Migraine with Aura

Author: Alessandro Mussa
Date: 17/04/2008



Migraine with aura


Genetics in migraine

1-Migraine as a channelopathy

2-Migraine as a channelopathy



Fortification Spectra


Left-sided fortification spectrum of migraine. Illustration by Dr. Hubert Airy of his own scotomas. A bright stellate object (a) appeared suddenly below and to left side of fixation (o). It rapidly enlarged, first as a circular zigzag, but on inner side of zigzag was faint (b); as arc increased in size, it was broken centrally ©. In (d) original circular outline had become oval. Rectangular lines that made up the fortification spectrum became larger as the process extended peripherally. When spectrum had extended through greater portion of the field (e), upper portion also began to expand (f). At this time lower part of spectrum disappeared. The phenomenon ended in a whirling focus of light (g) 20 minutes after it began. At this time a headache appeared on the right side. (Gowers WR: Visual sensations in migraine. In Subjective Sensations of Sight and Sound, Abiotrophy and Other Lectures. London, Churchill, 1907)

De Chirico: "Sole sul cavalletto"; 1966



2011-02-15T20:22:21 - nadia coggiola

MIGRAINE AURA: pathophysiological and biochemical events


Migraine is a widespread and debilitating disorder and one of the most common of the nervous system, according to the WHO.
Prevalence studies estimate that migraine affects 15-25% of women and 6-8% of men.


Visual aura is the most common feature associated with migraine, though it can occur separately. In both cases it often represents a dramatic event, expecially for patients who experiences it for the first time.



Despite the public health significance of this problem, the pathophysiology of migraine is not yet fully understood and no biomarkers are available.
Most of the cerebral blood flow (CBF) studies in migraine have introduced the concept of a different pattern in migraine with aura and migraine without aura. Migraine aura is characterized by a focal reduction of regional CBF in the posterior part of one hemisphere that usually corresponds to the topography and timing of the reported symptoms.
On the basis of genetic and epidemiological evidence, scientists suggest that changes in blood vessels and hypoperfusion disorders can cause neurovascular disfunction and evoke cortical spreading depression (CSD), an event that is thought to underlie aura symptoms.
In fact, recent experimental data have indicated that focal, mild and transient ischaemia can trigger cortical spreading depression without an enduring tissue signature. Blood oxygen level-dependent (BOLD) functional magnetic resonance imaging has shown cerebrovascular changes in the cortex of migraineurs while experiencing a visual aura that closely resemble CSD.
CSD is a slow, self-propagating wave of neuronal and glial depolarization that can be evoked in the cortex, cerebellum, basal ganglia, thalamus and hyppocampus, followed by long lasting suppression of neural activity.

What is the nature of the trigger for spontaneous waves of CSD?

Experimentally, strong focal stimulation is needed to evoke CSD. Various approaches have been used, including inserting a needle into the exposed cortex, electrical stimulation, or topical application of high K+ concentrations or glutamate agonists.
The CSD waves last longer in the ischaemic brain, and the frequency with which they are generated correlates with the degree of ischaemic damage. One of the leading hypothesis in migraine pathophysiology is that the brains of migraineurs are hyperexcitable. Enhanced neuronal excitation results in increased extracellular K+.
If the reuptake and other transport processes are not efficient in controlling glutamate release, a wave of cortical spreading depression (CSD) is likely to arise as a consequence.

Anatomical alterations of the visual motion processing network in migraine with and without aura, 2006

The hypoxia is caused not by a reduction in blood flow but by the enormous increased in O2 utilization that is required to restore ion homeostasis following CSD.
Neuronal and glial membrane potentials are almost zero following a wave of CSD, and the clearance of the high level of extracellular K+ associated with a sharp increased in O2 consumption

Figure 2: Association between CSD and CBF
After microemboli were injected into a rodent carotid artery, CSD occurrence was
associated with the extent of CBF perturbation. The time course of transient
oligaemia after microembolisation (shown at point 1), followed by a gradual
increase until CSD occurrence (shown at point 2). The shaded area (AUC) shows the
ischaemic burden, a measure of depth and duration of oligaemia, from point 1 to
point 2 or until CBF returned to baseline.

Migraine aura pathophysiology: the role of blood vessels and microembolisation, 2010


Neurons and glia can experience 1-2 minutes of hypoxia during CSD tissue O2 tension level falls below 4mmHg, resulting in dendritic swelling and a transient loss of dendritic spines. The changes in neuronal structure are reversible and neurons do recover.


Is this relative posterior hypoperfusion specific to migraine or is it related to a non-specific pain process? Posterior hypoperfusion in relationship to pain and not specific to migraine seems unlikely, since this hypoperfusion persists after total pain relief by sumatriptan and could appear before headache. This hypoperfusion would be specific to migraine because it has been demonstrated only during migraine attacks. Considering that posterior hypoperfusion is present at the beginning of migraine without aura and migraine aura, two hypotheses could be advanced to explain this hypoperfusion: is hypoperfusion a consequence of CSD or is it a primary neurovascular event?




Hypoperfusion as a consequence of CSD

Recent research in animals has shown that CSD could induce posterior hypoperfusion and would be able to activate the trigeminal meningeal afferents consistent with the development of headache. However, this is much debated. If CSD is a primary event common in migraine aura and without aura, CSD must be predominantly asymptomatic, because only a minority of patients report aura. If the relationship between the aura symptoms and CSD seems to be clear, the temporal link between posterior hypoperfusion and CSD remains unclear. According to some studies, the oligaemia starts before the onset of aura and extends into the headache phase, outlasting the aura symptoms. Long lasting hypoperfusion could not be explained by a single wave of CSD. To produce such a long lasting event, a succession of waves would be required. All of them asymptomatic, which seems unlikely. The hypoperfusion after sumatriptan is even more important in the occipital region and appears in the frontal lobe. CSD could not explain this frontal area of hypoperfusion, since CSD classically does not cross prominent sulci. Combining electophysiological measurements with optic intrinsic signal imaging, it has been shown that, during experimentally induced CSD in mice and rats, vasomotor changes in cortex travelling at significantly greater velocity than the neuronal changes. These results suggest that there is a dissociation of metabolic demand and vascular response and that the cortical surface arteriolar changes associated with CSD appear to have independent mechanisms of propagation.
Other evidence show that CSD induces long-lasting changes in extracranial blood flow, including dilatation of the middle meningeal artery and extravasation of plasma protein.

Fig 3. The link between CSD and migraine pain. CSD is most often initiated in the occipital cortex in patients with visual migraine aura. It is believed that CSD is ignited by local elevation ok extracellular K+ levels in pockets of intense excitatory transmission. When K+ levels reach a critical threshold of 10-12 mM, a self propagating CSD wave is initiated and advances across th cortex with a slow velocity of 3 mm/min. The threshold for CSD initiation is reduced in FHM patients with mutation in the Cav 2. 1 Ca 2+ channel because the higher Ca2+ level in dendrites facilitates glutamate release and thereby increases the likelihood that K+ levels will reach the CSD threshold. A combination of stress and food intake may be sufficient to ignite CSD in patients with FHM, whereas stronger stimulation is required in the rest of the population. The lower diagram depicts the cortical events linking CSD to migraine pain. The high extracellular K+ level at the edge of the CSD wavefront is key for wave propagation. K+ is normalized within minutes but the restoration of normal membrane potential of neurons and glial cells is a high energy–demanding process. The cortical tissue experiences a minutes-lasting period of severe reduction of tissue O2 tension (hypoxia) during CSD because O2 consumption transiently exceeds the vascular supply of O2. This hypoxia has several consequences: (a) Neurons exhibit severe morphological distortions, swelling, and transient loss of dendritic spines. Normal dendritic structures are re-established 15–20 minutes later, coinciding with the reappearance of a normal EEG pattern. This hypoxic phase is followed by prolonged vasoconstriction and reduction of local blood flow. (b) The CSD wave activates MMP9, resulting in opening of the blood-brain barrier (BBB) and extravasation of plasma protein. The leakage of blood-borne factors activates nociceptive afferent neurons from trigeminal ganglion innervating meningeal arteries, connecting to trigeminal nucleus caudalis, triggering the migraine pain. © CSD triggers preconditioning an endogenous mechanism of neuroprotection.

Deciphring migraine, 2009

The pathogenetic mechanisms of the visual aura seem to be based on the concept of cortical hyperexcitability: according to this current theory, a stimulus that in normal conditions would not reach the activation threshold, in a hyperexcitable cortex is instead able to cause a massive electrochemical response that ends up generating a widespread metabolic wave.
This metabolic “wavefront” by sequentially triggering the cortical receptive field cells tuned to orientation discrimination, induces their spontaneous activation.
The result is an illusory perception of segments with specific orientations, thus forming the typical “zig-zag” pattern. Therefore, teichopsia is considered pathognomonic and could be considered like a snap shot reflecting the entoptic perception which results from the sequential auto-activation of the receptive fields in the striate cortex.
Generally visual aura is referred to move across the visual field and the illusion usually arises around the fixation point as a glittering and moves horseshoe-shaped towards the periphery of the visual field where it fades after 20-25 minutes (nevertheless within an hour).
This “march” would reflect the metabolic “wavefront” progression across the cortical surface.
Hypoxia induced by hypoperfusion in the advanced stages of the aura would selectively damage the GABAergic system raising the global cortical excitatory level to the threshold value.
This condition would trigger the widespread metabolic wave, while an increased extracellular glutamate concentration seems to promote its propagation along the cortical surface.

Hypoperfusion as a primary neurovascular event

A primary brainstem dysfunction has been proposed as the origin of migraine attacks. Studies have shown activation in brainstem structures during migraine attacks, either spontaneous or triggered and either with or without aura. Activation has been described in the midbrain that could correspond to the dorsal raphe nucleus, periaqueductal grey, locus coeruleus, red nucleus, substantia nigra and the dorsolateral pons. These nuclei are involved in the central control of nociception and extra and intracerebral vascular control. Experimental work in animals has shown how brainstem nuclei disturbance could initiate the vascular changes seen in migraine. Activation of noradrenergic neurons in the locus coeruleus would be expected to produce bilateral reductions in cortical blood flow that would be more prominent in the occipital region, the part of the brain affected by hypoperfusion during migraine attacks. Some arguments from neuroimaging studies in migraineurs are in favour of a primary brainstem dysfunction responsible for posterior hypoperfusion. The persistence of both brainstem activation and posterior hypoperfusion after sumatriptan injection suggests that the hypoperfusion could be in relationship to the brainstem activation and then would persist as long as the brainstem activation does, independently of the migraine symptoms relieved by the action of the triptan on the peripheral trigeminovascular system. Concerning the absence of visual symptoms during the hypoperfusion phase, a primary vascular event below the ischaemic level seems to be a better explanation than an asymptomatic CSD. On this hypothesis, the primary event in both types of migraine could be an oligaemia triggered by the activation of brainstem nuclei. Cortical susceptibility to oligaemia could then trigger CSD, producing symptoms in migraine aura.
According to this view, brief periods of hypoperfusion, a final common event for CSD initiation develop as a consequence of local endothelial or smooth muscle dysfunction together with changes in circulating blood elements, or develop as a downstream complication of events that originate within larger blood vessels.



Migraine has a strong but complex genetic component that is susceptible to modulation by endogenous biological and environmental factors such as oestrogen withdrawal, sleep and stress, and might also be an expression of neuronal network excitability.


Additional mechanisms might also contribute, including the release of procoagulant factors and enhanced susceptibility to platelet aggregation, decreased endothelium dependent relaxation and increased oxidative stress.


Migraine with aura has been also identified as an independent risk factor for ischaemic stroke.
The multitude of clinical observations suggest a common pathophysiology for these disorders and indicate that, at least in a subset of patients, migraine aura exists on a continuum of hypoperfusion disorders that includes transient ischaemic attacks and cerebral infarcts.


The hypoxia-associated CSD represents an immediate danger but the long term effect might be a strengthening of cortical circuit. CSD is a preconditioning stimulus that might confer tolerance allowing cortical neurons to survive an otherwise and letal subsequent episode of ischaemia.
The mechanism by which CSD increases ischaemic tolerance is multifactorial and includes release of well known trophic factors, including brain derived neurotrophic factor.


CSD provides the most likely explanation for migraine visual aura but the significance of the hypoperfusion needs to be specified.


2008-04-21T06:29:11 - Alessandro Mussa

Link Principale

Migraine with aura

2008-04-20T18:48:40 - Gianpiero Pescarmona

Aquaporin 1, a potential therapeutic target for migraine with aura, 2010

Molecular biology of the blood-brain and the blood-cerebrospinal fluid barriers: similarities and differences, 2011

  • Human MTC8 transporter mediates transport of thyroid hormones and the importance of transport for thyroid hormone signaling was revealed by the discovery that inactivating mutations in the human monocarboxylate transporter-8 (MCT8) cause Allan-Herndon-Dudley syndrome, an X-linked developmental disorder characterized by hypotonia, spasticity, muscle weakness, neurological problems, and cognitive impairment due to thyroid hormone deficiency in the CNS . Matched in Text: aquaporin 1.

Effect of the excess of thyroid hormone administration on water and sodium chloride intake in the rat. 1988

  • By using the two-bottle, self-selection method it was found that an excess of thyroid hormone administration to rats increased water and sodium intake. Thyroidectomy changed the initial preference from water to sodium chloride. Oral treatment of the thyroidectomized rats with thyroid hormones brought salt ingestion back to normal levels and greatly augmented the water intake. Two-week treatment was followed by an increase in salt intake, which was characterized by large oscillations resembling the corresponding effects of adrenalectomy and treatment with deoxycorticosterone.

Emicrania con aura e rischio suicidio giovanile
I giovani adolescenti con cefalee giornaliere croniche (CDH), ed in particolare quelli con emicranie con aura, presentano un aumento di sei volte del rischio di suicidio rispetto alle loro controparti che non soffrono di mal di testa. Questi soggetti dunque dovrebbero ricevere un monitoraggio delle malattie psichiatriche, in modo da ottenere l'aiuto e le terapie di cui necessitano. L'emicrania con aura è stata solo raramente indicata come un possibile problema nei soggetti con CDH, dato che la maggior parte degli esperti di cefalee sostiene che i pazienti con emicrania cronica di solito presentano forme senza aura. (Neurology. 2007; 68: 1468-73)

Il tipo di cefalea influenza gravità allodinia
I pazienti con emicrania hanno maggiori probabilità di sviluppare allodinia cutanea rispetto a quelli che soffrono di altri tipi di cefalee. Nei pazienti che soffrono di emicrania, inoltre, sussiste un'associazione fra allodinia cutanea e sesso femminile, frequenza delle cefalee, obesità disabilità e depressione. L'allodinia cutanea è una patologia neurologica caratterizzata da dolore durante le normali attività, e potrebbe anche essere un fattore di rischio per la progressione dell'emicrania. L'identificazione dei fattori di rischio di progressione della malattia rappresenta una priorità molto importante per la sanità pubblica: ad esempio, i soggetti con allodinia dovrebbero essere trattati più aggressivamente per prevenire la progressione dell'emicrania, nonché per prevenire questo tipo di sensibilità cutanea. (Neurology 2008; 70: 1525-33)

AddThis Social Bookmark Button