Sex and age-related patterns in pediatric primary headaches: observations from an outpatient headache clinic

Background Age reportedly affects headache prevalence differently in boys and girls. However, little empirical data exists regarding pediatric headache prevalence and headache-related burden in children and adolescents according to age and sex. In the present study, we considered age and sex while evaluating the distribution, characteristics, and impairment of primary headache disorders at a pediatric headache center in Germany. Methods Medical records of children and adolescents attending the headache clinic of the Interdisciplinary Pain Center of the Carl Gustav Carus University Hospital in Dresden during the period 2015–2022 were retrospectively grouped and analyzed depending on age (< or ≥14 years) and sex. Results The study population consisted of 652 children and adolescents, aged between 3 and 18 years. Almost two-thirds of the patients (≈60%) were females, and almost two-thirds of these females (58%) were ≥14 years of age. Generally, the most prevalent headache diagnoses as defined by the International Classification of Headache Disorders 3rd edition were episodic migraine without aura and the combination of tension-type headache and episodic migraine with or without aura i.e., mixed-type headache (each ≈27%). In the younger group (<14 years), the mixed-type headache was the most prevalent in girls (28.6%), whereas, for boys, episodic migraine without aura was the most prevalent headache diagnosis (47.4%). In the older group (≥14 years), the mixed-type headache continued to be the most prevalent for girls (30%), and it became the most prevalent for boys (26.3%). Before the age of 14, about 16% of children were severely affected by their headaches. After the age of 14, this proportion increased to roughly one-third (33%) of adolescents, driven mainly by teenage girls (26%) who were severely affected by their headaches. Furthermore, the prevalence of comorbidities was significantly higher among girls (67%), particularly in the adolescent group (74%). Conclusions Our data shows that headache disorders in a specialized pediatric clinic impose a significant burden, especially among teenage girls indicating high therapy needs. Enhancing awareness of early diagnosis and preventive care is crucial to mitigate the development of chronic headaches, and mitigate their adverse effects on life quality and educational capability.

Background: Age reportedly a ects headache prevalence di erently in boys and girls.However, little empirical data exists regarding pediatric headache prevalence and headache-related burden in children and adolescents according to age and sex.In the present study, we considered age and sex while evaluating the distribution, characteristics, and impairment of primary headache disorders at a pediatric headache center in Germany.
Methods: Medical records of children and adolescents attending the headache clinic of the Interdisciplinary Pain Center of the Carl Gustav Carus University Hospital in Dresden during the period -were retrospectively grouped and analyzed depending on age (< or ≥ years) and sex.

Results:
The study population consisted of children and adolescents, aged between and years.Almost two-thirds of the patients (≈ %) were females, and almost two-thirds of these females ( %) were ≥ years of age.Generally, the most prevalent headache diagnoses as defined by the International Classification of Headache Disorders rd edition were episodic migraine without aura and the combination of tension-type headache and episodic migraine with or without aura i.e., mixed-type headache (each ≈ %).In the younger group (< years), the mixed-type headache was the most prevalent in girls ( .%), whereas, for boys, episodic migraine without aura was the most prevalent headache diagnosis ( .%).In the older group (≥ years), the mixed-type headache continued to be the most prevalent for girls ( %), and it became the most prevalent for boys ( .%).Before the age of , about % of children were severely a ected by their headaches.After the age of , this proportion increased to roughly one-third ( %) of adolescents, driven mainly by teenage girls ( %) who were severely a ected by their headaches.Furthermore, the prevalence of comorbidities was significantly higher among girls ( %), particularly in the adolescent group ( %).

Introduction
Primary headache disorders are a major public health concern.According to the latest Global Burden of Disease study, headache disorders remain the top third leading cause of years lived with disability worldwide (1)(2)(3).In adults, the overall prevalence of headache is estimated between 46 and 79%, for tensiontype headache 38 and 42%, for migraine 11 and 35%, and probable medication overuse headache 3.1% (4).The reported high prevalence in adults, plus the headache-related loss of daily activities and productivity, the development of comorbid disorders, and an early onset of the headache disease increase the overall burden of headache disorders (5).Even though the burden of headaches is not as well-documented in children as compared to adults (6,7), pediatric headache disorders have the added potential effect of impacting education and social functioning during decisive developmental years that will most likely impose an increased burden throughout life for both individuals and society at large (8).
In pediatrics, headache is the most common neurological symptom and the most common reported pain (9).The estimated lifetime prevalence of overall primary headaches in children is about 62% with prevalence in females and males of 38 and 27%, respectively (10), and with up to 47% of children and adolescents reporting recurrent headaches (11).The prevalence of tensiontype headache varies between 58% in Norway (12) and 6.2% in Kuwait (7) depending on the age of investigated children and other methodological differences.Concerning migraine, prevalence between 23 and 10.9% are reported (7,12).A recent meta-analysis suggested a global prevalence of 11% for migraine overall, 8% for migraine without aura, 3% for migraine with aura, and 17% for tension-type headache (10).The prevalence of primary headaches increases throughout childhood (13), and by the age of 18 years, 90% of adolescents have had a headache (14).Whereas, before puberty headache prevalence is similar between boys and girls, after puberty, headache disorders become significantly more prevalent in girls.This difference is greatly determined by an increased prevalence of migraine in females after puberty (female 12-17%; male 4-6%), which then display a ratio similar to what is known from adult studies (10), highlighting the potential role of sex hormones in headache pathophysiology but likely sociocultural factors as well (15).
Migraine is thought to be a cyclic disorder with a complex sequence of symptoms, which can vary with age.The overall clinical presentation of migraine in children as compared to adults consists of shorter, mainly bilateral attacks, and a display of vegetative gastro-intestinal and non-nociceptive symptoms, the latter characterized as migraine variants (6).Age-dependent differences in headache clinical symptoms seem to be less prominent in tension-type headache (16).However, tension-type headache symptoms in children are often a mixed headache with migraine and the differentiation can be challenging (17).Even though specific pediatric criteria have been included in the headache diagnostic criteria (ICHD-3) (18), symptom variability in children of different ages and sex may lead to classification difficulties.Classifying pediatric headache disorders, especially but not only in younger children, has additional clinical challenges that possibly underlie the lack of specific diagnostic markers which may result in underdiagnosed, underestimated, and most likely untreated pediatric headache disorders.
Accumulating evidence suggests an increasing prevalence of pediatric headaches (19), that are arguably responsible for a remarkable impact on physical and psychological wellbeing (20).However, the impairment caused by headache disorders in the pediatric population is still poorly understood, particularly the differential impact of puberty on headache prevalence in boys and girls.The goal of this study is to provide a comprehensive description of the distribution, characteristics, and impairment of everyday function of pediatric primary headache disorders according to age and sex in a headache outpatient clinic in Germany.Prospectively, this can be used to address specific public and individual interventions for awareness, education, and management of headaches in children and adolescents.

Methods
In this monocentric study, medical records of children and adolescents who attended the headache outpatient clinic at the interdisciplinary pain center of the Carl Gustav Carus University Hospital in Dresden from September 2015 to July 2022 were retrospectively reviewed.Headache diagnoses and classifications were performed according to the International Classification of Headache Disorders, Third Edition (ICHD-3) by a pediatrician (MR) and pain therapist (AH), experienced in pediatric headache diagnosis and treatment under supervision of a neurologist (GG), specialized in headache (18).During their visits to the Headache clinic, all patients and their parents were interviewed using a format based on the ICHD-3 criteria (18), in addition personal and family medical history, and were requested to complete a questionnaire (PedMIDAS) and demographic questions as published elsewhere (13).In addition, the headache diary provided by the German Society for Migraine and Headache was used, where children and adolescents entered their headache days, intensity (according to a numerical analog scale), and accompanying symptoms such as i.e., nausea, aura, or photophobia (English version of the diary shown here: https://www.dmkg.de/files/Kopfschmerzkalender_PDF/Kopfschmerzkalender_ENGLISCH_18.3.2021.pdf).

Headache diagnoses
Based on ICHD-3 criteria (18), headache disorders were divided into seven groups consisting of (1) Episodic migraine with aura; (2) Episodic migraine without aura; (3) Chronic migraine; (4) Episodic Tension-type headache; (5) Chronic tension-type headache; (6) Migraine and tension-type headache mixed i.e., Mixed-type headache (any form of tension-type headache and episodic migraine with or without aura); (7) Other primary headaches (e.g., new daily persistent headache, vestibular migraine, trigeminal autonomic headaches).Headaches of included patients were carefully assessed and patients with secondary headaches were not included in this study.Only in one case, a patient with a secondary headache due to a craniopharyngioma was included since the secondary headache resolved after appropriate tumor treatment and the same patient experienced migraine attacks.

Comorbidities
The comorbidities commonly encountered in primary headache disorders were assessed and allocated into six main disease groups, based on the affected biological system:

Statistical analysis
Statistical analyses were performed using SPSS software version 29 (SPSS, Chicago, IL, USA).Categorical variables were defined as frequencies and percentages and continuous variables were expressed as means and standard deviations or medians (with interquartile range).To compare groups, Chi-square tests, t-tests, and the Mann-Whitney U-test were used as appropriate.

Headache diagnosis
Overall, the mixed-type headache (any form of tension-type headache and episodic migraine with or without aura) (n = 164, 26.7%), together with episodic migraine without aura (n = 163, 26.5%) were the most prevalent headache diagnoses in our headache sample followed by chronic tension-type headache (n = 104, 16.9%).Chronic migraine (n = 9, 1.5%) was generally the least prevalent headache diagnosed in the overall patient sample, followed by other headaches (that included new daily persistent headache, vestibular migraine, trigeminal autonomic headaches, n = 38, 6.2%).Table 1 shows the distribution of the distinct headache diagnoses between girls and boys according to age group.In younger children (<14 years), the mixed-type headache was the most prevalent diagnosis in girls (girls n = 45, 28.6%), whereas, for boys, episodic migraine without aura was the most prevalent

Headache intensity
When it comes to reports of headache intensity, there were no significant differences between girls and boys before [girls Median

Headache disability
We found a significant relationship between sex, age group, and the level of headache disability, measured with PedMIDAS [χ ²(1, N = 400) = 13.56,p < 0.001].Figure 5 illustrates the disability reported by boys and girls within distinct age groups as a result of headaches.Whereas, before the age of 14, roughly one-third of children (34%) seemed to be less affected by their headaches and about 16% of children seem to be severely affected by their headaches.After the age of 14, the lives of roughly one-third of adolescents (33%) become severely or extremely affected by their headaches.This increase is especially driven by the percentage of teenage girls who become severely/extremely affected by their headaches (26%).Within the older female group, more than onethird of teenage girls (35.3%) were severely to extremely affected by headache disorders, whereas within the older male group less than

Comorbidities
With regards to comorbidities, 44% of our patients (64% females) reported having at least one comorbidity.Notably, 27.6% (74.6% females) of these patients reported having at least 2 comorbidities and 5% (92.9% females) reported having three comorbidities.The prevalence of comorbidities was significantly higher among girls compared to boys (girls n = 184; boys n = 103; χ ² = 22.86; df = 1, p < 0.001).The overall sex difference is driven by the significant disparity observed in the adolescent group (girls n = 119; boys n = 48; χ ² = 30.19;df = 1, p < 0.001) a difference not evident in the younger group (girls n = 65; boys n = 54; χ ² = 1.017; df = 1, p > 0.05).Table 2 indicates the reported comorbidities by sex and age group (note that 27% of patients reported having more than one comorbidity).The most common comorbidity, with almost one-third of patients' reports, regardless of sex and age group, was internal disorders (30%), which include a wide spectrum of diseases.Within girls, the most commonly listed comorbidities were internal disorders (27.1%) followed by other pain disorders (25.1%) both under and above the age of 14.Among younger boys internal disorders were the most common reported comorbidities (42.8%) followed by neurological disorders (19%).In older boys, internal disorders (30%), were followed by mental disorders (20%).Within the older group of children, girls reported a significantly higher prevalence of internal disorders as compared to boys (χ ² = 9.600, df = 1, p = 0.002).A sex difference in the prevalence of internal disorders was not observed in the younger group (χ ² = 0.74, df = 1, p > 0.05).When it comes to other commonly reported comorbidities such as other pain disorders, a significantly higher prevalence was reported for both younger (χ ² = 6.760, df = 1, p = 0.009) and older (χ ² = 19.800,df = 1, p < 0.01) girls as compared to younger and older boys.In neurological disorders, no significant sex differences were found within the younger and older age groups (p > 0.05).

Discussion
In the present study, we considered age and sex while evaluating the distribution, characteristics, and impairment of primary headache disorders at a pediatric headache center in Germany.

Sample characteristics and headache diagnosis by age group and sex
Almost two-thirds of 652 children and adolescents attending the headache clinic between 2015 and 2022 were females.After stratifying our headache population according to age and sex, we attested that the observed sex differences were driven by the adolescent (≥14) group and no sex differences were noted within the younger group.This goes in line with previous data suggesting that in childhood boys and girls are equally likely to be affected by primary headache disorders (15).In the adolescent group (≥14), girls were notably older than boys and significantly outnumbered adolescent boys, emulating adult headache prevalence ratios (22).These findings underscore the potential role of sex hormones in headache pathophysiology (23).During puberty, sexual steroid hormones have been shown to affect neural circuits and cause permanent changes in relevant brain areas such as the hypothalamus and the insula (24).Moreover, studies suggest that the onset of migraine typically coincides with the cyclic hormonal changes that begin around the time of menarche.Early onset of menarche seems to constitute a risk factor for the development of migraine (25).However, the contribution of sociocultural factors likely plays an additional role (26).In our sample, the mixed headache type (including any form of tension-type headache and episodic migraine with or without aura), together with the diagnosis of migraine without aura were the most prevalent headache diagnoses.Regarding the mixedtype headache, whereas no sex prevalence differences were found within the younger population (<14 years), a significantly higher prevalence of girls was found in the adolescent group.This goes in line with adult studies showing that tension-type headaches, the most prevalent headache in clinical practice (27), and migraine have a female preponderance (28).This female preponderance has also been observed in persistent post-traumatic headache, predominantly characterized by somatic symptoms (29).Similar findings were observed in our tension-type headache diagnosis group, where a significantly higher prevalence of adolescent girls was observed.On the other hand, in episodic migraine without aura, a significantly higher prevalence of boys was noted within the younger group of children.This sex difference was no longer evident in the teenage group.This finding contrasts with the above-reported absence of sex prevalence differences within the younger group of headache disorders, emphasizing the importance of investigating distinct headache diagnoses separately.However, our results might represent the selection bias of a tertiary headache center or a sociocultural phenomenon, where migraine in girls tends not to be appreciated as a disease and therefore young girls are not enrolled for specific treatment.Importantly, however, most headache literature evaluating the effect of sex in primary headaches comes from the migraine field, and there is a high need for research evaluating the variance of epidemiological patterns in distinct primary headache disorders by sex and age (10).This information holds the potential to advance our understanding of differential sex prevalence, and associated headache pathophysiology that in turn will guide the development of more successful therapies.For example, the onset of cluster headaches in women is often related to hormonal changes as milestones in biological development (30).Besides hormonal changes, behavioral and socioeconomic factors might influence sex-differences in headache prevalence (31).
Within our sample, chronic migraine emerged as the least prevalent among diagnosed headache disorders.This outcome likely mirrors deficient diagnostic criteria, with a considerable portion of children included in the mixed group potentially experiencing chronic migraine.In addition, it might be the result of fluctuations in migraine frequency in adolescents.A study of 2,517 migraine attacks in 115 children has shown a seasonal increase in migraine between November and January and a minimum in summer school vacation (32).This observation calls for a review of current diagnostic criteria for chronic migraine in children and adolescents.In line with this, the guidelines of the International Headache Society for controlled trials of preventive treatment of migraine in children and adolescents have been recently updated (33).Frequently starting in childhood and extending into adulthood (34), migraine is one of the highest specific cause of adult disability worldwide (1).Hence, early recognition and successful management of the disorder becomes vital.

Headache-related impairment by age group and sex
Headache disorders are known to significantly impact children and adolescents' quality of life (8).In our headache sample, both younger and older girls reported having more headache days than younger and older boys.This pattern corroborates with literature suggesting that females are more affected than men, especially in their late teenage years (8).When considering the distinct headache diagnoses separately, no significant sex differences in reported headache days were observed in our younger group or our teenage group.This most likely reflects the insufficient sample size within distinct headache diagnoses or constitutes a selection bias of a tertiary headache center, where patients with higher headache frequencies are treated.Within our sample, children with other headache disorders and with chronic tension-type headaches displayed the highest headache frequency.This is expected and goes in line with the ICHD-III diagnostic criteria (18) for chronic tension-type headaches that request at least 15 headache days per month.The most common headache diagnosis in the group of other headaches is a new daily persistent headache, where per definition persistent daily headache is requested.When it comes to chronic tension-type headaches, results are in line with the latest report of the Global Burden of Disease study presenting staggering estimates of global disability-adjusted life years for chronic tensiontype headaches (35).With regards to headache intensity and school absenteeism, no sex differences were observed in younger or older children in the overall headache sample.However, when considering the distinct diagnoses separately, results suggested that younger girls with episodic migraine without aura have higher headache intensity levels as compared to boys.Moreover, data suggests that within the younger population, school attendance was more affected in boys with chronic tension-type headaches than in girls.The scenario seems to be reversed for other headache disorders, with girls reporting more absenteeism than boys.In teenagers, girls with episodic migraine with aura had higher levels of school absenteeism than boys.However, teenage boys with chronic tension-type headaches reported higher levels of absenteeism than girls.Even though this data suggests the existence of differences within specific headache disorders, our samples in some of these groups are very limited, which restrains robust inferences and underscores the need for further studies to delve into this matter with greater certainty provided by more extensive and diverse sample sizes.Looking at the overall pattern of headacherelated disability, whereas before the age of 14, only about 16% of children seemed to be severely affected by their headaches, after the age of 14, the lives of roughly one-third of the adolescents were severely or extremely affected by their headaches.This increase seemed to be particularly driven by the percentage of teenage girls who were severely/extremely affected by their headaches.More than one-third of teenage girls (35.3%) over the age of 14 were severely to extremely affected by headache disorders.These findings are in line with recent data suggesting that the burden of headache disorders after the age of 15 is severe, particularly among females (36).

Comorbidities by sex and age group
Headache disorders are commonly associated with several comorbidities, which substantially add to the global burden of headaches (37).In the present study, almost half of the pediatric patients reported having at least one comorbidity, which constitutes a high additional burden for the pediatric population.Notably, however, the prevalence of reported comorbidities was higher among girls than boys, particularly in the older group of patients, further supporting the literature showing a higher burden of headache disorders for females.In our pediatric sample, internal disorders (encompassing a broad spectrum of diseases) were the most commonly reported comorbidities.These results, however, were mostly driven by teenage girls.When it comes to pain disorders, the second most common comorbidity in our sample, again girls reported significantly more comorbid pain disorders than boys.Our findings provide additional evidence supporting the impact of sex and age when it comes to the distribution and trends of headache burden, particularly in later teenage years where girls seem to bear a greater burden of headache disorders (10).However, it is worth noting that the burden of headache disorders has been increasing over the past decades for teenage boys (36).Overall the presence of comorbidities adds complexity to the clinical management and outcomes of primary headaches.Understanding the mechanisms leading to these comorbid conditions remains challenging.Comorbidities can function as risk factors for the chronicity of headaches and as triggers for headache episodes (38).They might result from repeated headache attacks, treatments, or other shared factors, contributing to the progression of headaches into chronic forms.
Besides migraine, there is a notable gap in the understanding of other headache-diagnosis-related comorbidities.Exploring the relationships between primary headache disorders and specific comorbidities can offer valuable epidemiological and clinical insights guiding accurate diagnoses and effective treatments.

Limitations
Our disorder-specific sub-analysis is suggestive of age and sex differences within specific headache disorders, however, limited sample sizes in some subgroups significantly constrain robust inferences.This highlights the importance of large-scale research in the area (more extensive and diverse sample sizes).Due to our limited sample size, especially when it comes to the stratification of distinct headache diagnoses, our study does not assess the relationship between specific headache disorders and comorbidities, a critical avenue that has the potential to inform both pediatric diagnosis and pediatric treatment strategies.The lack of detailed recording of menarche variability, is an important factor to consider in future studies.Furthermore, the variability in subject numbers for our analyses, driven by the uneven availability of data, stands as a limitation.Yet, this discrepancy serves to echo the complexities encountered in the clinical realm, providing a realistic portrayal of the clinical challenges.Another limitation is that the data was collected from a single specialized center, which may affect the generalizability of the results to a broader population.In our study, there were no unclassified cases, which are commonly observed in other studies using different diagnostic methodologies (39).Additionally, the retrospective nature of the study may introduce biases due to the reliance on existing records.Despite this limitation, retrospective reviews of medical records remain a widely used and invaluable method in clinical research, facilitating the extraction of significant insights from large clinical datasets.Finally, in our study, about 27% of patients presented with symptoms characteristic of both migraine and TTH, meeting the diagnostic criteria for both conditions.This dual diagnosis highlights the clinical challenges in differentiating between these headache types in pediatric populations (17,40), reflecting the need for refined diagnostic approaches.

Conclusion
Overall, our data supports the assertion that headache disorders impose a significant burden, especially among teenage girls.The sex difference remains a work assignment, and additional efforts are needed to study headache disorders beyond migraine, in children and adolescents.Enhancing awareness of early diagnosis and preventive therapies is crucial to mitigate the development of chronic headaches and their adverse effects on life quality.Despite advancements in migraine management, the strong inequalities in care persist globally, exacerbated by socioeconomic disparities, limited access to novel therapies, and the ongoing impacts of the COVID-19 pandemic (41,42).Future work should assess the feasibility and long-term tolerability of implementing successful therapies globally.Additionally, awareness campaigns ./fneur. .and institutionalized education on headaches in schools are needed to combat stigma and misconceptions about migraines.

FIGURE
FIGUREClustered bar median of missing school days in the last months in younger (< ) (A) and older children (≥ ) (B) according to main diagnosis and sex.eMwoA, episodic Migraine without Aura; eMwA, episodic Migraine with Aura; CM, chronic Migraine; eTTH, episodic Tension-Type Headache; cTTH, chronic Tension-Type Headache; Mixed type, includes coexisting TTH and episodic Migraine; Other HA, other headaches.
displays missing schooldays distribution according to age group, sex, and headache diagnose.Before the age of 14, school attendance seems to be mostly affected in girls with other headaches [Median = 14, IQR (−2.66, 30.66)], and in boys with chronic tension-type headaches [Median = 11, IQR (10.56, 32.56)].In teenage boys, chronic tension-type headache continues to represent the biggest burden when it comes to missing school days [Median = 8.5, IQR (−22.28,39.28)], whereas in teenage girls chronic migraine takes the lead in affecting school attendance [Median = 15, IQR (5.72, 24.28)].While investigating sex differences in reported school absenteeism, results suggest that in older children with episodic migraine with aura, teenage girls miss significantly more school days as compared with teenage boys [girls Median