Migraine aura

Migraine aura is probably the best characterized phase of a migraine attack. Most typically (>92%) aura is visual (Russell and Olesen 1996, Eriksen et al. 2004, Kelman 2004). The aura can also be a speech symptom (30–38%) or a sensory (33–44%) disturbance, and very rarely a motor paralysis in hemiplegic migraine. Visual aura typically starts with flickering zigzag lines that are followed by defects in visual fields (i.e. scotomas or heminanopia; Russell and Olesen 1996). The gradual spreading of visual symptoms and complete reversibility within 5–

60 minutes suggests the episodic involvement of the central nervous system, especially the visual cortex, in the pathophysiology of migraine aura.

In 1944, a Brazilian scientist A. Leão described a neurophysiological phenomenon, cortical spreading depression (CSD), in a rodent brain (Leão 1944). CSD was later suggested to be a correlate of visual migraine aura (Bowyer et al. 2001). CSD is a slow propagating wave (2–6 mm/min) of neuronal and glial depolarization that has also been recorded in the cortex, hippocampus, striatum and cerebellum (Davies et al. 1995, Moskowitz 2008). CSD induces changes in K⁺, Na⁺ and Ca²⁺ ions, nitric oxide, arachidonic acid and prostaglandin concentrations (Wei et al. 1992, Strassman et al. 1996). These changes may theoretically sensitize trigeminovascular afferents to generate migraine pain, and thus form a link between the aura and headache phases of migraine.

2.3.2.1 Cortical spreading depression in migraine aura

The triggering mechanisms for spontaneous CSD are unknown, but brain injury in human, potassium, pin brick, glutamate or electrical stimuli in rodents can trigger it (reviewed by Sanchez-del-Rio and Reuter 2004). Among the various substances that have been shown to trigger CSD, endothelin1 (EDN1) is especially interesting since, as a potent vasoconstrictor, it has been shown to induce CSD in rats (Dreier et al. 2002, Kleeberg et al. 2004). Furthermore, elevated plasma EDN1 levels have been measured in migraine attacks (Färkkilä et al. 1992, Gallai et al. 1994, Kallela et al. 1998, Hasselblatt et al. 1999), but contradictory result has also been presented (Nattero et al. 1996).

Modern neuroimaging techniques have contributed substantially to a better understanding of the vascular and neuronal changes that occur during the aura. In the scintillating scotoma type of aura, a regional increase in cerebral blood flow (CBF) has been recorded during scintillations that is followed by long lasting regional hypoperfusion during scotoma in the occipital lobe (Welch et al. 1998, Hadjikhani et al. 2001). A similar cascade is considered to happen in CSD in which activation is followed by depression. This may explain why typical (positive) visual aura symptoms like, scintillations, during migraine aura are followed by defects in visual field (e.g. scotomas; Smith et al. 2006, personnal communication by doc.

Mikko Kallela). Similarly, sensory aura is considered a positive symptom while both motor and dysphasic auras have been considered as negative symptoms.

A recent study in mice describes the increase in CBF on a molecular level. CSD causes an increase in the concentration of extracellular potassium. In order to compensate the ionic imbalance, neurons adjacent to the vessels consume free O2 at the expense of more distant tissues, thereby producing anoxic depolarization (Takano et al. 2007). In other words, excitable neurons cause the oxygen deprivation of more distant neurons. However, a study by Brennan and colleagues (2007) showed that vascular changes can precede CSD. This may suggest that vascular changes are not only a passive response to metabolic demands. These studies do not explain the triggering factors for CSD, however, they do give an intriguing insight into the propagation of CSD.

Auras with motor or sensory symptoms have been suggested to originate from events similar to those in CSD (Pietrobon and Striessing 2003), because the spreading of these symptoms occurs at a similar rate as visual aura. Most migraine attacks are without aura and thus the spreading depression has been proposed to occur on clinically silent areas of cerebral cortex (Goadsby 2001). For example, hippocampal spreading depression could be clinically silent and has been reported to activate the trigeminal fibers that may further trigger the migraine headache (Kunkler and Kraig 2003). However, a role of the visual cortex in MO is unlikely since the visual cortex of MO patients is similar to healthy individuals, whereas MA patients lack the inhibitory activity of visual cortex. This may suggest a greater cortical excitability in MA patients, who are more prone to CSD in occipital cortex than MO patients (Palmer et al.

2000). Alternatively, it has also been proposed that aura and headache may be parallel processes of episodic dysfunction in brainstem nuclei, because an increase of CBF has been

detected in several areas of brainstem in MO patients (Weiller et al. 1995, Pietrobon and Striessing 2003).

2.3.2.2 Role of ion channel genes in migraine aura

So far, no undisputed predisposing genes have been identified for common migraine.

However, for a rare monogenic subtype of MA, familial hemiplegic migraine (FHM), three genes has have been identified (Table 3).

Table 3. Genes predisposing to familial hemiplegic migraine (FHM).

FHM type Chr Gene Protein Function Reference FHM1 19p13 CACNA1A α2A subunit of

voltage gated Ca²⁺

channel

Mediates the entry of Ca²⁺ ions into

excitable cells Ophoff et al.

1996

FHM3 2q24 SCN1A Voltage-gated sodium channel α

Although the main symptoms of aura and headache of FHM are very similar to MA, the distinctive characteristic of FHM is motor aura that mainly consists of unilateral motor weakness or paralysis that may last to several days (Thomsen et al. 2002). At the worst, some FHM patients can suffer from disturbance of consciousness, fever and permanent cerebellar symptoms and progressive ataxia and/or nystagmus (Pietrobon and Striessing 2003, Headache Subcommittee of the International Headache Society 2004).

Due to similarities and co-occurance between common migraine and FHM, dysfunction of neuronal ion transportation can provide a model for predisposition for common forms of migraine. Mutations in genes encoding ion channels disturb the rhythmic function of exposed tissue that may also explain the episodic nature of migraine (Gargus 2006, Bernad and Shevell 2008). The common feature in FHM mutations seems to be the increased extracellular glutamate and potassium concentrations that increase susceptibility to CSD, especially with the FHM1 mutation (van den Maagdenberg et al. 2004, 2007).