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.

Diagnosis and Treatment of Spontaneous Intracranial Hypotension: Role of Epidural Blood Patching.

Purpose of Review: This review focuses on the challenges of diagnosing and treating spontaneous intracranial hypotension (SIH), a condition caused by spinal CSF leakage. It emphasizes the need for increased awareness and advocates for early and thoughtful use of empirical epidural blood patches (EBPs) in suspected cases. Recent Findings: SIH diagnosis is hindered by variable symptoms and inconsistent imaging results, including normal brain MRI and unreliable spinal opening pressures. It is crucial to consider SIH in differential diagnoses, especially in patients with connective tissue disorders. Early EBP intervention is shown to improve outcomes. Summary: SIH remains underdiagnosed and undertreated, requiring heightened awareness and understanding. This review promotes proactive EBP use in managing suspected SIH and calls for continued research to advance diagnostic and treatment methods, emphasizing the need for innovative imaging techniques for accurate diagnosis and timely intervention.

The Pseudotumor Cerebri Syndrome.

Pseudotumor cerebri syndrome is a syndrome of increased cerebrospinal fluid pressure without ventriculomegaly, mass lesion, or meningeal abnormality. It is either primary (idiopathic intracranial hypertension, IIH) or secondary. A secondary cause is unlikely when adhering to the diagnostic criteria. Permanent visual loss occurs if undetected or untreated, and the associated headaches may be debilitating. Fulminant disease may result in blindness despite aggressive treatment. This study addresses the diagnosis and management of IIH including new insights into the pathobiology of IIH, updates in therapeutics and causes of overdiagnosis.

Approach to the Patient With Headache.

OBJECTIVE: The evaluation of patients with headache relies heavily on the history. This article reviews key questions for diagnosing primary and secondary headache disorders with a rationale for each and phrasing to optimize the information obtained and the patient's experience. LATEST DEVELOPMENTS: The availability of online resources for clinicians and patients continues to increase, including sites that use artificial intelligence to generate a diagnosis and report based on patient responses online. Patient-friendly headache apps include calendars that help track treatment response, identify triggers, and provide educational information. ESSENTIAL POINTS: A structured approach to taking the history, incorporating online resources and other technologies when needed, facilitates making an accurate diagnosis and often eliminates the need for unnecessary testing. A detailed yet empathetic approach incorporating interpersonal skills enhances relationship building and trust, both of which are integral to successful treatment.

Quality of Life in Patients With Confirmed and Suspected Spinal CSF Leaks.

BACKGROUND AND OBJECTIVES: Spontaneous intracranial hypotension (SIH) is a debilitating condition typically producing orthostatic headache limiting upright time. SIH is often difficult to diagnose and treat, negatively affecting quality of life (QoL) in patients with the disorder. We studied QoL in patients with confirmed and suspected SIH using standardized instruments, including suicidality. METHODS: We performed a cross-sectional survey of adult patients with confirmed and clinically suspected SIH evaluated in our Headache and Facial Pain Program from 2016 to 2022. Using an online data collection tool (REDCap V 11.2.2), participants completed validated questionnaires assessing general well-being (SF-36), depression (PHQ-9), generalized anxiety disorder-7 (GAD-7), spiritual well-being during chronic illness therapy (FACIT-Sp-12), and headache impact (HIT-6). Subsequently, we interviewed willing participants to administer the Columbia-Suicide Severity Rating Scale (C-SSRS) assessing suicidal behavior and ideation. RESULTS: A total of 234 patients met inclusion criteria and were invited to participate in the study, and 95 patients (59 confirmed and 36 clinically suspected) completed the questionnaires. The average age of the cohort was 51.1 years (SD: 15.5), predominantly female (69.5%), White (91.6%), and married (69.5%). Three-quarters (74.5%) scored within the most severe headache category (HIT-6). SF-36 scores were significantly inferior (p < 0.0001) to the general population and lower than reported values for patients with multiple sclerosis and idiopathic intracranial hypertension. Almost half (49.1%) of respondents scored in the moderate depression range or worse (>10), and 25.4% scored with moderate anxiety or worse (>10). FACIT-Sp-12 scores were significantly worse (p < 0.0001) in symptomatic participants than in the validation cohorts of patients with AIDS and cancer. Of the 67 respondents who completed the C-SSRS, more than half (64.2%) endorsed a wish to be dead, and 22.4% had demonstrated suicidal behavior. Patients with symptom-free SIH (n = 22) scored significantly better than symptomatic patients, comparable with the general population. DISCUSSION: Based on our single-center cohort, SIH is associated with severe headache pain and high rates of depression, anxiety, and disability, affecting basic activities of daily living. Individuals with confirmed and suspected spinal CSF leaks scored similarly on these measures including suicidality. Outcomes were comparable with the general population after successful treatment or spontaneous remission. Improved identification and treatment of SIH are imperative to improve patients' QoL.

Improving to Four or Fewer Monthly Headache Days Per Month Provides a Clinically Meaningful Therapeutic Target for Patients with Chronic Migraine.

INTRODUCTION: Treatment target goals for patients receiving preventive migraine treatment are complicated to assess and not achieved by most patients. A headache "number" could establish an understandable treatment target goal for patients with chronic migraine (CM). This study investigates the clinical impact of reduced headache frequency to ≤ 4 monthly headache days (MHDs) as a treatment-related migraine prevention target goal. METHODS: All treatment arms were pooled for analysis from the PROMISE-2 trial evaluating eptinezumab for the preventive treatment of CM. Patients (N = 1072) received eptinezumab 100 mg, 300 mg, or placebo. Data for the 6-item Headache Impact Test (HIT-6), Patient Global Impression of Change (PGIC), and acute medication use days were combined for all post-baseline assessments and analyzed by MHD frequency (≤ 4, 5-9, 10-15, > 15) in the 4 weeks preceding assessment. RESULTS: Based on pooled data, the percentage of patient-months with ≤ 4 MHDs associated with "very much improved" PGIC was 40.9% (515/1258) versus 22.9% (324/1415), 10.4% (158/1517), and 3.2% (62/1936) of patient-months with 5-9, 10-15, and > 15 MHDs, respectively. Rates of patient-months with ≥ 10 days of acute medication use were 1.9% (21/1111, ≤ 4 MHDs), 4.9% (63/1267, 5-9 MHDs), 49.5% (670/1351, 10-15 MHDs), and 74.1% (1232/1662, > 15 MHDs). Of patient-months with ≤ 4 MHDs, 37.1% (308/830) were associated with "little to none" HIT-6 impairment versus 19.9% (187/940), 10.1% (101/999), and 3.7% (49/1311) of patient-months with 5-9, 10-15, and > 15 MHDs, respectively. CONCLUSION: Participants improving to ≤ 4 MHDs reported less acute medication use and improved patient-reported outcomes, suggesting that 4 MHDs may be a useful patient-centric treatment target when treating CM. TRIAL REGISTRATION: ClinicalTrials.gov (Identifier: NCT02974153) ( https://clinicaltrials.gov/ct2/show/NCT02974153 ).

The impact of resilience on headache disability as measured by the Migraine Disability Assessment (MIDAS).

OBJECTIVE: Our objectives were to examine cross-sectional correlations of headache disability with measures of resilience, anxiety, and depression, and to determine if resilience modified the association between headache severity/frequency and disability. BACKGROUND: Resilience is associated with quality of life and functioning among patients with chronic conditions. We investigated whether resilience strongly mitigates headache-related disability as measured by the Migraine Disability Assessment (MIDAS). METHODS: We prospectively recruited 160 patients with primary headache disorders seen in a tertiary headache medicine program between February 20, 2018 and August 2, 2019. Each participant completed the MIDAS, Conner Davidson Resilience Scale (CDRS-25), Patient Health Questionnaire-9 (PHQ-9), Generalized Anxiety Disorder-7 (GAD-7), and WHO-5 Well-Being Index. RESULTS: The CDRS-25 score was negatively correlated with the total MIDAS (r = -0.21, p = 0.009), GAD-7 (r = -0.56, p < 0.001), and PHQ-9 scores (r = -0.34, p < 0.001). Well-being inversely correlated with disability (r = -0.37, p < 0.001). Increases in anxiety and depression increased the odds of disability. A 1 point increase in the CDRS-25 score decreased the odds of being severely disabled by 4% (OR = 0.96, 95% CI: 0.94 to 0.99, p = 0.001). However, the CDRS-25 score did not significantly moderate the association between headache days and disability. CONCLUSION: Traits associated with resilience decreased the odds of severe disability from headaches, whereas anxiety, depression, and headache frequency were strongly associated with higher disability from headache.

Brachial Artery Vasospasm From Sequential Use of Intravenous Promethazine and Dihydroergotamine for Treatment of Status Migrainosus: A Case Report.

Promethazine, a common antiemetic, can cause severe tissue injury with intravenous (IV) injection. Dihydroergotamine (DHE), commonly used for the acute treatment of migraine, can cause arterial vasoconstriction. We report a rare complication of brachial artery vasospasm in a patient receiving IV promethazine and DHE sequentially through the same midline IV catheter. A 40-year-old woman with history of migraine headaches and Raynaud phenomenon was admitted for treatment of status migrainosus with scheduled IV DHE infusions. While receiving the DHE infusions, IV promethazine was added to the patient's regimen to treat nausea. During an infusion of DHE, the patient developed acute pain near the catheter insertion site due to active extravasation of IV DHE. An arterial Doppler ultrasound demonstrated stenosis in the right brachial artery near the region of infusion. The patient ultimately required balloon angioplasty and intra-arterial injection of nitroglycerin to restore adequate blood flow. We hypothesize that caustic injury to the right brachial vein from IV promethazine predisposed the patient to the extravasation of DHE, which, in turn, caused adjacent brachial artery vasospasm. This case suggests the need for careful consideration, if not strict avoidance, of the use of concurrent IV promethazine and DHE.

The Safety of Celecoxib as an Acute Treatment for Migraine: A Narrative Review.

INTRODUCTION: Nonsteroidal anti-inflammatory drugs (NSAIDs) have been the first-line choice for the acute treatment of migraine attacks for decades; however, the safety of a particular NSAID is related to its treatment dose, duration, and mechanism of action. Although adverse event (AE) risks differ substantially among individual migraine treatments, increased or prolonged exposure to any NSAID elevates risks and severity of AEs. METHODS: For this narrative review, we conducted a literature search of PubMed until July 2022, focusing on the history, mechanism of action, and treatment guidelines informing the safety and efficacy of celecoxib oral solution for the acute treatment of migraine attacks. RESULTS: Here we discuss the mechanisms of action of nonselective NSAIDs vs. cyclooxygenase-2 (COX-2) inhibitors, and how these mechanisms underlie the AEs associated with these treatments. We review the clinical trials that influenced the regulatory history of NSAIDs, specifically COX-2 inhibitors, the role of traditional and new formulations of NSAIDs including celecoxib oral solution, and special considerations in the acute treatment of migraine attacks. CONCLUSIONS: Low-dose formulations of NSAIDs, such as celecoxib oral solution, provide acute migraine analgesia with similar or fewer associated cardiovascular and gastrointestinal events than previous formulations.

Unexpected Etiology in a Case of Bilateral Maculopathy.

A 74-year-old woman with a history of rheumatoid arthritis using hydroxychloroquine presented with gradually progressive decreased vision in both eyes and was found to have a bilateral maculopathy. Initial genetic testing was negative, and after discussing the low likelihood of her severe findings being secondary to her relatively low hydroxychloroquine exposure, the possibility of an autoimmune retinopathy was entertained. Updated data on the genetic testing reclassified one of her mutations in HGSNAT as pathogenic. This case highlights the value of genetic testing and the need to keep a high index of suspicion even after initial negative results, given the fact that our knowledge of mutations leading to retinal degeneration is constantly evolving.

Long term safety, tolerability, and efficacy of intracutaneous zolmitriptan (M207) in the acute treatment of migraine.

OBJECTIVE: To determine the long-term safety and tolerability profile of M207 in the acute treatment of migraine. BACKGROUND: M207 is an investigational microneedle-based system for intracutaneous delivery of zolmitriptan for the treatment of migraine attacks. Following on the positive results of a Phase 2/3 placebo-controlled efficacy study (ZOTRIP), this study was designed to evaluate the safety of this novel product during repeated use for the treatment of migraine attacks. METHODS: In this 6-12 month open-label, multicenter observational study, participants used an eDiary to record headache symptoms and adverse events at specified intervals up to 48 h following treatment of a qualifying attack with M207 3.8 mg (intracutaneous zolmitriptan). Participants underwent clinical evaluations at specified intervals up to 12 months. RESULTS: Among 335 participants who treated ≥1 migraine attack, 257 completed 6 months and 127 completed 1 year of treatment. The most common reason for withdrawal from the study was a low frequency of reported attacks post randomization. Overall, 5963 migraine attacks were treated. Most participants (96%) experienced at least 1 adverse event, the vast majority of which concerned the application site, and > 95% of which were mild. Fifteen participants (4%) withdrew due to adverse events; 4 withdrew due to 7 application site reactions, 6 of which were mild. Participants achieved pain freedom in 2477/5617 (44%) of attacks, most bothersome symptom freedom in 3315/5330 (62%) of attacks, and pain relief 2 h post-dose in 4552/5617 (81%) of attacks. Sustained pain freedom 2-24 h was seen in 1761/4698 (38%) of attacks, and 2-48 h in 1534/4429 (35%) of attacks. CONCLUSIONS: The majority of participants experienced cutaneous adverse reactions such as application site erythema, swelling, and bleeding, and most reactions were scored as mild. These results are consistent with what was observed in the single migraine attack treatment ZOTRIP trial indicating that M207 is well tolerated in the setting of longer-term repeated use. Efficacy findings were also similar to those in the ZOTRIP trial. TRIAL REGISTRATION: Clinicaltrials.gov on September 13, 2017 ( NCT03282227 ).

Lasmiditan efficacy in migraine attacks with mild vs. moderate or severe pain.

OBJECTIVE: To evaluate the efficacy of lasmiditan (LTN) in treating migraine attacks of mild vs. moderate or severe pain intensity. METHODS: Pooled data from two single-attack, placebo-controlled studies (SAMURAI [NCT02439320] and SPARTAN [NCT02605174]), and a prospective, randomized, open-label study (GLADIATOR [NCT02565186]) were assessed. Efficacy measures included the proportion of attacks with 2-h pain freedom (PF), 2-h most bothersome symptom (MBS) freedom, and 24-h sustained pain freedom (SPF). Fisher's exact test was used to compare the proportion of PF, SPF, or MBS freedom outcomes among attacks treated at mild, moderate, or severe pain. RESULTS: In SAMURAI and SPARTAN, most treated attacks were of moderate (N = 2768) or severe (N = 1147) intensity, compared to mild (N = 65). Numerically greater 2-h PF and 24-h SPF response rates were observed in attacks treated at mild compared to moderate or severe pain. Analysis of GLADIATOR data included 273 (1.5%), 11,644 (65.1%), and 5948 (33.3%) attacks treated when pain was mild, moderate, and severe, respectively. In general, a significantly greater proportion of attacks treated at mild pain achieved 2-h PF and MBS freedom, as well as 24-h SPF. The incidence of treatment-emergent adverse events in LTN treatment groups were similar regardless of baseline head pain intensity. CONCLUSIONS: Data from two placebo-controlled, single-attack trials, and an open-label study including treatment of multiple attacks, suggested a tendency to relatively better efficacy outcomes when LTN treatment was initiated at mild vs. moderate to severe pain. Further research is needed to better understand the relationship of lasmiditan outcomes to the time of administration in the course of a migraine attack.

Trochleaectomy: An Effective Treatment of Trochlear Pain in Monocular Patients.

BACKGROUND: Conventional treatment options for trochlear pain arising from trochleitis or primary trochlear headache include oral anti-inflammatory medications and/or local injection of corticosteroids and local anesthetic. Trochleaectomy is an additional option to consider for monocular patients with intractable trochlear pain. METHODS: We report 3 patients undergoing trochleaectomy for refractory trochlear pain syndromes. RESULTS: Trochleaectomy resulted in resolution of their periocular discomfort. CONCLUSIONS: Trochleaectomy is an effective procedure to treat trochlear pain syndrome in functionally monocular patients.

Galcanezumab for the prevention of migraine.

Migraine is a common and disabling disorder affecting approximately 1.02 billion people worldwide. Calcitonin gene-related peptide (CGRP) has been identified as playing an important role in the pathophysiology of migraine and several migraine-specific therapies targeting the CGRP ligand or its receptor have been approved since 2018 for the acute and preventive treatment of migraine. This review focuses on the pharmacology, clinical efficacy and safety/tolerability of galcanezumab, an anti-CGRP monoclonal antibody approved for the prevention of migraine.

Fremanezumab: a disease-specific option for the preventive treatment of migraine, including difficult-to-treat migraine.

Fremanezumab is a fully humanized monoclonal antibody (IgG2Δa) that targets calcitonin gene-related peptide (CGRP), a key neuropeptide involved in the pathophysiology of migraine. Fremanezumab is approved for quarterly and monthly subcutaneous dosing for the preventive treatment of migraine in adults. The phase 3 clinical development program for fremanezumab aimed to evaluate the efficacy of this preventive treatment across different patient populations, including those with difficult-to-treat migraine. Two pivotal 12-week, phase 3, placebo-controlled studies investigated quarterly and monthly dosing of fremanezumab in participants with chronic migraine (HALO CM) and episodic migraine (HALO EM). The efficacy of fremanezumab was further explored in individuals with difficult-to-treat chronic or episodic migraine in the 12-week FOCUS study, which enrolled participants who had previously experienced an inadequate response to 2-4 pharmacological classes of migraine preventive medications. The long-term efficacy of fremanezumab was assessed in a 12-month long-term study (HALO LTS), which enrolled participants completing the 12-week HALO studies and new participants. Across these studies, treatment with fremanezumab dosed quarterly or monthly provided significant reductions in the frequency of migraine days, headache days of at least moderate severity, and migraine- and headache-related disability compared with placebo. Sustained improvements were seen with long-term fremanezumab treatment. Subgroup analyses of participants with difficult-to-treat migraine (those with comorbid depression, overuse of acute headache medications, and concomitant use of other migraine preventive medications) demonstrated the effectiveness of quarterly or monthly fremanezumab in these populations. Ongoing studies are further exploring the potential benefits of fremanezumab in difficult-to-treat migraine and other headache and pain disorders.

The state of the headache fellowship application process and attitudes toward the match.

OBJECTIVE: To examine the current headache medicine fellowship application process and to propose recommendations for a more unified, systematic, and transparent process. METHODS: We identified 42 headache fellowship programs using the United Council for Neurologic Subspecialties certification database. After an initial contact via e-mail, we conducted individual telephone interviews with program directors. Qualitative data coding allowed identification of emerging themes. Quantitative data were summarized with descriptive statistics. RESULTS: Forty (95%) program directors (34 adult, 6 pediatric) responded. Emerging themes included the following. (1) There are benefits and disadvantages to having a match. (2) If the match were reinstated, programs would participate only if all programs participated. (3) There should be consequences for programs that do not participate. If the match were reinstated, 37.5% of program directors responded that their program would participate without conditions; 37.5% would participate only if every program were required to participate. Fifteen percent would not participate, and 10% were not sure if they would participate. Forty percent supported sanctions against programs that did not participate in the match. CONCLUSION: The fellowship match potentially makes the process more systematic for both programs and applicants; however, it does not currently appear to be a feasible option for the field of headache medicine. Until the number of applicants exceeds the number of programs, we recommend instituting a universal timeline for applications and offers.