Cephalalgia

Pituitary adenylate cyclase-activating polypeptide-38 (PACAP38) and vasoactive intestinal polypeptide can provoke cluster headache attacks in up to half of cluster headache patients in their active phase. At present, it is unknown whether provoked attacks are mediated via calcitonin gene-related peptide or mast cell activation.

All enrolled patients with cluster headache were randomly allocated to receive a continuous infusion of either PACAP38 (10 pmol/kg/min) or vasoactive intestinal polypeptide (8 pmol/kg/min) over 20 min. We collected clinical data and measured plasma levels of calcitonin gene-related peptide and markers of mast cell activation (tryptase and histamine) at fixed time points: at baseline (T₀), at the end of the infusion (T₂₀), 10 min after the infusion (T₃₀), and 70 min after the infusion (T₉₀).

Blood was collected from episodic cluster headache patients in active phase (n = 14), episodic cluster headache patients in remission (n = 15), and chronic cluster headache patients (n = 15). At baseline, plasma levels of calcitonin gene-related peptide, tryptase, and histamine were not different among the three study groups. Plasma levels of calcitonin gene-related peptide (p = 0.7074), tryptase (p = 0.6673), or histamine (p = 0.4792) remained unchanged during provoked attacks compared to attack-free patients.

Cluster headache attacks provoked by either PACAP38 or vasoactive intestinal polypeptide were not accompanied by alterations of plasma calcitonin gene-related peptide, tryptase or histamine. The provoked attacks may not be mediated by calcitonin gene-related peptide or mast cell activation.

Trial Registration: The study is registered at ClinicalTrials.gov (NCT03814226).

This post hoc subgroup analysis evaluated the efficacy and safety of eptinezumab for migraine prevention in patients with migraine and self-reported aura.

PROMISE-1 (NCT02559895; episodic migraine) and PROMISE-2 (NCT02974153; chronic migraine) were randomized, double-blind, placebo-controlled trials that evaluated eptinezumab for migraine prevention. In both studies, the primary outcome was the mean change from baseline in monthly migraine days over Weeks 1–12. Patients in this analysis included those who self-reported migraine with aura at screening.

Of patients with episodic migraine, ∼75% reported a history of aura at screening; of patients with chronic migraine, ∼35% reported a history of aura. Changes in monthly migraine days over Weeks 1–12 were –4.0 (100 mg) and –4.2 (300 mg) with eptinezumab versus –3.1 with placebo in patients with episodic migraine with aura, and were –7.1 (100 mg) and –7.6 (300 mg) with eptinezumab versus –6.0 with placebo in patients with chronic migraine with aura. Treatment-emergent adverse events were reported by 56.0% (100 mg), 57.4% (300 mg), and 55.4% (placebo) of patients.

The preventive migraine efficacy of eptinezumab in patients in the PROMISE studies who self-reported aura was comparable to the overall study populations, demonstrating a similarly favorable safety and tolerability profile.

Trial registration: ClinicalTrials.gov Identifiers: NCT02559895 and NCT02974153

We aimed to provide real-world data on the effectiveness of an anti-calcitonin gene-related peptide monoclonal antibody administered for treating migraine in Korean patients.

We prospectively recruited patients with migraine who received galcanezumab treatment at a single university hospital from June 2020 to April 2021. The treatment response was assessed after three consecutive monthly injections. A 50% responder rate was evaluated based on ≥50% reduction in the number of moderate/severe headache days.

Overall, 87 patients were included in the analysis. Most patients were women (83.9%). They had a mean age of 41.7 ± 12.3 years (range 17–72). Sixty-five patients (74.7%) had chronic migraine, 35 patients (40.2%) had a history of medication-overuse headache, and 32 patients (36.8%) were previously unresponsive to or found intolerable five classes of preventive medication. After three months of treatment, mean changes in numbers of monthly headache days, moderate/severe headache days, crystal clear days, and days of acute medication use were −7.2 ± 8.43, −4.3 ± 9.76, 7.3 ± 8.50, and −4.1 ± 7.93, respectively. The 50% responder rates were 58.3%, 44.2%, and 40.6% for patients with unsuccessful previous use of 0–1, 2–4, and 5 preventive medication classes, respectively. Headache Impact Test-6 and Migraine Disability Assessment Test scores also decreased (−4.4 ± 8.09 and −32.9 ± 77.04, respectively).

In our cohort, the effectiveness and safety of galcanezumab were comparable with those reported in clinical trials, whereas a higher response rate was observed in the difficult-to-treat patient subset than that reported in trials. We provide real-world evidence of galcanezumab treatment benefits in Asian patients with migraine.

A positive family history predisposes to the development of cluster headache. The distinct characteristics of familial cluster headache have yet to be confirmed, however, evidence suggests a younger age of onset and higher proportion of females in this subgroup.

To assess the rate and mode of inheritance of familial cluster headache in a tertiary referral centre for headache. To describe the clinical features of familial cluster headache.

A retrospective study conducted between 2007 and 2017. Cluster headache was confirmed in probands and affected relatives. Differences in demographics, clinical characteristics, and response-to-treatment in familial cluster headache were delineated through multivariate analysis using a control cohort of 597 patients with sporadic cluster headache.

Familial cluster headache was confirmed in 48 (7.44%) patients and predominantly reflected an autosomal dominant mode of inheritance with reduced penetrance. Familial cases were more likely to report nasal blockage (OR 4.06, 95% CI; 2.600–6.494, p < 0.001) during an attack and a higher rate of concurrent short-lasting unilateral neuralgiform headache with conjunctival injection and tearing (OR 3.76, 95% CI; 1.572–9.953, p = 0.004).

These findings add to evidence suggesting a genetic component to cluster headache. Here, we demonstrated prominent nasal blockage, and a higher occurrence of concomitant short-lasting unilateral neuralgiform headache with conjunctival injection and tearing in this subgroup, further delineating the phenotype.

Increased sensitivity to light and patterns is typically associated with migraine, but has also been anecdotally reported in cluster headache, leading to diagnostic confusion. We wanted to assess whether visual sensitivity is increased ictally and interictally in cluster headache.

We used the validated Leiden Visual Sensitivity Scale (L-VISS) questionnaire (range 0-36 points) to measure visual sensitivity in people with episodic or chronic cluster headache: (i) during attacks; (ii) in-between attacks; and in episodic cluster headache (iii) in-between bouts. The L-VISS scores were compared with the L-VISS scores obtained in a previous study in healthy controls and participants with migraine.

Mean L-VISS scores were higher for: (i) ictal vs interictal cluster headache (episodic cluster headache: 11.9 ± 8.0 vs. 5.2 ± 5.5, chronic cluster headache: 13.7 ± 8.4 vs 5.6 ± 4.8; p < 0.001); (ii) interictal cluster headache vs controls (5.3 ± 5.2 vs 3.6 ± 2.8, p < 0.001); (iii) interictal chronic cluster headache vs interictal ECH in bout (5.9 ± 0.5 vs 3.8 ± 0.5, p = 0.009), and (iv) interictal episodic cluster headache in bout vs episodic cluster headache out-of-bout (5.2 ± 5.5 vs. 3.7 ± 4.3, p < 0.001). Subjective visual hypersensitivity was reported by 110/121 (91%; 9 missing) participants with cluster headache and was mostly unilateral in 70/110 (64%) and ipsilateral to the ictal pain in 69/70 (99%) participants.

Cluster headache is associated with increased ictal and interictal visual sensitivity. In contrast to migraine, this is mostly unilateral and ipsilateral on the side of the ictal pain.

To evaluate the frequency, distribution, and clinical associations of the dilated appearance of cerebral cortical veins, termed cortical veins sign on T2*-weighted gradient recalled-echo (T2*-GRE) in the acute setting of migraine with aura attack in adult patients.

We conducted a retrospective analysis of 60 consecutive patients admitted for acute neurological symptoms with a final diagnosis of migraine with aura (42%) or probable migraine with aura (58%) who underwent emergency brain magnetic resonance imaging and 60 non-migrainous control adults. The cortical veins sign was defined as a marked hypo-intensity and/or an apparent increased diameter of at least one cortical vein. We examined the prevalence, the spatial distribution, and the associations of cortical veins sign with clinical characteristics of migraine with aura.

We detected the cortical veins sign in 25 patients (42%) with migraine with aura, compared to none in the control group (p < 0.0001). The spatial distribution of cortical veins sign was characterised by the predominantly bilateral and posterior location. Presence of cortical veins sign was associated with increased severity of aura (p = 0.05), and shorter delay to MRI (p = 0.02).

In the setting of acute neurological symptoms, the presence of cortical veins sign is frequent in patients with migraine with aura and can be detected with good reliability. This imaging marker may help clinicians identify underlying migraine with aura.

First, we investigated whether the exposure to different visual feedback conditions may modulate pain perception by means of visual induced analgesia in patients with chronic migraine. Second, to comprehend the way emotional face expressions could induce visual analgesia, we evaluated the degree of identification with the four experimental conditions.

In a 1 × 4 within-subject study design, 38 female chronic migraine patients were exposed to different visual stimuli – positive face, neutral face, negative face, and control (white screen) – during a migraine attack. Visual stimuli were presented 3 times in a randomized order (each condition lasted 40 seconds). Migraine pain ratings and identification scores were assessed immediately after the observation of each visual condition.

We observed a significant difference in pain ratings between the positive (median: 30, 95% CI 26.69 to 38.20) and the negative (median: 30, 95% CI 33.09 to 44.13) (z = −4.46, p < 0.0001) facial expressions or the neutral facial expression (median: 30, 95% CI 31.89 to 42.41) (z = 3.41, p < 0.001). Participants identified more with the neutral face condition than with the other conditions.

Observation of a positive emotional face resulted sufficient to modulate pain perception possibly via the mediation of emotion regulation for positive emotions. This study paves the way for the integration of new cognitive behavioural interventions based on the adoption of visual induced analgesia to further control pain perception in chronic migraine patients.

Immunogenicity of erenumab, a human anti-calcitonin gene-related peptide receptor monoclonal antibody developed for migraine prevention, has been evaluated throughout clinical development.

Integrated post hoc analysis assessing immunogenicity of erenumab across six clinical trials in patients with episodic and chronic migraine (N = 2985). Anti-erenumab antibody incidence and potential impact on pharmacokinetics, efficacy, and safety were evaluated in short-term (double-blind treatment phase 12–24 weeks) and long-term (double-blind treatment phase plus extensions of up to 5 years) analyses.

Anti-erenumab binding antibody incidence was low with few patients developing neutralizing antibodies. Antibody responses were mostly transient with low magnitude. Binding antibodies developed as early as 2–4 weeks after the first dose; the majority developed within the first 6 months and very few after the first year. Serum concentrations of erenumab in antibody-positive patients were generally lower than, but within the range of, antibody-negative patients. There was no impact of anti-erenumab antibodies on erenumab efficacy or safety with no differences between antibody-positive and antibody-negative patients in change in monthly migraine days or adverse event rates.

This pooled analysis showed that immunogenicity had no meaningful clinical impact on efficacy or safety of erenumab in patients with migraine.

Clinical Trial Registration: ClinicalTrials.gov, NCT01952574; ClinicalTrials.gov, NCT02456740; Clinicaltrials.gov NCT02483585; Clinicaltrials.gov, NCT02174861; Clinicaltrials.gov, NCT02630459; Clinicaltrials.gov, NCT03812224

Individuals with migraine present ictal elevation of endothelin-1 levels. Migraine can be subclassified into episodic migraine and chronic migraine. Apart from the inconsistent reports on interictal endothelin-1 levels, most studies did not distinguish between episodic migraine and chronic migraine.

We measured plasma endothelin-1 levels in participants with episodic migraine (n = 87), with chronic migraine (n = 88), and controls (n = 50).

Interictal endothelin-1 levels were not significantly different among participants with episodic migraine, those with chronic migraine, and controls (pg/ml, median and interquartile range, 10.19 [7.76–13.69] vs. 9.25 [6.91–10.73] vs. 9.46 [7.00–14.19], p = 0.131). After excluding participants with fibromyalgia (n = 50) and medication-overuse headache (n = 21), endothelin-1 levels were still similar among groups (10.51 [7.96–14.10] vs. 9.24 [6.96–10.81] vs. 9.46 [7.00–14.19], p = 0.230). Endothelin-1 levels did not significantly differ among participants with migraine with aura, those with migraine without aura, and controls (9.36 [4.26–13.35] vs. 9.50 [7.23–13.02] vs. 9.46 [7.00–14.19], p = 0.975). There was no significant association of endothelin-1 with headache intensity (mild, 8.99 [8.99–8.99] vs. moderate, 8.71 [6.85–12.15] vs. severe, 9.55 [7.23–13.13], p = 0.517) or headache frequency per month (exponential and 95% confidence interval, 0.709 [0.296–1.698], p = 0.440) in participants with episodic migraine and chronic migraine.

Interictal plasma endothelin-1 level is an unlikely marker for episodic migraine and chronic migraine.

Fremanezumab, a fully humanized monoclonal antibody that selectively targets calcitonin gene-related peptide, has demonstrated efficacy for preventive treatment of episodic and chronic migraine. Since calcitonin gene-related peptide is expressed within the cardio- and cerebrovascular system and may have cardioprotective effects, it is critical to understand the cardio- and cerebrovascular safety of fremanezumab.

This was a pooled analysis of three randomized, double-blind, placebo-controlled, phase 3, 12-week trials in which patients with episodic migraine or chronic migraine received quarterly fremanezumab, monthly fremanezumab, or placebo. Incidences of overall and serious adverse events were analyzed. Cardio- and cerebrovascular adverse events (CVAEs) were analyzed in subgroups stratified by cardio- and cerebrovascular medical history, cardiovascular risk factors (CVRFs), and use of cardio- and cerebrovascular medications or triptans.

Two thousand, eight hundred and forty-two patients were included in the study. Overall (58–65%) and serious adverse events (<1–2%) occurred in similar proportions across fremanezumab and placebo groups. CVAEs were infrequent, regardless of cardio- and cerebrovascular medical history (2–6%). CVAEs occurred in low, similar proportions of patients with CVRFs and those using cardio- and cerebrovascular medications or triptans. No cardio- and cerebrovascular signals were identified.

Fremanezumab demonstrated a favorable overall and cardio- and cerebrovascular safety profile in more than 2800 patients with episodic migraine or chronic migraine, regardless of cardio- and cerebrovascular medical history, CVRFs, or medication use.

Trial Registrations: NCT02629861 (HALO EM, https://clinicaltrials.gov/ct2/show/NCT02629861), NCT02621931 (HALO CM, https://clinicaltrials.gov/ct2/show/NCT02621931), NCT03308968 (FOCUS, https://clinicaltrials.gov/ct2/ show/NCT03308968)

To systematically review clinical studies investigating the involvement of adenosine and its receptors in migraine pathophysiology.

Adenosine is a purinergic signaling molecule, clinically used in cardiac imaging during stress tests. Headache is a frequent adverse event after intravenous adenosine administration. Migraine headache relief is reported after intake of adenosine receptor antagonist, caffeine. These findings suggest a possible involvement of adenosine signaling in migraine pathophysiology and its potential as a drug target.

A search through PubMed and EMBASE was undertaken for clinical studies investigating the role of adenosine and its receptors in migraine, published until September 2021.

A total of 2510 studies were screened by title and abstract. Of these, seven clinical studies were included. The main findings were that adenosine infusion induced headache, and plasma adenosine levels were elevated during ictal compared to interictal periods in migraine patients.

The present systematic review emphasizes a potentially important role of adenosine signaling in migraine pathogenesis. Further randomized and placebo-controlled clinical investigations applying adenosine receptors modulators in migraine patients are needed to further understand the adenosine involvement in migraine.

Headaches with marked, specific response to indomethacin occur in children, but the phenotypic spectrum of this phenomenon has not been well-studied.

We reviewed pediatric patients with headache showing ≥80% improvement with indomethacin, from seven academic medical centers.

We included 32 pediatric patients (16 females). Mean headache onset age was 10.9 y (range 2–16 y). Headache syndromes included hemicrania continua (n = 13), paroxysmal hemicrania (n = 10), primary stabbing headache (n = 2), short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (n = 1), primary exercise headache (n = 1) and primary cough headache (n = 1). Adverse events were reported in 13, most commonly gastrointestinal symptoms, which often improved with co-administration of gastro-protective agents.

Indomethacin-responsive headaches occur in children and adolescents, and include headache syndromes, such as primary cough headache, previously thought to present only in adulthood. The incidence of adverse events is high, and patients must be co-treated with a gastroprotective agent.

To investigate how cluster headache preventatives verapamil, lithium and prednisone affect expression of hypothalamic genes involved in chronobiology.

C57Bl/6 mice were exposed to daily, oral treatment with verapamil, lithium, prednisone or amitriptyline (as negative control), and transcripts of multiple genes quantified in the anterior, lateral and posterior hypothalamus.

Verapamil, lithium or prednisone did not affect expression of clock genes of the anterior hypothalamus (Clock, Bmal1, Cry1/2 and Per1/2). Prednisone altered expression of hypothalamic neuropeptides melanin-concentrating hormone and histidine decarboxylase within the lateral and posterior hypothalamus, respectively. The three preventatives did not affect expression of the neurohypophyseal hormones oxytocin and arginine-vasopressin in the posterior hypothalamus. Conversely, amitriptyline reduced mRNA levels of Clock, oxytocin and arginine-vasopressin.

Data suggest that cluster headache preventatives act upstream or downstream from the hypothalamus. Our findings provide new insights on hypothalamic homeostasis during cluster headache prophylaxis, as well as neurochemistry underlying cluster headache treatment.

Headache is a frequent symptoms of coronavirus disease 2019 (COVID-19). Its long-term evolution remains unknown. We aim to evaluate the long-term duration of headache in patients that presented headache during the acute phase of COVID-19.

This is a post-hoc multicenter ambisective study including patients from six different third-level hospitals between 1 March and 27 April 2020. Patients completed 9 months of neurological follow-up.

We included 905 patients. Their median age was 51 (IQR 45–65), 66.5% were female, and 52.7% had a prior history of primary headache. The median duration of headache was 14 (6–39) days; however, the headache persisted after 3 months in 19.0% (95% CI: 16.5–21.8%) and after 9 months in 16.0% (95% confidence interval: 13.7–18.7%). Headache intensity during the acute phase was associated with a more prolonged duration of headache (Hazard ratio 0.655; 95% confidence interval: 0.582–0.737).

The median duration of headache was 2 weeks, but in approximately a fifth of patients it became persistent and followed a chronic daily pattern.