Advocacy Connection Team-Now educational program for headache fellows and patients/caregivers: Assessment of educational objectives.

OBJECTIVE: To assess for improvement in comfort in participating in advocacy for migraine and headache disorders and knowledge needed for successful advocacy. BACKGROUND: The Advocacy Connection Team (ACT)-Now program is an educational program offered through Miles for Migraine, a non-profit advocacy organization. It is designed to teach headache fellows and patients advocacy skills. METHODS: In a cross-sectional pre-test-post-test design, the 2021 ACT-Now cohort of 98 participants were administered a set of 11 pre-course survey questions identifying their role (healthcare provider/headache fellow or patient/caregiver), baseline knowledge of migraine-related disability and stigma, and baseline engagement and comfort with advocating. The post-course survey questions were the same as the pre-course questions, with the addition of one question assessing knowledge of migraine-related disability, additional questions addressing comfort levels advocating with insurance and policymakers, as well as creating an advocacy plan. RESULTS: For the pre-course survey, 69 participants responded and for the post-course survey, 40 participants responded. Compared to the pre-course survey, participants were able to correctly identify epidemiological data about migraine following the ACT-Now course (pre-course 46% correct, post-course 58% correct, p = 0.263). There was also an increase in the comfort level of participants in advocacy activities, including the creation of an advocacy action plan (pre-course 23% were "very comfortable" advocating, post-course 63%, p < 0.05). CONCLUSION: These results demonstrate that ACT-Now is effective at improving advocacy skills in a mixed cohort of patients and headache fellows, giving them the skills to create advocacy plans and engage with other patients and physicians, payers, and policymakers to create a more understanding, equitable and compassionate world for persons with migraine and other headache diseases.

Short-lasting unilateral neuralgiform headache attacks (SUNCT/SUNA): a narrative review of interventional therapies.

Short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT) and short-lasting unilateral neuralgiform headache with autonomic symptoms (SUNA) are disabling primary headache disorders. The advent of advanced imaging technologies and surgical techniques has translated to a growing arsenal of interventional therapies capable of treating headache disorders. This literature review sheds light on the current evidence available for interventional therapies in medically intractable SUNCT/SUNA. PubMed and EMBASE were searched for publications between 1978 and 2022. Inclusion criteria were SUNCT/SUNA studies reporting outcomes following occipital nerve stimulation (ONS), pulsed radiofrequency (PRF) of sphenopalatine ganglion (SPG), stereotactic radiosurgery (SRS), deep brain stimulation (DBS) or microvascular decompression (MVD) of the trigeminal nerve. A greater than 50% reduction in severity or a greater than 50% reduction in the number of attacks was defined as a successful response. The rate of successful responses for the various treatment modalities were as follows: ONS 33/41 (80.5%), PRF of SPG 5/9 (55.6%), DBS of the ventral tegmental area 14/16 (86.7%), SRS to the SPG and/or trigeminal nerve 7/9 (77.8%) and MVD 56/73 (76.7%). Mean follow-up time in months was 42.5 (ONS), 24.8 (PRF), 25.3 (DBS), 20.8 (SRS) and 42.4 (MVD). A significant proportion of SUNCT/SUNA patients remain refractory to medical therapy (45%-55%). This review discusses existing literature on interventional approaches, including neuromodulation, radiofrequency ablation, gamma knife radiosurgery and MVD. The outcomes are promising, yet limited data exist, underscoring the need for further research to develop a robust surgical management algorithm.

Safety, tolerability, and effectiveness of repetitive intravenous dihydroergotamine for refractory chronic migraine with cardiovascular risk factors: A retrospective study.

BACKGROUND: Dihydroergotamine (DHE), like triptans, is contraindicated in patients with ischemic heart disease or coronary vasospasm. Its true safety, tolerability, and efficacy in patients with cardiovascular risk without ischemic heart disease or coronary vasospasm remain unclear. OBJECTIVES: To assess the safety, tolerability, and effectiveness of repetitive intravenous DHE in patients with cardiovascular risk factors. METHODS: A single-center, retrospective cohort study was conducted at the Jefferson Headache Center inpatient unit for refractory chronic migraine patients treated with our intravenous DHE protocol between January 1, 2019, and October 15, 2019. We evaluated tolerability and effectiveness outcomes based on atherosclerotic cardiovascular disease 10-year calculated risk scores, stratified into low (<5.0%) and elevated (≥5.0%) risk. Data were presented in mean ± standard deviation or median (25th percentile, 75th percentile) if non-normally distributed. RESULTS: Among 347 patients (median age of 46 [36, 57], female n = 278 [80.1%]), who received inpatient intravenous DHE, 227 patients (age 53 [45, 60], female 81.1%) had calculable risk scores, 64 (28.2%) had elevated risk, and 38 (16.7%) had cardiology consultations. There were no clinically significant electrocardiogram abnormalities or cardiovascular adverse events. The median hospital length of stay was 6 (5, 7) days. Compared to the low-risk group, those with elevated risk had higher nausea (31.3% vs. 14.1%, p = 0.008), but similar initial DHE dose (0.5 [0.25, 0.5] vs. 0.5 [0.25, 0.5], p = 0.009), lower final DHE dose (0.75 [0.5, 1] vs. 1 [0.75, 1] p < 0.001), and lower pain reduction after admission (-3.8 [2.1, 6] vs. -5 [3, 7] p = 0.037). CONCLUSION: Patients receiving intravenous DHE by the Jefferson Headache Center inpatient headache protocol had significantly reduced pain severity at discharge. No clinically significant cardiac or electrocardiogram abnormalities were detected in patients with elevated (or low) atherosclerotic cardiovascular disease risk. Repetitive intravenous DHE used by our protocol was safe in refractory chronic migraine patients.

Most bothersome symptoms in patients with migraine: A hospital-based study in Taiwan.

OBJECTIVE: To investigate the distribution, clinical associations, and treatment responses for the most bothersome symptoms of migraine in a large sample of patients with migraine in Taiwan. BACKGROUND: The most bothersome symptom is recently recommended as a co-primary endpoint in clinical trials of acute treatment of migraine. However, most clinical trials and observational studies have been conducted in the United States and Europe, with photophobia representing the most common most bothersome symptom. METHODS: Patients who were newly diagnosed with migraine by headache specialists in Taipei Veterans General Hospital were recruited. All participants completed a questionnaire for headache profile, including the most bothersome symptom. Clinical associations of the most bothersome symptoms and response rates to previous acute treatments were analyzed. RESULTS: Among the recruited 1188 patients with migraine (female 79.4%, mean age 39.0 ± 12.1 years) in this cross-sectional study, nausea (n = 729/1188, 61.4%) was the most common symptom that was most bothersome, followed by phonophobia (n = 280/1188, 23.6%), and photophobia (n = 122/1188, 10.3%). The frequency ranking was the same regardless of sex and age. Compared to migraine without aura, migraine with aura was associated with photophobia (adjusted odds ratio [OR] = 2.97, 95% confidence interval [CI] 1.76-5.0, p < 0.001). Chronic migraine was associated with phonophobia (adjusted OR = 1.51, 95% CI 1.13-2.01, p = 0.005), but there was a lower chance for nausea (adjusted OR = 0.68, 95% CI 0.53-0.88, p = 0.004), as the most bothersome symptom. Patients with different most-bothersome symptoms responded similarly to previous acute treatments, with an overall response rate of 52.2% (n = 550/1053). CONCLUSION: Patients with migraine in Taiwan reported a distinct ranking of the most bothersome symptom. However, the response rates of the most bothersome symptom and headache were similar, which supports the most bothersome symptom as an outcome measure for acute treatment of migraine. Further studies recruiting different populations are required to investigate regional differences in most bothersome symptoms.

Guidelines of the International Headache Society for clinical trials with neuromodulation devices for the treatment of migraine.

BACKGROUND: Although the European Medicines Agency and the US Food and Drug Administration have cleared several devices that use neuromodulation to provide clinical benefits in the acute or preventive treatment of migraine, the Clinical Trials Committee of the International Headache Society has not developed guidelines specifically for clinical trials of neuromodulation devices. In recognition of the distinct needs and challenges associated with their assessment in controlled trials, the Committee provides these recommendations for optimizing the design and conduct of controlled trials of neuromodulation devices for the acute and/or preventive treatment of migraine. METHODS: An international group of headache scientists and clinicians with expertise in neuromodulation evaluated clinical trials involving neuromodulation devices that have been published since 2000. The Clinical Trials Committee incorporated findings from this expert analysis into a new guideline for clinical trials of neuromodulation devices for the treatment of migraine. RESULTS: Key terms were defined and recommendations provided relative to the assessment of neuromodulation devices for acute treatment in adults, preventive treatment in adults, and acute and preventive treatment in children and adolescents. Ethical and administrative responsibilities were outlined, and a bibliography of previous research involving neuromodulation devices was created. CONCLUSIONS: Adoption of these recommendations will improve the quality of evidence regarding this important area in migraine treatment.

Intravenous ibuprofen for acute treatment of migraine: A double-blind, randomized, placebo-controlled pilot study.

OBJECTIVE: To evaluate the efficacy and safety of intravenous (IV) Ibuprofen for acute treatment of migraine. BACKGROUND: IV nonsteroidal anti-inflammatory drugs (NSAIDs) are an alternative to oral NSAIDs, especially in patients with severe migraine who have emesis or gastroparesis. To date, only three IV NSAIDs (ketorolac, ibuprofen, and meloxicam) are available in the United States for use in moderate and severe pain, but no placebo-controlled trial is available for migraine. We performed a single-center, double-blind, randomized, placebo-controlled pilot study to evaluate the efficacy and safety of IV ibuprofen as an acute treatment of migraine (NCT01230411). METHODS: Individuals with episodic migraine were screened at the Jefferson Headache Center. Qualified subjects were treated for migraine attacks within 2-72 h following the headache onset with either 800 mg of IV ibuprofen or placebo in 250 ml saline bolus. Migraine pain intensity (4-point Likert scale) and associated symptoms were assessed at predetermined time points (0.25, 0.5, 1, 1.5, 2, 4, 8, 24 h). The primary endpoint was pain relief at 2 h after infusion. Important secondary endpoints included pain freedom at 2 h, sustained relief over 24 h, use of rescue therapy, and absence of associated symptoms. Adverse events (AEs) were also collected. RESULTS: Seventy-four participants were enrolled between 2011 and 2017. Forty-four subjects (female 33/44; 75.0%) with mean (SD) age 41.0 (11.2)   11.2 years came for the treatment. All treated subjects (n = 44) were included in the analysis. Among them, 23 were randomized to receive IV ibuprofen. Both groups were demographically similar except for longer migraine duration (i.e., years lived with disease) in the active treatment than in the placebo group. At 2 h posttreatment, pain relief was found in 74% (17/23) and 48% (10/21) after IV ibuprofen and placebo, respectively (odds ratio [OR] 3.12, 95% CI: 0.88-11.0; p = 0.078). Other secondary endpoints at 2 and 24 h were not significant. The longitudinal repeated-measures analysis within 2 h on ibuprofen treatment showed significant pain relief (OR 2.47, 95% CI 1.08-5.7; p = 0.033) and absence of associated symptoms: photophobia (OR 4.0, 95% CI 1.57-10.3; p = 0.004), phonophobia (OR 3.12, 95% CI 1.16-8.4; p = 0.025), and osmophobia (OR 3.45, 95% CI 1.01-11.8; p = 0.048). AEs were observed in seven subjects in both groups, with arm pain being the most common. No serious AE was reported. CONCLUSION: This study did not meet the primary endpoint but showed pain relief and elimination of several associated symptoms within 2 h on repeated-measures analysis. Although limited by small sample size and high placebo response, our results indicate that IV ibuprofen may be a safe and effective option for acute treatment of migraine, but more extensive studies are necessary.

Update of Neuromodulation in Chronic Migraine.

PURPOSE OF REVIEW: Neuromodulation devices have become an attractive alternative to traditional pharmacotherapy for migraine, especially for patients intolerant to medication or who prefer non-pharmacological options. In the past decades, many studies demonstrated the efficacy of neuromodulation devices in patients with episodic migraine (EM). However, the benefit of these devices on chronic migraine (CM), which is typically more debilitating and refractory than EM, remains not well studied. RECENT FINDINGS: We reviewed the literature within the last five years on using FDA-cleared and investigational devices for CM. There were eight randomized controlled trials and 15 open-label observational studies on ten neuromodulation devices. Neuromodulation is promising for use in CM, although efficacy varies among devices or individuals. Noninvasive devices are usually considered safe with minimal adverse events. However, stimulation protocol and methodology differ between studies. More well-designed studies adhering to the guideline may facilitate FDA clearance and better insurance coverage.

The Use of Botulinum Toxin in the Management of Headache Disorders.

Tremendous progress has been made in the past decades for the treatment of headache disorders. Chronic migraine is the most disabling type of headache and requires the use of acute and preventive medications, many of which are associated with adverse events that limit patient adherence. Botulinum toxin (BoNT) serotype A, a neurotoxin derived from certain strains of Clostridium, disrupts neuropeptide secretion and receptor translocation related to trigeminal nociception, thereby preventing pain sensitization through peripheral and possibly central mechanisms. Ever since the first randomized controlled trial on onabotulinumtoxinA (onabotA) for migraine was published two decades ago, onabotA has been the only BoNT formulation approved for use in the prevention of chronic migraine. Superior tolerability and efficacy have been demonstrated on multiple migraine endpoints in many controlled trials and real-life studies. OnabotA is a safe and efficacious treatment for chronic migraine and possibly high-frequency episodic migraine. Further research is still needed to understand its mechanism of action to fully develop its therapeutic potential.

Non-invasive vagus nerve stimulation for primary headache: A clinical update.

BACKGROUND: Non-invasive vagus nerve stimulation (nVNS) is a proven treatment for cluster headache and migraine. Several possible mechanisms of action by which nVNS mitigates headache have been identified. METHODS: We conducted a narrative review of recent scientific and clinical research into nVNS for headache, including findings from mechanistic studies and their possible relationships to the clinical effects of nVNS. RESULTS: Findings from animal and human studies have provided possible mechanistic explanations for nVNS efficacy in headache involving four core areas: Autonomic nervous system functions; cortical spreading depression inhibition; neurotransmitter regulation; and nociceptive modulation. We discuss how overlap and interplay among these areas may underlie the utility of nVNS in the context of clinical evidence supporting its safety and efficacy as acute and preventive therapy for both cluster headache and migraine. Possible future nVNS applications are also discussed. CONCLUSION: Significant progress over the past several years has yielded valuable mechanistic and clinical evidence that, combined with the excellent safety and tolerability profile of nVNS, suggests that it should be considered a first-line treatment for both acute and preventive treatment of cluster headache, an effective option for acute treatment of migraine, and a highly relevant, practical option for migraine prevention.

Adherence to the 2008 IHS guidelines for controlled trials of drugs for the preventive treatment of chronic migraine in adults.

INTRODUCTION: Since the definition of chronic migraine as a new disease entity in 2004, numerous clinical trials have examined the efficacy of preventive treatments in chronic migraine. Our aim was to assess the adherence of these trials to the Guidelines of the International Headache Society published in 2008. METHODS: We searched PubMed for controlled clinical trials investigating preventive treatment for chronic migraine in adults designed after the release of the Guidelines and published until December 2017. Trial quality was evaluated with a 13-item scoring system enlisting essential recommendations adapted from the Guidelines. RESULTS: Out of 3352 retrieved records, we included 16 papers in the analysis dealing with pharmacological treatment of chronic migraine. The median score was 6.5 (range 2-13). All trials were randomized, the large majority (81.25%) were placebo-controlled and double-blinded (87.5%). Adherence was lowest on i) a priori definition of outcomes (31.25%), ii) primary endpoint definition (37.5%%) and iii) trial registration (37.5%). DISCUSSION: Most clinical trials adhered to the recommendations of the IHS, whereas adherence to migraine-specific recommendations was lower. Greater awareness and adherence to the guidelines are essential to improve the quality of clinical trials, validity of publications and the generalizability of the results.

Non-invasive sensitive brain tumor detection using dual-modality bioimaging nanoprobe.

Despite decades of efforts, non-invasive sensitive detection of small malignant brain tumors still remains challenging. Here we report a dual-modality 124I-labeled gold nanostar (124I-GNS) probe for sensitive brain tumor imaging with positron emission tomography (PET) and subcellular tracking with two-photon photoluminescence (TPL) and electron microscopy (EM). Experiment results showed that the developed nanoprobe has potential to reach sub-millimeter intracranial brain tumor detection using PET scan, which is superior to any currently available non-invasive imaging modality. Microscopic examination using TPL and EM further confirmed that GNS nanoparticles permeated the brain tumor leaky vasculature and accumulated inside brain tumor cells following systemic administration. Selective brain tumor targeting by enhanced permeability and retention effect and ultrasensitive imaging render 124I-GNS nanoprobe promise for future brain tumor-related preclinical and translational applications.

Targeting CGRP for the Prevention of Migraine and Cluster Headache: A Narrative Review.

Calcitonin-gene-related peptide (CGRP), a neuropeptide broadly distributed in neuronal and non-neuronal regions throughout the body, plays a fundamental role in migraine and cluster headache (CH) pathophysiology. CGRP functional blockade alleviates neurogenic inflammation and reduces pain pathway sensitization. Two types of CGRP function-blocking modalities, monoclonal antibodies (MAbs), and small molecules (gepants), have been designed to target the CGRP ligands and CGRP receptors. In this narrative review, we summarized the latest clinical trials on gepants and CGRP function-blocking MAbs for migraine and CH prevention. At the time of writing, newer gepants are currently under Federal Drug Administration (FDA) review for migraine management, but there is no study yet on the usage of gepants for CH. Erenumab, fremanezumab, and galcanezumab have been approved by the FDA for migraine prevention while eptinezumab is under FDA review. CGRP MAbs are as effective as and more tolerable than conventional migraine preventives. For CH prevention, galcanezumab has shown some promising findings and was recently approved for use in episodic cluster prevention. CGRP function-blocking therapy not only demonstrates high efficacy and superior safety profile, but also improves headache frequency and quality of life. Convenient monthly dosing for the MAbs can further improve medication adherence, hence better headache control. With CGRP function-blocking therapy showing efficacy even in individuals who failed other preventives, it has become an exciting new therapeutic option in the field of migraine and CH.

Histamine and Migraine.

BACKGROUND: Histamine is an ancient "tissue amine" preceding multicellular organisms. In the central nervous system (CNS), its fibers originate solely from the tuberomammillary nucleus and travel throughout the brain. It is mainly responsible for wakefulness, energy homeostasis, and memory consolidation. Recently, several studies suggest a potential role of histamine in migraine pathogenesis and management. METHODS: Narrative review of current literature regarding histamine and migraine. RESULTS: Histamine plays a crucial role in migraine pathogenesis: sustaining the neurogenic inflammation pathway. Interaction between mast cells (MC) and calcitonin-gene related protein (CGRP) results in sensitization of trigeminal afferents and trigeminal ganglia (TG). Histamine binds with differing affinities to four different histaminergic G-protein coupled receptors, activating protein kinases, or triggering calcium release with subsequent mode of actions. Histamine 1 receptor (H1 R) and histamine 2 receptor (H2 R) antagonists are frequently used for the treatment of allergy and gastric acid secretion, respectively, but their antagonism is probably ineffective for migraine. Histamine 3 receptor (H3 R) and histamine 4 receptor (H4 R) have a threefold higher affinity than H1 R/H2 R for histamine and are found almost exclusively on neurons and immune tissues, respectively. H3 R acts as an autoreceptor or as a heteroreceptor, lowering the release of histamine and other neurotransmitters. This is a potential target for anti-nociception and anti-neurogenic inflammation. To date, several small clinical trials using low dose histamine or Nα -methylhistamine have demonstrated migraine prophylactic efficacy, probably via H3 R or other undetermined pathways. CONCLUSION: The histamine system interacts with multiple regions in the CNS and may hypothetically modulate the migraine response. Low dose histamine may be a promising option for migraine prevention.

Vagus Nerve Stimulation and Headache.

Neuromodulation is an emerging area in headache management. Through neurostimulation, multiple brain areas can be modulated to alleviate pain, hence reducing the pharmacological need. In this review, we discuss the recent development of the vagus nerve stimulation (VNS) for headache management. Early case series from epilepsy and depression cohorts using invasive VNS showed a serendipitous reduction in headache frequency and/or severity. Noninvasive VNS (nVNS), which stimulates the carotid vagus nerve with the use of a personal handheld device, also demonstrated efficacy for acute migraine or cluster headache attacks. Long-term use of nVNS seemed to exert a prophylactic effect for both chronic migraine and chronic cluster headache. In animal studies, nVNS modulated multiple pain pathways and even lessen cortical spreading depression. Progression in nVNS clinical efficacy over time suggests an underlying disease-modifying neuromodulation. Noninvasive VNS appears to be as effective as the invasive counterpart for many indications. With an enormous potential therapeutic gain and a high safety profile, further development and application of nVNS is promising.

Vagus Nerve and Vagus Nerve Stimulation, a Comprehensive Review: Part II.

The development of vagus nerve stimulation (VNS) began in the 19th century. Although it did not work well initially, it introduced the idea that led to many VNS-related animal studies for seizure control. In the 1990s, with the success of several early clinical trials, VNS was approved for the treatment of refractory epilepsy, and later for the refractory depression. To date, several novel electrical stimulating devices are being developed. New invasive devices are designed to automate the seizure control and for use in heart failure. Non-invasive transcutaneous devices, which stimulate auricular VN or carotid VN, are also undergoing clinical trials for treatment of epilepsy, pain, headache, and others. Noninvasive VNS (nVNS) exhibits greater safety profiles and seems similarly effective to their invasive counterpart. In this review, we discuss the history and development of VNS, as well as recent progress in invasive and nVNS.

Vagus Nerve and Vagus Nerve Stimulation, a Comprehensive Review: Part I.

The vagus nerve (VN), the "great wondering protector" of the body, comprises an intricate neuro-endocrine-immune network that maintains homeostasis. With reciprocal neural connections to multiple brain regions, the VN serves as a control center that integrates interoceptive information and responds with appropriate adaptive modulatory feedbacks. While most VN fibers are unmyelinated C-fibers from the visceral organs, myelinated A- and B-fiber play an important role in somatic sensory, motor, and parasympathetic innervation. VN fibers are primarily cholinergic but other noncholinergic nonadrenergic neurotransmitters are also involved. VN has four vagal nuclei that provide critical controls to the cardiovascular, respiratory, and alimentary systems. Latest studies revealed that VN is also involved in inflammation, mood, and pain regulation, all of which can be potentially modulated by vagus nerve stimulation (VNS). With a broad vagal neural network, VNS may exert a neuromodulatory effect to activate certain innate "protective" pathways for restoring health.

Vagus Nerve and Vagus Nerve Stimulation, a Comprehensive Review: Part III.

Vagus nerve stimulation (VNS) is currently undergoing multiple trials to explore its potential for various clinical disorders. To date, VNS has been approved for the treatment of refractory epilepsy and depression. It exerts antiepileptic or antiepileptogenic effect possibly through neuromodulation of certain monoamine pathways. Beyond epilepsy, VNS is also under investigation for the treatment of inflammation, asthma, and pain. VNS influences the production of inflammatory cytokines to dampen the inflammatory response. It triggers the systemic release of catecholamines that alleviates the asthma attack. VNS induces antinociception by modulating multiple pain-associated structures in the brain and spinal cord affecting peripheral/central nociception, opioid response, inflammation process, autonomic activity, and pain-related behavior. Progression in VNS clinical efficacy over time suggests an underlying disease-modifying neuromodulation, which is an emerging field in neurology. With multiple potential clinical applications, further development of VNS is encouraging.

Plasmonic gold nanostars for multi-modality sensing and diagnostics.

Gold nanostars (AuNSs) are unique systems that can provide a novel multifunctional nanoplatform for molecular sensing and diagnostics. The plasmonic absorption band of AuNSs can be tuned to the near infrared spectral range, often referred to as the "tissue optical window", where light exhibits minimal absorption and deep penetration in tissue. AuNSs have been applied for detecting disease biomarkers and for biomedical imaging using multi-modality methods including surface-enhanced Raman scattering (SERS), two-photon photoluminescence (TPL), magnetic resonance imaging (MRI), positron emission tomography (PET), and X-ray computer tomography (CT) imaging. In this paper, we provide an overview of the recent development of plasmonic AuNSs in our laboratory for biomedical applications and highlight their potential for future translational medicine as a multifunctional nanoplatform.

How early can we treat migraine attacks? A perspective based on prodrome.

Treating migraine attacks early at the onset of a headache is a common proven strategy. But does this strategy work before headache onset? In the PRODROME trial, Dodick et al. showed that ubrogepant taken during the prodrome can prevent headache attacks and reduce functional disability.1.