Efficacy of Atogepant in Chronic Migraine With and Without Acute Medication Overuse in the Randomized, Double-Blind, Phase 3 PROGRESS Trial.

BACKGROUND AND OBJECTIVES: Atogepant is an oral, calcitonin gene-related peptide receptor antagonist approved for the preventive treatment of migraine. We evaluated the efficacy of atogepant for the preventive treatment of chronic migraine (CM) in participants with and without acute medication overuse. METHODS: This subgroup analysis of the phase 3, 12-week, randomized, double-blind, placebo-controlled PROGRESS trial evaluated adults with a ≥1-year history of CM, ≥15 monthly headache days (MHDs), and ≥8 monthly migraine days (MMDs) during the 4-week baseline period. Participants were randomized (1:1:1) to placebo, atogepant 30 mg twice daily (BID), or atogepant 60 mg once daily (QD) for 12 weeks and were analyzed by acute medication overuse status (triptans/ergots for ≥10 days per month, simple analgesics for ≥15 days per month, or combinations of triptans/ergots/simple analgesics for ≥10 days per month). Outcomes included change from baseline in mean MMDs, MHDs, and monthly acute medication use days; ≥50% reduction in mean MMDs across 12 weeks; and patient-reported outcome (PRO) measures. RESULTS: Of 755 participants in the modified intent-to-treat population, 500 (66.2%) met baseline acute medication overuse criteria (placebo, n = 169 [68.7%]; atogepant 30 mg BID, n = 161 [63.6%]; atogepant 60 mg QD, n = 170 [66.4%]). The least squares mean difference (LSMD) (95% CI) from placebo in MMDs was -2.7 (-4.0 to -1.4) with atogepant 30 mg BID and -1.9 (-3.2 to -0.6) with atogepant 60 mg QD. Mean MHDs (LSMD [95% CI] -2.8 [-4.0 to -1.5] and -2.1 [-3.3 to -0.8]) and mean acute medication use days (LSMD [95% CI] -2.8 [-4.1 to -1.6] and -2.6 [-3.9 to -1.3]) were reduced and a higher proportion of participants achieved ≥50% reduction in MMDs (odds ratio [95% CI] 2.5 [1.5-4.0] and 2.3 [1.4-3.7]) with atogepant 30 mg BID and atogepant 60 mg QD. There was a 52.1%-61.9% reduction in the proportion of atogepant-treated participants meeting acute medication overuse criteria over 12 weeks. Atogepant improved PRO measures. Similar results were observed in the subgroup without acute medication overuse. DISCUSSION: Atogepant was effective in participants with CM, with and without acute medication overuse, as evidenced by reductions in mean MMDs, MHDs, and acute medication use days; reductions in the proportion of participants meeting acute medication overuse criteria; and improvements in PROs. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov NCT03855137. Submitted: February 25, 2019; first patient enrolled: March 11, 2019. clinicaltrials.gov/ct2/show/NCT03855137. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that atogepant reduces mean MMDs, MHDs, and monthly acute medication use days in adult patients with or without medication overuse.

Safety and tolerability of atogepant for the preventive treatment of migraine: a post hoc analysis of pooled data from four clinical trials.

BACKGROUND: Conventional, non-specific preventive migraine treatments often demonstrate low rates of treatment persistence due to poor efficacy or tolerability. Effective, well-tolerated preventive treatments are needed to reduce migraine symptoms, improve function, and enhance quality of life. Atogepant is a migraine-specific oral calcitonin gene-related peptide receptor antagonist that is indicated for the preventive treatment of migraine in adults. This analysis evaluated the safety and tolerability profile of atogepant for the preventive treatment of migraine, including adverse events (AEs) of interest, such as constipation, nausea, hepatic safety, weight changes, and cardiac disorders. METHODS: This post hoc analysis was performed using data pooled from 2 (12-week) randomized, double-blind, placebo-controlled trials (RCTs) and 2 (40- and 52-week) open-label long-term safety (LTS) trials of oral atogepant for episodic migraine (EM). RESULTS: The safety population included 1550 participants from the pooled RCTs (atogepant, n = 1142; placebo, n = 408) and 1424 participants from the pooled LTS trials (atogepant, n = 1228; standard care [SC], n = 196). In total, 643/1142 (56.3%) atogepant participants and 218/408 (53.4%) placebo participants experienced ≥ 1 treatment-emergent AEs (TEAEs) in the RCTs. In the LTS trials, 792/1228 (64.5%) of atogepant participants and 154/196 (78.6%) of SC participants experienced ≥ 1 TEAEs. The most commonly reported TEAEs (≥ 5%) in participants who received atogepant once daily were upper respiratory tract infection (5.3% in RCTs, 7.7% in LTS trials), constipation (6.1% in RCTs, 5.0% in LTS trials), nausea (6.6% in RCTs, 4.6% in LTS trials), and urinary tract infection (3.4% in RCTs, 5.2% in LTS trials). Additionally, weight loss appeared to be dose- and duration-dependent. Most TEAEs were considered unrelated to study drug and few led to discontinuation. CONCLUSIONS: Overall, atogepant is safe and well tolerated in pooled RCTs and LTS trials for the preventive treatment of EM in adults. TRIAL REGISTRATION: ClinicalTrials.gov identifiers: NCT02848326 (MD-01), NCT03777059 (ADVANCE), NCT03700320 (study 302), NCT03939312 (study 309).

Special considerations in management of migraine in the elderly.

Migraine in elderly patients requires an individualized approach, with unique considerations and challenges in both diagnosing and managing the disorder. Aging brains differ from younger ones in many ways, with distinct trajectories impacting brain volume, neurotransmitter systems, and functional systems, such as the descending pain inhibitory system. In this chapter, we will deconstruct migraine in the elderly by discussing the definitions of the elderly and migraine, the prevalence of migraine, and the management of migraine including the challenges posed by its comorbidities, limitations of treatments, and its effects on cognition. Studying, quantifying, characterizing, diagnosing, or managing migraine in the elderly is a challenge. However, it is clear that migraine in the elderly is not an uncommon occurrence, and providers should be aware that many elderly patients will not present with the complete phenotypic profile. Fortunately, the weight of evidence has not established migraine as a risk factor for dementia in the elderly, although migraine and its pharmacologic treatments may adversely impact cognition. Successful management requires understanding the interactions of migraine with comorbidities in the elderly and the adverse impacts of polypharmacy.

Frequency of headache in emergency department patients with anaphylaxis: A cross-sectional study.

BACKGROUND: Multiple anaphylaxis mediators have been demonstrated to provoke migraine-like attacks following intravascular infusion, suggesting that anaphylaxis could cause headache; however, headache is rarely noted in anaphylaxis and is not included among diagnostic criteria. OBJECTIVE: Our study objectives were to estimate the frequency of headache among prospectively enrolled emergency department (ED) patients with anaphylaxis and assess the association of headache with patient and anaphylaxis characteristics. METHODS: A cross-sectional study of ED patients aged ≥5 years who met anaphylaxis diagnostic criteria from January 8, 2020 to September 9, 2022 was conducted. The primary outcome of interest was headache frequency among patients who met at least one anaphylaxis criterion. We explored the association of headache with patient characteristics and anaphylaxis characteristics. RESULTS: We included 63 patients with anaphylaxis. In all, 17 (27%, 95% confidence interval [CI] 17%-40%) patients reported the presence of a headache. Female patients had more than a nine times increased odds of having headache (odds ratio [OR] 9.3, 95% CI 1.14-77.1, p = 0.016). Presentation with headache was associated with the presence of dyspnea (OR 5.5, 95% CI 1.56-19.7, p = 0.006). CONCLUSION: Headache in anaphylaxis may be more common than previously recognized, especially in females. Larger prospective studies are needed to characterize headache as a marker of neurological involvement in anaphylaxis.

Incidence of Status Migrainosus in Olmsted County, Minnesota, United States: Characterization and Predictors of Recurrence.

BACKGROUND AND OBJECTIVES: SM is recognized as a complication of migraine in which pain and/or associated symptoms are unremitting and debilitating for more than 72 hours. The epidemiology of SM in the general population is not known. The aim of this study is to determine the incidence, recurrence rate, and clinical associations of status migrainosus (SM) in care-seeking residents of Olmsted County, Minnesota. METHODS: The Rochester Epidemiology Project was used to identify the incident cases of SM according to the International Classification of Headache Disorders, Third Edition criteria and based on the first physician-encountered case in the record. The clinical characteristics of the incident cases were abstracted from the medical record. One-year recurrence-free survival was evaluated and compared between clinically relevant groups, including baseline demographics, migraine characteristics, and treatment exposures. RESULTS: Between January 1, 2012, and December 31, 2017, 237 incident cases of SM were identified. The median age was 35 (IQR 26-47) years, and 210 (88.6%) were female. A history of chronic migraine was recorded in 82/226 (36.3%) and a history of aura in 76/213 (35.7%). At the time of the incident case, medication reconciliation included a triptan or ergotamine in 127/233 (53.6%) and/or an opioid-containing analgesic in 43/233 (18.5%). The overall age- and sex-adjusted incidence rate was 26.60 per 100,000 [95% CI, 23.21-29.97], with a peak incidence between ages 40 and 49 years. The median (95% CI) attack duration was 5 (4.48-5.42) days. The most frequent triggers were stress (40/237, 16.9%) and too much or too little sleep (27/237, 11.4%). Recurrence occurred in 35/237 (14.8%) at a median of 58 (IQR 23-130) days following the initial attack. In our age- and sex-adjusted multivariable model, too much or too little sleep as a trigger was associated with 12-month risk of recurrence (adjusted OR 3.59 [95% CI 1.58-8.14], p = 0.0022). DISCUSSION: Our study provides a population-based estimate of SM incidence. We identified aberrant sleep patterns as a potentially modifiable risk factor for 1-year SM recurrence.

Other Primary Headache Disorders.

PURPOSE: This article provides an overview of a diverse group of primary headache disorders that are categorized in the International Classification of Headache Disorders, 3rd Edition (ICHD-3), as "other primary headache disorders." This article provides clinicians with a distilled understanding of the diagnoses and their epidemiology, pathophysiology, and management. RECENT FINDINGS: Cough-induced headache requires neuroimaging to exclude posterior fossa pathology and recently has been reported as a common symptom in patients with CSF-venous fistula. Clinical overlap is observed between patients with primary exercise headache and primary headache associated with sexual activity. Patients with recurrent thunderclap headache associated with sexual activity should be presumed to have reversible cerebral vasoconstriction syndrome until proven otherwise. De novo external-pressure headache is a common sequela among health care workers using personal protective equipment during the COVID-19 pandemic. New daily persistent headache is an important mimicker of chronic migraine or chronic tension-type headache and is distinguished by a daily-from-onset progression of persistent headache; a treatment-refractory course is often observed, and early involvement of a multidisciplinary team, including a psychotherapist, is advised. SUMMARY: Patients with primary headache disorders that are classified as "other primary headache disorders" have presentations with unique diagnostic and management considerations. The disorders are highly recognizable, and an appreciation of the diagnoses will aid clinicians in providing safe and effective care for patients presenting with headache.

Trigeminal nerve electrophysiological findings in hemifacial atrophy: A systematic literature review and retrospective chart review.

OBJECTIVE: Hemifacial atrophy (HFA) is a rare disorder characterized by progressive unilateral wasting facial soft tissue, muscle, and/or bone. Trigeminal nerve abnormalities may contribute to or result from disease pathophysiology. We aimed to gain further insights into the role of trigeminal pathophysiology along the HFA severity spectrum. METHODS: A systematic literature review was performed according to PRISMA standards. Retrospective cases of HFA from the literature and Mayo Clinic EMG database were pooled for descriptive and semi-quantitative analysis. RESULTS: Overall, 13 total HFA patients were identified through literature and database reviews. Trigeminal nerve testing was abnormal in 9/13 (69%), exclusively in moderate-severe cases. Abnormalities suggested a peripheral (7/9, 78%) or mixed central/peripheral (2/9, 22%) localization. Trigeminal nerve abnormalities were not identified in any of the 4 cases with mild disease severity. CONCLUSION: Moderate to severe cases of HFA were associated with electrophysiological trigeminal abnormalities. No abnormalities were seen in mild cases of HFA. SIGNIFICANCE: Trigeminal nerve electrophysiology may serve as a biomarker of moderate-severe disease progression, likely reflecting the consequences of progressive soft tissue atrophy.

Characterization of thunderclap headache in a reversible cerebral vasoconstriction syndrome case series.

OBJECTIVES: To empirically address how thunderclap headache (TCH) is described in a relevant real-world setting. BACKGROUND: TCH refers to a highly recognizable description of a severe headache that reaches maximum severity within 1 minute and endures for at least 5 minutes. The use of a numerical rating scale (NRS) to appraise TCH severity, as well as assessment of TCH progression in patients with pre-existing headache at the time of TCH onset has not been previously evaluated. METHODS: This was a retrospective case series of adults with a diagnosis of reversible cerebral vasoconstriction syndrome (RCVS), identified through a search of the electronic health record. Individuals meeting International Classification of Headache Disorders, 3rd Edition criteria for acute headache attributed to RCVS were included. Attacks described using a verbal descriptor scale (VDS), NRS, or both were recorded to evaluate acute headache characteristics. RESULTS: In all, 56 individuals with available descriptions of 120 acute headaches were included in the study analysis. Patients were female (35, 62.5%) with a median age of 46 (range: 19-67). The majority of patients reported a RCVS trigger (39, 69.6%). Acute headaches were characterized using a VDS (52, 43.3%), NRS (51, 42.5%), or both (17, 14.1%). Acute headaches were always described as severe when a VDS was utilized, and with a median NRS of 10 (range: 4-10). Four patients (7%) did not have a single headache characterized as either severe or with a NRS 8 or greater. In the 10 cases for which there was a pre-TCH baseline headache, it was either rated as mild or with a median NRS of 3 (range: 2-6). CONCLUSIONS: TCH in RCVS can be recognized using either VDS or NRS, with a broader range of peak intensities than previously recognized. TCH remains recognizable despite pre-existing baseline headache.

COVID-19 and Headache Medicine: A Narrative Review of Non-Steroidal Anti-Inflammatory Drug (NSAID) and Corticosteroid Use.

OBJECTIVE: To summarize the current literature on non-steroidal anti-inflammatory drug and corticosteroid use during the coronavirus disease 2019 (COVID-19) pandemic, recognizing that these are commonly used treatments in the field of headache medicine. BACKGROUND: The use of non-steroidal anti-inflammatory drugs and corticosteroids in patients during the COVID-19 pandemic has been a controversial topic within the medical community and international and national health organizations. Lay press and social media outlets have circulated opinions on this topic despite the fact that the evidence for or against the use of these medications is sparse. In the field of headache medicine, these medications are used commonly and both patients and clinicians may have questions or hesitations pertaining to their use during the COVID-19 pandemic. METHODS: A detailed search of the scientific and popular literature was performed. RESULTS: There is limited literature pertaining to the safety of non-steroidal anti-inflammatory drugs and corticosteroids during the COVID-19 pandemic. To date, there are no clear scientific data that preclude the use of non-steroidal anti-inflammatory drugs in the general population who may acquire COVID-19 or in those acutely infected with the virus. Several health organizations have concluded that treatment with corticosteroids during active infection should be avoided due to concerns of prolonged viral shedding in the respiratory tract and the lack of survival benefit based on the data from past coronaviruses and influenza virus; specific exceptions exist including treatment for underlying asthma or chronic obstructive pulmonary disease, septic shock, and acute respiratory distress syndrome. CONCLUSION: Scientific information regarding the COVID-19 pandemic is constantly evolving, and limited or contradictory information can lead to confusion for both patients and clinicians. It is recommended that prior to prescribing non-steroidal anti-inflammatory drugs and steroids for the treatment of headache, clinicians have open discussions with their patients about the potential risks and benefits of using these medications during the COVID-19 pandemic. This manuscript summarizes the currently available evidence and understanding about these risks and benefits to help clinicians navigate such discussions.

When the Temporal Artery Biopsy is Negative: A Case Series of Headache Attributed to Polymyalgia Rheumatica.

INTRODUCTION: Older adults presenting with a new or changed headache pattern in the setting of a diagnosis of polymyalgia rheumatica (PMR) are at risk for incident giant cell arteritis. However, the differential diagnosis of headache has not been evaluated in patients with a negative temporal artery biopsy (TAB). Headache has not been described as a symptom of PMR. METHODS: After prospectively identifying an individual felt to have headache attributed to PMR, we performed a chart review to identify additional cases. As a secondary outcome, we summarized alternative headache diagnoses in patients with PMR, headache and a negative TAB. RESULTS: A 75-year-old woman presented with a subacute history of radiating cervical pain in the setting of a 3 month history of lower back stiffness at rest and fatigue. Clinical examination was suggestive of a cervicogenic headache. Following treatment with low-dose corticosteroid for PMR, headaches, cervical mobility and systemic findings resolved with treatment of PMR with low-dose corticosteroid. In our cohort of 36 patients, we identified a single additional patient meeting our study criteria for headache attributed to PMR. Three additional patients met all but 1 diagnostic criterion. The retrospective case was a 73-year-old woman with a subacute history of both morning-predominant headaches and muscle stiffness, diagnosed with PMR. Headaches remitted with low-dose corticosteroid and relapsed with corticosteroid taper. CONCLUSIONS: Headache attributed to PMR is a steroid-responsive syndrome which should be considered in an older adult presenting with features of PMR, when the TAB is negative. Diagnostic criteria for headache attributed to PMR are proposed.

Pediatric tracheostomy: A large single-center experience.

OBJECTIVES: To describe the epidemiology, specifically the indications, complications, and outcomes, of pediatric tracheostomies performed in one tertiary referral unit. METHODS: Single-center retrospective cohort study of pediatric patients undergoing tracheostomy between May 2010 and May 2018 at the Newcastle upon Tyne Hospitals, United Kingdom. RESULTS: One hundred seventy-two pediatric tracheostomies were performed during the study period with a median age of 141 (interquartile range [IQR] 51-484) days. The most common primary indication was long-term ventilation (38.4%, 66 of 172), followed by weaning from ventilation in cardiac patients (22.1%, 38 of 172). Only 5.2% (9 of 172) of our cohort underwent tracheostomy for subglottic stenosis. The vast majority of tracheostomies were performed electively, with just 6.4% (11 of 172) performed as an emergency procedure. Early and late complication rates were 9.8% (15 of 153) and 40.0% (61 of 153), respectively. Tracheostomy decannulation was successful in 44.4% of children (68 of 153). The median duration the tracheostomy was in situ was 397 (IQR 106-708) days. All-cause mortality was 22.1% (38 of 172), with tracheostomy-related mortality at 1.2% (2 of 172). CONCLUSION: We report one of the largest contemporary case series of pediatric tracheostomies. Present-day pediatric tracheostomy is primarily performed as an elective procedure in ventilated children under the age of 1 year. Pediatric tracheostomy should be considered as a long-term intervention in many children. Nevertheless, a large proportion of children are ultimately decannulated. It is important to acknowledge the significant morbidity associated with this intervention and the small-but-present risk of tracheostomy-related mortality. LEVEL OF EVIDENCE: 4 Laryngoscope, 130:E375-E380, 2020.

Triptan and ergotamine overdoses in the United States: Analysis of the National Poison Data System.

OBJECTIVE: To examine the clinical outcomes of intentional overdoses involving triptans and ergotamines with a retrospective review of the National Poison Data System (NPDS). METHODS: This was a 5-year retrospective cross-sectional study (2014-2018) using the NPDS. Demographics, exposure characteristics, and outcomes were described. Univariate logistic regression was used to estimate the odds ratio (OR) for major effect or death. A multivariable logistic regression model with inclusion criteria of p < 0.1 in univariate analysis was implemented with backwards selection. RESULTS: In this population (n = 1,489), multiple exposure was most common (n = 1,145). The mean age was 31.2 years and 1,197 (80.4%) participants were female. Major effects from a single exposure were seen in <1% with no recorded deaths. Triptan ingestion (n = 328) resulted in hypertension (14%), tachycardia (10.7%), drowsiness (11%), nausea (6.4%), vomiting (4.6%), vertigo (4%), chest pain (3.7%), and diaphoresis (2.4%). Ergotamine ingestion (n = 16) resulted in abdominal pain (16%), vomiting (12.5%), numbness (12.5%), nausea (6.3%), diarrhea (6.3%), and vertigo (6.3%). No clinical effect was seen in 90 (26.2%). No cases met Hunter criteria for serotonin syndrome. There is risk of major event or death due to age (OR 1.02; 95% confidence interval [CI] 1.01-1.04; p = 0.004), multiple product exposure (OR 9.50; 95% CI 2.29-39.48; p = 0.002), and concomitant overdose with benzodiazepines (OR 1.71; 95% CI 1.05-2.78; p = 0.032) or tricyclic antidepressants (OR 3.16; 95% CI 1.88-5.31; p < 0.001). CONCLUSION: The risk of major effect or death was low and predicted by age, multiple product exposure, and concomitant benzodiazepine or tricyclic antidepressant. The triptan toxidrome consists of hypertension, tachycardia, and drowsiness. The toxic effects of ergotamine are acute gastrointestinal syndrome with vertigo and numbness. No cases of serotonin syndrome were seen.

Paediatric donation after circulatory determined death heart transplantation using donor normothermic regional perfusion and ex situ heart perfusion: A case report.

This is a report of a unique DCD paediatric heart transplant whereby normothermic regional perfusion was used to assess DCD heart function after death followed by ex situ heart perfusion of the graft during transportation from donor to recipient hospitals. The DCD donor was a 9-year-old boy weighing 84 kg. The recipient was 7-year-old boy with failing Fontan circulation and weighed 23 kg. It was an ABO-compatible heart transplantation. The DCD heart was reperfused and assessed using normothermic regional perfusion followed by portable ex situ heart perfusion during transportation. The orthotopic heart transplantation was successful with good graft function and no evidence of rejection on endomyocardial biopsy at 30 days post-transplant. At 1-year follow-up, excellent graft function is maintained, and he is attending school with a good quality of life. DCD heart transplantation in children is a promising solution to reducing paediatric waiting times. The case demonstrates the feasibility of using normothermic regional perfusion in the donor and ex situ heart perfusion during graft transportation. This combination allowed a functional assessment whilst minimizing warm ischaemia resulting in a successful outcome. More research and long-term follow-up are needed in order to benefit from the huge potential that paediatric DCD heart transplantation has to offer.