Remote electrical neuromodulation for migraine prevention: A double-blind, randomized, placebo-controlled clinical trial.

OBJECTIVE: To assess the clinical efficacy of remote electrical neuromodulation (REN), used every other day, for the prevention of migraine. BACKGROUND: Preventive treatment is key to managing migraine, but it is often underutilized. REN, a non-pharmacological acute treatment for migraine, was evaluated as a method of migraine prevention in patients with episodic and chronic migraine. METHODS: We conducted a prospective, randomized, double-blind, placebo-controlled, multi-center trial, with 1:1 ratio. The study consisted of a 4-week baseline observation phase, and an 8-week double-blind intervention phase in which participants used either REN or a placebo stimulation every other day. Throughout the study, participants reported their symptoms daily, via an electronic diary. RESULTS: Two hundred forty-eight participants were randomized (128 active, 120 placebo), of which 179 qualified for the modified intention-to-treat (mITT) analysis (95 active; 84 placebo). REN was superior to placebo in the primary endpoint, change in mean number of migraine days per month from baseline, with mean reduction of 4.0 ± SD of 4.0 days (1.3 ± 4.0 in placebo, therapeutic gain = 2.7 [confidence interval -3.9 to -1.5], p < 0.001). The significance was maintained when analyzing the episodic (-3.2 ± 3.4 vs. -1.0 ± 3.6, p = 0.003) and chronic (-4.7 ± 4.4 vs. -1.6 ± 4.4, p = 0.001) migraine subgroups separately. REN was also superior to placebo in reduction of moderate/severe headache days (3.8 ± 3.9 vs. 2.2 ± 3.6, p = 0.005), reduction of headache days of all severities (4.5 ± 4.1 vs. 1.8 ± 4.6, p < 0.001), percentage of patients achieving 50% reduction in moderate/severe headache days (51.6% [49/95] vs. 35.7% [30/84], p = 0.033), and reduction in days of acute medication intake (3.5 ± 4.1 vs. 1.4 ± 4.3, p = 0.001). Similar results were obtained in the ITT analysis. No serious device-related adverse events were reported in any group. CONCLUSION: Applied every other day, REN is effective and safe for the prevention of migraine.

Migraine diagnosis and treatment: A knowledge and needs assessment of women's healthcare providers.

BACKGROUND: Studies suggest that migraine is often underdiagnosed and inadequately treated in the primary care setting, despite many patients relying on their primary care provider (PCP) to manage their migraine. Many women consider their women's healthcare provider to be their PCP, yet very little is known about migraine knowledge and practice patterns in the women's healthcare setting. OBJECTIVE: The objective of this study was to assess women's healthcare providers' knowledge and needs regarding migraine diagnosis and treatment. METHODS: The comprehensive survey assessing migraine knowledge originally developed for PCPs was used in this study, with the addition of a section regarding the use of hormonal medications in patients impacted by migraine. Surveys were distributed online, and primarily descriptive analyses were performed. RESULTS: The online survey was completed by 115 women's healthcare providers (response rate 28.6%; 115/402), who estimated that they serve as PCPs for approximately one-third of their patients. Results suggest that women's healthcare providers generally recognize the prevalence of migraine, but experience some knowledge gaps regarding migraine management. Despite 82.6% (95/115) of survey respondents feeling very comfortable or somewhat comfortable with diagnosing migraine, only 57.9% (66/114) reported routinely asking patients about headaches during annual visits. Very few were familiar with the American Academy of Neurology guidelines on preventative treatment (6.3%; 7/111) and the Choosing Wisely Campaign recommendations on migraine treatment (17.3%; 19/110), and many prescribed medications known to contribute to medication overuse headache. In addition, only 24.3% (28/115) would order imaging for a new type of headache, 35.7% (41/115) for worsening headache, and 47.8% (55/115) for headache with neurologic symptoms; respondents cited greater tendency with sending patients to an emergency department for the same symptoms. Respondents had limited knowledge of evidence-based, non-pharmacological treatments for migraine (i.e., biofeedback or cognitive behavioral therapy), with nearly none placing referrals for these services. Most providers were comfortable prescribing hormonal contraception (mainly progesterone only) to women with migraine without aura (80.9%; 89/110) and with aura (72.5%; 79/109), and followed American College of Obstetricians and Gynecologists (ACOG) guidelines to limit combination hormonal contraception for patients with aura. When queried, 6.3% or less (5/79) of providers would prescribe estrogen-containing contraception for women with migraine with aura. Only 37.3% (41/110) of respondents reported having headache/migraine education. Providers indicated interest in education pertaining to migraine prevention and treatment (96.3%; 105/109), migraine-associated disability (74.3%; 81/109), and diagnostic testing (59.6%; 65/109). CONCLUSION: Women's healthcare providers appear to have several knowledge gaps regarding the management of migraine in their patients. These providers would likely benefit from access to a headache-specific educational curriculum to improve provider performance and patient outcomes.

Remote Electrical Neuromodulation (REN) Relieves Acute Migraine: A Randomized, Double-Blind, Placebo-Controlled, Multicenter Trial.

OBJECTIVE: To assess the efficacy and safety of a remote electrical neuromodulation (REN) device for the acute treatment of migraine. BACKGROUND: There is a significant unmet need for novel effective well-tolerated acute migraine treatments. REN is a novel acute migraine treatment that stimulates upper arm peripheral nerves to induce conditioned pain modulation - an endogenous analgesic mechanism in which conditioning stimulation inhibits pain in remote body regions. A recent pilot study showed that REN can significantly reduce headache. We have conducted a randomized, double-blind, sham-controlled study to further evaluate the efficacy and safety of REN for the acute treatment of migraine. METHODS: This was a randomized, double-blind, sham-controlled, multicenter study conducted at 7 sites in the United States and 5 sites in Israel. Two hundred and fifty-two adults meeting the International Classification of Headache Disorders criteria for migraine with 2-8 migraine headaches per month were randomized in a 1:1 ratio to active or sham stimulation. A smartphone-controlled wireless device was applied for 30-45 minutes on the upper arm within 1 hour of attack onset; electrical stimulation was at a perceptible but non-painful intensity level. Migraine pain levels were recorded at baseline, 2, and 48 hours post-treatment. Most bothersome symptoms (MBS) were also recorded. The primary efficacy endpoint was the proportion of participants achieving pain relief at 2 hours post-treatment (improvement from severe or moderate pain to mild or none, or from mild pain to none). Relief of MBS and pain-free at 2 hours were key secondary endpoints. RESULTS: Active stimulation was more effective than sham stimulation in achieving pain relief (66.7% [66/99] vs 38.8% [40/103]; therapeutic gain of 27.9% [CI95% , 15.6-40.2]; P < .0001), pain-free (37.4% vs 18.4%, P = .003), and MBS relief (46.3% vs 22.2%, P = .0008) at 2 hours post-treatment. The pain relief and pain-free superiority of the active treatment was sustained 48 hours post-treatment. The incidence of device-related adverse events was low and similar between treatment groups (4.8% [6/126] vs 2.4% [3/126], P = .499). CONCLUSIONS: REN provides superior clinically meaningful relief of migraine pain and MBS compared to placebo, offering a safe and effective non-pharmacological alternative for acute migraine treatment.

Psychological Factors Associated With Chronic Migraine and Severe Migraine-Related Disability: An Observational Study in a Tertiary Headache Center.

OBJECTIVE: To evaluate the relationships among modifiable psychological factors and chronic migraine and severe migraine-related disability in a clinic-based sample of persons with migraine. BACKGROUND: Evidence evaluating relationships between modifiable psychological factors and chronic migraine and severe migraine-related disability is lacking in people with migraine presenting for routine clinical care. METHODS: Adults with migraine completed surveys during routinely scheduled visits to a tertiary headache center. Participants completed surveys assessing chronic migraine (meeting criteria for migraine with ≥15 headache days in the past month), severe migraine disability (Migraine Disability Assessment Scale score ≥ 21), and modifiable psychological factors (depressive symptoms [Patient Health Questionnaire-9], anxious symptoms [Generalized Anxiety Disorder-7], Pain Catastrophizing Scale and Headache Specific Locus of Control). Logistic regression evaluated relationships between modifiable psychological factors and chronic migraine and severe migraine disability. RESULTS: Among 90 eligible participants the mean age was 45.0 (SD = 12.4); 84.8% were women. One-third (36.0%) met study criteria for chronic migraine; half of participants (51.5%) reported severe migraine-related disability. Higher depressive symptoms (OR = 1.99, 95% CI = 1.11, 3.55) and chance HSLC (OR = 1.85, 95% CI = 1.13, 1.43) were associated with chronic migraine. Higher depressive symptoms (OR = 3.54, 95%CI = 1.49, 8.41), anxiety symptoms (OR = 3.65, 95% CI = 1.65, 8.06), and pain catastrophizing (OR = 1.95, 95% CI = 1.14, 3.35), were associated with severe migraine-related disability. CONCLUSIONS: Psychiatric symptoms and pain catastrophizing were strongly associated with severe migraine-related disability. Depression and chance locus of control were associated with chronic migraine. This study supports the need for longitudinal observational studies to evaluate the relationships among naturalistic variation in psychological factors, migraine-related disability, and migraine chronification.

Phantosmia and Migraine With and Without Headache.

Phantosmia is a rare migraine aura. We present two cases of phantosmias occurring before migraine headaches and also without headaches. To our knowledge, these are the third and fourth cases of phantosmias ever reported due to migraine aura without headache.

Auditory hallucinations associated with migraine: Case series and literature review.

OBJECTIVE: The objective of this review is to describe auditory hallucinations (paracusias) associated with migraine attacks to yield insights into their clinical significance and pathogenesis. BACKGROUND: Isolated observations have documented rare associations of migraine with auditory hallucinations. Unlike visual, somatosensory, language, motor, and brainstem symptoms, paracusias with acute headache attacks are not a recognized aura symptom by the International Headache Society, and no systematic review has addressed this association. METHODS: We retrospectively studied patients experiencing paracusias associated with migraine at our center and in the literature. RESULTS: We encountered 12 patients (our center = 5, literature = 7), 58% were female, and 75% had typical migraine aura. Hallucinations most commonly featured voices (58%), 75% experienced them during headache, and the duration was most often <1 hour (67%). No patients described visual aura evolving to paracusias. Most patients (50%) had either a current or previous psychiatric disorder, most commonly depression (67%). The course of headache and paracusias were universally congruent, including improvement with headache prophylaxis (58%). CONCLUSION: Paracusias uncommonly co-occur with migraine and usually feature human voices. Their timing and high prevalence in patients with depression may suggest that paracusias are not necessarily a form of migraine aura, though could be a migraine trait symptom. Alternative mechanisms include perfusion changes in primary auditory cortex, serotonin-related ictal perceptual changes, or a release phenomenon in the setting of phonophobia with avoidance of a noisy environment.

Methodological issues in studying trigger factors and premonitory features of migraine.

OBJECTIVE: In this review, we focus on migraine as a chronic disorder with episodic attacks (CDEA). We aim to review methodological approaches to studying trigger factors and premonitory features that often precede a migraine attack. BACKGROUND: Migraine attacks are sometimes initiated by trigger factors, exposures which increase the probability of an attack. They are heralded by premonitory features, symptoms which warn of an impending attack. DESIGN/METHODS: We review candidate predictors of migraine attack and discuss the methodological issues and approaches to studying attack prediction and suggest that electronic diaries may be the method of choice. CONCLUSION: Establishing the relationship between antecedent events and headaches is a formidable challenge. Successfully addressing this challenge should provide insights into disease mechanisms and lead to new strategies for treatment. In the second paper in this series, we review the available literature on trigger factors and premonitory features.

Trigger point injections for headache disorders: expert consensus methodology and narrative review.

OBJECTIVE/BACKGROUND: To review the existing literature and describe a standardized methodology by expert consensus for the performance of trigger point injections (TPIs) in the treatment of headache disorders. Despite their widespread use, the efficacy, safety, and methodology of TPIs have not been reviewed specifically for headache disorders by expert consensus. METHODS: The Peripheral Nerve Blocks and Other Interventional Procedures Special Interest Section of the American Headache Society over a series of meetings reached a consensus for nomenclature, indications, contraindications, precautions, procedural details, outcomes, and adverse effects for the use of TPIs for headache disorders. A subcommittee of the Section also reviewed the literature. RESULTS: Indications for TPIs may include many types of episodic and chronic primary and secondary headache disorders, with the presence of active trigger points (TPs) on physical examination. Contraindications may include infection, a local open skull defect, or an anesthetic allergy, and precautions are necessary in the setting of anticoagulant use, pregnancy, and obesity with unclear anatomical landmarks. The most common muscles selected for TPIs include the trapezius, sternocleidomastoid, and temporalis, with bupivacaine and lidocaine the agents used most frequently. Adverse effects are typically mild with careful patient and procedural selection, though pneumothorax and other serious adverse events have been infrequently reported. CONCLUSIONS: When performed in the appropriate setting and with the proper expertise, TPIs seem to have a role in the adjunctive treatment of the most common headache disorders. We hope our effort to characterize the methodology of TPIs by expert opinion in the context of published data motivates the performance of evidence-based and standardized treatment protocols.

Retinal migraine.

Retinal migraine is usually characterized by attacks of fully reversible monocular visual loss associated with migraine headache. Retinal migraine is most common in women of child-bearing age who have a history of migraine with aura. In the typical attack, monocular visual features consist of partial or complete visual loss lasting less than 1h. Although the current diagnostic criteria for retinal migraine require fully reversible visual loss, our findings suggest that irreversible visual loss is part of the retinal migraine spectrum. Nearly half of reported cases with recurrent transient monocular visual loss subsequently experienced permanent monocular visual loss.

Characterizing Cannabis Use and Perceived Benefit in a Tertiary Headache Center Patient Sample.

Background and Objectives: Research suggests a potential role for cannabinoids in the etiology and treatment of migraine. However, there is a paucity of research on usage patterns and perceived benefits of cannabis use in clinical headache patient populations. Methods: Patients from a tertiary headache center completed a 1-time online survey regarding cannabis use patterns and perceived benefits of cannabis-based products in treating migraine symptoms, clinical features, and risk factors (e.g., depression, sleep disturbance). Descriptive analyses were performed. Results: Data were collected from 1373 patients (response rate 25.4% [1,373/5,400]), with 55.7% reporting cannabis-based product use in the past 3 years and 32.5% indicating current use. The most frequently cited reasons for cannabis-based product use were treating headache (65.8%) and sleep concerns (50.8%). Inhaled products (i.e., smoked/vaped) and edibles were the most commonly reported delivery methods, with THC/CBD (∆9 tetrahydrocannabinol/cannabidiol) blends as the most-cited product composition. A majority of participants reported cannabis-related improvements in migraine headache characteristics (i.e., intensity: 78.1%; duration: 73.4%; frequency: 62.4%), nausea (56.3%), and risk factors (sleep disturbance: 81.2%; anxiety: 71.4%; depression: 57.0%). Over half (58.0%) of the respondents reported only using cannabis products when experiencing a headache, while 42.0% used cannabis most days/daily for prevention. Nearly half (48.9%) of the respondents reported that cannabis use contributed to a reduction in medication amount for headache treatment, and 14.5% reported an elimination of other medications. A minority (20.9%) of participants reported experiencing side effects when using cannabis products for headache, most commonly fatigue/lethargy. For those participants who reported no use of cannabis-based products in the previous 3 years, approximately half indicated not knowing what cannabis product to take or the appropriate dosage. Discussion: This is the largest study to date to document cannabis product usage patterns and perceived benefits for migraine management in a clinical headache patient sample. A majority of patients surveyed reported using cannabis products for migraine management and cited perceived improvements in migraine characteristics, clinical features, and associated risk factors. The findings warrant experimental trials to confirm the perceived benefits of cannabis products for migraine prevention and treatment.

Nummular headache update.

Nummular headache (NH) is a rare headache disorder characterized by focal and well-circumscribed pain fixed within a rounded or oval/elliptical-shaped area of the head, typically 2 to 6 cm in diameter (Grosberg et al. Curr Pain Headache Rep 11:310-2, 2007). The disorder most commonly affects the parietal region and is almost always unilateral and side-locked. The pain is typically characterized as pressure-like, sharp, or stabbing and is usually mild to moderate in intensity. Many patients experience superimposed exacerbations of pain, lasting from seconds to days (Grosberg et al. Curr Pain Headache Rep 11:310-2, 2007). Distortions of sensation including hyperesthesia, hypoesthesia, allodynia, and paresthesias are frequently reported in the affected area. The temporal pattern may be episodic or chronic. Rarely, the disorder may be bifocal or multifocal, affecting various regions of the head simultaneously or in sequence. Treatment with gabapentin, tricyclic antidepressants, or botulinum toxin may be helpful. In this review of the more than 250 cases now reported in the literature, the epidemiology, clinical features, pathogenesis, differential diagnosis, and management of this disorder are discussed.

Depression and anxiety in episodic and chronic cluster headache: a pilot study.

BACKGROUND: In contrast to migraine and tension-type headache, the psychiatric comorbidities of cluster headache (CH) have not been well-studied. OBJECTIVE: We assessed the presence of depression and anxiety in groups of episodic CH (ECH) and chronic CH (CCH) patients and compared CH patients with and without depression and anxiety. METHODS: Sociodemographics, comorbidities, and selected headache features were ascertained from a clinic-based sample in a cross-sectional fashion from January 2007 to July 2010. Active depression and anxiety were assessed using the Patient Health Questionnaire (PHQ-9) and the Generalized Anxiety Disorder 7-item (GAD-7) scales. RESULTS: Of 49 CH patients, ECH patients (n=32) had an earlier age of onset and consumed less caffeine than CCH patients (n=17). Rates of depression as defined by a PHQ-9 score ≥10 were low in both ECH (6.3%) and in CCH (11.8%) with similar mean PHQ-9 scores (3.1 vs 3.7, P=.69). Rates of anxiety as defined by a GAD-7 score ≥10 were also low in both ECH (15.6%) and CCH (11.8%) with similar mean GAD-7 scores (3.8 vs 3.4, P=.76). ECH patients in and out of active attack periods had similar levels of depression and anxiety. Depression and anxiety usually occurred together in ECH and CCH patients. CH patients who were depressed or anxious were more likely to present at a younger age and have attack-related nausea and prodromal symptoms. Depressed CH patients were also more likely to have another pain disorder and had undertaken twice as many prophylactic medication trials. CONCLUSION: In this clinic-based cross-sectional study, ECH and CCH patients had similarly low rates of depression and anxiety. Rates were lower than those reported for both episodic and chronic migraine.

Olfactory hallucinations in primary headache disorders: case series and literature review.

BACKGROUND: Olfactory hallucinations (phantosmias) have rarely been reported in migraine patients. Unlike visual, sensory, language, brainstem, and motor symptoms, they are not recognized as a form of aura by the International Classification of Headache Disorders. METHODS: We examined the clinical features of 39 patients (14 new cases and 25 from the literature) with olfactory hallucinations in conjunction with their primary headache disorders. RESULTS: In a 30-month period, the prevalence of phantosmias among all patients seen at our headache center was 0.66%. Phantosmias occurred most commonly in women with migraine, although they were also seen in several patients with other primary headache diagnoses. The typical hallucination lasted 5-60 minutes, occurred shortly before or simultaneous with the onset of head pain, and was of a highly specific and unpleasant odor, most commonly a burning smell. In the majority of patients, phantosmias diminished or disappeared with initiation of prophylactic therapy for headaches. CONCLUSIONS: We propose that olfactory hallucinations are probably an uncommon but distinctive form of migraine aura, based on their semiology, timing and response to headache prophylaxis.

Cluster headache associated with a sixth nerve palsy: a case report.

BACKGROUND: Cluster headache is a rare primary headache disorder characterized by recurrent, stereotyped short-lasting attacks of severe, unilateral head pain accompanied by autonomic symptoms. METHODS/RESULTS: Ophthalmic features such as conjunctival injection, lacrimation, ptosis and miosis occur in the vast majority of patients with cluster headache, whereas co-existent ocular movement disorders are rare. CONCLUSIONS: To the best of our knowledge, only two documented cases of cluster headache with external ocular movement disorders have been reported. We describe herein an additional case with this unusual finding and discuss the putative pathophysiology of cluster headache associated with ophthalmoparesis.

Elective Hospitalizations for Intractable Headache: Outcomes and Response Predictors.

OBJECTIVE: To review our inpatient experience treating a variety of headache disorders with heterogeneous therapies and to determine outcomes and predictors of response. METHODS: We conducted an institutional review board-approved retrospective chart review of elective inpatient headache admissions from the Montefiore Headache Center from 2014 to 2018. We examined factors associated with response and outcomes at discharge and posthospitalization follow-up in an intractable population. Patients received different classes of IV medications including antiemetics, neuroleptics, dihydroergotamine, lidocaine, steroids, valproic acid, and nerve blocks, and home preventive medications were either continued or changed before discharge. Improvements were defined at discharge by headache intensity compared with before hospitalization. RESULTS: Among the 83 admissions, pain improvement at discharge occurred in 90.4% (n = 75) of the overall sample, 89.5% (n = 60) of those with chronic migraine, 75.0% (n = 9) of patients with new daily persistent headache, and 89.5% (n = 34) of all those with acute medication overuse. Fifty-six patients (67.5%) reported improvement of a 3-or-more-point reduction in headache intensity at discharge, with a mean reduction of 4.84 ± SD 2.51 (range 1-10). Of the 66 patients who received IV dihydroergotamine, 59 (89.4%) of them improved at discharge. Of the 11 (13.2%) patients who received IV lidocaine, 7 (63.6%) improved. Of the 14 (16.9%) patients who received nerve blocks, all 14 (100%) improved at discharge. Of the 75 patients who had improved at discharge, 63 (84%) followed up and 50 (79.4%) of those patients remained improved. At the second follow-up, 68 (81.9%) patients returned for follow-up on average of 71 days (range 10-283) after discharge. CONCLUSIONS: Our inpatient headache experience featured numerous treatments with high rates of improvement in the short and intermediate term for all headache disorders. These results may suggest that stratified hospitalized care including polytherapy may be useful for many patients.

Coexisting trigeminal autonomic cephalalgias and hemicrania continua.

The trigeminal autonomic cephalalgias (TACs) and hemicrania continua (HC) share many clinical characteristics including unilateral pain and ipsilateral autonomic features. We report a patient with a history of migraine without aura who developed cluster headache and HC simultaneously. The distinctive clinical features and differential response profiles to various treatments indicates that they are distinct disorders. We then review previous reports of patients with coexisting TACs and HC and discuss the relationship between these families of primary headache disorders.