Evaluation of vascular risk in patients with migraine with and without aura treated with erenumab: Post hoc analysis of pooled long-term clinical trial data.

OBJECTIVE: To assess cardiovascular (CV) safety of erenumab in clinical trial patients associated with degree of CV risk. BACKGROUND: Hypertension has been considered a theoretical risk associated with the inhibition of the calcitonin gene-related peptide pathway in migraine management, particularly in a patient population with pre-existing CV risk factors. METHODS: Data pooled from four double-blind, randomized trials were used to assess blood pressure (BP) changes and CV safety in patients grouped based on 10-year risk of cardiac, cerebrovascular, and peripheral artery disease as no-risk-factors, low-risk (>0% to ≤10%), moderate-risk (>10% to ≤20%), and high-risk (>20%) categories. CV safety was assessed as ischemic cardiovascular and cerebrovascular adverse events (ICCAE). RESULTS: There was no apparent difference between placebo- (N = 1032) and erenumab-treatment groups (70 mg, N = 885; 140 mg, N = 504) in clinical worsening of BP category from baseline to Months 1-3 (14% [143/1032] placebo vs. 13% [114/885] and 14% [71/504] for erenumab 70 and 140 mg, respectively) regardless of baseline BP category. The adverse event (AE) profile of erenumab was similar across CV risk categories throughout the long-term analysis. Erenumab-treated patients with high and moderate 10-year CV risk (N = 107) did not experience any ICCAEs during the double-blind treatment period; there was a single ICCAE (a cerebral dural venous sinus thrombosis) observed in the low-risk erenumab group (N = 273). There were no increases in AEs during the long-term extensions of up to 5 years (N = 2499; 3482 patient-years of exposure to erenumab) with exposure-adjusted incidence rates of cardio/cerebrovascular disorder AEs of 0.4, 0.5, 0.0, and 1.1 (per 100 patient-years) for no risk factor (N = 1805), low (N = 492), moderate (N = 121), and high (N = 81) 10-year CV risk groups, respectively. CONCLUSIONS: Ischemic CV and cerebrovascular AEs were uncommon and the incidence rates were similar across the 10-year CV risk categories. This analysis helps provide more detail on the CV safety of erenumab.

Raynaud's phenomenon associated with calcitonin gene-related peptide receptor antagonists case report.

BACKGROUND: Calcitonin gene-related peptide (CGRP) is a potent vasodilator that regulates the cerebrovascular and peripheral circulation. A new class of migraine therapies decreases CGRP through various mechanisms. One unknown off-target effect is the impact decreasing CGRP will have on the peripheral circulation. The following cases report new onset Raynaud's phenomenon (RP) following the use of CGRP receptor antagonists (-gepants) for both the acute and preventive treatment of migraine. These cases describe the development of RP in two individuals after using each of the currently available gepant medications. To our knowledge these are the first cases reported of RP associated with the use of gepants. RP has previously been reported in association with monoclonal antibodies to the CGRP ligand and CGRP receptor indicated in the prevention of migraine. CASE PRESENTATION: One case involved oral CGRP receptor antagonists for acute treatment inducing RP. In this case, rimegepant and ubrogepant used separately for different migraine attacks each led to RP in the digits. The other case involved oral CGRP receptor antagonist, atogepant, used as a preventive treatment and induced RP in the digits. This patient had a prior history of areolar tissue RP while breastfeeding, but never in her fingers. In both cases, the offending medications were discontinued, and the patients reported no further episodes of RP. CONCLUSION: Two cases are reported of people with migraine with new onset digital RP while taking CGRP receptor antagonists (rimegepant, ubrogepant, atogepant) for acute and preventive treatment.

Dermatologic Symptoms and Syndromes Associated with Headache.

PURPOSE OF REVIEW: Headache disorders are often accompanied by associated symptoms involving organ systems other than the central and peripheral nervous system, including the integumentary, cardiovascular, and musculoskeletal system. However, skin changes or conditions are not commonly associated with headache disorders. Recognition of possible etiologies of headache in patients with bruising, rash, or neurocutaneous disorders can help guide workup and management. The purpose of this article is to review the various dermatologic presentations associated with headache. RECENT FINDINGS: Multiple review articles and retrospective studies have noted the association between head pain with dermatologic changes including ecchymoses, inflammatory skin conditions, and neurocutaneous disorders. Postulated mechanisms include activation of the trigeminal autonomic system and involvement of similar pro-inflammatory molecules. In this review, we discuss three different classes of rashes including ecchymoses, inflammatory skin conditions, and neurocutaneous disorders, all of which have been associated with migraine and/or headache. We discuss the possible underlying pathophysiology and treatment options.

A retrospective evaluation of the combination of erenumab and onabotulinum toxin A for the prevention of chronic migraine.

OBJECTIVE: Prior to the approval of erenumab, onabotulinum toxin A (onabot A) was the only Food and Drug Administration-approved chronic migraine preventive treatment. In this study, we assess the safety and efficacy of the combination of erenumab and onabot A for chronic migraine prevention. METHODS: This is a retrospective cohort study of patients with a diagnosis of chronic migraine receiving onabot A, who were additionally started on erenumab. Primary endpoint was a decrease in number of migraine days while on the combination treatment as compared to onabot A alone. Secondary endpoints included a decrease in headache days and reported side effects. RESULTS: When erenumab was added to onabot A, participants (n = 50) experienced significantly lower number of monthly migraine days (11.3 ± 9.3 vs. 14.9 ± 9.4, p < 0.001). The treatment of onabot A and erenumab also significantly lowered the number of monthly headache days (18.2 ± 10.3 vs. 20.7 ± 9.1, p = 0.042). There were no "severe" adverse effects reported in the combined treatment group. CONCLUSION: This retrospective case series showed a reduction in monthly migraine and headache days with the treatment combination of erenumab and onabot A compared to onabot A alone in patients with chronic migraine.

Erenumab dosage for migraine prevention: An evidence-based narrative review with recommendations.

BACKGROUND: Therapeutic monoclonal antibodies against the calcitonin gene-related peptide (CGRP) receptor or its ligand have changed the landscape of treatment options for migraine. Erenumab is the first and only fully human monoclonal antibody designed to target and block the CGRP receptor. It is approved by the Food and Drug Administration for preventive treatment of migraine in adults. The recommended dose of erenumab is 70 mg monthly, with guidance that some patients may benefit from the 140 mg monthly dose. There is a need for information to guide clinical practice on the comparative efficacy and safety of these two dosing options. OBJECTIVE: To evaluate therapeutic and tolerability differences between erenumab 70 and 140 mg based on evidence from published literature. METHODS: This narrative review evaluates therapeutic and tolerability differences between erenumab 70 and 140 mg based on a literature search using PubMed interface, Embase and Ovid MEDLINE(R) databases. The key search terms included migraine, AMG 334, AMG334, erenumab, erenumab-aooe, and Aimovig. The search was limited to English language articles or conference abstracts published up to May 2021. RESULTS: From the literature search, we retrieved 23 relevant articles/conference abstracts (19 articles [5 randomized, double-blind studies] and 4 conference abstracts) for inclusion in this narrative review. Although the recommended starting dosage of erenumab is 70 mg, this narrative review of the literature indicates that some patients may benefit from a dosage of 140 mg erenumab once monthly-especially those with difficult-to-treat disease and prior treatment failures. The evidence indicates that erenumab at 140 mg has a numerically better efficacy than 70 mg across a broad spectrum of migraine outcomes, including preventing progression to chronic migraine. CONCLUSION: Cumulative data from the literature support a therapeutic gain with an increase from erenumab 70 to 140 mg and a rationale for initiating 140 mg in selected patients.

Indomethacin-Induced Headache: Causing the Problem You Are Trying to Solve.

PURPOSE OF REVIEW: Indomethacin is an important medication in the headache medicine toolbox given its utility for both of the diagnosis and treatment of several primary headache disorders. Despite its prevalence in earlier rheumatologic studies, the possibility of drug-induced headache is a not commonly discussed in headache literature. RECENT FINDINGS: Herein, we describe a case of drug-induced headache after indomethacin trial for the treatment of an undifferentiated trigeminal autonomic cephalgia. Recognition of indomethacin-induced headache has important implications for patient education and interpreting the response to indomethacin when used both as a therapeutic and as a diagnostic tool.

Real-world Experience with Remote Electrical Neuromodulation in the Acute Treatment of Migraine.

OBJECTIVE: Remote electrical neuromodulation (REN) is a nonpharmacological acute migraine treatment that stimulates upper-arm peripheral nerves. The aim of this investigation was to evaluate the effectiveness and safety of REN for acute treatment of migraine in a real-world setting. METHODS: Real-world data were collected from patients who were using REN (Nerivio®, Theranica Bio-Electronics Ltd., Israel) between October 1, 2019, and March 31, 2020. Patients recorded their symptoms at baseline, two hours, and 24 hours post-treatment. Patients were stratified based on the type of visit and provider; in-person visits with headache specialists (HS group) or virtual visits with nonheadache specialists (NHS group). Efficacy outcome focused on intra-individual consistency of response across multiple attacks. RESULTS: We found that 58.9% (662/1,123) of the patients in the HS group and 74.2% (23/31) of the patients in the NHS group experienced pain relief at two hours in at least 50% of their treated attacks and 20.0% (268/1,339) of the patients in the HS group and 35.6% (16/45) of the patients in the NHS group experienced pain freedom at two hours in at least 50% of their treated attacks. The effects of REN on associated symptoms and improvement in function were also consistent in both groups. The incidence of device-related adverse events was very low (0.5%). CONCLUSIONS: Real-world data confirm that REN results in meaningful clinical benefits with minimal side effects. REN may provide an effective drug-free treatment option for achieving consistent relief from migraine symptoms and may reduce the use of acute medications.

Cephalgia Alopecia.

PURPOSE OF REVIEW: In this review, we examine reported cases of cephalgia alopecia including the initial case report from 2006. The goal is to review the clinical description, pathophysiology, diagnosis, and treatment of cephalgia alopecia. RECENT FINDINGS: The pathophysiology of the headache and hair loss in cephalgia alopecia is believed to be related to neuroregulation of skin and nerve. It is hypothesized that the headache causes recurrent activation of trigeminal and upper cervical branches that innervate the hair cells. The repetitive activation of C fibers results in depletion of substance P and calcitonin gene-related peptide (CGRP), which leads to loss of hair growth promotion and disruption of immune system regulation. A case report suggests that cephalgia alopecia and nummular headache with trophic changes may represent a spectrum of disease involving head pain and cutaneous changes. Cephalgia alopecia is a rare headache disorder described as recurrent burning, stabbing head, and neck pain that is followed by hair loss in the corresponding region of the scalp. The mainstay treatment for both pain and hair loss is OnabotulinumtoxinA (onabotA). A patient's clinical history and response to onabotA treatment is used to make the diagnosis. Future research is needed to examine the hypothesized disease continuum of head pain and cutaneous changes. It will also be beneficial to assess if the grid-like onabotA technique used in nummular headache is effective in cephalgia alopecia. In addition, further studies are needed to assess the proposed pathophysiology.

Presentation and Management of Headache in Pituitary Apoplexy.

PURPOSE OF REVIEW: Pituitary apoplexy (PA) occurs in the setting of an infarction and/or hemorrhage of a pre-existing adenoma. The most common presenting symptom is a severe, sudden onset headache. However, the characteristics of headache in the setting of PA are varied and can sometimes mimic primary headache disorders. The purpose of this article is to review the various presentations of headache in PA. We also outline treatment options for persistent headaches following PA. RECENT FINDINGS: A recent retrospective review of patients undergoing transsphenoidal resection of sellar lesions, including PA, found that gross total resection and short duration of preoperative headache were predictors of improvement in headaches postoperatively. This strengthens the importance of timely recognition of PA as potential etiology of headache. The most common presentation of PA is thunderclap headache; however, several other primary HA disorders have been described including status migraine, SUNCT, and paroxysmal hemicrania.

Clinical Presentation and Management of Headache in Pituitary Tumors.

PURPOSE OF REVIEW: This article provides an overview of headache in the setting of pituitary adenoma. The purpose of this article is to educate providers on the association, possible pathophysiology, and the clinical presentation of headache in pituitary tumor. RECENT FINDINGS: Recent prospective evaluations indicate that risk factors for development of headache in the setting of pituitary adenoma include highly proliferative tumors, cavernous sinus invasion, and personal or family history of headache. Migraine-like headaches are the predominant presentation. Unilateral headaches are often ipsilateral to the side of cavernous sinus invasion. In summary, this paper describes how the size and type of pituitary tumors play an important role in causation of headaches. Pituitary adenoma-associated headache can also mimic primary headache disorders making recognition of a secondary process difficult. Therefore, this paper highlights the association of between trigeminal autonomic cephalgias and pituitary adenomas and urges practitioners to maintain a high index of suspicion when evaluating patients with these uncommon headache presentations. However, on balance, given the prevalence of both primary headache disorders and pituitary adenomas, determining causality can be challenging. A thoughtful and multidisciplinary approach is often the best management strategy, and treatment may require the expertise of multiple specialties including neurology, neurosurgery, and endocrinology.

Recognizing CADASIL: a Secondary Cause of Migraine with Aura.

PURPOSE OF REVIEW: CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) is an important disease to consider in the differential diagnosis of migraine with aura. This review examines current literature regarding migraine in CADASIL, as well as diagnostic and treatment modalities. RECENT FINDINGS: Recent studies have shown that smoking is a modifiable risk factor for progression of CADASIL (Chabriat et al. in Stroke 47:4-11, 2015). Specific imaging changes and findings on clinical exam can predict disease progression. However, migraine symptoms often precede MRI changes (Guey et al. in Cephalalgia 36:1038-47, 2015). A recent paper on migraine treatment in CADASIL reevaluates the prevailing belief that vasoconstrictive abortive medications are contraindicated in these patients (Tan and Markus in PLoS ONE 11:e0157613, 2016). CADASIL is an autosomal dominantly inherited vasculopathy causing ischemic pathology in younger individuals due to a mutation in the NOTCH3 gene. The mutation results in impaired arterial contractility due to accumulation of granular osmiophilic extracellular material (GOM) in vascular smooth muscle cells (VSMCs). Clinical manifestations include migraine with and without aura, cognitive decline, ischemic events, and mood disorders. The presenting symptom is often migraine with aura. Characteristic MRI changes are often present. Genetic screening is available to confirm NOTCH3 mutation and pathognomic changes are often seen in skin biopsy. Treatment of migraine is similar to the general population, but with some notable and specific differences. Further studies in CADASIL, other small vessel arteriopathies, and migraine may help us understand more about the pathophysiology of these conditions and help with treatment development.

An Unusual Case of Post-Traumatic Headache Complicated by Intracranial Hypotension.

We present a case of post-traumatic headache complicated by intracranial hypotension resulting in an acquired Chiari malformation and myelopathy with syringomyelia. This constellation of findings suggest a possible series of events that started with a traumatic cerebral spinal fluid (CSF) leak, followed by descent of the cerebellar tonsils and disruption of CSF circulation that caused spinal cord swelling and syrinx. This unusual presentation of post-traumatic headache highlights the varying presentations and the potential sequelae of intracranial hypotension. In addition, the delayed onset of upper motor neuron symptoms along with initially normal head computerized tomography scan (CT) findings, beg the question of whether or not a post-traumatic headache warrants earlier magnetic resonance imaging (MRI).

Neck-Tongue Syndrome.

Neck-tongue syndrome (NTS) is a headache disorder often initiated by rapid axial rotation of the neck resulting in unilateral neck and/or occipital pain and transient ipsilateral tongue sensory disturbance. In this review, we examine reported cases of NTS since its initial description in 1980 to highlight the significance of this condition in the differential diagnosis of headache in patients presenting with neck pain and altered tongue sensation. The anatomical basis of NTS centers on the C1-C2 facet joint, C2 ventral ramus, and inferior oblique muscle in the atlanto-axial space. NTS may be categorized as complicated (secondary to another disease process) or uncomplicated (hereditary, related to trauma, or idiopathic). Diagnosis is based on clinical suspicion after a thorough history and physical without a pathognomonic radiologic finding. It is typically treated conservatively with medications, local injections, immobilization with cervical collars, or physical therapy; rarely is surgical intervention pursued.

Cardiac cephalgia.

"Cardiac cephalgia" is a type of secondary headache disorder, usually initiated by exertion that is related to myocardial ischemia. Primary exertional headaches such as sex-, cough-, or exercise-induced headaches are typically benign. Cardiac cephalgia, on the other hand, can have life-threatening complications. Due to overlapping features and similarities in presentation, cardiac cephalgia can be misdiagnosed as a primary headache disorder such as migraine. However, the management of these conditions is unique, and treatment of cardiac cephalgia with vasoconstrictors intended for migraine can potentially worsen myocardial ischemia. Thus, it is important to make the correct diagnosis by evaluating cardiac function with an electrocardiogram and/or stress testing. In this review, we examine reported cases of cardiac cephalgia from the past 5 years to highlight the importance of this condition in the differential diagnosis of a headache in a patient with a history of cardiovascular risk factors, as well as to discuss the appropriate approach to diagnosis and the proposed pathogenic mechanisms of this condition.

Providing Care for Patients with Chronic Migraine: Diagnosis, Treatment, and Management.

Chronic migraine, a subtype of migraine defined as ≥ 15 headache days per month for ≥ 3 months, in which ≥ 8 days per month meet criteria for migraine with or without aura or respond to migraine-specific treatment, is a disabling, underdiagnosed, and undertreated disorder associated with significant disability, poor health-related quality of life, and high economic burden. The keys to caring for chronic migraine patients include: (1) making a proper diagnosis; (2) identifying and eliminating exacerbating factors; (3) assessing for medication overuse (patients with chronic headache often overuse acute medications); and (4) continued management. Communication between patient and physician about treatment goals is important. The patient management guidelines presented in this article should help physicians improve treatment success and proactively address common comorbidities among their patients with chronic migraine.

Occipital neuralgia.

Occipital pain is a common complaint amongst patients with headache, and the differential can include many primary headache disorders such as cervicogenic headache or migraine. Occipital neuralgia is an uncommon cause of occipital pain characterized by paroxysmal lancinating pain in the distribution of the greater, lesser or third occipital nerves. Greater occipital nerve blockade with anesthetics and/or corticosteroids can aid in confirming the diagnosis and providing pain relief. However, nerve blocks are also effective in migraine headache and misdiagnosis can result in a false positive. Physical therapy and preventive medication with antiepileptics and tricyclic antidepressants are often effective treatments for occipital neuralgia. Refractory cases may require intervention with pulsed radiofrequency or occipital nerve stimulation.