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Abstract

Background

Cranial autonomic parasympathetic symptoms (CAPS) appear in at least half of migraine patients theoretically as a result of the release of peptides by the trigemino-vascular system (TVS). Cranial pain pathways become sensitised by repeated episodes of TVS activation, leading to migraine chronification.

Objective

The objective of this article is to correlate the presence of CAPS with serum levels of vasoactive intestinal peptides (VIP) and calcitonin gene-related peptide (CGRP).

Patients and methods

Patients with chronic migraine (CM) were asked about the presence – during migraine attacks – of five CAPS, which were scored from 0 to 10 by using a quantitative scale. Serum VIP and CGRP levels were determined by ELISA.

Results

We interviewed 87 CM patients (82 females; mean age 44.7 ± 10.6 years). Seventeen had no CAPS, while 70 reported at least one CAPS. VIP levels ranged from 20.8 to 668.2 pg/ml (mean 154.5 ± 123.2). There was a significant positive correlation between scores in the CAPS scale and VIP levels (Spearman correlation coefficient = 0.227; p = 0.035). VIP levels were significantly higher in CM patients by at least one point in the scale vs those with 0 points (p = 0.002). Analysing symptoms individually, VIP levels were numerically higher in those patients with symptoms, though they were significantly higher only in those patients with lacrimation vs those without it (p = 0.013). There was no significant correlation between CGRP levels and the score in the CAPS scale.

Conclusions

Serum VIP, but not CGRP, levels seem to reflect the rate of activation of the parasympathetic arm of the TVS in migraine.

Keywords

Chronic migraine cranial autonomic parasympathetic symptoms CGRP VIP

Introduction

Migraine pain is the result of the activation of the trigemino-vascular system (TVS), which releases vasoactive neuropeptides, mainly calcitonin gene-related peptide (CGRP) and vasoactive intestinal peptide (VIP) around leptomeningeal and extracranial vessels (1). It is hypothesised that cranial pain pathways become sensitised by repeated episodes of TVS activation, leading to migraine chronification (2,3). CGRP has an important role in migraine. CGRP is the only neurotransmitter reliable released, by the afferent arm of the TVS, in acute migraine attacks at present (4,5), and intravenous (iv) CGRP causes headaches in patients with migraine (6). Continuous release of CGRP is able to induce central sensitisation of pain pathways (7 –9), and plasma CGRP levels have been shown to be increased in patients with chronic migraine (CM) (10). In addition, CGRP antagonists are effective in the acute (11) and preventive (12) treatment of migraine.

Unquestionably, the trigeminal nerve, with its main transmitter CGRP, is crucial, but activation of the cranial autonomic parasympathetic efferent arm of the TVS seems to play a role in migraine pathophysiology (13,14). Cranial parasympathetic autonomic symptoms (CAPS) appear in more than half of migraine patients (15 –22). Using a quantitative scale we were able to show that CAPS are not the exception but the rule in CM patients (23). This concurs with the reported increase in plasma levels of the parasympathetic marker VIP in CM patients (24), though this elevation was less consistent than that seen for CGRP (10).

The aim of our work was to correlate the presence and grade cranial parasympathetic activation as measured by a numeric CAPS scale with blood levels of CGRP and VIP in a series of CM patients.

Patients and methods

Consecutive adult patients attending our headache clinic diagnosed as having CM according to current criteria (25) were included in this study. CAPS were evaluated by using an ad hoc scale (23). As in previous work (23), patients were interviewed by a neurologist and explicitly asked whether they experienced each of the following five CAPS with their headaches: lacrimation, conjunctival injection, eyelid oedema, sensation of ear fullness and nasal congestion and/or rhinorrhoea. We graded each CAPS as 0 (absent), 1 (present but mild) and 2 (present and conspicuous). Therefore, the score in this CAPS scale ranges from 0 to 10 points. Clinicians interviewing CM patients and biologists performing laboratory determinations were blinded to VIP levels and CAPS scores, respectively.

Patients rested in supine position and blood samples were obtained from the right cubital vein between 9:30 a.m. and noon in a fasting condition. The blood was collected and allowed to clot and serum was separated after centrifugation at 2000 g. Aliquots were stored at −80℃ until assayed. All samples were obtained in the absence of acute moderate-severe pain and the participants had taken no symptomatic medication in the previous 24 hours. Serum levels of CGRP and VIP were determined using commercial enzyme-linked immunosorbent assay (ELISA) kits (USCN Life Science Inc., Hubei, China) strictly following the manufacturer’s instructions. Absorption levels were measured with a spectrophotometer from Bio-Rad (Hercules, CA, USA). The detection limit of the assay was <4.3 pg/ml for CGRP and <2.34 pg/ml for VIP. The protocol was approved by our ethics committee and all patients signed an informed consent.

Mean ± standard deviation, median and range were used to describe continuous variables while absolute and relative frequencies were used to describe the categorical ones. Kolmogorov-Smirnov goodness of fit test was used in order to check the normal distribution. Standard robust Student-Welch (SW) or non-parametric Mann-Whitney (MW) tests, depending on the normal distribution, were applied to compare the values of the variables among groups. Spearman correlation coefficient was used to measure the linear relationship between CAPS scale and VIP and CGRP levels; 95% confidence intervals (CIs) were also provided. Naïve Bootstrap method was employed in order to make inferences on the Spearman correlation coefficient, both CIs and hypothesis testing. P values below 0.05 were considered significant. All analyses were performed with the free available software R.3.1 (www.r-project.org)

Results

A total of 87 CM patients were included in the study. Their mean age was 44.7 ± 10.6 years (median 45, range 19–65); only five (5.7%) were males. Seventeen (19.5%) CM patients had no CAPS, while 70 (80.5%) reported at least one CAPS. Both the mean and median of CAPS were two (Figure 1).

Figure 1.

Frequencies histogram for the score distribution.

VIP levels ranged from 20.8 to 668.2 pg/ml (mean 154.5 ± 123.2, median 109.8) and were higher in patients with one or more points in the scale than in patients with zero points (MW p = 0.002). Analysing individual symptoms, VIP levels were only significantly higher in those patients with lacrimation vs those without it (Table 1). In addition, a significant positive correlation of small magnitude between scores in the CAPS scale and VIP levels was found (Spearman correlation coefficient = 0.227 (0.021–0.452) (p = 0.034) (Figure 2).

Figure 2.

Box-plot for vasoactive intestinal peptide (VIP) levels by score punctuation. Dots represent mean values and the dashed line stands for the regression trend.

Table 1.

VIP and CGRP levels in CM patients with and without CAPS.

	VIP levels			CGRP levels
	No	Yes	p value	No	Yes	p value
Conjunctival injection	137.1 ± 112.8	176.8 ± 133.7	0.146	62.9 ± 31.6	70.3 ± 29.6	0.270
Lacrimation	125.7 ± 108.3	185.4 ± 131.8	0.024	62.5 ± 30.7	70.1 ± 30.8	0.252
Eyelid oedema	135.2 ± 94.9	187.6 ± 146.9	0.093	63.2 ± 31.6	71.3 ± 29.2	0.230
Nasal congestion	158.4 ± 126.8	138.5 ± 108.9	0.521	65.2 ± 32.9	69.9 ± 20.5	0.455
Ear fullness	150.0 ± 130.6	164.9 ± 105.5	0.579	65.7 ± 31.1	67.1 ± 30.8	0.855
CAPS	87.7 ± 66.8	170.7 ± 129.1	<0.001	60.8 ± 34.9	67.4 ± 29.9	0.479

VIP: vasoactive intestinal peptides; CGRP: calcitonin gene-related peptide; CM: chronic migraine; CAPS: cranial autonomic parasympathetic symptoms.

CGRP levels ranged from 11.4 to 157.7 (mean 66.1 ± 30.8; median 61.4). There was a non-significant correlation between CGRP levels and the general score in the CAPS scale (Spearman correlation coefficient = 0.097 (–0.121; 0.302) (p = 0.370). CGRP levels were also similar in those patients with or without positive punctuation in CAPS and no relationship with the individual CAPS symptoms was found (Table 1).

Discussion

The main finding of this study was that serum VIP, but not CGRP, levels correlate with the presence of CAPS symptoms as measured by a quantitative scale. VIP levels in patients with one or more points in the scale were higher than the levels in patients with zero points. As already shown for cluster headache (26), serum VIP levels, therefore, seem to reflect the rate of activation of the cranial parasympathetic system in migraine. According to our data the increased activity of the cranial parasympathetic system in CM does not seem to be just a passive phenomenon secondary to the release of CGRP due to trigeminal activation.

In theory, together with CGRP, peripheral VIP levels could contribute to objectively monitor migraine status and response to preventive treatments (27,28), which could be of specific help for a more objective follow-up of patients included in clinical trials, especially in those involving the cranial parasympathetic system, such as the stimulation of the sphenopalatine ganglion (29). As an example of this, both CGRP and VIP blood levels have been shown to be significantly higher in CM patients responding to onabotulinumtoxinA as compared to nonresponders (27). CGRP levels were sensitive, very specific and had a high potency to predict response to onabotulinumtoxinA, but about half of CM patients with good response can have CGRP levels in the range of controls. These results could suggest that, together with CGRP, there are probably other molecules involved in the pathophysiology of CM, such as VIP, pituitary adenylate cyclase-activating polypeptide (PACAP) or peptide histidine methionine (PHM), which are stored and released by the parasympathetic arm of the TVS (7,13).

There are several arguments supporting an involvement of the cranial parasympathetic system in CM pathophysiology, at least in some patients. Leaving the high prevalence of CAPS in migraine and specifically in CM patients aside (23), VIP levels are increased in CM outside of migraine attacks (24), which could be interpreted as a distant sign of a rather permanent activation of the parasympathetic arm of the TVS contributing to sensitisation of perivascular leptomeningeal sensory afferents and, as a result of this, to chronification of migraine pain. Facts such as the increased VIP levels in a high proportion of CM with excellent response to onabotulinumtoxinA (27) and normal CGRP levels or the response of some CM patients to sphenopalatine ganglion stimulation (29) further support a role for the cranial parasympathetic system in the pathophysiology of CM. This would also explain in part why some migraine patients do not seem to respond to gepants (12), the pure CGRP antagonists, or even to the new monoclonal CGRP antibodies (30,31), according to the first reported data.

This study has several limitations. First, data shown here include a limited number and selected clinical population of CM patients. Second, the true specificity of VIP (and CGRP) increase in CM is not known. One of our potential confounders could be the fact that, due to ethical reasons, most CM patients tested here were on oral preventives. However, this could make our results even more relevant as these drugs should theoretically reduce the TVS activation and as a consequence would decrease neuropeptide release. Third, we have not measured the levels of other parasympathetic peptides, especially PACAP, which seem to play a crucial role in migraine and CM pathophysiology (32,33). Finally, we are aware that, as occurs with the numeric 0–3 pain scale, our CAPS scale contains an unquestionable subjective component. To try to avoid potential bias, both clinicians interviewing CM patients and biologists performing the VIP ELISA assays were blind to laboratory determinations and CAPS scores, respectively. Considering all these limitations, our results confirm that some rate of non-passive activation of the cranial parasympathetic arm of the TVS occurs in CM patients, as shown by our concurring clinical and laboratory data. This activation can be quantified, which could be of interest for a more objective follow-up of our CM patients.

Article highlights

Low-grade cranial autonomic parasympathetic symptoms (CAPS) appear in around 80% of chronic migraineurs (CM) during attacks.

Serum levels of vasoactive intestinal peptides (VIP) correlate with the presence of CAPS and seem to reflect the activation of the trigemino-vascular system (TVS).

The absence of correlation of CAPS and calcitonin gene-related peptide (CGRP) plasma levels suggests that the increased activity of cranial parasympathetic system in CM may be not just a passive phenomenon secondary to the release of CGRP due to trigeminal activation.

Footnotes

Acknowledgements

Authors were responsible for conception and design (JP, ECM), acquisition of clinical data (NR, AIP, LV, CG, JM, JP), analysis and interpretation of data (ECM, NR, PMC, ESP, JP), drafting of the manuscript (JP), obtaining funding (JP, ECM) and supervision (JP).

Declaration of conflicting interests

The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: JP reports consultancy for Allergan. The rest of authors report no disclosures.

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: this study was supported by the PI14/0020 FISSS grants (Plan Nacional I + D + I, Fondos Feder, ISCIII, Ministry of Economy, Spain).

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Relationship between serum levels of VIP,but not of CGRP,and cranial autonomic parasympathetic symptoms: A study in chronic migraine patients

Abstract

Background

Objective

Patients and methods

Results

Conclusions

Keywords

Introduction

Patients and methods

Results

Discussion

Article highlights

Footnotes

Acknowledgements

Declaration of conflicting interests

Funding

References