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Abstract

Aim

To review reports suggesting a role for neurovascular scalp structures in migraine.

Main data reported

(A) Scalp periarterial nervous fibres contain all the main peptides and receptors involved in pain. (B) It is possible to interrupt or alleviate migraine pain with a prolonged compression of the main scalp arteries, which decreases blood flow through the pain-sensitized vessels and probably induces a temporary conduction block of periarterial nociceptive fibres. (C) Painful points are present on the scalp arteries of a considerable percentage of migraine sufferers. (D) It is possible to stop or alleviate pain by intervening on nociceptive periarterial fibres, as for example with the injection of lidocaine or 3–5 ml saline, and with percutaneous application of a capsaicin cream.

Conclusion

The data reported suggest a role for neurovascular scalp structures in at least some patients with migraine. It would be of interest to find a clinical distinction between patients according to the prevalence of an intracranial or extracranial peripheral pain mechanism. This could lead to more efficacious treatments.

Keywords

Migraine arteries scalp arteries neurovascular periarterial nociceptive fibres

Introduction

The origin of pain in migraine is still a matter of debate, because of different evidence in favour and against one or another mechanism. A unified theory suggests the cooperation of a central and of a peripheral component. Different peripheral structures have been advocated to have a main role. The activation of peripheral nociceptors in pial or dural arteries in migraine has been supported by numerous data, recently reviewed by Olesen et al. (1). In that review, some arguments were also put forward in favour of a role for extracranial structures, and the authors suggest that ‘different subtypes of migraine might be associated with the activation of nociceptors that supply different groups of arteries’.

The assessment of a role for extracranial structures should be based on several elements, and particularly on their modification during a migraine attack, on the presence in perivascular fibres of appropriate peptides and receptors involved in pain and on the possibility of direct intervening on them to relieve pain.

An article on the extracranial vascular theory has recently been published (2).

This is a short report of data supporting a role for extracranial (scalp) neurovascular structures in migraine pain (note that in this review the term ‘neurovascular’ did not refer to a prevalent effect of nervous–central structures, as in the review by Dodick (3), it is used only to stress the role of nociceptive fibres and receptors pertaining to the arteries).

The effect of scalp arterial compression

The effect of the compression of scalp arteries has been the object of several older studies. Blau and Dexter (4) compressed one superficial temporal artery (STA) for 20 s during a migraine attack and obtained decrease of pain in 16 of 50 migraineurs. During a unilateral anterior migraine attack, Drummond and Lance (5) compressed the STA ipsilateral to pain for 20 s on 63 patients, obtaining relief in 23 patients (75 to 100% relief in 11 and 50 to 74% relief in 12), with no relief in 40. According to Lipton (6), a vigorous bilateral compression and massage of the frontal branches of the STA during the aura phase, initiated at the first sign of visual aura and continuing until the aura has completely subsided, has been successful in blocking 34 of 42 attacks (81%). Vijayan (7) reported that the application of a tight headband relieved pain in 87% of 69 attacks in 23 patients, with pain resuming when the band was removed.

Better results were obtained by introducing the practice of a prolonged (more than 3 minutes) compression of major scalp arteries, STA and occipital (8); this procedure caused relevant or complete and enduring pain relief in 68% of patients. These positive results were confirmed by the use of a simple device permitting a very prolonged compression of the STA, applied at the beginning of migraine attacks, both in adults (9) and in children and adolescents (10). A control procedure consisted of applying the device alongside and detached from the arteries, which was significantly less efficacious.

Arterial pain derives from the activation of nociceptive fibres around the arterial wall. Arterial dilatation could stimulate hyperexcitable/hypersensible nociceptors causing pain (1). The simple interruption of the arterial flux, as obtained with a 20 s arterial compression, could therefore temporarily reduce pain. The greater effect of a prolonged compression might be due to a different mechanism. Prolonged compression might also deprive perivascular nerve fibres of nutrients, leading to a temporary conduction block. This block can interrupt an initial attack, when the pain is not strong enough and probably fewer nociceptive neurofibres are involved, with fewer pain-activating molecules in the periarterial perineural milieu.

Presence of painful points on scalp arteries

Iversen et al. (11) found that 7 patients of 23 during a migraine attack felt local pain on a gentle palpation of STA. With a stronger digital pressure (between 1.0 and 2.5 kg/cm²), our group found that a large percentage of migraineurs have one or more scalp arteries painful to pressure, both during and in absence of a migraine attack (12). This is also the case in children and adolescents (13). As a control procedure we applied finger pressure alongside the arteries, which was significantly less efficacious.

Pain to pressure is usually localized in discrete points of the artery, and not along its entire length, and suggests nociceptive-fibre hyperexcitability, which could be due to a local chemical inflammation, e.g. the presence of pain-activating peptides. This is also present in a small percentage of healthy people (12,13). It should be noted that scalp muscles also frequently present pressure-painful points in migraine (14,15), and sometimes in healthy people (16). This could be due to a general hypersensitivity of cranial structures in migraine, as occurs for allodynia; however, it is different from allodynia, which is characterized by a more superficial and less precisely localized pain sensation and occurs during a migraine attack (17). Moreover, the close connection of small arteries and sensory nerve fibres in the muscles should also be considered (18).

The effect of local actions on the periarterial area

The periarterial infiltration of an anaesthetic (3 ml of lidocaine 2%) blocked a migraine attack; the same, however, also occurred after injection of simple saline (3–5 ml) (19). In a subsequent controlled trial (20), our group showed the possibility of ameliorating or interrupting a migraine attack with the periarterial infiltration of 3–5 ml saline in 82.5% of 40 patients having scalp artery tenderness (cessation of pain in 52.5% and >50% relief in 30.0%). Infiltration was effected around the painful arteries (STA, frontal branch of the STA, occipital artery, mono- or bilaterally) and the beneficial effect occurred a few minutes later. It was correlated with the presence of arterial tenderness, but not with the type of pain (explosive vs. implosive) reported by the patient. Control procedure consisted of saline infiltration 2.5–3 cm in front of the STA or lateral to the occipital arteries, which was significantly less efficacious.

The procedure is very simple and harmless; it was carried out with a 30 G (0.3 mm diameter) needle; no adverse effects ever occurred. It is advisable to inject a very small dose of lidocaine (0.2 ml of 2% solution) before saline 3–5 ml, to prevent pain due to the subcutaneous distension by the liquid, causing an evident wheal.

Migraine pain does not have the same characteristics as neural pain. The immediate beneficial effect of 3–4 ml saline around the occipital artery, localized by pulse perception (20), should be compared with the several reports on the benefit of lidocaine or bupivacaine injection around the greater occipital nerve (GON) in migraine and in chronic migraine. Some authors report an immediate beneficial effect of the injection of the anaesthetic in a high percentage of patients (21–24). However, they did not perform a control procedure with saline, with the exception of Bovim and Sand (25), who with a 2 ml saline control obtained immediate minor relief in 4/16 patients with ‘cervicogenic headache’. The GON and the occipital artery are located close to each other (for a review of the anatomical studies see (26)), therefore the dilemma is whether the anaesthetic acted on the nerve or on the periarterial nociceptive nerve fibres. Again, the presence of post-lidocaine/bupivacaine anaesthesia on the area supplied by the GON (i.e. the occiput and the posterior parieto-temporal scalp) was not verified, except by Afridi et al. (27), who found anaesthesia in only 50% of the lidocaine-injected patients, suggesting the effect in several patients was not due to a blockage of the GON.

Similar considerations could be made in relation to the effect of the electrical neurostimulation by means of subcutaneously-implanted electrodes. This may involve the GON and the auricolo-temporal nerve (28), but at the same time the perivascular nociceptors of the nearby occipital and temporal arteries.

On the other hand, one may object that the effect observed is due to an action of saline on the nervous trunks, rather than on perivascular receptors. However, no data exist indicating that nervous trunk may be stimulated or inhibited by saline around it.

The mechanism of the effect of periarterial saline is unknown. It is important to remember the positive effect on migraine pain saline injection may have in tender points of scalp and neck muscles (29), similar to that obtained by injecting a local anaesthetic (30). The intramuscular quantity of saline injected is rather small. There are no data indicating a possible direct effect of saline on nociceptors, while a dilution of algogenic peptides could be hypothesized when larger quantities of saline are used (like 3–5 ml, as in our trials (20)).

Scalp arteries calibre during migraine attack

The role of arterial dilatation in migraine is still a matter of debate. It is in any case obvious that arterial pain derives from the activation of periarterial nociceptive neurofibres, not necessarily by means of a vasodilatatory mechanism. Therefore the role of scalp neurovascular structure in migraine is not disputed by the fact that the ‘dilatation of extracranial arteries does not necessarily cause headache’ (31, page 20). Wolff’s classic observations on dilated STA in migraine attacks (32) were further supported by Iversen et al. (11, page 838): during a unilateral migraine attack, ‘the median luminal diameter of the frontal branch of the temporal artery of the affected side was greater than that on the other side’.

A principal role of STA is probable in the headaches caused by nitroglycerin (33) and by calcitonin gene related peptide (CGRP) (34) in healthy subjects. These headaches were found to be associated with intra-extracranial vasodilatation. Pre-administration of, respectively, sumatriptan (33) or olcegepant (BIBN4096BS) (34) inhibited headache and vasodilatation in STA, but not vasodilatation of the middle cerebral artery (MCA), therefore apparently acting only on STA.

Epoprostenol (analogue of prostaglandin I₂) induces migraine-like attacks in migraineurs with dilatation of both STA and MCA (35), but in healthy subjects the provoked headache occurred with dilatation of STA and not of MCA (36). On the other hand, carbachol in healthy subjects induced headache and dilated both STA and MCA (37), and in migraineurs induced headache that was not migraine-like and dilated MCA, not significantly changing the STA (38).

Vasodilatation of STA and of MCA can be provoked by different substances, not always causing headache. Prostaglandin D₂ in healthy subjects markedly dilated STA and MCA, but caused only mild headache (39). The vasoactive intestinal peptide in healthy subjects (40) and in migraineurs (41) dilated STA and, to a lesser extent, MCA, but caused only mild headache. Adrenomedullin dilated the STA but not MCA, not inducing more headache compared with placebo in people suffering from migraine (42).

Vasodilatation may not be necessary for headache, because nociceptive-fibre activation causing headache may be provoked by other mechanisms. This is suggested by the absence of any arterial dilatation, both of STA and MCA, in headache caused by sildenafil (43). Moreover, olcegapant is a specific anti-migraine drug without vasoactive effect on STA and on MCA (44), and there is no linear relationship between the headache provoked by various vasodilator agents in healthy subjects and the vasodilatation of the MCA and STA (45).

Recent studies employing magnetic resonance angiography added further data, not fully concordant, concerning intracranial arteries. In nitroglycerine-induced migraine attacks in migraineurs, Shoonman et al. (46) did not find significant changes in MCA and extracranial MMA (they did not report data on STA), while Asghar et al. (47) in CGRP-induced migraine attacks in migraineurs showed dilatation of both MCA (not dilated by CGRP in healthy subjects (48)) and extracranial MMA, with reduction of the calibre of MMA, but not of MCA, after regression of pain by sumatriptan (a comparative evaluation of STA was not reported). This result appears to agree with what has been reported, although to a lesser extent, possibly due to some technical limitations, in a single case of spontaneous migraine attack (49).

Therefore, STA and MCA behave differently on some occasions, as also occurs between MCA and MMA. Comparing the behaviour of STA and MMA (both being part of the ramifications of the external carotid artery) could be of interest. Data on this at the moment are only derivable from comparing two experiments (50,51): during migraine-like attacks, caused in healthy subjects by infusion of pituitary adenylate cyclase activating peptide-38 (PACAP38), STA is dilated (MCA minimally) (50), as well as MMA (51).

To summarize, no data excluding the role of STA in migraine emerge from the studies on the behaviour of cranial arteries.

As a collateral notation concerning artery calibre, it should be remembered that the pulsating quality of pain did not correlate with the pulsatile arterial activity (52), therefore suggesting a central pain-pacemaker.

It remains to be determined whether or how much the hypersensibility/hyperexcitability of perivascular nociceptive fibres causing arterial pain is due to central dysfunction or to a peripheral effect, such as the presence of substances increasing nociception.

5-HT receptors and peptides in scalp arteries

Because the most efficacious drugs for migraine attack are the triptans, the presence in scalp arteries of 5-HT receptors necessary for their action, i.e. 5-HT1B/D, is suggestive. They are not prevalent in STA (53), as confirmed by Verheggen et al. (54), who found that in STA (arterial segments obtained from non-migraineurs undergoing brain surgery), 5-HT receptors were of type 5-HT_2A in 83–86% and of 5-HT_1B/D in the remainder. However, in STA the vasoconstriction by sumatriptan was blocked by a 5-HT_1B antagonist (55,56). Similar data were obtained with the occipital artery (57).

The main peptides involved in pain, i.e. CGRP, substance P (SP) and neuropeptides Y (NPY), are present and co-localized in adventitia or the adventitia-media border of normal human STA and occipital arteries (58–60). No differences in the presence of NPY, VIP, SP and CGRP were found between MMA and STA (61).

Olcegepant, effective in acute treatment of migraine attacks, has high affinity for CGRP receptors in STA (62).

In summary, receptors and peptides involved in pain are present in scalp arteries and appear specific to the site of action of anti-migraine drugs.

Scalp artery ligation

There are two uncontrolled trials reporting a beneficial effect subsequent to the ligation of scalp arteries (63,64). If confirmed, this would probably be due to the interruption of the afferent nociceptive filaments located around those arteries, and not to the scarcely relevant changes in arterial flux.

Botulinum toxin (BoNT/A) infiltration on scalp structures

The efficacy in chronic migraine of multiple infiltration of BoNT/A in pericranial and cervical muscles has been shown by multicentre studies (65,66). However, the mechanism has not been clarified. Gazerani et al. (67) suggest that the injection of BoNT/A acts by ‘decreasing the mechanical sensitivity of muscle nociceptors through inhibition of glutamate release and by attenuating the provoked release of CGRP from muscle nociceptors’ (67, page 606). Although, as reported above, scalp muscles frequently present pressure-painful points in migraine, a clear role of muscle nociceptors in migraine has not been demonstrated. In any case, an action on scalp structures is probably implicated. BoNT/A could spread to perivascular afferent fibres and inhibit their activity, so the action of BoNT/A on these afferent fibres should be evaluated.

The effect of percutaneous drug application

Capsaicin 0.1% jelly applied to tender scalp arteries may reduce their tenderness, and may block a migraine attack if administered at the onset (68). The irritating effect of capsaicin prevents its use at higher concentrations. Capsaicin action occurs through TRPV1 receptors, present in scalp arteries (69) and suggested to be a site of sumatriptan action (70), although the role of TRPV1 in headache pain has been challenged (71).

Capsaicin is not so easily absorbed transdermally, so its effect is very probably extracranial. This is at variance with the local application of glyceryl trinitrate (72,73), whose effect on STA dilatation and headache cannot be considered probative, as pointed out by Olesen et al. (1), because the drug is easily absorbed transdermally and acts systemically.

Menthol, acting on TRPM8, has also been reported to improve migraine when spread on the forehead and temporal area of the painful side (74), presumably involving the STA and its frontal branch.

The slow, partial penetration of the drugs through the skin might be the cause of limited efficacy, and trials with other drugs or vehicles are needed.

Conclusion

The above-mentioned reports suggest a role of scalp neurovascular structures in at least part of the migraine patient population. Some relevant points are: (a) the pressure-painfulness of scalp arteries; (b) the efficacy of a prolonged artery compression on migraine attack; (c) the possibility of blocking an attack by injecting lidocaine or 3–5 ml saline around scalp arteries; (d) the positive effect of percutaneous application of a capsaicin cream on arterial tenderness and on an initial attack.

The trigeminovascular hypothesis, proposed by Moskowitz (75), of an exclusive intracranial neurovascular involvement, may otherwise remain valid for some or perhaps most patients. Moreover, other sources and paths of nociceptive stimuli could be involved (76). On the other hand, a relevant role of central structures is demonstrated by several data (77).

Future perspectives

The involvement of scalp neurovascular structures in a number of migraine patients suggests the possibility of alternative treatments, like local acute treatments limiting systemic drug use. Moreover, the repeated or continual use of the above-reported procedures must be evaluated as regards possible new ways of preventive treatment.

Criteria for a clinical differentiation between patients or attacks with a prevalent involvement of scalp or intracranial neurovascular structures are a further step in the clinical evaluation of migraine patients. In this perspective, the regular, accurate examination of scalp structures, particularly neurovascular ones, may be relevant.

Footnotes

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Acknowledgements

The author would like to thank Drs Maria Giuseppina Ledda, Yousef Hmaidan, Francesco Madeddu and Maria Celeste Serci for their valuable collaborations. The English language of the manuscript was revised by Dr Mary Groeneweg.

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The role of the neurovascular scalp structures in migraine

Abstract

Aim

Main data reported

Conclusion

Keywords

Introduction

The effect of scalp arterial compression

Presence of painful points on scalp arteries

The effect of local actions on the periarterial area

Scalp arteries calibre during migraine attack

5-HT receptors and peptides in scalp arteries

Scalp artery ligation

Botulinum toxin (BoNT/A) infiltration on scalp structures

The effect of percutaneous drug application

Conclusion

Future perspectives

Footnotes

Funding

Acknowledgements

References