Cephalalgia

Impaired oxygen utilization and cerebrovascular dysfunction are implicated in migraine. High-flow oxygen is effective in cluster headache and has shown promise in animal models of migraine, but has not been adequately studied in patients with migraine.

In this randomized, crossover-design, placebo-controlled trial, adult migraineurs self-administered high-flow oxygen or medical air at 10–15 l/min via face mask in blinded fashion starting soon after symptom onset for 30 minutes, for a total of four migraine attacks. Participants recorded the severity of headache, nausea, and visual symptoms on visual analog scales periodically up to 60 minutes.

We enrolled 22 individuals (mean age 36 years, 20 women) who self-treated 64 migraine attacks (33 oxygen, 31 air). The pre-specified primary endpoint (mean decrease in pain score from baseline to 30 minutes) was 1.38 ± 1.42 in oxygen-treated and 1.22 ± 1.61 in air-treated attacks (p = 0.674). Oxygen therapy resulted in relief (severity score 0–1) of pain (24% versus 6%, p = 0.05), nausea (42% versus 23%, p = 0.08) and visual symptoms (36% versus 7%, p = 0.004) at 60 minutes. Exploratory analysis showed that in moderately severe attacks (baseline pain score <6), pain relief was achieved in six of 13 (46%) oxygen versus one of 15 (7%) air (p = 0.02). Gas therapy was used per protocol in 91% of attacks. There were no significant adverse events.

High-flow oxygen may be a feasible and safe strategy to treat acute migraine. Further studies are required to determine if this relatively inexpensive, widely available treatment can be used as an adjunct or alternative migraine therapy.

Familial hemiplegic migraine (FHM) is a rare monogenic migraine subtype characterised by attacks associated with transient motor weakness. Clinical information is mainly based on reports of small families with only short follow-up. Here, we document a prospective 15-year follow-up of an extended family with FHM type 2.

After diagnosing FHM in a patient with severe attacks associated with coma and fever, we identified eight more family members with FHM and one with possible FHM. All family members were prospectively followed for 15 years. In total 13 clinically affected and 21 clinically non-affected family members were genetically tested and repeatedly investigated.

A novel p.Arg348Pro ATP1A2 mutation was found in 14 family members: 12 with clinical FHM, one with psychomotor retardation and possible FHM, and one without FHM features. In 9/12 (75%) family members with genetically confirmed FHM, attacks were severe, long-lasting, and often associated with impaired consciousness and fever. Such attacks were frequently misdiagnosed and treated as viral meningitis or stroke. Epilepsy was reported in three family members with FHM and in the one with psychomotor retardation and possible FHM. Ataxia was not observed.

FHM should be considered in patients with recurrent coma and fever.

Chronic cluster headache is rare and some of these patients become drug-resistant. Occipital nerve stimulation has been successfully employed in open studies to treat chronic drug-resistant cluster headache. Data from large group of occipital nerve stimulation-treated chronic cluster headache patients with long duration follow-up are advantageous.

Efficacy of occipital nerve stimulation has been evaluated in an experimental monocentric open-label study including 35 chronic drug-resistant cluster headache patients (mean age 42 years; 30 men; mean illness duration: 6.7 years). The primary end-point was a reduction in number of daily attacks.

After a median follow-up of 6.1 years (range 1.6–10.7), 20 (66.7%) patients were responders (≥50% reduction in headache number per day): 12 (40%) responders showed a stable condition characterized by sporadic attacks, five responders had a 60–80% reduction in headache number per day and in the remaining three responders chronic cluster headache was transformed in episodic cluster headache. Ten (33.3%) patients were non-responders; half of these have been responders for a long period (mean 14.6 months; range 2–48 months). Battery depletion (21 patients 70%) and electrode migration (six patients – 20%) were the most frequent adverse events.

Occipital nerve stimulation efficacy is confirmed in chronic drug-resistant cluster headaches even after an exceptional long-term follow-up. Tolerance can occur years after improvement.

Neuroimaging studies revealed structural and functional changes in medication-overuse headache (MOH), but it remains unclear whether similar changes could be observed in other chronic pain disorders.

In this cross-sectional study, we investigated functional connectivity (FC) with resting-state functional magnetic resonance imaging (fMRI) and white matter integrity using diffusion tensor imaging (DTI) to measure fractional anisotropy (FA) and mean diffusivity (MD) in patients with MOH (N = 12) relative to two control groups: patients with chronic myofascial pain (MYO; N = 11) and healthy controls (CN; N = 16).

In a data-driven approach we found hypoconnectivity in the fronto-parietal attention network in both pain groups relative to CN (i.e. MOH < CN and MYO < CN). In contrast, hyperconnectivity in the saliency network (SN) was detected only in MOH, which correlated with FA in the insula. In a seed-based analysis we investigated FC between the periaqueductal grey (PAG) and all other brain regions. In addition to overlapping hyperconnectivity seen in patient groups (relative to CN), MOH had a distinct connectivity pattern with lower FC to parieto-occipital regions and higher FC to orbitofrontal regions compared to controls. FA and MD abnormalities were mostly observed in MOH, involving the insula.

Hyperconnectivity within the SN along with associated white matter changes therein suggest a particular role of this network in MOH. In addition, abnormal connectivity between the PAG and other pain modulatory (frontal) regions in MOH are consistent with dysfunctional central pain control.

Stress is the most commonly reported migraine trigger. Dynorphin, an endogenous opioid peptide acting preferentially at kappa opioid receptors (KORs), is a key mediator of stress responses. The aim of this study was to use an injury-free rat model of functional cephalic pain with features of migraine and medication overuse headache (MOH) to test the possible preventive benefit of KOR blockade on stress-induced cephalic pain.

Following sumatriptan priming to model MOH, rats were hyper-responsive to environmental stress, demonstrating delayed cephalic and extracephalic allodynia and increased levels of CGRP in the jugular blood, consistent with commonly observed clinical outcomes during migraine. Nor-binaltorphimine (nor-BNI), a long-acting KOR antagonist or CYM51317, a novel short-acting KOR antagonist, were given systemically either during sumatriptan priming or immediately before environmental stress challenge. The effects of KOR blockade in the amygdala on stress-induced allodynia was determined by administration of nor-BNI into the right or left central nucleus of the amygdala (CeA).

KOR blockade prevented both stress-induced allodynia and increased plasma CGRP. Stress increased dynorphin content and phosphorylated KOR in both the left and right CeA in sumatriptan-primed rats. However, KOR blockade only in the right CeA prevented stress-induced cephalic allodynia as well as extracephalic allodynia, measured in either the right or left hindpaws. U69,593, a KOR agonist, given into the right, but not the left, CeA, produced allodynia selectively in sumatriptan-primed rats. Both stress and U69,593-induced allodynia were prevented by right CeA U0126, a mitogen-activated protein kinase inhibitor, presumably acting downstream of KOR.

Our data reveal a novel lateralized KOR circuit that mediated stress-induced cutaneous allodynia and increased plasma CGRP in an injury-free model of functional cephalic pain with features of migraine and medication overuse headache. Selective, small molecule, orally available, and reversible KOR antagonists are currently in development and may represent a novel class of preventive therapeutics for migraine.

In the CAMERA population-based MRI study, migraineurs below the age of 50 had decreased T2-values indicative of increased iron deposition in several deep brain nuclei. Longer migraine history was associated with lower T2-values, suggesting an association between migraine attacks and iron accumulation. In the present nine-year follow-up study of the CAMERA cohort we re-measured the T2-values in deep brain nuclei to assess the evolution over time.

Baseline and follow-up T2-values measured in several basal ganglia of 128 participants (38 control, 90 migraine) were analyzed using quantitative T2 measurements and multivariate regression analysis.

T2-values of most deep brain nuclei were increased – instead of an expected further decrease when only age-related iron accumulation would have played a role – compared to baseline (both among controls and migraineurs) and were not different in either group. In migraineurs, no differences were found by gender, migraine severity or subtype.

This study did not provide supportive data for migraine related increased iron accumulation in deep brain nuclei, but neither is it able to reject such hypotheses. Increased T2-values probably point at microstructural tissue changes that counteracted earlier accumulated iron effects. We hypothesize that, with aging, migraine-induced iron-related brain changes are obscured by other age-related tissue changes.

Autonomic dysfunction and light sensitivity are core features of the migraine attack. Growing evidence also suggests changes in these parameters between attacks. Though sensory and autonomic responses likely interact, they have not been studied together across the spectrum of disease in migraine.

We performed digital infrared pupillometry while collecting interictal photophobia thresholds (PPT) in 36 migraineurs (14 episodic; 12 chronic; 10 probable) and 24 age and sex-matched non-headache controls. Quantitative pupillary light reflexes (PLR) were assessed in a subset of subjects, allowing distinction of sympathetic vs parasympathetic pupillary function. A structured questionnaire was used to ascertain migraine diagnosis, headache severity, and affective symptoms.

Photophobia thresholds were significantly lower in migraineurs than controls, and were lowest in chronic migraine, consistent with a disease-related gradient. Lower PPT correlated with smaller dark-adapted pupil size and larger end pupil size at PPT, which corresponded to a reduced diameter change. On PLR testing, measures of both parasympathetic constriction and sympathetic re-dilation were reduced in migraineurs with clinically severe migraine.

In summary, we show that severity of photophobia in migraine scales with disease severity, in association with shifts in pupillary light responses. These alterations suggest centrally mediated autonomic adaptations to chronic light sensitivity.

Presently, there is no evidence to guide the acute treatment of migraine aura. We aimed to describe the effect of greater occipital nerve (GON) anaesthetic block as a symptomatic treatment for long-lasting (prolonged or persistent) migraine aura.

Patients who presented with migraine aura lasting > 2 hours were consecutively recruited during one year at the Headache Unit and the Emergency Department of a tertiary hospital. All patients underwent a bilateral GON block with bupivacaine 0.5%. Patients were followed up for 24 hours.

A total of 22 auras were treated in 18 patients. Auras consisted of visual (n = 13), visual and sensory (n = 4) or sensory symptoms alone (n = 5). Eleven episodes met diagnostic criteria for persistent aura (>1 week) without infarction. The response was complete without early recurrence in 11 cases (50%), complete with recurrence in < 24 hours in two cases (9.1%), and partial with ≥ 50% improvement in six cases (27.3%). Complete responses without recurrence were more common in cases with prolonged auras lasting < 1 week than in those with persistent auras (72.7% vs. 27.3%; p = 0.033).

GON block could be an effective symptomatic treatment for prolonged or persistent migraine aura. Randomised controlled trials are still required to confirm these results.