide and is currently a major therapeutic target for migraine treatment. Despite the importance of both cortical spreading depression and calcitonin gene-related peptide in migraine, the relationship between these two players has been relatively unexplored. However, recent data suggest several potential vascular and neural connections between calcitonin gene-related peptide and cortical spreading depression. CONCLUSION: This review will outline calcitonin gene-related peptide-cortical spreading depression connections and propose a model in which cortical spreading depression and calcitonin gene-related peptide act at the intersection of the vasculature and cortical neurons, and thus contribute to migraine pathophysiology.

Differences in treatment response between migraine with aura and migraine without aura: lessons from clinical practice and RCTs.

Migraine is a major public health problem afflicting approximately 10% of the general population and is a leading cause of disability worldwide, yet our understanding of the basis mechanisms of migraine remains incomplete. About a third of migraine patients have attacks with aura, consisting of transient neurological symptoms that precede or accompany headache, or occur without headache. For patients, aura symptoms are alarming and may be transiently disabling. For clinicians and scientists, aura represents an intriguing neurophysiological event that may provide important insight into basic mechanisms of migraine. Several observations point toward important differences between migraine with and without aura. Compared with migraine without aura, migraine with aura has different heritability, greater association with different conditions including stroke, different alterations of brain structure and function as revealed by imaging studies. A number of studies also indicate that migraine with aura may respond differently to acute and preventive therapies as compared to migraine without aura. The purpose of this review is to provide an overview of these differences in treatment responses, and to discuss the possibility of different therapeutic strategies for migraine with vs. without aura.

Frequency of Patent Foramen Ovale and Migraine in Patients With Cryptogenic Stroke.

BACKGROUND AND PURPOSE: Individuals with migraine are at higher risk for stroke, but the mechanism has not been established. On the basis of the association between migraine and intracardiac right-to-left shunt, it has been proposed that stroke in migraineurs could be caused by a paradoxical embolus passing through a patent foramen ovale (PFO) or pulmonary arteriovenous malformation. The aim of this study was to determine the prevalence of PFO with right-to-left shunt in patients who presented with cryptogenic stroke and had a history of migraine. METHODS: Patients between 18 and 60 years old who presented with an ischemic stroke were characterized based on ASCOD phenotyping (atherosclerosis; small-vessel disease; cardiac pathology; other causes; dissection). A migraine diagnosis was identified by reviewing physician notes, and frequent aura was defined if present in at least 50% of attacks. A PFO with right-to-left shunt diagnosis was identified by the presence of a positive bubble contrast study with either transcranial Doppler, transthoracic, or transesophageal echocardiography. RESULTS: Of the 712 patients who presented with ischemic stroke, 127 (18%) were diagnosed as cryptogenic; 68 patients had adequate testing for PFO and a documented migraine history. The prevalence of PFO in patients with cryptogenic stroke without migraine was elevated (59%) compared with the general population (18%). Patients with both cryptogenic stroke and migraine had a higher prevalence of PFO (79%). In patients with cryptogenic stroke who had migraine with frequent aura, the prevalence of PFO was 93%. Only 5 patients (4%) had a history compatible with migrainous infarction. CONCLUSIONS: In patients with cryptogenic stroke who have migraine, there is a high prevalence (79%) of PFO with right-to-left shunt. The timing of the stroke in migraineurs is usually not related to a migraine attack. These observations are consistent with the hypothesis that the mechanism of stroke in migraineurs is most likely because of a paradoxical embolus. Future cryptogenic stroke classification schemes should consider including PFO as a separate etiologic category.

A multicenter, prospective, single arm, open label, observational study of sTMS for migraine prevention (ESPOUSE Study).

Objective To evaluate the efficacy and tolerability of single pulse transcranial magnetic stimulation (sTMS) for the preventive treatment of migraine. Background sTMS was originally developed for the acute treatment of migraine with aura. Open label experience has suggested a preventive benefit. The objective of this trial was to evaluate the efficacy and tolerability of sTMS for migraine prevention. Methods The eNeura SpringTMS Post-Market Observational U.S. Study of Migraine (ESPOUSE) Study was a multicenter, prospective, open label, observational study. From December 2014 to March 2016, patients with migraine (n = 263) were consented to complete a 1-month baseline headache diary followed by 3 months of treatment. The treatment protocol consisted of preventive (four pulses twice daily) and acute (three pulses repeated up to three times for each attack) treatment. Patients reported daily headache status, medication use, and device use with a monthly headache diary. The primary endpoint, mean reduction of headache days compared to baseline, was measured over the 28-day period during weeks 9 to 12. The primary endpoint was compared to a statistically-derived placebo estimate (performance goal). Secondary endpoints included: 50% responder rate, acute headache medication consumption, HIT-6, and mean reduction in total headache days from baseline of any intensity. Results Of a total of 263 consented subjects, 229 completed a baseline diary, and 220 were found to be eligible based on the number of headache days. The device was assigned to 217 subjects (Safety Data Set) and 132 were included in the intention to treat Full Analysis Set. For the primary endpoint, there was a -2.75 ± 0.40 mean reduction of headache days from baseline (9.06 days) compared to the performance goal (-0.63 days) ( p < 0.0001). The 50% responder rate of 46% (95% CI 37%, 56%) was also significantly higher ( p < 0.0001) than the performance goal (20%). There was a reduction of -2.93 (5.24) days of acute medication use, headache impact measured by HIT-6, -3.1 (6.4) ( p < 0.0001), and total headache days of any intensity -3.16 days (5.21) compared to the performance goal (-0.63 days) ( p < 0.0001). The most common adverse events were lightheadedness (3.7%), tingling (3.2%), and tinnitus (3.2%). There were no serious adverse events. Conclusions This open label study suggests that sTMS may be an effective, well-tolerated treatment option for migraine prevention. Trial registration number NCT02357381.

Posttraumatic Headache: Basic Mechanisms and Therapeutic Targets.

Frequent or continuous headache, often refractory to medical therapy, is a common occurrence after head trauma. In addition to being the most common acute symptom after traumatic brain injury (TBI), headache is also one of the most persistent and disabling symptoms. Different studies indicate that 18-58% of those suffering a TBI will have significant headache at 1 year following the trauma. In addition to being disabling on its own, posttraumatic headache (PTH) is a predictor of overall outcome after concussion. Despite its remarkable prevalence and associated social and economic costs, many fundamental and important questions about PTH remain unanswered. The purpose of this review is to identify key questions regarding the clinical characteristics of posttraumatic headache, its basic mechanisms, and its optimal management. We discuss phenotypic features of PTH, pathophysiological mechanisms of TBI including potential overlaps with those of migraine and other primary headache disorders, and potential novel targets for treatment. We suggest different strategies to finding answers to the questions regarding PTH in order to advance the understanding of the disorder and develop more effective therapies.