The location of pain in cluster headache: Data from the International Cluster Headache Questionnaire.

OBJECTIVE: To identify the most common locations of cluster headache pain from an international, non-clinic-based survey of participants with cluster headache, and to compare these locations to other cluster headache features as well as to somatotopic maps of peripheral, brainstem, thalamic, and cortical areas. BACKGROUND: Official criteria for cluster headache state pain in the orbital, supraorbital, and/or temporal areas, yet studies have noted pain extending beyond these locations, and the occipital nerve appears relevant, given the effectiveness of suboccipital corticosteroid injections and occipital nerve stimulation. Furthermore, cranial autonomic features vary between patients, and it is not clear if the trigeminovascular reflex is dermatome specific (e.g., do patients with maxillary or V2 division pain have more rhinorrhea?). Finally, functional imaging studies show early activation of the posterior hypothalamus in a cluster headache attack. However, the first somatosensory area to be sensitized is unclear; the first area can be hypothesized based on the complete map of pain locations. METHODS: The International Cluster Headache Questionnaire was an internet-based cross-sectional survey that included a clickable pain map of the face. These data were compared to several other datasets: (1) a meta-analysis of 22 previous publications of pain location in cluster headache (consisting of 6074 patients); (2) four cephalic dermatome maps; (3) participants' survey responses for demographics, autonomic features, and effective medications; and (4) previously published somatotopic maps of the brainstem, thalamus, primary somatosensory cortex, and higher order somatosensory cortex. RESULTS: One thousand five hundred eighty-nine participants completed the pain map portion of the survey, and the primary locations of pain across all respondents was the orbital, periorbital, and temporal areas with a secondary location in the lower occiput; these primary and secondary locations were consistent with our meta-analysis of 22 previous publications. Of the four cephalic dermatomes (V1, V2, V3, and a combination of C2-3), our study found that most respondents had pain in two or more dermatomes (range 85.7% to 88.7%, or 1361-1410 of 1589 respondents, across the four dermatome maps). Dermatomes did not correlate with their respective autonomic features or with medication effectiveness. The first area to be sensitized in the canonical somatosensory pathway is either a subcortical (brainstem or thalamus) or higher order somatosensory area (parietal ventral or secondary somatosensory cortices) because the primary somatosensory cortex (area 3b) and somatosensory area 1 have discontinuous face and occipital regions. CONCLUSIONS: The primary pain locations in cluster headache are the orbital, supraorbital, and temporal areas, consistent with the official International Classification of Headache Disorders criteria. However, activation of the occiput in many participants suggests a role for the occipital nerve, and the pain locations suggest that somatosensory sensitization does not start in the primary somatosensory cortex.

Regulation of headache response and transcriptomic network by the trigeminal ganglion clock.

OBJECTIVE: To characterize the circadian features of the trigeminal ganglion in a mouse model of headache. BACKGROUND: Several headache disorders, such as migraine and cluster headache, are known to exhibit distinct circadian rhythms of attacks. The circadian basis for these rhythmic pain responses, however, remains poorly understood. METHODS: We examined trigeminal ganglion ex vivo and single-cell cultures from Per2::LucSV reporter mice and performed immunohistochemistry. Circadian behavior and transcriptomics were investigated using a novel combination of trigeminovascular and circadian models: a nitroglycerin mouse headache model with mechanical thresholds measured every 6 h, and trigeminal ganglion RNA sequencing measured every 4 h for 24 h. Finally, we performed pharmacogenomic analysis of gene targets for migraine, cluster headache, and trigeminal neuralgia treatments as well as trigeminal ganglion neuropeptides; this information was cross-referenced with our cycling genes from RNA sequencing data to identify potential targets for chronotherapy. RESULTS: The trigeminal ganglion demonstrates strong circadian rhythms in both ex vivo and single-cell cultures, with core circadian proteins found in both neuronal and non-neuronal cells. Using our novel behavioral model, we showed that nitroglycerin-treated mice display circadian rhythms of pain sensitivity which were abolished in arrhythmic Per1/2 double knockout mice. Furthermore, RNA-sequencing analysis of the trigeminal ganglion revealed 466 genes that displayed circadian oscillations in the control group, including core clock genes and clock-regulated pain neurotransmitters. In the nitroglycerin group, we observed a profound circadian reprogramming of gene expression, as 331 of circadian genes in the control group lost rhythm and another 584 genes gained rhythm. Finally, pharmacogenetics analysis identified 10 genes in our trigeminal ganglion circadian transcriptome that encode target proteins of current medications used to treat migraine, cluster headache, or trigeminal neuralgia. CONCLUSION: Our study unveiled robust circadian rhythms in the trigeminal ganglion at the behavioral, transcriptomic, and pharmacogenetic levels. These results support a fundamental role of the clock in pain pathophysiology. PLAIN LANGUAGE SUMMARY: Several headache diseases, such as migraine and cluster headache, have headaches that occur at the same time each day. We learned that the trigeminal ganglion, an important pain structure in several headache diseases, has a 24-hour cycle that might be related to this daily cycle of headaches. Our genetic analysis suggests that some medications may be more effective in treating migraine and cluster headache when taken at specific times of the day.

Managing Cluster Headache in Patients with Medical, Psychiatric, and Surgical Comorbidities.

PURPOSE OF REVIEW: What should a provider know about medications and other treatments in patients with cluster headache who have medical, psychiatric, and surgical comorbidities? What conversations should providers have with patients about living with and managing cluster headache? RECENT FINDINGS: While the number of treatments used in cluster headache is relatively small, numerous considerations were identified related to managing patients with comorbidities. Many of these touch on cardiac, cardiovascular, and cerebrovascular health, but full histories are needed to guide safe and effective treatment. Both older and newer treatments may be contraindicated in certain patients with cluster headache or should be considered carefully. In addition to incorporating medical, psychiatric, and surgical histories in the management plan, collaboration with other providers may be beneficial. Providers should also inquire about patient practices and discuss participation in clinical trials that might be a good fit for the individual.

Disability in cluster headache is more than attack frequency - results from and validation of the English version of the Cluster Headache Impact Questionnaire (CHIQ).

BACKGROUND: Cluster headache (CH) is associated with high disability. The Cluster Headache Impact Questionnaire (CHIQ) is a short, disease-specific disability questionnaire first developed and validated in German. Here, we validated the English version of this questionnaire. METHODS: The CHIQ was assessed together with nonspecific headache-related disability questionnaires in CH patients from a tertiary headache center and an American self-help group. RESULTS: 155 active episodic and chronic CH patients were included. The CHIQ showed good internal consistency (Cronbach's α = 0.91) and test-retest reliability (ICC = 0.93, n = 44). Factor analysis identified a single factor. Convergent validity was shown by significant correlations with the Headache Impact Test™ (HIT-6™, ρ = 0.72, p < 0.001), the Hospital Anxiety and Depression Scale (HADS depression: ρ = 0.53, HADS anxiety: ρ = 0.61, both p < 0.001), the Perceived Stress Scale (PSS-10, ρ = 0.61, p < 0.001) and with CH attack frequency (ρ = 0.29, p < 0.001). Chronic CH patients showed the highest CHIQ scores (25.4 ± 7.9, n = 76), followed by active episodic CH and episodic CH patients in remission (active eCH: 22.2 ± 8.7, n = 79; eCH in remission: 14.1 ± 13.1, n = 127; p < 0.001). Furthermore, the CHIQ was graded into 5 levels from "no to low impact" to "extreme impact" based on the patients' perception. Higher CHIQ grading was associated with higher attack and acute medication frequency, HIT-6™, HADS and PSS scores. CONCLUSION: The English version of the CHIQ is a reliable, valid, and disease-specific patient-reported outcome measure to assess the impact of headaches on CH patients.

Commentary on 2022 guidelines on clinical trial design in cluster headache and further suggestions.

BACKGROUND: New guidelines for cluster headache clinical trials were recently published. We welcome these new guidelines and raise additional considerations in trial methodologies. MAIN BODY: We present non-inferiority trials to overcome ethical issues with placebo use, and additionally discuss issues with trial recruitment. CONCLUSIONS: We highlight some possible issues and solutions to be considered with the recently published cluster headache trial guidelines.

Photophobia is associated with lower sleep quality in individuals with migraine: results from the American Registry for Migraine Research (ARMR).

BACKGROUND: Patients with migraine often have poor sleep quality between and during migraine attacks. Furthermore, extensive research has identified photophobia as the most common and most bothersome symptom in individuals with migraine, second only to headache. Seeking the comfort of darkness is a common strategy for managing pain during an attack and preventing its recurrence between episodes. Given the well-established effects of daily light exposure on circadian activity rhythms and sleep quality, this study aimed to investigate the relationship between photophobia symptoms and sleep quality in a cohort of patients with migraine. METHODS: A cross-sectional observational study was conducted using existing data extracted from the American Registry for Migraine Research (ARMR). Participants with a migraine diagnosis who had completed the baseline questionnaires (Photosensitivity Assessment Questionnaire (PAQ), Generalized Anxiety Disorder-7 (GAD-7), Patient Health Questionnaire-2 (PHQ-2)), and selected questions of the ARMR Sleep questionnaire were included. Models were created to describe the relationship of photophobia and photophilia with various sleep facets, including sleep quality (SQ), sleep disturbance (SDis), sleep onset latency (SOL), sleep-related impairments (SRI), and insomnia. Each model was controlled for age, sex, headache frequency, anxiety, and depression. RESULTS: A total of 852 patients meeting the inclusion criteria were included in the analysis (mean age (SD) = 49.8 (13.9), 86.6% (n = 738) female). Those with photophobia exhibited significantly poorer sleep quality compared to patients without photophobia (p < 0.001). Photophobia scores were associated with SQ (p < 0.001), SDis (p < 0.001), SOL (p = 0.011), SRI (p = 0.020), and insomnia (p = 0.005) after controlling for age, sex, headache frequency, depression, and anxiety, signifying that higher levels of photophobia were associated with worse sleep-related outcomes. Conversely, photophilia scores were associated with better sleep-related outcomes for SQ (p < 0.007), SOL (p = 0.010), and insomnia (p = 0.014). CONCLUSION: Results suggest that photophobia is a significant predictor of poor sleep quality and sleep disturbances in migraine. These results underscore the necessity for comprehensive and systematic investigations into the intricate interplay between photophobia and sleep to enhance our understanding and develop tailored solutions for individuals with migraine.

Management of cluster headache: Treatments and their mechanisms.

BACKGROUND: The management of cluster headache is similar to that of other primary headache disorders and can be broadly divided into acute and preventive treatments. Acute treatments for cluster headache are primarily delivered via rapid, non-oral routes (such as inhalation, nasal, or subcutaneous) while preventives include a variety of unrelated treatments such as corticosteroids, verapamil, and galcanezumab. Neuromodulation is becoming an increasingly popular option, both non-invasively such as vagus nerve stimulation when medical treatment is contraindicated or side effects are intolerable, and invasively such as occipital nerve stimulation when medical treatment is ineffective. Clinically, this collection of treatment types provides a range of options for the informed clinician. Scientifically, this collection provides important insights into disease mechanisms. METHODS: Two authors performed independent narrative reviews of the literature on guideline recommendations, clinical trials, real-world data, and mechanistic studies. RESULTS: Cluster headache is treated with acute treatments, bridge treatments, and preventive treatments. Common first-line treatments include subcutaneous sumatriptan and high-flow oxygen as acute treatments, corticosteroids (oral or suboccipital injections) as bridge treatments, and verapamil as a preventive treatment. Some newer acute (non-invasive vagus nerve stimulation) and preventive (galcanezumab) treatments have excellent clinical trial data for episodic cluster headache, while other newer treatments (occipital nerve stimulation) have been specifically tested in treatment-refractory chronic cluster headache. Most treatments are suspected to act on the trigeminovascular system, the autonomic system, or the hypothalamus. CONCLUSIONS: The first-line treatments have not changed in recent years, but new treatments have provided additional options for patients.

Trigeminal Autonomic Cephalalgias and Neuralgias in Children and Adolescents: a Narrative Review.

PURPOSE OF REVIEW: To summarize the available literature as well as the authors' experience on trigeminal autonomic cephalalgias (TACs) and cranial neuralgias in children and adolescents. RECENT FINDINGS: While TACs and cranial neuralgias are rare in children, several recent case series have been published. TACs in children share most of the clinical features of TACs in adults. However, there are many reported cases with clinical features which overlap more than one diagnosis, suggesting that TACs may be less differentiated in youth. Indomethacin-responsive cases of cluster headache and SUNCT/SUNA have been reported in children, whereas in adults indomethacin is usually reserved for paroxysmal hemicrania and hemicrania continua. Neuralgias appear to be rare in children. Clinical features are often similar to adult cases, though clinicians should maintain a high index of suspicion for underlying causes.

Pediatric-onset trigeminal autonomic cephalalgias: A systematic review and meta-analysis.

BACKGROUND AND OBJECTIVE: There are five headache disorders composing the trigeminal autonomic cephalalgias (cluster headache, paroxysmal hemicrania, short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT), short-lasting unilateral neuralgiform headache attacks with cranial autonomic symptoms (SUNA), and hemicrania continua). Little is known about these disorders in the pediatric population. The objectives of this study are to report the full age ranges of pediatric trigeminal autonomic cephalalgias and to determine if pediatric-onset trigeminal autonomic cephalalgias display similar signs and symptoms as adult onset. METHODS: Search criteria in Medline Ovid, Embase, PsycINFO, and Cochrane Library were created by a librarian. The remainder of the steps were independently performed by two neurologists using PRISMA guidelines. Inclusion criteria for titles and abstracts were articles discussing cases of trigeminal autonomic cephalalgias with age of onset 18 or younger, as well as any epidemiological report on trigeminal autonomic cephalalgias (as age of onset data was often found in the results section but not in the title or abstract). Data extracted included age of onset, sex, and International Classification of Headache Disorders criteria for trigeminal autonomic cephalalgias (including pain location, duration, frequency, autonomic features, restlessness) and some migraine criteria (photophobia, phonophobia, and nausea). Studies that did not meet full criteria for trigeminal autonomic cephalalgias were examined separately as "atypical trigeminal autonomic cephalalgias"; secondary headaches were excluded from this category. RESULTS: In all, 1788 studies were searched, 86 met inclusion criteria, and most (56) examined cluster headache. In cluster headache, onset occurred at every pediatric age (range 1-18 years) with a full range of associated features. Autonomic and restlessness features were less common in pediatric patients, while migrainous features (nausea, photophobia, and phonophobia) were found at similar rates. The sex ratio of pediatric-onset cluster headache (1.8, 79 male and 43 female) may be lower than that of adult-onset cluster headache. Data for other trigeminal autonomic cephalalgias, while more limited, displayed most of the full range of official criteria. The data for atypical trigeminal autonomic cephalalgias were also limited, but the most common deviations from the official criteria were abnormal frequencies and locations of attacks. CONCLUSIONS: Trigeminal autonomic cephalalgias can start early in life and have similar features to adult-onset trigeminal autonomic cephalalgias. Specifically, pediatric-onset cluster headache patients display the full range of each criterion for cluster headache (except maximum frequency of six instead of eight attacks per day). However, cranial autonomic features and restlessness occur at a lower rate in pediatrics. Additional information is needed for the other trigeminal autonomic cephalalgias. As for expanding the ICHD-3 criteria for pediatric-onset trigeminal autonomic cephalalgias, we have only preliminary data from atypical cases, which suggests that the frequency and location of attacks sometimes extend beyond the official criteria.Trial Registration: This study was registered as a systematic review in PROSPERO (registration number CRD42020165256).

A brief diagnostic screen for cluster headache: Creation and initial validation of the Erwin Test for Cluster Headache.

OBJECTIVE: To use 1) newly generated data, 2) existing evidence, and 3) expert opinion to create and validate a new cluster headache screening tool. METHODS: In phase 1 of the study, we performed a prospective study of an English translation of an Italian screen on 95 participants (45 with cluster headache, 17 with other trigeminal autonomic cephalalgias, 30 with migraine, and 3 with trigeminal neuralgia). In phase 2, we performed a systematic review in PubMed of all studies until September 2019 with diagnostic screening tools for cluster headache. In phase 3, a 6-person panel of cluster headache patients, research coordinators, and headache specialists analyzed the data from the first two phases to generate a new diagnostic screening tool. Finally, in phase 4 this new screen was validated on participants at a single headache center (all diagnoses) and through research recruitment (trigeminal autonomic cephalalgias only, as recruitment was essential but was otherwise low). RESULTS: In total, this study included 319 unique participants including 109 cluster headache participants (95 total participants/45 cluster headache participants in phase 1, and 224 total participants/64 cluster headache participants in phase 4). It also found 123 articles on potential screening tools in our systematic review. In phase 1, analysis of the English translation of an Italian screen generated 7 questions with high sensitivity and specificity against migraine, trigeminal neuralgia, and other trigeminal autonomic cephalalgias, but had grammatical and other limitations as a general screening tool. In phase 2, the systematic review revealed nine studies that met inclusion criteria as diagnostic screening tools for cluster headache, including four where sensitivity and specificity were available for individual questions or small groups of questions. In phase 3, this data was reviewed by the expert panel to generate a brief (6-item), binary (yes/no), written screening test. In phase 4, a total of 224 participants completed the new 6-item screening test (81 migraine, 64 cluster headache, 21 other trigeminal autonomic cephalalgias, 35 secondary headaches, 7 neuralgias, 5 probable migraine, and 11 other headache disorders). Answers to the 6 items were combined in a decision tree algorithm and three items had a sensitivity of 84% (confidence interval or 95% confidence interval 73-92%), specificity of 89% (95% confidence interval 84-94%), positive predictive value of 76% (95% confidence interval 64-85%), and negative predictive value of 93% (95% confidence interval 88-97%) for the diagnosis of cluster headache. These three items focused on headache intensity, duration, and autonomic features. CONCLUSION: The 3-item Erwin Test for Cluster Headache is a promising diagnostic screening tool for cluster headache.

Grand rounds education in neurology, with a focus on headache medicine.

OBJECTIVE: To quantify the proportion of headache-related grand rounds in academic neurology programs and to compare this with adult neurology residency director views on the need for an increase in headache-related grand rounds. BACKGROUND: Although headache are among the most prevalent and most burdensome neurologic conditions, headache medicine is often considered underrepresented in neurology departments. Additionally, prior studies have shown that many neurology residency directors feel that training programs do not include an adequate amount of exposure to headache clinics or headache-related didactics. One important aspect of didactic education in neurology departments is adult neurology grand rounds. Previous publications have evaluated neither the proportion of headache-related grand rounds in academic neurology departments nor the residency program directors' views on appropriate amount of headache-related grand rounds. Our study has attempted to quantify this information to elucidate opportunities to improve practice educational gaps. METHODS: In this cross-sectional study, we surveyed adult neurology residency directors (from the Accreditation Council for Graduate Medical Education [ACGME] listing of academic adult neurology residency programs) between October 2018 and September 2019. In addition, we used two methods to obtain the proportion of headache-related grand rounds in neurology: (1) emailing residency directors a questionnaire asking for a list of prior grand rounds topics and (2) an online search for each academic neurology program. RESULTS: First, for our grand rounds analysis, headache medicine consisted of 3.7% of the lectures in 2017-2018 and 6.3% of the lectures in 2018-2019 (average of each institution; 17 institutions and 411 total lectures in 2017-2018, 21 institutions and 463 total lectures in 2018-2019). The most common number of lectures on headache medicine for each grand rounds series was zero (for 7 of 17 grand rounds series in 2017-2018 and 7 of 21 in 2018-2019), followed closely by one lecture (for 6 of 17 grand rounds series in 2017-2018 and 6 of 21 in 2018-2019). Second, for our survey, the response rate was 19.3% (29/150). No residency director thought their institution had too many grand rounds dedicated to headache medicine, and 62.1% (18/29) thought they had an adequate amount of headache grand rounds. Within the survey responders, 75.9% (22/29) of adult neurology residency programs have a board-certified headache specialist at their institution. CONCLUSIONS: Although most adult neurology residency directors believe that headache is adequately represented in adult neurology grand rounds, headache medicine makes up 4%-6% of all neurology grand rounds. Compared with other neurology subspecialties and the other core ACGME milestones, headache makes up the fewest grand rounds lectures that were assessed in this study.

Cluster headache epidemiology including pediatric onset, sex, and ICHD criteria: Results from the International Cluster Headache Questionnaire.

OBJECTIVE: To validate the diagnoses and to investigate epidemiological data from an international, non-clinic-based, and large (n = 1604) survey of participants with cluster headache. BACKGROUND: There are several limitations in current epidemiological data in cluster headache including a lack of large non-clinic-based studies. There is also limited information on several aspects of cluster headache, such as pediatric incidence. METHODS: The International Cluster Headache Questionnaire was an internet-based survey that included questions on cluster headache demographics, criteria from the International Classification of Headache Disorders (ICHD), and medications. RESULTS: A total of 3251 subjects participated in the survey, and 1604 respondents met ICHD criteria for cluster headache. For validation, we interviewed a random sample of 5% (81/1604) of participants and confirmed the diagnosis of cluster headache in 97.5% (79/81). Pediatric onset was found in 27.5% (341/1583) of participants, and only 15.2% (52/341) of participants with pediatric onset were diagnosed before the age of 18. Men were more likely to have episodic cluster headache between ages 10 and 50, but the sex ratio was approximately equal for other ages. An overwhelming majority of respondents had at least one autonomic feature (99.0%, 1588/1604) and had restlessness (96.6%, 1550/1604), but many also had prototypical migrainous features including photophobia or phonophobia (50.1%, 804/1604), pain aggravated by physical activity (31.4%, 503/1604), or nausea and vomiting (27.5%, 441/1604). Interestingly, the first-line medications for acute treatment (oxygen) and preventive treatment (calcium channel blockers) were perceived as significantly less effective in chronic cluster headache (3.2 ± 1.1 and 2.1 ± 1.0 respectively on a 5-point ordinal scale) compared with episodic cluster headache (3.5 ± 1.0 and 2.4 ± 1.1, respectively, p < 0.001 for both comparisons). CONCLUSIONS: Cluster headache often occurs in the pediatric population, although they are typically not diagnosed until adulthood. The onset of cluster headache is the inverse of that in migraine; in migraine women are more likely to have migraine between ages 10 and 50 but the sex ratio is approximately equal otherwise. Prototypical migrainous features are not useful in differentiating cluster headache from migraine. Participant data from a large international study also suggest that chronic cluster headache is not only less responsive to newer treatments (like noninvasive vagus nerve stimulation and galcanezumab), but to traditional first-line treatments as well.

Cluster headache is one of the most intensely painful human conditions: Results from the International Cluster Headache Questionnaire.

OBJECTIVE: To determine the pain intensity of cluster headache through a large survey by comparing it to other painful disorders. Furthermore, to investigate the relationship between maximal pain, autonomic, and other clinical symptoms, as well as demographic attributes of cluster headache. BACKGROUND: The pain of cluster headache is anecdotally considered to be one of the worst pains in existence. The link between pain and autonomic features of cluster headache is understood mechanistically through the trigeminovascular reflex, though it is not clear if this is a graded response. Links between pain and other features of cluster headache are less well understood. METHODS: This Internet-based cross-sectional survey included questions on cluster headache diagnostic criteria, which were used as part of the inclusion/exclusion criteria for the study. Respondents were asked to rate a cluster headache attack on the 0-10 numerical rating scale. Additionally, they were asked if they had experienced a list of other painful conditions such as labor pain or nephrolithiasis; if so they were asked to rate that pain as well. The survey also included demographics, mood scores, and treatment responses. RESULTS: A total of 1604 cluster headache respondents were included in the analysis. Respondents rated cluster headache as significantly (p < 0.001) more intense than every other pain condition examined. Cluster headache attacks were rated as 9.7 ± 0.6 (mean ± standard deviation) on the numerical rating scale, followed by labor pain (7.2 ± 2.0), pancreatitis (7.0 ± 1.5), and nephrolithiasis (6.9 ± 1.9). The majority of cluster headache respondents rated a cluster headache attack at maximal or 10.0 pain (72.1%, 1157/1604). Respondents with maximal pain were statistically significantly more likely to have cranial autonomic features compared to respondents with less pain: conjunctival injection or lacrimation 91% (1057/1157) versus 85% (381/447), eyelid edema 77% (887/1157) versus 66% (293/447), forehead/facial sweating 60% (693/1157) versus 49% (217/447), fullness in the ear 47% (541/1157) versus 35% (155/447), and miosis/ptosis 85% (1124/1157) versus 75% (426/447) (all p values <0.001). Respondents with maximal pain also had other statistically significant findings: more frequent attacks (4.0 ± 2.0 attacks per day vs. 3.5 ± 2.0 attacks per day), higher Hopelessness Depression Symptom Questionnaire scores (24.5 ± 16.9 vs. 21.1 ± 15.2), decreased overall effectiveness from calcium channel blockers (on a 5-point Likert scale), and more likely female: 34% (389/1157) versus 24% (108/447) (all p values <0.001). Pain intensity was not associated with restlessness, headache duration, age of onset, episodic/chronic status, or the effectiveness of any acute or preventive medication other than calcium channel blockers. CONCLUSIONS: Cluster headache is an intensely painful disorder, even in the context of other disorders considered intensely painful. Maximal pain intensity is associated with more cranial autonomic features, suggesting a graded response between pain and autonomic features. Maximal pain intensity is also associated with headache frequency but not duration, suggesting a relationship between pain intensity and mechanisms controlling headache onset, but not between pain intensity and mechanisms controlling headache offset.

Chronic versus episodic migraine: The 15-day threshold does not adequately reflect substantial differences in disability across the full spectrum of headache frequency.

OBJECTIVE: To evaluate whether the 15-day threshold of headache days per month adequately reflects substantial differences in disability across the full spectrum of migraine. BACKGROUND: The monthly frequency of headache days defines migraine subtypes and has crucial implications for epidemiological and clinical research as well as access to care. METHODS: The patients with migraine (N = 836) who participated in the American Registry for Migraine Research, which is a multicenter, longitudinal patient registry, between February 2016 and March 2020, were divided into four groups based on monthly headache frequency: Group 1 (0-7 headache days/month, n = 286), Group 2 (8-14 headache days/month, n = 180), Group 3 (15-23 headache days/month, n = 153), Group 4 (≥24 headache days/month, n = 217). Disability (MIDAS), Pain intensity (NRS), Work Productivity and Activity Impairment (WPAI), Pain Interference (PROMIS-PI), Patient Health Questionnaire-4 (PHQ-4), and General Anxiety Disorder-7 (GAD-7) scores were compared. RESULTS: Mean (standard deviation [SD]) age was 46 (13) years (87.9% [735/836] female). The proportion of patients in each group was as follows: Group 1 (34.2% [286/836]), Group 2 (21.5% [180/836]), Group 3 (18.3% [153/836]), and Group 4 (26.0% [217/836]). There were significant relationships with increasing disability, lost productive time, and pain interference in higher headache frequency categories. There were no significant differences between Group 2 and Group 3 for most measures (NRS, all WPAI scores, PROMIS-PI, GAD-7, and PHQ-4), although MIDAS scores differed (median [interquartile range (IQR)]; 38 [20-58] vs. 55 [30-90], p < 0.001). Patients in Group 1 had significantly lower MIDAS (median [IQR];16 [7-30], p < 0.001), WPAI-% total active impairment (mean (SD): Group 1 [30.9 (26.8)] vs. Group 2 [39.2 (24.5), p = 0.017], vs. Group 3 [45.9 (24.1), p < 0.001], vs. Group 4 [55.3 (23.0), p < 0.001], and PROMIS-PI-T score (Group 1 [60.3 (7.3)] vs. Group 2 [62.6 (6.4), p = 0.008], vs. Group 3 [64.6 (5.6), p < 0.001], vs. Group 4 [66.8 (5.9), p < 0.001]) compared to all other groups. Patients in Group 4 had significantly higher MIDAS (median (IQR): Group 4 [90 (52-138)] vs. Group 1 [16 (7-30), p < 0.001], vs. Group 2 [38 (20-58), p < 0.001], vs. Group 3 [55 (30-90), p < 0.001], WPAI-%Presenteeism (Group 4 [50.4 (24.4)] vs. Group 1 [28.8 (24.9), p < 0.001], vs. Group 2 [34.9 (22.3), p < 0.001], vs. Group 3 [40.9 (22.3), p = 0.048], WPAI-% total work productivity impairment (Group 4 [55.9 (26.1)] vs. Group 1 [32.1 (37.6), p < 0.001], vs. Group 2 [38.3 (24.0), p < 0.001], vs. Group 3 [44.6 (24.4), p = 0.019]), and WPAI-%Total activity impairment (Group 4 [55.3 (23.0)] vs. Group 1 [30.9 (26.8), p < 0.001], vs. Group 2 [39.2 (24.5), p < 0.001], vs. Group 3 [45.9 (24.1), p = 0.025]) scores compared with all other groups. CONCLUSION: Our data suggest that the use of a 15 headache day/month threshold to distinguish episodic and chronic migraine does not capture the burden of illness nor reflect the treatment needs of patients. These results have important implications for future refinements in the classification of migraine.

The American Registry for Migraine Research: Research Methods and Baseline Data for an Initial Patient Cohort.

BACKGROUND: The American Registry for Migraine Research (ARMR) is a multicenter, prospective, longitudinal patient registry, biorepository, and neuroimaging repository that collects clinical data, electronic health record (EHR) data, blood samples, and brain imaging data from individuals with migraine or other headache types. In this manuscript, we outline ARMR research methods and report baseline data describing an initial cohort of ARMR participants. METHODS: Adults with any International Classification of Headache Disorders (ICHD) diagnosis were prospectively enrolled from one of the 8 participating headache specialty centers. At baseline, ARMR participants complete web-based questionnaires, clinicians enter the participant's ICHD diagnoses, an optional blood specimen is collected, and neuroimaging data are uploaded to the ARMR neuroimaging repository. Participants maintain the ARMR daily headache diary longitudinally and follow-up questionnaires are completed by participants every 3 months. EHR data are integrated into the ARMR database from a subset of ARMR sites. Herein, we describe the ARMR methodology and report the summary data from ARMR participants who had, from February 2016 to May 2019, completed at least 1 baseline questionnaire from which data are reported in this manuscript. Descriptive statistics are used to provide an overview of patient's sociodemographics, headache diagnoses, headache characteristics, most bothersome symptoms other than headache, headache-related disability, comorbidities, and treatments. RESULTS: Data were available from 996 ARMR participants, enrolled from Mayo Clinic Arizona, Dartmouth-Hitchcock Medical Center, University of Utah, University of Colorado, Thomas Jefferson University, University of Texas Health Science Center at Houston, Georgetown University Medical Center, and DENT Neurological Institute. Among ARMR participants, 86.7% (n = 864) were female and the mean age at the time of enrollment was 48.6 years (±13.9; range 18-84). The most common provider-reported diagnosis was chronic migraine (n = 622), followed by migraine without aura (n = 327), migraine with aura (n = 196), and medication overuse headache (n = 65). Average headache frequency was 19.1 ± 9.2 days per month (n = 751), with 68% reporting at least 15 headache days per month. Sensitivity to light was the most frequent (n = 222) most bothersome symptom overall, other than headache, but when present, cognitive dysfunction was most frequently (n = 157) the most bothersome symptom other than headache. Average migraine disability assessment (MIDAS) score was 52 ± 49 (n = 760), (very severe headache-related disability); however, 17% of the ARMR population had MIDAS scores suggesting "no" or "mild" disability. The most common non-headache health issues were allergies (n = 364), back pain (n = 296), neck pain (n = 296), depression (n = 292), and anxiety (n = 278). Nearly 85% (n = 695) of patients were using preventive medications and 24.7% were using non-medication preventive therapy (eg, vitamins and neuromodulation). The most common preventive medication classes were neurotoxins, anticonvulsants, antidepressants, vitamins/supplements, and anticalcitonin gene-related peptide ligand or receptor-targeted monoclonal antibodies. Nearly 90% (n = 734) of ARMR participants was taking medications to treat migraine attacks, with the most common classes being triptans, non-steroidal anti-inflammatory drugs, antiemetics, acetaminophen, and combination analgesics. CONCLUSIONS: ARMR is a source of real-world patient data, biospecimens, and brain neuroimaging data that provides comprehensive insight into patients with migraine and other headache types being seen in headache specialty clinics in the United States. ARMR data will allow for longitudinal and advanced analytics that are expected to lead to a better characterization of patient heterogeneity, healthcare resource utilization, identification of endophenotypes, factors that predict treatment outcomes and clinical course, and ultimately advance the field toward precision headache medicine.

Effectiveness of Oxygen and Other Acute Treatments for Cluster Headache: Results From the Cluster Headache Questionnaire, an International Survey.

OBJECTIVE: To assess the effectiveness and adverse effects of acute cluster headache medications in a large international sample, including recommended treatments such as oxygen, commonly used medications such as opioids, and emerging medications such as intranasal ketamine. Particular focus is paid to a large subset of respondents 65 years of age or older. BACKGROUND: Large international surveys of cluster headache are rare, as are examinations of treatments and side effects in older cluster headache patients. This article presents data from the Cluster Headache Questionnaire, with respondents from over 50 countries and with the vast majority from the United States, the United Kingdom, and Canada. METHODS: This internet-based survey included questions on cluster headache diagnostic criteria, which were used as part of the inclusion/exclusion criteria for the study, as well as effectiveness of medications, physical and medical complications, psychological and emotional complications, mood scores, and difficulty obtaining medications. The diagnostic questions were also used to create a separate group of respondents with probable cluster headache. Limitations to the methods include the use of nonvalidated questions, the lack of a formal clinical diagnosis of cluster headache, and the grouping of some medications (eg, all triptans as opposed to sumatriptan subcutaneous alone). RESULTS: A total of 3251 subjects participated in the questionnaire, and 2193 respondents met criteria for this study (1604 cluster headache and 589 probable cluster headache). Of the respondents with cluster headache, 68.8% (1104/1604) were male and 78.0% (1245/1596) had episodic cluster headache. Over half of respondents reported complete or very effective treatment for triptans (54%, 639/1139) and oxygen (54%, 582/1082). Between 14 and 25% of respondents reported complete or very effective treatment for ergot derivatives (dihydroergotamine 25%, 42/170; cafergot/ergotamine 17%, 50/303), caffeine and energy drinks (17%, 7/41), and intranasal ketamine (14%, 5/37). Less than 10% reported complete or very effective treatment for opioids (6%, 30/541), intranasal capsaicin (5%, 7/151), and intranasal lidocaine (2%, 5/241). Adverse events were especially low for oxygen (no or minimal physical and medical complications 99%, 1077/1093; no or minimal psychological and emotional complications 97%, 1065/1093), intranasal lidocaine (no or minimal physical and medical complications 97%, 248/257; no or minimal psychological and emotional complications 98%, 251/257), intranasal ketamine (no or minimal physical and medical complications 95%, 38/40; no or minimal psychological and emotional complications 98%, 39/40), intranasal capsaicin (no or minimal physical and medical complications 91%, 145/159; no or minimal psychological and emotional complications 94%, 150/159), and caffeine and energy drinks (no or minimal physical and medical complications 89%, 39/44; no or minimal psychological and emotional complications 91%, 40/44). This is in comparison to ergotamine/cafergot (no or minimal physical and medical complications 83%, 273/327; no or minimal psychological and emotional complications 89%, 290/327), dihydroergotamine (no or minimal physical and medical complications 81%, 143/176; no or minimal psychological and emotional complications 91%, 160/176), opioids (no or minimal physical and medical complications 76%, 416/549; no or minimal psychological and emotional complications 77%, 423/549), or triptans (no or minimal physical and medical complications 73%, 883/1218; no or minimal psychological and emotional complications 85%, 1032/1218). A total of 139 of 1604 cluster headache respondents (8.7%) were age 65 and older and reported similar effectiveness and adverse events to the general population. The 589 respondents with probable cluster headache reported similar medication effectiveness to respondents with a full diagnosis of cluster headache. CONCLUSIONS: Oxygen is reported by survey respondents to be a highly effective treatment with few complications in cluster headache in a large international sample, including those 65 years or over. Triptans are also very effective with some side effects, and newer medications deserve additional study. Patients with probable cluster headache may respond similarly to acute medications as patients with a full diagnosis of cluster headache.

Large-scale changes in cortical dynamics triggered by repetitive somatosensory electrical stimulation.

BACKGROUND: Repetitive somatosensory electrical stimulation (SES) of forelimb peripheral nerves is a promising therapy; studies have shown that SES can improve motor function in stroke subjects with chronic deficits. However, little is known about how SES can directly modulate neural dynamics. Past studies using SES have primarily used noninvasive methods in human subjects. Here we used electrophysiological recordings from the rodent primary motor cortex (M1) to assess how SES affects neural dynamics at the level of single neurons as well as at the level of mesoscale dynamics. METHODS: We performed acute extracellular recordings in 7 intact adult Long Evans rats under ketamine-xylazine anesthesia while they received transcutaneous SES. We recorded single unit spiking and local field potentials (LFP) in the M1 contralateral to the stimulated arm. We then compared neural firing rate, spike-field coherence (SFC), and power spectral density (PSD) before and after stimulation. RESULTS: Following SES, the firing rate of a majority of neurons changed significantly from their respective baseline values. There was, however, a diversity of responses; some neurons increased while others decreased their firing rates. Interestingly, SFC, a measure of how a neuron's firing is coupled to mesoscale oscillatory dynamics, increased specifically in the δ-band, also known as the low frequency band (0.3- 4 Hz). This increase appeared to be driven by a change in the phase-locking of broad-spiking, putative pyramidal neurons. These changes in the low frequency range occurred without a significant change in the overall PSD. CONCLUSIONS: Repetitive SES significantly and persistently altered the local cortical dynamics of M1 neurons, changing both firing rates as well as the SFC magnitude in the δ-band. Thus, SES altered the neural firing and coupling to ongoing mesoscale dynamics. Our study provides evidence that SES can directly modulate cortical dynamics.