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

To the editor:

We have read the articles “Relationship between serum levels of VIP, but not of CGRP, and cranial autonomic parasympathetic symptoms: A study in chronic migraine patients” by J Pascual et al. (1), published online first in Cephalalgia, with great interest. The authors performed a cross-sectional survey of 87 chronic migraine (CM) patients (82 females; mean age 44.7 ± 10.6 years) to correlate the presence of cranial autonomic parasympathetic symptoms (CAPS) with serum levels of vasoactive intestinal peptides (VIP) and calcitonin gene-related peptide (CGRP). The authors concluded serum VIP, but not CGRP, levels seem to reflect the rate of activation of the parasympathetic arm of the trigemino-vascular system (TVS) in migraine. There is the major strength that this study focused on the neurotransmitters such as CGRP and VIP which were associated with chronic migraine. However, we would like to make some comments about this study for the benefit of the readers.

First, even if it was important that the authors compared CGRP and VIP serum levels depending on CAPS in chronic migraine patients, we think the authors should compare CGRP and VIP serum levels between CM patients and control healthy subjects, free of any type of headache. Normal values of serum VIP range from less than 75 to 190 pg/mL, although normal value ranges may vary slightly among different laboratories (2).

Second, the authors described the participants’ information focusing on CAPS associated with CM. However, the authors did not mention other conditions and diseases that can cause the elevation of serum VIP and CGRP. So far, there are some studies that have found serum VIP levels are significantly higher in patients with acute exacerbation of chronic obstructive pulmonary disease, atopic dermatitis, adenocarcinomas of the gastrointestinal tract, and allergic rhinitis (3–6). In particular, an elevated serum VIP level (>200 pg/mL) is diagnostic for VIPoma, a pancreatic neuroendocrine tumor that secretes VIP (7). Since serum VIP levels in this study ranged from 20.8 to 668.2 pg/ml, we wonder if the authors ruled out various diseases.

Third, a significant positive correlation between scores in the CAPS scale and serum VIP levels was found in this study, but the magnitude of the correlation is small (Spearman correlation coefficient = 0.227). We think the factor that can affect this correlation is the effect of plasma hemodiultion, as serum CGRP and VIP levels are very low. Hemodilution refers to reduced concentrations of analytes in the blood secondary to increased fluid volume. Given that obesity is associated with expanded vascular volume, hemodilution may result in a lower ratio of blood concentrations of analytes among heavier subjects (8). Therefore, we think the authors should perform the statistical analysis after calibration of serum VIP and CGRP levels according to individual BMI.

Last, we want to emphasize the trigemino-vascular system (TVS). TVS consists of a brainstem connection between trigeminal afferents and parasympathetic efferents of the facial nerve that synapse in the sphenopalatine ganglion. Activation of this reflex releases pain-producing, vasoactive neuropeptides, mainly CGRP in the case of the afferent trigeminal arm and VIP and pituitary adenylate cyclase activating polypeptide (PACAP) via the parasympathetic efferents around the leptomeningeal and extracranial vessels (9). Therefore, we think the conclusion of this study was somewhat predictable.