Cephalalgia

To investigate the role of calcitonin gene-related peptide (CGRP) in persistent post-traumatic headache (PTH) attributed to mild traumatic brain injury (TBI).

A total of 100 individuals with persistent PTH attributed to mild TBI and 100 age- and gender-matched healthy controls were enrolled between July 2018 and June 2019. Blood was drawn from the antecubital vein and subsequently analyzed using a validated radioimmunoassay for human CGRP. Measurements were performed on coded samples by a board-certified laboratory technician who was blind to clinical information.

CGRP plasma levels were lower in subjects with persistent PTH (mean, 75.8 pmol/L; SD, 26.4 pmol/L), compared with age- and gender-matched healthy controls (mean, 88.0 pmol/L; SD, 34.1 pmol/L) (p = 0.04). No correlation was found of CGRP plasma levels with monthly headache days (r = −0.11; p = 0.27), monthly migraine-like days (r = 0.15; p = 0.13), headache quality (r = −0.14; p = 0.15), or a chronic migraine-like headache phenotype (r = −0.02; p = 0.85).

CGRP plasma measurements are unlikely a feasible blood-based biomarker of persistent PTH. Future studies should assess whether CGRP plasma measurements can be used to predict development of persistent PTH.

Recent clinical findings suggest that oxytocin could be a novel treatment for migraine. However, little is known about the role of this neuropeptide/hormone and its receptor in the trigeminovascular pathway. Here we determine expression, localization, and function of oxytocin and oxytocin receptors in rat trigeminal ganglia and targets of peripheral (dura mater and cranial arteries) and central (trigeminal nucleus caudalis) afferents.

The methods include immunohistochemistry, messenger RNA measurements, quantitative PCR, release of calcitonin gene-related peptide and myography of arterial segments.

Oxytocin receptor mRNA was expressed in rat trigeminal ganglia and the receptor protein was localized in numerous small to medium-sized neurons and thick axons characteristic of A∂ sensory fibers. Double immunohistochemistry revealed only a small number of neurons expressing both oxytocin receptors and calcitonin gene-related peptide. In contrast, double immunostaining showed expression of the calcitonin gene-related peptide receptor component receptor activity-modifying protein 1 and oxytocin receptors in 23% of the small cells and in 47% of the medium-sized cells. Oxytocin immunofluorescence was observed only in trigeminal ganglia satellite glial cells. Oxytocin mRNA was below detection limit in the trigeminal ganglia. The trigeminal nucleus caudalis expressed mRNA for both oxytocin and its receptor. K⁺-evoked calcitonin gene-related peptide release from either isolated trigeminal ganglia or dura mater and it was not significantly affected by oxytocin (10 µM). Oxytocin directly constricted cranial arteries ex vivo (pEC₅₀ ∼ 7); however, these effects were inhibited by the vasopressin V_1A antagonist SR49059.

Oxytocin receptors are extensively expressed throughout the rat trigeminovascular system and in particular in trigeminal ganglia A∂ neurons and fibers, but no functional oxytocin receptors were demonstrated in the dura and cranial arteries. Thus, circulating oxytocin may act on oxytocin receptors in the trigeminal ganglia to affect nociception transmission. These effects may help explain hormonal influences in migraine and offer a novel way for treatment.

Several neurotransmitters are expressed in the neurons of the trigeminal ganglion. One such signalling molecule is the pituitary adenylate cyclase-activating peptide (PACAP). PACAP signalling has been suggested to have a possible role in the pathophysiology of primary headaches.

The present study was designed to investigate the relationship between PACAP and calcitonin gene-related peptide, currently the two most relevant migraine peptides.

In the current study, we used ELISA to investigate PACAP and calcitonin gene-related peptide release in response to 60 mM K⁺ or capsaicin using a rat hemi-skull model. We combined this analysis with qPCR and immunohistochemistry to study the expression of PACAP and calcitonin gene-related peptide receptors and ligands.

Calcitonin gene-related peptide (CGRP) is released from the trigeminal ganglion and dura mater. In contrast, PACAP is only released from the trigeminal ganglion. We observed a weak correlation between the stimulated release of the two neuropeptides. PACAP-38 immunoreactivity was expressed alone and in a subpopulation of neurons in the trigeminal ganglion that also store calcitonin gene-related peptide. The receptor subtype PAC₁ was mainly expressed in the satellite glial cells (SGCs), which envelop the neurons in the trigeminal ganglion, in some neuronal processes, inside the Aδ-fibres and in the outermost layer of the myelin sheath that envelopes the Aδ-fibres.

Unlike CGRP, PACAP is only released within the trigeminal ganglion. This raises the question of whether a migraine therapy aimed at preventing peripheral PACAP signalling would be as successful as the CGRP signalling targeted treatments.

The Transient Receptor Potential Ankyrin 1 (TRPA1) channel might play a role in migraine. However, different mechanisms for this have been suggested. The purpose of our study was to investigate the localization and significance of TRPA1 channels in rat pial and dural arteries.

Immunofluorescence microscopy was used to localize TRPA1 channels in dural arteries, pial arteries, dura mater and trigeminal ganglion. The genuine closed cranial window model was used to examine the effect of Na₂S, a donor of the TRPA1 channel opener H₂S, on the diameter of pial and dural arteries. Further, we performed blocking experiments with TRPA1 antagonist HC-030031, calcitonin gene-related peptide (CGRP) receptor antagonist olcegepant and K_Ca3.1 channel blocker TRAM-34.

TRPA1 channels were localized to the endothelium of both dural and pial arteries and in nerve fibers in dura mater. Further, we found TRPA1 expression in the membrane of trigeminal ganglia neuronal cells, some of them also staining for CGRP. Na₂S caused dilation of both dural and pial arteries. In dural arteries, this was inhibited by HC-030031 and olcegepant. In pial arteries, the dilation was inhibited by TRAM-34, suggesting involvement of the K_Ca3.1 channel.

Na₂S causes a TRPA1- and CGRP-dependent dilation of dural arteries and a K_Ca3.1 channel-dependent dilation of pial arteries in rats.

The current study explored whether the chances of having migraine are influenced by a youth’s friendship with a migraineur.

The study was centered on a community-based non-referral cohort of eighth graders from two middle schools in Taiwan. Among the 642 recruited adolescent students, 610 (95%) (mean age 14.1 years, male ratio 51.2%) nominated three good friends and completed a validated headache questionnaire for migraine diagnosis at the follow-up survey 1 year later. To explore social influences on incident migraine, we used longitudinal statistical models to examine whether the development of migraine in one adolescent during the 1-year observational period was associated with that in his/her friends.

Overall, 1700 social ties were established in the social network based on the reported lists of good friends. Randomization test for the homophily effect demonstrated that the students with migraine tended to cluster together in the social network even when those with incident migraine were also considered (p = 0.003). Besides, when friendship choices were mutual, the relative risk of an adolescent becoming a migraineur was 3.26 (95% CI: 1.25–8.47, p = 0.015) if his/her friend became a migraineur (induction) during the 1-year observational period.

To the best of our knowledge, this is the first study to demonstrate that migraine may spread through social networks in young adolescents. Both homophily and induction effects are possibly contributory.

Pain freedom after 2 hours is the recommended primary endpoint by the International Headache Society in randomized trials investigating drug treatment of acute migraine attacks. In order to demonstrate an early effect of a drug, some drug companies, however, have promoted headache relief (improvement from severe or moderate pain to mild or no pain) at earlier time points than 2 hours as outcome parameter.

We analyzed the relationship between pain freedom and headache relief in acute migraine trials and observed that persistent mild headache constituted 90% of headache relief after 0.5 hour and 40% of headache relief after 2 hours.

Headache relief at 2 hours should in our view only be used as an outcome measure for comparison with historic data. Prior to 2 hours, headache relief varies with time from intake and the therapeutic gain is very small. Therefore, pain freedom should be used at these early time points.

Anti-calcitonin gene-related peptide antibodies proved effective in the preventive treatment of chronic migraine. In this open label study, we aim to assess the effects of erenumab administration on neurophysiological and biomolecular profiles in a representative cohort of chronic migraine patients.

Forty patients with a history of chronic migraine for at least 12 months prior to enrollment, and previous failure of at least two different preventive therapies, were enrolled. After a 1-month observation period (T0), patients were treated with erenumab 70 mg s.c. (every 28 days) for a total of three administrations. At week 12, they returned for the end-of-protocol visit (T3). At T0 and T3, patients underwent recording of clinical features, recording of single stimulus (RTh), temporal summation (TST) thresholds of the nociceptive withdrawal reflex, venous blood sampling for miR-382-5p, and miR-34a-5p quantification.

At T3, 31 patients (77.5%) qualified as 30% Responders (reduction in monthly migraine days by at least 30% in the last 4-week observation period). RTh (T0: 15.4 ± 8.1 mA, T3: 19.7 ± 8.2 mA) as well as TST (T0: 11.2 ± 5.8 mA, T3: 13.4 ± 5.0 mA) significantly increased at T3 in 30% Responders (p = 0.001 for both), while we did not observe significant changes in NON-responder patients. MiR-382-5p and miR-34a-5p levels were significantly lower after erenumab administration in the overall study population (p = 0.015, and p = 0.001, respectively), without significant differences between 30% Responder and NON-responder groups.

Different migraine phenotypes, characterized by different treatment susceptibility, may exist as suggested by the divergent behavior between neurophysiological and biomolecular findings in 30% Responder vs. NON-responder patients.

The study protocol was registered at clinicaltrials.gov (NCT04361721).

Damage of the optic nerve is the major complication of idiopathic intracranial hypertension. A biomarker indicative for optic nerve damage would help identifying high-risk patients requiring surgical procedures. Here, we studied the potential of cerebrospinal fluid neurofilament to predict idiopathic intracranial hypertension-induced optic nerve damage.

In two centers, serum and cerebrospinal fluid of 61 patients with clinically suspected idiopathic intracranial hypertension were prospectively collected. Neurofilament concentrations were measured and related to ophthalmological assessment.

The average cerebrospinal fluid neurofilament concentration in patients with moderate and severe papilledema was increased compared to patients with minor and no papilledema (1755 ± 3507 pg/ml vs. 244 ± 102 pg/ml; p < 0.001). Cerebrospinal fluid neurofilament concentrations correlated with the maximal lumbar puncture opening pressure (r = 0.67, p < 0.001). In patients fulfilling the Friedman criteria for idiopathic intracranial hypertension with or without papilledema (n = 35), development of bilateral visual field defects and bilateral atrophy of the optic nerve were associated with increased average age-adjusted cerebrospinal fluid neurofilament concentrations. At last follow-up (n = 30), 8/13 of patients with increased, but only 3/17 with normal, cerebrospinal fluid neurofilament had developed bilateral visual field defects and/or bilateral optic nerve atrophy resulting in a sensitivity of 72.7% and a specificity of 73.7% of cerebrospinal fluid neurofilament to detect permanent optic nerve damage.

Cerebrospinal fluid neurofilament is a putative biomarker for optical nerve damage in idiopathic intracranial hypertension.

Reduced blood or cerebrospinal fluid levels of allopregnanolone are involved in menstrual cycle-linked CNS disorders, such as catamenial epilepsy. This condition, like menstrually-related migraine, is characterized by severe, treatment-resistant attacks. We explored whether there were differences in allopregnanolone, progesterone and testosterone serum levels between women with menstrually-related migraine (MM, n = 30) or postmenopausal migraine without aura who had suffered from menstrually-related migraine during their fertile age (PM, n = 30) and non-headache control women in fertile age (FAC, n = 30) or post-menopause (PC, n = 30).

Participants were women with migraine afferent to a headache centre; controls were female patients’ acquaintances. Serum samples obtained were analyzed by HPLC-ESI-MS/MS.

In menstrually-related migraine and postmenopausal migraine groups, allopregnanolone levels were lower than in the respective control groups (fertile age and post-menopause) (p < 0.001, one-way analysis of variance followed by Tukey-Kramer post-hoc comparison test) while progesterone and testosterone levels were similar. By grouping together patients with migraine, allopregnanolone levels were inversely correlated with the number of years and days of migraine/3 months (p ≤ 0.005, linear regression analysis).

Decreased GABAergic inhibition, due to low allopregnanolone serum levels, could contribute to menstrually-related migraine and persistence of migraine after menopause. For the management of these disorders, a rise in the GABAergic transmission by increasing inhibitory neurosteroids might represent a novel strategy.

YouTube is the most widely used video hosting website in the world; however, the quality and reliability of information is unknown. The aim of this study is to evaluate the content and distribution of the most popular videos on YouTube about migraine.

We searched for migraine-related videos on the online video hosting resource YouTube (http://youtube.com/). Two authors screened the titles and video descriptions independently for all videos with a view count of ≥ 10,000 views. For each video we recorded descriptive data, the source/author and the primary purpose/content.

We identified 351 eligible videos. In total, there was more than 3 days of content viewed more than 163 million times. Only 9% of these videos were authored by healthcare professionals. The majority (44%) of videos focused on complementary and alternative medicine.

YouTube provides a wide array of easily accessible information on migraine, ranging from authoritative sources to potentially questionable content. If used uncritically, this may result in inadequate clinical management. Peer-reviewed information on migraine mechanisms and treatment is needed to provide the best available evidence for the public and patients. Ideally, a professional society or foundation such as the International Headache Society would develop, curate, and distribute content.

Non-invasive vagus nerve stimulation (nVNS) is a proven treatment for cluster headache and migraine. Several possible mechanisms of action by which nVNS mitigates headache have been identified.

We conducted a narrative review of recent scientific and clinical research into nVNS for headache, including findings from mechanistic studies and their possible relationships to the clinical effects of nVNS.

Findings from animal and human studies have provided possible mechanistic explanations for nVNS efficacy in headache involving four core areas: Autonomic nervous system functions; cortical spreading depression inhibition; neurotransmitter regulation; and nociceptive modulation. We discuss how overlap and interplay among these areas may underlie the utility of nVNS in the context of clinical evidence supporting its safety and efficacy as acute and preventive therapy for both cluster headache and migraine. Possible future nVNS applications are also discussed.

Significant progress over the past several years has yielded valuable mechanistic and clinical evidence that, combined with the excellent safety and tolerability profile of nVNS, suggests that it should be considered a first-line treatment for both acute and preventive treatment of cluster headache, an effective option for acute treatment of migraine, and a highly relevant, practical option for migraine prevention.

Trigemino-autonomic cephalalgias are very rare disorders and even rarer in children and adolescents. We report the onset of paroxysmal hemicrania in a very young girl and reviewed the scientific literature for similar cases.

We describe the case of a 1.6-year-old girl with left-sided headache attacks fulfilling the criteria of paroxysmal hemicrania including prompt responsiveness to indomethacin. In addition, we detected at least two children for every trigemino-autonomic cephalalgias subtype with an age of under 7 years at the onset of the trigemino-autonomic cephalalgias. Remarkable features were a vast majority of chronic course from onset on and left-sided attacks.

Although very rare, trigemino-autonomic cephalalgias can occur even in very young children under the age of 6 years. This should be known in neuropaediatrics.

Topiramate is a drug commonly used by physicians. However, it has various systemic and ocular adverse effects. Bilateral angle closure crisis is a potentially blinding adverse reaction that is seldom reported in non-ophthalmic journals.

This article aims to report a case series of topiramate-induced angle closure crisis in the eyes.

Most patients presented to us with blurred vision and high intra-ocular pressure within days of starting topiramate tablet for headache. However, the attack resolved in those who presented early with prompt treatment, which included stopping topiramate.

Physicians prescribing topiramate must be well aware of this potentially blinding adverse effect. Educating the patient about this possible side effect is important. Timely referral and treatment can prevent blindness in these individuals.

Eagle’s syndrome, also called stylohyoid complex syndrome, is a rare syndrome pathology characterised by latero-cervical pain radiating to the face, linked to an abnormal enlargement of the styloid or calcification of the stylo-hyoid ligament.

We report here the case of a young man of 25 suffering from cluster headache resistant to treatments, revealing Eagle’s syndrome.

Only surgery led to a real improvement of his condition.