See Moskowitz (doi:10.1093/brain/awx099) for a scientific commentary on this article.The migraine aura is characterized by transient focal cortical disturbances causing dramatic neurological symptoms ...that are usually followed by migraine headache. It is currently not understood how the aura symptoms are related to the headache phase of migraine. Animal studies suggest that cortical spreading depression, the likely mechanism of migraine aura, causes disruption of the blood-brain barrier and noxious stimulation of trigeminal afferents leading to activation of brainstem nuclei and triggering of migraine headache. We used the sensitive and validated technique of dynamic contrast-enhanced high-field magnetic resonance imaging to simultaneously investigate blood-brain barrier permeability and tissue perfusion in the brainstem (at the level of the lower pons), visual cortex, and brain areas of the anterior, middle and posterior circulation during spontaneous attacks of migraine with aura. Patients reported to our institution to undergo magnetic resonance imaging during the headache phase after presenting with typical visual aura. Nineteen patients were scanned during attacks and on an attack-free day. The mean time from attack onset to scanning was 7.6 h. We found increased brainstem perfusion bilaterally during migraine with aura attacks. Perfusion also increased in the visual cortex and posterior white matter following migraine aura. We found no increase in blood-brain barrier permeability in any of the investigated regions. There was no correlation between blood-brain barrier permeability, brain perfusion, and time from symptom onset to examination or pain intensity. Our findings demonstrate hyperperfusion in brainstem during the headache phase of migraine with aura, while the blood-brain barrier remains intact during attacks of migraine with aura. These data thus contradict the preclinical hypothesis of cortical spreading depression-induced blood-brain barrier disruption as a possible mechanism linking aura and headache.awx089media15422686892001.
Evidence for a vascular factor in migraine Asghar, Mohammad S.; Hansen, Adam E.; Amin, Faisal M. ...
Annals of neurology,
April 2011, Volume:
69, Issue:
4
Journal Article
Peer reviewed
Open access
Objective
It has been suggested that migraine is caused by neural dysfunction without involvement of vasodilatation. Because dismissal of vascular mechanisms seemed premature, we examined diameter of ...extra‐ and intracranial vessels in migraine without aura patients.
Methods
A novel high‐resolution direct magnetic resonance angiography imaging technique was used to measure arterial circumference of the extracranial middle meningeal artery (MMA) and the intracranial middle cerebral artery (MCA). Data were obtained at baseline, during migraine attack, and after treatment with the migraine abortive drug sumatriptan (a 5‐hydroxytryptamine agonist).
Results
We found dilatation of both MMA and MCA during migraine attack (p = 0.001). Sumatriptan administration caused amelioration of headache (p
< 0.001) and contraction of MMA (p < 0.001), but MCA remained unchanged (p = 0.16). Exploratory analysis revealed that in migraine attacks with half‐sided headache, there was only dilatation on the headache side of MMA of 12.49% (95% confidence interval CI, 4.16–20.83%) and of MCA of 12.88% (95% CI, 3.49–22.27%) and no dilatation on the nonheadache side of MMA (95% CI, −4.27 to 11.53%) and MCA (95% CI, −6.7 to 14.28%). In double‐sided headache we found bilateral vasodilatation of both MMA and MCA (p
< 0.001).
Interpretation
These data show that migraine without aura is associated with dilatation of extra‐ and intracerebral arteries and that the headache location is associated with the location of the vasodilatation. Furthermore, contraction of extracerebral and not intracerebral arteries is associated with amelioration of headache. Collectively, these data suggest that vasodilatation and perivascular release of vasoactive substances is an integral mechanism of migraine pathophysiology. ANN NEUROL 2011
Endothelin-1 (ET-1) is a highly potent vasoconstrictor peptide released from vascular endothelium. ET-1 plays a major role in cerebrovascular disorders and likely worsens the outcome of acute ...ischaemic stroke and aneurismal subarachnoid haemorrhage through vasoconstriction and cerebral blood flow (CBF) reduction. Disorders that increase the risk of stroke, including hypertension, diabetes mellitus, and acute myocardial infarction, are associated with increased plasma levels of ET-1. The in vivo human cerebrovascular effects of systemic ET-1 infusion have not previously been investigated. In a two-way crossover, randomized, double-blind design, we used advanced 3 tesla MRI methods to investigate the effects of high-dose intravenous ET-1 on intra- and extracranial artery circumferences, global and regional CBF, and cerebral metabolic rate of oxygen (CMRO2) in 14 healthy volunteers. Following ET-1 infusion, we observed a 14% increase of mean arterial blood pressure, a 5% decrease of middle cerebral artery (MCA) circumference, but no effects on extracerebral arteries and no effects on CBF or CMRO2. Collectively, the findings indicate MCA constriction secondarily to blood pressure increase and not due to a direct vasoconstrictor effect of ET-1. We suggest that, as opposed to ET-1 in the subarachnoid space, intravascular ET-1 does not exert direct cerebrovascular effects in humans.
Objective
To demonstrate that calcitonin gene–related peptide (CGRP) induces headache exacerbation with migraine‐like features in patients with persistent post‐traumatic headache (PTH) attributed to ...mild traumatic brain injury (TBI).
Methods
A randomized, double‐blind, placebo‐controlled, two‐way crossover study was conducted. Analyses were intention‐to‐treat. Eligible patients were aged 18 to 65 years and had a history of persistent PTH after mild TBI for at least 12 months. Patients were randomized to receive an intravenous infusion of 1.5μg/min of CGRP or placebo (isotonic saline) over 20 minutes on two separate experimental days. A 12‐hour observational period was used to evaluate the following outcomes: (1) difference in incidence of headache exacerbation with migraine‐like features and (2) difference in area under the curve for headache intensity scores.
Results
Thirty patients (mean age = 37 years, 25 women 83%) were randomized and completed the study. During the 12‐hour observational period, 21 of 30 patients (70%) developed headache exacerbation with migraine‐like features after CGRP, compared with 6 patients (20%) after placebo (p < 0.001). The baseline‐corrected area under the curve for headache intensity scores was significantly larger after CGRP, compared with placebo (p < 0.001).
Interpretation
Patients with persistent PTH are hypersensitive to CGRP, which underscores its pathophysiological importance. Furthermore, CGRP‐targeted therapies might provide a novel mechanism‐based treatment option for patients with persistent PTH. ANN NEUROL 2020;88:1220–1228
Background
Persistent post-traumatic headache (PTH) is a common sequela of mild traumatic brain injury (TBI) and retrospective assessments have found a migraine-like phenotype to be very frequent. ...This has raised a discussion of shared underlying mechanisms and whether persistent PTH is simply trauma-triggered migraine.
Methods
A 28-day prospective diary study with daily entries and acquisition of data on headache characteristics, associated symptoms, and acute medication use. A total of 64 patients with persistent PTH were enrolled from April 2019 to August 2019. Outcomes were the proportion of monthly headache days of any intensity that met the criteria for a migraine-like day or TTH-like day, as well as the corresponding figures for monthly headache days of moderate to severe intensity. Headache phenotypes were initially assigned based on diagnostic evaluation by semi-structured interview, whilst final headache phenotypes were assigned by diary review.
Results
After diary review, we found that monthly headache days were exclusively migraine-like in 24 of 64 patients (38%) and exclusively TTH-like days in 8 of 64 patients (13%). Considering only monthly headache days of moderate to severe intensity, the corresponding figures were 35 of 64 patients (55%) for migraine-like days and 8 of 64 patients (13%) for TTH-like days. The following headache phenotypes were assigned based on diary review: chronic migraine-like (
n
= 47, 73%), combined episodic migraine-like and chronic TTH-like (
n
= 9, 13%), and ‘pure’ chronic TTH-like (
n
= 8, 13%).
Conclusions
A migraine-like phenotype is common in patients most adversely affected by persistent PTH, although some patients did have a pure chronic TTH-like phenotype. At minimum, these findings suggest that persistent PTH is – at least in some – not ‘trauma-triggered migraine’.
Vascular changes during spontaneous headache attacks have been studied over the last 30 years. The interest in cerebral vessels in headache research was initially due to the hypothesis of cerebral ...vessels as the pain source. Here, we review the knowledge gained by measuring the cerebral vasculature during spontaneous primary headache attacks with the use of single photon emission tomography (SPECT), positron emission tomography (PET), magnetic resonance imaging (MRA) and transcranial Doppler (TCD). Furthermore, the use of near-infrared spectroscopy in headache research is reviewed. Existing TCD studies of migraine and other headache disorders do not provide solid evidence for cerebral blood flow velocity changes during spontaneous attacks of migraine headache. SPECT studies have clearly shown cortical vascular changes following migraine aura and the differences between migraine with aura compared to migraine without aura. PET studies have shown focal activation in brain structures related to headache, but whether the changes are specific to different primary headaches have yet to be demonstrated. MR angiography has shown precise changes in large cerebral vessels during spontaneous migraine without aura attacks. Future development in more precise imaging methods may further elucidate the pathophysiological mechanisms in primary headaches.
Objective
Migraine displays clinical heterogeneity of attack features and attack triggers. The question is whether this heterogeneity is explained by distinct intracellular signaling pathways leading ...to attacks with distinct clinical features. One well-known migraine-inducing pathway is mediated by cyclic adenosine monophosphate and another by cyclic guanosine monophosphate. Calcitonin gene-related peptide triggers migraine via the cyclic adenosine monophosphate pathway and sildenafil via the cyclic guanosine monophosphate pathway. To date, no studies have examined whether migraine induction mediated via the cyclic adenosine monophosphate and cyclic guanosine monophosphate pathways yields similar attacks within the same patients.
Methods
Patients were subjected to migraine induction on two separate days using calcitonin gene-related peptide (1.5 µg/min for 20 minutes) and sildenafil (100 mg) in a double-blind, randomized, double-dummy, cross-over design. Data on headache intensity, characteristics and accompanying symptoms were collected until 24 hours after drug administration.
Results
Thirty-four patients were enrolled and 27 completed both study days. Seventeen patients developed migraine after both study drugs (63%; 95% CI: 42–81). Eight patients developed migraine on one day only (seven after sildenafil and one after calcitonin gene-related peptide). Two patients did not develop migraine on either day. Headache laterality, nausea, photophobia and phonophobia were similar between drugs in 77%, 65%, 100%, and 94%, respectively, of the 17 patients who developed attacks on both days.
Conclusion
A majority of patients developed migraine after both calcitonin gene-related peptide and sildenafil. This supports the hypothesis that the cyclic adenosine monophosphate and cyclic guanosine monophosphate intracellular signaling pathways in migraine induction converge in a common cellular determinator, which ultimately triggers the same attacks.
Trial registration: ClinicalTrials.gov Identifier: NCT03143465.
Background
Several previous studies have investigated cortical abnormalities, specifically cortical thickness, in patients with migraine, with variable results. The relatively small sample sizes of ...most previous studies may partially explain these inconsistencies.
Objective
To investigate differences of cortical thickness between control subjects and migraineurs in a large cohort.
Methods
Three Tesla MRI data of 131 patients (38 with and 93 without aura) and 115 control subjects were analysed. A vertex-wise linear model was applied controlling for age, gender and MRI scanner to investigate differences between groups and determine the impact of clinical factors on cortical thickness measures.
Results
Migraineurs showed areas of thinned cortex compared with controls bilaterally in the central sulcus, in the left middle-frontal gyrus, in left visual cortices and the right occipito-temporal gyrus. Frequency of migraine attacks and the duration of the disorder had a significant impact on cortical thickness in the sensorimotor cortex and middle-frontal gyrus. Patients without aura showed thinner cortex than controls bilaterally in the central sulcus and in the middle frontal gyrus, in the left primary visual cortices, in the left supramarginal gyrus and in the right cuneus. Patients with aura showed clusters of thinner cortex bilaterally in the subparietal sulcus (between the precuneus and posterior cingulate cortex), in the left intraparietal sulcus and in the right anterior cingulate.
Conclusion
These results indicate cortical abnormalities in specific brain regions in migraineurs. Some of the observed abnormalities may reflect a genetic susceptibility towards developing migraine attacks, while others are probably a consequence of repeated head pain attacks.
The middle meningeal artery is a proposed surrogate marker for activation of trigeminal nociceptors during migraine. Previous studies focused on the extracranial part of the artery; hence, ...vasoreactivity in the intradural arteries during migraine is unknown. Thirty-four patients with migraine without aura were given sildenafil on one day and calcitonin gene-related peptide on another in double-blind crossover fashion. Patients were scanned with 3.0 T MR angiography before drug administration and again 6 hours later during induced attacks of migraine. We measured circumference of the intradural segment of the middle meningeal artery before and during induced migraine attacks. The middle cerebral and superficial temporal arteries were also examined. Fourteen patients had attacks during the second scan after both study drugs and 11 had a migraine after either one or the other, resulting in a total of 39 attacks included in the final analysis. Mean circumference of the intradural middle meningeal artery at baseline was 3.18 mm with an increase of 0.11 mm during attacks (P = 0.005), corresponding to a relative dilation of 3.6% 95% CI: 1.4%-5.7%. Middle cerebral artery dilated by 9.4% 95% CI: 7.1%-11.7% and superficial temporal artery by 2.3% 95% CI: 0.2%-4.4%. Our study shows that the intradural middle meningeal artery and the middle cerebral artery are dilated during migraine induced by calcitonin gene-related peptide as well as sildenafil. We propose that intradural vasculature is affected by migraine-driven activation of trigeminal afferents during migraine attacks.
Headache and facial pain are among the most common, disabling and costly diseases in Europe, which demands for high quality health care on all levels within the health system. The role of the Danish ...Headache Society is to educate and advocate for the needs of patients with headache and facial pain. Therefore, the Danish Headache Society has launched a third version of the guideline for the diagnosis, organization and treatment of the most common types of headaches and facial pain in Denmark. The second edition was published in Danish in 2010 and has been a great success, but as new knowledge and treatments have emerged it was timely to revise the guideline. The recommendations for the primary headaches and facial pain are largely in accordance with the European guidelines produced by the European Academy of Neurology. The guideline should be used a practical tool for use in daily clinical practice for primary care physicians, neurologists with a common interest in headache, as well as other health-care professionals treating headache patients. The guideline first describes how to examine and diagnose the headache patient and how headache treatment is organized in Denmark. This description is followed by sections on the characteristics, diagnosis and treatment of each of the most common primary and secondary headache disorders and trigeminal neuralgia. The guideline includes many tables to facilitate a quick overview. Finally, the particular challenges regarding migraine and female hormones as well as headache in children are addressed.
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