DrE is a multi-factorial OS disease that is also known to occur with other ocular symptoms, tear film homeostasis imbalance/loss, OS damage as well as inflammation, in addition to neurosensory abnormalities which are involved in its etiology [15]. In ophthalmology, histopathological studies for diagnostic purposes in OS-related diseases have been increasing in recent years. The findings that resulted from this current study might provide important information about the pathogenetic effects of migraine on the OS in pediatric patients diagnosed with migraine.
Currently, within the literature, there is not a high volume of articles evaluating tear function in adult migraine patients [15, 18]. Evaluated in this current study, were the OSDI questionnaire, TBUT, STT, and CIC by dividing pediatric patients with migraine into subtypes as migraine with and without aura to investigate whether or not OS changes developed in children diagnosed with migraine and then compare the results obtained with those of healthy children. With CIC, morphological, cytological, and immunocytological changes associated with DrE can be analyzed by taking samples from the conjunctival surface [19]. With this method, it is possible to detect OS changes like squamous metaplasia or goblet cell loss during the early stages [20, 21]. When the pathological materials taken were grouped according to the Nelson classification, grades 0–1 was normal; grades 2–3 was considered abnormal [16].
Among the important aspects of our research was our investigation of cytological changes in pediatric patients with migraine by CIC, which has been recommended by some researchers as the gold standard when testing for DrE-D. The findings that resulted from this current study might provide important information about the pathophysiological effects of migraine on tear functions in pediatric participants [15].
Based on the findings obtained in this current study, there were no participants that had abnormal cytology such as grade 2 and grade 3. A decrease that was statistically significant was seen in the GCD in both of the PMP sub-Groups compared to the HPP Group. Some of the patients in the PMP Group exhibited grade-1 cytology, which was characterized by the presence of epithelial cells that were slightly large and polygonal, a nucleus-to-cytoplasm ratio of 1/3, and the GCD which exhibited a slight decrease.
There may be several reasons why the CIC on the OS did not change as morphological grades 2 and 3 in the participants in the PMP Group: 1) Because the study population was made up of pediatric patients, morphological changes on the OS may not have occurred yet, since the disease duration was shorter 2) It may be that the regeneration capacity of the cells in the pediatric population is higher than in the adult population and that the regeneration ability has prevented the changes in the conjunctival morphology. 3) Due to the nature of our study, it may be that we did not choose to include patients diagnosed with DrE who were morphologically grades 2 and 3. Another important finding of this study was that the histopathological abnormalities as well as the GCD, exhibiting a decrease, were strongly associated with migraine with aura. The low TBUT and STT values shown in children with migraine were also supported by histopathological findings in the conjunctival material taken.
In the literature, it has been shown that DrE that is immune-mediated and/or inflammatory can occur in adult patients with migraine [18]. The histopathological abnormalities and decreased goblet count observed in the CIC in this study can be considered as the cause of migraine causing inflammatory pathways, which may in fact play a role in changes seen in clinical manifestations related to tear function in children.
Mucin, water, and lipid are the main constituents making up the tear film. Pediatric patients with migraine are at risk of adverse effects on these components. The low STT results in our study may be related to lacrimal gland dysfunction (GD), which is the gland in control of secreting the watery parts of tear film. The cornea is densely packed with nerves, which transverse along the path of the ophthalmic section of the trigeminal nerve. Some animal studies have suggested the reason for the decreased tear secretion may have a connection with decreased trophic effect from the trigeminal sensory nerves that are located on the cornea and conjunctiva [22]. In another study, it was shown that the length as well as the density of the trigeminal nerve fiber decreased in patients diagnosed with migraine [23]. The reason for the low STT results in our study may be the effect of a reduction in the excitatory signals coming from the OS and going to the lacrimal gland as a result of decreased corneal sensation.
The TBUT test shows any instability that is present in the tear film. This test is not just for the absence of the film’s aqueous layer, it is also for the deficiency of the mucin and/or lipid component of the film which is produced via the meibomian glands as well as the conjunctival goblet cells. The low detection of the TBUT test may be related to the decreased mucin content together with the decreased goblet cells. Another possible mechanism for the low TBUT values in these patients may be the effects of lipid metabolism detected in patients with migraine [24]. The lipid layer protects against premature film evaporation and ensures its continuity. Another possible mechanism for the low TBUT values in these patients is thought to be associated with an accompanying lipid layer disorder and meibomian GD in pediatric patients with migraine [24].
Meibomian GD should be taken into consideration as possibly being a mechanism for these changes in the OS associated with pediatric migraine patients and DrE. However, the validity of this hypothesis should be tested with further investigations such as meibography, with further studies investigating the association with pediatric migraine patients and DrE at longer follow-up.
According to the consensus in both the literature and ophthalmology practice, the detection of TBUT results < 10 s and STT results < 5 mm is considered to be in favor of DrE. According to the results obtained this current study, although the measurements for the STT and TBUT were not as high in the children diagnosed with migraine, the median values obtained for these groups were not considered to be low enough to be seen as abnormal for either test or to diagnose DrE-D.
However, it is of high importance to detect early changes in objective clinical examinations related to tear function, especially when taking into consideration the chronic course of DrE-D starting from the point of diagnosis until the end of the patient’s life.
Köktekir et al.25 with 33 adult migraine patients and 33 control patients, and also Saraç et al.18 with 46 adult migraine patients and 50 control patients, found statistically significantly lower TBUT and STT values in adult patients with migraine. Similarly, Çelikbilek et al.15 found lower TBUT and STT values in adult patients with migraine, although it was not statistically significant. In this context, the findings obtained in this current study, which comprised pediatric participants, are quite consistent with reported results in the literature. Another important outcome determined in our study was that worse STT and TBUT values were seen in the PMP aura-positive group. These results are in agreement with previous studies. Although all these studies were performed on adult participants, our results in this study have indicated that one should expect to see effects that are similar to this in pediatric participants with migraine. The strength of this study is that it evaluates DrE parameters in pediatric participants diagnosed with migraine and is the first study on this subject.
When OSDI scores are evaluated, there are 2 possible outcomes: first, values of 0–25 are normal; Second, values > 25 are considered in favor of DrE-D. The OSDI is a clinician's quantitative measure of the effects of DrE-related ocular irritation symptoms, consisting of subjective assessments of the patient to assess how severe the DrE is. Schiffman et al.16 reported a specificity of 79% and a sensitivity of 60% for the OSDI questionnaire. The sample of this current research did not include DrE patients. Moreover, the OSDI scores recorded in both of the groups were well within a normal range. In this study, the results of the OSDI scores and the objective test results, like the TBUT and STT, which were determined to be worse in the participants diagnosed with migraine, were not combined. There could be several reasons for this situation. The first reason may be that the patients in the study group consisted of a pediatric population. A study done by Han et al.26 showed that children diagnosed with DrE may not exhibit the same number of symptoms of as adults diagnosed with similar DrE conditions. A possible explanation for this might possibly be that children may not have the same level of discomfort or pain, and therefore they may describe the discomfort caused by OS disorder less [26]. Second, it may have something to do with the method in OSDI scoring having a subjective nature and the fact that the sample was not made up of actual DrE patients. Also, this is not that unusual, because in previous studies, some researchers likewise reported a discrepancy similar to this between the OSDI score and tests like the TBUT and STT [16].
Although the pathogenesis of migraine has not been clarified, it is thought to be a type of neurovascular headache [18]. Neural events have an effect on blood vessels by causing them to dilate, exacerbating pain, and leading to greater activation of the nerves [27]. Trigeminovascular input coming from the meningeal vessels is the main pain pathway. However, the exact mechanism by which migraines are triggered and the sequence of events after being activated have not yet been fully understood. The cornea is made up of very densely packed trigeminal nerve endings that are believed to have involvement in the process of headaches with pain [28]. Kinard et al. conducted an investigation of the structural differences occurring in corneal nerve plexuses in patients diagnosed with chronic migraine via in vivo corneal confocal microscopy [23]. The density and length of nerve fibers were found to be lower in the patients diagnosed with migraine than in the healthy individuals in their study. These results are supportive of the hypothesis that the trigeminal system has a vital role in the way in which migraines develop [18]. These findings showed consistency with the results obtained for the CIC, STT and TBUT, which were determined to be more significant in the aura-positive migraine patients in our study. Future studies with focus on treatments for objective DrE in patients diagnosed with migraine, and especially with aura-positive migraine patients, may be able to reveal clearer insight regarding this connection.
Compared to the literature, the patient population was pediatric, and the patients were grouped as aura-positive migraine patients and aura-negative migraine patients, which were strengths of this research. This study expands our knowledge on this subject and makes two important contributions to the literature: 1) Although there is no DrE in patients diagnosed with migraine, DrE may start in the pediatric period, especially in the aura-positive migraine patients. 2) Contrary to the previous studies, it is important to remember that patients with migraine may have DrEs, not only in the adult population but also in the pediatric population. Based on this information, possible DrE findings should be considered, especially in pediatric patients with migraine resistant to conventional treatments.
The limitations of our study are as follows: meibography, in vivo confocal microscopy, and the absence of tear film osmolarity were not used. In addition, whether the diseases are acute or chronic does not have the same effect on tear function. Conducting a sub-group analysis with the aim of determining the duration of migraine in patients could provide important insight regarding the risk that is associated with OS damage. As far as we have been able to determine, this study represents the first research to have evaluated tear function parameters in pediatric patients with migraine and divided and evaluated pediatric patients based on whether they were aura-positive or aura-negative. Examination of tear function by subjective (OSDI questionnaire), objective (STT and TBUT), clinical and laboratory investigations (CIC), and then reporting these results comprise the important strengths of this work.
In summary, changes occur in the OS in children diagnosed with migraine. These changes are also demonstrated by the STT, TBUT measurements, and histopathological evaluation from the conjunctiva. Significant changes in the histopathological as well as the clinical findings are seen more prominently, especially in aura-positive migraine patients.