Can migraine aura be provoked experimentally? A systematic review of potential methods for the provocation of migraine aura

Abstract

Background

The nature of the migraine aura and its role in migraine pathophysiology is incompletely understood. In particular, the mechanisms underlying aura initiation and the causal relation between aura and headache are unknown. The scientific investigation of aura in patients is only possible if aura can be triggered. This paper reviews potential methods for the experimental provocation of migraine aura.

Methods

We systematically searched PubMed for studies of experimental migraine provocation, including case reports of patients with aura and reports of the occurrence of aura following exposure to any kind of suspected trigger.

Results

We identified 21 provocation studies, using 13 different prospective provocation methods, and 34 case reports. In the prospective studies, aura were reported following the administration of intravenous and sublingual glyceryl trinitrate, visual stimulation, physical activity, calcitonin gene-related peptide infusion, chocolate ingestion, and the intravenous injection of insulin. In addition, carotid artery puncture has consistently been reported as a trigger of aura.

Conclusions

No safe and efficient method for aura provocation exists at present, but several approaches could prove useful for this purpose.

Keywords

Migraine aura provocation experimental human model

Introduction

Migraine ranks seventh among the highest causes of disability in the world (1) and has a high economic cost to society (2). There is a clear need to identify target points for new anti-migraine drugs (3). Approximately one-third of patients with migraine experience aura (4), which presents as transient, gradually developing neurological symptoms, most often in the form of visual, sensory or speech disturbances, and usually appearing before the onset of migraine headache (5). The aura is an integral feature of the migraine attack in this subset of patients, but the nature of this phenomenon and its role in migraine pathophysiology remains incompletely understood. Cortical spreading depression (CSD), a neuronal and glial depolarization wave that slowly propagates in brain tissue at a rate of around 3 mm/min, is most probably the underlying mechanism of aura (6). The spatial and temporal characteristics of both migraine aura symptoms and the changes in blood flow and functional magnetic resonance imaging (fMRI) signals observed in patients with migraine are indeed consistent with CSD (7,8). However, despite the longstanding assumption that CSD is the substrate of migraine aura, there has, as yet, been no definitive electrophysiological evidence of CSD in patients with migraine. Further, it is not known how this intense cortical disturbance arises seemingly spontaneously in the normal-appearing tissue of patients with migraine. Also, the casual relation between aura and headache is not known. Could patients avoid having a migraine headache if the aura was stopped or prevented? Unravelling the pathophysiology of aura and the relation between aura and headache is essential for understanding migraine. Unfortunately, it is extremely difficult to systematically study migraine aura in patients due to the unpredictable and short-lasting nature of the phenomenon. This can only be achieved through the experimental provocation of aura. A variety of methods currently exists for inducing migraine attacks without aura using experimental human models (9). The human models give the opportunity of studying the neurobiology of migraine under controlled conditions and provide an understanding of the events that constitute a migraine attack. They also give an insight into the mechanisms of action of the current anti-migraine drugs and an opportunity to identify new target points for future drugs. The current human migraine models have facilitated the development of new pharmaceutical migraine treatments (10). At present, however, no human model of migraine aura has been developed.

The aim of this study was to systematically review the available literature of aura provocation studies and case reports of triggering migraine aura and to evaluate the usefulness of these methods for a human model of migraine aura.

Methods

We searched PubMed for reports of provocation of migraine with aura (MA) using all possible combinations of the following free text keywords: ‘migraine’, ‘aura’, ‘visual disturbances’ with ‘provocation’, ‘induction’, ‘triggering’ in combination with MeSH keywords (‘migraine’ and the subheading ‘chemically induced’), while excluding animal studies and studies of epilepsy, the entire string thus being: ‘migraine disorders/chemically induced’(MeSH)) OR migraine provocation OR migraine induction OR migraine triggering OR aura provocation OR aura induction OR aura triggering OR visual disturbances provocation OR visual disturbances induction OR visual disturbances triggering NOT epilepsy NOT animals’.

The search was limited to English and German language publications. We also reviewed the reference lists of relevant articles to identify studies that might have been missed in the search. Reports fulfilling the following criteria were considered eligible for review: reports of studies of experimental migraine provocation, including patients diagnosed with MA, reports of occurrence of MA following exposure to any kind of suspected trigger, and reports of occurrence of symptoms similar to those of migraine aura, as defined by the International Headache Society classification, following exposure to any kind of suspected trigger. Retrospective questionnaire-based studies of self-reported migraine trigger factors and reports of MA occurring secondarily to intracranial pathology were excluded from the review.

Results

The PubMed search identified a total of 725 articles, which were screened based on title and abstract. Seventy articles were retrieved as full text and further assessed for eligibility. Of these, 33 articles were included in the review: 14 provocation studies and 20 case reports. In addition, seven provocation studies and 14 case reports identified through other sources, primarily references from other articles, were added to the review. Thus 21 provocation studies and 34 case reports were available for review.

Provocation studies

The 21 studies were published between 1977 and 2013. The median number of patients included was 22 (range 3–27). Thirteen different potential provocation methods were identified. The triggering of aura was reported for seven of these methods. The most commonly used method was the intravenous infusion of glyceryl trinitrate (GTN) (11 –15), with a total successful trigger rate of 4% (2/49). An aura was reported after sublingual GTN in 14% (3/22) of patients (16). Visual stimulation triggered aura in 18 of 60 patients, yielding a trigger rate of 30%, although the type of visual stimulation varied among the studies (17 –20). The combination of physical activity and visual stimulation had a trigger rate of 29% (2/7), whereas physical activity alone had a trigger rate of 18% (4/22) (8,20). Infusion of calcitonin gene-related peptide (CGRP) had a trigger rate of 29% (4/14) in patients with typical migraine aura, 12% (4/34) when including patients with familial hemiplegic migraine (FHM) (21 –23), 17% (2/12) for chocolate ingestion (24) and 10% (2/20) for intravenous insulin (25). Transdermal GTN (26), somatostatin (27), hypoxia (28), tyramine (29,30) and the injection of air microbubbles (31) did not induce aura in any of the patients. Table 1 gives an overview of the provocation studies.

Table 1.

Aura provocation studies.

Reference	Design	No. of patients with MA	Provocation method	Outcome	Type of aura/latency^a	Reproducibility
Afridi et al. (2004) (11)	Non-randomized, non-blinded	21	IV infusion of GTN 0.5 µg/kg/min for 20 min	Aura: 2/21 (1 without headache) Migraine headache: 14/21	Visual/70–160 min	Aura provocation reproduced in one patient
Bonuso et al. (1989) (26)	Randomized, double-blinded	3	Transdermal GTN	Aura: 0 Migraine headache: 2/3	NA	Not attempted
Bowyer et al. (2001) (17)	Non-randomized, non-blinded	8	Visual stimulation: black/white checkerboard	Aura: 8/8 (3 without headache) Migraine headache: 5/8	Visual (identical to spontaneous visual aura)	Not attempted
Cao et al. (2002) (18)	Non-randomized, non-blinded	23	Visual stimulation: red/green checkerboard	Aura: 6/23 (2 without headache) Migraine headache: 4/23	Visual (four identical to spontaneous aura)/2–8.5 min	Not attempted
Cao et al. (1999) (19)	Non-randomized, non-blinded	10	Visual stimulation: red/green checkerboard	Aura: 2/10 (both with headache) Migraine headache: 6/10	Visual (atypical of spontaneous aura)/3–6 min	Not attempted
Christiansen et al. (1999) (13)	Non-randomized, non-blinded	12	IV infusion of GTN 0.5 µg/kg/min for 20 min	Aura: 0 Migraine headache: 12/12	NA	Not attempted
Ghose et al. (1984) (30)	Randomized, placebo-controlled	8	400 mg disulfiram or placebo for 6 days followed by dopamin/tyramine pressor test	Aura: 0	NA	Not attempted
Ghose et al. (1984) (30)	Non-randomized, single-blinded	5	Propanolol 40 mg twice daily for 4 weeks followed by tyramine pressor test	Aura: 0	NA	Not attempted
Gibb et al. (1991) (24)	Randomized, double-blinded, placebo-controlled	Not specified	Chocolate	Aura: 2/12 (both with headache) Placebo: 0/12 Migraine headache: 5/12	Visual/3.5–27 h	Not attempted
Hadjikhani et al. (2001) (8)	Non-randomized, non-blinded	1	Exercise	Aura: 1 (followed by headache)	Visual/80 min	Reproduced in one of two trials
Hansen et al. (2011) (23)	Non-randomized, non-blinded	11 (FHM)	IV infusion of CGRP 1.5 mg/min for 20 min	Aura: 0 Migraine headache 1/11	NA	Not attempted
Hansen et al. (2010) (21)	Non-randomized, non-blinded	14	IV infusion of CGRP 1.5 mg/minute for 20 minutes.	Aura: 4/14 (all with headache) Migraine headache: 12/14	Visual 3, visual + sensory 1/10 min to 6 h	Not attempted
Hansen et al. (2008a) (14)	Non-randomized, non-blinded	8 (FHM)	IV infusion of GTN 0.5 µg/kg/min for 20 min	Aura: 0 Migraine headache: 1/8	NA	Not attempted
Hansen et al. (2008b) (15)	Non-randomized, non-blinded	8 (FHM)	IV infusion of GTN 0.5 µg/kg/min for 20 min	Aura: 0	NA	Not attempted
Hansen et al. (2008c) (22)	Non-randomized, non-blinded	9 (FHM)	IV infusion of CGRP 1.5 mg/min for 20 min.	Aura: 0	NA	Not attempted
Hougaard et al. (2013) (20)	Non-randomized, non-blinded	27	Physical activity and/or visual stimulation	Aura: 3/27 (all with headache) Migraine headache: 6/27	Visual and sensory	Not attempted
Levy et al. (2002) (27)	Non-randomized, non-blinded	2	IV infusion of somastostatin 250 µg/h for 3.5 h	Aura: 0 Migraine headache: 2/2	NA	Not attempted
Pearce (1971) (25)	Non-randomized, non-blinded	20	IV injection insulin 0.15 units/kg body weigh	Aura: 2/20 (one without headache) Migraine headache: 1/20	Visual/30 min	Not attempted
Sances et al. (2004) (16)	Non-randomized, non-blinded	22	Sublingual GTN 0.9 mg	Aura: 3/22 (all with headache) Migraine headache: 9/22	Visual	Not attempted
Schoonman et al. (2006) (28)	Randomized, placebo-controlled, double-blinded	8	Normobaric hypoxia or IV GTN	Aura: 0 Migraine headache: 6	NA	Not attempted
Sevgi et al. (2002) (31)	Non-randomized, non-blinded	22	IV injected air microbubbles	Aura: 0 Migraine headache: 2	NA	Not attempted
Ziegler et al. (1977) (29)	Randomized, placebo-controlled, double-blinded	Not specified (‘80 migraine patients’)	Tyramine 200 mg by mouth	Aura: 0 Migraine headache: 8	NA	Not attempted

MA: Migraine with aura; FHM: familial hemiplegic migraine; GTN: glyceryl trinitrate; NA: Not applicable; IV: intravenous.

Time from stimulation to onset of aura.

Case reports

The 34 case reports and case series were published between 1964 and 2012. Thirteen articles reported the triggering of aura after intravascular procedures. Seven of these reported the triggering of aura by carotid or vertebral angiography in single or several patients (7,32 –37). In one large retrospective study, aura was triggered by carotid angiography in 30% (16/54) of patients with ‘migraine accompagné’, i.e. migraine with sensory or hemiplegic migraine (31). Three studies reported aura following sclerotherapy for varicose veins using the injection of foam or liquid sclerosant agents (38 –40). An aura was reported following endovascular procedures (41), after cardiac catheter ablation (42) and after aortic stenting (43). Two reported cases of aura were triggered following air microbubble injection during transcranial Doppler ultrasound examination (44,45). Three studies reported aura induced by physical activity (46 –49) and one following orgasm (47). Two studies reported aura after the consumption of two different food sources (50,51). Hypoxia (52) and 11 different pharmaceutical drugs were reported to precipitate aura in one patient each (50,52 –62). One article reported aura after GTN infusion (63) and one following the transdermal application of GTN (64). Table 2 gives an overview of the case reports.

Table 2.

Case reports.

Reference	Number of patients studied	Number previously diagnosed with migraine with aura	Trigger mechanism	Reported symptoms	Reproduced aura
Afridi et al. (2005) (63)	1	1	GTN 0.5 µg/kg/min IV for 20 min	Visual: flashing bright zig-zag patterns across visual field for 10 min 150/165 min after infusion of GTN	Aura provoked on two occasions
Barnes et al. (1979) (53)	30	1	Viloxazine 150–300 mg/day as treatment for depression	Two patients with no history of migraine and one patient with a history of classic migraine developed aura-like visual symptoms	No
Beekman et al. (2001) (41)	3	1	Embolization of dural atrioventricular fistula/angiography after embolization of carotic aneurism/embolization of atrioventricular malformation	Patient 1: visual aura + headache after 1 h Patient 2: Migraine headache + unilateral light flashes, hypesthesia after several hours Patient 3: Migraine headache and transient hemianopia 2 h after procedure	No
Bigal et al. (2006) (50)	1	1	Sucralose	Migraine with typical visual aura following ingestion of sucralose	No
Brown et al. (1995) (54)	1	1	Adenosine 10 mg IV	Visual aura, similar to usual aura, immediately after infusion	No
Caputi et al. (2010) (44)	159	159	Microbubble injection during contrast-enhanced transcranial Doppler ultrasound	Aura: 12/159 patients. All 12 patients had permanent right-to-left shunt due to patent foramen ovale. In total, 56/159 patients had permanent right-to-left shunts	No
Cauchy et al. (2002) (52)	8	1	Simulated ascent from sea-level to 8848 m and back to sea-level during a 30 day trial	One patient, previously diagnosed with MA developed transient visual changes, floaters, decreased visual field and blurred vision, followed by headache and vomiting	No
Corbelli et al. (2011) (46)	3	3	Physical activity (football, swimming)	Visual aura (fortification spectrum) and ipsilateral paraesthesia shortly after strenuous activity	No
Dinn et al. (2006) (55)	1	0	Tadalafil	Visual aura without headache after about 72 h	No
Dukes et al. (1964) (35)	1	1	Carotid angiography	Usual migraine aura: bilateral scotomata starting about 15 min after puncture	No
Engel et al. (2002) (51)	1	0	Soy isoflavone supplements, 135–177 mg daily for 9 months	Migraine with visual aura: right-sided fortification scotoma and left temporal headache	No
Evans et al. (2002) (49)	1	Not reported	Athletic activity in cold and hot weather and at high altitude	Central scotoma and peripheral visual field blurring lasting 10–20 min starting 20 min after activity	Yes
Friberg et al. (1994) (37)	8	8	Carotid angiography	Aura in 4/8 patients following the procedure. Visual aura (n = 4), hemiparalysis (n = 1). Aura with (n = 3) and without (n = 1) headache
D'Andrea et al. (2002) (47)	1	0	Orgasm	Fortification spectra and hemianopsia, 2–5 min after orgasm	Yes
Gil-Gouveia et al. (2004) (56)	1	1	Midazolam 6 mg, fentanyl 50 µg	Following fentanyl sedation: coma, right hemiparesis and hemisensory loss, horizontal nystagmus, reduced swallowing, migraine, headache	No
Janzen et al. (1972) (32)	97	54 ‘Migraine accompagné’; 43 ‘common migraine’ (five with visual aura)	73 one-sided carotid angiographies, six double-sided carotid angiographies, seven vertebral angiographies, seven vertebral + carotid angiographies	Aura following angiography in 16/54 of patients with ‘migraine accompagné’, i.e. migraine with sensory or aphasic aura Aura in 3/43 of patients with ‘common migraine’, i.e. migraine without aura or migraine with visual aura. 14/43 of ‘common migraine’ patients developed migraine-like headache. Symptoms occurred 30–60 min following angiography	No
Kluger et al. (2009) (57)	1	0	Subcutaneous injection with efalizumab 0.7 mg/kg	Central scotoma and peripheral visual field blur lasting 10–20 min starting 20 min after injection	Yes (consistently after each of nine injections)
Koyama et al. (2007) (42)	1	1	Cardiac catheter ablation in patient with Wolff-Parkinson-White syndrome	Scintillating scotoma and migraine headache. Onset during procedure	No
Künzlberger et al. (2006) (38)	1	0	Liquid sclerotherapy with polidocanol 1%	Homonymous hemianopia and paraesthesia in hands and feet 5 min after treatment	No
Larson (1993) (58)	1	0	Oral fluoxetine	Right-sided paresthesia (and ‘clumsiness’)	No
Lauritzen et al. (1983) (33)	13	13	Carotid angiography/xenon-133 injection	Nine of 13 patients with hemiplegic migraine who underwent carotid angiography developed attacks of migraine with aura after the procedure	No
MacGregor et al. (1999) (59)	4	2	Oestrogen replacements	Four women reported typical aura following oestrogen replacement treatment. In all patients, reducing the dose of oestrogen or changing the route of delivery was associated with loss of aura	Yes
Marano et al. (2001) (64)	1	0	Topical transdermal GTN administration	Visual aura for 1 h preceding familiar migraine headache lasting 60 min in a patient with a history of migraine without aura. Onset 45 min after application	No
Mossman et al. (1992) (60)	1	1	Intranasal cocaine	Flashing light in the peripheral vision of left visual field drifting towards and away from the centre of vision. Onset 24-36 h after use	Yes
Olesen et al. (1981) (34)	8 (250)	6	Carotid angiography/xenon-133 injection	Of 250 neurological patients who underwent carotid angiography, eight developed migraine aura, headache and changes in cerebral blood flow during investigation. Attacks were similar to the patients’ usual attacks. Attacks occurred during or shortly after the procedure	No
Olesen et al. (1990) (7)	20	Not reported	Carotid angiography/xenon-133 injection	Twenty patients reported attacks of migraine with typical aura following the procedure	No
Ratinahirana et al. (2002) (40)	4	Not reported	IV polidocanol foam injections	Patients reported typical visual aura. The visual symptoms lasted 20 min without subsequent headache. Symptom onset 3-10 min after injection	No
Razavi et al. (2000) (48)	1	1	Physical activity (moving furniture for 30 min)	Recurrent attacks of exertion-induced hemiplegic migraine. Onset 20 min after exercise	Yes
Skinhøj et al. (1969) (36)	1	1	Carotid angiography	Usual migraine prodromal symptoms: paraesthesia, agnosia, apraxia and aphasia	No
Staals et al. (2007) (43)	1	0	Stenting for coarctation of aorta	Two days after procedure, patient experienced a typical scintillating visual scotoma that resolved completely in <1 h and was followed by a severe diffuse headache accompanied by nausea. Attacks of migraine with aura once a week the following months	No
Thurlow (1998) (62)	1	1	General anaesthesia: propofol 170 mg, alfentanil 0.5 mg, atropin 0.6 mg, vecuronium 3 mg	Hemiplegic aura, no headache. Onset immediately after general anaesthesia	No
Toth et al. (2005) (61)	1	1	Oral tacrolimus 10 mg daily	Aura, symptoms not described in detail, and headache	No
Zaletel et al. (2010) (45)	1	1	Microbubbles injected during diagnostic contrast transcranial Doppler ultrasound and transoesophageal echocardiography	Visual scotoma in the left visual field followed by paraesthesia involving the left side of the face and the left upper limb, which lasted for 20 min, and then by a severe generalized headache with nausea and photophobia. Onset immediately after injection	No
Zouitina et al. (2014) (39)	1	0	Liquid sclerotherapy with lauromacrocol 0.25%	The patient reported typical visual aura immediately after injection. Transoesophageal echocardigraphy revealed a patent foramen ovale.	Yes (symptoms in two of three treatments)

GTN: glyceryl trinitrate; IV: intravenous.

Discussion

We identified several potential methods for the experimental provocation of migraine aura. Prospective studies reported successful triggering of aura in up to 30% of patients. Many possible triggers have been reported retrospectively. Of these, angiography involving carotid puncture seems to be the most effective and consistent.

According to questionnaire-based surveys, more than 50% of patients with MA can identify at least one trigger mechanism that always or often precipitates an MA attack (65). The most common individual trigger mechanism reported by up to 70% of patients with MA is stress, with aura occurring both during and after the course of a stressful episode (65,66). Bright lights, physical activity, not eating, sleep disturbance (too much and too little), intense emotional experiences, perfume or odour, weather and hormones (in women) are other common trigger mechanisms (65 –67). Interestingly, in line with the self-reported trigger factors, the studies identified in this review found both physical activity and visual stimulation to induce aura in prospective studies of patients with MA.

Aura induced by visual stimulation

Four of the reviewed studies used visual stimulation to trigger aura, with a total trigger rate of 30% (17 –20). The studies used different methods: Bowyer et al. (17) used a black/white circular checkerboard, whereas Cao and coworkers (18,19) used a red/green checkerboard in both their studies. Interestingly, numerous electrophysiological studies (68) and fMRI studies (69,70) have applied similar checkerboard stimulation, but without any report of triggering aura. Hougaard et al. (20) used three different light stimulation techniques: a therapeutic lamp; a xenon arc photo-stimulator designed for flash visual-evoked potentials; and a 1500 W stroboscope flickering at 20 Hz. In this study, an aura was only triggered when visual stimulation was combined with physical activity. How visual stimulation can lead to aura provocation is not clear. It has been suggested that an increased responsiveness to visual stimuli in the interictal state predisposes patients with migraine to develop attacks, possibly by triggering CSD (71,72). Psychophysical studies have demonstrated increased photosensitivity (73,74) and aversion to exposure to certain visual patterns outside attacks among patients with MA (75). Functional MRI studies have shown hypersensitivity to visual stimulation in the primary visual cortex and parietal and prefrontal areas, similar to the areas activated during the photoparoxymal response in epilepsy (69,70,76). Triggering aura using visual stimulation would be an ideal human model as it is non-invasive, but reproducible models are still needed. Optimization of the method and characterization of the optimum spatial and temporal frequencies of the patterns and wavelengths of light are needed.

Aura induced by physical activity

Two of the reviewed studies used physical activity for the provocation of aura, with a total trigger rate of 18% (8,20). In addition, three case reports of aura triggered by physical activity were identified (46,48,49). These studies suggested that different types of strenuous physical activity may induce aura. The mechanism is still unclear. Hyperthermic exercise reduces cerebral oxygenation in humans (77), an effect that theoretically could trigger CSD and thereby induce aura in patients with MA. Changes in blood pH from lactate production could also contribute to the triggering of CSD following exercise (most probably the post-exercise normalization of blood pH because acidosis increases the CSD elicitation threshold (78)). Physical activity could be suitable for aura provocation in an experimental setting. The optimum types of activity, duration and intensity still need to be characterized. One study suggested that the trigger rate is increased by combining visual stimulation and physical activity and, in general, a combination of self-reported stimuli could be a more efficient method of triggering aura (20).

Aura induced by intravascular procedures

Cerebral angiography by carotid puncture appears to be a consistent trigger, which probably induces the patients’ usual aura symptoms in at least 30% of patients after a lag phase of about 30–60 minutes (32). The method made possible a series of seminal studies of changes in regional cerebral blood flow during aura (7,33,34). Similar changes were observed in spontaneous aura attacks (7,79), indicating that these were no different from the induced attacks. Angiographies were performed in these patients by direct carotid artery puncture and the injection of contrast through the needle. Janzen et al. (32) reported the triggering of aura by vertebral angiography in only one of 14 patients. Vertebral angiographies were obtained in most patients from contrast injection through a femoral artery catheter. The mechanism behind this triggering of aura is not clear. Shuaib (80) reviewed the records of 142 patients with migraine who underwent cerebral angiography and found that seven had any complications, of which only three could be migrainous (hemisensory change and hemiparesis). This low incidence was attributed to the fact that the retrograde Seldinger technique was used and not direct arterial puncture. Thus the symptoms may have been a result of simple mechanical irritation caused by direct needle puncture of a cervical artery. Very large reviews (81,82) of the neurological complications of cerebral angiography through the femoral artery support this suggestion, since they did not report any occurrence of migraine aura. One notable exception is the report by Hauge (83) of migraine-like symptoms following vertebral angiography using a catheter inserted into the brachial artery. Hauge (84) noted that the contrast media used at this time (the early 1950s) were relatively toxic compared with modern substances and may have caused endothelial damage or disruption of the blood–brain barrier. In patients in whom a migraine aura was triggered, the angiographies were generally normal and did not suggest vasospasm (32). Olesen et al. (85) further highlighted a number of possible explanations, including the low temperature of the injected material, pressure from the injection distending the artery and ultra-short hypoxia resulting from the passage of the contrast material. Also, because the topical application of endothelin-1 potently induces CSD in rats, the release of this substance from the carotid endothelium is a possible explanation of how this procedure induces aura (86). The procedure very rarely triggers aura in patients with no previous history of aura (7), indicating the need for susceptibility to aura, perhaps from increased cortical excitability.

Another intravascular procedure that has been reported to cause migraine aura is sclerotherapy for varicose veins. This relation is well known, even though the incidence of aura following these procedures is generally very low (around 1%) (87). The mechanism for aura provocation by polidocanol is not understood. It is possible that aura can only be triggered using this method in patients with a patent foramen ovale (88). Interestingly, the endogenous production of endothelin increases after sclerotherapy in both rats (89) and human patients (90). It would be of interest to prospectively investigate the relationship between sclerotherapy and aura among patients undergoing this procedure.

Aura induced by pharmaceutical drugs

Fifteen of the provocation studies used a pharmaceutical method and we found 11 case reports of aura triggered by pharmaceutical drugs. Here we discuss only CGRP and GTN, which have been used in several studies.

Three of the reviewed studies used CGRP for migraine provocation. One study included patients with MA without hemiplegic migraine (21) and two only included patients with FHM (22,23). All studies used a continuous intravenous infusion of 1.5 µg/min CGRP over 20 minutes to induce migraine. Among the patients with MA, visual aura was induced at a trigger rate of 28% (4/14) and in three patients the aura was similar to the patients’ usual aura. The four MA patients were later rechallenged in an identical provocation setup and here only one patient developed aura (Hougaard, unpublished data). No aura was induced in the patients with FHM. Thus CGRP infusion does not seem to be an efficient method for the experimental triggering of aura. The same seems to be true for GTN, a well-known trigger of migraine without aura (91). Despite its use in many migraine studies, only two cases of the triggering of aura following GTN infusion have been reported (11) and three cases after sublingual GTN (16). Interestingly, patients with MA generally report attacks of migraine without aura in GTN and CGRP provocation studies, even in patients who never experience spontaneous attacks without aura, suggesting that these drugs exert their migraine-provoking actions ‘downstream’ of the aura in the pathophysiological process.

Experimental triggering of aura

To expand our understanding of migraine aura, a triggering method for experimental use is needed. Such a method must be absolutely safe for the patients, but also efficient. At present, there is no good approach that meets these requirements. Direct carotid artery puncture consistently provokes aura in patients with MA, but this method is not currently suitable for experimentation due to its invasive nature. The pharmaceutical migraine triggers appear to primarily trigger attacks of migraine without aura even in patients with MA. The self-reported ‘natural’ trigger factors that patients report (e.g. stress, weather changes and exposure to sunlight) are often non-specific or difficult to handle in an experimental setting. It seems that a certain threshold of trigger exposure most be reached to initiate an attack and this can possibly be achieved by combining several suspected triggers. In one provocation study, exercise combined with visual stimulation was a more potent trigger than exposure to these each of these factors separately (20). Thus combining factors such as exercise, light, sleep deprivation and fasting would potentially consistently trigger aura. However, there is obviously an ethical limit to what patients can be subjected to for this purpose. A different approach would be to attempt the induction of CSD in patients by increasing cortical excitability. CSD can be elicited in rabbits by directing flashes of light into the animal’s eyes after the intravenous administration of pentylenetetrazol, a GABA-A receptor blocker (92). Excitability can also be modulated through transcranial electrical stimulation (93). Hypoxia could also theoretically be a potential trigger, although normobaric hypoxia did not trigger aura in one provocation study (28).

Many of the reviewed studies did not give detailed descriptions of the provoked aura symptoms or information about whether the symptoms were similar to the patients’ usual aura. For future studies of potential triggers of migraine aura it is important to provide this type of information to detect potential differences in the properties of aura between different provocation methods. This would also allow the determination of whether the reported symptoms fulfil the current diagnostic criteria for MA.

Thus the search for a human model of migraine aura continues. This review has suggested a number of potential approaches that could prove useful in triggering aura and thus for disentangling the highly complex mechanisms of migraine.

Article highlights

Systematic investigation of migraine aura in patients is only possible through aura provocation.

At present, no safe and efficient method of experimental aura provocation is known.

Exposure to known triggers, pharmaceutical drugs or neurostimulation may prove useful for this purpose.

Footnotes

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was supported by the University of Copenhagen, the Lundbeck Foundation (R155-2014-171), the Danish Council for Independent Research-Medical Sciences (FSS) (grant 271-08-0446), the Novo Nordisk Foundation (grant R172-A14333) and the Research Foundation of the Capital Region of Denmark.

References

Steiner

Stovner

Birbeck

. Migraine: the seventh disabler. J Headache Pain 2013; 14: 1–1.

Gustavsson

Svensson

Jacobi

. Cost of disorders of the brain in Europe 2010. Eur Neuropsychopharmacol 2011; 21: 718–779.

Tfelt-Hansen

Olesen

. Taking the negative view of current migraine treatments: the unmet needs. CNS Drugs 2012; 26: 375–382.

Russell

Rasmussen

Thorvaldsen

. Prevalence and sex-ratio of the subtypes of migraine. Int J Epidemiol 1995; 24: 612–618.

Russell

Olesen

. A nosographic analysis of the migraine aura in a general population. Brain 1996; 119: 355–361.

Charles

Brennan

. Cortical spreading depression – new insights and persistent questions. Cephalalgia 2009; 29: 1115–1124.

Olesen

Friberg

Olsen

. Timing and topography of cerebral blood flow, aura, and headache during migraine attacks. Ann Neurol 1990; 28: 791–798.

Hadjikhani

Sanchez del Rio

. Mechanisms of migraine aura revealed by functional MRI in human visual cortex. Proc Natl Acad Sci USA 2001; 98: 4687–4692.

Schytz

Schoonman

Ashina

. What have we learnt from triggering migraine? Curr Opin Neurol 2010; 23: 259–265.

10.

Edvinsson

Linde

. CGRP antagonists for the treatment of migraine: rationale and clinical data. Clin Invest 2012; 2: 73–88.

11.

Afridi

. Glyceryl trinitrate triggers premonitory symptoms in migraineurs. Pain 2004; 110: 675–680.

12.

Afridi

. A PET study exploring the laterality of brainstem activation in migraine using glyceryl trinitrate. Brain 2005; 128: 932–939.

13.

Christiansen

Thomsen

Daugaard

. Glyceryl trinitrate induces attacks of migraine without aura in sufferers of migraine with aura. Cephalalgia 1999; 19: 660–667. discussion 626.

14.

Hansen

Thomsen

Olesen

. Familial hemiplegic migraine type 1 shows no hypersensitivity to nitric oxide. Cephalalgia 2008; 28: 496–505.

15.

Hansen

Thomsen

Marconi

. Familial hemiplegic migraine type 2 does not share hypersensitivity to nitric oxide with common types of migraine. Cephalalgia 2008; 28: 367–375.

16.

Sances

Tassorelli

Pucci

. Reliability of the nitroglycerin provocative test in the diagnosis of neurovascular headaches. Cephalalgia 2004; 24: 110–119.

17.

Bowyer

Aurora

Moran

. Magnetoencephalographic fields from patients with spontaneous and induced migraine aura. Ann Neurol 2001; 50: 582–587.

18.

Cao

Aurora

Nagesh

. Functional MRI-BOLD of brainstem structures during visually triggered migraine. Neurology 2002; 59: 72–78.

19.

Cao

Welch

Aurora

. Functional MRI-BOLD of visually triggered headache in patients with migraine. Arch Neurol 1999; 56: 548–554.

20.

Hougaard

Amin

. Provocation of migraine with aura using natural trigger factors. Neurology 2013; 80: 428–431.

21.

Hansen

Hauge

Olesen

. Calcitonin gene-related peptide triggers migraine-like attacks in patients with migraine with aura. Cephalalgia 2010; 30: 1179–1186.

22.

Hansen

Thomsen

Olesen

. Calcitonin gene-related peptide does not cause the familial hemiplegic migraine phenotype. Neurology 2008; 71: 841–847.

23.

Hansen

Thomsen

Olesen

. Calcitonin gene-related peptide does not cause migraine attacks in patients with familial hemiplegic migraine. Headache 2011; 51: 544–553.

24.

Gibb

Davies

Glover

. Chocolate is a migraine-provoking agent. Cephalalgia 1991; 11: 93–95.

25.

Pearce

. Insulin induced hypoglycaemia in migraine. J Neurol Neurosurg Psychiatry 1971; 34: 154–156.

26.

Bonuso

Marano

di Stasio

. Source of pain and primitive dysfunction in migraine: an identical site? J Neurol Neurosurg Psychiatry 1989; 52: 1351–1354.

27.

Levy

Matharu

Bhola

. Somatostatin infusion withdrawal: a study of patients with migraine, cluster headache and healthy volunteers. Pain 2003; 102: 235–241.

28.

Schoonman

Sandor

Agosti

. Normobaric hypoxia and nitroglycerin as trigger factors for migraine. Cephalalgia 2006; 26: 816–819.

29.

Ziegler

Stewart

. Failure of tyramine to induce migraine. Am Acad Neurol 1977; 27: 725–726.

30.

Ghose K and Carroll JD. Mechanism of tyramine-induced migraine: similarity with dopamine and interactions with disulfiram and propranolol in migraine patients. Neuropsychobiology 1984; 12: 122–126.

31.

Sevgi

Erdener

Demirci

. Paradoxical air microembolism induces cerebral bioelectrical abnormalities and occasionally headache in patent foramen ovale patients with migraine. J Am Heart Assoc 2012; 1: e001735–e001735.

32.

Janzen

Tänzer

Zschocke

. Delayed postangiographic reactions of cerebral vessels in patients with migraine [in German]. Z Neurol 1972; 201: 24–42.

33.

Lauritzen

Skyhøj Olsen

Lassen

. Changes in regional cerebral blood flow during the course of classic migraine attacks. Ann Neurol 1983; 13: 633–641.

34.

Olesen

Larsen

Lauritzen

. Focal hyperemia followed by spreading oligemia and impaired activation of rCBF in classic migraine. Ann Neurol 1981; 9: 344–352.

35.

Dukes

Vieth

. Cerebral arteriography during migraine prodrome and headache. Neurology 1964; 14: 636–639.

36.

Skinhoj

Paulson

. Regional blood flow in internal carotid distribution during migraine attack. Br Med J 1969; 3: 569–570.

37.

Friberg

Olsen

. Absence of vasoactive peptide release from brain to cerebral circulation during onset of migraine with aura. Cephalalgia 1994; 14: 47–54.

38.

Künzlberger

Pieck

Altmeyer

. Migraine ophthalmique with reversible scotomas after sclerotherapy with liquid 1% polidocanol. Dermatol Surg 2006; 32: 1410–1413.

39.

Zouitina

Terrier

Hyra

. Prolonged acute migraine with aura and reversible brain MRI abnormalities after liquid sclerotherapy. J Headache Pain 2014; 15: 41–41.

40.

Ratinahirana

Benigni

J-P

Bousser

. Injection of polidocanol foam (PF) in varicose veins as a trigger for attacks of migraine with visual aura. Cephalalgia 2003; 23: 850–851.

41.

Beekman

Nijssen

van Rooij

. Migraine with aura after intracranial endovascular procedures. Headache 2001; 41: 410–413.

42.

Koyama

. Persistent visual aura following catheter ablation in a patient with WPW syndrome. Behav Neurol 2007; 18: 187–192.

43.

Staals

JEA

Braun

KPJ

van Loo-Maurus

KEH

. Stenting for coarctation of the aorta precipitating migraine with aura. J Child Neurol 2007; 22: 321–323.

44.

Caputi

Usai

Carriero

. Microembolic air load during contrast-transcranial Doppler: a trigger for migraine with aura? Headache 2010; 50: 1320–1327.

45.

Zaletel

Zvan

Kozelj

. Migraine with aura induced by artificial microbubbles. Cephalalgia 2009; 29: 480–483.

46.

Corbelli

D’Amore

Caproni

. Migraine with aura in the locker room: three case reports. J Headache Pain 2012; 13: 91–93.

47.

D'Andrea

Granella

Verdelli

. Migraine with aura triggered by orgasm. Cephalalgia 2002; 22: 485–486.

48.

Razavi

Fattal

. Hemiplegic migraine induced by exertion. Arch Neurol 2000; 57: 1363–1365.

49.

Evans

Finkel

. Triggering migraine in a 20-year-old athletic male. Headache 2002; 42: 690–692.

50.

Bigal

Krymchantowski

. Migraine triggered by sucralose – a case report. Headache 2006; 46: 515–517.

51.

Engel

. New onset migraine associated with use of soy isoflavone supplements. Am Acad Neurol 2002; 59: 1289–1290.

52.

Cauchy

Larmignat

Boussuges

. Transient neurological disorders during a simulated ascent of Mount Everest. Aviat Space Environ Med 2002; 73: 1224–1229.

53.

Barnes

Kidger

Greenwood

. Viloxazine and migraine. Lancet 1979; 2: 1368–1368.

54.

Brown

Waterer

. Migraine precipitated by adenosine. Med J Aust 1995; 162: 389–391.

55.

Dinn

Wall

. Tadalafil associated with typical migraine aura without headache. Cephalalgia 2006; 26: 1344–1346.

56.

Gil-Gouveia

Wilkinson

Kaube

. Severe hemiplegic migraine attack precipitated by fentanyl sedation for esophagogastroscopy. Neurology 2004; 63: 2446–2447.

57.

Kluger

Heroum

Michot

. Migraine with aura induced by efalizumab. Clin Exp Dermatol 2009; 34: e401–e402.

58.

Larson

. Migraine with typical aura associated with fluoxetine therapy: case report. J Clin Psychiatry 1993; 54: 235–236.

59.

MacGregor

. Estrogen replacement and migraine aura. Headache 1999; 39: 674–678.

60.

Mossman

Goadsby

. Cocaine abuse simulating the aura of migraine. J Neurol Neurosurg Psychiatry 1992; 55: 628–628.

61.

Toth

Burak

Becker

. Recurrence of migraine with aura due to tacrolimus therapy in a liver transplant recipient successfully treated with sirolimus substitution. Headache 2005; 45: 245–246.

62.

Thurlow

. Hemiplegia following general anaesthesia: an unusual presentation of migraine. Eur J Anaesthesiol 1998; 15: 610–612.

63.

Afridi

Kaube

Goadsby

. Occipital activation in glyceryl trinitrate induced migraine with visual aura. J Neurol Neurosurg Psychiatry 2005; 76: 1158–1160.

64.

Marano

di Stasio

Bonuso

. Induction of a migraine aura in a patient suffering from migraine without aura. Headache 2001; 41: 612–613.

65.

Hauge

Kirchmann

Olesen

. Trigger factors in migraine with aura. Cephalalgia 2010; 30: 346–353.

66.

Kelman

. The triggers or precipitants of the acute migraine attack. Cephalalgia 2007; 27: 394–402.

67.

Russell

Rasmussen

Fenger

. Migraine without aura and migraine with aura are distinct clinical entities: a study of four hundred and eighty-four male and female migraineurs from the general population. Cephalalgia 1996; 16: 239–245.

68.

Ambrosini

de Noordhout

Sándor

. Electrophysiological studies in migraine: a comprehensive review of their interest and limitations. Cephalalgia 2003; 23(suppl 1): 13–31.

69.

Datta

Aguirre

. Interictal cortical hyperresponsiveness in migraine is directly related to the presence of aura. Cephalalgia 2013; 33: 365–374.

70.

Hougaard

Amin

Hoffmann

. Interhemispheric differences of fMRI responses to visual stimuli in patients with side-fixed migraine aura. Hum Brain Mapp 2014; 35: 2714–2723.

71.

Aurora

Wilkinson

. The brain is hyperexcitable in migraine. Cephalalgia 2007; 27: 1442–1453.

72.

Welch

D'Andrea

Tepley

. The concept of migraine as a state of central neuronal hyperexcitability. Neurol Clin 1990; 8: 817–828.

73.

Drummond

. A quantitative assessment of photophobia in migraine and tension headache. Headache 1986; 26: 465–469.

74.

Main

Dowson

Gross

. Photophobia and phonophobia in migraineurs between attacks. Headache 1997; 37: 492–495.

75.

Haigh

Karanovic

Wilkinson

. Cortical hyperexcitability in migraine and aversion to patterns. Cephalalgia 2012; 32: 236–240.

76.

Moeller

Siebner

Ahlgrimm

. fMRI activation during spike and wave discharges evoked by photic stimulation. Neuroimage 2009; 48: 682–695.

77.

Rasmussen

Nybo

Volianitis

. Cerebral oxygenation is reduced during hyperthermic exercise in humans. Acta Physiol (Oxf) 2010; 199: 63–70.

78.

Tong

Chesler

. Modulation of spreading depression by changes in extracellular pH. J Neurophysiol 2000; 84: 2449–2457.

79.

Lauritzen

Olesen

. Regional cerebral blood flow during migraine attacks by xenon-133 inhalation and emission tomography. Brain 1984; 107: 447–461.

80.

Shuaib

Hachinski

VC.

. Migraine and the risks from angiography. Arch Neurol 1988; 45: 911–912.

81.

Willinsky

Taylor

terBrugge

. Neurologic complications of cerebral angiography: prospective analysis of 2,899 procedures and review of the literature 1. Radiology 2003; 227: 522–528.

82.

Kaufmann

Huston

III Mandrekar

. Complications of diagnostic cerebral angiography: evaluation of 19 826 consecutive patients 1. Radiology 2007; 243: 812–819.

83.

Hauge

. Catheter vertebral angiography. Acta Radiol Suppl 1954; 109: 1–219.

84.

Hauge

. Vertebral artery angiography and migraine-like symptoms: Hauge's studies reconsidered. Cephalalgia 1986; 6: 197–203.

85.

Olesen

del Rio

Diener

Hemodynamics and neuroimaging of migraines. In: Olesen

Goadsby

Ramadan

(eds). The headaches, Philadelphia: Lippincott Williams & Wilkins, 2006, pp. 351–362.

86.

Dreier

. Endothelin-1 potently induces Leao's cortical spreading depression in vivo in the rat: a model for an endothelial trigger of migrainous aura? Brain 2002; 125: 102–112.

87.

Sarvananthan

Shepherd

Willenberg

. Neurological complications of sclerotherapy for varicose veins. J Vasc Surg 2012; 55: 243–251.

88.

Raymond-Martimbeau

. Transient adverse events positively associated with patent foramen ovale after ultrasound-guided foam sclerotherapy. Phlebology 2009; 24: 114–119.

89.

Frullini

Felice

Burchielli

. High production of endothelin after foam sclerotherapy: a new pathogenetic hypothesis for neurological and visual disturbances after sclerotherapy. Phlebology 2011; 26: 203–208.

90.

Frullini

Barsotti

Santoni

. Significant endothelin release in patients treated with foam sclerotherapy. Dermatol Surg 2012; 38: 741–747.

91.

Thomsen

Kruuse

Iversen

. A nitric oxide donor (nitroglycerin) triggers genuine migraine attacks. Eur J Neurol 2011; 1: 73–80.

92.

van Harreveld

Stamm

. Cortical responses to metrazol and sensory stimulation in the rabbit. Electroencephal Clin Neurophysiol 1955; 7: 363–370.

93.

Nitsche

Paulus

. Sustained excitability elevations induced by transcranial DC motor cortex stimulation in humans. Am Acad Neurol 2001; 57: 1899–1901.