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Nappi et al. The Journal of Headache and Pain 2013, 14:66
http://www.thejournalofheadacheandpain.com/content/14/1/66
REVIEW ARTICLE
Open Access
Hormonal contraception in women with migraine:
is progestogen-only contraception a better
choice?
Rossella E Nappi1,2,5*, Gabriele S Merki-Feld3, Erica Terreno1,2, Alice Pellegrinelli1,2 and Michele Viana4
Abstract
A significant number of women with migraine has to face the choice of reliable hormonal contraception during
their fertile life. Combined hormonal contraceptives (CHCs) may be used in the majority of women with headache
and migraine. However, they carry a small, but significant vascular risk, especially in migraine with aura (MA) and,
eventually in migraine without aura (MO) with additional risk factors for stroke (smoking, hypertension, diabetes,
hyperlipidemia and thrombophilia, age over 35 years). Guidelines recommend progestogen-only contraception as
an alternative safer option because it does not seem to be associated with an increased risk of venous
thromboembolism (VTE) and ischemic stroke.
Potentially, the maintenance of stable estrogen level by the administration of progestins in ovulation inhibiting
dosages may have a positive influence of nociceptive threshold in women with migraine. Preliminary evidences
based on headache diaries in migraineurs suggest that the progestin-only pill containing desogestrel 75 μg has a
positive effect on the course of both MA and MO in the majority of women, reducing the number of days with
migraine, the number of analgesics and the intensity of associated symptoms. Further prospective trials have to be
performed to confirm that progestogen-only contraception may be a better option for the management of both
migraine and birth control. Differences between MA and MO should also be taken into account in further studies.
Keywords: Migraine with aura (MA); Migraine without aura (MO); Combined hormonal contraceptives (CHCs);
Combined oral contraceptives (COCs); Progestogen-only contraception; Desogestrel-only pill; Venous
thromboembolism (VTE); Stroke
Introduction
Migraine is a disabling headache, characterized by moderate to severe head pain, usually accompanied by nausea,
photophobia, phonophobia and osmophobia (migraine
without aura, MO). In about 30% of patients migraine attacks are preceded by transient focal neurologic symptoms
which are called aura (migraine with aura, MA). Migraine
has a high socio-economical impact. In fact during migraine attacks most migraineurs reported severe impairment or the need of the bed rest and almost 40% of
migraine patients have five or more headache days
monthly [1]. The Global Burden of Disease survey 2010
* Correspondence: [email protected]
1
Research Center for Reproductive Medicine, Gynecological Endocrinology
and Menopause, IRCCS S. Matteo Foundation, Pavia, Italy
2
Department of Clinical, Surgical, Diagnostic and Paediatric Sciences,
University of Pavia, Pavia, Italy
Full list of author information is available at the end of the article
(GBD) recently published showed that migraine is the
seventh highest cause of disability in the world [2].
Review
In the last few years significant advance in the field of
reversible hormonal methods has been achieved in order
to maximize the benefits and to minimize the risks.
We believe it is relevant for clinical practice to briefly
review in here potential vascular risks according to the
category of migraine, with and without aura, and to the
type of hormonal contraceptive option.
Epidemiology of migraine and combined hormonal
contraceptive (CHC) use
Migraine affects about 18% of women and 6% of men in
USA and Western Europe [3,4] and its cumulative lifetime
prevalence is 43% in women and 18% in men [5]. It is then
© 2013 Nappi et al.; licensee Springer. This is an Open Access article distributed under the terms of the Creative Commons
Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction
in any medium, provided the original work is properly cited.
mostly a female disorder, that it is active in particular during the fertile period of the women’ life with a peak of
prevalence in their 20s and 30s [6]. The reproductive life
is characterized by the need of reliable and convenient
methods of contraception. Among the several forms of
contraceptives available, hormonal contraceptives are the
most popular reversible method, both in USA and Europe
and the “Pill” is the most used [7-9]. Low dose [20 to
30 μg ethynil estradiol (EE2) per day] combined hormonal
contraceptives (CHCs) have become the method of choice
and the availability of new progestins (third- and fourthgeneration) has allowed to achieve non-contraceptive
benefits in comparison to older progestins (second –
generation) [10]. CHCs are available in several regimens
and routes of administration (oral, transdermal vaginal) in
the attempt to improve tolerability, adherence and convenience of use [11]. Moreover, two new CHCs containing
natural estradiol (E2), instead of EE2, have been introduced to increase safety and future developments are ongoing [12]. Interestingly, many gynecological conditions
that are comorbid with migraine can be treated with
CHCs. This enhances the likelihood of their use in migraine population [13]. The prescription of CHCs may
have different effects on migraine with not univocal results
because of many methodological limitations (diverse hormonal combinations, variable research settings, retrospective and/or cross-sectional designs, lack of a clear
phenotyping of the headache according to IHS criteria, inadequate duration of observation) [14-16]. Historically,
combined oral contraceptive (COCs) is the category best
studied in migraineurs with an aggravation of migraine
reported in 18-50% of cases, an improvement in 3-35%
and no change in 39-65% [17]. A more recent crosssectional study on a large population found that migraine
is significantly associated with COCs assumption. Yet
because of the design of the study it is not possible to define a causal relationship between exposure and disease
[18]. Analysis on the different effect of the COCs on the
two forms of migraine revealed that MA worsen more
(56.4%) than MO (25.3%) [19]. Furthermore, women can
present MA for the first time during the initiation of
COCs [20]. During the last decade, a specific “window” of
vulnerability triggered by the 7 days free hormone interval
has been identified and the definition of hormonallyassociated headaches (exogenous hormone-induced headache and estrogen-withdrawal headache) encompasses
several patho-physiological mechanisms which are likely
to explain nociceptive threshold in women [21,22]. Strategies to minimize estrogen withdrawal at the time of
expected bleeding or to stabilize circulating estrogen at
lower concentration include, respectively, 1) to use transdermal E2 during the free interval of hormonal contraception [22] or to shorten the interval from 7 to 4 and even
to 2 days [23,24]; 2) to administer low dose COCs in
Page 2 of 6
extended/flexible regimens [25] or to use extended vaginal
contraception [26].
Very recently, Mac Gregor [27] reviewed the effects of
currently available contraceptive methods in the context
of the risks and benefits for women with migraine and
non-migraine headaches and concluded that for the majority of women with headache and migraine, the choice
of contraception is unrestricted. Indeed, the contraceptive method is unlikely to have an impact on headache,
whereas migraine deserves accurate diagnosis and recognition of the impact of different methods on such
condition.
Vascular risks associated with CHCs and migraine
MA, and to a lesser extent also MO, may increase vascular
risk, especially the risk for ischemic stroke in younger
women [27-30]. Moreover, evidences that need to be corroborated by further studies suggest an association between MA and cardiac events, intracerebral hemorrhage,
retinal vasculopathy and mortality [31]. Even though the
association between migraine and stroke appears to be
independent of other cardiovascular risk factors [32], the
presence of some risk factors, such as smoking and/or
COCs use or their combination, further increase risk [33].
MA is associated with a twofold increased risk of ischemic
stroke but the absolute risk associated with CHC use is
very low in healthy young women with no additional risk
factors and mostly related to the estrogen dose [34]. In
spite of the considerable advances in terms of safety and
tolerability of CHCs in migraine sufferers [13], their use is
still questioned especially in women with additional risk
factors for stroke, including, smoking, hypertension, diabetes, hyperlipidemia and thrombophilia, age over 35 years
[35]. New evidences [36-38] have warned clinicians on the
use of CHCs and the risk of venous thromboembolism
(VTE) which is likely to be dependent on the type
of the progestin [RR 1.6–2.4 by using third- and
fourth-generation CHCs (namely, desogestrel, gestodene
norgestimate and drospirenone, respectively) in comparison with those containing LNG (second-generation)] and
the total estrogenicity of CHCs [39,40]. Even new routes
(trandermal patch and vaginal ring) seem to be associated
with an increased VTE risk, but data are contradictory
[41-43]. Indeed, according to a statement very recently released [44] many factors contribute to VTE risk (e.g. age,
duration of use, weight, family history) which makes epidemiological studies vulnerable to bias and confounders.
In addition, the decision-making process should take into
account non only the small VTE risk (absolute risk depending on the background prevalence rate between 2 to
8 per 10,000 users per year [45]) of the contraceptive
method but also other elements such as efficacy, tolerability, additional health benefits, and acceptability which have
to be discussed with the individual woman. In any case, it
is essential to follow the appropriate guidelines by
avoiding the prescription of CHCs to women at elevated
risk for VTE. In the context of migraine and CHCs use, it
is very important to remember that the World Health
Organization Medical Eligibility Criteria for Contraceptive
Use stated that MA at any age is an absolute contraindication to the use of COCs (WHO Category 4) [46]. The US/
WHO MEC is more restrictive than the UK/WHO MEC
as regard to MO, rating CHCs as a category 4 for any
migraineur over age 35 [47]. That being so, the personal
risk assessment should guide the prescription of CHCs in
selected conditions. When there is the sole need of contraception, without the added benefits of a peculiar hormonal
compound and/or combination, CHCs with the lower vascular risk or alternative methods for birth control should
be considered.
Progestogen-only contraception: a class on its own
The progestin component of hormonal contraceptives accounts for most of their contraceptive effects (inhibition of
ovulation, suppression of endometrial activity, thickening of
cervical mucus). Progestin-only methods includes pills (the
pill most used in Europe contains low doses of desogestrel),
injectables [depot Medroxyprogesteroneacetate (DMPA)],
implants (the most recent long-acting reversible contraception contains Etonogestrel single-rod implant for at
least 3 years), and intrauterine devices (levonorgestrel for
at least 5 years) [48]. By providing effective and reversible
contraception, progestin-only contraception has many
noncontraceptive health benefits including improvement
in dysmenorrhea, menorrhagia, premenstrual syndrome,
and anemia [49]. Indeed, there is a general reduction of
the amount of menstrual bleeding but cycle control may
be erratic, a feature that may influence acceptability
[50-52]. Progestin-only methods are appropriate for
women who cannot or should not take CHCs because
they have some contraindications to estrogen use and
therefore display a higher risk of VTE [35,36]. The
progestogen-only contraception is a safe alternative to
CHCs and the avoidance of the estrogen component has
many advantages not only for breastfeeding women but
also for women with vascular diseases or risk factors for
stroke [46,47]. The use of progestin-only contraception is
not associated with an increased risk of VTE compared
with non-users of hormonal contraception [53]. In
addition, progestin-only pills, injectables, or implants are
not associated with increased risk of ischemic stroke
according to a recent metanalysis (OR 0.96; 95% CI: 0.701.31) [54]. Since the 1-year prevalence rates for migraine
in women are 11% for MO and 5% for MA, respectively
[55], there is potentially a high number of women in
whom CHCs may be contraindicated according to WHO
guidelines and progestogen-only contraception may be
safely used [35,36].
Page 3 of 6
Evidence of progestogen-only contraception in women
with migraine
Given the evidence that progestogen-only contraception
is a safer option for women with migraine, the main
question is whether such contraceptive choice may influence the course of both MA and MO and offer a better management of the disease. Indeed, even though the
excess risk of death for a woman taking modern CHCs
is 1 in 100,000, which is much lower than the risk of
everyday activities such as cycling [56], there is a biological plausibility that in women with migraine should
be wiser to use an estrogen-free containing contraception to avoid any potential vascular risk. Two recent
very large epidemiologic studies [36,57] reported the association between CHC and progestogen-only methods
and cardiovascular risk, thrombo-embolic risk and
stroke. Whereas no increased risk for deep venous
thormbosis, myocardial infarction and thrombotic
stroke was found for the progestogen-only methods, the
risk were two-sixfold elevated in CHC users. The role of
progesterone/progestins in the pathophysiology of migraine has been overshadowed by Somerville’s early observations that it was the prevention of estrogen but not
of progesterone withdrawal in the late phase of the cycle
to be able to prevent the occurrence of migraine attacks
[58,59]. Indeed, at variance with the influence of estrogens
upon the cerebral structures implicated in the pathophysiology of migraine [60], cyclic variations in progestin levels
were not related to migrainous headaches, but they rather
seem to be protective. Progesterone apparently attenuates
trigemino-vascular nociception [61] and its receptors are
localized in areas of the central nervous system, which are
involved in neuronal excitability and neurotransmitter
synthesis release and transport [62]. It has been shown
that progesterone can antagonize neuronal estrogenic effects by downregulating estrogen receptors [63]. Whereas
estrogen peak decrease the threshold for cortical spreading
depression (CSD), the neurobiological event underlying
MA, estrogen withdrawal increased the susceptibility to
CSD in an animal model [64]. Therefore, the maintenance
of low estrogen levels and the avoidance of estrogen withdrawal by the administration of progestins in ovulation
inhibiting dosages might decrease cortical excitability. Indeed, progestogen-only contraception has a continuous
administration, without the hormone-free interval, and
does not induce withdrawal stabilizing circulating estrogens, but some fluctuations according to different preparations may still occur [65]. Clinical data are scarce and no
comparative studies with progestogen-only contraceptives
and placebo or COCs are available in the literature [27].
Diagnoses are often inaccurate, without distinction between headache and migraine, and headache is reported in
contraceptive progestin implant users as a potential cause
of discontinuation [66]. Similarly, there is an increase in
headache, but not migraine, reported over time with both
norethisterone enanthate and, especially with depot
medroxyprogesterone acetate [67]. Anecdotally, migraine
is more likely to improve in women who achieve amenorrhea [68]. In a large, cross-sectional, population-based
study in Norway of 13944 women, a significant association
between CHC and headaches, but no significant association between progestin-only pills and migraine (OR 1.3,
95% CI: 0.9–1.8) was found but the number of users was
small [18]. To date two diary-based studies pilot studies
on the effect of desogestrel 75 μg on migraine have been
published [69,70]. Such oral daily pill inhibits ovulation
and the dose allows the ovary to synthesize stable amounts
of estrogen which are relevant for wellbeing and bone
density [71]. The first study included thirty women with
MA [69]. The use of desogestrel 75 μg resulted in a significant reduction in MA attacks and in the duration of aura
symptoms, already after three months of observation.
Interestingly, the beneficial effect of desogestrel 75 μg on
visual and other neurological symptoms of aura was
significantly present only in those women in whom MA
onset was related to previous COCs treatment. These
findings suggest that the reduction in estrogen levels may
be relevant to the amelioration of MA, but do not exclude
a direct effect of the progestin on CSD. The second study
on the effect of desogestrel 75 μg included women with
MA (n°=6) and with MO (n°=32) and evaluated migraine
days, pain score and pain medication [70]. An improvement of each parameter was observed during 3 months
use of desogestrel 75 μg in comparison to a three months
pretreatment interval. A subanalyses of the effect on 32
women with MO revealed significant improvements in
number of migraine days, pain medication and pain intensity. The mean number of migraine attacks at baseline was
higher in comparison to that in the study of Nappi et al.
[69], indicating that also very severe migraineurs might
profit from such a progestin-only contraception. Chronic
migraineurs often develop medication overuse headaches
with severe limitation of their quality of life. The reduction
of pain medication by progestin-only contraception is an
interesting approach and it should be studied further. Indeed, there is a broad variation in the intensity of improvement with a reduction in migraine frequency ranging
from 20% and 100% [70]. No indicators to identify those
women who will profit from desogestrel 75 μg could be
ascertained. On the other hand, there were few dropouts
of women experiencing more migraine after starting
contraception with this progestin in both studies, indicating that progestins can also deteriorate migraine in few
cases.
A very recent study investigating the changes of quality
of life in migraineurs 3 months after initiation of the
progestagen-only pill desogestrel 75 μg demonstrates a
highly significant reduction in Midas Score and Midas
Page 4 of 6
grades [72]. However, clinical experience with desogestrel
75 μg in migraineurs further shows that during the initial
4 weeks migraine frequency can raise slightly before headaches improve. This information has to be mentioned and
discussed during counseling.
In summary, the potential advantages of using
progestogen-only contraception in women with migraine are the following:
1) Continuous use
2) Absence of estrogen peak
3) No influence on threshold for cortical spreading
depression (CDS)
4) No evidence of increase in cardiovascular, stroke
and thrombo-embolic risk
5) No data on progestins inducing migraine
Conclusions
In conclusion, contraceptive counseling in migraine should
take into account the risk-benefit profile of the individual
woman before prescribing CHCs. In order to reduce
potential vascular risks, recommendations should be a
main point of guidance for prescribers. Progestogen-only
contraception is a safer option in MA and eventually in
MO with additional risk factors. Given preliminary evidences of a positive effect of the progestin-only pill
desogestrel 75 μg on MA and MO in many, but not all
women, further prospective trials have to be performed to
confirm that progestogen-only contraception may be a
better option for the management of both migraine and
birth control. Differences between MA and MO should
also be taken into account in further studies.
Competing interests
Dr. Rossella E. Nappi has had financial relationships (lecturer, member of advisory
boards, and/or consultant) with Bayer Pharma, Eli Lilly, Gedeon Richter, HRA
Pharma, MSD, Novo Nordisk, Pfizer Inc., Shionogi Limited, Teva/Theramex.
Dr. Gabriele S. Merki-Feld has had financial relationships (lecturer, member of
advisory boards) with Bayer Pharma and MSD.
Authors’ contributions
Conception and design: REN, GSM. Acquisition of data: ET, AP. Analysis and
interpretation of data: REN, MV, GSM. Drafting the article: REN, MV, GSM.
Revising it for intellectual content: REN, MV, GSM. Final approval of the
completed article: REN, REN, GSM, ET, AP, MV. All authors read and approved
the final manuscript.
Author details
1
Research Center for Reproductive Medicine, Gynecological Endocrinology
and Menopause, IRCCS S. Matteo Foundation, Pavia, Italy. 2Department of
Clinical, Surgical, Diagnostic and Paediatric Sciences, University of Pavia,
Pavia, Italy. 3Clinic for Reproductive Endocrinology, University Hospital Zürich,
Zürich, Switzerland. 4Headache Science Center - National Neurological
Institute C. Mondino, Pavia, Italy. 5Research Center for Reproductive
Medicine, Unit of Obstetrics and Gynecology, IRCCS Policlinico ‘San Matteo’,
Piazzale Golgi 2, 27100, Pavia, Italy.
Received: 9 June 2013 Accepted: 28 July 2013
Published: 1 August 2013
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REVIEW ARTICLE
Open Access
Peripheral vascular dysfunction in migraine:
a review
Simona Sacco1*, Patrizia Ripa1, Davide Grassi2, Francesca Pistoia1, Raffaele Ornello1, Antonio Carolei1
and Tobias Kurth3,4
Abstract
Numerous studies have indicated an increased risk of vascular disease among migraineurs. Alterations in
endothelial and arterial function, which predispose to atherosclerosis and cardiovascular diseases, have been
suggested as an important link between migraine and vascular disease. However, the available evidence is
inconsistent. We aimed to review and summarize the published evidence about the peripheral vascular
dysfunction of migraineurs.
We systematically searched in BIOSIS, the Cochrane database, Embase, Google scholar, ISI Web of Science, and
Medline to identify articles, published up to April 2013, evaluating the endothelial and arterial function of
migraineurs.
Several lines of evidence for vascular dysfunction were reported in migraineurs. Findings regarding
endothelial function are particularly controversial since studies variously indicated the presence of
endothelial dysfunction in migraineurs, the absence of any difference in endothelial function between
migraineurs and non-migraineurs, and even an enhanced endothelial function in migraineurs. Reports
on arterial function are more consistent and suggest that functional properties of large arteries are
altered in migraineurs.
Peripheral vascular function, particularly arterial function, is a promising non-invasive indicator of the
vascular health of subjects with migraine. However, further targeted research is needed to understand
whether altered arterial function explains the increased risk of vascular disease among patients
with migraine.
Keywords: Migraine; Migraine with aura; Arterial stiffness; Endothelial function; Flow mediated dilation;
Pulse wave velocity; Augmentation index; Stroke; Coronary artery disease; Cardiovascular disease;
Risk factors
Introduction
Numerous studies have indicated that migraineurs have
an increased risk of vascular diseases. The association
between migraine and ischemic stroke was the earliest
to be recognized [1-3]. Thereafter, migraine has been
associated also with myocardial infarction, hemorrhagic
stroke, retinal vasculopathy, cardiovascular mortality,
incidental brain lesions, including infarct-like lesions,
and in some instances also with peripheral artery disease
(Table 1) [4-7]. Mechanisms which may explain these
1
Department of Neurology and Regional Headache Center, University of
L’Aquila, Piazzale Salvatore Tommasi 1, L’Aquila 67100, Italy
associations have been discussed previously [5,8-10]. One
of the plausible mechanisms predisposing individuals to
atherosclerosis and vascular diseases is endothelial and
arterial dysfunction [11]. Consequently, several studies
have evaluated the vascular function of migraineurs outside the brain, providing equivocal results. The aim of
the present study was to review the published evidence
linking peripheral arterial function with migraine.
Background information about arterial and endothelial
function and its measurements
The endothelium, i.e. the inner layer of cells of blood
vessels, has physiologically favorable and atheroprotective
© 2013 Sacco et al.; licensee Springer. This is an Open Access article distributed under the terms of the Creative Commons
Table 1 Evidence referring to the association between
migraine and the risk of vascular disease
Ischemic stroke
Numerous studies demonstrating an association with any
migraine [e1-e22];
Definite association with migraine with aura
[e1,e3-e4,e7-e8,e11-e12,e15-e16,e19-e21];
No definite association with migraine without aura
[e1,e3,e7,e11-e12,e16,e19-e20];
Association with migraine with aura confirmed by three
meta-analyses [e23-e25].
Transient ischemic attack
The risk seems to be increased in migraineurs, although
this issue has not been extensively investigated due to a
challenging overlap of symptoms with migraine aura [e6,e19].
Hemorrhagic stroke
Several studies addressing the topic and providing
inconsistent results [e5,e8-e10,e26-e29];
A meta-analysis of those studies indicating a small but
significant association [e30];
No definite conclusion regarding migraine type.
Cardiac events
Two large studies indicating an association with any
migraine in men and women and with migraine with aura
in women (data not available for men) [e1,e2]; Conflicting
results provided by other available studies [e4,e31-e33];
No association with any migraine in meta-analysis of data
but few studies available [e23]; No analysis according to
migraine type due to lack of data.
A recent study reporting an association between migraine
(any migraine, migraine with aura and migraine without aura)
and myocardial infarction [e4].
Vascular death
A meta-analysis and a large study supporting an association
with migraine with aura [e23];
No association with any migraine according to meta-analysis
of data [e23].
Other vascular diseases
Studies indicating a possible association with any migraine and
retinal disease [e34,e35] and peripheral artery disease [e36-e37].
Brain lesions
Page 2 of 10
cells capacity. This leads to “endothelial dysfunction” with
a reduction in endothelium-dependent vasodilation and
the induction of a specific state of “endothelial activation,”
characterized by a proinflammatory, proliferative, and
procoagulatory milieu which favors all stages of atherogenesis, pathological inflammatory processes, and vascular
disease [14]. Endothelial dysfunction represents an early
step in the development of atherosclerosis [15]. Endothelial
function can be investigated by invasive and non-invasive
tests [16]. Invasive tests are based upon intra-arterial infusion of vasoactive agents. Among the several non-invasive
methods of measuring endothelial function, flow-mediated
dilation (FMD), laser Doppler flowmetry, and digital pulse
amplitude tonometry (PAT) are the most widely adopted
[16-18]. Figure 1 shows details about measurement of
FMD [16-19].
Measures of arterial elasticity are also being investigated as non-invasive means of gauging vascular health
[14]; the most commonly considered parameters are
pulse wave velocity (PWV), augmentation index (AIx)
and local arterial distensibility in the carotid artery or
in the aorta. While FMD addresses functional status of
the endothelium, PWV, AI, and local arterial distensibility are better related to structural changes in the
vessel wall. PWV is an indicator of segmental arterial
stiffness. Carotid-femoral PWV is the gold standard of
assessment (Figure 2), but it is difficult to measure, so
in clinical practice it can be replaced by the measurement
of brachial-ankle PWV (although this measurement includes some muscular arteries and not only the elastic
ones). The AIx (Figure 3) is an index related to the
stiffness of the systemic arterial tree. An increase in
arterial stiffness leads to a more proximal point of
reflection, thus altering the wave profile as measured
by the instruments. Local arterial distensibility is assessed
by measuring the minimum and maximum diameter of
central arteries – such as the carotid artery or aorta –
by ultrasound or MRI with simultaneous recording of
the blood pressure in the arterial district from which the
diameters are obtained.
Migraine has been associated with white-matter hyperintensities
and infarct-like lesions [e38-e42];
Association of migraine with white matter hyperintensities
confirmed in two meta-analyses [e41,e43]; no definite
association with infarct-like lesions [e43]
References are listed in the online supplement.
effects [12]. It works as both a receptor and effector organ
and responds to each physical or chemical stimulus with
the release of substances, including nitric oxide (NO), with
which the endothelium maintains vasomotor balance and
vascular-tissue homeostasis [13]. The established cardiovascular risk factors cause oxidative stress initiating a
chronic inflammatory process which alters the endothelial
Search strategy and selection criteria
Data for this review were obtained through searches in
BIOSIS, the Cochrane database, Embase, Google scholar,
ISI Web of Science, and Medline from their first availability up to April 2013. The search terms included “migraine”
OR “headache” AND (“endothelial function”, “endothelial
injury”, “arterial stiffness”, “arterial distensibility”, “vascular
resistance”, “vascular reactivity”, “flow-mediated dilation”,
“forearm blood flow”, “arterial pulse wave velocity”, “augmentation index”). We also searched reference lists of
identified articles and papers quoting identified articles.
We reviewed only studies published in English.
Page 3 of 10
Figure 1 Flow-mediated dilation. Flow-mediated dilation (FMD) measures endothelial function by inducing a temporary ischemia in a
brachial artery and observing the amount of vasodilation following the stressor event. After a baseline measurement of the artery diameter
via an ultrasound probe, a sphygmomanometer blood pressure cuff is positioned on the right forearm 2 cm below the elbow and inflated
to 250 mmHg to produce ischemia in the forearm. The cuff is deflated after some minutes, usually 5, thus causing a reactive hyperemia
which in turn produces a shear stress stimulus that induces the endothelium to release nitric oxide as a vasodilator. FMD is considered as
diameter after reactive hyperemia - basal diameter/basal diameter × 100. The figure shows the diameter (upper part) and shear rate (lower
part) of brachial artery during FMD before (grey-shaded part on the left), during (black-shaded part), and after (grey-shaded part on the
right) ischemia.
Figure 2 Carotid-Femoral Pulse Wave Velocity. Increased arterial stiffness leads to increased velocity of the pulse wave generated in the
arteries by the contraction of the left ventricle. Pulse wave velocity (PWV) consists in measuring pulse wave profiles by tonometry at two distant
locations (carotid and femoral) and measuring the delay in the onset of the wave between those two locations. PWV is calculated as the distance
traveled by the wave divided by the time taken to travel that distance. Surface distance between the two recording sites and simultaneously
recorded electrocardiograms are used to calculate wave transit time. The figure shows tonometric (white lines) recordings of the carotid (above)
and femoral (below) artery waves according with simultaneous electrocardiographic (yellow lines) ‘R’ wave of the electrocardiogram as a
timing reference.
Figure 3 Augmentation Index. The interaction between the
incident pulse wave and the reflected pulse wave, which is
generated by the arterial resistance, is expressed by the
augmentation index, which is the amount of pulse wave induced
only by arterial resistance. In the figure, the upper arrow indicates
the first systolic peak (incident wave), while the lower arrow
indicates the second systolic peak (reflected wave). The ratio
between the reflected wave/incident wave × 100 is the
augmentation index.
Review
Arterial and endothelial function in migraineurs
Several lines of evidence for vascular dysfunction have been
identified in migraineurs and there is increasing evidence to
suggest that in migraineurs the vascular system is impaired
not only within the brain.
Endothelial function in migraineurs
The many studies assessing endothelial function in
migraineurs have used heterogeneous techniques and
indicators as shown in Tables 2, 3 and 4. Most of them
assessed endothelial function by measuring FMD
(Table 2) [20-30], some used PAT (Table 3) [31,32],
some measured peripheral vasodilation in response
to pharmacological stimuli (Table 3) [20,30,33-35], and
others assessed endothelial progenitor cells (EPCs)
(Table 4) [23,36,37]. Findings were not consistent
across the studies. Several among the available studies
did not reveal any alteration in the endothelial function
of migraineurs. Six of them did not find any difference
in FMD between migraineurs and control subjects
(Table 2) [20-23,25,26] and a further study confirmed
the lack of any alteration in endothelial function
assessed by PAT ratio (Table 3) [32]. Three studies
assessing peripheral vasodilation after pharmacological
stimuli found comparable responses in subjects with
Page 4 of 10
and without migraine (Table 3) [20,33,35]. However,
other studies supported the presence of endothelial
dysfunction in migraineurs. Four studies reported decreased FMD in migraineurs [24,27,29,30]; in one of
those studies, FMD correlated with dysfunction of the
autonomic nervous system (Table 2) [24]. Another
study, using PAT, reported that subjects with chronic
migraine had worse endothelial function (Table 3) [31].
A further study found an abnormal vascular response
to dilating pharmacological stimuli (Table 3) [34]. The
possible underlying mechanisms of endothelial dysfunction in those studies were unclear. Since the impairment of FMD was demonstrated also in individuals
with recent onset of migraine it is unlikely that the disturbance was a consequence of longstanding and repeated exposure to the vasoconstrictor agents used for
migraine treatment [27]. In addition, the results of one
study suggested that the impaired vascular reactivity
in migraineurs is entirely attributable to a reduced
response of vascular smooth muscle cells to NO while
the endothelial response to NO appeared intact [34].
Some additional studies supported the presence of
an endothelial dysfunction in migraineurs by documenting a decreased number of EPCs [23,36] or a
higher number of more mature EPCs (which could
be associated with potential endothelial damage) in
migraineurs (Table 4) [37]. EPCs maintain the integrity of damaged endothelium and are considered a
marker of endothelial function [38]. At variance with
other studies, Vernieri et al., found that subjects
with migraine with aura had higher FMD than both
control subjects and migraine without aura subjects
indicating an excessive arterial response to hyperemia.
It is suggested that this is probably an effect of an
increased sensitivity to endothelium-derived NO or of
increased release of NO induced by shear stress (Table 2)
[28]. In agreement, Yetkin et al., found that migraineurs
have an increased nitrate-mediated response showing
a major role of NO supersensitivity in migraine pathophysiology (Table 3) [30].
Several studies support the presence of biochemical
changes in the endothelial activation of migraineurs.
These biochemical changes may precede structural
damage. In particular, alterations in the NO pathway
have been described [30,39,40] as well as increased
levels of calcitonin gene-related peptide (CGRP), vascular endothelial growth factors (VEGF), von Willebrand
factor (vWF) activity, tissue plasminogen activator antigen, C-reactive protein and endothelin-1 [21,23,40]. Recently, a study involving 40 non-hypertensive subjects
with migraine without aura randomized to treatment
with enalapril 5 mg twice a day for 3 months or to placebo, showed that active treatment was associated with
an increase in FMD values [41].
Page 5 of 10
Table 2 Studies on endothelial function using flow-mediated dilation in migraineurs
Study (First
author, year)
De Hoon, 2006 [20]
Study
design
Patients
included (n)
%
women
Exclusion
criteria
Migraine
diagnosis
CC
Migraine: 10
60
CVD, HYP, DM, dyslipidemia, CS
ICHD-I
No differences in FMD
between migraineurs
and controls
89
CVD and vascular RF, DM, CS,
alcoholism, active gastrointestinal
disease, gout, epilepsy, recent
infection, renal failure, pregnancy
or lactation, regular use FANS or
antimigrainous drugs and OC
ICHD-II
between migraineurs
and controls
80
CVD, obesity, HYP, dyslipidemia,
pregnancy or lactation and regular
use of vasoactive drugs
ICHD-II
between migraineurs
and controls
98
CAD, inflammatory disease, obesity,
HYP, DM, dyslipidemia, CS, infectious
disease, severe systemic disease,
ovarium pathology, pregnancy or
lactation, use of vasoactive drugs
ICHD-II
between migraineurs
and controls
75
Age ≥50, vascular RF, CS, use of
vasoactive drugs
88
None
ICHD-II
between migraineurs
and controls
100
Use of any daily drugs
ICHD-I
between migraineurs
and controls
78
Age >50, CVD, HYP, obesity, DM,
dyslipidemia, pregnancy or lactation,
use of vasoactive drugs (except OC)
Controls: 10
Hamed, 2010 [21]
CC
Migraine: 38
(MwA: 14;
MwoA: 24)
Controls: 35
Perko, 2011 [22]
CC
MwA: 20
MwoA: 20
Results
Controls: 20
Rodriguez-Osorio, 2012 [23]
CC
Migraine : 47
(MwA:14;
MwoA: 33)
Controls: 23
Rossato, 2011 [24]
CC
Migraine: 20
Controls: 20
Silva, 2007 [25]
CC
Migraine: 50
(MwA: 25; MwoA: 25)
Not reported
Controls: 25
Thomsen, 1996 [26]
CC
MwoA: 12
Controls: 12
Vanmolkot, 2007 [27]
CC
Migraine: 50
Controls: 50
Vernieri, 2010 [28]
CC
Migraine:21
Validated
questionnaire
Decreased FMD in
migraineurs
Decreased FMD in
migraineurs
None
ICHD-II
FMD increased from
controls to MwoA to
MwA patients
80
CAD, HYP, obesity, DM, infectious
disease, ovarium pathology
ICHD-I
Decreased FMD in
migraineurs
89
HYP, CAD, DM, infectious disease
ICHD-I
Decreased FMD in
migraineurs
(MwA: 11; MwoA: 10)
Controls: 13
Yetkin, 2006 [29]
CC
Migraine: 45
Yetkin, 2007 [30]
CC
Migraine: 24
Controls: 45
Controls: 26
CC case–control; MwA migraine with aura; MwoA migraine without aura; CVD cardiovascular disease; HYP arterial hypertension; DM diabetes mellitus; CS cigarette
smoking; RF risk factors; FANS non steroid anti-inflammatory drugs; OC oral contraceptives; CAD coronary artery disease; ICHD International classification headache
disorders; FMD flow-mediated dilation.
Arterial function in migraineurs
Compared with studies on endothelial function, reports
on arterial function measured with PWV, AIx, and local
arterial distensibility are more consistent and suggest
that functional properties of large arteries are altered in
migraineurs [27,42-46] (Table 5).
Four studies addressed PWV in migraineurs (Table 5)
[27,42-44]. Ikeda et al. evaluated peripheral PWV [42]
while the other authors assessed central PWV [27,43,44].
Three studies on PWV [27,42,43] found higher values
of this parameter in migraineurs with respect to nonmigraineurs. However, in one of the studies PWV did
not correlate with the presence of migraine after adjustment for age and mean arterial pressure [27]. The
inclusion in the study of patients with a short history
of migraine and with less use of vasoconstrictive agents
may explain the difference [27]. Schillaci et al., also
addressed PWV according to migraine type and reported
that subjects with migraine either with or without aura
had increased PWV with respect to controls while migraine with aura subjects had higher aortic PWV than
those without aura [43]. A more recent populationbased study, involving a larger number of migraineurs,
has challenged the suggestion of possible impairment
Page 6 of 10
Table 3 Studies on endothelial function by arterial tonometry or vasodilation in response to pharmacological stimuli
in migraineurs
Study (First
author, year)
Study
design
Patients
included (n)
%
women
Exclusion
criteria
Migraine
diagnosis
Results
CM: 21
71
Age ≥50, CVD, inflammatory
disease, obesity, HYP, DM,
dyslipidemia, CS, active
cancer, ovarium pathology,
pregnancy or lactation,
regular use of vasoactive
drugs
ICHD-II
Smaller RHI in migraineurs
100
CVD, obesity, HYP, DM,
pregnancy, use of drugs
(statins, anticoagulants or
antiplatelet and intake of
triptans within the
previous 24 h)
ICHD-II
No differences in PAT ratio
between migraineurs
and controls
60
CVD, HYP, DM,
dyslipidemia, CS
ICHD-I
No differences between
migraineurs and controls in
vasodilation response to
serotonin, sodium
nitroprusside, and CGRP
78
None
ICHD-I
migraineurs and controls in
vasodilation response after
local heating and iontophoretic
administration of acetylcholine,
sodium nitroprusside, and CGRP
58
HYP, DM,
hypercholesterolemia,
CVD, CS
ICHD-I
Reduced response to
endothelium-dependent
vasodilation and production
of cGMP in migraineurs; no
difference in production of NO
75
Age >50, CVD, HYP,
obesity, DM, CS,
dyslipidemia, pregnancy
or lactation, use of
vasoactive drugs
(except OC)
ICHD-II
migraineurs and controls to
sodium nitroprusside, substance
P, and NG-monomethyl-L-arginine
89
HYP, CAD, DM,
infectious disease
ICHD-I
Higher nitrate-mediated dilation
in migraineurs
Arterial tonometry
Jiménez-Caballero, 2013 [31]
CC
Controls: 21
Liman, 2012 [32]
CC
MwA: 29
Controls: 30
Vasodilation in response to pharmacological stimuli
De Hoon, 2006 [20]
CC
Migraine: 10
Controls: 10
Edvinsson, 2008 [33]
CC
MwoA: 9
Controls: 9
Napoli, 2009 [34]
CC
MwoA: 12
Controls: 12
Vanmolkot, 2010 [35]
CC
Migraine:16
Controls: 16
Yetkin, 2007 [30]
CC
Migraine: 24
Controls: 26
CC case–control; CM chronic migraine; MwA migraine with aura; MwoA migraine without aura; CVD cardiovascular disease; HYP arterial hypertension; DM,diabtes
mellitus; CS cigarette smoking; OC oral contraceptive; ICHD International classification headache disorders; RHI reactive hyperhemia index; PAT peripheral arterial
tonometry; CGRP Calcitonin Gene Related Peptide; cGMP cyclic guanosine monophosphate; NO nitric oxide.
of arterial function in migraineurs [44]. In fact, Stam
et al. reported no differences in PWV among subjects
with migraine with aura, migraine without aura, and
controls [44]. In this latter study subjects with known
cardiovascular risk factors were included and this may
explain the differences in the results [44].
Higher values of AIx were found in migraineurs by five
studies [27,31,32,43,45], which variously measured AIx
in the radial artery [45], in the aorta [27,43] or by finger
tonometry [31,32]. One of those studies involved only
women with migraine with aura [32] and one involved
only subjects with chronic migraine [31]. Schillaci et al.
reported increased AI in migraine with and without aura
with respect to controls and no differences between the
two groups of migraineurs [43]. All the studies about
AIx had a case–control design, except for a populationbased one [45] which involved cases and controls older
than those of the other studies.
Two studies assessed static arterial parameters [27,46].
De Hoon et al. found that migraineurs had larger temporal artery diameter compared with control subjects
but a decreased distensibility and buffering capacity of
the brachial artery in the absence of significant alterations in the common carotid and femoral arteries
Page 7 of 10
Table 4 Studies on endothelial function by endothelial progenitor cells in migraineurs
Study (First
author, year)
Study
design
Patients
included (n)
Lee, 2008 [36]
CC
Migraine: 92
%
Exclusion
women criteria
Migraine Results
diagnosis
70
CVD, diabetic retinopathy
ICHD-II
Decreased number and migratory
capacity and higher senescence
levels of endothelial progenitor
cells in migraineurs versus
controls
73
CVD, inflammatory disease,
cancer or treatment with
antimitogen agents, pregnancy
in the last year
ICHD-I
Higher number of activated
endothelial progenitor cells
in migraineurs
98
CAD, inflammatory disease,
obesity, HYP, DM, dyslipidemia,
CS, infectious disease, severe
systemic disease; ovarium
pathology, pregnancy or
lactation, use of vasoactive
drugs
ICHD-II
Lower endothelial progenitor cell
counts in migraineurs
(MwoA: 67; MwA: 25)
Controls: 37
Oterino, 2013 [37]
CC
CM: 51
EM: 48
Controls: 35
Rodriguez-Osorio, 2012 [23]
CC
Migraine : 47
(MwA:14; MwoA: 33)
Controls: 23
CC case–control; CM chronic migraine; EM episodic migraine; MwA migraine with aura; MwoA migraine without aura; CVD cardiovascular disease;
CAD coronary artery disease; HYP arterial hypertension; DM diabetes mellitus; CS cigarette smoking; ICHD International classification
headache disorders.
[46]. Vanmolkot et al. found that migraineurs had a decreased diameter and compliance of superficial muscular
arteries [27].
Discussion
The results of the systematic review suggest the presence
of a peripheral vascular dysfunction in migraineurs.
However, while several studies support an alteration of
arterial function among subjects with migraine, findings
on the endothelial function are less clear.
Endothelial function in migraineurs has sometimes
been reported as impaired and sometimes as altered,
while some studies found no difference compared with
endothelial function in controls. Differences among available studies may be explained by various inclusion/
exclusion criteria and the generally small number of
participants. Migraine, and particularly migraine with
aura, has been associated with an elevated cardiovascular profile. The exclusion of subjects with cardiovascular
risk factors from some of the studies may at least partly
explain the described differences. Duration of migraine,
severity of attacks and the active or inactive state of the
disease may also have played a role in the betweenstudy differences in results. To clarify the status of
endothelial function in migraineurs further, studies are
required that need to involve large number of subjects
of properly selected individuals, applying rigorous
inclusion and exclusion criteria, and including subjects
with a wide range of migraine conditions in terms of
frequency, duration, and severity of the attacks. In
addition, further studies should also adopt a standardized and reliable methodology to address endothelial
function.
Regarding arterial function, most of the available evidence supports greater stiffness or impaired compliance
of the arterial system in migraineurs. The mechanisms
underlying the association between migraine and altered
arterial function are likely to be complex and may
involve both structural and functional changes in the
arterial wall. Since all the studies had a cross-sectional
design, a cause-effect relationship between migraine and
increased arterial stiffness cannot be established. However, migraine usually starts in early adulthood, at an age
in which arterial wall pathologies are rare. In the general
population alteration in arterial function has been associated with the presence of vascular risk factors and
is considered a marker of vascular disease associated
with risk of future vascular events [47,48]. Since
most studies addressing arterial function in migraineurs
excluded subjects with comorbid vascular risk factors,
other mechanisms can be hypothesized. The possible
hypotheses include alterations in vessel wall structure in
migraineurs as supported by the presence of impaired
serum elastase activity [49], higher sympathetic tone
[50,51], use of drugs such as triptans and ergot derivatives, or it may represent a primary alteration linked to
the presence of migraine itself [52]. At the moment it is
unknown whether the duration of migraine and the
frequency and severity of the attacks has an impact on
arterial stiffness. Moreover, gender differences may also
play a role in determining arterial stiffness in migraineurs
with females being more susceptible to changes [43].
In addition, possible clinical implications of arterial
dysfunction in migraineurs have to be clarified. In the
general population, arterial dysfunction has been linked to
an increased risk of vascular disease through an atherothrombotic mechanism [47,48]. However, in migraineurs
Page 8 of 10
Table 5 Studies on arterial function in migraineurs
Study (First
author, year)
De Hoon,
2003 [46]
Study
design
Patients
included (n)
CC
MwA: 11
%
Exclusion
women criteria
Migraine
diagnosis
CVD, inflammatory
disease, HYP, DM,
dyslipidemia
ICHD-I
Diameter and compliance
parameters of brachial,
carotid, femoral, and
temporal arteries
Smaller diameter and
distension of brachial artery
and larger right temporal
artery diameter in
migraineurs; no differences
in carotid and femoral
arteries
73
CVD, vascular RF
ICHD-II
Brachial PWV
Higher PWV in migraineurs
71
Age ≥50, CVD,
inflammatory disease,
obesity, HYP, DM,
dyslipidemia
ICHD-II
Radial AIx
Higher AIx in migraineurs
100
CVD, obesity,
arterial HYP, DM
ICHD-II
Peripheral AIx
Higher Aix in migraineurs
93
Stroke
85
CVD, inflammatory
disease, HYP, DM,
dyslipidemia
ICHD-II
Aortic PWV and
aortic AIx
Higher PWV and AIx in
migraineurs, especially
in MwA
75
None
ICHD-II
Carotid and femoral
PWV
migraineurs and controls
78
None
ICHD-I
Diameter and compliance
parameters of brachial and
femoral arteries, aortic AIx
and aortic PWV
Smaller brachial artery
diameter and compliance
and smaller femoral artery
diameter in migraineurs;
higher aortic AIx in
migraineurs; higher PWV
in migraineurs not
confirmed after adjustment
for age and mean arterial
pressure
MwoA: 39
CC
MwA:22
Results
76
Controls: 50
Ikeda, 2011 [42]
Parameters
assessed
MwoA:89
Controls:110
Jiménez-Caballero,
2013 [31]
CC
CM: 21
Liman, 2012 [32]
CC
MwA: 29
Nagai, 2007 [45]
PB
Group A:134
Controls: 21
Controls: 30
Validated
Radial AIx
questionnaire
(5% migraineurs)
Higher AIx in migraineurs
Group B:138
(17% migraineurs)
Schillaci, 2010 [43]
CC
MwA:17
MwoA: 43
Controls:60
Stam, 2013 [44]
PB
MwA: 123
MwoA: 167
Controls: 542
Vanmolkot,
2007 [27]
CC
Migraine: 50
Controls: 50
CC case–control; PB population-based; CM chronic migraine; MwA, migraine with aura; MwoA, migraine without aura; CVD, cardiovascular disease; HYP, arterial
hypertension; DM, diabetes mellitus; RF, risk factors; ICHD, International classification headache disorders; AIx, augmentation index; PWV, pulse wave velocity.
the evidence of an atherothrombotic mechanism leading
to vascular events is not supported and much evidence
points against this possibility. [53,54] In fact, intima-media
thickness (IMT), which is a surrogate marker of subclinical
atherosclerosis has not been consistently linked to migraine
status [20,24,27,55,56]. In addition, despite little information being available on the frequency of the different subtypes of ischemic stroke in migraineurs, the available
studies do not support an increased atherosclerotic load
[57,58]. Also the cardiac events observed in migraineurs
did not seem to be attributable to atherothrombosis and
alternative mechanisms have been hypothesized [59-61].
Future studies should also clarify whether the vascular
dysfunction may represent a marker able to identify those
migraineurs who are at higher risk of presenting vascular
events and who might be the target of possible preventive
strategies.
Conclusion
The study of systemic vascular function is a promising
tool for non-invasively investigating the vascular health
of subjects with migraine. At the moment, evidence is too
scarce to support the clinical application of the techniques
and further research studies are needed to better clarify all
the pending issues.
Competing interests
The authors declare that they have no competing interests.
All authors of this manuscript (SS, PR, DG, RO, FP, AC, TK) have made
substantial contributions to conception and design of the review, have been
involved in drafting the manuscript and revising it critically for important
intellectual content and have given final approval of the version to be
published.
Author details
1
Department of Neurology and Regional Headache Center, University of
L’Aquila, Piazzale Salvatore Tommasi 1, L’Aquila 67100, Italy. 2Department of
Life, Health, and Eviromental Sciences, University of L’Aquila, L’Aquila 67100,
Italy. 3Inserm Research Center for Epidemiology and Biostatistics, Team
Neuroepidemiology, Bordeaux F-33000, France. 4University of Bordeaux,
Bordeaux F-33000, France.
Received: 5 August 2013 Accepted: 20 September 2013
Published: 1 October 2013
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doi:10.1186/1129-2377-14-80
Cite this article as: Sacco et al.: Peripheral vascular dysfunction in
migraine: a review. The Journal of Headache and Pain 2013 14:80.
Page 10 of 10
Benemei et al. The Journal of Headache and Pain 2013, 14:71
REVIEW ARTICLE
Open Access
TRPA1 and other TRP channels in migraine
Silvia Benemei*, Francesco De Cesaris, Camilla Fusi, Eleonora Rossi, Chiara Lupi and Pierangelo Geppetti
Abstract
Ever since their identification, interest in the role of transient receptor potential (TRP) channels in health and
disease has steadily increased. Robust evidence has underlined the role of TRP channels expressed in a subset
of primary sensory neurons of the trigeminal ganglion to promote, by neuronal excitation, nociceptive responses,
allodynia and hyperalgesia. In particular, the TRP vanilloid 1 (TRPV1) and the TRP ankyrin 1 (TRPA1) are expressed
in nociceptive neurons, which also express the sensory neuropeptides, tachykinins, and calcitonin gene-related
peptide (CGRP), which mediate neurogenic inflammatory responses. Of interest, CGRP released from the
trigeminovascular network of neurons is currently recognized as a main contributing mechanism of migraine
attack. The ability of TRPA1 to sense and to be activated by an unprecedented series of exogenous and endogenous
reactive molecules has now been extensively documented. Several of the TRPA1 activators are also known as triggers
of migraine attack. Thus, TRP channels, and particularly TRPA1, may be proposed as novel pathways in migraine
pathophysiology and as possible new targets for its treatment.
Keywords: Migraine; Transient receptor potential ankyrin 1 (TRPA1); Transient receptor potential vanilloid 1
(TRPV1); Calcitonin gene-related peptide (CGRP); Neurogenic inflammation; ThermoTRP; Headache; Pain
Review
TRP channels
The observation that the stimulation of a specific receptor,
and the consequent, associated transient inward current
[1,2] are necessary to vision in Drosophila melanogaster
has been the primal evidence of the transient receptor
potential (TRP) family of channels, which currently
encompasses more than 50 different channels [3]. TRP
channels represent a heterogeneous system oriented
towards environment perception, and participating in
sensing visual, gustatory, olfactive, auditive, mechanical,
thermal, and osmotic stimuli. TRP channels consist of
six transmembrane domains (S1-S6) with both the NH2
and COOH termini localized into the cytosol. The COOH
region is highly conserved among TRPs, whereas the
NH2 region usually contains different numbers of
ankyrin repeats, the 33-residue motifs with a conserved
backbone and variable residues that mediate proteinprotein interactions [4]. The entry of cations through
homo- or heterotetramers occurs via the pore formed
by loops between the S5 and S6 domains. TRPs are
Headache Center and Clinical Pharmacology Unit, Department of Health
Sciences, Careggi University Hospital, University of Florence, viale Pieraccini 6,
Florence 50139, Italy
commonly described as nonselective Ca2+-permeable
channels, however, their Ca2+/Na+ permeability ratio
may vary widely between different members of the TRP
family [5].
TRP channel gating is operated by both the direct
action on the channel of a plethora of exogenous and
endogenous physicochemical stimuli, and changes in
the intracellular machinery, including activation of
G-protein coupled receptor (GPCR) or tyrosine kinase
receptor [6]. In mammals, the TRP family consists of
28 proteins grouped into 6 subfamilies according to
sequence identity, namely TRP canonical (TRPC), TRP
vanilloid (TRPV), TRP melastatin (TRPM), TRP polycystin
(TRPP), TRP mucolipin (TRPML), and TRP ankyrin (TRPA)
[7,8]. The mammalian TRPC subfamily enlists 7 members
(TRPC1-7), activated by the stimulation of GPCR and
receptor tyrosine kinases [9], although TRPC1 seems to be
directly activated by membrane stretch [10]. The TRPM
has 8 members (TRPM1-8), and TRPM8 is activated by
menthol and low temperatures (< 25°C). Of the three
TRPML members, TRPML1 is widely expressed and
has been described as an H+-sensor of endosomes/lysosomes, where it probably prevents overacidification
[11]. The TRPP family can be subdivided into PKD1like (TRPP1-like) and PKD2-like (TRPP2-like) proteins,
© 2013 Benemei et al.; licensee Springer. This is an Open Access article distributed under the terms of the Creative Commons
which couple to act as a signaling complex at the plasma
membrane plasma membrane [12]. Various diseases have
been attributed to mutations of TRP channels. However,
only a few TRP channelopathies, commonly known as
“TRPpathies”, have been conclusively identified so far.
TRPpathies include neurological disorders, renal diseases,
and complex skeletal dysplasias [13].
TRPA1 and other thermo-TRPs
Primary sensory neurons express different TRP channels,
including four of the six members of the TRPV subfamily.
TRPV1, TRPV2, TRPV3, and TRPV4 channels sense
warm-hot temperatures and are chemosensors for a
large series of naturally occurring and synthetic ligands.
TRPV1, the receptor of the vanilloid compound capsaicin
(which promoted the labeling of the group with the V),
is responsive to high proton concentrations (pH 5–6)
[14,15], anandamide [16] and various lipid derivatives
[17]. Camphor and hypotonic solutions are non-selective
activators of the TRPV3 and TRPV4, respectively [18,19].
The synthetic compound 4α-phorbol 12,13-didecanoate
(4α-PDD), low pH, citrate, endocannabinoids, and arachidonic acid metabolites may also gate TRPV4 [20,21].
Activators of TRPV2 are not well identified, although
the uricosuric agent probenecid can activate the channel
[22]. Additional TRPs expressed in nociceptors are TRPA1
and TRPM8. Finally, there is also evidence that TRPM3,
rather uniquely activated by pregnenolone sulfate, seems
to be also expressed in primary sensory neurons [23].
A large NH2-terminal domain with 17 predicted ankyrin
repeat domains characterizes TRPA1, the sole member
of the TRPA subfamily. TRPA1, first cloned from human
fetal lung fibroblasts, is widely expressed in mammals,
where it has been found in hair cells, pancreas, heart,
brain, keratinocytes [24], urinary bladder [25], prostate
[26], arteries [27], enterochromaffin cells [28], odontoblasts and dental pulp [29,30], synovial fibroblasts [31],
and epithelial and smooth muscle cells of the airways
and lung [32]. A large amount of evidence shows that
TRPA1 plays a key role in the detection of pungent or
irritant compounds, including principles contained in
different spicy foods, such as allyl isothiocyanate (mustard
oil) in horseradish [33], allicin and diallyldisulfide in
garlic [34], and cinnamaldehyde in cinnamon [35]. Gingerol
(in ginger), eugenol (in cloves), methyl salicylate (in
wintergreen), carvacrol (in oregano), thymol (in thyme and
oregano) [36], are also able to gate TRPA1. In addition,
environmental irritants and industry pollutants, such as
acetaldehyde, formalin, hydrogen peroxide, hypochlorite,
isocyanates, ozone, carbon dioxide, ultraviolet light, and
acrolein (a highly reactive α,β-unsatured aldehyde present
in tear gas, cigarette smoke, smoke from burning vegetation, and vehicle exhaust), have been recognized as TRPA1
activators [37-45]. The dispute regarding the role of TRPA1
Page 2 of 8
as a sensor of mechanical stimuli and noxious cold (< 17°C)
remains unresolved [36]. Electrophilic molecules have
been found to activate TRPA1 via a unique mechanism,
mediated by a Michael addition with specific cysteine
and lysine residues identified in both the rat and human
channel [46,47]. Finally, TRPA1-expressing neurons also
express other TRP channels, in particular TRPV1, and, even
more importantly, the sensory neuropeptides substance
P (SP), neurokinin A (NKA), and calcitonin gene-related
peptide (CGRP). SP/NKA and CGRP release from peripheral endings of nociceptors promoted by TRPV1 or
TRPA1 activation produces a series of responses collectively described as neurogenic inflammation [48].
TRPA1, pain and neurogenic inflammation
It is generally recognized that C and Aδ-fibre sensory
neurons convey pain signals, while neurons with largersize fibres mediate touch sensation. Thermo-TRPs, which
under normal conditions are expressed in C and Aδ-fibre
neurons, have been proposed to contribute to transmission and modulation of nociceptive signals. This conclusion originates from empirical observation that TRPV1
or TRPA1 agonists, derived from foods and spices, are
able to cause, in a dose-dependent fashion, a range from
appreciated hot feelings to unpleasant pain sensation,
as in the case of capsaicin, the selective TRPV1 agonist
contained in hot peppers, and piperine, another TRPV1
agonist present in black pepper, or allyl isothiocyanate,
the TRPA1 agonist contained in mustard or wasabi [5,49].
Another finding that enlists thermo-TRPs as major pain
controlling mechanisms is the clinical use of topical (cutaneous) capsaicin application that, by defunctionalizing
sensory nerve terminals, alleviates several pain conditions,
including post-herpetic neuralgias or pain associated with
diabetic neuropathy [50].
Generation of deleted mice and, more importantly,
identification and preclinical development of selective
antagonists for thermo-TRPs, have greatly increased our
knowledge of the role of these channels in the regulation
of acute nociceptive responses and the development of
allodynia and hyperalgesia. While TRPV1-deleted mice
exhibit decreased hyperalgesia to elevated temperatures
[51], TRPA1-deletion abrogated the two classical nociceptive phases to formalin [38]. However, gene deletion
may not completely recapitulate the effects of channel
blockade, as compensatory mechanism may counterbalance
the function of the absent gene-protein. Thus, findings
produced by using selective thermo-TRP antagonists
may better unveil the role of these channels in models
of pain diseases.
For detailed information on other thermo-TRPs, the
reader is referred to previous review articles [5-8] whereas
we will focus on the increasing evidence that supports
the role of TRPA1 in models of both inflammatory and
neuropathic pain. Mechanical hyperalgesia [52] and ongoing
neuronal discharge [53,54] evoked by complete Freund’s
adjuvant (CFA) and tumour necrosis factor-α (TNFα),
and mechanical hyperalgesia induced by low doses of
monosodium iodoacetate (MIA) [55] are inhibited by
TRPA1 receptor antagonists in rodents. Convergent findings indicate that TRPA1 contributes to carrageenanevoked inflammatory hyperalgesia [56,57]. Carrageenan
administration, among a number of lipid derivatives,
notably increases metabolites of 12-lipoxygenases, particularly hepoxilins A3 (HXA3) and HXB3, whose hyperalgesic/allodynic effect is abrogated by TRPA1 antagonism
[58]. It has also been found that TRPA1 mediates ongoing
nociception in chronic pancreatitis [59], and that both
TRPV1 and TRPA1 initiate key pathways to transform
acute into chronic inflammation and hyperalgesia in
pancreatitis [60]. The clinical observation that an antioxidant afforded protection in patients with pancreatitis
[61] indirectly supports the role of the oxidative stress
sensor, TRPA1, in this condition.
The underlying mechanisms that from neural tissue
injury produce the chronic allodynia and hyperalgesia
typical of neuropathic pain are largely unknown. However, recent reports have pointed to the role of TRPA1
in different models of neuropathic pain. Several metabolic pathways in glycolysis or lipid peroxidation produce methylglyoxal (MG), which appears in the plasma
in diabetic patients as hyperglycemia strongly enhances
MG accumulation. MG has been recently described to
react reversibly with cysteine residues, and probably due
to this property stimulates TRPA1, thus representing a
likely candidate metabolite to promote neuropathic pain
in metabolic disorders [62]. Chemotherapeutic induced
peripheral neuropathy (CIPN) is a scarcely understood
and poorly treated condition, which, characterized by
spontaneous pain, and mechanical and cold allodynia and
hyperalgesia, causes significant discomfort, and often
therapy discontinuation. CIPN may outlast the time
period of chemotherapeutic drug administration for weeks
or months [63].
Alteration of several ion channels has been advocated
to explain this painful condition, but a univocal consensus
has not emerged. Recently, in mouse models of CIPN
produced by a single administration of oxaliplatin, paclitaxel or bortezomib, TRPA1 has been shown to play a
major role in the development and maintenance of cold
and mechanical [64-66]. In a therapeutic perspective, it
is of relevance that treatment with a TRPA1 antagonist
just before and shortly after (about 6 hours) the administration of bortezomib or oxaliplatin totally prevented
the development and maintenance (for 10–15 days) of
mechanical and cold hypersensitivity [66]. This finding
suggests that TRPA1 is key in initiating CIPN and promoting the transition from an acute to a chronic condition.
Page 3 of 8
In addition, TRPA1 antagonists could represent novel
therapeutic strategies of CIPN. In this context, it could
be better understood that the unexpected attenuation
by etodolac, a nonsteroidal anti-inflammatory drug of
mechanical allodynia in a mouse model of neuropathic
pain, might be due to its ability to inhibit TRPA1 [67].
In addition, to contribute to mechanical hyperalgesia,
TRPA1 seems to be involved in the development of cold
allodynia [68]. Cold allodynia was reduced in models of
neuropathic (peripheral nerve injury) and inflammatory
(CFA) pain [69,70] or in models of CIPN, which typically
exhibit this type of hypersensitivity [64-66]. Interestingly,
a familial episodic pain syndrome has been attributed
to a gain of function mutation of TRPA1 TRPA1 [71].
Coincidence between TRPA1 and neuropeptide expression has been suggested [72,73], although evidence for
coexistence of isolectin B4-positive and non-peptidergic
neurons with TRPA1 has also been reported [74,75].
Notwithstanding, exposure of tissues containing either
peripheral or central sensory nerve terminals to TRPA1
agonists invariably results in a calcium-dependent release
of SP/NKA and CGRP. Thus, TRPA1 stimulation has been
proven to increase sensory neuropeptide release from
oesophagus and urinary bladder, meninges, or dorsal
spinal cord [76-78]. The outcome of such a release in
peripheral tissues encompasses the series of responses
commonly referred to as ‘neurogenic inflammation’ [48]
(Figure 1). Although implication in transmission of nociceptive signals has been proposed, the pathophysiological
outcome of the central release of sensory neuropeptides
within the dorsal spinal cord or brain stem is less clear
(Figure 1).
TRPA1, TRPV1, and migraine
One of the first findings that, although indirectly, suggested the role of TRP channels in cluster headache and
migraine was represented by the protective effect of the
topical, desensitizing application of capsaicin to the patient nasal mucosa [79,80]. Capsaicin treatment couples
the unique ability of the drug to first activate, and,
subsequently, upon repeated administration, desensitize
both the afferent pathway that from channel activation
conveys nociceptive signals, and the ‘efferent’ function
that results in sensory neuropeptide release [48]. Within
the fifth cranial nerve, capsaicin desensitization causes
the defunctionalization of peripheral and possibly central
nerve endings, thus preventing SP/NKA-dependent plasma
protein extravasation within the dura mater, CGRPdependent dilatation of meningeal arterioles, and inhibition of afferent nociceptive impulses. Further support
to the contribution of TRPV1 to migraine mechanism
derived from the observation that ethanol, a known
trigger of migraine attacks, activates CGRP release from
sensory neurons, and promotes CGRP-dependent menin-
Page 4 of 8
Figure 1 Schematic representation of the probable mechanisms of the action of antimigraine remedies, either currently used, or
proven effective in clinical trials (gray boxes) or of novel medicines (empty box), regarding their ability to modulate the release of
calcitonin gene related peptide (CGRP) or the activation of its receptor (CGRP-R). (1) Non steroidal antiinflammatory drugs (NSAIDs) block
prostaglandin synthesis and the ensuing nociceptor sensitization and CGRP release evoked by prostaglandin receptor (PG-R) activation. (2)
Triptans, by activating neuronal 5HT1D receptors, inhibit CGRP release. (3) CGRP-R antagonists inhibit the action of CGRP on effector cells. (4)
Antagonists of transient receptor potential channels (TRPs), including TRP ankyrin 1 (TRPA1), block the ability of a series of stimulants (for TRPA1,
cigarette smoke, acrolein, nitric oxide, umbellulone, and others) to release CGRP. All medicines may act at both peripheral and central endings of
trigeminal nociceptors. Receptor/channel activation may trigger/facilitate (+) or inhibit (−) CGRP release.
geal vasodilatation by reducing the threshold temperature
for channel activation, a phenomenon that eventually
results in TRPV1 activation [81,82].
TRPV4 is stimulated by hypoosmotic stimuli that cause
plasma membrane stretch and mechanical distension.
Although this effect could, in principle, be implicated
in the throbbing pain often described by migraine patients
during their headache attacks, no evidence has yet been
reported in support of TRPV4 in any model of head pain.
In contrast, a series of observational findings has recently
been obtained regarding a possible association between
TRPA1 and migraine. In this respect, it is of interest
that a number of compounds, recently identified as TRPA1
agonists, including cigarette smoke, ammonium chloride,
formaldehyde, chlorine, garlic and others [34,38,41,78,83]
are known triggers of migraine attacks in susceptible
individuals [84-89].
Nitric oxide (NO) donor drugs, including nitroglycerine,
are known inducers of migraine attacks and have been
extensively used in migraine provocation studies in
humans [90]. Although their pro-migraine action has
been attributed to their intrinsic vasodilatatory action
[91], the temporal mismatch between vasodilatation
and the onset of migraine-like attacks argues against a
close association between the two phenomena. In fact,
at the time of the maximum vasodilatation, a mild to
moderate headache develops both in migraineurs (more)
and in healthy subjects (less), while delayed migraine-like
attacks, present only in migraine patients, are observed
only 5–6 hours after nitroglycerine administration [92,93].
Although not confirmed in vitro [94]. NO may release
CGRP from trigemino-vascular neurons [95]. More
recently, NO has been revealed to target TRPA1 by
nitrosylation of channel cysteine residues [96], that
seem to differ from those targeted by other reactive
molecules [97], and this novel molecular mechanism
could contribute to the nociceptive response evoked by
NO [98]. It is possible that the S-nitrosylation process
[99], produced by NO, contributes to channel sensitization
to eventually (hours after the exposure to NO) amplify
CGRP release by other agents, thus leading to exaggerated neurogenic inflammation and potentiation of pain
responses.
The environmental pollution agent, acrolein, is produced by the combustion of organic material which causes
its accidental inhalation, which, however, occurs also with
cigarette smoking [100]. Several components of cigarette
smoke, such as acrolein, crotonaldehyde [78], acetaldehyde
[37] and nicotine [101], are TRPA1 agonists. Recently,
acrolein application to the rat nasal mucosa has been
shown to produce ipsilateral meningeal vasodilatation
by a TRPA1- and CGRP-dependent mechanism [102],
thus offering a mechanistic explanation for the association
between the exposure to cigarette smoke and migraine
attack appearance or worsening [103,104].
Herbalism has been instrumental for the development
of pharmacology and also to a better understanding of
pathophysiological mechanisms. These principles also
apply to the migraine field. Umbellularia californica
(California bay laurel) is also known as the ‘headache
tree’ because of the ability of its scent to trigger headache
attacks in susceptible individuals [105]. A case of cluster
headache-like attacks preceded by cold sensations perceived in the ipsilateral nostril following inhalation of
Umbellularia californica scent has recently been described
in a cluster headache patient whose attacks had ceased
10 years before [106]. The irritant monoterpene ketone,
umbellulone, one of the most abundant reactive molecules of Umbellularia californica, was found to activate
the human recombinant and the constitutive rat/mouse
TRPA1 in trigeminal ganglia (TG) neurons, and via this
mechanism to produce nociceptive behaviour and the
release of CGRP from TG or meningeal tissue in rats [77].
In addition, similar to acrolein, umbellulone application
to the rat nasal mucosa evoked ipsilateral TRPA1- and
CGRP-dependent meningeal vasodilatation [77].
Ligustilide, an electrophilic volatile dihydrophthalide of
dietary and medicinal relevance, has been found to
produce a moderate activation of TRPA1, but also to
inhibit allyl isothiocyanate-evoked stimulation of TRPA1
[107]. This newly identified target of ligustilide offers a
novel mechanistic explanation for the use of the compound
in traditional medicine to treat pain diseases, including
headaches. Finally, although several hypotheses have
been advanced, the mechanism of the analgesic action of
acetaminophen (paracetamol) in different pain conditions
is far from clear. The reactive metabolite of acetaminophen, N-acetyl-p-benzo-quinoneimine (NAPQI), is able to
activate the TRPA1 channel and thereby evoke a moderate
and reversible neurogenic inflammatory response, which,
in susceptible individuals, may contribute to emphasizing
inflammation in peripheral tissues [76]. However, NAPQI
may also be produced by cytochrome activity within
the spinal cord, and NAPQI action at the spinal level
results in channel desensitization [108]. Inhibition of
central TRPA1 has been advocated as the mechanism,
which may be responsible the hitherto unexplained analgesic and possibly antimigraine action of its parent
molecule [108]. Importantly, this novel spinal mechanism
could be of general relevance also for other TRPA1
agonists which share with NAPQI the ability of desensitizing the channel.
A host of endogenous inflammatory mediators possibly
released during migraine attacks can activate and sensitize
peripheral and central sensory neurons, including trigeminal neurons. Sensitization of first-order neurons is
involved in the perception of headache throbbing pain
[109], while sensitization of second‐order neurons contributes to cephalic allodynia and muscle tenderness
[110,111]. Recently, it has been shown that innocuous
brush and heat stimuli induce larger activation in the
thalamus of patients who exhibit allodynia during mi-
Page 5 of 8
graine, as compared to pain‐free state, and that topical
application of inflammatory molecules on the rat meninges sensitizes thalamic trigeminovascular neurons [112].
Each component of the nociceptive pathways could contribute differently to sensitization of the neural tissues.
TRP channels could be sensitized by different compounds
and via different mechanisms [5,36,66,81,113]. Although
there is no specific information on the role of these channels to peripheral nociceptor sensitization or central sensitization in migraine, it is possible that TRP channels, and
in particular TRPV1 and TRPA1, contribute to this key
mechanism.
Conclusions
The still largely unfinished puzzle of the migraine mechanism is being completed by novel unexpected pieces of
information, which compose a clearer picture. The first,
corner of the picture, known for decades, is that cyclooxygenase (namely cyclooxygenase 2) inhibition has a
beneficial effect on migraine attack. The second corner,
predicted by scientists and appreciated by clinicians and
patients, is that targeting 5-HT1 receptors is also highly
effective. The third corner is that a series of clinical trials
show that CGRP antagonists afford a protection similar
to that of triptans. To complete at least the frame, a
fourth corner, which should reconcile the other three in
an intelligible sequence of events, is needed. While prostaglandins sensitize nociceptors and eventually promote
CGRP release, triptans inhibit such release, thus producing an indirect anti-migraine effect, and CGRP antagonists abrogate the final common pathway of migraine
mechanism. The pathway, which, sensitized by prostaglandins and inhibited by serotonin receptor stimulation,
results in trigeminal neuron activation and the promigraine release of CGRP could represent the fourth
corner of the picture. Emerging information on TRP channels, and particularly TRPA1, which, targeted by migraine
triggers, contribute, by activating the trigeminal CGRPdependent pathway, to the genesis of pain and the accompanying symptoms of the attack, seems to be of paramount
importance to solve what still remains the enigma of the
migraine mechanism.
Competing interests
Authors’ contribution
FDC, CF, ER, and CL searched for the literature. SB and PG wrote and revised
the text. All authors read and approved the final manuscript.
Acknowledgements
We acknowledge Regione Toscana (Regional Health Research Program 2009, P.G.).
Received: 22 May 2013 Accepted: 10 August 2013
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Page 8 of 8
Rainero et al. The Journal of Headache and Pain 2013, 14:61
REVIEW ARTICLE
Open Access
Genes and primary headaches: discovering new
potential therapeutic targets
Innocenzo Rainero1*, Elisa Rubino1, Koen Paemeleire2, Annalisa Gai1, Alessandro Vacca1, Paola De Martino1,
Salvatore Gentile1, Paola Sarchielli3 and Lorenzo Pinessi1
Abstract
Genetic studies have clearly shown that primary headaches (migraine, tension-type headache and cluster headache)
are multifactorial disorders characterized by a complex interaction between different genes and environmental
factors. Genetic association studies have highlighted a potential role in the etiopathogenesis of these disorders for
several genes related to vascular, neuronal and neuroendocrine functions. A potential role as a therapeutic target is
now emerging for some of these genes. The main purpose of this review is to describe new advances in our
knowledge regarding the role of MTHFR, KCNK18, TRPV1, TRPV3 and HCRTR genes in primary headache disorders.
Involvement of these genes in primary headaches, as well as their potential role in the therapy of these disorders,
will be discussed.
Keywords: Primary headaches; Genes; MHTFR; KCNK18; HCRTR1; HCRTR2
Introduction
Primary headache disorders, according to the International Classification of Headache Disorders 2nd edition
(ICHD-II), include migraine, tension-type headache, cluster headache, and other primary headaches [1]. Primary
headaches represent a common and major health problem
worldwide and significantly impair patients’ quality of life
[2,3]. These disorders may affect individuals from childhood and are most troublesome in the productive years
of life, thus generating an economic burden for both
society and healthcare systems [4,5]. Recently, Global
Burden of Disease (GBD) studies have rated primary
headaches among the top ten disorders causing significant disability [6].
In recent years, genetic studies have provided substantial evidence supporting the notion that primary
headaches are complex, multifactorial disorders. Population, family and twin studies have shown that migraine,
tension-type headache and cluster headache have a significant heritable component [7,8]. Different genetic factors may, therefore, be involved in the generation of a
specific “headache threshold”. In rare primary headache
subtypes, such as Familial Hemiplegic Migraine (FHM),
single gene mutations co-segregate with disease phenotype [9-11]. In the more common forms of primary
headaches, as in other complex diseases, the phenotype
is thought to be caused by an interaction of multiple
genetic variants, each of them having a small to medium
effect, with different environmental factors.
Due to the complexity of these disorders, the isolation of different genetic factors involved in primary
headaches has proven to be difficult. Genetic association
studies have provided evidence that genes involved in
vascular, neuronal and endocrine functions may have a
significant role in primary headaches [12,13]. The purpose of this review is to highlight recent discoveries, in
particular about methylenetetrahydrofolate reductase
(MTHFR), potassium channel, subfamily K member 18
(KCNK18), transient related potential vanilloid type 1
(TRPV1), transient related potential vanilloid type 3
(TRPV3), hypocretin (orexin) receptor 1 (HCRTR1) and
hypocretin (orexin) receptor 2 (HCRTR2) genes which
are involved in different subtypes of primary headaches
and that, in the near future, might be of relevance as
novel therapeutic targets.
1
Headache Center, Neurology I, Department of Neuroscience, University of
Torino, Via Cherasco 15, 10126 Torino, Italy
© 2013 Rainero et al.; licensee Springer. This is an Open Access article distributed under the terms of the Creative Commons
Page 2 of 8
Review
In the last two decades, molecular genetic studies provided substantial evidence concerning the potential role
of multiple genes in primary headaches. The majority of
these studies evaluated genetic factors involved in migraine, while molecular genetics of cluster headache and
tension-type headache has been little studied, so far.
Vascular genes and primary headaches
Migraine and cluster headache have long been considered vascular disorders. Even if the so-called “vascular
theory” of migraine has been shown to be inadequate in
explaining the complex symptoms of the disorder, both
migraineurs and cluster headache patients show abnormalities in both cranial and extracranial vascular
reactivity [14,15]. In addition, both disorders are characterized by a significant comorbidity with diseases
such as stroke, myocardial infarction, hypertension and
Raynaud’s phenomenon [16-18]. Several genes involved
in vascular functions, such as endothelin-1 (ETA-1),
angiotensin-converting enzyme (ACE), Neurogenic Locus
Notch Homolog Protein 4 (NOTCH4) and methylenetetrahydrofolate reductase (MTHFR) genes have been studied in patients with primary headaches and some of these,
such as the MTHFR gene, were significantly associated
with migraine [19-24].
The MTHFR gene is located on chromosome 1p36.3; it
consists of 11 exons and encodes for the methylenetetrahydrofolate reductase, a crucial enzyme involved in
purine and thymidylate biosynthesis, methylation of
DNA and amino acids, and neurotransmitters synthesis.
The MTHFR enzyme catalyzes the reduction of 5, 10methylenetetrahydrofolate to 5-methyltetrahydrofolate, a
substrate needed for the conversion of homocysteine to
methionine (Figure 1). This pathway is folate-dependent
and a lack of dietary folate can produce an increase in
homocysteine levels. The clinical consequences of increased homocysteine plasma concentrations include
endothelial cells injury and alterations in coagulant properties of blood [25-27]. Furthermore, homocysteine derivatives act as NMDA receptor agonists and they may
enhance glutamatergic neurotransmission, thereby increasing the spontaneous trigeminal cells firing and predisposing cortical neurons to hyperexcitability [28,29].
Several genetic variants have been described in the
MTHFR gene. Genetic research investigating the role of
MTHFR in primary headaches has focused almost exclusively on two common polymorphisms, due to their
functional activity. These are a cytosine (C) > thymine
(T) change at position 677 in exon 4, that results in
a substitution of an alanine into a valine amino acid
(Ala222Val) in the catalytic domain, and an adenine
(A) > cytosine (C) change occurring at position 1298 in
exon 8, that changes a glutamate into an alanine amino
acid (Glu429Ala). The C677T genetic variant allele
produces a 35% reduction of MTHFR enzyme activity
whereas the A1298C variant results in decreased MTHFR
activity to a somewhat lesser degree [30]. These two variants have been extensively associated with the pathogenesis of several disorders, such as cardiovascular disease,
cerebrovascular disease, and psychiatric disorders [31-35].
A large number of studies also provided evidence of
an association between migraine and the C677T polymorphism in the MTHFR gene [22-24]. This association
seems significant mainly in patients affected by migraine
with aura (MA) while in patients affected by migraine
without aura (MO) the results are conflicting. Two recent genetic meta-analysis provided clear evidence of a
significant association between MA and the MTHFR
gene: the carriage of the T allele was shown to be
Folate
NADPH + H
+
+
NADP
DHF
Methionine
NADPH + H
+
SAM
DNA RNA
proteins phospholipids
neurotransmitters
methylation
NADP
THF
MTR +
MTRR
+B12
SAH
Homocysteine
CBS
Adenosine
+ B6
Cystathionine
+
DNA synthesis
and repair
Ser
Gly
5,10-methylene-THF
MTHFR
5-methyl-THF
CTH
+ B6
Cysteine
Glutathione
redox cycle
Figure 1 Production of homocysteine as part of the amino acid and purine biosynthesis pathway. DHF = dihydrofolate,
THF = tetrahydrofolate, MTHFR = methylene-tetrahydrofolate-reductase, TS = thymidylate-synthase, MTR = methionine-synthase, MTRR o
MSR = methionine-synthase-reductase.
associated with an approximately two-fold increased
risk [36,37].
More recently, in Norfolk Island Population, three
MTHFR single nucleotide polymorphisms (SNPs) were
associated with migraine. These three SNPs are located
in intron 7 (rs6696752), in the 3′ untranslated region
(rs4846048), and in exon 11 (rs2274976, non synonymous, producing a substitution of arginine to glutamine,
R594Q) and have not previously been reported to show
any genetic association with migraine. These findings
reinforced the potential role of MTHFR in migraine susceptibility [37].
A recent case–control study examined the association
between MTHFR polymorphisms and cluster headache
in a group of 147 cases and 599 Caucasians controls.
This study found no evidence of association between
genotypes of the MTHFR 677C>T polymorphism and
cluster headache overall. However, subgroup analyses
suggested that carriers of the MTHFR 677 T allele may
have an increased risk for chronic cluster headache,
suggesting a need for additional studies in order to
evaluate a possible role of MHTFR as modifier gene
in the disorder [38]. At present, no study examined
the potential association between tension-type headache and MTHFR polymorphisms.
Hyperomocysteinemia has been reported in patients
with migraine [39]. Folic acid, vitamin B6 and vitamin
B12 supplementation has been found to be effective in
reducing the occurrence of migraine attacks [40]. Therefore, a recent pharmacogenetic study evaluated the
effects of different MTHFR and 5-methyltetrahydrofolatehomocysteine methyltransferase reductase (MTRR) genotypes on the occurrence of migraine in a double-blinded
placebo-controlled trial of daily vitamin B supplementation. Patients carrying the C allele of the MTHFR C677T
variant showed a higher reduction in homocysteine levels,
severity of pain and migraine disability, when compared
with those with the T allele. MTRR catalyzes the remethylation of homocysteine to methionine, and, similarly,
the A allele carriers of the MTRR A66G variants showed a
higher degree of reduction in homocysteine levels, severity
of pain and percentage of severe migraine disability, when
compared with those carrying the GG genotypes [41].
This pivotal study suggests that both MTHFR and MTRR
gene variants may influence the response to treatment
with vitamin B in migraineurs. Conversely, genetic data
concerning the role of vascular genes in tension-type
headache are still scarce. A recent meta-analysis investigated the genetic role of the endothelin type A receptor
(EDNRA) – one of the two receptors of the potent vasoconstrictor ETA-1 – in migraineurs and in patients with
tension-type headache [42]. This meta-analysis included
440 migraineurs, 222 patients with tension-type headaches
and 1323 controls from three previous studies reporting
Page 3 of 8
conflicting results about EDNRA -231G>A polymorphism.
It found a significant difference in the frequency of AA
genotype between migraine subjects and healthy controls.
However, no differences were found in the distribution of
the EDNRA -231G>A SNP between patients with tensiontype headaches and controls.
Neuronal genes and primary headaches
Several clinical and experimental data support the concept of abnormal cortical excitability as the pivotal physiological disturbance in migraine [43,44]. Mutations in
genes that code for ion channels or pumps (CACNA1A,
ATP1A2, and SCN1A) have been described in FHM,
strongly supporting the hypothesis that migraine may
be classified as a “cerebral ionopathy” [45]. CaV 2.1
(CACNA1A) calcium channels are located in the presynaptic terminal of both excitatory and inhibitory neurons, NaV 1.1 (SCN1A) sodium channels are expressed in
inhibitory interneurons while Na+/K+ATPase (ATP1A2) is
located at the surface of glial cells (astrocytes). Knock-in
mouse models carrying such mutations showed an increased susceptibility to cortical spreading depression, the
likely underlying mechanism of migraine aura [46,47].
Finally, an interesting comorbidity between migraine and
epilepsy has been described, further supporting a role
for ion homeostasis genes in migraine pathophysiology
[48,49]. However, until few years ago, no ion channel gene
involvement has been described in the common form of
migraine or in other primary headaches disorders.
In 2010, a frameshift mutation in the KCNK18 gene
which segregates perfectly with typical MA in a large,
multigenerational pedigree was reported [50]. This gene
codes for TWIK-related spinal cord potassium channel
(TRESK), a member of the two-pore domain (K2P) potassium channel family. Functional characterization of
the F139WfsX24 mutation demonstrated that it causes a complete loss of TRESK function and that the
mutant subunit suppresses the wild-type channel function
through a dominant-negative effect.
The KCNK18 gene is located on chromosome 10; it
encodes a protein containing 4 transmembrane domains
(TMDs), and two pore-forming domains. The extracellular domain located between TMD1 and TMD2 contains
a conserved cysteine residue that may form a disulfide
bridge to aid channel dimerization, and a conserved
N-linked glycosylation site, important for surface expression of the channel [51]. In humans, the family of KP2
channels includes 15 related channels but TRESK is
unique in having a large intracellular regulatory domain
located between TMD2 and TMD3. TRESK is abundantly expressed in the dorsal root ganglion (DRG), and
in other sensory ganglia such as the trigeminal ganglion (TG). TRESK was also found in human autonomic
nervous system ganglia, such as the stellate ganglion and
paravertebral sympathetic chain [50,52].
The TRESK is an outwardly rectifying K+ current
channel that contributes to the resting potential and is
the most important background potassium channel in
DRG. TRESK is activated in a complex manner by intracellular calcium signalling. The calcium/calmodulindependent protein phosphatase, calcineurin, activates
TRESK function [53,54]. Calcineurin also regulates nuclear factor of activated T cells (NFATs), transcription
factors that regulate inducible expression of many cytokines. In addition, recent studies have identified volatile
anesthetics as highly potent TRESK agonists, interacting
directly with the channel. On the contrary, cyclosporin
A and tacrolimus, two potent immunosuppressants that
specifically inhibit the calcineurin activation of NFATs,
mimic a TRESK loss of function by keeping the channel
insensitive to increases in intracellular Ca2+.
The physiological functions of TRESK have been
mainly investigated in knock-out (KO) mice. The KO
mice show no gross anatomical or behavioral phenotype.
The gene ablation has minimal effect on the resting membrane potential. However, DRG neurons from TRESK KO
mice displayed a lower threshold for activation, reduced
action potential duration, and slightly higher amplitudes
of after-hyperpolarization, suggesting that DRG neurons
from KO mice were more excitable than wild-type DRG
neurons [55]. In addition, due to the coupling of TRESK
to the histamine H1 receptor, the channel may reduce
neuronal excitability in inflammatory conditions when histamine or other inflammatory modulators are released
into the surrounding tissue. Taken together, these data
suggest an important role of TRESK in both acute and
chronic pain conditions [56].
After the identification of KCNK18 gene mutation in a
Canadian MA pedigree, a large cohort of unrelated MA
patients and healthy controls was screened for gene mutation. Several missense variants (R10G, A34V, C110R,
S231P and A233V) were found. These variants either
had no apparent functional effect, or they caused a reduction in channel activity. The A34V was identified in
a single Australian migraine proband for which family
samples were not available, but it was not detected in
controls. By contrast, the R10G, C110R, and S231P variants were found in both migraineurs and controls. The
authors concluded that the presence of a single nonfunctional variant in the KCNC18 gene is probably not
sufficient to determine whether an individual develops
migraine [57].
In a recent study, we examined the presence of
KCNK18 gene mutations in a large data set of Italian migraine patients (both with MA and MO) and healthy
controls. We confirmed the presence of KCNK18 gene
mutations in MA and also found gene mutations in MO
Page 4 of 8
patients [58]. Some of these gene variants have not previously been described. However, the functional relevance of
these mutations still need further investigations. Finally,
KCNK18 gene involvement in tension-type headache or
cluster headache has not been investigated yet.
The TRESK K2P channel is a novel and interesting
component of the migraine pathogenesis pathway and
represents an excellent opportunity for development of
antimigraine therapy, given its highly selective expression pattern in neuronal structures, which is known to
be important in disease pathogenesis. Its highly specific
expression pattern in TG, DRG and parasympathetic
neurons and the presumed role in abating neuronal
excitability under inflammatory conditions make it an
excellent target for development of new migraine
therapeutics [59,60]. Specific agonists could upregulate TRESK activity and may have a potential in both
acute and preventive migraine therapy, as well as in
other pain disorders.
Recently, the transient receptor potential (TRP) channels gained increased interest for their potential involvement in primary headaches [61,62]. There are at least 30
members of the mammalian TRP family, which are
coded by several, different genes. TRP channels are distributed in many peripheral tissues as well as central and
peripheral nervous system. Several TRP family members, including the TRPV1 (Transient Related Potential
Vanilloid Type 1), TRPV2 (Transient Related Potential
Vanilloid Type 2), TRPV3 (Transient Related Potential
Vanilloid Type 3) and TRPV4 (Transient Related Potential Vanilloid Type 4), TRPM8 (Transient Related Potential Metastatin Type 8) channels, are polymodal sensors
expressed in the sensory neurons of dorsal root ganglia
(DRG) and trigeminal ganglia (TG) [63]. In particular,
TRPV1 receptor is highly co-expressed with calcitoningene related peptide (CGRP) a potent vasodilator with
an important role in migraine. TRPV1 is also coexpressed with other pain signalling molecules such as
substance P, P2X3 purinergic receptors and other markers of nociceptive C and Aδ fibers [64]. It has been proposed to play a crucial role as mediators of neuropathic
pain and have been proposed to play a role in migraineous allodynia and sensitization phenomena [65].
Using a genetic association strategy, in 2012 Carreno
et al. found a significant association between SNPs within the TRPV1 and TRPV3 genes and migraine in the
Spanish population [66]. Interestingly, TRPV1 and TRPV3
are located in close proximity on the 17p13 chromosomal
region and they share a high sequence homology. In the
meanwhile, two genome-wide association studies (GWAS)
found evidence of a significant association between genetic markers in or near the TRPM8 gene and migraine
[67,68]. TRPM8 gene is expressed by a different TRPV1negative neuronal subpopulation in DRG and TG. These
preliminary data significantly support a role for TRP channels in the pathogenesis of primary headaches.
TRP channels have been among the most aggressively
pursued drug targets over the past few years and several
studies suggested these channels as potential therapeutic
targets in migraine. Both peripheral and central nerve
terminals at the spinal cord can be targeted to induce
pain relief by TRPV1 agonists. In particular, the analgesic effects of the TRPV1 antagonist SB-705498 on
trigeminovascular sensitization and neurotransmission
have been studied in an animal model of neurovascular head pain [69,70]. Recently, a phase II clinical
trial using SB-705498 has been conducted for the
acute treatment of migraine attacks but results are
pending (ClinicalTrials.gov).
Neuroendocrine genes and primary headaches
A large number of endocrine abnormalities has been described in patients with primary headaches [71,72]. The
hypothalamus, with its paramount control of the endocrine system, as well as its widespread connections with
both central and autonomic nervous system, exerts a
pivotal role in the pathogenesis of both migraine and
cluster headache [73]. Therefore, genes that code for
proteins involved in endocrine functions are candidate
genes for primary headache disorders. Polymorphisms in
genes that code for estrogen and progesterone receptors
have been intensively studied in migraineurs, with contrasting results [74,75].
In 1998, two research groups independently discovered
a new hypothalamic peptidergic system. The former
group named the peptides “hypocretins”, because of
their hypothalamic location and structural similarity to
the incretin family of hormones [76]. The latter group
named the peptides “orexins”, due to the appetiteenhancing properties when administered centrally to
rats [77].
Subsequent studies revealed complex and interesting
neurobiological effects of these peptides, with particular
relevance to the pathophysiology of primary headaches
[78].
The hypocretins (Hcrt-1 and Hcrt-2), also called
orexins, are peptides derived by proteolytic cleavage
from the same 130 amino acid precursor peptide
(prepro-hypocretin). A single gene located on chromosome 17q21 in humans is responsible for encoding
prepro-hypocretin. The human prepro-hypocretin gene
consists of 2 exons and 1 intron. The hypocretins bind to
2 G-protein coupled receptors, termed HCRTR1 and
HCRTR2. The HCRTR1 gene in humans is located on
chromosome1p33 whereas the HCRTR2 gene is located
on chromosome 6p11. Both genes consist of 7 exons and
6 introns. Hcrt-1 has equal affinity for both HCRTR1 and
HCRTR2, with Hcrt-2 demonstrating a 10-fold higher
Page 5 of 8
affinity for HCRTR2 than HCRTR1. Activation of both receptors results in elevated levels of the intracellular Ca2+
concentrations, and this in turn results in the enhancement of the Gq-mediated stimulation of phospholipase C.
Hypocretin immunoreactive cell bodies have been observed mainly in the hypothalamus [79]. Hypocretincontaining neurons have widespread projections throughout the CNS with particularly dense excitatory projections
to monoaminergic and serotonergic brainstem centers
[80]. The hypocretin system influences a wide range of
physiological processes in mammals, such as feeding,
arousal, rewards, and drug addiction [81,82]. Recently, a
number of studies in experimental animals showed that
hypocretins are involved in pain modulation within the
CNS, and suggested an important role for these peptides
in primary headaches [83].
In 2004, our research group investigated the possible
involvement of the hypocretin transmission in cluster
headache. We selected several DNA polymorphisms of
the three genes that constitute the hypocretin system
and, using a case–control strategy, we evaluated possible
allelic and genotypic differences in a group of 109 CH
patients and 211 controls. Genetic analysis revealed that
both allelic and genotypic frequencies of the G1246A
polymorphism in the HCRTR2 gene were significantly
different between CH patients and controls [84]. Subjects homozygous for the G allele, in comparison with
the remaining genotypes, were 5-fold more likely to develop the disease. This association was confirmed in a
large group of CH patients and controls from Germany
[85]. On the contrary, Baumber et al. found no association between CH and the HCRTR2 gene in a cohort of
259 patients of Danish, Swedish, and British origin [86].
To resolve this issue, we performed a genetic metaanalysis of the previous studies (593 cases and 599 controls) and a haplotype analysis: both these studies confirmed the presence of a significant association between
the HCRTR2 gene and CH [87]. At present, the possible involvement of the hypocretin system in migraine
has been scarcely investigated. Studies in CH patients
prompted two independent research groups to evaluate
the association of the G1246A polymorphisms in the
HCRTR2 gene with migraine. Both studies found no association between this polymorphism and migraine or
its clinical subtypes [88,89]. Recently, we performed a
genetic case–control study to investigate whether genetic variants in the HCRTR1 gene could modify the occurrence and the clinical features of migraine. Using a
case–control strategy we genotyped 384 migraine patients and 259 controls for three SNPs in the HCRTR1
gene. Genotypic and allelic frequencies of the rs2271933
non-synonymous polymorphism were different between
migraineurs and controls [90]. The carriage of the A allele was associated with an increased migraine risk. This
study supports the hypothesis that the HCRTR1 gene
could represent a genetic susceptibility factor for migraine and suggests that the hypocretin system may have
a role also in the pathophysiology of migraine. Unfortunately, no data regarding involvement of HCRTR genes
in tension-type headache are currently available.
The growing knowledge concerning the role of hypocretins/orexins in different neurological conditions has
generated considerable interest in developing smallmolecule hypocretin receptor antagonists as a novel
therapeutic strategy. Hypocretin antagonists, especially
those that block Hcrtr1 or both Hcrtr1 and Hcrtr2 receptors, have been studied mainly as new drugs for sleep
disorders. In experimental animals hypocretin/orexin antagonists (almorexant, suvorexant) clearly promote sleep,
and clinical results are encouraging [91-94]. Considering
the high frequency of sleep disorders occurring in patients with migraine and CH, these drugs offer a new
perspective in the treatment of these disorders. Finally, a
pivotal role for these peptides in drug reward and drug
seeking has been established and their potential role as
anti-relapse medication in drug addiction is currently
under investigation in experimental animals [95].
Conclusions
The main goal of genetic studies is to unravel molecular
pathways underlying primary headache disorders, in
order to discover new therapeutic targets. Recent studies
have highlighted a potential role for new genes, like
MTHFR, KCNK18, TRPV1, TRPV3, and new neurotransmission systems, like the hypocretin system, both in migraine and cluster headache. Additional experimental
and clinical studies are needed to better elucidate the involvement of these new genes in primary headaches and
to evaluate new therapeutic strategies.
Competing interest
The authors declare no competing interest regarding this manuscript.
IR and ER planned the review and wrote the manuscript, with input from
other authors. KP reviewed the manuscript. AG and AV performed
bibliographic research and draw the pictures. PDM, SG, PS and LP supervised
the project. All authors read and approved the final manuscript.
Acknowledgements
This Review Article will be presented at the XXVII National Congress of the
Italian Society for the Study of Headaches – 26–28 September 2013.
Author details
1
Headache Center, Neurology I, Department of Neuroscience, University of
Torino, Via Cherasco 15, 10126 Torino, Italy. 2Department of Neurology,
Ghent University Hospital, Ghent, Belgium. 3Headache Centre, Neurologic
Clinic, University of Perugia, Perugia, Italy.
Received: 17 May 2013 Accepted: 20 June 2013
Published: 12 July 2013
Page 6 of 8
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and Pain 2013 14:61.
Costa et al. The Journal of Headache and Pain 2013, 14:62
REVIEW ARTICLE
Open Access
Cortical spreading depression as a target for
anti-migraine agents
Cinzia Costa1,3, Alessandro Tozzi1,3, Innocenzo Rainero2, Letizia Maria Cupini5, Paolo Calabresi1,3, Cenk Ayata4
and Paola Sarchielli1*
Abstract
Spreading depression (SD) is a slowly propagating wave of neuronal and glial depolarization lasting a few minutes,
that can develop within the cerebral cortex or other brain areas after electrical, mechanical or chemical depolarizing
stimulations. Cortical SD (CSD) is considered the neurophysiological correlate of migraine aura. It is characterized by
massive increases in both extracellular K+ and glutamate, as well as rises in intracellular Na+ and Ca2+. These ionic
shifts produce slow direct current (DC) potential shifts that can be recorded extracellularly. Moreover, CSD is
associated with changes in cortical parenchymal blood flow.
CSD has been shown to be a common therapeutic target for currently prescribed migraine prophylactic drugs. Yet,
no effects have been observed for the antiepileptic drugs carbamazepine and oxcarbazepine, consistent with their
lack of efficacy on migraine. Some molecules of interest for migraine have been tested for their effect on CSD.
Specifically, blocking CSD may play an enabling role for novel benzopyran derivative tonabersat in preventing
migraine with aura. Additionally, calcitonin gene-related peptide (CGRP) antagonists have been recently reported to
inhibit CSD, suggesting the contribution of CGRP receptor activation to the initiation and maintenance of CSD not
only at the classic vascular sites, but also at a central neuronal level. Understanding what may be lying behind this
contribution, would add further insights into the mechanisms of actions for “gepants”, which may be pivotal for the
effectiveness of these drugs as anti-migraine agents.
CSD models are useful tools for testing current and novel prophylactic drugs, providing knowledge on mechanisms
of action relevant for migraine.
Keywords: Cortical spreading depression; Calcium channels; Sodium channels; Glutamate; Ionotropic glutamate
receptors; Calcitonin gene-related peptides; Current prophylactic drugs; Antiepileptics; Tonabersat; Gepants
Introduction
Spreading depression (SD) is an intense self-propagating
wave of depolarization involving neuronal and glial cells
in the cerebral cortex, subcortical gray matter or retina,
irrespective of functional divisions or arterial territories.
This depolarization is followed by a longer lasting wave
of inhibition characterised by massive changes in ionic
concentrations and slow chemical waves, propagating at
a rate of approximately 3–6 mm/min [1]. In both
lissencephalic and gyrencephalic cortices, SD can be
evoked pharmacologically by the application of K+,
1
Neurologic Clinic, Department of Public Health and Medical and Surgical
Specialties, University of Perugia, Ospedale Santa Maria della Misericordia,
Sant'Andrea delle Fratte, 06132, Perugia, Italy
glutamate, and Na+/K+-pump inhibitors or by either
electrical or mechanical stimulation. SD can develop
over the course of epileptic crises or can be induced by
brain tissue injury, as in the case of trauma, hemorrhage
or ischemia [2-6].
Several clinical and neuroimaging findings support the
concept that cortical SD (CSD) is the pathophysiological
correlate of the neurological symptoms in migraine aura
[7-9]. Moreover, different experimental models of CSD
have been developed which help to better understand
the underlying neuronal mechanisms and related vascular changes [10,11]. They also, albeit not consistently,
suggest that CSD is able to activate central and peripheral trigemino-vascular nociceptive pathways with a latency matching, generally occurring between aura and
headache in migraineurs [12].
© 2013 Costa et al.; licensee Springer. This is an Open Access article distributed under the terms of the Creative Commons
Familial Hemiplegic Migraine 1 (FHM1) and 2 (FHM2)
mutations share the ability to facilitate the induction and
propagation of CSD in mouse models, further supporting
the role of CSD as a key migraine trigger [13]. CSD is further modulated by endogenous and environmental factors,
such as hormones and drugs, and also might be influenced
by weather, stress and food [14-16]. Current prophylactic
treatments have been investigated for their effects on
CSD. Novel drugs can also target CSD and this can account, at least in part, for their mechanisms of action on
migraine [17].
Review
In this review, we illustrate the main findings concerning
basic mechanisms underlying CSD as neurophysiologic
substrate of aura and report results on the effects on
CSD from available drugs and new therapeutic options.
Clinical, neurophysiological and neuroimaging evidence
of a link between migraine aura and CSD
About a third of migraine patients complain of transient
focal aura symptoms beginning from minutes to hours
before headache, or occurring during either the headache phase or even in its absence [18]. Usually, migraine
aura consists of fully reversible visual, sensory and/or
dysphasic symptoms [19]. These aura symptoms are accompanied by fully reversible motor weakness in hemiplegic migraine. This is referred to as familial (i.e., FHM)
subtype when the condition is present in at least one
first- or second-degree relative, and a sporadic subtype
in the absence of family history [20].
Specific genetic subtypes of FHM have been identified.
Mutations of three genes all encoding ion-channels or
membrane ionic pumps were discovered from 1996 to
2005. They involve a neuronal Ca2+ channel (CACNA1A,
FHM1), a glial Na+/K+ pump (ATP1A2, FHM2) and a
neuronal Na+ channel (SCN1A, FHM3), respectively [13].
However, these mutations have not been identified in the
more common types of migraine with typical aura. These
forms are considered polygenic, with an overall heritability
nearing 50%, and should be regarded as the result of the
interaction of genetic and environmental factors [21].
Descriptions of migraine with aura (MwA) from the
year 1870 onwards have reported a slow, gradual progression of aura symptoms. Specifically, in 1941, Lashley,
from the meticulous chartering of his own auras, suggested that aura symptoms reflect a cortical process
progressing with a speed of 3 mm/min across the primary visual cortex [22].
CSD was first described by Aristides Leão in 1944
[23,24]. Studying experimental epilepsy for his PhD thesis, Leão came across a depression of electroencephalographic (EEG) activity moving through the rabbit cortex
at a rate of 3–6 mm/min after electrical or mechanical
Page 2 of 18
stimulations. The negative wave was sometimes preceded by a small, brief positivity, and always followed by
a positive overshoot of 3–5 min [25]. He observed that
the threshold of CSD varied among cortical areas also in
pigeons and cats, and once triggered, it spread in all
directions. During CSD, neither sensory stimulation nor
direct cortical stimulation evoked potential waves. Ongoing
experimental seizure discharge was also suppressed by
CSD, even if sometimes tonic-clonic activity preceded or
followed SD [23]. Based on similar propagation of the two
processes, Leão hypothesized an association between CSD
and seizures [1].
Using microscopy and photography of pial vessels to
assess cortical circulation, the researcher was also able
to see both arteries dilated “as scarlet as the arteries”
and veins, as a consequence of CSD. This latter observation, for the first time, indicated that the cerebral
blood flow increase exceeded the increase in oxygen
demand. This topic has become a matter of interest for
all investigators studying changes in cerebral circulation
over the course of CSD [24].
In the early 20th century, aura was considered a vascular process involving an initial vasoconstriction followed
by a reactive vasodilation responsible for head pain
[8,26]. Later observations by Olesen et al. modified this
idea by demonstrating a spreading reduction in cerebral
blood flow, called “spreading oligemia”, occurring in
patients with MwA [27]. This finding completely
redefined the underlying pathogenesis of aura by attributing blood flow changes during aura to changes in
neuronal activity [28].
Single photon emission computerized tomography
(SPECT) [29] and perfusion-weighted magnetic resonance imaging (MRI) [30] studies have further supported
the hypothesis that “spreading oligemia” observed during
aura is primarily due to changes in neuronal activity.
Additionally, perfusion abnormalities have been suggested to be a response of the autoregulatory mechanisms to underlying neuronal depression. However, in
most SPECT and hyper-emia and subsequent spreading
hypo-perfusion, patients never experienced symptoms of
typical visual auras [7,31].
The first-ever study investigating occipital cortex activation during visual stimulation with functional magnetic resonance (fMRI) by blood oxygenation level
(BOLD)-dependent contrast imaging in MwA patients
demonstrated that the onset of headache or visual
change (only in 2 patients), or both, were preceded by a
suppression of the initial activation. This suppression
slowly propagated into contiguous occipital cortex at a
rate ranging from 3 to 6 mm/min. and was accompanied
by baseline contrast intensity increases, indicating that
vasodilatation and tissue hyper-oxygenation are associated with the induction of headache [32]. Later, in 2001,
Hadjikhani at al. [33], strongly suggested that electrophysiological events consistent with CSD are involved in
triggering aura in the human visual cortex. Using highfield fMRI with near-continuous recording during visual
aura, the authors identified specific BOLD events in the
visual cortex that were strictly linked to the aura percept, in both space (retinotopy) and time. Throughout
the progression of each aura, unique BOLD perturbations were found in the corresponding regions of the retinotopic visual cortex. Like the progression of the aura
in the visual field, the BOLD perturbations progressed
from the paracentral to more peripheral eccentricities, in
only the hemisphere corresponding to the aura. The
source of the aura-related BOLD changes were localized
in the extrastriate visual cortex (area V3A) rather than in
the striate cortex (V1). Strikingly, the spread rate of the
BOLD perturbations across the flattened cortical gray
matter was consistent with previous measures of CSD.
As for diffusion changes on MRI, these have been especially observed in cases of prolonged complex migraine aura, suggesting cytotoxic edema in the absence
of ischemic lesions [34-37]. To this regard, it is noteworthy the finding of a spreading of cortical edema with
reversibly restricted water diffusion from the left occipital to the temporo-parietal cortex in a case of persistent
visual migraine aura [38]. In another case of migraine
with prolonged aura, hyper-perfusion with vasogenic
leakage was detected by diffusion-weighted MRI [39]. A
further patient experienced a series of MwA attacks
accompanied by slight pleocytosis and gadolinium (GdDTPA) enhancement in proximity of the left middle
cerebral artery. In this patient, the migraine attacks and
Gd-DTPA enhancement were reversed by prophylactic
treatment [40].
Magneto-electroencephalography (MEG) allows the
study of direct current (DC) neuromagnetic fields in
spontaneous and visually induced migraine patients. Few
MEG studies have been conducted with this approach in
MwA patients due to technical difficulties. The most
relevant study to date has shown multiple cortical areas
activated in spontaneous and visually induced MwA patients, unlike activation limited to the primary visual
cortex in control subjects. This finding supports the hypothesis that a CSD-like neuro-electric event arises
spontaneously during migraine aura or can be visually
triggered in widespread regions of the hyper-excitable
occipital cortex [41].
MEG has also been used to directly register changes in
cortical oscillatory power during aura. Specifically, alpha
band desynchronization has been demonstrated with this
technique in both the left extra-striate and temporal cortex over the period of reported visual disturbances.
These terminated abruptly on the disappearance of scintillations, whereas gamma frequency desynchronization
Page 3 of 18
in the left temporal lobe continued for 8 to 10 minutes
following the reported end of aura [42].
Neuronal mechanisms of CSD in experimental models
When evoked by local extracellular K+ concentrations
exceeding a critical threshold, CSD is associated with the
disruption of membrane ionic gradients. Both massive
K+ (with extracellular concentration increases up to 60
mM) and glutamate effluxes are believed to depolarize
adjacent neurons to facilitate spread [43]. Results from
studies on ion-selective microelectrodes have shown that
an extracellular K+ rise is accompanied by falls in extracellular Na+ and Cl- during CSD, whereas water leaves
the extracellular space with significant changes in extracellular pH [44,45].
Specifically, in chick retina, SD induced an initial increase in intracellular pH, which was associated with elevated levels of ADP, P-Creatine, lactate and pyruvate.
This was followed by an intermediary acid shift, increases in ATP values and decreases in ADP, a late alkaline rebound, a decrease in P-Creatine levels, and
elevations in both ADP and lactate levels. These transient changes in intracellular pH occurring parallel to
changes of energy metabolite levels during SD, may be
expressions of rapidly modifying metabolic activities of
neurons and glial cells. The first alkaline shift was attributed to glial cells, whereas the intermediary acid shift
was attributed to neurons. No specific cells were thought
to be responsible for the late alkaline shift, which could
explain the refractoriness of the neurons in this phase
[46]. Accordingly, in rat cerebellum, an initial decrease
in [H+] (pH increase) followed by a increase in [H+] (pH
decrease) was observed during SD [45]. Further results
obtained from a model of CSD showed acidification and
a marked depression in the cortical energy status at the
wavefront of SD. Afterwards, a residual activation of glycolysis and an accumulation of cGMP persisted for minutes after relatively rapid restorations of high-energy
phosphates and pHi [47]. Recovery from this process
occurs usually within a few minutes without any tissue
damage [43,45].
A causative link between enhanced glutamate release
and facilitation of CSD, induced by brief pulses of high
K+, has been reported in mouse models of CSD [48-51].
In some of these models, CSD could not be recorded
after perfusing cortical slices by Ca2+ free medium or
after blocking Ca2+ channels [50,52-55]. Glutamate involvement in CSD is further supported by the finding
of CSD blockage by N-methyl- D-aspartate receptor
(NMDA-R) antagonists, but not by non-NMDA-R antagonists, in vivo [56-59] or in hippocampal and neocortical slices of rats [5,55]. CSD has also been reported to
be blocked by the NMDA-R antagonist 2-amino-5phosphonovaleric acid, in slices of human neocortical
tissue [60]. Furthermore, data have demonstrated that
NR2B-containing NMDA-R are key mediators of CSD,
providing the theoretical basis for the usefulness of
memantine and some NR2B-selective antagonists for the
treatment of MwA and other CSD-related disorders,
such as stroke or brain injury [50,61].
According to the above findings, CSD cannot be induced in brain slices of FHM1 KI mice if either P/Qtype Ca2+ channels or NMDA receptors are blocked.
Conversely, blocking N- or R-type Ca2+ channels seems
to have only small inhibitory effects on the CSD threshold and velocity of propagation. This suggests that Ca2+
influx through presynaptic P/Q-type Ca2+ channels with
consequent release of glutamate from cortical cell synapses and activation of NMDA-R is required for initiation
and propagation of the CSD [62]. This is in contrast
with results of in vitro and in vivo pharmacological studies where CSD was induced by perfusing cortical slices
with a high K+ solution (rather than with brief K+ pulses
or electrical stimulation). In these models, NMDA-R
antagonists only slightly increased CSD threshold without affecting its velocity. Accordingly, blocking P/Q-type
(or the N-type) Ca2+ did not significantly affect the
CSD threshold obtained from perfusing cortical slices
with progressively increasing K+ concentrations [51,63].
Interestingly, removal of extra-cellular Ca2+ did not
block CSD but reduced it to about half the rate of propagation [64].
Different results have been obtained for multiple CSD
models induced in vivo by continuous K+ microdialysis
or topical application of KCl, where P/Q-type (Cav2.1),
or N-type, Ca2+ channel blockers and NMDA-R antagonists led to a strongly reduced frequency, amplitude and
duration, but not a complete suppression, of CSD events
[50,65,66]. Furthermore, Ca2+ channel blockers have not
been reported to affect CSD induced by pinprick in vivo
[66]. Therefore, results seem to be strongly influenced
by the model used. Currently, electrical stimulation and/
or brief applications of high K+ are considered to be the
most appropriate CSD-inducing stimuli, rather than
prolonged applications of high K+, for the better understanding of “spontaneous” CSD mechanisms occurring
in migraine aura [62]. Specifically, these models best reveal that the excitatory synaptic transmission, involved
in CSD initiation and propagation at the pyramidal cortical cells, predominantly depends on presynaptic P/Qtype Ca2+ channels.
Earlier studies reported that the Na+ channel blocker
TTX was not able to consistently inhibit CSD [67-69].
More recently, Na+ channels have been shown to be involved in the initiation of CSD in hippocampal slices [5].
Their contribution to CSD was confirmed by Tozzi et al.
[70] in rat neocortical slices by reducing CSD propagation after applying the voltage sensitive Na+ channel
Page 4 of 18
blocker TTX. In another study, Na+ ion channel blockage was also seen to inhibit relative cerebral blood flow
(rCBF) changes occurring during CSD induced on both
cats and rats. In the same model, voltage-dependent
Ca2+ channel blockers had little effect on either the initiation or propagation of CSD spread, as was the case for
ATP-activated K+ channel blockers also [71].
It has been demonstrated that the activation of alphaamino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA)
receptors (AMPA-R) can suppress the actions of NMDA-R
in the neocortex [72]. Earlier findings, however, suggested
that NMDA-R blockers, but not AMPA-R antagonists,
were able to inhibit CSD in rats [70,72,73]. Conversely, a recent study has demonstrated that both 50 μM AMPA, as
well as 10 μM of the NMDA-R antagonist 2-amino-5phosphono-pentanoic acid (2AP5), significantly reduce
the number of CSD cycles. Additionally, the gammaaminobutyric acid (GABA)-mimetic drug clomethiazole
(100 mg/kg i.p.) did not significantly affect the number of
CSD cycles [74]. Being so, the suppression of NMDA-R actions in the neocortex by AMPA-R activation, may represent an intrinsic protective mechanism against CSD and
could, thus, be a potential therapeutic strategy against
CSD-related neurological conditions including migraine
aura.
In line with the above finding, AMPA-R, as well as
GABA(A) and GABA(B)-R agonists, have been shown
to inhibit cerebral blood flow changes associated to
mechanically-induced CSD in all rats and in a proportion of cats. Furthermore, non-responders showed altered speeds of propagation and times to induction [75].
In contrast, in a recent investigation, reproducible CSD episodes, induced by high extracellular K+ concentrations in
rat neocortical slices, were inhibited by antagonists of
NMDA-R, but not by AMPA-R [70]. Methodological
differences (CSD models, dosages of agonists, outcome
measures) could explain discrepancy in the results of
the different studies carried out on this topic.
Recent autoradiographic findings suggest that selective
changes in several receptor-binding sites, in both cortical
and subcortical regions, are related to the delayed excitatory phase after CSD. In fact, in neocortical tissues, local
increases of ionotropic glutamate receptors NMDA,
AMPA, and kainate receptor binding sites have been observed. In addition, receptor binding sites of GABA(A),
muscarinic M1 and M2, adrenergic alpha(1) and alpha
(2), and serotonergic 5-HT(2) receptors were seen increased in the hippocampus. CSD also up-regulated
NMDA, AMPA, kainate, GABA(A), serotonergic 5-HT
(2), adrenergic alpha(2) and dopaminergic D1 receptor binding sites in the striatum [76]. Therefore, not
only glutamatergic mechanisms, but also changes in
monaminergic and cholinergic pathways seem to be involved in CSD.
Vascular changes associated to CSD in
experimental models
CSD has been reported to be associated with changes in
the caliber of surface cortical blood vessels.
Leão was the first to report arteriole dilatation accompanying electrophysiological changes in CSD of rabbits
[24], which was later confirmed in rats and cats [77,78].
A further study using laser Doppler flowmetry, focusing
on tissue perfusion rather than arterial diameter, has
suggested that CSD is associated with an initial increase
in cortical blood flow, which is thought to correspond
to arteriolar dilatation [79]. Triggering CSD results in a
sustained wave of reduced cortical blood flow after
initial vasodilation, as shown by single modality blood
flow measurements, including autoradiographic methods
[80,81] and laser Doppler flowmetry [82]. Moreover,
sustained hypo-perfusion was accompanied by a concurrent reduction in reactivity to vasoactive stimuli [83].
Dual modality methods, such as laser Doppler flowmetry
and extracellular electrophysiology, allowed for the concurrent assessment of changes in neuronal firing and
cerebral blood flow in CSD but lacked parallel spatial
and temporal resolutions [84]. Optical intrinsic signal
(OIS) imaging also enables visualization of CSD on the
cortical surface with high temporal and spatial resolution
[85-87]. The optical correlates of CSD have been evaluated on both a mouse and a rat model by Ayata et al.
[88]. Vascular response to CSD propagates with temporal and spatial characteristics, which are distinct from
those of the underlying parenchyma, suggesting a distinct mechanism for vascular conduction.
Using OIS imaging and electrophysiology to simultaneously examine the vascular and parenchymal changes
occurring with CSD in anesthetized mice and rats, Brennan
et al. [89] observed vasomotor changes in the cortex
which travelled at significantly greater velocities compared to neuronal changes. This observation further reinforces the idea that dissociation between vasomotor
and neuronal changes during CSD exists. Specifically,
dilatation travelled in a circuitous pattern along individual arterioles, indicating specific vascular conduction
as opposed to concentric propagation of the parenchymal signal. This should lead to a complete rethinking
of flow-metabolism coupling in the course of CSD. Vascular/metabolic uncoupling with CSD has also been
reported by Chang et al. using a combination of OIS
imaging, electrophysiology, K+-sensitive electrodes and
spectroscopy in mice [90]. The authors identified two
distinct phases of altered neurovascular function. In the
first phase of the propagating CSD wave, the DC shift
was accompanied by marked arterial constriction and
desaturation of cortical hemoglobin. After recovery
from the initial CSD depression wave, a second phase
was identified where a novel DC shift appeared to be
Page 5 of 18
accompanied by arterial constriction and a decrease in
tissue oxygen supply, lasting at least an hour. Persistent
disruption of neurovascular coupling was supported by
a loss of consistency between electrophysiological activity and perfusion.
Nitric oxide (NO) may play a relevant role in determining
changes in cerebro-vascular regulation following CSD. In
fact, the NO precursor L-arginine prevented the development of prolonged oligemia after CSD but had no influence
on a marked rise of CBF during CSD. Moreover, rats
treated with L-arginine recovered their vascular reactivity
to hyper-capnia after CSD much faster than controls [91].
The NO donor, 2-(N,N-diethylamino)-diazenolate-2-oxide
(DEA/NO) had little effect on CSD but reversed the effects
of NO synthase (NOS) inhibition by 1 mM L-NAME, in a
concentration-dependent manner, suggesting that the increased formation of endogenous NO associated with CSD
is critical for subsequent, rapid recovery of cellular ionic
homeostasis. Molecular targets for NO may be either brain
cells, through the suppression of mechanisms directly involved in CSD or local blood vessels by means of coupling
flow with the increased energy demand associated with
CSD.
The potent vasoconstrictor endothelin-1 (ET-1) applied
on rat neocortices has been demonstrated to induce CSDs
through the ET(A) receptor and phospholipase C (PLC)
activation. Primary targets of ET-1 mediating CSD seem
to be either neurons or vascular smooth muscle cells [92].
This finding provides a bridge between the vascular and
the neuronal theories of migraine aura. However, the micro area of selective neuronal necrosis, induced by ET-1
application suggests a role by vasoconstriction/ischemia
mechanisms. This observation contrasts with the lack of
neuronal damage in several CSD models [93].
Genetic evidence of CSD involvement in migraine
Genetic factors are known to enhance susceptibility
to CSD, as results from transgenic mice expressing
mutations associated with FHM or cerebral autosomal
dominant arteriopathy with subcortical infarcts and
leuko-encephalopathy (CADASIL) have shown [94-99].
Specifically, P/Q-type Ca2+ channels, located in somatodendritic membranes and presynaptic terminals in the
brain, play a pivotal role in inducing potential-evoked
neurotransmitter release at CNS synapses [100]. Missense mutations in the gene encoding the pore-forming
α1 subunit of voltage-gated P/Q-type Ca2+ channel, responsible for the rare autosomal dominant subtype of
MwA FHM1, induce a gain-of-function of human recombinant P/Q-type Ca2+ channels, due to a shift to
channel activation at lower voltages [101]. Increased P/
Q-type Ca2+ current density in cortical pyramidal cells
has been demonstrated in Knock-in (KI) mice carrying
FHM1 mutations [101-103]. Furthermore, FHM1 KI
mice have shown a reduced threshold for CSD induction
and an increased velocity of CSD propagation [63,104].
These mice represent a powerful tool for exploring presynaptic regulation associated with expression of P/Qtype Ca2+ channels. Mutated P/Q-type Ca2+ channels
activate at more hyper-polarizing potentials and lead to a
gain-of-function in synaptic transmission. This gain-offunction might be responsible for alterations in the excitatory/inhibitory balance of synaptic transmission, favoring
a persistent state of hyper-excitability in cortical neurons
which may increase the susceptibility for CSD [101]. In
contrast, spontaneous CACNA1a mouse carrying mutations producing partial loss-of-function of the P/Q-type
Ca2+ channel, need approximately a 10 fold higher electrical stimulation intensity in order to evoke a CSD compared to wild-type mice [105].
FHM2, the autosomal dominant form of MwA, is caused
by mutations of the α2-subunit of the Na+,K+-ATPase,
an isoform almost exclusively expressed in astrocytes
in the adult brain. In a FHM2 KI mouse model
carrying the human W887R mutation in the Atp1a2
orthologous gene, in vivo analysis of CSD in heterozygous F Atp1a2 (+/R887) mutants revealed a decreased
induction threshold and an increased velocity of
propagation. While several lines of evidence suggest a
specific role on the part of glial α2 Na+/K+ pump in active reuptake of glutamate from the synaptic cleft, it is
plausible that CSD facilitation in the FHM2 mouse
model is sustained by inefficient glutamate clearance
by astrocytes, leading to an increase in cortical excitatory neurotransmission [106].
MwA is often the first manifestation of cerebral autosomal dominant arteriopathy with subcortical infarcts and
leukoencephalopathy (CADASIL), caused by NOTCH3
gene mutations expressed predominantly in vascular
smooth muscles. In a recent study, CSD was reported to
be enhanced in mice expressing either a vascular Notch
3 CADASIL mutation (R90C) or a Notch 3 knock-out
mutation. These findings further support the role of the
trigeminal neurovascular unit in the development of migraine aura [107].
Influence of sexual steroids on CSD
A relation between migraine and changes in the level of
sexual steroids has been well documented and both estrogens and androgens may influence migraine attacks.
Accordingly, it has been found that in women with
MwA, plasma estrogen concentrations were higher during normal menstrual cycle. Furthermore, it has also
been reported that the occurrence of migraine attacks is
associated with high circulating estrogen levels as during
ovulation, pregnancy and the use of certain oral contraceptives [18-110]. Notably, sex difference in the presentation of attacks has been shown to disappear after
Page 6 of 18
oophorectomy and with senescence [111]. Testosterone
and its synthetic derivatives have also been demonstrated to improve migraine in both men and women
[112-116]. Moreover, males treated with gonadotropins
for infertility experienced a marked improvement in
their MwA attacks [117]. Conversely, anti-androgen
therapy increased MwA frequency in a small cohort of
male-to-female transsexuals [118].
Some experimental findings support the excitatory
neuronal effect associated with estradiol and the inhibitory effect associated with progesterone. Compared to
female hormones, mechanisms of androgenic modulation of excitability are not as well known. Gonadic hormones have been suggested to have a modulating role in
CSD susceptibility, which would, at least in part, explain
the gender differences in the prevalence of migraine. Accordingly, female FHM1 mutant mice have been shown
to be more susceptible to CSD when compared to their
male counterparts [119]. On the other hand, testosterone have been reported to suppress CSD via androgen
receptor-dependent mechanisms and, accordingly, its inhibitory effect on CSD was prevented by the androgen
receptor blocker flutamide. Furthermore, it has been
shown that chronic testosterone replacement reversed
the effects of orchiectomy on CSD [120].
Astrocytes and gap-junction involvement in CSD
Astrocytes, a subset of glial cells, reside next to neurons,
establishing together a highly interactive network [121].
Astrocytes play a pivotal role in limiting CSD by acting
as a buffer for the ionic and neurochemical changes
which initiate and propagate CSD [122]. On the other
hand, astrocyte interconnections are believed to contribute to propagating the CSD wave, by way of K+ liberation, allowed for by an opening of remote K+ channels.
Moreover, energy failure in astrocytes increases the vulnerability of neurons to CSD [123]. There is increasing
evidence suggesting that, while synapses connect neuronal networks, gap-junctions most likely connect astrocyte networks [124]. Clusters of these tightly packed
intercellular channels allow for the direct biochemical
and electrical communications among astrocytes, contributing to a syncytium-like organization of these cells
[125]. Membranes of adjacent astrocytes have connexincontaining hemi-channels which can bridge an intercellular gap to form a gap-junction [126]. This interaction
between the two hemi-channels opens them both,
allowing for the intercellular passage of ions and small
molecules [127]. Approximately 1.0–1.5 nm in diameter,
gap-junctions permit the transport of molecules up to
about 1 kDa in size. Astrocytes express at least three different connexins at gap-junctions with regional differences in their distributions.
Experimental studies have suggested an involvement
of gap-junctions in CSD by regulating the milieu around
active neurons including extracellular K+, pH and neurotransmitter levels (especially glutamate and GABA), as
well as propagating intercellular Ca2+ waves [128]. Nonjunctional connexin hemi-channels may also contribute
to the release of adenosine triphosphate (ATP). This
extracellular messenger is able to mediate Ca2+ wave
propagation directly or via the transfer of a messenger
which triggers ATP release from one cell to another
[129]. Generation and propagation of CSD may depend
on neuronal activation and Ca2+ influx triggered by
NMDA-R. Interestingly, NMDA-R antagonists block
CSD but, unlike the gap-junction blockers, do not inhibit Ca2+ wave propagation.
Astrocytes are known to express several types of glutamate receptors, including NMDA-R. Glutamate release
from astrocytes has also have been reported to be mediated via the opening of connexin hemi-channels [127].
For this, gap-junction-mediated propagation of Ca2+
waves may represent the advancing front of CSD, contributing to the triggering of the secondary depolarization of the surrounding neurons, leading to further
releases of K+ and glutamate into the extracellular space.
Glutamate may then stimulate cytosolic Ca2+ oscillations
in astrocytes, providing a feedback loop involved in CSD
propagation. If so, gap-junction blockage would represent a viable pharmacological strategy for MwA prevention. Evidence of a gap-junction coupling Ca2+ waves
between pia-arachnoid cells and astrocytes has also been
reported, suggesting a transfer of Ca2+ signals from cells
of the cortical parenchyma into the meningeal trigeminal
afferents, all of which might mediate the induction of
neurovascular changes responsible for migraine headache [130].
Altered blood–brain barrier (BBB) permeability in CSD
CSD alters blood–brain barrier (BBB) permeability by
activating matrix metalloproteases (MMPs) [131]. From
3 to 6 hours, MMP-9 levels increase within the cortex
ipsilateral to CSD, reaching a maximum at 24 hours
and persisting for at least 48 hours. At 3–24 hours, immunoreactive laminin, endothelial barrier antigen, and
zona occludens-1 diminish in the ipsilateral cortex,
suggesting that CSD altered proteins are critical to the
integrity of BBB.
Subclinical infarct-like white matter lesions (WMLs)
in the brain of some migraine patients, especially those
with aura, have been reported to be consistent with
CSD-related BBB disruption. Furthermore, increases in
plasma levels of matrix MMPs (especially MMP-9 and
MMP-2) in migraine patients, in the headache phase,
suggest a potential pathogenic role for MMP elevation
in both migraine attacks and WMLs [132-135]. Different
Page 7 of 18
circulating MMP profiles in MwA and migraine without
aura (MwoA) may reflect pathophysiological differences
between these conditions. According to Gupta et al.
MMPs are responsible for the loosening of the intercellular tight junctions and the expansion of the extracellular matrix of the BBB, consequent to the sudden
increase in cerebral blood flow during migraine attacks
[136]. In this condition, WML could result from a transient and discrete breakdown of the BBB following
sustained cerebral hyper-perfusion rather than hypoperfusion.
The relationship between CSD and headache
Recent electrophysiological data has provided direct evidence that CSD is a powerful endogenous process which
can lead to persistent activation of nociceptors innervating the meninges. Regardless of the method of cortical
stimulation, CSD in rat visual cortices induces a twofold increase in meningeal nociceptor firing rates,
persisting for 30 min or more. Meningeal nociceptors
represent the first-order neurons of the trigeminovascular system, whose activation is involved in the initiation of migraine headache [137]. CSD waves moving
slowly across the cortex can promote the releases of K+,
arachidonic acid, hydrogen ions, NO and ATP. Critical
levels of these substances are thought to cause sensitization and activation of trigeminal neurons in the afferent loop and, in turn, activate second-order neurons
in the trigemino-cervical complex. These second-order
neurons transmit sensory signals to the brainstem and
parasympathetic efferents, the latter projecting from the
sphenopalatine ganglion. CSD has been suggested to
promote persistent sensitization, thereby provoking the
activation of meningeal nociceptors through a mechanism involving local neurogenic inflammation, with contribution of mast cells, macrophages and the release of
inflammatory mediators. Local action of such nociceptive mediators increases the responsiveness of meningeal
nociceptors. Recent research has provided key experimental data suggesting the role of complex meningeal
immuno-vascular interactions leading to an enhancement in meningeal nociceptor responses [137]. CSD also
induces increased neuronal activity of central trigeminovascular neurons in the spinal trigeminal nucleus (C1-2)
as measured by single-unit recording. It therefore
represents a "nociceptive stimulus" capable of activating
both peripheral and central trigemino-vascular neurons
underlying the headache phase of MwA [137].
Recent evidence suggests that central trigeminal neurons are activated by CSD. Specifically, an increase
in the spontaneous discharge rate, following the induction of CSD by cortical injection of KCl was not reversed
through the injection of lignocaine into the trigeminal ganglion 20 min after CSD induction. Lignocaine
injection prior to the initiation of CSD also failed to prevent the subsequent development of CSD-induced increases in discharge rates [138]. In these experiments,
lignocaine at a dosage of 10 μg (capable of interrupting
stimulus-induced responses to either electrical stimulation of the dura mater or mechanical stimulation of
the craniofacial skin) reduced basal the discharge rate
of second-order trigeminovascular neurons. This increased traffic in the second-order neurons induced
by CSD, however, was not influenced by the blockage of conduction in first-order neurons which was
due to lignocaine injection into trigeminal ganglion
after CSD induction by cortical pinprick. A time point
of 20 min post-lignocaine injection was chosen because responses to evoked stimulation reached a minimum at this time.
It has been suggested that CSD may produce a rapid
sensitization at first sensory neurons which could become
“locked-in” and, therefore, would not be influenced by a
later reduction in sensory traffic, like that induced by the
injection of lignocaine into the trigeminal ganglion [139].
An increase in discharge rate produced by CSD has also
been observed when lignocaine is injected into trigeminal
ganglion, prior to the induction of CSD. This is further
evidence that CSD does not act solely by increasing
continuous traffic in primary trigemino-vascular fibers
through a peripheral action alone, but rather exerts its effect through a mechanism intrinsic to the CNS. Accordingly, pain in MwA may not always be the result of
peripheral sensory stimulation, but may arise via a central
mechanism [140].
The principal opposition to this hypothesis is based
upon the belief that mediators released as a consequence
of CSD induction cannot be sustained in the perivascular space to induce persistent trigeminal sensitization
and the subsequent hours-lasting headache because of
the glia limitans barrier (astrocyte foot processes associated with the parenchymal basal lamina surrounding the
brain and spinal cord, regulating the movement of small
molecules and cells into the brain parenchyma) and the
continuous cerebrospinal fluid (CSF) flow [141]. Additionally, the delay of 20–30 min between aura and headache suggests that a time lag is required for the
transduction of algesic signals beyond glia limitans via
inflammatory mediators. In support to this rebuttal,
Karatas et al. demonstrated that intense depolarization
and NMDA receptor overactivation due to CSD, opens
neuronal Pannexin1 (Panx1) mega-channels [142]. Panx1
activation induces a downstream inflammasome formation involving caspase-1 activation and the sustained release of pro-inflammatory mediators from glia limitans
such as high-mobility group box 1 (HMGB1) and IL-1β,
both of which take part in the initiation of the inflammatory
response [143-146]. A subsequent NF-kB translocation was
Page 8 of 18
observed inside the cortex, involving astrocytes, forming or
abutting glia limitans, followed by the activations of both
cyclooxygenase (COX)2 and inducible NOS (iNOS). The
inhibition of Panx1 channels or HMGB1 resulted in a reversal of this effect.
A CSD-induced neuronal megachannel opening may
therefore promote sustained stimulus required for both
sensitization and activation of meningeal trigeminal
afferents through the maintenance of inflammatory
responses which may be involved in the subsequent
headache pain.
The effects of anti-migraine drugs on CSD
Symptomatic drugs
There is no evidence that acute anti-migraine drugs
affect CSD due to the fact that they are not able to block
or reduce aura symptoms. In one of the few studies carried out on this, sumatriptan was reported to decrease
the amplitude of NO release but was seen to enhance
extracellular superoxide concentrations in both lissencephalic and gyrencephalic cortices during CSD [147]. In
another study, the same drug failed to inhibit CSD and
CSD-related events [148].
Preventive treatment
Currently, numerous drugs are available for the prophylactic treatment of migraine, including: tricyclic antidepressants, beta-blockers, calcium channel blockers and
antiepileptics. Many of these have been demonstrated to
be effective for both MwA and MwoA, suggesting that
multiple targets are involved not only in cortical areas
but also in sub-cortical structures [17,149]. Results from
studies investigating the effects of currently available or
novel drugs in animal models for CSD are reported in
Additional file 1: Table S1.
Current prophylactic drugs
Kaube and Goadsby were the first to investigate the
effectiveness of anti-migraine agents in the prevention of
CSD by measuring cortical blood flow with laser Doppler flowmetry and cortical single unit activity in alphachloralose-anaesthetised cats [150]. None of the tested
drugs, including dihydroergotamine (DHE), acetylsalicylic acid, lignocaine, metoprolol, clonazepam and valproate at a single dose prior to CSD induction, were able
to inhibit CSD, reduce the rate of propagation or change
the amplitude of the cortical blood flow increase. CSD,
on the other hand, was blocked by both the NMDA-R
blocker MK-801 and halothane. More recently, diverse
prophylactic drugs, which are efficacious for the prophylactic treatment of MwA and MwoA, have been shown
to experimentally suppress SD susceptibility. In particular, chronic daily administration of topiramate (TPM),
valproate, propranolol, amitriptyline, and methysergide
dose-dependently were seen to inhibit CSD frequency by
40 to 80% and increase the cathodal stimulation threshold. Longer treatment durations produced stronger CSD
suppression. However, the acute administration of these
drugs was ineffective [151]. In a further study, peroral
administration of TPM, once-daily for 6 weeks, inhibited
KCl-induced CSD frequency and propagation. This effect emerged for high plasma levels of the drug, while
low levels were ineffective [152]. According to these results, prophylactic drugs should be administered daily
for at least 1 month to up 3–6 months, in order to be effective on CSD. This prolonged treatment is necessary
to reduce attack frequency and severity in migraineurs.
This is due to the fact that pharmacokinetic factors,
which determine the gradual achievement of therapeutic
tissue levels, as well as the mechanisms involved in gene
expression and ultrastructural changes, require such a
time period to be effective. In contrast, Akerman and
Goadsby demonstrated that mechanically-induced CSD
could be prevented by a single dose of topiramate 30
min after administration [153]. Similarly, Hoffmann observed a suppression of CSD susceptibility within 1 hour
after a single intravenous dose of gabapentin [154]. No
data are available on the effect of high doses of chronic
oral gabapentin treatment.
Lamotrigine, a potent Na+ channel blocker and glutamate receptor antagonist, has been demonstrated to
affect MwA in open-label studies but not MwoA in controlled trials vs placebo or vs an active drug [155-159].
The drug has also been tested for its effect on CSD.
Chronic treatment with this drug appeared to exert a
marked suppressive effect on CSD, which is in line with
its selective action on the migraine aura [160]. Specifically, lamotrigine was seen to suppress CSD by 37% and
60% at proximal and distal electrodes, respectively. Conversely, valproate had no effect on distal CSD, but reduced and slowed propagation velocity by 32% at the
proximal electrodes. In the same study, riboflavin had
no significant effect. Furthermore, frontal Fos expression
was decreased by lamotrigine and valproate, but not by
riboflavin. Single dose lamotrigine has never been tested
for its specific effects on CSD.
Conflicting results have been obtained regarding the
effects of the Ca2+ channel blocker flunarizine on CSD
events [161-166]. These discrepancies are likely due to
the different experimental designs utilized, as well as
technical limitations characteristic of earlier studies.
Moreover, this drug has never been tested on currently
used CSD models.
For many years it has been suggested that magnesium
(Mg2+) deficiency could be involved in migraine pathogenic mechanisms by increasing neuronal excitability via
glutamate receptors. To this regard, several studies have
reported low values of Mg2+ in serum and blood cells
Page 9 of 18
over the interictal periods, as well as reduced Mg2+ ionized levels in more than 50% of migraine patients during
attacks [167-170]. Low brain Mg2+ levels have also been
detected in migraineurs by brain phosphorus spectroscopy [171]. Furthermore, in MwA patients, magnesium
sulphate administration was seen to significantly relieve
pain and alleviate migraine-associated symptoms [172].
Accordingly, systemic administration of Mg2+ has been
shown to reduce CSD frequency induced by topical KCl
in rat neocortices [173].
The predictive values of CSD models, specifically for
the efficacy of drugs in migraine prophylaxis, can be further reinforced by negative findings from the testing of
molecules demonstrated to be ineffective in migraine.
This was the case for oxcarbazepine which failed to suppress CSD susceptibility either acutely after a single dose
or after chronic treatment for 5 weeks [174] and carbamazepine tested in vitro on a CSD rat model [70]. Dpropranolol, which is anecdotally ineffective in migraine,
also did not suppress CSD, indicating an enantiomer
specificity for its efficacy [151].
Novel therapeutic options
The novel benzopyran compound tonabersat is a unique
molecule, which has been demonstrated to exert activity
as a gap-junction inhibitor in animal studies. It has been
suggested to be useful in both acute treatment and
prophylaxis of migraine [175]. However, conflicting results have been obtained in two-dose ranging, placebocontrolled trials concerning its ability to relieve attacks
[176] and also in the two randomized clinical trials
aimed at investigating its effectiveness as a preventive
drug [177,178]. This lack of efficacy was attributed to
the slow absorption of tonabersat, suggesting that a daily
administration of higher dosages should be tested for
migraine prophylaxis. Interestingly, in another randomised,
double-blind, placebo-controlled crossover trial, 40 mg
tonabersat, administrated once daily, had a significant
preventive effect on MwA but not MwoA, compared to
placebo [179]. These findings concur with results of preclinical studies where the drug was reported to markedly
reduce CSD and CSD-associated events, compared to sumatriptan [148]. Additionally, a study using repetitive diffusion weighted MR imaging (DWI) detected in vivo CSD
modulation for tonabersat and, in part, also for sumatriptan [180]. Another mechanism of action of tonabersat includes its ability to inhibit gap-junction communication
between neurons and satellite glial cells in the trigeminal
ganglion [181]. This mechanism, together with its suppressive effect on CSD and its good pharmacokinetic profile,
render the drug a potential candidate for preventive treatment of MwA.
A recent open-labeled pilot study on the Na+/H+ exchanger amiloride showed that it was clinically effective
by reducing aura and headache symptoms in 4 of 7 patients with intractable MwA. Preclinical findings from
the same study suggested that the drug blocks CSD and
inhibits trigeminal activation in in vivo migraine models,
via the acid-sensing ion channel (ASIC)1 mechanism
[182]. This mechanism could be a novel therapeutic target for MwA. ASIC3 are expressed in most trigeminal
neurons where they mediate proton stimulation of calcitonin gene-related peptide (CGRP) secretion [183]. The
stimulatory effects of protons (pH 5.5) on CGRP secretion, due to ASIC3 activation, appear not to be limited
to peripheral trigeminal neurons, but may also involve
dural trigeminal afferents. Activation of dural trigeminal
afferents by acidic pH has been shown to be mediated
by ASICs channels (most likely ASIC3) but not TRPV1
[184]. Amiloride, due its nonselective inhibitory effect,
might influence the activation of these extracellular
proton key sensors in trigeminal neurons, therefore reducing CGRP release at both peripheral and central
levels.
CGRP is the main mediator of trigeminal pain signals.
This neuropeptide acts at several steps in the cascade,
from the trigeminal nerve to the CNS. It is released from
trigeminal ganglion neurons, both peripherally at the
dura and centrally in the spinal trigeminal nucleus and
other sites within the CNS. Specifically, both CGRP and
CGRP receptors have been observed in structures implicated in the pathogenesis of migraine including cortex
and meninges [185]. Activation of CGRP receptors on
terminals of primary afferent neurons facilitates transmitter release on spinal neurons and increases glutamate
activation of AMPA receptors. Both effects are mediated
by cAMP-dependent CGRP mechanisms. CGRP also
regulates glia activity within the spinal cord and this activity contributes to central sensitization [186]. Whal
et al. investigated for the effect of the CGRP competitive
inhibitor CGRP-(8–37) (10−7 M) and NO inhibitor
NOLAG (10−4 M) on dilation of pial arteries accompanying transient negative DC shift during KCl-induced
CSD in cats. The authors reported a 75% inhibition of
the CSD-induced dilatation during simultaneous application of both compounds, indicating that the initial dilatation during CSD is mediated, at least in part, by
releases of CGRP and NO [187]. The latter two may act
as mediators of the coupling between neuronal activity
and cerebral blood flow during migraine aura. In a
further study, topical administration of 12.8 μM CGRP(8–37) reduced CSD-induced pial vasodilation in urethaneanesthetized rabbits. In the same experiment, the removal of the receptor antagonist from the brain surface
restored CSD-induced dilation, further supporting a
pivotal role for CGRP in determining transient arteriolar dilation in the first phases of CSD [188]. The above
results argue in favor of a local release of CGRP in the
Page 10 of 18
meninges, where this neuropeptide may contribute to
sensitizing local sensory neurons. However, a recent investigation on cultured cortical astrocytes has shown
that CGRP possesses a modest proinflammatory action,
as does satellite glia [189].
CSD does not seem to significantly influence CGRP
outflow in jugular blood, but local increases of CGRP in
the cortex during CSD cannot be excluded [190].
Furthermore, peripheral injection of CGRP in MwA patients has triggered a typical aura in 28% of patients, and
migraine-like attacks without aura in the remaining. If
this induction of aura can be confirmed, it will indicate
that this neuropeptide has an upstream role in CSD
[191]. Recent OIS imaging findings support the release
of endogenous CGRP during CSD in rat neocortical
slices in a calcium-dependent manner [70]. Additionally,
three different CGRP receptor antagonists have shown
dose-dependent inhibitory effects on CSD events, suggesting the critical role of CGRP in CSD. If so, antagonists targeting central CGRP receptors could be useful
as anti-migraine agents [70].
Presently, gepants, a CGRP antagonist class of molecules, might offer a new non-vasoconstrictive approach
in the acute treatment of migraine. Four chemically unrelated CGRP receptor (CGRP-R) antagonists (olcegepant,
telcagepant, MK-3207 and BI 44370 TA) have displayed
efficacy in the treatment of migraine [192]. They have
fewer adverse effects, and act for a longer period than
triptans [193]. Their development has been slowed by a
liver toxicity when used as preventives. New CGRP-R antagonists, such as BMS-927711 and BI 44370 TA, are
currently under study. The latter has shown a dosedependent effectiveness as an acute anti-migraine drug in
a recent trial [194]. It remains to be established if these
molecules are effective in antagonizing MwA.
Other molecules of interest
Kynurenic acid, a derivative of tryptophan metabolism,
is an endogenous NMDA-R antagonist whose cerebral
concentrations can be increased by the systemic administration of its precursor L-kynurenine. L-Kynurenine
administration suppresses CSD in adult Sprague–Dawley
rats, most likely by increasing kynurenic acid levels in
the cortex. Females are more sensitive to the suppressive
effects of L-kynurenine, further highlighting the role of
sex hormones in migraine [195]. Ketamine, is a drug primarily used for the induction and maintenance of general anesthesia (usually in combination with a sedative)
and also for sedation in intensive care, analgesia (particularly in emergency medicine), and the treatment of
bronchospasm. Like other drugs of the same class, such
as tiletamine and phencyclidine, it is also used as a recreational drug.
From a pharmacologic point of view, ketamine is an
NMDA-R antagonist which, at high fully anesthetic level
doses, binds to μ-opioid receptors type 2, without agonist activity and to sigma receptors in rats [196,197]. The
drug also interacts with muscarinic receptors, monoaminergic receptors in descending pain pathways and
voltage-gated Ca2+ channels.
In earlier experiments, ketamine was shown to block
CSD in rats [56,198]. As for MK-801, tolerance to ketamine was observed after repeated injections. That is,
there was a gradual decline in their CSD blocking effects, which might have been due to some conformational changes at binding site(s) in NMDA-R [199].
Ketamine has been proposed as a putative treatment
option for severe and prolonged aura. The first study on
ketamine was carried out on 11 patients with severe,
disabling auras resulting from FHM. In five of these, the
drug reproducibly reduced the severity and duration of
Page 11 of 18
the neurologic deficits, whereas in the remaining 6 patients
no benefits were observed [200]. A recent double-blind,
randomized, parallel-group, controlled study including patients with prolonged aura, reported that intranasal 25 mg
ketamine, but not intranasal 2 mg midazolam, reduced aura
severity but not duration [201]. However, ketamine has several side effects, including hallucinations, elevated blood
pressure, dissociative anesthesia which strictly limit its use
in clinical practice.
Early anecdotal evidence indicated that propofol could
have been effective in terminating refractory migraine.
This rapidly acting water-insoluble non-barbiturate anesthetic agent has been recently reported to be effective on
CSD. Specifically, intraperitoneal propofol hemisuccinate
(PHS), a water-soluble prodrug of propofol, administered 15 min prior to KCl–induced CSD on the cortex
of mice, decreased the number of CSD deflections at
doses of 120 and 200 mg/kg without any effect on CSD
Figure 1 Mechanisms and structures involved in the pathogenesis of migraine with aura. CSD underlies aura symptoms. Initiation and
propagation of CSD are determined by massive increases in extracellular potassium ion concentration and excitatory glutamate. CSD biochemical
changes may trigger the activations of meningeal trigeminal endings and trigemino-vascular system, causing the headache phase. The latter can
occur through matrix metalloproteases activation that increases vascular permeability and also through the release of nociceptive molecules from
mastcells, including proinflammatory cytokines. The pain phase is due to peripheral and central sensitization of the trigeminal system, as well as
to the release of CGRP, both peripherally and centrally. CGRP is considered a key mediator in migraine and, together with NO, is the main
molecule responsible for vasodilation consequential to neurogenic inflammation. CGRP is also released from cortical slices during CSD and this
calcium-dependent release can mediate the dilatation of cortical arterioles. Periacqueduttal gray matter (PAG), locus coeruleus (LC), nucleus of
raphe magnum (NRM) are brainstem structures implicated in the processing of trigeminal pain. Functional and structural PAG abnormalities
occurring in migraineurs, contribute to the hyper-excitability of trigeminal nociceptive pathways. Functional alteration of noradrenergic nuclei of
the LC are believed to be involved in cortical vasomotor instability. Thus, dysfunction in brainstem pain-inhibiting circuitry may explain many
facets of the headache phases, even in MwA. CSD participates in this dysregulation by antagonizing the suppressive effect exerted by NRM on
the responses of trigeminal neurons. In this scenario, amitriptyline may influence CSD by preserving 5-HT and perhaps NA neurotransmission in
the cortex and/or inhibiting high-voltage-activated (HVA) Ca2+ channels and Ca2+ currents. Propranolol, on the other hand, may reduce neuronal
excitability and susceptibility to CSD via a beta-adrenergic blockage. Original brain template was designed by Patrick J. Linch, medical illustrator
and C. Carl Jeffe, MD, cardiologist.
amplitude [202]. In contrast, Kudo et al. failed to demonstrate any inhibitory effect of propofol on the frequency of KCl-induced CSD in rats [203]. This result
may have been due to the fact that a water-insoluble
formulation of propofol widely administered as a anesthetic in clinical setting was used. In above mentioned
study by Dhir et al. a water-soluble, non-commercially
available prodrug PHS, was tested [202]. Considering
these contrasting findings, it should be investigated
whether metabolites produced during PHS activation,
rather than propofol per se, can mediate an inhibitory
effect on CSD. Given the varying effects of anesthetics
on CSD, future studies will have to follow uniform protocols using only anaesthetics having a minimal impact
on CSD in order to guarantee reliability and comparability of the results [204].
Page 12 of 18
TRPV1 receptors play an important role in modulating
trigeminal sensory processing and for this have been
proposed as potential targets for migraine treatment.
The TRPV1 receptor antagonist, A-993610, has been
tested in a model of mechanically-induced CSD but it
failed to show any effects. This lack of effect should be
confirmed for other TRPV1 receptor antagonists in future research [205].
Finally, cannabis has been empirically used for centuries for both symptomatic and prophylactic treatment of
different types of headaches including migraine. Recent
findings have demonstrated a dose-dependent suppression of CSD amplitude, duration and propagation velocity after Delta9-tetrahydrocannabinol (THC) in rat
neocortical slices, which had been antagonized by cannabinoid CB1 agonist, WIN 55,212-2 mesylate but not by
Figure 2 Main potential targets of currently utilized preventive drugs and those under-investigation for migraine. The mechanisms
mediating CSD inhibition by several migraine preventive drugs are not completely understood. However, it is believed that this inhibitory action
is exerted by influencing ion channels and neurotransmission. In particular, topiramate and valproate are believed to exert their antagonizing
effects on CSD by blocking Na+ channels, inhibiting glutamatergic transmission and increasing GABaergic transmission. Topiramate, but not
valproate, can also block L-type Ca2+ channels. Lamotrigine has a marked suppressive effect on CSD, which may be due to its selective action on
Na+ channels. Furthermore, gabapentin is able to modulate the activities of P/Q- and, to a lesser extent, N-type high voltage-activated channels
located presynaptically at the cortical level and controls the neurotransmitter release, in particular that of glutamate. This effect and the
modulation of GABA-mediated transmission might explain CSD inhibition by gabapentin. Magnesium exerts an inhibitory effect on CSD by
interfering with NMDA receptor function and reducing glutamatergic transmission as well as regulating glutamate uptake by astrocytes and
modulating NO system in the cortex. The blockage of L-type Ca2+ channels may also account for the inhibitory effects of flunarizine on CSD (not
shown). The novel benzopyran compound tonabersat seems to inhibit CSD in experimental models and has shown some efficacy in the
prophylactic treatment of MwA. It is not known if tonabersat acts on gap-junctions in CNS, as it has already been demonstrated for trigeminal
ganglion. CSD inhibition can also be achieved by CGRP-R blockage due to CGRP antagonists, such as olcegepant. This class of drugs might exert
its inhibitory effects at both cortical neuronal and cerebrovascular levels.
cannabinoid CB2 agonist, JWH-133 [206]. These finding
suggests that cannabinoids might have inherent therapeutic effects for MwA but their known side effects and
risk of dependence must be properly weighed before
cannabinoid being considered for treatment.
Conclusions
A number of mechanisms have been shown to have a
role in fostering CSD wave initiation and propagation including: ion diffusion, membrane ionic currents, osmotic
effects, spatial buffering, neurotransmitter substances,
gap junctions, metabolic pumps, and synaptic connections (Figure 1).
In spite of this knowledge, CSD remains an enigma
necessitating further theoretical investigations.
Experimental findings to date suggest that chronic
daily administration of certain migraine prophylactic
drugs (topiramate, valproate, propranolol, amitryptiline,
and methysergide) dose-dependently suppress CSD. At
a molecular level, targets of the inhibitory effects of
antiepileptic drugs tested exert their inhibitory effects
on CSD targeting Ca2+ and Na2+ channels, as well as
glutamatergic and/or GABAergic transmissions based
on their mechanisms of action. Additionally, the antiepileptic drug lamotrigine has a proven suppressive
effect on CSD, which could explain its selective action
on migraine aura. Preservation of 5-HT, and maybe
even NA neurotrasmission in the cortex, could in some
way be responsible for the effects of amitryptiline on
CSD, while beta-adrenergic blockage by propranolol
might facilitate a reduction in cortical neuronal excitability and thus in turn reduce susceptibility to CSD
(Figure 2).
Mechanisms of action for some novel molecules are
currently under investigation. To date, it has been found
that CGRP-R antagonists exert a dose-dependent inhibitory effect on CSD. For this reason, it can be hypothesized that CGRP plays a determining role in CSD and its
modulation may be effective for the preventive treatment of MwA (Figure 2). Additionally, tonabersat, a
novel benzopyran compound, has been reported to exert
an inhibitory action on CSD and on neurogenic inflammation in animal models of migraine. These inhibitory
actions might be an effect of the blockage of neuronalglial cell gap-junctions, as it has only been demonstrated
to be for the trigeminal ganglion. The most significant
anti-migraine action on the part of tonabersat seems to
derive from its inhibitory action on CSD. In fact, clinical
trials on tonabersat have shown its preventive effect on
MwA attacks but not on MwoA attacks.
Based on recent clinical findings, intranasal ketamine,
has been shown to be effective in CSD models, and
therefore it has been administered for cases of migraine
with prolonged aura, but its use is limited due to its
Page 13 of 18
relevant side effects. Noteworthy, the effectiveness of ketamine adds to the existing evidence that glutamatergic
transmission plays a role in human aura. The proven
capacities of other molecules (i.e. amiloride) in blocking
CSD suggests that they might also have a role in preventing
MwA.
Further investigations on molecules with evidence of
targeting CSD not only would lead to a better understanding of the underlying mechanisms for CSD, but
also supply meaningful insight into their potential roles
in MwA, as well as other diseases, such as epilepsy, ischemic stroke, intracranial hemorrhage, and trauma,
where CSD is thought to be a pathogenic mechanism.
Additional file
Additional file 1: Table S1. A summary of the most relevant studies on
CSD experimental models regarding the effects of currently used drugs
and drugs under investigation for migraine prophylaxis.
Abbreviations
5-HT: 5-hydroxytryptamine, serotonin; AMPA: Alpha-amino-3-hydroxy-5methyl-4-isoxazole propionate; AMPA-R: Alpha-amino-3-hydroxy-5-methyl-4isoxazole propionate receptor; ATP: Adenosine-5'-triphosphate;
ATP1A2: ATPase, Na+/K+ transporting, alpha 2 (+) polypeptide; BBB:
Blood–brain barrier; BOLD: Blood oxygenation level dependent; Ca2
+
: Calcium; CACNA: Ca2+ channel alpha 1A; CADASIL: Cerebral autosomal
dominant arteriopathy with subcortical infarcts and leukoencephalopathy;
CBFLDF: Cortical blood flow laser Doppler flowmetry; CGRP: Calcitonin
gene-related peptide; COX: Cyclooxygenase; CSD: Cortical spreading
depression; CSF: Cerebrospinal fluid; DC: Direct current; DEA:
(N,N-diethylamino)-diazenolate-2-oxide; DHE: Dihydroergotamine;
EEG: Electroencephalographic; ET-1: Endothelin-1; FHM: Familial Hemyplegic
migraine; fMRI: Functional magnetic resonance imaging; GABA:
Gamma-aminobutyric acid; GABA-R: Gamma-aminobutyric acid receptor;
Gd-DTPA: Gadolinium-diethylenetriaminepenta-acetic acid; HMGB1:
High-mobility group box 1; IL-1β: Interleukin-1 β; iNOS: Inducible NO
synthase; K+: Potassium; KCl: Potassium chloride; KI: Knockin; L-NAME:
L-NG-Nitroarginine Methyl Ester; MEG: Magnetoelectroencephalography; Mg2
+
: Magnesium; MMP(s): Metalloprotease(s); MR: Magnetic resonance;
MwA: Migraine with aura; MwoA: Migraine without aura; Na+: Sodium;
NA: Noradrenalin; NMDA-R: N-methyl- D-aspartate receptor; NO: Nitric oxide;
NOLAG: NO-nitro-L-arginine; NOS: NO synthase; OIS: Optical intrinsic signal;
Panx1: Pannexin1; PET: Positron Emission Tomography; PHS: Propofol
hemisuccinate; PLC: Phospholipase C; SCN1A: Sodium channel, voltage-gated
, type I, alpha subunit; SD: Spreading depression; SPECT: Single-photon
emission computed tomography; THC: Tetrahydrocannabinol;
TPM: Topiramate; TRPV1: Transient receptor potential cation channel
subfamily V member 1; TTX: Tetrodotoxin; WMLs: White matter lesions.
Competing interests
All authors equally contributed to the conception and drafting of the
manuscript. PC, CA, and PS critically revised the manuscript for important
intellectual content. PS, CC, and AT also contributed in the preparation of
figures and table. All authors read and approved the final manuscript.
Acknowledgements
We thank Mr. Thomas Kilcline for editing the English. This Review Article will
be presented at the XXVII National Congress of the Italian Society for the
Study of Headaches – 26–28 September 2013.
Author details
1
Neurologic Clinic, Department of Public Health and Medical and Surgical
Specialties, University of Perugia, Ospedale Santa Maria della Misericordia,
Sant'Andrea delle Fratte, 06132, Perugia, Italy. 2Neurology II, Department of
Neuroscience, University of Torino, Ospedale Molinette, Via Cherasco 15,
10126, Turin, Italy. 3Fondazione Santa Lucia I.R.C.C.S., Via del Fosso di Fiorano,
00143, Rome, Italy. 4Neurovascular Research Lab., Department of Radiology,
Stroke Service and Neuroscience Intensive Unit Department of Neurology
Massachusetts Hospital, Harvard Medical School, 02115, Boston, MA, USA.
5
Neurologic Clinic, Ospedale S. Eugenio, Piazzale Umanesimo, 00144,
Rome, Italy.
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doi:10.1186/1129-2377-14-62
Cite this article as: Costa et al.: Cortical spreading depression as a target
for anti-migraine agents. The Journal of Headache and Pain 2013 14:62.
Lionetto et al. The Journal of Headache and Pain 2013, 14:55
REVIEW ARTICLE
Open Access
The omics in migraine
Luana Lionetto1*, Giovanna Gentile2, Elisa Bellei3, Matilde Capi1, Donata Sabato1, Francesco Marsibilio4,
Maurizio Simmaco1,2, Luigi Alberto Pini5 and Paolo Martelletti4,6
Abstract
The term omics consist of three main areas of molecular biology, such as genomics, proteomics and metabolomics.
The omics synergism recognise migraine as an ideal study model, due to its multifactorial nature. In this review, the
plainly research data featuring in this complex network are reported and analyzed, as single or multiple factor in
pathophysiology of migraine. The future of migraine biomolecular research shall be focused on networking among
these different and hierarchical disciplines. We have to look for its Ariadne’s tread, in order to see the whole
painting of migraine molecular biology.
Keywords: Genomics; Proteomics; Metabolomics; Migraine
Review
The omics synergism
Personalized Medicine aims to evaluate the individual
profile of the subject and according to it to proceed to a
specific therapeutic strategy.
This strategy is made possible by the shift from a hierarchical to a holistic vision of the biological system. In the
first case the control of the biological system is generated
from the genome up to the lower hierarchical levels represented by proteomics and metabolomics; in the second
case, the interactions among these disciplines are evaluated
in a synergic way (Figure 1). This new approach is certainly
the most appropriate for the understanding of the physiopathology of migraine that, as a multifactorial disease, can
only be assessed through the integrated study of the omics
sciences. Nowadays, it is evident that migraine patients
react differently to given drugs, but the exact mechanism
has not yet been clarified. In this way, genomic and proteomic research aimed to the identification of molecular
pathways involved in drug action is of pivotal importance,
in order to focus attention of pharmacogenomics studies
on the right targets [1].
Genomics
In an effort to identify genetic variants involved in migraine
risk and influencing the appropriate pharmacological
1
Sant’Andrea Hospital, Advanced Molecular Diagnostics Unit, Via di
Grottarossa 1035 – 1039, Rome 00189, Italy
treatments, many genomic studies have been performed in
the last years. Due to neurological origin of migraine,
some researchers have studied receptors involved in mediation of neuronal activities. Chen et al. [2] characterized
one polymorphism in GABRG2 gene encoding the GABAA
receptor gamma-2-subunit (rs211037) on a migraine case–
control population of 546 subjects. No significant correlation was found. Carreno et al. [3] studied the transient
receptor potential (TRP) superfamily of non-selective cationic channels accountable of multimodal sensory and pain
perception, central and peripheral sensitization, and regulation of calcium homeostasis, relevant steps of migraine
physiopathology. They carried out a migraine-control genetic association study genotyping 149 SNPs covering 14
TRP genes. Consistent results were obtained for TRPV3
rs7217270 in the Migraine with aura group and TRPV1
rs222741 in the overall migraine group, suggesting the involvement of the vanilloid TRPV subfamily of receptors to
the genetic susceptibility to migraine [4]. Another gene
analyzed is the calcium-activated potassium ion channel
gene (KCNN3) involved in neural excitability and in migraine susceptibility. Cox et al. [5] performed a gene-wide
SNP genotyping in a high-risk genetic isolate from Norfolk
Island, characterized by high percentage of migraineurs. A
total of 85 SNPs spanning the KCNN3 gene were genotyped in a sub-sample of 285 related individuals. Only four
intronic SNPs displayed gene-wide significance: rs4845663,
rs7532286, rs6426929 and rs1218551, with the minor allele
in each case conferring protection against migraine
risk. Using the same population, Cox et al. [6] carried out
© 2013 Lionetto et al.; licensee Springer. This is an Open Access article distributed under the terms of the Creative Commons
Page 2 of 6
AMBP, CYTC, IGKC,
ITH4, UROM, ZAZG
ADARB2, EDNRA,
GABRG2, GNB3, GRM7,
HTR7, KCNN3, MTHFR,
OPRM1, TRPV,
BDNF, CRP, Lactate,
NAA, PCT, sCD40L
THE “OMICS”
SYNERGISM
IN MIGRAINE
Figure 1 Framework of the multiple interactions taking place in the migraine omics scenario.
another pedigree-based genome-wide association (GWA)
study found a significant statistical association with SNP
rs4807347 in ZNF555 gene, coding for a zing finger protein.
This result has been confirmed in unrelated cohort with
more than 500 patients affected by migraine. They also
found 4 SNPs in neurotransmitter-related genes (ADARB2,
GRM7 and HTR7 genes) suggesting an alteration in the serotoninergic pathway. Maher et al., characterized the entire
X chromosome in an association study on the Norfolk
population and provides evidence for the SNP rs102834 in
the UTR of the HEPH gene, which is involved in iron
homeostasis [7,8]. Ligthart et al. [9] performed a metaanalysis of GWA studies for migraine in six populationbased European cohorts consisting of 2446 cases and 8534
controls. A total of 32 SNPs showed marginal evidence for
association to migraine and the best result was obtained
for SNP rs9908234 in the nerve growth factor receptor NGFR- gene but those results were not replicated in other
cohorts. Besides, they found a modest gene-based significant association between migraine and the rs1835740 near
the metadherin gene, but further replication studies did not
validated this association [10,11].
The opioid system plays an important role in various biological functions including analgesia, drug response and
pain reduction. Menon et al. [12] studied the influence of
polymorphism in gene coding for the μ-opioid receptor
highlighting the association between the OPRM1 A118G
SNP and head pain severity in a clinical cohort of 153 female migraineurs with aura. In particular, G118 allele carriers were more likely to be high pain sufferers compared
to homozygous carriers of the A118 allele.
Migraine is a complex condition that may in part be related by endothelial and cerebrovascular disruption [13].
Some studies showed that supplementation of B vitamins
lowered homocysteine levels and reduced the occurrence of
migraine in women [14]. Besides, polymorphisms in genes
coding for key player enzymes in the folate metabolic pathway have been investigated in order to define a relation
with the pathology and its treatment. The C677T variant in
the methylenetetrahydrofolate reductase (MTHFR) has
been associated with increased risk of migraine with aura
[15,16]. The C allele carrier is also related to higher reduction in homocysteine levels, severity of pain in migraine
and percentage of high migraine disability in patient
supplemented with B vitamins [14]. The same approach
has been adopted for the polymorphism A66G in methionine synthase reductase gene (MTRR): the A allele carriers
showed a better response to B vitamin administration
[14]. Roecklein et al. [17] performed a haplotype analysis
of migraine risk and MTHFR, MTRR and methionine synthase (MTR), including subjects with non-migraine headache (N = 367), migraine without aura (N = 85), migraine
with aura (N = 167), and no headache (N = 1347). Haplotype analysis suggested an association between MTRR
haplotypes and reduced risk of migraine with aura.
Miao J et al. [18] performed a meta-analysis to determine
if polymorphisms in genes linked to the vascular system
could be related to migraine. They focused their attention
on the receptor for endothelin-1, (EDNRA) known as a potent vasoconstrictor investigating the EDNRA -231G > A
SNP. Three studies were included in their meta-analysis for
a total of 440 migraineurs, 222 subjects with tension-type
headaches (TTHs) and 1323 controls. They found statistical difference between migraineurs and controls with AA
genotype vs. AG + GG, suggesting a potential association
of -231G > A SNP and migraine. These data suggest that
individual SNPs will provide only a small piece of a much
larger puzzle composed by a variety of (un) know clinical
(phenotypic) information.
Gentile et al. [19] genotyped panel of SNPs involved in
triptans pharmacokinetics and pharmacody-namics in a
chronic migraine (CM) population. In particular they
studied the 30 bp VNTR in MAO A (monoamine oxidase
A) promoter, CYP 1A2 *1C and *1 F, CYP3A4 *1B and
C825T SNP in the gene coding the G protein b3 subunit
(GNB3). A significant association with CM was found for
the long allele of monoamine oxidase A 30 bp VNTR and
CYP1A2*1 F variant. The same authors performed an analysis of the association between genotypic and allelic frequencies of the analyzed SNPs and the grade of response
to triptan administration: a significant correlation for
MAOA uVNTR polymorphism was found. Further stratification of patients in abuser and non-abuser groups revealed a significant association with triptan overuse and,
within the abusers, with drug response to the CYP1A2*1 F
variant [20].
Proteomics
With the completion of the human genome project in
2002, it has become clear that organism complexity is generated more by a complex proteome than by a complex
genome.
Actually, the term “clinical proteomics” defines proteomic technologies employed to examine clinical samples
[21]. The available genomic data have now been translated to proteomics, making the discovery of biomarkers
increasingly feasible. With its high-throughput and
Page 3 of 6
unbiased approach to the analysis of variation in protein
expression patterns (actual phenotypic expression of genetic variation), proteomics promises to be the most suitable platform for biomarker discovery. This hopefulness is
based on the increasing advances and ability of proteomic
technologies to identify thousands of proteins and peptides in complex biological tissues and biofluids, such as
plasma, serum and urine [22]. In the past decade, many
novel proteomic technologies were emerged and applied
to several biological systems for the understanding of cellular activities, disease development and physiological responses to therapeutic interventions and environmental
perturbations [23]. One of such emerging field is the application of proteomic technologies to toxicological research,
which has given rise to a new area called toxicoproteomics
[24]. Drug induced toxicity represents a significant problem
in healthcare delivery, therefore the early detection of organ
toxicity may provide great benefits to patients, preventing
further onset of adverse events and complications of disease
management. Incidences of toxicity in liver, heart, brain,
kidney and other organs have been reported with the use of
different therapeutic drugs. In particular, various epidemiologic investigations proved that different drug types could
cause nephrotoxicity, especially in chronic patients.
In this regard, Bellei and co-authors reported two proteomic studies in which they analysed the urinary proteome
of medication-overuse headache (MOH) patients, in comparison with healthy non-abuser individuals as control,
with the purpose to identify possible differences in excreted proteins induced by the excessive consumption
of antimigraine drugs, that could lead to nephrotoxicity
[25,26]. Comparing the proteomic profiles of patients and
controls, they found a significantly different protein expression at various MW levels, especially in the NSAIDs
group, in which six proteins over-secreted from kidney
were strongly correlated with various forms of kidney
disorders: uromodulin (UROM), alpha-1-microglobulin
(AMBP), zinc-alpha-2-glycoprotein (ZAZG), cystatin C
(CYTC), Ig-kappa-chain (IGKC), and inter-alpha-trypsin heavy chain H4 (ITIH4). These preliminary results
have allowed to define the urinary protein pattern of
MOH patients, that was found to be correlated to the
abused drug. While adverse effects from long-term triptans
use are unknown, the overuse of analgesics may cause wellknown unwanted events, including liver dysfunction,
gastrointestinal bleeding, addiction and renal insufficiency
[27]. Moreover, a recent review concerning the epidemiology of drug-induced disorders has demonstrated that
medication overuse could lead to nephrotoxicity and potential renal damage [28]. Currently, the most pertinent application in nephrotoxicology is the proteomic analysis of
urine. In recent years, it has proposed a broad range of
urinary enzymes and proteins as possible early biomarkers
of drug-induced nephrotoxicity [29-31].
Metabolomics
While the genomics and proteomics suggest a possible
mode of operation of the system, metabolomics gives the
actual representation of the system. In agreement with the
multifactorial nature of the disease, the studies conducted
to date relate to different classes of analytes. In fact, several different mechanisms, such as neuro-inflammatory,
neurological and cerebrovascular, have so far been suggested in migraine pathophysiology [32].
Whereas the presence of inflammatory processes during
migraine attacks, serum levels of different proinflammatory
molecules have been investigated. Several studies have
found elevated levels of C-Reactive Protein (CRP), a marker
of chronic low-grade inflammation, in patients with migraine [33,34]. Also the procalcitonin levels were investigated as indicators of inflammation in migraine patients
with and without aura. Turan et al. found significantly high
levels of PCT in patients with migraine during the attack
compared to the interictal period (0.0485 vs 0.0298 ng/ml)
[35]. An interesting fact was found by Guldiken et al. about
the increase of soluble CD40 ligand (sCD40L). In this study,
sCD40L amount was higher in the subgroup of migraineurs
with aura than in those without aura and in rare attacks rather than in the frequent ones. In both comparisons the difference in the levels of sCD40L was not significant but
these data may be related to the association of migraine
with cardiovascular diseases [36].
Also the correlation between migraine and molecules of
pain was investigated. Several observation suggested a relationship between low serum levels of vitamin D and higher
incidence of chronic pain [37,38]. However, in a large
cross-sectional study, Kjaergaard et al. have found that low
level of serum vitamin D were associated with nonmigraine type of headache [39]. Further studies should be
conducted to clarify the potential association of vitamin
D and migraine pain. Brain-derived neurotrophic factor
(BDNF) is a neurotrophin associated with pain modulation
and central sensitization [40]. Fisher et al. have demonstrated that in migraineurs, BDNF was significantly
elevated during migraine attacks (31.24 ± 9.31 ng/ml) compared with headache-free periods (24.50 ± 9.17 ng/ml),
tension-type headache (20.97 ± 2.49 ng/ml) and healthy
controls (21.20 ± 5.64 ng/ml) [41]. This study, showing a
correlation between migraine and BDNF, supports the hypothesis that BDNF has a role in the pathophysiology of
migraine. The results are in agreement with a pilot study
of Tanure et al. [42].
However, NMR or mass spectrometry techniques are
able to provide, with an acceptable probability, the description of the current biochemical state of an organism.
The development of proton magnetic resonance spectroscopy (1H-MRS) has been used to assess noninvasively the
metabolic status of human brain [43]. Several studies
have employed 1H-MRS achieving numerous results for
Page 4 of 6
metabolites including N-acetylaspartate (NAA), as a marker
of neuronal functioning [44], choline (Cho), as a marker for
membrane turnover [45], total creatine (tCr) and lactate,
for energy metabolism [46], and myo-inositol (a glial
marker) [47]. With the exception of NAA, the results
obtained for these molecules are heterogeneous and sometimes contradictory. Indeed the levels of NAA are also increased in the serum [48]. In our opinion, to date, it has
not been identified molecules that can be used as a marker
for migraine.
Undoubtedly, spectroscopy Nuclear Magnetic Resonance and Mass Spectrometry represent the most powerful
and most widely used techniques for the simultaneous
analysis of different molecules, allowing together with
functional genomics and proteomics to open new roads
knowledge in the pathophysiology of migraine. We can
suppose that also the progression of the disease may be
evaluated by a therapeutic metabolite monitoring approach [49].
Conclusions
A conclusive scene of omics network in migraine pathophysiology is still far to be sharpened. We know a lot of
genomics, but less of proteomics and metabolomics of migraine. However, there are numerous scientific evidences
assigning an increasingly dominant role to external factors, environmental or behavioural, that interact with the
pathophysiology of migraine. Although genomics represents the hierarchical basis of migraine mechanism, proteomics and metabolomics mirror its real image. We have
to continue to study the connections among omics in
order to unsnarl the Ariadne’s tread of migraine.
Abbreviations
SNP: Single nucleotide polymorphism; CM: Chronic migraine;
MOH: Medication-overuse headache; MW: Molecular weight;
NSAIDs: Nonsteroidal anti-inflammatory drugs; PCT: Procalcitonin;
NMR: Nuclear magnetic resonance.
Competing interests
All authors declared no competing interest related to the content of this
manuscript.
LL, GG, EB contributed equally in the preparation of the manuscript. LAP and
PM conceived the study, provided overall and oversaw the implementation
of the study. All the authors approved the final draft of the manuscript. No
external assistance in selection, writing or reviewing data has been utilized.
Author details
1
Sant’Andrea Hospital, Advanced Molecular Diagnostics Unit, Via di
Grottarossa 1035 – 1039, Rome 00189, Italy. 2NESMOS Department, Sapienza
University of Rome, Rome, Italy. 3Department of Diagnostic Medicine, Clinic
and Public Health, University of Modena and Reggio Emilia, Modena, Italy.
4
Regional Referral Headache Centre, Sant’Andrea Hospital, Rome, Italy.
5
Inter-Department Headache and Drug Abuse Centre, University of Modena
and Reggio Emilia, Modena, Italy. 6Department of Clinical and Molecular
Medicine, Sapienza University of Rome, Rome, Italy.
Received: 6 June 2013 Accepted: 22 June 2013
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doi:10.1186/1129-2377-14-55
Cite this article as: Lionetto et al.: The omics in migraine. The Journal of
Headache and Pain 2013 14:55.
Bellini et al. The Journal of Headache and Pain 2013, 14:79
REVIEW ARTICLE
Open Access
Headache and comorbidity in children and
adolescents
Benedetta Bellini1, Marco Arruda2, Alessandra Cescut1, Cosetta Saulle1, Antonello Persico3, Marco Carotenuto4,
Michela Gatta5, Renata Nacinovich6, Fausta Paola Piazza7, Cristiano Termine8, Elisabetta Tozzi9,
Franco Lucchese10 and Vincenzo Guidetti1*
Abstract
Headache is one of the most common neurological symptom reported in childhood and adolescence, leading to
high levels of school absences and being associated with several comorbid conditions, particularly in neurological,
psychiatric and cardiovascular systems. Neurological and psychiatric disorders, that are associated with migraine, are
mainly depression, anxiety disorders, epilepsy and sleep disorders, ADHD and Tourette syndrome. It also has been
shown an association with atopic disease and cardiovascular disease, especially ischemic stroke and patent foramen
ovale (PFO).
Keywords: Headache; Comorbidity; Children; Adolescents
Review
Introduction
Headache is one of the most common somatic complaints in children and adolescents [1]. The prevalence is
estimated to be 10–20% in the school-age population,
with progressive increase with age, up to values about
27–32% at the age of 13–14 years (considering monthly
crisis), 87–94% (considering the presence of headache at
least once a year).
Until puberty, it hasn’t been seen gender differences
(with a slight male predominance), at a later stage it has
been noted an increase among females with a ratio of
2.5:1, except that lasts into adulthood [2,3]. Prevalence of
migraine in the pediatric population ranges from 3,3% to
21,4% and it increases from childhood to adolescence [4].
Children and adolescents with headache, and in particular migraine, have worse outcomes, compared to those
without migraine, as far as quality of life and school attendance [5] are concerned and they are more likely to
have other somatic symptoms (e.g. abdominal pain) [6],
anxiety and mood disorders, such as depression [7,8]. Due
to its negative impact, on the World Health Organization’s
ranking of causes of disability, headache disorders are
1
Department of Pediatrics and Child Neuropsychiatry, Sapienza University of
Rome, Via Dei Sabelli 108, Rome, Italy
brought into the 10 most disabling conditions for the two
genders, and into the five most disabling for women [9].
In fact, primary headaches, and in particular migraine,
is associated with several comorbid conditions.
Comorbidity is the presence of coexisting additional
condition in a patient with particular disease index, or
the association of non-random two disorders [10].
In children and adolescents, headache and migraine are
commonly associated with various diseases, such as psychiatric and neurological comorbidity, in particular depression and anxiety, epilepsy, sleep disorders, ADHD. It
also has been shown an association with atopy, cardiovascular disease, especially ischemic stroke and PFO [11-14].
Headache and psychiatric disorders: anxiety and
depression
Since past decades, numerous population- and hospitalbased studies have revealed a relationship between migraine or headache and psychopathology in children
[15-17]. Depression is more prevalent in headache patients than in the headache-free population [18]. Recently, Pavone et al. (2012) [19] studied the frequency of
some comorbidities in primary headaches in childhood.
They enrolled two hundred and eighty children (175
males and 105 females), aged 4 to 14 years, affected by
primary headaches. In direct interviews, parents and
children gave information about the association of their
© 2013 Bellini et al.; licensee Springer. This is an Open Access article distributed under the terms of the Creative Commons
headaches with different conditions. The Authors found
a significant association of primary headache with anxiety and depression.
Migraine is probably the best studied pain disorder in
the context of comorbidity with anxiety and/or depression [20]. In a psychiatric setting Masi and collegues
[21], in an exploratory study, examine the prevalence of
somatic symptoms in a sample of 162 Italian children
and adolescents from emotional and/or behavioral disorders. The sample was divided according to gender (96
males, 66 females), age (70 children younger and 92 adolescents older than 12 years), and psychiatric diagnosis
(Anxiety, Depression, Depression/Anxiety, Other). The
Authors observed that headache was the most frequent
somatic symptom in children and adolescents referred
for anxiety, depression and behavioral disorders, with a
prevalence of females.
Cahill and Cannon [22] defined migraine as a subtype
of headache of particular interest for psychiatrists, as
they found a linkage between migraine, psychiatric disorders (mainly anxiety and depression), personality traits
and stress.
The nature of the relationship between migraine and
anxiety is still not clear and we do not know if that relationship is specific to migraine or related to attack frequency [23], even if some evidence confirms that linkage
[24]. It is well known that the risk of migraine is higher in
patients with comorbid anxiety and/or depression [25]
and that anxiety predicts the persistence of migraine and
tension-type headache [26]. While only phobic disorder
seems to be a predictor of the onset of migraine [27], anxiety, more than depression, predicts long-term migraine
persistence, headache-related disability and reduces perceptions of efficacy with acute treatment [26,28]. Phobic
disorder is also associated with more frequent and longer
migraine attacks, particularly among males [29].
The increased risk of anxiety disorder in children and
adolescents with migraine, compared to patients without migraine, is noticed in many studies. Arruda and
Bigal [5], in their population-based study, confirmed
the higher prevalence of anxious symptoms in children
and adolescents with migraine.
In a meta-analysis of 10 studies published between
1996–2011 (406 patients, mean age 11,6 ± 2,3 ys) Ballottin
and collegues [23] found that migraine children show
more psychological symptoms, detected by using Child
Behavior Checklist (CBCL), than healthy controls. They
also emphasized the need for studies to compare migraine
children with children affected by other chronic pain in
order to understand whether the psychopathological profile is migraine- related or chronic pain-related.
Some studies suggest that psychiatric disorders might
not specifically relate to migraine, but to chronic illness in
general: comparing migraine and chronic non-headache
Page 2 of 11
pain samples, Cunningham [30] found no difference in
anxiety and depression levels between the two groups with
chronic pain, with respect to pain-free controls. Another
study [6] comparing headache patients and patients with
recurrent abdominal pain did not find differences by the
psychological point of view (internalizing vs. externalizing
disorders). One of the hypotheses for the comorbidity is
that common genetic and/or environmental risk factors
may underlie both migraine and psychiatric disorders [27].
Gonda and collegues [31] found that high levels of
anxiety and migraine were associated with specific gene
polymorphism, supporting the hypothesis of a shared
genetic linkage between these two conditions.
Instead other studies show no correlation between migraine, anxiety and depression, as Kowal and Pritchard
[32] that studied twenty-three volunteer subjects, compared with 23 (matched) control subjects on self and parental ratings of anxiety, depression, shyness-sensitivity,
sleeping difficulties, perfectionism, psychosomatic problems (unrelated to headache), other behavioural disturbances, major life stress events and parental expectations
(i.e. achievement orientation). Results indicated that the
headache children showed significantly higher shynesssensitivity, psychosomatic problems and behavioural disturbances and significantly lower parental expectations
than the control group children. No other differences were
found. While none of the variables were predictive of the
frequency or intensity of head pain, measures of anxiety,
perfectionism, and life stress events contributed significantly to the prediction of the severity of head pain. Also
the study by Laurell et al. [33] show conflicting data. The
Authors interviewed 130 schoolchildren and their parents
and showed a predominance of comorbidity with other
pains rather than psychological and social problems.
In addition to migraine, Chronic daily headache (CDH),
defined as 15 or more headaches per month, is associated
with increased functional disability and impaired quality
of life [34]. Functional disability in children with recurrent
headache has also been shown to be a risk factor for psychiatric conditions such as depression [35]. While research
in the area of adult headache has made great strides, little
is known about the prevalence of psychiatric comorbidity
in children with chronic headache conditions. Some researchers have suggested that children with headaches are
at increased risk for psychological adjustment problems,
including symptoms of anxiety and depression [36,37]. A
single published study of a large sample of school-children
in Taiwan that did utilize standardized interviews, written
by Wang SJ et al. [15], indicated that nearly half (47%) of
the sample of 122 children (out of more than 7000 children) who reported chronic headaches had one or more
psychiatric disorders, primarily mood or anxiety disorders.
Two years later the same Authors identified a higher frequency of suicidal ideation in younger adolescents with
migraine with aura or high headache frequency. These associations were independent of depressive symptoms [38].
Parisi P. [39] stressed that antidepressant and antiepileptic
usage in adolescents was potentially associated with an increasing suicide risk and that these two medications are
frequently used in adolescents with migraine. Moreover,
Wang SJ et al. [38] did not exclude the diagnosis of early
onset juvenile bipolar disorders (JBD). Although the onset
of JBD before the age of 10 is rare and the first manifestation occurs most frequently between the ages of 13 and
15, the diagnosis of JBD is more difficult in children and
adolescent populations vs the adult population due to
varying symptoms. For example, in children and adolescents, dysphoria is more likely than a euphoric or depressive mood. Asymptomatic intervals rarely exist, yet rapid
cycling prevails. In addition, it has been shown that antidepressants in JBD-affected children can have severe adverse effects, particularly the amplification of suicidal
ideation. Parisi P., in this respect, indeed, stressed that the
possibilities of manic switching and occurrence of suicidal
ideation have to be closely monitored when clinicians prescribe antidepressants for treatment of either migraine or
depression in adolescents.
Slater et al. (2012) [34] assessed comorbid psychiatric
diagnoses in youth with CDH and examined relationships
between psychiatric status and CDH symptom severity, as
well as headache-related disability. Results showed that
29.6% of CDH patients met criteria for at least one current
psychiatric diagnosis. Of those, anxiety disorders were the
most common (16.6% of the sample). Mood disorders, on
the other hand, were less prevalent (9.5%). The most common anxiety diagnoses were specific phobia (14 of 169),
generalized anxiety disorder (10 of 169) and obsessive
compulsive disorder (eight of 169). Of the 16 participants
with a depressive disorder diagnosis, eight had major depressive disorder, four had a diagnosis of dysthymia, and
four met criteria for other mood disorders.
Moreover, 34.9% met criteria for at least one lifetime
psychiatric diagnosis. No significant relationship between psychiatric status and headache frequency, duration, or severity was found. However, children with at
least one lifetime psychiatric diagnosis had greater functional disability and poorer quality of life than those
without a psychiatric diagnosis.
It is, furthermore, important to consider the impact of
headache on family life and dynamics.
Children with migraine seem to be characterized by a
higher prevalence of familial headache recurrence and
parents’ psychiatric disorders than children with other
headache subtypes [40]. Only in the case of migraine,
higher familial headache recurrence correlates with
higher psychiatric comorbidity in children.
The association between migraine and anxiety leads us
to think of the need for an integrated, medical and
Page 3 of 11
psychological, approach to the taking care of these young
patients and their families.
Headache and sleep disorders
The existence of an intimate relationship between sleep
and headache has been recognized for over a century,
although the nature of this association is still enigmatic.
It is known as sleep deprivation, or, on the contrary, a
prolonged sleep, can favor the onset of headache, in
particular migraine attack [41]. On the other hand, in
many cases, and especially in children, sleep, spontaneous or induced by hypnotics, constitutes the decisive
factor for resolution of a migraine attack [42]. Also
melatonin seems to effectively reduce the number, intensity and duration of headache attacks per month in
the children but the mechanism remains unclear, even
though there is much evidence to support the analgesic
and anti-inflammatory effects of melatonin [43].
Headaches are known to occur during sleep, after
sleep, and in relationship with various sleep stages.
Nocturnal migraine attacks can be a result of disrupted
sleep, and primary headaches may also emerge during
nocturnal sleep, causing sleep disruption [44].
About the variety of phenomena that can disrupt the
sleep macrostructure and can impact its restorative function, the periodic limb movements disorder (PLMd)
can be considered as the most powerful. No studies are
known about the role of PLMd in the pathophysiology
of migraine in children. Esposito et al. [45] assess the
prevalence of PLMd and migraine and their relationship with disability and pain intensity in a pediatric
sample, referred for migraine without aura by pediatricians. This study indicates the potential value of the
determination of the PLMd signs, and the importance
of the nocturnal polysomnography evaluation in children affected by migraine, particularly when the clinical and pharmacological management tend to fail in
the attacks control.
Children who suffer from headache have usually a high
rate of sleep difficulties, such as insufficient sleep, cosleeping with parents, difficulties falling asleep, anxiety
related to sleep, restless sleep, night waking, nightmares,
and fatigue during the day [46]. Furthermore, an higher
prevalence of parasomnias in children, particularly of
sleepwalking, bedwetting and pavor, has been documented in migraine patients than in controls [47,48].
The prevalence of sleepwalking in migraineurs seems
to swing between 30% and 55% [49]. Different studies
propose a model of interaction between headache and
sleep [50]. Table 1 shows a model combining clinical
data and experimental evidence.
To date, there are no epidemiological studies to investigate systematically specific comorbidity between headache
and the spectrum of sleep disorders. The lack of such
Table 1 Models of relations between sleep and headache
1 Sleep as trigger factor for headache (excessive, reduced or disrupted,
increased deep sleep)
2 Sleep as relieving factor for headache
3 Sleep disturbance as cause of headache (es. sleep apnea)
4 Headache as cause of sleep disturbance (es. attacks occurring
during sleep)
5 Sleep disorders in headache patients (parasomnias, sleepwalking)
6 Sleep related headache:
a) Temporal relationship (during or after sleep)
b) Sleep stage relationship:
1. REM sleep (migraine, cluster headache, chronic paroxysmal
hemicrania)
2. Slow-wave sleep (migraine)
7 Headache/sleep association:
a) Intrinsic origin (modulation through the same neurotransmitters)
b) Extrinsic origin (i.e. fibromyalgia syndrome)
c) Reinforcement (bad sleep hygiene)
studies is compounded by the difficulties of classification
of the two disease entities.
Among the epidemiological studies carried out so far,
who have analyzed the relationship between sleep and
headache, there is a European study, performed by
18,980 telephone interviews. This study showed the
presence of chronic headache in the morning in 7.6% of
subjects [51]. These, also, than non-sufferers, had more
frequently sleep disorders including insomnia, circadian
rhythm disorders, snoring, sleep-related breathing disorders, frightening dreams and other dyssomnia.
Headache and epilepsy
Migraine and epilepsy are the commoner brain diseases and comorbidity of these conditions is well
known. This comorbidity is most frequent in childhood
and adolescence.
The International Classification of Headache Disorders
(ICHD-2) committee recognizes three nosographic entities concerning the relationship between epilepsy and
headache: migralepsy, hemicrania epileptica, post-ictal
headache [52].
Recent scientific evidences on the ictal epileptic headache have demonstrated that the ‘migralepsy’ concept is
exceptional or even it does not exist [53]. On the other
hand, migralepsy is neither included in the currently used
International League Against Epilepsy (ILAE) seizure classification nor in the recent recommendations of the ILAE
Commission on Classification and terminology. In particular, migralepsy, which in the recent ICHD-II is defined as a seizure developing during or within 1 h of a
migraine aura, is extremely rare. The concept of migralepsy,
Page 4 of 11
according to the current definition, is too narrow and inadequate and it should be revised keeping in the mind that
headache or visual symptoms can be the epileptic “aura” of
a seizure [54].
Parisi et al. [52] suggest to add, to the forthcoming
ICHD-3 classification, the term “ictal epileptic headache”
(IEH) which defines a condition diagnosed when a headache attack is the only clinical feature of epileptiform
discharges [52-56].
The classification criteria for “ictal epileptic headache”
(IEH), was based on twelve well-documented cases that
have been published in the literature. The “migraine-epilepsy” sequence, defined, as said, “migralepsy”, may often
merely be a seizure starting with an ictal headache, followed
by a sensory-motor partial or generalized seizure, which fits
into the codified “Hemicrania Epileptica” [53,57].
To date, headache and epilepsy classifications have ignored each other. In the International League Against
Epilepsy (ILAE) classification, headache is considered
exclusively as a possible semiological ictal phenomenon
among the “non-motor” features. In particular, headache
is described as a “cephalic”sensation and is not considered as the sole ictal expression of an epileptic seizure.
Moreover, headache is not classified as a “pain” (among
the “somatosensory” features) or “autonomic” sensation,
whereas signs of involvement of the autonomic nervous
system, including cardiovascular, gastrointestinal, “vasomotor” and thermoregulatory functions, are classified as
“autonomic” features. Now, although still considered a
controversial issue, we must consider that headache pain
could originate in the terminal nervous fibers (“vasomotor”) in cerebral blood vessels; consequently, headache should be classified as an “autonomic” sensation in
the ILAE Glossary and Terminology. Headache could
thus be interpreted as the sole expression of an epileptic
seizure and classified as an autonomic seizure [53].
In according to these criteria, Parisi et al. [58] propose the term “ictal epileptic headache” for cases in
which headache is the sole ictal manifestation, whereas
the term “ictal headache” should be applied when the
headache, whether brief or long-lasting, is part of a
more complex seizure including other sequential or overlapping (sensory-motor, psychiatric or non-autonomic)
ictal manifestations.
This new classification proposal (headache as an isolated
ictal autonomic manifestation in IEH) has very different
prognostic implications because the outcome in people
with long-lasting autonomic status epilepticus is very different (i.e., benign) from that of people with additional
ictal motor-sensitive semiology. In addition, headache as
an autonomic phenomenon is crucial when attempting
to understand why headache may be the sole ictal epileptic manifestation: the reasons have been thoroughly
explained in Panayiotopoulos syndrome, whereas the
threshold required to trigger an ictal autonomic phenomenon is believed to be lower than that required to
trigger sensitive sensorial or motor ictal semiology [53].
The criteria of IEH have been proposed by Belcastro
et al. [59] to identify the case of headache (as sole ictal
manifestation) of epileptic origin in order to promptly
obtain an EEG recording and confirm the diagnosis.
Table 2, taken from the paper of Parisi et al. [52], shows
the proposed criteria for ictal epileptic headache (Diagnostic criteria A–D must all be fulfilled to make a diagnosis of ‘IEH’).
This clinical picture is extremely rare and has only
been documented in about 10–12 cases and its epileptic
nature is documented with ictal EEG. For this reason, it
is difficult to obtain firm conclusions about the frequency of IEH based on epidemiological studies. Using
these criteria, we will be able to clarify if IEH represents
an underestimated phenomenon or not [59].
Regarding the third entity concerning the relationship
between epilepsy and headache, the post-ictal headache,
a multicentric italian study from 2006 at 2009 on 142
children, shows that post-ictal headaches were most frequent (62%). Pre-ictal headaches were less common
(30%). Inter-ictal headaches were described in 57.6%.
Clear migrainous features were present in 93% of preictal and 81.4% of post-ictal headaches. Inter-ictal headaches meet criteria for migraines in 87%. The association
between partial epilepsy and migraine without aura is
most common and reported in 82% of our patients with
peri ictal headache and in 76.5% of patients with postictal headache [60]. The term “hemicrania epileptica”
should be maintained in the ICHD-II, introduced into
the ILAE, and be used to classify all cases in which an
“ictal epileptic headache” “coexists” and is associated
synchronously or sequentially with other ictal sensorymotor events [55].
As regards the possible causes of comorbidity, the first
hypothesis provides a causal relationship of migraine and
epilepsy, which seems, however, unlikely considering that
some epileptic syndromes such as benign partial epilepsies
Table 2 Proposed criteria for ictal epileptic headache (IEH)
A.
Headache lasting seconds, minutes, hours or days;
B.
Headache that is ipsilateral or contralateral to lateralized ictal
epileptiform EEG discharges (if EEG discharges are lateralized);
C.
Evidence of epileptiform (localized, lateralized or generalized)
discharges on scalp EEG concomitantly with headache; different
types of EEG anomalies may be observed (generalized spike-andwave or polyspike-and-wave, focal or generalized rhythmic activity
or focal subcontinuous spikes or theta activity that may be
intermingled with sharp waves) with or without photoparoxysmal
response (PPRs)
D.
Headache resolves immediately after i.v. antiepileptic medication
Page 5 of 11
are observed more frequently [61]. If the association of the
two disorders were purely random, the expected prevalence of epilepsy was 1% in migraineurs and the prevalence of migraine was 12% in epileptics, while the
literature reports prevalence data significantly higher than
expected on basis of random association. The risk for
unprovoked seizures was increased in children with migraine with aura and not in patients with migraine without
aura [62].
Several epidemiological studies indicate an association
of migraine and epilepsy with an increased prevalence of
migraine in patients with epilepsy and vice versa. In particular, the prevalence of epilepsy in patients with migraine varies from 1 to 17%, with an average of 5.9%, but
this percentage greatly exceeds that of the general population that is approximately 0.5–1%.
The overall prevalence of migraine in children with
epilepsy varies from 8 to 15%, with values also increased
in children with central-temporal EEG spikes (63%) and
epilepsy with absences (33%) [63,64]. The risk of migraine is more than twice as high in subjects with epilepsy both in probands than in relatives, compared to
people without epilepsy [65].
As a second hypothesis has been suggested a causal unidirectional relationship, for instance in case of migraine
can cause cerebral ischemia or cerebral damage, and consequently epilepsy, or in the case of "migralepsy", where
migraine aura can trigger a seizure. More often a seizure
triggers an attack of headache post-critical, often with migraine characteristics, in this case it has been hypothesized
that epilepsy can trigger migraines through activation of
the trigeminal-vascular system or through mechanismsencephalic trunk [66].
However, the unidirectional hypothesis has been contradicted in a study for verified the relationship between migraine and epilepsy in 395 adult seizure
patients, conducted by Marks et al. [67], since in the
majority of patients with migraine and epilepsy (66/79,
84%) attacks were completely independent. A third hypothesis requires that common environmental risk factors, such as head injury, can cause both migraine and
epilepsy. In fact, it has been found an increased risk of
migraine in people with epilepsy caused by head
trauma, and that in each subgroup of epilepsy, defined
on the basis of seizure type, age at onset, etiology, and
family history [68]. On the other hand, the presence
of shared environmental factors do not explain the
increased risk of migraine in patients with idiopathic
epilepsy and several studies have documented the association between migraine and rolandic epilepsy and
idiopathic occipital epilepsy [69,70].
Headache may occur before, during or after an epileptic seizure, as well as vomiting. In idiopathic occipital epilepsy, crises are, in fact, often characterized by
vomiting associated with visual symptoms, focal seizures and headache.
The existence of a possible constitutional common
ground between migraine and epilepsy was initially proposed on the basis of significantly greater familiarity of migraine in epileptics (28%) and for epilepsy in migraineurs
(2–3%) [70].
The genetic hypothesis (fourth hypothesis) was tested
by Ottman et al. [65], which have suggested a higher incidence of migraine in families with genetic forms of migraine than those with non-genetic forms and that the
relatives of patients with migraine and epilepsy had an
increased incidence of epilepsy compared to the relatives
of patients with only epilepsy. However, this hypothesis
was not confirmed by other studies [68].
Subsequent work reported data in favor of possible genetic factors common to the two conditions. In fact, in some
families with idiopathic temporal lobe epilepsy was found a
higher prevalence of migraine [71,72]. An extended family
with several individuals with occipital and temporal lobe
epilepsy was also featured, which segregated with an autosomal dominant mode of transmission; epileptic patients
had migraines with aura are independent of seizures [73].
Most obvious is the association between migraine with
aura (MWA) and epilepsy. In fact, in a study of 134 children and adolescents with headache, there was a high
prevalence of MWA (30.4%) than other types of primary
headache in children with seizures [74]. Another study of
population-based case–control study documented that the
risk of seizures was increased in children with MWA and
not in those with migraine without aura (MOA) [75]. In
addition, in a study of adult patients, the frequency of
MWA was significantly higher in patients with epilepsy in
comorbidity (41%) compared to patients only with migraine (25.8%) [76].
Finally, considering the comorbidities as a result of an
alteration in brain excitability, Leninger et al. [76] investigated whether the clinical features associated with diffuse
cortical depression (the so-called “Spreading Depression,”
CSD) were more severe in patients with comorbidities.
Despite the frequency of epileptic seizures and syndromes
did not differ between patients with epilepsy alone, compared to subjects with comorbidy, migraine with aura,
worsening pain with physical activity, phonophobia and
photophobia were significantly more frequent in patients
with comorbidities compared with patients with epilepsy
or migraine alone.
These differences are in favor of the hypothesis that the
link between migraine and epilepsy is based on the CSD as
an expression of neuronal hyperexcitability. The altered
neuronal excitability may cause an increased sensitivity to
the CSD resulting in an increased activation of the trigeminal nociceptive fibers and consequently in more severe migraine attacks [76].
Page 6 of 11
Therefore it is likely that the altered neuronal excitability threshold, involved in migraine and epilepsy, and
due to altered levels of neurotransmitters, is attributable
to genetic factors, in particular the disorders of membrane ion channels, the so-called channelopathies.
The epilepsy and migraine, in fact, share common
pathogenetic mechanisms partially related to the dysfunction of ion channels, it is assumed, therefore, that
channelopathies may be the link between epilepsy and
migraine, particularly when these disturbances are in
comorbidy.
However, when headache and epilepsy overlap as a result of the crossing of the cascade of events at the cortical level, in both of the events (CSD and epileptic
focus), their onset and propagation are triggered when
these events reach a certain threshold, which is lower for
CSD than for seizure. These two phenomena may be
triggered by more than one pathway converging (at cortical level) upon the same destination: depolarization
and hypersynchronization [53].
Finally, further studies are warranted to better delineate the complex link between epilepsy and migraine.
Headache and general medical conditions
Compared to comorbidity between headache and general
medical conditions, an interesting epidemiological study,
led by Lateef et al. [77] on the child population, highlights the correlation between headache and other general medical conditions, including asthma, hay fever and
frequent ear infections. The 41.6% of children with headache had at least one of these conditions, and in general,
the group examined had a probability of 3.2 times higher
to present two of the above conditions and a probability
of 13.6 times greater to submit all three. The increased
comorbidity between headache and general medical conditions was found from 4 to 11 years.
Other conditions most frequently observed in children
with frequent or severe headaches are: ADHD, especially
as regards hyperactive/impulsive behavior [78], learning
disabilities, stuttering, anemia, obesity, bowel disease.
Regarding the girls, it was found that most of those who
had frequent headaches had their first menstrual cycle
before the age of 12 years [77].
It was also found a higher comorbidity of headache, in
particular migraine, with atopic disorders (asthma, rhinitis or eczema), studied in a sample of children presenting with such disorders. The prevalence of migraine was
significantly higher in children with atopic disorders
than those without. In particular, the greater association
was detected with rhinitis [12].
Recent researches suggest that obesity was significantly
correlated with migraine frequency and disability in children, as well as in adult population studies. Translational
and basic science research shows multiple areas of overlap
between migraine pathophysiology and the central and
peripheral pathways regulating feeding. Specifically,
neurotransmittors such as serotonin, peptides such as
orexin, and adipocytokines such as adiponectin and leptin have been suggested to have roles in both feeding and
migraine. A relationship between migraine and body mass
index exists, and therefore, interventions to modify body
mass index may provide a useful treatment model for investigating whether modest weight loss reduces headache
frequency and severity in obese migraineurs [79].
The effect of obesity and weight change on headache outcomes may have important implications for clinical care.
Recently, Verrotti et al. [80] investigated the real impact of a weight loss treatment on headache in a sample
of obese adolescents. In all, 135 migraineurs, aged 14–
18 years, with body mass index (BMI) greater than or
equal 97th percentile, participating in a 12-month-long
program, were studied before and after treatment. The
program included dietary education, specific physical
training, and behavioral treatment.
Decreases in weight, BMI, waist circumference, headache frequency and intensity, use of acute medications,
and disability were observed at the end of the first 6month period and were maintained through the second
6 months. Both lower baseline BMI and excess change
in BMI were significantly associated with better migraine
outcomes 12 months after the intervention program.
So, initial body weight and amount of weight loss may
be useful for clinicians to predict migraine outcomes [80].
Headache and cerebro and cardio-vascular diseases
Although migraine is an accepted cause of cerebral infarction in adults, this association is not recognized in
children. The mean annual incidence of stroke in children is about 2.5 per 100,000 [78].
The causes of cerebral infarction in children may include:
heart disease, vascular disease, blood disorders, primary
hypercoagulable states or congenital metabolic disorders,
but 50% of strokes are considered idiopathic [81].
In the adult population is generally accepted that cerebral infarction may occur during a migraine attack [82]. In
young adults, ischemic strokes could be the result of migraine in a percentage ranging from 10% to 27% [83]. In
contrast, in children, the diagnosis of stroke caused by migraine is still questioned, in fact, until now, only a few
cases have been reported in subjects under the age of
16 years [84,85]. In most patients, the ischemic stroke occurred in a middle cerebral artery territory [85] but may
be involved also areas of the brain sprayed from basic.
In particular, there appears to be a complex relationship in a bidirectional association between migraine and
stroke, including migraine as a risk factor for cerebral ischemia, migraine caused by cerebral ischemia, migraine
as a cause of stroke, the presence of a common cause for
Page 7 of 11
migraine and cerebral ischemia or migraine associated
with subclinical vascular injury of the brain.
Some studies of young adults seem to confirm this association [86,87]. A history of migraine with aura seems
to be more common among victims of ischemic stroke
than among controls and an acute attack of migraine
may precede, accompany or follow a thromboembolic
transient ischemic attack or a stroke, this seems to occur
more often among migraineurs compared patients without migraine [88,89]. Adults suffering from migraine
with aura are at increased risk of cardiovascular disease
and stroke [90], but it is necessary to consider that in
adults, the analysis of this association is complicated by
a frequent presence of additional risk factors such as
smoking, hypertension and diabetes mellitus. In children, these and other potential confounding factors are
much less common. There are relationships arising from
small clinical samples of pediatric age who demonstrate
the association of migraine with dyslipidemia [91],
hyperhomocysteinemia and genetic variants related to
homocysteine which appear to be risk factors for the development of stroke in children [92].
Furthermore, in a national representative sample of
children, the severe or recurrent headache was associated with higher levels of adiposity measured by the
body mass index (BMI) [77].
In general, below the age of 55, migraine with aura is a
risk factor for ischemic strokes. However, it’s important
to point out that part of the latter, can be linked to the
presence of a patent foramen ovale (PFO).
The PFO is the result of incomplete fusion of the
septum “primum” and “secundum”, which normally occurs shortly after birth, when the left atrial pressure exceeds that of the right atrium.
Epidemiological studies have shown a clear comorbidity between migraine with aura and PFO. In fact, the
available data suggest that PFO is more common in
women with migraine with aura (present in about 50%
of cases) and that migraine with aura is more common
in patients with PFO [93-95]. The mechanism underlying the possible relationship between migraine and
PFO is not yet very clear: is there a causal relationship
with migraine attacks, or have common genetic factors?
The pathophysiological mechanism is considered a passage of microemboli and vasoactive chemicals through
the PFO, which would circumvent the filtering pulmonary triggering migraine symptoms. The widespread cortical depression, which is the mechanism behind the
migraine aura, could be favored by the presence of a
PFO. Among the various hypotheses, it seems interesting to Pierangeli et al., who claim that a particular genetic predisposition could lead to a co-development of
atrial septal abnormalities and migraine [96]. In fact,
if the aura has occurred due to a malfunction of the
cerebral perfusion, the symptoms should occur with a
sudden onset and not gradual. It’s likely that the association of migraine and PFO is random, given the frequency of both disorders.
Recently, Steenblik et al. [97] sought to examine the
familial risk of isolated interatrial shunt, caused by either
atrial septal defect or patent foramen ovale, and explore
associated comorbidities of stroke, transient ischemic attack (TIA), and migraine using a population database.
They found that there is a strong familial inheritance
pattern for isolated interatrial shunt, with significantly
higher risk of interatrial shunt among affected patients’
siblings, first-, and second-degree relatives. Relatives of
affected individuals also had a higher risk of TIA, a
trend toward an increased risk for stroke, but no increased risk of migraine headache.
The relevance of genetic factors with respect to the
preparation and transmission of PFO and migraine with
aura is still under discussion [98-100].
Page 8 of 11
A recent study of Ghosh et al. (2012) [104] analyzed
the frequency of occurrence of headaches in children
and adolescents with TS to address their possible inclusion as a comorbidity.
Using a prospective questionnaire, administered directly, the author interviewed a total sample size of 109
patients with TS ≤21 years of age. The questionnaires
were then analyzed according to the International Headache Society’s diagnostic criteria. The author found that
headaches were present in 55% of patients, with two
most common headache types being migraine headaches
and tension-type headaches. The rate of migraine headache within the TS group was found to be 4 times
greater than that of general pediatric population, as
reported in literature. In addition, the rate of tensiontype headache was found to be more than 5 times
greater than that of general pediatric population. Overall, the high rates of migraine and tension-type headache
within this population support the proposition that
headaches are a comorbidity of TS.
Headache and tourette syndrome
Tourette syndrome (TS) is recognized as one of the
most common childhood movement disorders, characterized by motor and phonic tics often associated
with neurobehavioral comorbidities, such as obsessivecompulsive disorder. Neurotransmitter dysregulation,
particularly involving the serotonin system, has been implicated in the pathogenesis of TS, obsessive-compulsive
disorder, and migraine headache. The frequency of migraine headache in a clinic sample of TS subjects was
nearly 4-fold more than the frequency of migraines
reported in general population. In particular, of 100
patients with TS, 25 (25.0%) satisfied the diagnostic criteria for migraine headache, significantly greater than
the estimated 10% to 13% in general adult population
and the estimated 2% to 10% in general pediatric population [101].
The first study that has examined the comorbidity between Tourette syndrome and headache was conducted
by Barabas et al. (1984) [102]. The authors studied the
incidence of migraine among children with Tourette’s
Syndrome (TS). Among 60 children with TS (mean age
of 11.9 yrs), migraine was prevalent in 26.6%. This figure
is substantially greater than that reported for general
population of school-aged children (4.0–7.4%) or for 2
control groups consisting of 72 children with seizure
disorders and 62 children with learning disabilities. The
prevalence rates for these two control groups were 11.3%
and 8.0%, respectively.
Subsequently, in 1986, Lacey D.J. [103] have shown a
correlation between Tourette’s syndrome and several
other disorders in children, including: thought and behavioral disorders, sleep disturbances, headaches, and
school difficulties-including attention deficit disorder.
Headache and ADHD
Primary headache syndromes (eg, migraine and tensiontype headache [TTH]) and attention-deficit/hyperactivity
disorder (ADHD) are prevalent in childhood and may
cause impairment in social and academic functioning.
In particular, Migraine and ADHD are highly prevalent, affecting between 5 to 10% of the pediatric population [4,105]. Coincidentally, the burden caused by both
neuropsychiatric disorders reaches a common range of
negative outcomes impairing quality of life [106,107],
school achievement [108,109], social [7,110], and family
functioning [111,112]. Thus, studying the association of
both conditions is of utmost clinical importance.
According to a systematic review of clinical studies on
psychological functioning and psychiatric comorbidity of
migraine in children, there is no evidence that ADHD is
more frequently diagnosed in this group compared with
no headache controls [7].
In a cross-sectional epidemiological study specifically
designed to examine this association, we have found
that migraine are not comorbid to ADHD overall, but
are comorbid to hyperactive-impulsive behavior [88].
In this study ADHD was assessed according to the
fourth edition of the Diagnostic and Statistical Manual
of Mental Disorders (DSM-IV) criteria by the validated
Brazilian version of the Multimodal Treatment Study
of Children with ADHD – Swanson, Nolan, and Pelham
IV (MTA-SNAP-IV) scale [113] fulfilled by parents and
teacher. Mental health status was assessed with the validated Brazilian version of the Child Behavior Checklist
(CBCL) [114]. The prevalence of ADHD was not significantly different comparing children with migraine
to controls (no headache). For inattention symptoms,
no significant differences were found. The prevalence of
hyperactivity-impulsivity symptoms was 8.1% in children
without headache, 23.7% in children with migraine (relative risk [RR] = 2.6; 95% confidence interval [CI] = 1.6–
4.2), and 18.4% in children with probable migraine (RR =
2.1; 95% CI = 1.4–3.2). According to the multivariate
analyses, ADHD or inattention symptoms were not predicted by headache subtypes or headache frequency. On
the other hand, hyperactivity-impulsivity symptoms
were significantly associated with any headache (p <
0.01), tension-type headache (TTH) (p < 0.01), or migraine (p < 0.001) [88].
An association between childhood migraine and inattention symptoms have been reported by some populational
[115,116] and clinical [6] studies. However, the findings
must be understood in the context of some methodological
limitations. The behavior rating scales adopted by these
studies add symptoms of inattention and hyperactivity/impulsivity in the same domain preventing the distinction between them. Among the 11 questions comprising the
attention domain in the CBCL, only three capture symptoms of inattention (“Can’t concentrate, can’t pay attention
for long”, “Daydreams or gets lost in his/her thoughts”, and
“Stares blankly“). The remaining questions focus on hyperactivity, impulsivity, executive dysfunctions and lack of coordination (“Acts too young for his/her age”, “Can´t sit still,
restless, or hyperactive”, “Confused or seems to be in a fog”,
“Impulsive or acts without thinking”, “Nervous, high strung,
or tense”, “Nervous movements or twitching”, “Poor school
work”, and “Poorly coordinated or clumsy”) [117]. Likewise,
of the five questions that encompass the hyperactivity scale
of the Strengths and Difficulties Questionnaire (SDQ), two
are destined to identify inattention symptoms and three to
hyperactivity/impulsivity [118]. Adopting the MTA-SNAPIV scale we could separate both dimensions of ADHD
symptoms in our study [88].
In accordance to our findings, neuropsychological studies with clinical samples have found no attentional impairment in children with migraine compared to controls, in
spite of a rather impulsive response profile [119-121].
Given the possible comorbidity between migraine and
hyperactivity-impulsivity symptoms, providers and educators should be aware of the association.
Conclusions
Primary Headaches In Childhood and Adolescence are
often associated with,and deeply influnced by,many comorbid situations.
In this review are analyzed the most relevant of them.
It is foundamental to take care of any kind of comorbidity to establish the most effective treatment strategy.
Competing interest
The authors declare that they have no competing interest.
Page 9 of 11
All authors contributed to the writing of each paragraph of the manuscript.
All authors read and approved the final manuscript.
Author details
1
Department of Pediatrics and Child Neuropsychiatry, Sapienza University of
Rome, Via Dei Sabelli 108, Rome, Italy. 2Riberao Preto, Sao Paulo, Brasil.
3
University “Campus Biomedico”, Rome, Italy. 4II University of Naples, Naples,
Italy. 5Padua University, Padua, Italy. 6San Gerardo Hospital University of
Milano-Bicocca, Monza, Italy. 7Mondino Institute, Pavia University, Pavia, Italy.
8
Insubria University, Varese, Italy. 9L’Aquila University, L’Aquila, Italy.
10
Department of Dynamic and Clinical Psychology, Sapienza University of
Rome, Rome, Italy.
Received: 5 August 2013 Accepted: 17 September 2013
Published: 24 September 2013
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doi:10.1186/1129-2377-14-79
Cite this article as: Bellini et al.: Headache and comorbidity in children
and adolescents. The Journal of Headache and Pain 2013 14:79.
Coppola et al. The Journal of Headache and Pain 2013, 14:65
REVIEW ARTICLE
Open Access
Habituation and sensitization in primary
headaches
Gianluca Coppola1*, Cherubino Di Lorenzo2, Jean Schoenen3 and Francesco Pierelli4
Abstract
The phenomena of habituation and sensitization are considered most useful for studying the neuronal substrates of
information processing in the CNS. Both were studied in primary headaches, that are functional disorders of the
brain characterized by an abnormal responsivity to any kind of incoming innocuous or painful stimuli and it’s
cycling pattern over time (interictal, pre-ictal, ictal). The present review summarizes available data on stimulus
responsivity in primary headaches obtained with clinical neurophysiology. In migraine, the majority of
electrophysiological studies between attacks have shown that, for a number of different sensory modalities, the
brain is characterised by a lack of habituation of evoked responses to repeated stimuli. This abnormal processing of
the incoming information reaches its maximum a few days before the beginning of an attack, and normalizes
during the attack, at a time when sensitization may also manifest itself. An abnormal rhythmic activity between
thalamus and cortex, namely thalamocortical dysrhythmia, may be the pathophysiological mechanism subtending
abnormal information processing in migraine. In tension-type headache (TTH), only few signs of deficient
habituation were observed only in subgroups of patients. By contrast, using grand-average responses indirect
evidence for sensitization has been found in chronic TTH with increased nociceptive specific reflexes and evoked
potentials. Generalized increased sensitivity to pain (lower thresholds and increased pain rating) and a dysfunction
in supraspinal descending pain control systems may contribute to the development and/or maintenance of central
sensitization in chronic TTH. Cluster headache patients are chrarcterized during the bout and on the headache side
by a pronounced lack of habituation of the brainstem blink reflex and a general sensitization of pain processing. A
better insight into the nature of these ictal/interictal electrophysiological dysfunctions in primary headaches paves
the way for novel therapeutic targets and may allow a better understanding of the mode of action of available
therapies.
Keywords: Migraine; Tension-type headache; Cluster headache; Trigeminal autonomic cephalalgias; Sensitization;
Habituation; Evoked potentials; Reflex; Pain mechanisms; Thalamocortical dysrhythmia
Review
Introduction
Among the general population, headaches are highly
prevalent and receive growing attention not only because they affect people’s quality of life, but also because
they have a significant economic impact. Idiopathic or
primary headache syndromes are disorders in which there
is a temporary or permanent dysfunction of the central
nervous system, often genetically determined, without apparent organic lesion. They include migraine, tension
1
Department of Neurophysiology of Vision and Neurophthalmology, G.B.
Bietti Foundation IRCCS, Via Livenza 3, 00198, Rome, Italy
headache, and the trigeminal autonomic cephalalgias
among which "cluster headache". Progress in headache research has benefited from the International Classification
of Headache Disorders (ICHD), and its revisions [1,2], because they have provided operational diagnostic criteria
allowing for a better comparison of clinical data between
headache centres.
In the recent publication of the Global Burden of
Disease survey 2010, tension-type headache and migraine are the second and third most prevalent disorders
in the world, and migraine is recognized as the seventh
highest cause of disability in the world [3]. The large and
still growing scientific knowledge on their pathophysiological mechanisms has contributed the recognition
© 2013 Coppola et al.; licensee Springer. This is an Open Access article distributed under the terms of the Creative Commons
of headaches as neurological conditions worth of interest. In fact, although scientists have not completely
disentangled the complicated puzzle of primary headache pathophysiology, great advances were made during
the last 2 decades with the help of the new research
armamentarium.
Clinical neurophysiology methods, in particular, have
allowed in vivo measurements of the headache patients’
electrocortical responses to various sensory stimuli. They
are atraumatic, non-invasive and complementary to
modern neuroimaging techniques, and thus suitable to
study functional disorders as primary headaches.
In their episodic forms, primary headaches are defined
as paroxysms (the attacks) separated by remissions of
variable lengths. Several studies focused therefore for
ictal versus interictal electrophysiological abnormalities,
in order to understand the predisposition and the recurrent character of attacks. In this respect, among the various primary headaches, migraine is doubtless the beststudied headache type.
Migraineurs are characterized interictally by a generally increased sensitivity to visual (sensitivity to light),
auditory (to sound), or somatic stimuli (allodynia) not
only during the attack, but also outside of the attack. Researchers, trying to explain this phenomenon, observed
that interictally migraineurs with and without aura show
a time dependent amplitude increase of scalp-evoked
potentials to repeated stereotyped stimuli with respect
to normal subjects. This phenomenon was called “deficient habituation” and was only seen during the painfree period for almost all sensory modalities. However,
this is not a static phenomenon, but, as shown in several
studies, habituation changes with the proximity to an
attack, during the attack and when episodic migraine
evolves to chronic migraine, a complication of migraine where sensitization, the opposite of habituation,
makes its appearance, changing fundamentally the response pattern.
The present article, after providing an overview of
the general concept of habituation and its opposite
“sensitization”, will review the studies on habituation/
sensitization in migraine and other primary headaches, performed with different clinical neurophysiology methods and emphasize in particular the more
recent data.
General concept
Habituation is defined as “a response decrement as a result of repeated stimulation” [4] and is a common feature of responses to any kind of sensory stimulation. It is
an ubiquitous phenomenon observed in different experimental settings and in neuronal circuits of a wide range
of complexity, from the withdrawal reflex of the gill and
siphon in Aplysia to the autonomic and behavioral
Page 2 of 13
component of the whole-of-body reflex called the
“orienting response” in humans [5-7].
Habituation is a multifactorial event of which the accompanying synaptic plastic mechanisms are still not
totally elucidated. Several theories, or at least hypotheses, have been proposed over the years to explain this
phenomenon [8]. In the 70's, Groves and Thompson
proposed the “dual-process” theory, stating that two
separate and opposing processes, depression (habituation) and facilitation (sensitization), compete to determine the final behavioural outcome after a sequence of
repetitive stimuli [6]. According to the dual-process theory, sensitization is the side of the pendulum that, when
present, prevails at the beginning of the stimulus session
and accounts for the initial transitory increase in response amplitude, whereas habituation occurs later
during the course of the recording session and accounts
for the delayed response decrement [6]. At the synaptic level, the stimulus–response pathway interacts
with an external “state” system represented by various
“tonic” non-specific and motivational circuits, including the ascending reticular activating system and related structures. In humans, these structures comprise
the monoaminergic nuclei in the brainstem, that are
critically involved in the central processing of arousal,
control of the signal-to-noise ratio generated by sensory stimuli at cortical and thalamic levels, and endogenous antinociception [9].
To avoid semantic misunderstanding, it should be
noted that a response dishabituation does not refer to
lack of habituation, but to a response sensitization or
“heterosynaptic facilitation” as termed by Kandel and associates in their works on Aplysia [10]. In fact,
dishabituation is an actual recovery of the habituated response caused by the interference of an unexpected
stimulus markedly different from the habituating ones.
Sensitization is an elementary form of behavioral plasticity, perhaps equal in importance to habituation and apparently generated by somewhat different neuronal
mechanisms [11].
Habituation depends on a series of parametric properties or characteristics [5], which were revised and refined
during a workshop in Vancouver in 2007 [12]. These
characteristics dealt with both short- as well as longterm habituation and its opposite dishabituation.
The phenomenon of habituation is considered useful
for studying the neuronal substrates of behavior, the
mechanisms of learning processes, or information processing in the CNS both in health and in disease.
It must be noted that, during the last three decades,
sensitization has assumed a wider meaning than habituation. Sensitization is not only considered a general behavioral response of augmentation to innocuous sensory
stimuli, but it has also acquired a particular significance
in the field of pain as an augmentation of sensory signalling in the central nervous system as a consequence of
noxious stimulation (for a review see Woolf, 2011 [13]).
The latter may be a peripheral injury activating smallfiber afferents that produce an increase in excitability,
i.e. sensitize, nociceptive spinal cord neurons. This increase in excitability is responsible for the plastic
changes in those neural structures belonging to the socalled “pain matrix”. It results in decreased nociceptive
thresholds and increased responsiveness to noxious and
innocuous peripheral stimuli, as well as expansion of
the receptive fields of central nociceptors [14]. Overall,
this transient or persistent state of higher reactivity
is called “central sensitization”. Studies in the headaches
field disclosed changes in pain sensitivity that were
interpreted as reflecting central sensitization. A wellrecognized clinical expression of central sensitization
is cutaneous allodynia, which is prevalent during episodic migraine attacks [15,16] and in chronic migraine
[17-19]. There is no common agreement yet about what
causes and where starts the cascade of events that lead
to central sensitization in migraine or in other primary
headaches. However, some evidences point towards
sequential sensitization of first-order or second-order
trigeminovascular nociceptors via overt (aura) or possibly silent (without aura) cortical spreading depression
waves or, more likely, via an indirect activation of pain
modulatory structures in the brainstem (raphe magnus, locus coeruleus and other aminergic nuclei) and
the forebrain (periaqueductal gray, rostroventral medulla) [20,21].
In human research, time-locked cortical potentials
(EP) evoked by a sensory stimulation and reflex responses (RR) after electric stimulation of a peripheral
nerve have been frequently used to study the habituation
and sensitization phenomena. A common way of analysing these responses consists of either analysing single trials or averaging in blocks single epochs of EP or RR per
subject, identifying the latencies and amplitudes or areaunder-the-curves of the considered components, and
using these parameters as a dependent variables in the
statistical analysis. Data are usually expressed either in
absolute or log-transformed values, and between single
trials or blocks habituation is calculated either with linear regression (slope of the linear regression line) or
with block ratios (change in amplitude expressed in
percentage).
Habituation in migraine
Neurophysiological data suggest that lack of habituation
during stimulus repetition despite an initial normal or
slightly lower response amplitude is a functional, probably genetically determined, property of the brain in
migraineurs between attacks.
Page 3 of 13
The very first study showing that habituation is decreased in patients affected by migraine without aura between attacks was carried out with contingent negative
variation (CNV), a slow negative cortical response
related to higher mental functions [22-26]. The CNV
abnormality was more evident for the early than for the
late component [24,27-33], and was assessed by visual
[34,35] or auditory [36-38] oddball paradigms. The lack
of habituation was confirmed several times by analyzing
visual evoked potentials (VEP) in response to checkerboard pattern [39-49], and also by using magneto electroencephalography [50-52]. The abnormal visual information
processing in migraine seems to be characterized by an
initial response of normal or slightly lower amplitude
followed by an amplitude increase, that, as stated above,
corresponds neither to response sensitization nor to
dishabituation, but to a lack of habituation [40-50]. The
same phenomenon was also found with somatosensory
[53-55] and auditory [56,57] evoked cortical potentials in
migraine between attacks. Sand et al. (2008) recorded
brainstem auditory evoked potentials (BAEPs) in migraine
interictally and found lack of habituation in the wave IV-V
[58], a datum that was recently confirmed also in a few
migraineurs experiencing vertigo, especially when symptomatic [59]. Moreover, Sand et al. also observed a positive
relationship between BAEP amplitudes and blood serotonin level in healthy controls, but not in migraine, a result
that was interpreted as an evidence in support of the notion that a dysregulation of the serotonin system is linked
to migraine pathogenesis [58].
Besides the innocuous evoked potentials, researchers
have verified if the same habituation deficit might
exist after noxious stimulation. The blink reflex (BR)
obtained after supraorbital stimulation with a so-called
“nociception-specific” electrode, a way to more specifically explore trigeminal nucleus caudalis activation, discloses an interictal habituation deficit during short
[60,61] as well as long time courses [44,62]. Amplitude
and habituation of another brainstem reflex, the clickevoked vestibulocollic reflex, was equally reduced in
migraineurs between attacks compared with healthy subjects [63,64].
Brief radiant heat pulses, produced by CO2 laser
stimulation, activate selectively Aδ and C fibres and generate an evoked potential that can be recorded from the
temples (early component, N1) and the vertex (late components, N2-P2) of the skull. In episodic migraine the
late component of laser evoked potentials (LEPs), mainly
generated in the insular and anterior cingulate cortices,
elicited by either cephalic (usually supraorbital) or
extracephalic (usually hand dorsum) stimulation does
not habituate during stimulus repetitions over short [65]
or long durations [66-68]. Deficient habituation was also
observed for the early N1 LEP component, mainly
generated in the secondary somatosensory cortex
[66,69]. In two studies performed in episodic migraine
between attacks using contact-heat evoked potentials
(CHEPS) and source localization with standardized
LORETA (sLORETA) mapping it was shown that the
lack of habituation to the noxious heat stimuli is probably related to the inability of the orbitofrontal cortex
(OFC) to filter out correctly the pain information
[70,71]. Since evidence from animal and human studies
suggests a role for serotonin in the OFC-mediated descending inhibition of pain [72], the authors argue that a
possible alteration of brain 5-HT neurotransmission may
be responsible for this abnormal pain information processing in migraine, where decreased serotonergic disposition was previously reported [73-75],
Genetic load seems to play an important role in the
mechanisms that produce physiologically altered habituation. In fact, the habituation deficit in migraineurs
has a family character. This abnormality is present
interictally not only in adults, but also in children in
whom it is significantly correlated with that of their parents [28,76]. Moreover, asymptomatic subjects defined
to be "at risk" for developing migraine, i.e. healthy but
with first-degree relatives with migraine, present the
same habituation deficit in evoked potentials and nociceptive blink reflex as established migraineurs, so that
deficient habituation can be regarded as neurophysiological marker of pre-symptomatic migraine [29,62].
Since migraine is a recurrent paroxysmal disease characterized by attacks (ictal period) and variable pain-free
periods (interictal), it was of interest to perform sequential recordings during the days preceding the attacks,
immediately before or during the attack. During the days
preceding the attack (pre-ictally) VEP and SSEP amplitudes increase and habituate normally [50,54,58,77,78],
whereas CNV and P300 habituation is minimal and
amplitude peaks [30,79,80], suggesting that, depending
on sensory modality, the habituation deficit worsens
interictally, reaches its maximum a few days before the
attack and then normalizes during the attack.
Finally, it must be mentioned that among more than
fifty positive studies, the habituation deficit in migraine
during the pain-free phase was not confirmed in some
studies [77,81-87]. It is not easy to explain why some research groups did not retrieve any habituation deficit in
migrainous patients between attacks. For some Authors
lack of blindness for diagnosis during the recording sessions may be an explanation [87], but the same research
group did not find lack of habituation even with no
blindness [77]. Another one could be the use of different
patients’ selection criteria, such as recruitment of university students or medical staff instead of patients who
spontaneously visited a Headache Clinic, the latter experiencing more day life discomfort from their migraine.
Page 4 of 13
Whatever the explanation, we must take into account
that habituation deficit is not constant in migrainous patients. In fact, habituation degree may change not only
interictally vs. pre-ictally vs. ictally, but also within the
pain-free period with the distance since the last or next
attack [88]. Moreover, specific genetics influence [76,89]
and clinical fluctuations, such as spontaneous clinical
worsening or improving of attacks frequency [90,91],
may vary the baseline level of thalamocortical activation
[92] and then the degree of habituation in migraine [55].
Mechanisms of the habituation deficit in migraine
As mentioned above, the neural mechanisms underlying
habituation remain poorly understood, and this uncertainty helps to explain why the abnormal habituation
pattern in migraine still lacks a definitive consensual interpretation [93-95].
Neuromodulatory techniques, like repetitive transcranial magnetic stimulations (rTMS) and transcranial direct current stimulations (tDCS), were used to shed more
light on the interictal abnormal information processing
in migraine. In migraineurs activating high frequency
rTMS over the visual or somatosensory cortices was able
to increase for some minutes the amplitude of the first
VEP and somatosensory evoked potentials (SSEP) block
and to normalize habituation over successive blocks,
whereas inhibiting low frequency rTMS had negligible
effects on both. By contrast, in healthy volunteers,
inhibiting rTMS reduced first VEP and SSEP amplitude
block as well as habituation, while the activating protocol had no effect [42,55]. A longer lasting effect (several
weeks) on VEP was induced with 5 consecutive daily
sessions of inhibiting rTMS over the visual cortex in
healthy subjects, while the effect of activating rTMS in
migraineurs lasted only hours or a few days [45]. Recently, Viganò et al. (2013) applied another activating
neuromodulation method, anodal tDCS over the visual
area in migraineurs, and reported that, similar to 10Hz
rTMS, the the 1st VEP block increased in amplitude and
habituation normalized [96]. In the second phase of their
study, the same authors performed a preventive pilot
trial with 2 sessions of anodal tDCS over the visual cortex per week for 8 weeks in 15 migraine patients and
found a clear beneficial effect on several clinical endpoints up to an average of 4.8 weeks after the tDCS
treatment period [96]. Overall, the neuromodulatory
studies indicate that only procedures that enhance cortical excitability are able to normalize the abnormal
interictal information processing in migraine.
Further information on the pathophysiology of the
interictal dysfunction in migraine was obtained from the
more sophisticated studies of the high-frequency oscillations (HFOs) embedded in common somatosensory and
visual evoked potentials. Early somatosensory HFOs,
reflecting spike activity in thalamo-cortical cholinergic
drives, were decreased interictally in migraine and normalized during the attack while late HFOs, reflecting
primary cortical activation, were normal [97] or decreased [98]. Moreover, the reduction early HFOs was
associated with a worsening in the clinical course of migraine [90]. In a recent study in migraineurs activating
rTMS over the sensorimotor cortex was able to increase
the interictal low thalamo-cortical drive. This was not
the case in healthy volunteers probably because their
thalamo-cortical activity was already maximal before the
rTMS [97]. This finding supports the hypothesis that deficient habituation in migraine is due to a reduced thalamic control of the activity in sensory cortices i.e. a low
pre-activation level. Further evidence for an abnormal
thalamic control in the migraine brain intericatlly comes
from the analysis of visual HFOs (gamma-band oscillations, GBO) [46]. We demonstrated a significant habituation deficit of the late GBO components in migraineurs
relative to healthy subjects, which we interpreted as indicative of a dysfunction in cortical oscillatory networks
that could in turn be due to an abnormal thalamic pacemaker rhythmic activity, namely “thalamo-cortical dysrhythmia” [46]. The latter may reconcile the long-lasting
controversy between excessive excitation and deficient
inhibition in migraine, since a deficient thalamo-cortical
drive, i.e. a low level of cortical preactivation, results in
dysfunction of both inhibition and excitation. Lower inhibition and preactivation may thus co-exist, since the
latter can promote the former via reduction of lateral inhibition [93]. Refined VEP techniques have shown that it
is possible to enhance the relative contributions that
arise from short- and longrange lateral inhibition between neurons through differential temporal modulation
of adjacent regions of radial windmill-dartboard (W-D)
or partial-windmill (P-W) visual patterns [99-101]. This
may represent a further tool for investigating migraine
pathophysiology. According to our recent study, the degree of short-range lateral inhibition in the visual cortex
during W-D visual stimulation is more pronounced in
migraine patients than in healthy volunteers at the beginning of the stimulus session (1st block). Over successive blocks of recordings, however, it decreases in
migraineurs, but remains unchanged in healthy controls.
During the migraine attack, short-range lateral inhibition
is on the contrary much reduced, but it increases during
stimulus repetition. There was no significant between
group difference in the P-W amplitude, reflecting longrange lateral inhibition, and its attenuation [88]. These
results favour a migraine cycle-dependent imbalance between excitation and inhibition in the visual cortex that
results in a heightened cortical response to repeated
stimuli, i.e. a lack of habituation. We hypothesized that
an interictal hypoactivity of monaminergic pathways
Page 5 of 13
may cause a functional disconnection of the thalamus in
migraine leading to an abnormal intracortical shortrange lateral inhibition, which could contribute to the
habituation deficit observed during stimulus repetition.
That in migraine the thalamus abnormally controls the
cortex via thalamorcortical loops is further underscored
by the recent study of the paired associative stimulation
(PAS) paradigm, a protocol that uses in humans a design
principle very similar to those producing long-term depression (LTD) or potentiation (LTP) in animal studies
[102-104]. In migraine, depressing PAS paradoxically
increased motor evoked potential amplitudes instead
of decreasing them, and enhancing PAS induced only
a slight non significant response potentiation [105].
This suggests that impaired long-term associative synaptic plasticity mechanisms characterize migraine
without aura patients between attacks. Because we
observed, at least in a subgroup of subjects, that the
PAS-induced plastic changes were inversely related
with thalamocortical activation, as assessed by early
somatosensory HFOs, we suggested that the malfunction in PAS-induced effects in migraine might reflect
low cortical preactivation, which prevents short-term
and longer-term changes in cortical synaptic effectiveness [105].
Sensitization in migraine
The majority of the studies on the dynamic behavior
of peripheral reflexes and evoked cortical responses
in migraine have focused on habituation instead of
sensitization, probably because it is particularly difficult
to assess sensitization by calculating “sliding” averages
using successive blocks of few responses.
However, if sensitization, defined as facilitation occurring at the beginning of the stimulus presentation, is
impaired in migraine (i.e. enhanced in comparison to habituation), it should be detectable as a higher first block
absolute amplitude value of the considered response.
Indirect signs of sensitization were observed during
migraine attacks and in chronic migraine patients with
or without medication overuse.
It was reported several times that within the 12–24 hours
preceding the attack the habituation pattern of reflex and
non-noxious evoked potentials normalize. This has been
shown with CNV [26,79,80], VEP [50,78,88], visual P300
latency [35], and nociceptive blink reflexes [60].
Pain-related responses may behave in a partially different way. During migraine attacks, the area-under-thecurve of the nociceptive blink reflex R2 component
is temporary increased on the affected side in comparison with the non-affected side was observed [106]. Similar results were obtained using another noxious
stimulation, the radiant laser CO2: amplitude of the
N2–P2 complex at the vertex was increased on the
affected side compared to the non-affected side
[107-109]. Interestingly, in episodic migraine LEPs did
not habituate not only interictally, but also during the
attacks, underscoring the different cerebral processing of
noxious versus innocuous stimuli. These data could represent the electrophysiological counterpart of central
sensitization of cerebral structures belonging to the
so-called “pain matrix” that seems to be related to
the mechanism of the migraine attack and of the
chronification of migraine. As abovementioned, from a
physiological point of view, sensitization refers to the
plastic changes in neural structures belonging to the
“pain matrix” that result in decreased nociceptive thresholds and increased responsiveness to noxious and innocuous peripheral stimuli, and expansion of the
receptive fields of CNS nociceptive neurons [14]. As a
matter of fact, reduced pain thresholds have been found
clinically with quantitative sensory testing immediately
before [110] and during [16] a migraine attack, but
sometimes even earlier in the interictal period in some
[111,112] but not all the studies [110,113-115]. During
attacks of migraine, reduced cutaneous pain thresholds
on both symptomatic and non-symptomatic sides are accompanied by significantly increased N2-P2 complex of
LEP [107] and changes in its dipolar source localization
[108]. These abnormalities worsen with the increase in
attack frequency [107,108]. In a group of chronic migraine (CM) patients, a trend for an increase in LEP N2P2 amplitudes [116] and a reorganization of the cortical
areas devoted to pain processing [117], was also
detected. Moreover, in CM due to medication overuse
LEP N2-P2 amplitude still showed reduced habituation
after both hand and face stimulation, similarly to the response behavior found with LEPs during interictal and
ictal periods [118]. Interestingly, withdrawal from the
acute medication overuse normalized the habituation
curve [118].
Recently, somatosensory evoked potentials (SSEPs)
proved to be ideal for disclosing sensitization (reflected
by an increased response amplitude to low numbers of
stimuli) and habituation (reflected by a decrease in response amplitude after high numbers of stimuli) in both
episodic and chronic forms of migraine. While SSEPs
confirmed a lower initial amplitude and late abnormal
habituation in migraineurs studied interictally [53,54], a
clear-cut sensitization, as reflected by a significant increase in SSEP 1st N20-P25 block amplitude, was found
during an attack, followed by a normal habituation [54].
In medication overuse headache (MOH) patients, we
managed to record SSEPs in a pain-free state or during
mild headaches and found that N20-P25 SSEP amplitude
was initially (1st block) greater in MOH patients than in
the subgroup of episodic migraineurs studied interictally
and healthy controls [54]. The increased SSEP amplitude
Page 6 of 13
in MOH was proportional to the duration of headache
chronification. We interpreted these results as reflecting
reinforcement and perpetuation of central sensitization
due to the medication overuse and increased headache
frequency [54]. We further noted that the presence of
such sensory sensitization depends on the class of drugs
overused, since initial SSEP amplitudes were smaller in
triptan overusers than in NSAIDs or combined overusers.
The abnormalities in cortical responses to somatosensory stimulation seem to be strongly influenced by
genetic factors. MOH patients carrying the D/D polymorphic variant of the angiotensin converting enzyme
(ACE), that plays a role in neural plasticity and dependence behaviour, showed less SSEP habituation, in
proportion with the duration of the overuse headache,
and increased sensitization depending on the overused
drug compared to I carriers [89].
Sensitization in migraine patients who evolved to
chronic daily headache due to medication overuse was
also demonstrated with pain-related evoked potentials
(PREPs). Ayzenberg and co-workers recorded PREPs
after electrical stimulations of cephalic (forehead) and
extracephalic (hand dorsum) sites with a nociceptionspecific electrode. They observed a significant increase
in PREP amplitudes both after cephalic and extracephalic
stimulations in all patients with MOH irrespective if they
overused NDAIDs or triptans. Withdrawal from the acute
medication overuse normalized the PREP amplitude [119].
Sensitization phenomena might also manifest themselves at the spinal level. Perrotta and coworkers explored
the spinal cord pain processing by studying threshold, area
and temporal summation threshold (TST) of the lower
limb nociceptive withdrawal reflex in a group of 31
MOH patients before and after acute drug withdrawal.
A significantly lower reflex threshold, higher amplitude
and lower TST was found in MOH patients before detoxification in comparison with episodic migraine and
controls [120]. All these neurophysiological abnormalities tended to improve after a detoxification program
[120], which was coupled with an increased activity of
the endocannabinoid system [121].
Habituation in tension-type headache
There are only a few reports about habituation in
tension-type headache (TTH).
No habituation deficit was observed with visual evoked
or event-related potentials in episodic [41] or chronic
TTH patients [34,41]. Episodic TTH sufferers had normal habituation of P300 latency, while P300 amplitude
also showed some degree of habituation, although not of
statistical significance [122].
Patients affected by chronic TTH showed a normal reducing behavior (habituation) in scalp potentials evoked
by CO2 laser stimulation (LEPs) of the hand and facial
skin [66]. Mismatch negativity, which is believed to reflect the automatic central processing of a novel stimulus, and P300 habituation were significantly lower in
migraine and TTH children than in healthy subjects in
one study, where P300 habituation also positively correlated with behavioral symptomatology [123]. In TTH,
habituation was also investigated using sympathetic skin
responses (SSR), a tool used to evaluate autonomic dysfunction. Ozkul and Ay explored SSR changes with the
same stimulus at a constant intensity by four blocks of
20 responses and found that in both episodic migraine
without aura and TTH patients there was a lack of habituation compared to normal controls [124]. The electrophysiological similarities between the episodic forms
of migraine and TTH support the hypothesis that some
patients with TTH might be at the mild end of the migraine spectrum. Since lack of habituation was not always observed in TTH, it seems to be relevant only for a
subgroup of patients.
Sensitization in tension-type headache
In TTH and in cluster headache, like in migraine, the
vast majority of neurophysiological studies have only indirectly assessed sensitization, through the measure of
the grand-average area under the curve or amplitude of
the given test.
The few studies in which the dynamic behavior of responses was analyzed using successive blocks of a few
averagings were unable to find clear evidence for
sensitization, i.e. for increased amplitude of the first
block. This was the case in episodic TTH for VEPs [41],
visual P300 [122], LEPs [123] and sympathetic skin responses [124], in chronic TTH for visual P300 [34], and
LEPs [66].
By contrast, some indirect evidence for sensitization
was found in TTH, chiefly in its chronic form, with
nociceptive specific reflexes and evoked potentials.
Normal amplitude, area, latency [125-128] and slower
recovery cycle [127] of the blink reflex R2 component
was found in chronic TTH. Two separate groups found
reduced latencies of the trigemonocervical reflex in patients with chronic TTH [129-131]. Using a nociceptionspecific electrode lower values of the normalized root
mean square and area under the curve of the blink with
control subjects [132].
More convincing evidence for central sensitization in
CTTH has come from studies of pain sensitivity in pericranial or lower limb tissues. Sandrini et al. (2006)
studying the nociceptive lower limb flexion RIII reflex
found significantly lower subjective pain thresholds and
RIII reflex threshold in chronic TTH than in controls
[115]. These findings were associated with a paradoxical
facilitation of the RIII reflex response during the cold
pressor test, which indicates deficient descending
Page 7 of 13
inhibition, an abnormality also found by others [133].
Previous studies have found normal pressure pain
thresholds (PPTs) in episodic TTH [134,135]. In chronic
TTH instead, PPTs were decreased [15,136,137] especially on the anterior part of the temporalis muscle
[15,135-139] and in the upper part of the trapezius
muscle [140]. Cathcart et al. (2010) investigated temporal summation, defined as the increase in pain perception to repeated noxious stimulation (indirect measure
of sensitization), by an algometer and heterotopic noxious conditioning stimulation (HNCS) in chronic TTH
vs. controls. Pain from repeated algometer pressures increased more in the CTTH sufferers compared with
healthy controls, both at finger and shoulder, and was
less inhibited by conditioned HNCS [141]. Lower pain
thresholds in muscle and skin of the cephalic region but
not of the extracephalic region with higher rating to
suprathreshold single and repetitive (2 Hz) electrical
stimulation were reported in patients with chronic TTH
than in healthy controls [142].
In a LEP study, the heat pain threshold was similar
in chronic TTH patients and controls at the level of
both the hand and pericranial skin. The total tenderness scores (TTS) at pericranial sites were higher in
TTH patients than in controls. The amplitude of the
N2a–P2 LEP complex elicited by stimulation of the
pericranial zone was greater in TTH patients than in
controls and this was significantly associated with the
TTS score [143].
Habituation in cluster headache and other trigeminal
autonomic cephalalgias (TACs)
During the last decades, great advance in the understanding of the cluster headache pathophysiology was
made with the modern techniques of functional neuroimaging [144]. Electrophysiological methods contributed
to the study of cognitive and nociceptive processes.
Normal cognitive habituation was found in two visual
event-related potential studies in cluster headache either
during the bout or outside, and in chronic paroxysmal
hemicrania [34,145].
Formisano et al. were the first to found abnormal habituation of the blink reflex in a small number of CH patients during the attack, but comparison with control
subjects was lacking [146]. Habituation of both the R2
and the R3 blink reflex components are impaired in CH
patients on the affected side compared to healthy controls [147]. The lack of habituation in CH patients was
even more pronounced than that found in episodic migraine [147]. We recently replicated these results by
using the nociception-specific concentric stimulating
electrode: R2 reflex area and habituation were reduced
on the affected CH side (data published in abstract form
[148]). Conversely, Holle et al. (2012) failed to detect
altered habituation of the nBR R2 in episodic and
chronic CH within or outside a bout. In the latter study,
however, the majority of CH patients were taking one or
several prophylactic medications at the time of recordings, which may biased the results [149].
Sensitization in cluster headache and other trigeminal
autonomic cephalalgias (TACs)
Classical blink reflex studies did not disclose any sign of
sensitization in CH [150,151]. In 10 episodic cluster
headache patients within a bout, Lozza et al. (1997)
found a significantly faster R2 blink reflex recovery curve
on the symptomatic side after paired supraorbital stimuli, probably reflecting an indirect sign of sensitization
within the spinal trigeminal nucleus. Furthermore, in the
same study the R2 recovery curve was faster on both affected and unaffected sides in CH patients when the
supraorbital stimulus was preconditioned by a peripheral
stimulation of the index finger. Since naloxone injection
transiently reverted this bilateral R2 sensitization, the
authors postulated that the faster R2 recovery reflects
hypoactivity of reticular nuclei, due to reduced descending opiatergic inhibition [152], a mechanism that was recently supported by functional neuroimaging studies
[153,154].
The threshold of the corneal reflex was reduced on
the affected side in a mixed group of episodic (during
the bout) and chronic CH patients, and normalized in
the remission phase [155]. Others were not able to confirm such lateralized abnormalities.
Researchers found that both in- and out-side the bout
patients had lower thresholds for pressure pain [156],
electric pain and RIII reflex [157] on the affected than
on the unaffected side both in episodic (in and outside
of a bout) and chronic CH [158]. These signs of
sensitization within the nociceptive system were coupled
with a phase shift of the normal circadian rhythmic variations in RIII threshold in episodic bouts of CH when
compared with the remission period, and with absence
of circadian rhythmicity in chronic CH patients [158].
Perrotta et al. (2013) recently studied the functional activity of the descending diffuse noxious inhibitory controls (DNIC) (or conditioned pain modulation system)
elicited by a cold pressor test (CPT) in a group of episodic CH patients during active and remission phases.
Compared to healthy subjects, the RIII reflex threshold
and TST were lower and the R2 area higher during, but
not outside of a bout. CH patients during the bout had a
significant reduction of TST compared both to controls
and to CH patients outside of a bout. Only during the
bout but not outside, the CPT had no effect on TST and
reflex area [159]. The authors concluded that CH patients have a dysfunction of the supraspinal control of
pain that depends on the clinical activity of the disease
Page 8 of 13
and leads to facilitation of pain processing predisposing
to the CH attacks.
Further evidence for lateralized abnormalities came
from the study of Procacci et al. (1989) who found cutaneous and deep hyperalgesia to both mechanical and
electrical stimuli with earlier appearance of pain after an
ischaemic test in the upper limbs on the affected side of
the body in episodic CH patients [160]. By contrast, with
quantitative sensory testing, perception of warmth, cold
and pressure pain was reduced on the cluster side as
compared with the contralateral asymptomatic side in a
pooled group of episodic and chronic CH patients
[161,162]; warm detection thresholds and thermal sensory limen on the affected side correlated negatively with
elapsed time since last attack [162].
We are aware of only one study on sensitization in other
trigeminal autonomic cephalalgias. In 12 patients with
chronic paroxysmal hemicrania and 12 with hemicrania
continua, pain pressure threshold, subjective pain perception after sural nerve stimulation as well as RIII reflex
threshold were reduced mostly on the affected side, compared to healthy subjects [163]. Moreover, although there
were no abnormalities in the blink reflex, corneal reflex
thresholds were significantly reduced on both sides only in
chronic paroxysmal hemicrania patients.
Discussion
Neurophysiological studies have disclosed various abnormalities of spinal, brainstem and cortical responsivity to
external innocuous or noxious stimuli in primary headaches. These abnormalities can be summarized as follows:
Abnormalities of the habituation/sensitization
mechanisms were discovered in migraine. In
episodic migraine, most published EP studies show
two characteristic changes: a lack of habituation on
recordings performed between attacks and
sensitization during the attack, especially with
somatosensory stimuli. The habituation deficit
normalizes during attacks, whereas sensitizations
vanishes between attacks, but in the immediate preictal phase both sensitization and deficient
habituation may variably co-exist in response to
non-noxious and pain stimuli. In patients who
developed MOH the cortical response pattern could
be locked in a pre-ictal state associating both initial
sensitization and late deficient habituation, which
contrasts with episodic migraine where these
cortical states alternate (Figure 1). Recent works
suggest that an abnormal rhythmic activity between
thalamus and cortex, namely thalamocortical
dysrhythmia, may be the pathophysiological
mechanism subtending abnormal information
processing in migraine.
Page 9 of 13
Figure 1 Schematic representation of the changes in habituation and sensitization in an healthy subject and over the migraine cycle
(interictal, ictal, and chronic migraine due to medication overuse [MOH]).
In tension-type headache, available studies are
limited. Some, though only in subgroups of patients,
found some evidence of deficient habituation, chiefly
with cognitive potentials (mismatch negativity and
P300) and sympathetic skin responses. By contrast,
using grand-average responses indirect evidence for
sensitization has been disclosed in chronic TTH
with nociceptive specific reflexes and evoked
potentials. These studies provide evidence for
generalized increased sensitivity to pain (lower
thresholds and increased pain ratings) and a
dysfunction in supraspinal conditioned pain
modulation in CTTH, which may contribute to the
development and/or maintenance of central
sensitization in this disorder.
The deficient habituation of the blink reflex found
in episodic CH patients during the bout suggests
that interictal migraine and cluster headache
probably share some pathophysiological
mechanisms. However, the more pronounced
habituation deficit found in the CH with respect
to the migraine group suggests that additional
dysfunctional neurobiological factors are at work
in CH patients. Only during the bout but not
outside, a sensitization of pain processing was
observed. Several possible non-mutually exclusive
causes could be responsible for this:
i) dysfunctioning descending aminergic, especially
dopaminergic, control [164,165], ii) malfunctioning
hypothalamo-trigeminal control [166], and iii)
altered descending opiatergic pain control system
[153,154]. Given that CH patients had no
habituation deficit of event-related potentials
[34,145], it is likely that the pathogenic factors
involved in CH produce functional changes at the
level of the trigeminal system but not at cortical
level. Altogether, these data indicate that in cluster
headache lateralised abnormalities may occur
throughout the body, probably because of
sensitization in the central nervous system and
activation of nociceptive reflexes.
Conclusions
In migraine research, progress will largely depend on a
better understanding of the mechanisms underlying the
habituation deficit, its variations with the migraine cycle
and its relation with changes in thalamo-cortical rhythms
and brain stem-(thalamo-)cortical aminergic pathways.
Future studies will have to determine whether there is
an interaction between abnormal sensory processing
and metabolic abnormalities, for instance decreased brain
ATP content.
It will also be of importance to gather more data on
the geno- phenotype correlations in migraine and in the
other primary headaches. Such genotype/phenotype correlations could help to tailor treatment to the individual
patient depending on his genetic profile [89].
In cluster headache, future electrophysiological works
should try to understand the role of the descending
monoamine and opioid systems in the mechanism of
sensitization and lateralization of pain. Moreover, they
may help to unravel the mechanisms that periodically ignite the cluster period and the culprits for the transformation of episodic into chronic CH.
Finally, better characterizing headache patients from a
neurophysiological point of view will allow to optimize
the protocols of the minimally invasive techniques and
non-invasive neurostimulation methods, and to improve
their therapeutic efficacy [96,167,168].
Abbreviations
BR: Blink reflex; CH: Cluster headache; CM: Chronic migraine;
CNV: Contingent negative variation; CPT: Cold pressor test; CTTH: Chronic
tension-type headache; EP: Evoked potential; GBOs: Gamma-band
oscillations; HFOs: High-frequency oscillations; HNCS: Heterotopic noxious
conditioning stimulation; LEP: Laser evoked potential; MOH: Medication
overuse headache; OFC: Orbitofrontal cortex; PAS: Paired associative
stimulation; PREPs: pain-related evoked potentials; PPTs: Pressure pain
thresholds; P-W: Partial-windmill; RR: Reflex response; rTMS: repetitive
Transcranial Magnetic Stimulations; SSEP: Somatosensory evoked potential;
SSR: Sympathetic skin responses; tDCS: transcranial Direct Current
Stimulations; TST: Temporal summation threshold; TTH: Tension-type
headache; TTS: Total tenderness score; W-D: Windmill-dartboard.
Competing interests
GC made substantial contributions to review the literature as well as in
drafting the manuscript. CDL, JS, and FP were implied in drafting the
manuscript. All authors read and approved the final manuscript.
Author details
1
Department of Neurophysiology of Vision and Neurophthalmology, G.B.
Bietti Foundation IRCCS, Via Livenza 3, 00198, Rome, Italy. 2Don Carlo
Gnocchi Onlus Foundation, Milan, Italy. 3Headache Research Unit, University
Department of Neurology & GIGA-Neurosciences, Liège University, Liège,
Belgium. 4IRCCS Neuromed, Pozzilli (IS), Italy.
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doi:10.1186/1129-2377-14-65
Cite this article as: Coppola et al.: Habituation and sensitization in
primary headaches. The Journal of Headache and Pain 2013 14:65.
Palmisani et al. The Journal of Headache and Pain 2013, 14:67
RESEARCH ARTICLE
Open Access
A six year retrospective review of occipital nerve
stimulation practice - controversies and challenges
of an emerging technique for treating refractory
headache syndromes
Stefano Palmisani1*, Adnan Al-Kaisy1, Roberto Arcioni2, Tom Smith1, Andrea Negro3, Giorgio Lambru1,
Vijay Bandikatla1, Eleanor Carson1 and Paolo Martelletti3
Abstract
Background: A retrospective review of patients treated with Occipital Nerve Stimulation (ONS) at two large tertiary
referral centres has been audited in order to optimise future treatment pathways.
Methods: Patient’s medical records were retrospectively reviewed, and each patient was contacted by a trained
headache expert to confirm clinical diagnosis and system efficacy. Results were compared to reported outcomes in
current literature on ONS for primary headaches.
Results: Twenty-five patients underwent a trial of ONS between January 2007 and December 2012, and 23 patients
went on to have permanent implantation of ONS. All 23 patients reached one-year follow/up, and 14 of them
(61%) exceeded two years of follow-up. Seventeen of the 23 had refractory chronic migraine (rCM), and 3 refractory
occipital neuralgia (ON). 11 of the 19 rCM patients had been referred with an incorrect headache diagnosis. Nine of
the rCM patients (53%) reported 50% or more reduction in headache pain intensity and or frequency at long term
follow-up (11–77 months). All 3 ON patients reported more than 50% reduction in pain intensity and/or frequency
at 28–31 months. Ten (43%) subjects underwent surgical revision after an average of 11 ± 7 months from
permanent implantation - in 90% of cases due to lead problems. Seven patients attended a specifically designed,
multi-disciplinary, two-week pre-implant programme and showed improved scores across all measured
psychological and functional parameters independent of response to subsequent ONS.
Conclusions: Our retrospective review: 1) confirms the long-term ONS success rate in refractory chronic headaches,
consistent with previously published studies; 2) suggests that some headaches types may respond better to ONS
than others (ON vs CM); 3) calls into question the role of trial stimulation in ONS; 4) confirms the high rate of
complications related to the equipment not originally designed for ONS; 5) emphasises the need for specialist
multidisciplinary care in these patients.
Keywords: Headache; Chronic migraine; Occipital neuralgia; Neuromodulation; Occipital nerve stimulation
1
Pain Management & Neuromodulation Centre, Guy’s & St Thomas NHS
Trust, London, UK
© 2013 Palmisani et al.; licensee Springer. This is an Open Access article distributed under the terms of the Creative Commons
Background
Chronic Daily Headache (CDH) is an umbrella term for
headache disorders with a high rate of reoccurrence (15
or more days per month for 3 consecutive months).
CDH represents a major worldwide health problem as
affects 3–5% of adults [1-3] who experience substantial
disability.
Chronic migraine (CM), the most prevalent form of
CDH, is defined as headache occurring more than 15 days/
month for at least 3 consecutive months, with headache
having the clinical features of migraine without aura
for at least 8 days per month [4]. Recently published
results from the American Migraine Prevalence and
Prevention Study (AMPP) found the prevalence of CM
in the United States is approximately 1% [5]. The World
Health Organization recognizes migraine as a major
public health problem, ranking it at 7th place among all
worldwide diseases leading to disability [6]. Compared
to episodic migraine, CM is associated with higher
disability, inferior quality of life and greater health
resource utilization [7].
Despite substantial advances in migraine therapy [8],
some individuals with chronic migraine are either resistant or intolerant to guideline-based treatments [9]. This
subset of patients requires the development of further
treatments and in recent years peripheral neuromodulation, in the form of occipital nerve stimulation (ONS),
has emerged as an option for this subset of patients
[8,10]. Several published small retrospective studies
reported promising safety and efficacy data for ONS in
primary headaches.
Open label studies in trigeminal autonomic cephalalgias have shown significant, long-term benefit in 67%
of refractory chronic cluster headache patients [10] and
in 89% of refractory SUNCT and SUNA (short-lasting
neuralgiform headache attacks with conjunctival injection and tearing/autonomic symptoms) patients [11].
Encouraging results in refractory chronic migraine patients led to three, commercially funded, multi-centre
randomized trials [12,13]. The benefits shown in these
trials were less dramatic than hoped for, however the
studies have been criticised for methodological weaknesses, unmitigated placebo effect, and a high rate of
surgical complications, which may have obscured the
full beneficial effect of ONS. Limited data on relevant
endpoints was available at the time of studies’ design
and poor endpoint choice may have masked the true
efficacy of ONS [13].
Thus, the literature leaves many questions unanswered
about the role for ONS in chronic daily headache. Our
institutions are large, tertiary neuromodulation centers
with a special interest in headaches. We agreed to pool
resources and retrospectively audit our own data on
ONS for CDH to help guide us on future clinical
Page 2 of 10
indications for ONS, identify areas for improved clinical
practice, technical practice and data collection.
This paper reports the results of our audit and relates
these to the literature. We discuss the importance of
specialists within a multidisciplinary treatment team,
question the use of temporary trials to select ONSresponders, and look at surgical strategies to limit
hardware-related complications.
Methods
Two large tertiary neuromodulation centers (Guy’s &
St Thomas NHS Trust, London, United Kingdom and
Sapienza University at Sant’Andrea Hospital, Rome,
Italy) retrospectively audited outcomes of patients receiving ONS from the previous 6 years. The audit results
were analyzed with reference to available literature on
ONS for CDH. Ethics committee approval was not required for this audit.
Audit process
All patients receiving a trial of ONS in the last 6 years
at both institutions were included in the audit. Patient
demographics, headache phenotype and technical details
of the surgical procedure(s) were collected from patient
medical records. Telephone reviews (up to three per
patient) were performed by one headache specialist for
each site (GL and PM) to confirm data accuracy, system
efficacy and, when needed, to re-code patients’ diagnosis
according to the ICHD-II classification [14].
ONS indication
At both sites, the indication for ONS was refractory
chronic headaches. Patients had failed to significantly
improve after adequate trials of four classes of preventive medicines and three classes of acute drugs with
established efficacy [15].
ONS candidates were advised not to proceed with
surgery when psychological evaluation identified conditions which could be aggravated by the treatment or
cause confusion in interpreting clinical results (including,
but not limited to, intractable epilepsy, active major
depression, psychosis, somatoform disorder, severe personality disorder).
Surgical procedure
The ONS surgical procedure was performed by four
different operators, with equipment and surgical technique (particularly lead insertion and anchoring) varying between operators and over time (Figure 1). All
patients underwent a trial of therapy. One or two percutaneous lead(s) were inserted under sedation in the
subcutaneous tissue above the peripheral branches of
the occipital nerves at approximately C1 level, and left
in place for 7 – 10 days to evaluate the efficacy and
Page 3 of 10
Figure 1 Example of 3 different approaches for ONS. From left to right, 1) single lead monolateral ONS; 2) dual lead, bilateral ONS; 3) single
lead bilateral ONS.
tolerability of the treatment before being removed. If the
trial was “successful”, i.e. the patient reported at least
50% decrease in headache intensity and/or frequency
associated with a decrease headache medication use, a
permanent implant was then performed under general
anaesthesia. Leads were implanted as in the trial, but
this time they were anchored to fascia, tunnelled, and
connected to an IPG sited in a subcutaneous abdominal
pocket. The practice of leaving stress relief loops in
each of the subcutaneous incisions was implemented in
some of the subjects implanted after the technique was
widely published as part of large multi-centre study [16].
Outcome
The patients were treated by different physicians in different centres across a 6-year timeframe and a variety of
outcomes were measured for both trial and full implant
efficacy. To homogenously evaluate ONS outcomes and
be consistent in neuromodulation trial evaluation, we
decided a patient implanted with a permanent ONS
system would be considered a “success” if a sustained
decrease of at least 50% in headache intensity and/or
frequency was reported by the patient during the telephone review. Those patients with whom we did not
make telephone contact were excluded from the outcome analysis regardless of the information reported in
their medical notes.
Cognitive Behavioural Therapy (CBT) based implant
preparation
In one of the two centres involved in the study (GSTT),
some patients were required to attend a pre-implant
programme (PIP) before proceeding to the trial stage.
The PIP involves groups of up to 11 patients engaging
in 7–9 days activity spread over two weeks. Physicians,
psychologists, physiotherapists, nurses and occupational
therapists provide a variety of broadly CBT based interventions, which explicitly seek to reduce emotional distress [17] and improve social and physical functioning
[18]. This is done by addressing an individual’s interpretation, evaluations and beliefs about their health
condition [19].
Several outcome measures are routinely collected during the course of the PIP, many of those reflecting the
IMMPACT recommendations [20] and measuring painrelated disability as a primary outcome variable. Among
those: 1) The Pain Disability Index (PDI), which measures
the extent to which chronic pain interferes with daily
activities [21]; 2) the Beck Depression Index (BDI), which
measures the severity of self-reported depressive symptoms [22]; 3) the Pain Self Efficacy Questionnaire (PSEQ),
which evaluates how confident patients feel about carry
out a variety of tasks despite their pain [23]; 4) the Pain
Catastrophizing Scale (PCS), which measures the extent
of catastrophising thoughts and feelings associated with
pain [24]; 5) the Tampa Scale of Kinesiophobia (TSK),
which is a measure of pain-related fear of movement or
re-injury [25].
Patients at GSTT who did not do a PIP attended a
“Technology Day” instead. This examines patient expectations of treatment with a psychologist, includes information and question and answer sessions given by a
physiotherapist and nurse on the stimulator itself and
briefly educates on chronic pain and ways of managing
this more effectively. Formal psychological data is not
gathered, and CBT-based interventions are not provided.
Statistics
Descriptive statistics has been used to interpret data as
appropriate, and data were presented mean ± standard
deviation if not stated otherwise. Wilcoxon signed-rank
non-parametric test has been used to compare psychological variables in the small subgroup of patients who
attended the PIP. Significance level was set at α = 0.05.
Results
Twenty-five patients underwent a trial of ONS between
January 2007 and December 2012 (Male/Female: 7/18;
Average age: 49 ± 14 years) (Table 1). Only three patients
did not report enough relief during the period of percutaneous stimulation to consider the trial a successful
(success rate = 88%), but one patient still requested and
received a permanent system. Therefore, 23 patients who
Page 4 of 10
received a permanent ONS system were included in the
following analysis (Table 2).
All patients reached one-year follow-up, and 14 of
them (61%) exceeded two years of follow-up (Average
36 ± 23 months, median 28 months). Ten (43%) subjects
underwent at least one surgical revision after an average
of 11 ± 7 months from permanent implantation, and 90%
of the revision surgeries were needed because of problems
with leads. Battery replacements were not considered as
surgical revisions, unless battery depletion was caused by
high lead impedances. Nine patients required at least one
surgical revision to replace the stimulating lead because of
displacement (3), high impedances (2), local infection/skin
erosion (2) or painful paresthesia (2). Eight subjects (35%)
had their system removed after an average implant time
of 30 ± 21 months (range 2 – 61 months), either for inefficacy (4/23), infection (1/23) or both (2/23). One
Table 1 Diagnoses, laterality and site of the pain of the sample of headache patients trialled with Occipital nerve
stimulation
Diagnosis
Pain distribution
Sex
Definitive
Preliminary
Trigger
Bilateral
Length
Area of origin
Radiation
1
F
CM
ON
No
Y
2 ys
Occipital
Vertex
2*
F
CM
CM
No
Y
16 ys
Neck/Occipital
Occipital
3
F
CM
ON
Yes (S)
Y
6 ys
Occipital
Forehead
4
F
CM
CDH
Yes (S)
Y
N/A
Ear
Ear/Face
5
F
CM
Migraine
No
N
15 ys
Eye
Eye
6*
M
CM
ON
No
N
17 ys
Eye
Forehead
7
F
CM
ON
Yes (T)
Y
1 ys
Occipital
Vertex
8
F
IIH
ON
No
Y
2 ys
Occipital
Holocranic
9*
M
CM
ON
No
Y
8 ys
Neck
Occipital
10
M
ON
ON
No
Y
10 ys
Occipital
Holocranic
11
F
ON
ON
No
Y
4 ys
Neck/Occipital
Vertex
12
F
CH
CH
No
N
5 ys
Occipital
Eye
13
M
CM
ON
No
N
N/A
N/A
N/A
14
F
ON
ON
No
Y
3 ys
Occipital
Shoulders
15
F
CM
ON
No
Y
15 ys
Neck
Temple
16
M
CM
Migraine
No
N
3 ys
Occipital
Hemicranium
17
M
CM
ON
No
Y
15 ys
Neck/Occipital
Forehead
18
F
CM
ON
No
Y
15 ys
Neck/Occipital
Eye
19
F
CM
ON
Yes (T)
Y
19 ys
Occipital
Forehead
20
M
Cerv.H.
ON
Yes (T)
Y
10 ys
Occipital
Forehead
21
F
CM
ON
Yes (T)
N
3 ys
Neck
Vertex/Eye
22
F
CM
CM
N/A
N
N/A
Temple
Temple
23
F
CM
CM
N/A
N
N/A
Temple
Forehead
24
F
CM
CM
N/A
N
N/A
Eye
Hemicranium
25
F
CM
CM
N/A
Y
N/A
Forehead
Holocranic
CM chronic migraine, IIH idiopathic intracranial hypertension, ON occipital neuralgia, CH Cluster Headache, CDH chronic daily headache, Cerv.H Cervicogenic
Headache, N/A data not available, T Post-traumatic, onset of the headache within a week following a head/neck injury, S Post-Surgical, onset of the headache
within a week from a scheduled or un-scheduled surgery; * Pts considered to have failed the ONS trial.
Diagnosis Side
shift
Origin
of pain
Implant
success
Lead(s)
Paraesthesia Last
coverage
Fw/up
Revision surgery
Time to
revision
Removal
Time to
removal
1
CM
Y
Occipital
No
1 Quadripolar
Good
77
–
–
–
–
2
CM
Y
Neck/ Occipital
No
1 Quadripolar
Excellent
–
–
–
Painful paraesthesia - inefficacy
10
3
CM
Y
Occipital
Yes (100%)
2 Quadripolar
Good
71
Battery site hyperalgesia
2
–
–
4
CM
Y
Ear
Yes (90%)
2 Octopolar
Moderate
–
–
–
Granuloma and skin erosion
29
5
CM
N
Eye
Yes (100%)
2 Octopolar
Moderate
42
–
–
–
–
6
CM
Y
Occipital
Yes (90%)
2 Octopolar
Excellent
18
Infection lead (×2)
11
–
–
7
IIH
Y
Occipital
Yes (100%)
2 Octopolar
Excellent
21
–
–
–
–
8
ON
Y
Occipital
Yes (100%)
1 Quadripolar
Excellent
28
–
–
–
–
9
ON
Y
Neck/ Occipital
Yes (70%)
N/A
Excellent
31
Tilted IPG
N/A
–
–
10
CH
N
Occipital
Yes (50%)
N/A
N/A
28
Lead replacement (High Imp.)
24
–
–
11
CM
N
N/A
No (<50%)
2 Octopolar
Poor
–
–
–
Inefficacy
54
12
ON
Y
Occipital
Yes (50%)
N/A
Good
28
–
–
–
–
13
CM
Y
Neck
Yes (100%)
N/A
Excellent
48
Skin erosion (×3)
N/A
–
–
14
CM
N
Occipital
No
N/A
N/A
–
–
–
Inefficacy and implant site infection
2
15
CM
Y
Neck/ Occipital
No
2 Octopolar
Excellent
–
1st: painful paraesthesia; 2nd: SO lead added
12
Inefficacy
35
16
CM
Y
Neck/ Occipital
No
1 Octopolar
Excellent
79
–
–
–
–
17
CM
Y
Occipital
No
1 Octopolar
Excellent
–
Lead migration
8
Inefficacy
20
18
Cerv.H.
Y
Occipital
No
2 Octopolar
Good
–
Several granulomas, lead breakage
N/A
Inefficacy and implant site infection
61
19
CM
N
Neck
Yes (50%)
2 Octopolar
Moderate
31
–
–
–
–
20
CM
N
Temple
Yes (70%)
2 Quadripolar
Poor
13
–
–
–
–
21
CM
N
Temple
Yes (50%)
2 Quadripolar
Poor
11
Lead and IPG replaced (High Imp.)
SO lead added
7
–
–
22
CM
N
Eye
Yes (50%)
2 Quadripolar
Poor
12
–
–
–
–
23
CM
Y
Forehead
No
2 Quadripolar
Poor
–
Lead migration
–
Pt request despite effective
12
Table 2 Paraesthesia coverage, types of implants, outcome, complications and removal rate of patients implanted with occipital nerve stimulation
FI full implant, IPG implanted pulse generator, N/A data not available, SO supraorbital, Paresthesia Coverage % of original painful area covered by paresthesia. Last follow/up (Fw/up), Time to Revision and Time to
removal all expressed in months.
Page 5 of 10
patient requested the removal of the system for psychological reasons despite receiving significant benefit
from it.
All 25 patients were reviewed by the headache specialists during the telephone interview. Nineteen patients
(76%) were diagnosed with refractory chronic migraine
(rCM), 3 (12%) with refractory occipital neuralgia, 1
(4%) with refractory chronic cluster headache and 2
(8%) with other forms of chronic headache (see Table 1).
Interestingly, only 7 of the rCM patients were referred
with this diagnosis for ONS, while 11/19 were wrongly
labelled as occipital neuralgia and 1/19 as chronic
headache refractory to medical treatment.
Seventeen patients with a diagnosis of rCM received a
permanent ONS system, and all but three had a successful trial before the implant (84% success rate). Two of
the subjects with an unsuccessful trial did not proceed
to the full implant. One patient, against medical recommendation, decided to undergo full implantation despite
limited benefit from the trial and reported a mild benefit
(< 50% relief ) after 5 years of follow-up.
Nine subjects (53%) reported significant pain relief
(> 50% relief in attacks’ intensity and/or frequency)
after an average follow-up of 40 ± 27 months (range
11–77 months).
In 5/17 (4 of which with sustained pain relief ), migraine attacks originated in the trigeminal nerve distribution, while 11/17 patients had their original pain in
the occipital area and of those, 5 reported significant relief over time. It should be noted that in most patients
headache pain radiates in both territories as the migraine
attacks progress.
Seven of the eight patients who had their system
removed were classified as rCM. Five were removed for
inefficacy (despite a successful initial percutaneous trial),
and one for acquired infection not responding to antibiotic therapy.
Three subjects were classified as refractory occipital
neuralgia, with a history of tenderness over the occipital area and temporary pain relief following at least one
occipital nerve block with local anaesthetic and/or steroids. All had a successful trial of stimulation and all of
them (100%) report significant relief (well over 50%
reduction in severity and frequency) after 28, 28 and
31 months of follow/up from the permanent insertion
of the ONS system, respectively.
Seven patients (6 rCM and 1 ON) attended a specifically designed, multi-disciplinary, two-week pre-implant
programme (PIP). Attending the programme was associated with improved scores across all measured psychological and functional parameters. Statistically significant
improvement occurred in the BDI scores, with a mean
decrease of 7.4 (95% CI: 2.3 – 12.5), and in the TSK
scores, with an average decrease of 8 points (95% CI:
Page 6 of 10
2.2 – 13.8). The analysed population was very small
and differences observed between responders and nonresponders did not reach statistical significance. However, long-term responders seemed to have higher values
of PCS scores before the PIP than non-responders, and
were able to decrease their BDI values during the course
more than those who failed ONS treatment.
Discussion
ONS is a promising treatment for some refractory primary headaches, but its role needs further definition.
We have presented 6 years ONS experience in two
European neuromodulation centres closely working as
twin teams with tertiary headache centres. Our data is
consistent with published studies that suggest ONS has
a place in the management of patients with refractory
chronic migraine and with refractory occipital neuralgia but that much work needs to be done to refine patient
selection and optimise the treatment. Our analysis has
highlighted important specific areas to focus on in the
future clinical and research use of ONS.
The concept of a multidisciplinary approach to
refractory headaches
In order to face the clinical challenge of refractory
chronic headaches there is a need of at least three
different specialists to be involved in the selection of
refractory headaches patients as potential candidate for
ONS: a referring headache specialist, a pain physician
with expertise in neuromodulation and a psychologist
with expertise in chronic pain. The presence of a headache specialist with expertise in ICDH-II diagnostic
classes must be considered mandatory in future. Many
patients included in our analyzed cohort were reclassified when reviewed by a trained headache specialist:
only 25% of the patients were correctly labelled as CM
at the time of the referral, and only 19% of the subjects
originally labelled as occipital neuralgia fulfilled the
ICDH-II criteria for this diagnosis. Our results are in
line with previous ONS retrospective analysis, where
patients reviewed by an headache specialist were often
re-coded [26]. As evidenced by the difference between
long-term efficacy (53% CM vs 100% ON) and system
removal rates (7 patients with CM vs 0 with ON) in
our series, correct diagnosis is essential for scientific
and economic evaluation of ONS.
Inappropriate use of the words “refractory” and “intractable” might also led healthcare professionals to improperly
label patients as “refractory” even if they have not been
on an appropriate trial of acute treatments or have never
been tried on a preventive medication at an adequate
doses for a reasonable period of time [9,15]. Efficacy of
onabotulinumtoxinA as a preventive treatment of chronic
migraine has been shown in the PREEMPT studies [27]
and it should now be added to the list of preventive
therapies to be tried before labeling a migraine patient
as refractory and offering them invasive treatments. 15
of the patients included in our series had their system
implanted before the PREEMPT publication (and therefore did not receive onabotulinumtoxinA treatment), it
is possible that some of them might have responded to
onabotulinumtoxinA treatment without the need of an
ONS implant.
Patients with chronic migraine experience the same
complex spectrum of biopsychosocial problems seen in
other chronic pain conditions [28,29]. Anxiety, depression, sleep interference, employment interference, relationship interference and decreased physical and social
activity are important factors in overall morbidity and
should be assessed and addressed. The GSTT subgroup
in our data who participated in a pre-implant pain
management approach (PIP) experienced improvement
across all measured psychosocial domains leading to
improved quality of life and health outcomes. However,
in our series more patients had a successful implant
who did not have a PIP (7/9 vs 3/7), suggesting that
while the PIP is efficacious itself, in its current form it
may not provide the best preparation of patients for an
implant. The current PIP focuses on encouraging patients to manage their pain and maximise activity and
does not focus on patient selection for ONS.
Careful assessment of psychosocial domains should
lead to improved ONS patient selection and outcomes this is widely observed recognised in other neuromodulation areas [19,30,31]. Pain duration, psychological
distress, pain catastrophising, psychiatric conditions including personality disorders, history of abuse, and significant cognitive deficits are associated with poor
outcomes from pain treatments in general [32]. Depression has been identified as the single most important
factor predictive of efficacious Spinal Cord Stimulation
[33], and other factors including somatization, anxiety,
poor coping also predict poor response [34]. Reports
on ONS to date have focussed on technical details and
patient outcomes have centred on pain scores as a
measure of patient benefit [10] and there is an absence
of literature looking at patients’ psychosocial and physical status and examining outcomes with quality of life
measures.
Stimulation trial as a reliable predictor for
long-term success
A successful temporary trial of stimulation has been
considered the best predictor of long-term outcome [35]
in different groups of chronic pain patients who are candidates for neuromodulation. However, a positive trial
does not guarantee long term success. The two largest,
multicenter, prospective trials of spinal cord stimulation
Page 7 of 10
for the treatment of chronic pain after spine surgery required a positive trial as key inclusion criteria for patients enrollment [36,37]. Despite an high initial trial to
implant ratio (83% in both studies), successful outcome
at one year dropped dramatically (55% - 47%) [37,38].
There is no available literature on the ability of a
percutaneous trial to predict long-term benefit of ONS
implant [39]. Subgroup analysis of data coming from
one large RCT of ONS in CM showed that patients
who positively responded during a percutaneous trial
before the permanent implant reported a decrease in
headache days per month significantly greater than
those who failed the trial [16]. However, only short
term data was published so we do not know if the
successful trial predicted long-term benefit. Moreover,
we do not know if a longer period of stimulation in
those who failed the trial might have resulted in benefit
in the longer term. In our series of patients, despite an
initial trial success rate of 88%, 7/23 systems were
removed due to inefficacy, and only nine subjects (53%)
with a diagnosis of chronic migraine reported significant pain relief (>50% relief in attacks’ intensity and/or
frequency) after an average follow-up of 40 months. A
retrospective review of ONS in heterogeneous headache patient population has been recently published
reporting similar data in terms of trial success rate
(89%), system efficacy (56%), and long-term benefit in
CM patients (42% at an average of 34 months) [40].
Rarely ONS-induced improvements are evident within
days, as the neuromodulatory processes involved are
believed to occur slowly in different areas of the whole
nociceptive system [10]. The reported benefit of a short
(7 – 10 days) percutaneous trial might represent a
placebo effect in a cohort of subjects who usually have
unrealistic expectations on the surgery, after having
failed most of the available treatments. The view of the
International Headache Society Clinical Trials Subcommittee is that the subjective nature of migraine features
and a high placebo effect invalidate open and singleblind trials of any prophylactic intervention and that
the number of migraine attacks and number of migraine
days should be collected prospectively for an interval of
time long enough to be compared with a prospective
baseline of at least 1 month [41]. A one or two weeks
percutaneous ONS trial will not satisfy this standard.
Furthermore, when a one-month, semi-permanent, tunnelled trial was employed to test ONS system efficacy
before implantation, the long-term outcome in CM patients was still only 47%, despite an accurate evaluation
of trial outcomes through specific pain questionnaires [26].
Therefore, the use of a trial test of ONS is now highly
questionable. Its ability to select long-term responders
appears poor and with >80% of patients going on to full
implantation anyway, a trial poses additional risk and
inconvenience for patients and an economic burden to
the health care system.
Long-term treatment efficacy
Neuromodulation is an invasive and expensive treatment,
and should be reserved for specific subset of chronic
pain patients following evidence-based guidelines [42].
350 patients have been enrolled in three large, industry
sponsored, randomized control trials in the efforts to
evaluate safety and efficacy of ONS to treat rCM
[12,13,16]. Two found no significant support for an adequate therapeutic effect (responders defined as 50%
reduction in headache days per month), and the other
found only a moderate benefit (responders defined as
30% improvement in pain) in 39% of the treated subjects.
Different study designs, with controversial end-point
choices, do not allow a direct comparison of the trials’
results. Furthermore, no conclusions on long-term treatment efficacy can be drawn as only 3 months follow/up
data have been reported to date. In our patients the
average time of system removals for inefficacy is around
23 months (range 2 – 54).
An analysis of the available ONS literature reported
long-term implant response rate is high (88% to 100%)
when peripheral stimulation is performed to elicit paresthesia in the whole painful area, compared to a low
response rate (40%) in those studies reporting nonconcordant paresthesia [43]. Some authors hypothesized that the combined stimulation of areas innervated
by both the occipital nerves (ON) and supraorbital
nerves (SON) might benefit those patients who perceived pain in a hemicephalic or global extent [43,44].
Interestingly, in our series we found no differences among
the patients who reported Excellent/Good paresthesia
in terms of long-term positive outcome (64% vs 66%),
and 4 out of 5 patients with migraine origin in the trigeminal area had good long-term outcome. Moreover
two patients had a supraorbital lead added later on in
the attempt of increase paresthesia coverage and system
efficacy, but only one of them reported significant
benefit. As adding supraorbital leads increases surgical
times and complexity, a carefully designed trial is warranted to establish the long-term benefit of this new
approach.
Hardware-related complications
Currently available ONS technology, originally designed
for epidural use, is associated with troublesome complications when used subcutaneously for ONS. Skin erosion, lead breakage, lead migration, and pain around the
battery site can occur. These are not only direct adverse
events for the patient, but also impact on ONS efficacy,
and dramatically increase health care expenditure as
further surgical procedures and new equipment are
Page 8 of 10
often required. In our series, almost 43% of the patients
required at least one surgical revision to treat such
problems. In 90% of cases leads or the intermediate
connections were the culprit. Similar numbers have
been reported in another recent retrospective review of
ONS in heterogeneous headache patient population,
with 58% of patients needing a surgical revision [40]. In
the larger RCTs, where only 3 months data have been
disclosed, surgical revision rates were already between
19% [13] and 37% [12].
Lead migration and lead breakage, major causes of
ONS-related surgical revision, are related to repeated
lead and extension traction events due to the high mobility of the implanted area. Over the years, some authors
have described techniques to minimize these complications. Bennett suggested securing each lead ipsilaterally
to the lateral pocket fascia using 2 suture sleeves separated by a strain relief loop, and anchoring each sleeve
to the fascia with 3 sutures and intraluminal medical
adhesive [16]. Franzini et al. recommend securing the
distal end of the lead to the lateral portion of the superficial cervical fascia (with two additional skin incisions)
to prevent lead migration and report no displacement
at 1 year follow-up in 17 patients [45]. Additional strain
relief loops are recommended at the upper thoracic level
(T2- T4), at the implantable pulse generator (IPG), and
at any other incisions [16]. Finally, IPG implantation
sites other than the traditional gluteal region may have
the advantage of less pathway length change during patient movement. Thus, infraclavicular and low abdomen
IPG sites may result in less lead migration/rupture [46].
This literature reveals that specialist expertise by the
neuromodulator is important factor in outcome.
Limitations
Our audit has several weaknesses. Its design is flawed
by the well-known limitations of retrospective case-series
studies [47]. Lead/anchor technology and our surgical
technique have evolved so some of the problems we
have highlighted are already being addressed. Different
measures were collected over the years, and our choice of
using patients’ subjective report of headache’s intensity/
frequency reduction to define long-term success is not
highly robust. Any prospective trial should now endorse
the outcome measures defined by Task Force of the International Headache Society Clinical Trials Subcommittee
[41]. Finally, we couldn’t collect enough information to
report and comment on medication-overuse headache.
Conclusions
Our audited series of 25 patients treated with ONS in
two tertiary neuromodulation centers is consistent with
literature suggesting that ONS is a therapeutic option
for patients with refractory chronic migraine (9 of 17
patients reporting >50% reduction in headache frequency
and or intensity at long-term follow up), and refractory
occipital neuralgia (all patients reporting >50% reduction
in pain frequency and or intensity at long-term follow up).
There is a need to refine patient selection for ONS
and ensure optimal medical, psychological and surgical
management at all stages - a multidisciplinary team comprising of headache, psychology, and neuromodulation
specialists is essential for this. Such teams should be used
in future randomized controlled trials with long-term
follow-up to further determine the place for ONS in refractory chronic headache management and improve
patient outcomes.
Page 9 of 10
9.
10.
11.
12.
13.
14.
15.
Competing interests
SP has received travel reimbursement from Medtronic and Nevro Corp.
AA has received travel sponsorship and speaker fees from Medtronic and
Nevro Corp, and he is the principal investigator in separate studies
sponsored by Medtronic and Nevro Corp.
RA has received travel reimbursement from Medtronic and Nevro Corp.
TS has received travel sponsorship and speaker fees from Medtronic and
Nevro Corp.
PM has received travel grants from Nevro Corp and St Jude Medical.
AN, EC, VB and GL do not declare any competing interest.
16.
17.
18.
19.
SP designed the study, supervised the data collection, performed data
analysis and drafted the initial manuscript. AA, RA, TS and SP performed the
surgical procedures. AN, GL and PM reviewed patient’s notes and diagnosis.
VB and EC collect data and took part in data analysis. All authors revised the
manuscript. All authors read and approved the final manuscript.
Author details
1
Pain Management & Neuromodulation Centre, Guy’s & St Thomas NHS
Trust, London, UK. 2Department of Medical and Surgical Science and
Translational Medicine, Sapienza University of Rome and Pain Therapy Unit
Sant’Andrea Hospital, Rome, Italy. 3Department of Clinical and Molecular
Medicine, Sant’Andrea Hospital, Sapienza University of Rome and Regional
Referral Headache Centre, Rome, Italy.
20.
21.
22.
23.
24.
25.
26.
27.
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Headache - Well Care Pharmacy