Nonspecific oral medications versus anti-calcitonin gene-related peptide monoclonal antibodies for migraine: A systematic review and meta-analysis of randomized controlled trials.

OBJECTIVE: To compare calcitonin gene-related peptide monoclonal antibodies (CGRP mAbs) versus nonspecific oral migraine preventives (NOEPs). BACKGROUND: Insurers mandate step therapy with NOEPs before approving CGRP mAbs. METHODS: Databases were searched for class I or II randomized controlled trials (RCTs) comparing CGRP mAbs or NOEPs versus placebo for migraine prevention in adults. The primary outcome measure was monthly migraine days (MMD) or moderate to severe headache days. RESULTS: Twelve RCTs for CGRP mAbs, 5 RCTs for topiramate, and 3 RCTs for divalproex were included in the meta-analysis. There was high certainty that CGRP mAbs are more effective than placebo, with weighted mean difference (WMD; 95% confidence interval) of -1.64 (-1.99 to -1.28) MMD, which is compatible with small effect size (Cohen's d -0.25 [-0.34 to -0.16]). Certainty of evidence that topiramate or divalproex is more effective than placebo was very low and low, respectively (WMD -1.45 [-1.52 to -1.38] and -1.65 [-2.30 to -1.00], respectively; Cohen's d -1.25 [-2.47 to -0.03] and -0.48 [-0.67 to -0.29], respectively). Trial sequential analysis showed that information size was adequate and that CGRP mAbs had clear benefit versus placebo. Network meta-analysis showed no statistically significant difference between CGRP mAbs and topiramate (WMD -0.19 [-0.56 to 0.17]) or divalproex (0.01 [-0.73 to 0.75]). No significant difference was seen between topiramate or divalproex (0.21 [-0.45 to 0.86]). CONCLUSIONS: There is high certainty that CGRP mAbs are more effective than placebo, but the effect size is small. When feasible, CGRP mAbs may be prescribed as first-line preventives; topiramate or divalproex could be as effective but are less well tolerated. The findings of this study support the recently published 2024 position of the American Headache Society on the use of CGRP mAbs as the first-line treatment.

Real-world approaches to outpatient treatment of status migrainosus: A survey study.

OBJECTIVES: Identify how the American Headache Society (AHS) membership manages status migrainosus (SM) among outpatients. BACKGROUND: SM is defined as a debilitating migraine attack lasting more than 72 h. There is no standard of care for SM, including whether a 72-h duration is required before the attack can be treated as SM. METHODS: The Refractory Headache Special Interest Group from AHS developed a four-question survey distributed to AHS members enquiring (1) whether they treat severe refractory migraine attacks the same as SM regardless of duration, (2) what their first step in SM management is, (3) what the top three medications they use for SM are, and (4) whether they are United Council for Neurologic Subspecialties (UCNS) certified. The survey was conducted in January 2022. Descriptive statistical analyses were performed. RESULTS: Responses were received from 196 of 1859 (10.5%) AHS members; 64.3% were UCNS certified in headache management. Respondents treated 69.4% (136/196) of patients with a severe refractory migraine attack as SM before the 72-h period had elapsed. Most (76.0%, 149/196) chose "treat remotely using outpatient medications at home" as the first step, 11.2% (22/196) preferred procedures, 6.1% (12/196) favored an infusion center, 6.1% (12/196) sent patients to the emergency department (ED) or urgent care, and 0.5% (1/196) preferred direct hospital admission. The top five preferred medications were as follows: (1) corticosteroids (71.4%, 140/196), (2) nonsteroidal anti-inflammatory drugs (NSAIDs) (50.1%, 99/196), (3) neuroleptics (46.9%, 92/196), (4) triptans (30.6%, 60/196), and (5) dihydroergotamine (DHE) (21.4%, 42/196). CONCLUSIONS: Healthcare professionals with expertise in headache medicine typically treated severe migraine attacks early and did not wait 72 h to fulfill the diagnostic criteria for SM. Outpatient management with one or more medications for home use was preferred by most respondents; few opted for ED referrals. Finally, corticosteroids, NSAIDs, neuroleptics, triptans, and DHE were the top five preferred treatments for home SM management.

The 2023 protocol for update to acute treatment of adults with migraine in the emergency department: The American Headache Society evidence assessment of parenteral pharmacotherapies.

OBJECTIVES: The primary objective of this proposed guideline is to update the prior 2016 guideline on parenteral pharmacotherapies for the management of adults with a migraine attack in the emergency department (ED). METHODS: We will conduct an updated systematic review and meta-analysis using the 2016 guideline methodology to provide clinical recommendations. The same search strategy will be used for studies up to 2023, with a new search strategy added to capture studies of nerve blocks and sphenopalatine blocks. Medline, Embase, Cochrane, clinicaltrials.gov, and the World Health Organization International Clinical Trial Registry Platform will be searched. Our inclusion criteria consist of studies involving adults with a diagnosis of migraine, utilizing medications administered intravenously, intramuscularly, or subcutaneously in a randomized controlled trial design. Two authors will perform the selection of studies based on title and abstract, followed by a full-text review. A third author will intervene in cases of disagreements. Data will be recorded in a standardized worksheet and subjected to verification. The risk of bias will be assessed using the American Academy of Neurology tool. When applicable, a meta-analysis will be conducted. The efficacy of medications will be evaluated, categorizing them as "highly likely," "likely", or "possibly effective" or "ineffective." Subsequently, clinical recommendations will be developed, considering the risk associated with the medications, following the American Academy of Neurology recommendation development process. RESULTS: The goal of this updated guideline will be to provide guidance on which injectable medications, including interventional approaches (i.e., nerve blocks, sphenopalatine ganglion), should be considered effective acute treatment for adults with migraine who present to an ED. CONCLUSIONS: The methods outlined in this protocol will be used in the design of a future systematic review and meta-analysis-informed guideline, which will then be assessed by and submitted for endorsement by the American Headache Society.

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).

Telemedicine in Headache Medicine: A Narrative Review.

PURPOSE OF REVIEW: The purpose of the study is to review and discuss the use of telemedicine in headache medicine. RECENT FINDINGS: Before the COVID-19 pandemic, the use of telemedicine for headache was most common in Europe. In recent years, however, telemedicine has been used broadly within headache medicine, including for pediatric patients and behavioral interventions. Several randomized clinical trials have shown that telemedicine is non-inferior to face-to-face visits. Multiple studies have reported substantial benefits associated with telemedicine, including high satisfaction rates, improved access to headache specialists, reduced travel, quicker visits, greater cost-effectiveness, reduced wait times, reduced no-show rates, and the increased comfort of remaining in one's home environment. The main limitation reported is the lack of a physical examination, including fundus assessment. Telemedicine has become a vital tool in headache patient care, with the data supporting its use for patient follow-up in particular.

Cardiovascular Disease and Migraine: Are the New Treatments Safe?

PURPOSE OF REVIEW: The authors present data on cardiovascular safety for the new acute and preventive migraine treatments including ditans, gepants, and calcitonin gene-related peptide monoclonal antibodies (CGRP mAbs) alongside older medications like triptans and ergotamines. RECENT FINDINGS: The authors conclude that there are no cardiovascular safety concerns for lasmiditan, and that it could be used in those with cardiovascular disease. In fact, the literature even suggests that triptans are safer in cardiovascular disease than their contraindications may suggest. At this time, there is insufficient evidence that gepants and CGRP mAbs should be contraindicated in those with cardiovascular disease including stroke or myocardial infarction, though erenumab has now been associated with hypertension. Vasodilation may be an important CGRP-mediated mechanism mid-ischemia especially in patients with small vessel disease; hence, CGRP antagonists should be use with caution in this context. Long-term data is still needed, and prescribers should ensure patients are aware of the limitations of our knowledge at this time, while still offering these effective and well-tolerated treatment options.

A pain in the ear: Two case reports of nervus intermedius neuralgia and narrative review.

OBJECTIVE: Present two cases of nervus intermedius neuralgia (NIN) in which patients described unilateral deep ear pain as their primary complaint and present a summary of NIN cases reported in the literature. BACKGROUND: The nervus intermedius is a tiny branch of the facial nerve that, with neuralgia, can present as a deep ear pain (NIN). The International Classification of Headache Disorders, 3rd edition, (ICHD-3) criteria for an NIN diagnosis include a unilateral deep ear pain with possible radiation that occurs in paroxysms with sharp pain and a tactile trigger. METHODS: A PubMed search was conducted for NIN and geniculate neuralgia. Two patients recently diagnosed with NIN at a single clinic were selected for case reports to highlight the variability of symptom presentation. RESULTS: The two cases reported here and the 127 cases reported in the literature show a wider range of presentations than included in the ICHD-3 criteria, including variable pain radiation sometimes diagnosed as concurrent trigeminal, glossopharyngeal, or occipital neuralgia. Pain was reported as constant or paroxysmal, as well as dull, sharp, or neuralgiform with inconsistent presence of triggers. While ICHD-3 does mention reported taste change, lacrimation, and salivation, the literature reports a much wider range of potential features associated with NIN. Optimal medical treatment is unclear given the predominance of surgical reporting of positive response to microvascular decompression, nerve sectioning, or other procedures. The two cases described here were successfully managed medically. CONCLUSION: NIN can present as described in the ICHD-3, but a more variable presentation may be possible. More studies are needed to clarify presentation, optimal medical treatment, and surgical indications for patients with NIN, especially when patients have no clear neurovascular conflict on neuroimaging.

Debunking Myths: Sinus Headache.

PURPOSE OF REVIEW: Although sinus headache has been extensively reviewed and described, misdiagnosis remains common. This paper discusses the myths and truths about sinus headaches. RECENT FINDINGS: Sinus headache is used colloquially to attribute facial pain to allergies or a sinus infection; however, most sinus headaches are migraine. Sinus-region pain from sinusitis and migraine share the same origins in the trigeminovascular system, but their causes are very different. After reviewing sinus anatomy and sinogenic pain, we provide information to assist clinicians in correctly diagnosing patients with the additional goal of avoiding unnecessary investigations and treatments. Migraine medications can be used as both a treatment and a diagnostic tool. Other differential diagnoses of facial pain are discussed. Sinus headache is not a diagnosis. All patients with facial pain or pressure with sinus symptoms should be evaluated for migraine because most sinus headache presentations are migraine and require migraine-directed treatment.

E-Consultation in Headache Medicine: A Quality Improvement Pilot Study.

INTRODUCTION: Access to headache consultations by a headache specialist is limited. E-consultations are an efficient approach shown to reduce costs and improve continuity of care with the primary care provider. Indications, suitability, and uptake in the headache population are not well studied. METHODS: This quality improvement pilot aims to explore the appropriateness of e-consultations for patients referred to a headache specialist. E-consultation feasibility was explored through (1) retrospective review of completed face-to-face consultations; (2) prospective survey of providers to identify face-to-face consultations appropriate for e-consultation; (3) cross-sectional review of the current waiting list to assess theoretical triaging to face-to-face vs e-consultation; and (4) prospective review of all e-consultations requested from an academic headache clinic to improve the understanding of e-consultation feasibility and referral triage. RESULTS: The retrospective review included 75 face-to-face consultations with a mean (SD) wait time of 33 (39.4) days for consultations, of which 28/75 (37.3%) were deemed to be feasible e-consultations. The prospective survey of providers identified 10 face-to-face consultations that were felt to be theoretically appropriate for e-consultation. The cross-sectional review identified 20 patients on the clinic waiting list, of whom 5/20 (25%) were theoretically triaged to e-consultation. Finally, the prospective review found 12 requested e-consultations, of which 6/12 (50%) were for migraine prophylaxis recommendations. Chart data often lacked details for complete assessments, with 5/12 (41.7%) converted to face-to-face consultations and only 4/12 (33.3%) deemed appropriate for e-consultation. CONCLUSION: E-consultation in headache medicine could be considered if appropriately triaged. Pathways are needed to reach patients earlier in their disease course to ensure headache care meets guideline recommendations, and e-consultation is 1 option. However, better communication with primary care is required for system optimization.

Real-World Patient Experience With Erenumab for the Preventive Treatment of Migraine.

BACKGROUND: Erenumab, a calcitonin gene-related peptide (CGRP) receptor monoclonal antibody, has been well tolerated with good efficacy for the preventive treatment of episodic and chronic migraine in phase 2 and phase 3 clinical trials. Limited post-market observations are available to validate these findings in a real-world tertiary headache clinic population with complex comorbidities and refractory migraine. OBJECTIVE: The goal of this study is to demonstrate the real-world performance of erenumab among patients in a tertiary care headache clinic by describing patient selection, experience, and clinical characteristics after 6 months of erenumab therapy. METHODS: A retrospective, exploratory, observational study was conducted on patients receiving at least 1 erenumab injection (70 or 140 mg). Baseline data obtained by chart review and telephone calls were compared to 6-month follow-up telephone calls. The primary outcome was the reduction in self-reported headache days per month at baseline compared to 6 months for those with complete 6-month data. The significance level was set at P < .05. Secondary analyses explored the distribution of headache severity, responder rates, Migraine Disability Assessment scores, adverse effects, ineffective preventives, comorbidities, wearing-off, and discontinuation. RESULTS: Of the 101 patients who consented to participate, 89.1% (90/101) were women, and the mean age of all patients was 49 years (range, 19-80 years). At baseline, 94.1% (95/101) of patients had chronic migraine, 5.0% (5/101) had episodic migraine, and 18.8% (19/101) had medication overuse headache. The mean (SD) number of baseline headache and migraine days per month for the entire cohort were 24.3 (8.2) and 18.2 (9.3) days, respectively. Participants had numerous comorbidities and had tried a mean of 11.2 unique oral medications and 4.8 unique medication categories before receiving erenumab, including 83.2% (84/101) who had also received onabotulinumtoxinA. Six-month post-erenumab follow-up data were available for 42.6% (43/101) of participants. For these 43 participants, the number of headache days per month decreased significantly by 6.5 days from a baseline mean (SD) of 24.8 (6.47) days to 18.3 (12) days at 6-month follow-up (P < .001); similarly, the monthly migraine days decreased significantly by 8.4 days from a baseline mean of 19.1 (9.3) days to 10.7 days at 6-month follow-up (P < .001). The 50% responder rate was 34.9% (15/43) for monthly headache days and 54.8% (23/43) for monthly migraine days. Of all 101 participants, 28 (27.7%) discontinued erenumab, primarily because it was ineffective (39.3%, 11/28) or because of adverse effects (42.9%, 12/28). CONCLUSION: This post-market observational study of patient experience describes response to erenumab in a real-world tertiary headache clinic with a complex patient population. Overall, these complex patients had a significant positive clinical response to erenumab, but with high rates of discontinuation. This study also noted a 1-week wearing-off response and high rates of constipation. Further post-market studies are needed to better characterize patient selection and real-world response to erenumab.

Ten Eleven Things Not to Say to Healthcare Professionals During the Coronavirus Disease 2019 Pandemic.

On March 11, 2020, the infection caused by the coronavirus disease 2019 (COVID-19) virus was declared a pandemic. Throughout this pandemic, healthcare professionals (HCPs) have experienced difficulties stemming from poor communications, resource scarcity, lack of transparency, disbelief, and threats to the safety of their loved ones, their patients, and themselves. As part of these hardships, negative statements have been heard repeatedly. This paper describes 11 scenarios of unhelpful and dysfunctional messages heard by the authors and their colleagues during the COVID-19 pandemic, reported to us by a combination of peers, administrative leadership, and the public. We explain why not to use such messaging, and we suggest more helpful and compassionate expressions based upon recommendations published by scientific organizations and well-established psychological principles. The first 10 scenarios discussed include (1) lack of understanding regarding the extent of the pandemic; (2) shaming over not seeing patients in person; (3) lack of clear and consistent communication from leadership on pandemic-related practice changes; (4) opinions that personal protective equipment (PPE) use by HCPs causes fear or is unnecessary; (5) forcing in-person care without appropriate PPE; (6) the risk of exposure to asymptomatic individuals as it relates to opening clinics; (7) media gag orders; (8) pay and benefit reductions; (9) spreading of misinformation about the COVID-19 pandemic; and (10) workload expectations. The 11th scenario addresses HCPs' psychological and physical reactions to this challenging and prolonged stressful situation. We close by discussing the need for support and compassion at this difficult and unpredictable time and by offering suggestions to foster resilience and feelings of self-efficacy among HCPs.

Emergency Department and Inpatient Management of Headache in Adults.

PURPOSE OF REVIEW: This article reviews treatment options for patients presenting with headache in the emergency department (ED) and for inpatients, including red flags and status migrainosus (SM). RECENT FINDINGS: Most patients presenting with headache in the ED will have migraine, but red flags must be reviewed to rule out secondary headaches. SM refractory to home treatment is a common reason for ED presentation or inpatient admission, but high-quality treatment evidence is lacking. Common treatments include intravenous fluids, anti-dopaminergic agents with diphenhydramine, steroids, divalproex, nonsteroidal anti-inflammatory drugs, intravenous dihydroergotamine, and nerve blocks. Other therapies (e.g., ketamine and lidocaine) are used with limited or inconsistent evidence. There is evidence for inpatient behavioral management therapy. This article details red flags to review in the workup of headache presentation in the ED and provides a step-wise approach to ED and inpatient management. However, more studies are needed to better optimize care.

Headache in the Older Population: Causes, Diagnoses, and Treatments.

PURPOSE OF REVIEW: Primary headaches are less common and differ in presentation in older versus younger individuals. Secondary headaches become more common among older patients. RECENT FINDINGS: Diagnosis and management of headaches in those > 65 years are discussed. Migraine and tension-type headaches are rarely new onset in this age group and should be a diagnosis of exclusion. In older individuals, migraine is more likely to be bilateral with less sensory sensitivities. Migraine aura may present without headache; careful assessment is needed to exclude stroke. Other primary headaches discussed include cough, hypnic, and other headaches. Secondary causes discussed include giant cell arteritis, trigeminal post-herpetic neuropathy, sleep apnea, cardiac cephalgia, cervicogenic pain, vascular etiologies, medications, and burning-mouth syndrome. In older individuals, primary headaches are diagnoses of exclusion, and treatment is affected by comorbidities and polypharmacy. Secondary headaches are a major consideration requiring appropriate workup. Many treatments can safely be offered regardless of age.

Schizophrenia is a later-onset feature of PCDH19 Girls Clustering Epilepsy.

OBJECTIVE: To investigate the occurrence of psychosis and serious behavioral problems in females with protocadherin 19 gene (PCDH19) pathogenic variants. METHODS: We evaluated whether psychosis and serious behavioral problems had occurred in 60 females (age 2-75 years) with PCDH19 pathogenic variants belonging to 35 families. Patients were identified from epilepsy genetics databases in Australia, New Zealand, the United States, and Canada. Neurologic and psychiatric disorders were diagnosed using standard methods. RESULTS: Eight of 60 females (13%) from 7 families developed a psychotic disorder: schizophrenia (6), schizoaffective disorder (1), or an unspecified psychotic disorder (1). Median age at onset of psychotic symptoms was 21 years (range 11-28 years). In our cohort of 39 females aged 11 years or older, 8 (21%) developed a psychotic disorder. Seven had ongoing seizures at onset of psychosis, with 2 continuing to have seizures when psychosis recurred. Psychotic disorders occurred in the setting of mild (4), moderate (2), or severe (1) intellectual disability, or normal intellect (1). Preexisting behavioral problems occurred in 4 patients, and autism spectrum disorder in 3. Two additional females (3%) had psychotic features with other conditions: an adolescent had recurrent episodes of postictal psychosis, and a 75-year-old woman had major depression with psychotic features. A further 3 adolescents (5%) with moderate to severe intellectual disability had onset of severe behavioral disturbance, or significant worsening. SIGNIFICANCE: We identify that psychotic disorders, including schizophrenia, are a later-onset manifestation of PCDH19 Girls Clustering Epilepsy. Affected girls and women should be carefully monitored for later-onset psychiatric disorders.

A Case of Epidural Lipomatosis in Pregnancy: Management during Labour and Caesarean Section.

BACKGROUND: Spinal epidural lipomatosis (SEL) is a rare condition of adipose tissue accumulation in the epidural space. As a result of excess adipose tissue, neuraxial anaesthesia has been reported to behave unpredictably in patients with this condition. CASE: A 36-year-old woman had worsening postural headaches during pregnancy. MRI revealed SEL involving the thecal sac between L3/L4 and L5/S1. She had induction of labour but ultimately required a CS for delivery. Her anaesthesia was managed with an epidural inserted at L3/4. She developed a high block with relative sacral sparing. CONCLUSION: Although neuraxial anaesthesia was thought to be contraindicated in patients with SEL, it can be done safely. Care must be taken to provide slow epidural titration to avoid high sensory block in patients with this condition.

The value of GRE, ADC and routine MRI in distinguishing Parkinsonian disorders.

OBJECTIVES: To study different radiological signs and sequences including apparent diffusion coefficient (ADC) and gradient echo (GRE) to differentiate degenerative parkinsonian syndromes. BACKGROUND: Multiple system atrophy (MSA), Parkinson's disease (PD), progressive supranuclear palsy (PSP) and corticobasal degeneration (CbD) differ in the pattern of neurodegeneration and cellular damage. Measuring the ADC, GRE sequences for paramagnetic substances and simple anatomical assessments have been reported individually to assist in separating some of these disorders, but have not been compared. METHODS: brain MRIs from May 2002 to February 2008 were retrospectively evaluated by raters blinded to the clinical diagnosis for predefined MRI signs on T1, T2 and GRE sequences. ADC values were quantitatively measured. Medical records were objectively analyzed using standard clinical criteria for different parkinsonian syndromes. RESULTS: 195 cases comprising of 61 PD, 15 MSA-P, 7 MSA-C, 21 PSP, 6 Corticobasal syndrome, 21 not fitting criteria and 64 controls were evaluated. 73% of patients with MSA-P had hypointensity of the putamen (compared to the pallidum) on GRE. The specificity of this sign to diagnose MSA-P was 90% versus PD and 76% versus PSP. When GRE hypointensity was combined with atrophy of the putamen the specificity improved to 98% (versus PD) and 95% (versus PSP) without altering the sensitivity. The ADC values were significantly higher in the middle cerebellar peduncle in cases with MSA-C versus controls, PD and PSP (p<0.001). CONCLUSIONS: The combination of hypointensity and atrophy of the putamen on GRE is useful in differentiating MSA-P from other parkinsonian syndromes.