JCN Open Access ORIGINAL ARTICLE pISSN 1738-6586 / eISSN 2005-5013 / J Clin Neurol 2020;16(3):416-422 / https://doi.org/10.3988/jcn.2020.16.3.416 Impact of Puberty in Pediatric Migraine: A Pilot Prospective Study Elena Fonsecaa Background and Purpose The short-term evolution of pediatric migraine remains un- Marta Torres-Ferrúsa clear. We aimed to describe the evolution of migraine before and after puberty and its rela- Víctor José Gallardob tionship with lifestyle habits. Alfons Macayac Methods We prospectively selected prepuberal patients from a neuropediatric unit who had Patricia Pozo-Rosicha a migraine diagnosis. Their medical history, migraine characteristics and impact, and lifestyle a Headache Unit. Neurology Department habits were recorded at the baseline visit. After 2 years we performed a telephone follow-up and cDepartment of Pediatric Neurology, assessment. Hospital Universitari Vall d’Hebron, Results Nineteen patients were recruited (age 10.2±2.9 years, mean±SD; 57.9% female), of Barcelona, Spain b Headache Research Group, whom 27.5% had migraine with aura. The accompanying symptoms had changed at the fol- Vall d’Hebron Research Institute (VHIR), low-up, with significantly higher prevalence rates of dizziness (44.4% vs. 88.9%), vertigo Universitat Autònoma de Barcelona, (11.1% vs. 66.7%), mood changes (38.9% vs 83.3%), confusion (5.6% vs. 77.8%), and allo- Barcelona, Spain dynia (27.8% vs. 61.1%). Sleep disturbances (5.6% vs. 38.9%) and schedule changes (0% vs. 38.9%) increased significantly as triggers. Prodromal symptoms became more prevalent (16.7% vs. 50%), with a higher proportion of sleep disturbances reported (50.0% vs. 87.5%). Conclusions Prodromal symptoms increase in pediatric migraine after 2 years, and some trigger factors for migraine become more prevalent, including sleep disturbances. New ac- companying symptoms are also identified. These changes provide information about how migraine changes during puberty along with physical and lifestyle changes, and represent a dynamic physiopathological process that deserves more research. Key Words migraine, puberty, adolescence, natural history; lifestyle. INTRODUCTION The estimated prevalence of migraine in children and adolescents has ranged from 3% to 10%.1,2 The prevalence of migraine increases with age, and it is well described that the prevalence is similar in males and females before puberty, switching to a female prepon- derance from adolescence.3-6 Several studies of long-term outcomes have shown that the annual remission rate of childhood migraine is around 6% within the first 3 years, but decreases to 1–2% over a long-term follow-up (10 to 50 years).5,7 Headache represents an important cause of disability in children, being one of the five Received December 31, 2019 most-important causes of illness-related school absenteeism.8 A study found that children Revised March 15, 2020 with migraine lose a mean of 7.8 school days a year due to all illnesses, of which 2.8 were Accepted March 16, 2020 a direct consequence of their migraine, compared with a mean of 3.7 lost days in children Correspondence without migraine.9 Pediatric migraine is associated with specific comorbidities such as Patricia Pozo-Rosich, MD, PhD Headache Unit. Neurology Department, asthma, allergy, sleep disorders, and a higher prevalence of psychopathological symp- Hospital Universitari Vall d’Hebron, toms,10,11 which might transfer into adulthood. Passeig Vall d’Hebron, 119-129, Barcelona 08035, Spain Most population-based studies of pediatric migraine have retrospective designs, include Tel +34-9348932479 cc This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Com- Fax +34-932746235 mercial License (https://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial E-mail ppozo@vhebron.net use, distribution, and reproduction in any medium, provided the original work is properly cited. 416 Copyright © 2020 Korean Neurological Association Fonseca E et al. JCN broad age groups of children and different headache types, (when necessary) were interrogated in order to obtain the and involve clinical data that were mainly obtained using most-accurate information. Lifestyle and eating habits, physi- self-administered questionnaires rather than by physician cal activity (measured as the proportion of time spent per- evaluations.12 Only a few prospective studies have investi- forming physical exercise and sedentary activities), sleeping gated the evolution of headache during the transition from routine, school performance, possible discrimination situa- childhood to adulthood.5,6,13 These studies have been partic- tions, and anxiety items were queried. Sleep habits were mea- ularly focused on describing prognostic factors and diag- sured using the BEARS (B, bedtime issues; E, excessive daytime nostic changes, with only a few analyses of the symptomatic sleepiness; A, night awakenings; R, regularity and duration of evolution over time as a secondary objective. Moreover, few sleep; S, snoring) sleep screening tool,18 and anxiety traits and studies have described the relationships between migraine state were measured using the Spanish adaptation of the State- and sleeping or eating habits, with very little or no informa- Trait Anxiety Inventory for Children scale.19 tion being available on the relationship between pediatric All patients were re-evaluated by a neurologist in a tele- migraine and lifestyle habits. phone 2-year follow-up visit (FUP). All of the migraine char- The aim of the present study was to describe the evolu- acteristics were newly recorded at this visit, and the patients tion of pediatric migraine during the years around puberty, completed a self-administered on-line questionnaire query- as well as its relationships with eating and lifestyle habits. ing their lifestyle and eating habits, sleeping habits, anxiety, and puberal physical changes. METHODS Descriptive and frequency statistical analyses were per- formed, and comparisons were made using the SPSS statistical We conducted an observational, prospective study of pa- package (version 23.0 for Windows, IBM Corp., Armonk, NY tients from a specialized neuropediatric unit that met the USA). The statistical significance of intergroup differences was International Classification Headache Disorders III beta cri- assessed using Pearson’s chi-square or Fisher’s exact text for di- teria14 for migraine (with or without aura) from January to chotomous and categorical variables, the linear-trend chi- December 2015. The study was approved by the local ethics square test for ordinal variables, and Student’s t-test or the committee [Vall d’Hebron Research Institute (VHIR) Clini- Mann-Whitney U test for quantitative variables. The paired t- cal Research Ethics Committee, PR (AMI)15/2013]. The le- test and the Wilcoxon signed-rank test were used to assess pre- gal representatives of all patients read and signed the in- post changes in numerical variables at 2 years after the BL. A formed consent for the study, including for the patient’s probability value of p<0.05 was considered statistically signifi- assent in all cases. All patients were developmentally staged cant for differences between the two study visits: BL and FUP. according to the Tanner Scale,15 and only patients in a Tan- ner I stage (prepuberal) were included. The presence of oth- RESULTS er primary headache diagnoses and/or puberty signs in a physical examination were exclusion criteria. This study recruited 19 patients with an age at inclusion of At the baseline visit (BL), all patients were assessed by a 10.2±2.9 years (mean±SD), which included 11 (57.9%) fe- trained neuropediatrician, recording demographic data, males. The diagnoses at inclusion were migraine without aura medical, personal, and familial histories, the time to the neu- in 13 (72.2%) and migraine with aura in 5 (27.8%), while rology visit, and the findings of a physical examination. Birth 73.7% had family history of headache, most commonly af- information was also recorded, and preterm births were de- fecting the patient’s mother (42.1%). The most-frequent con- fined as those that occurred before 37 complete weeks of ditions in their past medical histories were infant colic gestation. The migraine characteristics recorded included age (26.3%), recurrent abdominal pain (21.1%), preterm birth at migraine onset, attack frequency and duration, number of (15.8%), and asthma (15.8%). The findings of physical exami- attacks before this first evaluation, pain characteristics, de- nations were normal in all patients except for one who pre- scription of the aura symptoms, triggers, functional impact sented with generalized and symmetric hyperreflexia and an- [as measured on the Pediatric Migraine Disability Assess- other who presented with prognathism. Nine patients (47.4%) ment Score Scale16], and the history of received treatments. A had previously undergone neuroimaging, which had pro- specific anamnesis was performed in order to describe both duced no significant findings. The age at migraine onset was prodromal and accompanying symptoms, which included 8.2±3.6 years, the average time before a neurology visit was confusion (defined as the inability for clear and coherent longer than 12 months in 57.9% of the patients, and 78.9% thought) and vertigo (defined as the subjective sensation of had experienced more than 10 migraine attacks (Table 1). the movement of objects).17 Both patients and their parents Regarding pain characteristics, patients described their www.thejcn.com 417 JCN Impact of Puberty in Pediatric Migraine pain more frequently as compressive (61.1%) or throbbing (61.1% and 27.8%) (p<0.05) (Fig. 1). (50.0%), and bilateral (55.6%). The most frequently reported There were significant increases in the prevalence of mi- migraine triggers at the BL were stress or anxiety (50.0%) and graine triggers in patients who reported sleep disturbance weather changes (50.0%). Only three patients (16.7%) report- Table 2. Changes in migraine characteristics from the BL to the FUP ed prodromal symptoms, the most frequent of which was noise sensitivity (11.1%). BL FUP Follow-up was completed by 95% (n=18) of the 19 patients. Age, years 10.2±2.9 12.3±2.7 Diagnosis After 2 years, all patients had experienced puberal physical Migraine without aura 14 (77.8) 13 (72.2) changes. Migraine with aura 4 (22.2) 5 (27.8) We identified one patient whose migraine diagnosis Aura switched from migraine without aura to migraine with aura. Visual 5 (27.8) 5 (27.8) All patients with aura (27.8%) had visual aura. There was no Sensory 2 (11.1) 0 (0) significant change in the location or quality of head pain, nor Pain quality in the attack frequency or duration (Table 2). However, at the Throbbing 9 (50.0) 9 (50.0) FUP there was a significant change in some of the pain-ac- Compressive 11 (61.1) 10 (55.6) companying symptoms, with higher reported prevalence Explosive 2 (11.1) 4 (22.2) rates of dizziness (88.9% and 44.4% at BL and FUP, respec- Implosive 1 (5.6) 0 (0) tively), vertigo (66.7% and 11.1%), mood changes (83.3% Others 2 (11.1) 2 (11.1) and 38.9%), confusion (77.8% and 5.6%), and allodynia Pain location Unilateral 8 (44.4) 6 (33.3) Table 1. Demographic data, personal medical history, and headache family history Bilateral 10 (55.6) 12 (66.7) Attack duration Clinical characteristics <4 hours 0 (0.0) 4 (22.2) Sex 4–24 hours 13 (72.2) 9 (50.0) Male 8 (42.1) 25–48 hours 2 (11.1) 4 (22.2) Female 11 (57.9) 49–72 hours 2 (11.1) 1 (5.6) Body mass index, kg/m2 19.4±4.5 >72 hours 1 (5.6) 0 (0.0) Age at migraine onset, years 8.2±3.6 Monthly attack frequency Aura 5 (27.8) <3 attacks 10 (55.6) 9 (50.0) Family history of headache 14 (73.7) 3–6 attacks 5 (27.8) 7 (38.9) Number of attacks before initial visit 6–10 attacks 1 (5.6) 2 (11.1) <3 attacks 1 (5.3) >10 attacks 1 (5.6) 0 (0.0) 6–10 attacks 3 (15.8) Symptomatic medication use and response >10 attacks 15 (78.9) NSAIDs 18 (100.0) 15 (83.3) Time to the neurology visit NSAIDs improvement 15 (83.3) 15 (83.3) 1–6 months 3 (15.8) Simple analgesics 6 (33.3) 12 (66.7) 7–12 months 5 (26.3) Simple analgesics improvement 4 (22.3) 10 (55.5) >12 months 15 (57.9) Triptans 0 (0.0) 2 (11.1) Comorbidities Triptans improvement 0 (0.0) 2 (11.1) Preterm birth 3 (15.8) Preventive treatment Nocturnal enuresis 2 (10.5) Ongoing 4 (22.3) 2 (11.1) Head trauma 2 (10.5) Past 3 (16.7) 5 (27.8) Chronic recurrent abdominal pain 4 (21.1) PedMIDAS disability Infant colic 5 (26.3) Little or none 7 (38.9) 5 (27.8) Paroxysmal torticollis 1 (5.3) Mild 7 (38.9) 9 (50.0) Recurrent fever 1 (5.3) Moderate 2 (11.1) 3 (16.7) Sleep disorder 1 (5.3) Severe 2 (11.1) 1 (5.6) Asthma 3 (15.8) Cyclic vomiting syndrome 1 (5.3) Data are mean±SD or n (%) values. No significant changes were found in these characteristics. Scarlet fever 1 (5.3) BL: baseline visit, FUP: follow-up visit, NSAIDs: nonsteroidal anti-inflam- Data are mean±SD or n (%) values. matory drugs, PedMIDAS: Pediatric Migraine Disability Assessment Score. 418 J Clin Neurol 2020;16(3):416-422 Fonseca E et al. JCN (38.9% and 5.6% at FUP and BL, respectively) and schedule arche had identified this as a migraine trigger in the BL. Six fe- changes (38.9% and 0%) (p<0.05) (Fig. 2). One female patient male patients had experienced menarche at the FUP, with who had previously experienced an isolated premature men- menses identified as a migraine trigger in five (83.0%) of them. Prodromal symptoms were more prevalent at the FUP 61 * FUP (50.0%) than at the BL (16.7%, p<0.05), with a tendency of Allodynia 28 BL presenting with nausea that did not differ significantly be- Syncope 6 tween these two time points (22.2% vs. 0%, respectively; p= 6 89 0.052) (Figs. 3 and 4). Prostration 83 Eight patients completed all the items in the on-line ques- 72 Pallor 72 tionnaire regarding lifestyle and eating habits. We observed Confusion 78 * significant differences only in fruit intake, with a lower pro- 6 portion of patients eating fruit daily at the FUP (42.9%) than 83 * Mood changes 39 at the BL (84.6%, p<0.05). A higher proportion of patients Vertigo 67 * reported disturbances in sleep-time regularity and sleep du- 11 ration at the FUP (87.5%) than at the BL (50.0%, p<0.05). No Abdominal pain 56 33 significant differences were observed in other characteristics Dizziness 89 * such as eating habits, physical activity, school performance, 44 39 possible discrimination situations, sleeping habits, or anxiety Vomiting 39 items in the self-completed on-line questionnaire. Nausea 72 A subgroup analysis was performed to compare patients 72 17 with and without aura. Differences in physical exercise and Osmophobia 11 sleep duration were observed between the two groups, with Sonophobia 89 78 Photophobia 72 FUP 50 * 89 Yes BL 17 Worsening with 67 67 Occasionally 0 exercise 17 0 20 40 60 80 100 No 50 Prevalence (%) 67 Fig. 1. Pain-accompanying symptoms. Symptom frequencies are indi- 0 20 40 60 80 cated for both the BL and FUP. *p<0.05. BL: baseline visit, FUP: follow- Prevalence (%) up visit. Fig. 3. Presence of prodromal symptoms at the BL and FUP. *p<0.05. BL: baseline visit, FUP: follow-up visit. 33 BL Weather changes 50 FUP FUP Pallor 6 6 BL Menses 6 28 Blurred vision 6 Schedule changes 39 * 0 0 39 * Nausea 22 * Sleep disturbance 0 6 28 Phonophobia 11 Exercise 11 11 Photophobia 6 67 Stress/anxiety 6 50 Concentration 17 11 Food difficulties 6 0 17 Fatigue 22 Fasting 17 17 0 20 40 60 80 0 5 10 15 20 25 Prevalence (%) Prevalence (%) Fig. 2. Migraine triggers. Trigger frequencies (%) are indicated for Fig. 4. Prodromal symptoms. Symptom frequencies at the BL and FUP. both the BL and FUP. *p<0.05. BL: baseline visit, FUP: follow-up visit. *p<0.05. BL: baseline visit, FUP: follow-up visit. www.thejcn.com 419 JCN Impact of Puberty in Pediatric Migraine patients who had aura performing less regular exercise been widely reported as one of the main migraine triggers (12.5% vs. 68.4%, p<0.05) or not performing any exercise that appear over time,11 which the present study has con- (37.5% vs. 10.5%, p<0.05). Moreover, the sleeping time was firmed. A previous cross-sectional study of subjects older shorter in patients with aura (7.9±1.4 hours) than in those than 16 years identified some new triggers such as hormone without aura (9.2±1.1 hours, p<0.05). impact, alcohol, smoking, and neck pain.22 These results are consistent with our results showing that new triggers can DISCUSSION appear together with changes in habits during puberty and adolescence. We have performed a prospective 2-year follow-up study of prepuberal children with a migraine diagnosis with the aim Identification of accompanying symptoms of better describing the evolution of pediatric migraine After puberty, children tend to be more likely to identify cer- during puberty. tain accompanying symptoms. Our study found that confu- sion, allodynia, mood changes, vertigo, and dizziness were Change in migraine diagnoses during the more frequent at the FUP. The previous finnish study found peripuberty transition years that osmophobia, dizziness, and balance disturbances became Previous studies have produced inconsistent results for more common during the follow-up, whereas restlessness, changes in migraine diagnoses during the peripuberty tran- flushing, and abdominal symptoms became less frequent. sition years. The broad school-based epidemiological study Nevertheless, Kelman22 found that photophobia, phonopho- performed by Ozge et al.20 found a high rate (approximately bia, and dizziness declined with age. Also, motion sickness 70%) of diagnostic changes. A finnish prospective study of had been described as an accompanying symptom whose fre- preschool children that included different types of recurrent quency increases over time.11 These disparities must be treat- headache found that the diagnosis changed in 32% of the ed cautiously due to the heterogeneity of the studies and con- children from migraine to tension-type headache.21 Al- sidering that many of them included both migraine and though those studies included larger numbers of patients, tension-type headache. It is possible that changes in the the included patients also spanned wide age ranges and dif- pathophysiological mechanisms of migraine during adoles- ferent headache diagnoses. In contrast to previous studies, cence explain these new symptoms. Nevertheless, we cannot we analyzed a small series of very strictly selected patients ignore that children might be more capable of describing cer- who were diagnosed in detail and followed by headache tain specific conditions over their development, which might specialists in a specialized unit. introduce bias into the findings. Remission did not occur in any of the patients in our sample. It is known from previous longitudinal studies that Modifications in sleep and exercise habits 20–30% of children with migraine experience remission at This study also shows that during the transition from prepu- follow-up.5,11 However, the follow-up was longer in those berty to adolescence, children present modifications in sleep studies, and the reported remission rates mostly related to and exercise habits that may influence the evolution of their adult ages. Our study applied a different approach, focusing migraine. During adolescence, the presence of headache has on the changes in migraine during puberty. Since we exclu- been associated in different studies with irregular sleeping sively selected prepuberal patients and followed them for a and eating habits, low physical activity, smoking, and caffeine shorter period of time, it is not surprising that no patient intake.23 However, these results must be interpreted cautious- had experienced remission at follow-up. This would give an ly, since sleep disturbance might be more difficult to identify idea of how migraine is a dynamic process that changes dur- during childhood and some children may find it difficult to ing puberty, but perhaps remission might not occur until associate experiences of headaches with such problems. more-advanced maturative stages. It was particularly interesting that the patients with aura tended to perform less exercise and have a shorter daily Migraine triggers sleep duration. These findings are of special interest due to During puberty, the main characteristics and the location of its possible relationship with migraine pathophysiology, and pain remain roughly the same, whereas triggers change and give us a valuable clue for identifying other factors (aside prodromal symptoms start to appear. In particular, sleep from pharmacological treatment) that might interfere in the disturbances and irregular schedule changes are newly iden- course of this disease over time. tified as triggers by children, and nausea tends to become a This study performed a prospective follow-up with careful more-frequent prodromal symptom. Sleep deprivation has patient selection and specialized neuropediatric evaluations 420 J Clin Neurol 2020;16(3):416-422 Fonseca E et al. JCN for the migraine diagnosis and migraine features, as well as Alfons Macaya https://orcid.org/0000-0001-7998-4185 Patricia Pozo-Rosich https://orcid.org/0000-0003-0796-4702 other comorbidities and puberal development stage. It brings a specially interesting insight into a subject that has Conflicts of Interest never been directly assessed in previous studies—the chang- MTF reports personal fees and non-financial support from Allergan, es in migraine during the puberal transition. Moreover, the Novartis and Chiesi outside the submitted work. PP-R has received honoraria as a consultant and speaker for: Allergan, prospective follow-up of the cohort was performed by a Almirall, Chiesi, Eli Lilly, Novartis and Teva. Her research group has re- neurologist, and the survey of lifestyle and eating habits was ceived research grants from Allergan and has received funding for clini- completed by the patients themselves responding to the cal trials from Alder, Electrocore, Eli Lilly, Janssen Cilag, Novartis. And identical standardized questions asked at the BL. This a very Teva. PP-R does not own stocks from any pharmaceutical company. All of this, is outside the submitted work. accurate and homogeneous sample, which allowed us to ac- EF, AM, VJG declare no conflicts of interest. curately evaluate the evolution of this pathology. The main limitation of this study was the small size of the Acknowledgements None. sample, which made it difficult to obtain definite and compa- rable results, as well as a medium-term follow-up of 2 years that cannot represent the complete transition to adulthood. It REFERENCES 1. 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