Abstract
Background
Allodynia is prevalent in adults with migraine and has been associated with long disease duration and severe course. Studies of the pediatric population are sparse. The aim of this study was to evaluate the rate of cephalic cutaneous allodynia in children and adolescents within the first 6 months of migraine onset and to identify associated clinical and migraine-related parameters.
Methods
The electronic database of a tertiary pediatric headache clinic from 2014 to 2017 was retrospectively searched for all children and adolescents diagnosed with migraine headache within 6 months or less of symptom onset. Cephalic cutaneous allodynia was identified by validated questionnaire. Demographics, symptoms, and headache-related parameters were compared between patients with and without allodynia.
Results
The cohort included 119 patients, 69 girls (58.0%) and 50 (42.0%) boys, of mean age 11.6 ± 3.6 years. Mean time since onset of migraine disease was 3.6 ± 1.8 months. Cephalic cutaneous allodynia was reported by 31.1% of patients. It was significantly associated with female gender (p = 0.03), older age at admission (p = 0.037), older age at onset (p = 0.042) migraine with aura (p = 0.002), and higher rate of awakening pain (p = 0.017).
Conclusions
Cephalic cutaneous allodynia may occur in children and adolescents already in the first 6 months of migraine onset. Contrary to adult studies, we found no association of allodynia with migraine frequency or long disease duration. Allodynia was significantly associated with migraine with aura, female gender, and awakening pain. A genetic tendency may contribute to the appearance of allodynia in the pediatric age group.
Introduction
Cutaneous allodynia is defined as pain provoked by stimulation of the skin that would ordinarily not produce pain (1). It is considered a clinical expression of central nervous system sensitization in migraine. Migraine headache is characterized by dysfunction of central nervous system structures involved in the modulation of neuronal excitability and pain (2). Migraine is thought to be induced by activation of the trigeminovascular pathway by pain signals that originate in nociceptors innervating pial, arachnoid, and dural blood vessels, as well as large cerebral arteries and sinuses (2). There is evidence that activation and sensitization of the trigeminovascular system are also involved in the progressive development of cephalic and whole-body cutaneous allodynia during migraine attacks (3).
Studies in adults with migraine report an estimated prevalence of allodynia ranging from 57.1% to 79% (4–7). The allodynia was found to be associated with aura, nausea and vomiting, and phonophobia and photophobia in addition to longer duration of attacks, higher frequency and severity of attacks, and chronicity (7), especially when migraine is untreated (8). The presence of allodynia may also indicate a poor response to triptan treatment (9).
In children and adolescents with migraine, however, allodynia has hardly been investigated. The few small cohort studies that have been performed estimated that allodynia has a lower prevalence in the pediatric than the adult population (10,11). The aim of the present study was to investigate the rate of cephalic cutaneous allodynia in pediatric migraineurs within the first 6 months of migraine onset. We also sought to determine the association of allodynia with clinical and migraine-related parameters in this group.
Methods
Patients and setting
The electronic database of a headache clinic of a tertiary, university-affiliated, pediatric medical center was searched for all children and adolescents aged 3–18 years who were diagnosed with migraine headache within 6 months or less of disease onset during 2014–2017. The diagnosis was re-evaluated for this study according to the International Classification of Headache Disorders (ICHD)-III beta version (12).
The study was approved by the Research Ethics Committee of Rabin Medical Center (approval no. RMC-110-17). Owing to the retrospective design, the committee waived the need for informed consent.
Headache clinic protocol
At the first visit to the headache clinic, children and their parents, or only the parents of very young children, are interviewed by the senior physician who heads the clinic (T.E.-M.) or a departmental resident using a questionnaire based on the ICHD-IIII beta version. Questionnaire items include the frequency, duration, and nature of the headache attacks, time from the start of the headaches to presentation at the clinic, and related symptoms including allodynia. If a discrepancy arises between the reports of a child and his/her parent(s), the anamnesis is extended by requesting both the parent and the child to repeat the description of the headache episodes and other symptoms in greater detail. This also ensures that the child understands the questions. For very young children with limited verbal communication, headache frequency and symptoms are determined by the child’s complaints and the parents’ impression from the child’s behavior (according to the criteria of the ICHD-III beta version). All patients initially interviewed by a resident must also be seen by the head of the clinic before any decisions. The final diagnosis is reached only after follow-up with a review by the head of the clinic of all data collected during all the patient’s clinic visits.
In our pediatric headache clinic, allodynia is routinely identified by a positive response to at least two of the following questions (10):
During a headache attack, have you ever had an unpleasant sensation when combing your hair? Do you try to avoid combing your hair when you have an attack? During a headache attack, have you ever had an unpleasant sensation when touching your head? Do you try to avoid touching your head when you have an attack? During a headache attack, does it bother you to wear an object on your head or neck, such as jewelry, glasses, hat, etc.? During a headache attack, does it bother you to have a ponytail?
Study procedure
Data on demographics, headache symptoms, and other clinical headache-related parameters were retrospectively collected from the medical files of the patients who were found to be eligible to participate in the study. The findings were compared between patients with and without allodynia.
Statistical analysis
With a proposed sample size of 85 and 45 for patients with and without allodynia, respectively, the study would have 80.8% power to yield a statistically significant result. This computation assumes that the difference in proportions is 0.25 (specifically, 0.25 versus 0.50).
Data were analyzed using BMPD software (13). Continuous variables were calculated as means and standard deviations and compared between groups using analysis of variance. Parameters that did not have a Gaussian distribution were compared between groups using the nonparametric Mann-Whitney U-test. Discrete variables were calculated as numbers and percentages and compared between groups using Pearson’s chi-square. A p value of ≤ 0.05 was considered significant. Odds ratios (OR) and 95% confidence intervals (CI) were determined. The effect size for continuous variables was calculated with Cohen’s d.
Stepwise logistic regression was used to identify the variables most significantly associated with headache-related parameters.
Results
Of the 779 children and adolescents evaluated for migraine at the headache clinic during the study period, 119 were diagnosed within 6 months of symptom onset and formed the study cohort. The mean interval from onset of headache disease to presentation at the clinic was 3.6 ± 1.8 months (range 0.5–6, median 3). The cohort included 69 girls (58.0%) and 50 (42.0%) boys of mean age 11.6 ± 3.6 years at presentation to the clinic (range 4.3–18 years, median 10.9 years) and 11.3 ± 3.6 years at onset of headache disease (range 4.0–17.8, median 10.8). Migraine without aura was documented in 82 patients (68.9%), and migraine with aura in 37 (31.1%). Mean headache frequency was 20.2 ± 11.9 days per month (range 0.5–30, median 26). Forty-four patients (37.9%) had chronic migraine (≥ 15 days/month) and 72 (62.1%) had episodic migraine; three patients did not report headache frequency. The mean duration of follow-up after admission to the headache clinic was 13.9 ± 8.4 months.
Demographic and clinical data of 119 children with new onset migraines with and without cutaneous allodynia.
Note: Data are presented as n (%) or mean ± standard deviation.
There was no significant difference in the rate of psychiatric comorbidities between patients with or without allodynia. The following comorbidities were found in the patients with allodynia: three patients with attention deficit disorder. The following comorbidities were found In patients without allodynia: five patients with attention deficit disorder and two patients with tic disorder.
None of the patients received preventive treatment before admission to the headache clinic. However, all used a non-steroidal anti-inflammatory drug (ibuprofen) for acute migraine management. None was administered triptans, which are not approved for acute migraine in our country in patients less than 18 years old.
Logistic regression showing factors associated with allodynia.
Missing data
Data on several parameters were missing for a minority of the cohort. There was no significant difference in the rate of allodynia between patients missing these data and patients for whom these data were available, as follows: Headache frequency, missing in three patients (p = 0.456 on comparison with the other patients); duration of migraine attacks in hours, 16 patients (p = 0.373); unilateral pain, nine patients (p = 1.0); phonophobia, four patients (p = 0.186); photophobia, three patients (p = 0.681); nausea, three patients (p = 0.471); vomiting, three patients (p = 1.0).
Discussion
The present study, conducted in a tertiary pediatric headache clinic, showed that during the first 6 months of migraine disease in children and adolescents, about one-third reported having allodynia. Factors significantly associated with migraine-related allodynia were female gender, older age at migraine onset, older age at admission to the headache clinic, migraine with aura, and awakening pain.
Several previous studies have investigated the rate of allodynia in children and adolescents with a relatively long duration of migraine (mean 29.1 ± 30.39 months); in 40% of cases, the patients had had migraine for more than 4 years (10,11). The present study complements these findings, showing that even in pediatric migraineurs with a short duration of disease (median 3.6 months), allodynia may already be present in a considerable percentage. By contrast, in studies of adults, the mean duration of migraine in those with allodynia was 10 ± 8.3 years (4).
Allodynia prevalence
The reported prevalence of allodynia among adult migraineurs ranges from 57.1% to 79% (4,8) whereas the rate in the present pediatric study was 31.1% and in previous pediatric studies, 37% (8,10) . Although only a few studies applied quantitative methods such as the von Frey hair test to diagnose allodynia in adults (14), the clinical questions used here have been found to be a reliable means of identifying allodynia in children and adolescents (10,11,14,15) . Thus, although the difference in allodynia rates between adult and pediatric populations might be partly attributable to the use of questionnaires (5,14–16), there are probably additional reasons besides methodology. The shorter duration of migraine in children and adolescents by virtue of their age (11) cannot account for the difference from adults, as the reported rates of allodynia have been consistent across pediatric studies of migraine of various durations (10,11). Recently, Burstein et al. (17) proposed that at least some of the structural alterations seen in the migrainous brain may be inherited. As such, they may be the actual “cause” of migraine rather than secondary to the repeated headache attacks. Perhaps these structural changes may also contribute to the appearance of allodynia in some pediatric patients. Further studies are also needed to investigate the possible role of genetic factors in the pathogenesis of allodynia.
Allodynia and headache frequency
Both clinical observations and animal studies suggest that central sensitization to nociceptive stimuli plays an important pathogenetic role in both migraine and allodynia (2,3). Researchers hypothesize that repeated or prolonged noxious stimulation may lead to sensitization and, consequently, a lower threshold for pain that can manifest clinically as allodynia. Given clinical findings over the last two decades in adults that allodynia is more frequently associated with chronic than episodic migraine and with longer duration of disease (9), it has been suggested that repeated migraine attacks may increase the severity of the disease concomitant with an increase in the risk of allodynia (1).
Contrary to findings in adults, however, our analysis of pediatric migraineurs yielded no difference in migraine frequency between those with and without allodynia, and no association of allodynia with chronic migraine. Thus, it is possible that in children and adolescents who have had migraine for only a short duration, allodynia may be attributable to a different pathogenetic mechanism from allodynia in adult migraine. As suggested, genetic tendency may impact the appearance of allodynia in this age group.
Allodynia and female gender
An association of allodynia with female gender has been reported in several studies in adults (5,6,17). Ours is the first study to report a female predominance in pediatric migraineurs with allodynia. As the pathogenesis of allodynia is related to lower pain threshold, its higher presence in female patients is compatible with the finding that women have a lower threshold than men to pain from noxious stimuli (18). Furthermore, not only is migraine more common in women (19), it is now known that brain function differs between women and men, and women undergo different brain structural changes over time (20). Researchers suggest that sex steroids are the prominent modulators of brain function during migraine attacks (21). Particularly noteworthy is the finding that estrogen receptors in humans are located in the trigeminal nucleus (22) within the trigeminovascular system, which is apparently involved in the pathogenesis of allodynia (2,3), as discussed above. It is possible that alterations in sex hormones that function in brain areas involved in sensitization make females more susceptible to allodynia. This assumption may be strengthened by findings of a higher proportion of pubertal patients in the allodynia group in our study (Table 1), although the difference from the group without allodynia was not statistically significant. The nonsignificant difference in the rate of allodynia between pubertal and non-pubertal patients may be due to the small number of pubertal patients.
Allodynia and age of clinic presentation
In the present cohort, mean age was significantly higher in the patients with allodynia than in the patients without allodynia. It is possible that patients of different ages perceive and describe allodynia symptoms differently. Furthermore, the developing brain may undergo changes that affect the development of allodynia. There are reports that the maturity of the brain influences sensory perception (23), and as brain maturation is a continuous process, different brain areas mature at different ages (24).
Future pathophysiological studies are needed in order to determine whether developmental physiological changes that occur in the trigeminal pathway during adolescence affect the development of allodynia.
Allodynia and migraine with aura
Allodynia was significantly associated with migraine with aura in our cohort. This finding has been reported also by others, in both adults and children (4,5,10,17) . It may be related to a shared pathophysiology of aura and allodynia. Specifically, cortical spreading depression (CSD) is a slowly propagating wave of depolarization/excitation followed by hyperpolarization/inhibition in cortical neurons and glia (25) . There is growing clinical and experimental evidence that CSD is an important component of migraine with aura. The trigeminal nucleus caudalis, which is thought to play an essential role in the pathogenesis of migraine pain, is activated as part of the process of CSD (25). Therefore, researchers hypothesize that repeated activation of the nucleus caudalis may interfere with the modulatory pain pathways in migraine, lowering the threshold of nociceptive neurons at that area and leading to allodynia (5,17,25).
Allodynia and awakening pain
We found a significant association between allodynia and awakening pain. Previous reports have noted a high prevalence of sleep disorders in children and adults with migraine headache (26,27). The relationship between allodynia and sleep in migraine is known as well: Adult patients with allodynia and migraine tend to need more time to fall asleep, have initial insomnia more than 3 nights per month, and tend to wake up during more than 3 nights per month (28).
Lovati et al. (28) suggested that the relationship between sleep disorders and allodynia may be bidirectional. On the one hand, poor sleep quality might contribute to allodynia onset by influencing central sensitization mechanisms in the central nervous system. Accordingly, Okifuji and Hare (29) found that sleep deprivation is involved in increasing pain perception even in healthy volunteers. On the other hand, the worrisome sensations of allodynia on areas of the skull and face, and even extracephalic areas, may induce insomnia and cause nighttime awakening (28).
Limitations
This study was limited by the retrospective design and the smaller size of the study groups than defined by the power analysis. Moreover, the diagnosis of allodynia was based on self and parental and patients’ reports and other clinical parameters. There is an inherent difficulty in asking children (and their parents) about an abstract symptom such as allodynia. To help overcome this problem, we used a questionnaire consisting of four specific, concrete questions that have been used to diagnose allodynia in previous studies of migraine in the pediatric age group (10,11). Mechanical and thermal tests are the gold standard for diagnosis of allodynia in adults, but their use in children poses ethical concerns because they are painful to administer. It should also be noted that the results of the allodynia questionnaire may have been biased toward girls who are more likely than boys to have a ponytail (question 4). In addition, the question relating to jewelry is more appropriate for adults, although in Israel, even small children may wear jewelry in accordance with cultural habits.
Our sample was restricted to patients treated in a tertiary medical center and therefore may have had more severe disease than individuals in the general population. In our country, most young patients with migraine are treated by their primary pediatrician; this patient population is characterized by a usually low migraine frequency and good response to nonpharmacologic and pharmacologic treatment for acute attacks. Admission to our tertiary clinic is approved by health-care insurance companies only for patients with severe migraine. This factor may at least partly explain the high prevalence of chronic migraine in our cohort. Indeed, we also restricted the cohort to patients with a short duration of migraine. It is reasonable to assume that patients referred to a tertiary unit already at the first stage of headache disease might have a more severe course than patients referred later.
Finally, in young patients, reports of headache features by the parents may have been influenced by the parents’ own experiences with migraine and allodynia. Therefore, we assume the factors associated with allodynia in this study can be generalized only to patients admitted to a dedicated tertiary headache clinic and not to the general population. Further studies are needed to corroborate our findings.
Conclusion
Cephalic cutaneous allodynia may occur in children and adolescents diagnosed with migraine within 6 months of symptom onset. Contrary to adults, allodynia in children and adolescents is apparently not associated with long duration of migraine and chronic migraine. Allodynia in children and adolescents with migraine of up to 6 months’ duration is significantly associated with female gender, older age, migraine with aura, and awakening pain. Genetics may play a role in allodynia in pediatric migraine.
Article highlights
Contrary to adults, allodynia in children and adolescents is apparently not associated with long migraine duration and chronic migraine. Cephalic cutaneous allodynia may occur in children and adolescents already in the first 6 months of migraine onset. In young patients with a short duration of migraine, the presence of allodynia is associated with migraine with aura, female gender, and awakening pain.
Footnotes
Acknowledgment
The authors thank Ms Pnina Lilos for her statistical assistance and Ms Gloria Ginzach for her English language editing.
Declaration of conflicting interests
The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The authors received no financial support for the research, authorship, and/or publication of this article.