Response to Oterino et al.: Analysis of endothelial precursor cells in chronic migraine: A case-control study

We have carefully reviewed with great interest the article entitled “Analysis of endothelial precursor cells in chronic migraine: A case-control study” by Oterino et al. (1). The authors studied total endothelial progenitor cells (EPCs) (CD34+/KDR+), EPC colony-forming units (CFUs), “early” EPCs (CD62E-) and “late” EPCs (CD62E+). CFUs and total EPCs showed no differences among patients with chronic migraine, sporadic migraine or controls. However, mature EPCs with CD62E positivity were higher for both types of migraine. In contrast with these findings, we reported decreased EPCs for episodic migraine and our results reproduce those of Lee et al. (2,3).

These differences are conditioned by several factors such as the mean age of the subjects included and the migraine duration. They were lower in the study by Oterino and colleagues and this may influence the results considering we have reported a correlation between the duration of the disease and the number of EPCs. We showed a decrease of EPCs for those patients with a longer duration of migraine.

Endothelial dysfunction is thought to play a role in migraine pathophysiology. EPCs can help in analyzing the relationship between migraine and vascular damage. For this reason we excluded in a strict manner most of the known vascular factors related to vascular diseases. We did not include patients with chronic consumption of anti-inflammatory treatment either, in contrast with 54 patients in the present study. Anti-inflammatory treatment may have an influence in endothelium, thus the number of EPCs may vary. Interestingly this number did not change in relation to medication overuse. Information about antihypertensive drugs or statins consumption would have been useful, as they can also influence the endothelial function and the number of EPCs. Patients under these treatments were excluded from our study.

Likewise, it is possible that these facts can contribute to explain the lack of differences found by Oterino et al. for calcitonin gene-related peptide (CGRP) serum determinations between migraineurs and nonmigraineurs, which constitutes an unexpected result, as CGRP is a well-known marker for migraine. In contrast to the findings by Oterino et al., we reported significantly higher CGRP levels in migraine patients.

We confirmed the endothelial origin of our EPCs by immunohistochemistry (CD31 or KDR) but identification of early and late EPCs was not performed. Oterino et al. used flow cytometry with expression of CD34+/KDR+. At present the most accepted methodology is flow cytometry. Nevertheless, several studies have obtained the same results using both tecniques (4).

Migraine is a dynamic disease in which molecular factors may influence and be influenced by other biological markers, thus timing is crucial in the analysis of the different findings. Avoiding isolated determinations in order to clarify the interaction among biomarkers remains critical to elucidating the pathophysiology of this disease. Mechanisms determining progression from episodic to chronic migraine are still not well established. Disease duration, age, vascular risk factors, differentiation between ictal or interictal periods and symptomatic and preventive treatment are data of high interest and may modify the results of different studies. Therefore, more investigations are needed to establish the exact correlation between EPCs and migraine.