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Reconsideration of the diagnosis and treatment of childhood migraine: A practical review of clinical experiences
Brain & Development xxx (2016) xxx–xxx www.elsevier.com/locate/braindev
Original article
Reconsideration of the diagnosis and treatment of childhood migraine: A practical review of clinical experiences Yoshiaki Saito a,⇑, Gaku Yamanaka b, Hideki Shimomura c, Kazuhiro Shiraishi d, Tomoyuki Nakazawa e, Fumihide Kato f, Yuko Shimizu-Motohashi g, Masayuki Sasaki g, Yoshihiro Maegaki a a
Division of Child Neurology, Department of Brain and Neurosciences, Faculty of Medicine, Tottori University, Yonago, Japan b Department of Pediatrics, Tokyo Medical University, Shinjuku, Tokyo, Japan c Department of Pediatrics, Shiga Medical Center for Children, Moriyama, Japan d Department of Pediatric Neurology, National Hospital Organization, Utano National Hospital, Kyoto, Japan e Department of Pediatrics, Tokyo Metropolitan Health and Medical Treatment Corporation Toshima Hospital, Tokyo, Japan f Division of Pediatrics, Shimane Prefectural Central Hospital, Izumo, Japan g Department of Child Neurology, National Center of Neurology and Psychiatry, Kodaira, Japan Received 6 October 2016; received in revised form 22 November 2016; accepted 22 November 2016
Abstract Objective: To provide insight into the wide spectrum of migraine during childhood to establish practical and comprehensive treatment strategies. Background: Although recent studies have confirmed the effect of anti-migraine agents in childhood headaches fulfilling the criteria of migraine without aura, there have been no studies regarding the efficacy of these drugs in childhood migraine without aura not filling the diagnostic criteria. Methods: In total, 154 patients with a clinical diagnosis of migraine, with onset of repetitive headaches at the age of 615 years, were retrospectively included from clinics in seven tertiary medical centers. Results: Patients’ diagnoses included migraine with aura (n = 49), migraine without aura (n = 65), clinical migraine without aura not fulfilling International Classification of Headache Disorders-3 beta criteria (suspected migraine without aura; n = 38), and hemiplegic migraine (n = 2). Abortive medicine was effective in 74 of 97 patients, and preventive medicine was effective in 61 of 84 patients. Drugs with high efficacy were acetaminophen and ibuprofen for abortive therapy and cyproheptadine, amitriptyline, and propranolol for preventive therapy. Psychosocial problems were less common, and abnormalities on electroencephalography were more common in the suspected migraine without aura group. Otherwise, clinical features and drug responsibility were comparable among the migraine with aura, migraine without aura, and suspected migraine without aura groups. Retrospectively, experts clinically diagnosed childhood migraine without aura when the headache met at least one of the three criteria B, C, and D in International Classification of Headache Disorders-3 beta in addition to A and E. Abortive and preventive medication including paroxetine (n = 2) benefited 10 and 15 of the 33 patients with daily headache, respectively. Psychotherapy/counseling (n = 4), treatment for orthostatic dysregulation (n = 4), and elimination of stressors (n = 3) markedly alleviated headache in this group.
⇑ Corresponding author at: Division of Child Neurology, Department of Brain and Neurosciences, Faculty of Medicine, Tottori University, 36-1 Nishi-cho, Yonago 683-8504, Japan. Fax. +81 859 38 6779. E-mail address: [email protected] (Y. Saito).
http://dx.doi.org/10.1016/j.braindev.2016.11.011 0387-7604/Ó 2016 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: Saito Y et al. Reconsideration of the diagnosis and treatment of childhood migraine: A practical review of clinical experiences. Brain Dev (2016), http://dx.doi.org/10.1016/j.braindev.2016.11.011
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Conclusion: Our results indicated that those with suspected migraine without aura not filling International Classification of Headache Disorders diagnostic criteria should be included in the treatment for migraine. Treatment should also be targeted to comorbid developmental disorders, orthostatic dysregulation, and psychosocial problems in patients with refractory daily headaches. Ó 2016 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.
Keywords: Migraine; Childhood; Orthostatic dysregulation; Autism spectrum disorders; Pervasive developmental disorder
1. Introduction Migraines in childhood show distinct clinical features compared with those in adulthood, with short duration, bilateral headache distribution, and lack of phonophobia. These features mean that diagnostic criteria for childhood migraine without aura (MO) are limited in sensitivity, particularly as the International Headache Society (IHS) criteria (1988) defined duration as 2– 48 h with sensitivity in children of 39–66% [1,2]. Revised IHS criteria (IHS-R) [1] and the International Criteria of Headache Disorders (ICHD)-II [3] approved the duration of 1–72 h, which improved the sensitivity to 80–90%. Early case-control studies have failed to achieve statistical significance in terms of the effect of abortive agents for childhood migraine, which was attributed to a high placebo responder rate in children [4,5]. Recent reports have confirmed the efficacy of abortive agents using a crossover study design, enrollment of children with headache duration of longer than 4 h, and a primary endpoint of complete rather than partial recovery [6–8]. Given this background, the ICHD-3 beta (Table 1) criteria for childhood MO adopted 2 h as the shorter limit of duration [9]. Apart from criteria designed for the collection of homogeneous population data for clinical research [1], headache duration of 0.5 h or more has been classically referred to as childhood migraine [10]. In addition, even loose criteria including duration, laterality, severity, and photophobia/phonophobia did not reach sensitivities of above 80% [1]. We have experienced children whose symptoms did not initially fulfill ICHD criteria but evolved to classical migraine in adolescence. This suggests that more than 20% of children with MO may be missed for appropriate medication if physicians seek a strict diagnosis before treatment. Although recent studies have confirmed the effect of anti-migraine agents in childhood headaches fulfilling adult MO criteria [6–8], there have been no studies regarding the efficacy of these drugs in childhood MO ‘‘not filling the diagnostic criteria.” Statistical significance in the effects of medication for children with headaches of durations P4 h do not reflect the effects in children with shorter duration headaches. This prompted us to review our experience of childhood migraine, particularly whether medication was equally effective for children with definite and possible
Table 1 Diagnostic criteria for migraine without aura in the International Classification of Headache Disorders, 3rd edition (beta version) (ICHD-3b) [Ref. [9]]. 1.1 migraine without aura A. At least five attacks fulfilling criteria B-D B. Headache attacks lasting 4–72 h (untreated or unsuccessfully treated) C. Headache has at least two of the following four characteristics: 1. Unilateral location 2. Pulsating quality 3. Moderate or severe pain intensity 4. Aggravation by or causing avoidance of routine physical activity (eg, walking or climbing stairs) D. During headache at least one of the following: 1. Nausea and/or vomiting 2. Photophobia and phonophobia E. Not better accounted for by another ICHD-3 diagnosis 1.5.1 Probable migraine without aura A. Attacks fulfilling all but one of criteria A–D for 1.1 Migraine without aura B. Not fulfilling ICHD-3 criteria for any other headache disorder C. Not better accounted for by another ICHD-3 diagnosis. Note: In children and adolescents (aged under 18 years), attacks may last 2–72 h (the evidence for untreated durations of less than two hours in children has not been substantiated).
MO. In addition, few studies have examined the relative usefulness of abortive and preventive medicines (e.g., propranolol and valproate [11]) in a single study. Given that the anti-migraine effects of many triptans and antiepileptics have been confirmed in children, we wanted to clarify a rough scheme of the relative usefulness of each drug that had been proven to be effective for childhood migraine in the same population. Another aim of our study was to collect information on childhood migraine with long-term daily headaches as well as with particular types of comorbidity, including febrile acute encephalopathy, orthostatic dysregulation (OD), and developmental disorders (intellectual disability and/or autism-spectrum disorders). We determined the significance of these conditions in childhood migraine and desire to disseminate this knowledge in clinical settings. 2. Methods We recruited children clinically diagnosed with migraine by specialists in childhood headaches, with
Please cite this article in press as: Saito Y et al. Reconsideration of the diagnosis and treatment of childhood migraine: A practical review of clinical experiences. Brain Dev (2016), http://dx.doi.org/10.1016/j.braindev.2016.11.011
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onset before the age of 15 years from clinics in seven tertiary hospitals (two university hospitals, one medical center for children, two national centers specializing in neurology, and two general local hospitals). Enrolled patients first visited these hospitals between October 2012 and September 2015 (or between April 2006 and September 2015 in the case of Tottori University, Shimane Prefectural Central Hospital, and National Center of Neurology and Psychiatry). We used the clinical diagnosis by experts as the gold standard so that childhood MO not filling the diagnostic criteria would not be missed for assessment [1]. Resultantly, 38 patients with headaches of duration less than 2 h, bilateral/midline location, non-pulsatile quality, mild pain intensity, no aggravation by physical activity, or lacking nausea/vo miting/photophobia/phonophobia, i.e. not fulfilling the B (9/38), C (21/38), or D (26/38) criteria in ICHD-3 beta for MO (Table 1), were included in the study. Intellectual disability (ID) and/or autism-spectrum disorders (ASD) were regarded as co-morbidities with migraine, but patients with headaches attributed to psychiatric disorders were excluded. Clinical information was retrospectively collected from medical charts, including sex, onset age, age of first visit to the above hospitals, family history of migraine and/or seizure disorders, personal history of cyclic vomiting and/or seizure disorders, frequency, duration, location, nature (pulsatile or not), severity, and susceptibility to the emergence of headaches at a particular time of the day, accompanying symptoms, comorbidities, and electroencephalography (EEG) and magnetic resonance imaging (MRI) findings (when available). The efficacy of each abortive and preventive agent was assigned to four degrees by the doctor in charge: excellent = complete (100%) disappearance of headache; moderate = 50% or more but less than 100% improvement; fair = less than 50% improvement; and poor = no apparent improvement. Multiple drugs had Table 2 Diagnostic criteria for migraine with aura in the ICHD-3b [Ref. [9]]. 1.2 Migraine with aura A. At least two attacks fulfilling criteria B and C B. One or more of the following fully reversible aura symptoms: 1. Visual 2. Sensory 3. Speech and/or language 4. Motor 5. Brainstem 6. Retinal C. At least two of the following four characteristics: 1. At least one aura symptom spreads gradually over P 5 min, and/or two or more symptoms occur in succession 2. Each individual aura symptom lasts 5–60 min 3. At least one aura symptom is unilateral 4. The aura is accompanied, or followed within 60 min, by headache D. Not better accounted for by another ICHD-3 diagnosis, and transient ischaemic attack has been excluded
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been used in many patients, with various patterns in combination and/or the order of serial initiation. However, these were not considered in the assessment and analysis of their effects. Psychosocial problems in each child were included in our analyses, if such information had been reported. The study design was approved by the ethical committees of each of the seven institutes. The corresponding author had full access to the data for all patients from each institute under conditions of anonymity. Mann–Whitney test was used for comparison of onset/medical referral ages between the MA, MO and suspected MO groups, and chi-square tests were used for comparison of other points in these groups and groups with/without developmental disorders, as well as demographic data of younger and older patient groups. 3. Results 3.1. Patients’ demographic characteristics Retrospective data for 154 patients (76 males and 78 females) were collected. Clinical diagnoses based on the ICHD-3 beta (Tables 1 and 2) for these patients were: migraine with aura (MA; n = 49), MO (n = 65), clinical MO not fulfilling the ICHD-3 beta criteria (suspected MO; n = 38), and hemiplegic migraine (n = 2). Coexistence of tension-type headaches were reported in 15 out of 154 patients. In the suspected MO group, 21 patients did not fulfill one of the criteria B, C, or D (probable MO in Table 1), and 16 and 1 patients did not fulfill two and all of them, respectively. The MA group included three patients with headache duration shorter than 2 h. Onset age (mean ± standard deviation) of recurrent headaches was 9.34 ± 3.09 years, and the age of first referral to the study hospitals was 11.1 ± 2.8 years (Suppl. Fig. 1). Family history of headaches/migraine was present in 99 patients (64%), including mother (n = 66), father (n = 26), siblings (n = 22), and grandmother (n = 8). Five patients had a family history of febrile convulsion and four of epilepsy. Patients’ past history included rhinitis/sinusitis (n = 13), bronchial asthma (n = 13), epilepsy (n = 10), febrile convulsion (n = 7), and cyclic vomiting (n = 4). In addition, comorbid developmental disorders were reported in 33 subjects, including mild ID with intelligence quotient 50–73 or learning disability (n = 13), ASD (n = 17), and attention deficient hyperactivity disorder (n = 7; overlap with ASD in 4). Three patients had a history of febrile acute encephalopathy (Suppl. Table 1). EEG findings (n = 44) were normal for 25 patients, but showed epileptiform discharges in 18 patients and background laterality in one patient. MRI findings were available for 87 patients: 72 were normal, six showed non-specific high signal spots in the cerebral white matter (Suppl. Fig. 2, Suppl. Table 2), five showed sinusitis,
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one showed laterality of posterior horn, one showed cerebellar vascular anomaly, one showed hypoplastic vermis, and one showed chordoma in the clivus. These findings were not thought to be responsible for the headaches. Amelioration of the white matter spots in signal intensity and/or number was observed in one patient on follow-up imaging after headache resolution (Suppl. Fig. 2C and 2D). 3.2. Characteristics of headaches and comorbidities For the delineation of headache characteristics, we tentatively divided the 154 patients into those younger than 12 years (n = 76, male:female = 42:34), and those aged 12 years or older (n = 78, male:female = 34:44) at the first referral. The proportion of daily headache emergence at the first referral was higher, and the duration tended to be longer in the older group. Distribution of headache pain was more predominant in the frontal and parietal areas in the younger group and in the temporal areas in the older group. Children in both groups were susceptible to headache in the morning, followed by evening and/or night, with fewer headaches in the daytime (Suppl. Fig. 3). Vomiting was significantly (p = 0.029) more common in the younger group, while OD was significantly (p = 0.046) more common in the older group (Fig. 1). Limb pain tended to be common in the older group, but this did not reach a statistical significance (p = 0.051). The proportion of MA, MO, and
suspected MO was comparable in both groups (Suppl. Fig. 3F). In addition, the suspected MO group showed a family history of headache or seizure, and comorbidity of developmental disorders comparable with the MA and MO groups. Psychosocial problems were less common, and EEG abnormality was more common in the suspected MO group (Table 3). Accompanying gastrointestinal symptoms and history of seizure disorders were significantly higher in patients with developmental disorders compared with other patients (Table 4). 3.3. Effects of medication Among the 154 patients, abortive medicine showed excellent to moderate effects in 74 of 97 treated patients, and preventive medicine showed excellent to moderate effects 61 of 84 treated patients. Commonly used drugs with higher efficacy were acetaminophen (assessed as excellent or good in 51% of treated patients) and ibuprofen (77%) for abortive therapy, and cyproheptadine (77%), amitriptyline (59%), lomerizine (48%), and propranolol (70%) for preventive therapy. Among the triptans used in the older group, sumatriptan and rizatriptan were effective on some occasions. Valproate sodium appeared less supportive (11%) in this series of patients (Fig. 2). These trends were also common in the MO and suspected MO groups (Fig. 3), as well as in those with developmental disorders (Suppl. Fig.4). The degree of efficacy of acetaminophen, ibuprofen, amitriptyline, lomerizine,
Fig. 1. Accompanying symptoms and past history of patients younger than 12 years of age (gray column) and aged 12 years or older (black column). Asterisks (*) represent statistical significance of p < 0.05.
Please cite this article in press as: Saito Y et al. Reconsideration of the diagnosis and treatment of childhood migraine: A practical review of clinical experiences. Brain Dev (2016), http://dx.doi.org/10.1016/j.braindev.2016.11.011
MA MO MO susp
Onset age
Age at medical referreal
9.3 ± 3.3 9.4 ± 2.5 9.3 ± 3.3
11.3 ± 2.5 11.0 ± 2.6 11.0 ± 3.6
Familial Hx
Personal Hx
Developmental disorders
Headache
FC/epilepsy
FC/epilepsy
ADHD
ASD
ID
LD
Total
34/49 39/65 25/38
4/49 3/65 4/38
6/49 6/65 5/38
0/49 3/65 0/38
3/49 12/65 2/38
5/49 4/65 3/38
1/49 0/65 0/38
9/49 17/65 5/38
Psychosocial factors 12/49 22/65 4/38
EEG abnormality
p < 0.01
5/21 4/15 8/11
p < 0.05
ADHD: attention-deficit hyperactivity disorder, ASD: autism spectrum disorder, EEG: electroencephalography, FC: febrile convulsion ID: intellectual disorder, Hx: history, LD: learning disorder.
Table 4 Characteristics of children with migraine, with and without developmental disorders.
Developmental disorders (+) (n = 33) Developmental disorders ( ) (n = 141)
Familial history of headache
Frequency (d/w/m/y)
Duration (～1/1–3/ 3–6/6～) (hours)
Limbs pain
OD
19/33
13/13/5/2
2/8/7/14
5/33
7/33
80/141
49/31/33/5
8/35/28/41
13/141
35/141
FC/ epilepsy 3 8/33 5 9/141
Vertig 6/33 p < 0.01 30/141
Abdominal pain 3 8/33 5 14/141
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Diarrhea 4/33 p < 0.05
3 5
p < 0.05
4/141
FC: febrile convulsion, OD: orthostatic dysregulation.
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Table 3 Characteristics of children in groups of migraine with aura, migraine without aura, and suspected migraine without aura.
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Fig. 2. Effects of abortive (A) and preventive (B) medication for headache in 154 patients. White, light gray, dark gray, and black columns represent excellent (100% resolution), moderate (50% or more but less than 100% resolution), fair (amelioration less than 50%), and poor (no effect) responses, respectively.
propranolol, and valproate was not significantly different between the MA, MO and suspected MO groups. No abortive or preventive medication was effective in six patients (M:F = 4:2, MA 2 and MO 4; age at medical referral 13.0 ± 1.5 years, trial of 4–9 abortive/preventive agents). All of them presented with daily headaches at the referral, which were occurring on 30 or more consecutive days in four of them.
3.4. Childhood migraine with duration of less than 2 h (Suppl. Table 3) Seven of nine subjects with headache duration shorter than 2 h were younger than 12 years at their first referral. Five patients manifested with daily headaches at referral, and four (three with daily and one with weekly headaches) were treated with preventive medication. Cyproheptadine
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Fig. 3. Effects of medication for headache in the migraine without aura (A) and the suspected migraine without aura (B) groups. White, light gray, dark gray, and black columns represent excellent (100% resolution), moderate (50% or more but less than 100% resolution), fair (amelioration less than 50%), and poor (no effect) responses, respectively.
and lomerizine showed excellent effects in one daily patient, and lomerizine showed a moderate effect in another. Amitriptyline showed an excellent effect in the patient with weekly headaches. Valproate was ineffective in the remaining patient with daily headaches. 3.5. Characteristics of children with daily headaches Chronic daily headache (CDH) is defined as a headache frequency of 15 or more days per month over a period of 3 consecutive months, in the absence of organic pathology [12,13]. However, given our clinical concern of a high-morbidity group in childhood migraine, we collected and analyzed data from patients with daily headaches occurring on 30 or more consecutive days. Of the 62 subjects who presented with headaches of daily emergence at referral, daily headaches had lasted for more than one month in 33 patients (1–12 months). Epileptiform discharges were noted in two of six examined patients, and white matter spots on MRI were found in three of 14 patients. Diagnoses for these 33 patients were MA (n = 6), MO (n = 26), and suspected MO (n = 1). The onset of headache was at an age of
10.1 ± 2.9 years, and the first referral was at an age of 11.5 ± 2.3 years. Family history of headache was present in 18 patients (55%). Only one patient had a history of epilepsy. Comorbid OD was noted in 15 patients. In total, 24 of the 33 patients had a background of developmental disorders (n = 9: 6 ASD and 3 ID) and/or psychosocial problems (n = 18). Medication overuse was reported in one patient without such a background. Psychosocial problems included school phobia (n = 9), perfectionism, anxiety, and nervous traits (n = 3), transfer to foreign countries from Japan (n = 2), parental psychological/psychiatric problems (n = 2), death of parent, and traffic accident. Twelve patients suffered from persistent daily headaches during the waking period. Of these, 11 had psychosocial problems (n = 9) and/or developmental disorders (n = 3). OD was reported in six patients. Abortive medication benefited 10 of these 33 patients, and preventive medication benefited 15. Moderate effects were reported for acetaminophen (4 of 12 patients), ibuprofen (5/7), cyproheptadine (2/5), lomerizine (5/11), propranolol (2/9), valproate (5/9), gosyuyuto (5/7), and paroxetine (2/2).
Please cite this article in press as: Saito Y et al. Reconsideration of the diagnosis and treatment of childhood migraine: A practical review of clinical experiences. Brain Dev (2016), http://dx.doi.org/10.1016/j.braindev.2016.11.011
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Psychotherapy/counseling (n = 4), treatment for OD (n = 4), and elimination of stressors (n = 3) markedly alleviated the headaches in 11 patients with daily headache. 4. Discussion A limitation of this study is selection bias due to the retrospective data collection from tertiary medical centers, which, for example, might have resulted in a high proportion of patients with epilepsy. Assessment of the effects after treatment was dependent on medical charts. However, even with these limitations, the demographic characteristics of the patients were consistent with those in the childhood migraine literature described to date. In addition, the assumed efficacy of acetaminophen, ibuprofen, cyproheptadine, amitriptyline, and propranolol is comparable with previous prospective and case-controlled studies [14–17]. As mentioned, there is controversy regarding the minimum duration of headache in MO in the international criteria. The revision from 1 h in the IHS-R and ICHD-II to 2 h in the ICHD-3 beta has also been criticized [18]. Indeed, a duration of 0.5 h was accepted in childhood migraine in classical studies [10], and the proportion of children with headaches of a duration 61 h has been reported as 14–27% [19,20]. We tentatively enrolled 154 children with headaches of any duration with a clinical diagnosis of migraine by specialists, and found nine with such headache duration; at least three of these benefited from preventive medication. Antimigraine medication is effective for many children whose headaches do not fulfill ICHD-3 beta criteria; amitriptyline showed an excellent effect for children with repeated headaches, including 25.1% who were not classified by IHS criteria [17]. Broadening IHS-R and other criteria for childhood MO criteria not only for the duration of headache but also for laterality and the manifestations of vomiting/nausea/photophobia/phonophobia, could increase the sensitivity for clinically diagnosed migraine [1,2]. To our knowledge, this is the first study focused on the effect of anti-migraine drugs in children included in the MO population by these loose criteria. The efficacy in the suspected MO group was comparable with that in the MA and MO groups, which may support a practical attitude of accepting that ‘‘all recurrent paroxysmal (primary) headache in childhood is likely to be migraine” [21]. Among other drugs, the low efficacy of valproate contradicted the results of studies that proved its efficacy [11,22]. One explanation is that valproate is usually used in Japan as an antiepileptic at a dose 620 mg/kg/d, lower than the dosage of 30–40 mg/kg/d in these trials [11,22]. In contrast, valproate was fairly effective in the daily headache group. This might suggest a pathophysiology of this group distinct from usual childhood migraine.
In the daily headache group, prevalence of psychosocial stressors (55%; 68% in [23]), the proportion of certain benefit from medication (21 of 33, 63%; 68% in [23]), and the recovery not by medication (11 of 33, 33%; 21% in [23]) were comparable with previous results for childhood CDH. In particular, we want to emphasize the comorbidity of OD and ASD in this group. Although not scrutinized in this study, symptoms of OD are often markedly aggravated and persist for weeks after a bout of severe migraine headache, possibly with a similar pathophysiology to the complication of syncope in those who suffer from migraines [24]. A psychosomatic approach is often effective in the management of OD, for which a promising option is the addition of treatment for co-existing migraine. Eight of the nine patients with ASD/ID in the daily headache group did not have comorbid OD, which could be regarded as a distinct feature of this group. This point has not been discussed in the literature, but may suggest that children with ASD/ID are catastrophizing their headache pain and could be easily sensitized. Serotonin reuptake inhibitors [25], as well as elimination of stressors, may be worth trialing in such a situation. Defects in the serotonergic system are also hypothesized as a common pathology in migraine and autism [26,27], which requires further clarification. Lastly, the prevalence (6.9%, six of 86 cases examined with MRI) and distribution of high signal dots in the cerebral white matter was consistent with a report showing a prevalence of 2.9% and the distribution of small (multiple in some cases) high signal dots at the centrum semiovale and frontal white matter, and other areas of deep white matter [28]. We found one case where evolution of lesions supported the statement ‘‘although not proven, prevention and treatment of headaches may reduce the rate of accumulation of white matter lesions” [28]. In conclusion, patients with suspected MO not filling the ICHD diagnostic criteria should not be missed for treatment for migraine. In this study, experts clinically diagnosed essentially all of the childhood MO when the headache met one or more of the three criteria B, C, and D in ICHD-3 beta in addition to A and E (Table 1). This strategy was proven to be practically effective in the view of medication for these headaches. Treatment should be also targeted to comorbid developmental disorders, OD, and psychosocial problems in patients with refractory daily headaches. Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10. 1016/j.braindev.2016.11.011.
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Original article
Reconsideration of the diagnosis and treatment of childhood migraine: A practical review of clinical experiences Yoshiaki Saito a,⇑, Gaku Yamanaka b, Hideki Shimomura c, Kazuhiro Shiraishi d, Tomoyuki Nakazawa e, Fumihide Kato f, Yuko Shimizu-Motohashi g, Masayuki Sasaki g, Yoshihiro Maegaki a a
Division of Child Neurology, Department of Brain and Neurosciences, Faculty of Medicine, Tottori University, Yonago, Japan b Department of Pediatrics, Tokyo Medical University, Shinjuku, Tokyo, Japan c Department of Pediatrics, Shiga Medical Center for Children, Moriyama, Japan d Department of Pediatric Neurology, National Hospital Organization, Utano National Hospital, Kyoto, Japan e Department of Pediatrics, Tokyo Metropolitan Health and Medical Treatment Corporation Toshima Hospital, Tokyo, Japan f Division of Pediatrics, Shimane Prefectural Central Hospital, Izumo, Japan g Department of Child Neurology, National Center of Neurology and Psychiatry, Kodaira, Japan Received 6 October 2016; received in revised form 22 November 2016; accepted 22 November 2016
Abstract Objective: To provide insight into the wide spectrum of migraine during childhood to establish practical and comprehensive treatment strategies. Background: Although recent studies have confirmed the effect of anti-migraine agents in childhood headaches fulfilling the criteria of migraine without aura, there have been no studies regarding the efficacy of these drugs in childhood migraine without aura not filling the diagnostic criteria. Methods: In total, 154 patients with a clinical diagnosis of migraine, with onset of repetitive headaches at the age of 615 years, were retrospectively included from clinics in seven tertiary medical centers. Results: Patients’ diagnoses included migraine with aura (n = 49), migraine without aura (n = 65), clinical migraine without aura not fulfilling International Classification of Headache Disorders-3 beta criteria (suspected migraine without aura; n = 38), and hemiplegic migraine (n = 2). Abortive medicine was effective in 74 of 97 patients, and preventive medicine was effective in 61 of 84 patients. Drugs with high efficacy were acetaminophen and ibuprofen for abortive therapy and cyproheptadine, amitriptyline, and propranolol for preventive therapy. Psychosocial problems were less common, and abnormalities on electroencephalography were more common in the suspected migraine without aura group. Otherwise, clinical features and drug responsibility were comparable among the migraine with aura, migraine without aura, and suspected migraine without aura groups. Retrospectively, experts clinically diagnosed childhood migraine without aura when the headache met at least one of the three criteria B, C, and D in International Classification of Headache Disorders-3 beta in addition to A and E. Abortive and preventive medication including paroxetine (n = 2) benefited 10 and 15 of the 33 patients with daily headache, respectively. Psychotherapy/counseling (n = 4), treatment for orthostatic dysregulation (n = 4), and elimination of stressors (n = 3) markedly alleviated headache in this group.
⇑ Corresponding author at: Division of Child Neurology, Department of Brain and Neurosciences, Faculty of Medicine, Tottori University, 36-1 Nishi-cho, Yonago 683-8504, Japan. Fax. +81 859 38 6779. E-mail address: [email protected] (Y. Saito).
http://dx.doi.org/10.1016/j.braindev.2016.11.011 0387-7604/Ó 2016 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: Saito Y et al. Reconsideration of the diagnosis and treatment of childhood migraine: A practical review of clinical experiences. Brain Dev (2016), http://dx.doi.org/10.1016/j.braindev.2016.11.011
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Conclusion: Our results indicated that those with suspected migraine without aura not filling International Classification of Headache Disorders diagnostic criteria should be included in the treatment for migraine. Treatment should also be targeted to comorbid developmental disorders, orthostatic dysregulation, and psychosocial problems in patients with refractory daily headaches. Ó 2016 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.
Keywords: Migraine; Childhood; Orthostatic dysregulation; Autism spectrum disorders; Pervasive developmental disorder
1. Introduction Migraines in childhood show distinct clinical features compared with those in adulthood, with short duration, bilateral headache distribution, and lack of phonophobia. These features mean that diagnostic criteria for childhood migraine without aura (MO) are limited in sensitivity, particularly as the International Headache Society (IHS) criteria (1988) defined duration as 2– 48 h with sensitivity in children of 39–66% [1,2]. Revised IHS criteria (IHS-R) [1] and the International Criteria of Headache Disorders (ICHD)-II [3] approved the duration of 1–72 h, which improved the sensitivity to 80–90%. Early case-control studies have failed to achieve statistical significance in terms of the effect of abortive agents for childhood migraine, which was attributed to a high placebo responder rate in children [4,5]. Recent reports have confirmed the efficacy of abortive agents using a crossover study design, enrollment of children with headache duration of longer than 4 h, and a primary endpoint of complete rather than partial recovery [6–8]. Given this background, the ICHD-3 beta (Table 1) criteria for childhood MO adopted 2 h as the shorter limit of duration [9]. Apart from criteria designed for the collection of homogeneous population data for clinical research [1], headache duration of 0.5 h or more has been classically referred to as childhood migraine [10]. In addition, even loose criteria including duration, laterality, severity, and photophobia/phonophobia did not reach sensitivities of above 80% [1]. We have experienced children whose symptoms did not initially fulfill ICHD criteria but evolved to classical migraine in adolescence. This suggests that more than 20% of children with MO may be missed for appropriate medication if physicians seek a strict diagnosis before treatment. Although recent studies have confirmed the effect of anti-migraine agents in childhood headaches fulfilling adult MO criteria [6–8], there have been no studies regarding the efficacy of these drugs in childhood MO ‘‘not filling the diagnostic criteria.” Statistical significance in the effects of medication for children with headaches of durations P4 h do not reflect the effects in children with shorter duration headaches. This prompted us to review our experience of childhood migraine, particularly whether medication was equally effective for children with definite and possible
Table 1 Diagnostic criteria for migraine without aura in the International Classification of Headache Disorders, 3rd edition (beta version) (ICHD-3b) [Ref. [9]]. 1.1 migraine without aura A. At least five attacks fulfilling criteria B-D B. Headache attacks lasting 4–72 h (untreated or unsuccessfully treated) C. Headache has at least two of the following four characteristics: 1. Unilateral location 2. Pulsating quality 3. Moderate or severe pain intensity 4. Aggravation by or causing avoidance of routine physical activity (eg, walking or climbing stairs) D. During headache at least one of the following: 1. Nausea and/or vomiting 2. Photophobia and phonophobia E. Not better accounted for by another ICHD-3 diagnosis 1.5.1 Probable migraine without aura A. Attacks fulfilling all but one of criteria A–D for 1.1 Migraine without aura B. Not fulfilling ICHD-3 criteria for any other headache disorder C. Not better accounted for by another ICHD-3 diagnosis. Note: In children and adolescents (aged under 18 years), attacks may last 2–72 h (the evidence for untreated durations of less than two hours in children has not been substantiated).
MO. In addition, few studies have examined the relative usefulness of abortive and preventive medicines (e.g., propranolol and valproate [11]) in a single study. Given that the anti-migraine effects of many triptans and antiepileptics have been confirmed in children, we wanted to clarify a rough scheme of the relative usefulness of each drug that had been proven to be effective for childhood migraine in the same population. Another aim of our study was to collect information on childhood migraine with long-term daily headaches as well as with particular types of comorbidity, including febrile acute encephalopathy, orthostatic dysregulation (OD), and developmental disorders (intellectual disability and/or autism-spectrum disorders). We determined the significance of these conditions in childhood migraine and desire to disseminate this knowledge in clinical settings. 2. Methods We recruited children clinically diagnosed with migraine by specialists in childhood headaches, with
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onset before the age of 15 years from clinics in seven tertiary hospitals (two university hospitals, one medical center for children, two national centers specializing in neurology, and two general local hospitals). Enrolled patients first visited these hospitals between October 2012 and September 2015 (or between April 2006 and September 2015 in the case of Tottori University, Shimane Prefectural Central Hospital, and National Center of Neurology and Psychiatry). We used the clinical diagnosis by experts as the gold standard so that childhood MO not filling the diagnostic criteria would not be missed for assessment [1]. Resultantly, 38 patients with headaches of duration less than 2 h, bilateral/midline location, non-pulsatile quality, mild pain intensity, no aggravation by physical activity, or lacking nausea/vo miting/photophobia/phonophobia, i.e. not fulfilling the B (9/38), C (21/38), or D (26/38) criteria in ICHD-3 beta for MO (Table 1), were included in the study. Intellectual disability (ID) and/or autism-spectrum disorders (ASD) were regarded as co-morbidities with migraine, but patients with headaches attributed to psychiatric disorders were excluded. Clinical information was retrospectively collected from medical charts, including sex, onset age, age of first visit to the above hospitals, family history of migraine and/or seizure disorders, personal history of cyclic vomiting and/or seizure disorders, frequency, duration, location, nature (pulsatile or not), severity, and susceptibility to the emergence of headaches at a particular time of the day, accompanying symptoms, comorbidities, and electroencephalography (EEG) and magnetic resonance imaging (MRI) findings (when available). The efficacy of each abortive and preventive agent was assigned to four degrees by the doctor in charge: excellent = complete (100%) disappearance of headache; moderate = 50% or more but less than 100% improvement; fair = less than 50% improvement; and poor = no apparent improvement. Multiple drugs had Table 2 Diagnostic criteria for migraine with aura in the ICHD-3b [Ref. [9]]. 1.2 Migraine with aura A. At least two attacks fulfilling criteria B and C B. One or more of the following fully reversible aura symptoms: 1. Visual 2. Sensory 3. Speech and/or language 4. Motor 5. Brainstem 6. Retinal C. At least two of the following four characteristics: 1. At least one aura symptom spreads gradually over P 5 min, and/or two or more symptoms occur in succession 2. Each individual aura symptom lasts 5–60 min 3. At least one aura symptom is unilateral 4. The aura is accompanied, or followed within 60 min, by headache D. Not better accounted for by another ICHD-3 diagnosis, and transient ischaemic attack has been excluded
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been used in many patients, with various patterns in combination and/or the order of serial initiation. However, these were not considered in the assessment and analysis of their effects. Psychosocial problems in each child were included in our analyses, if such information had been reported. The study design was approved by the ethical committees of each of the seven institutes. The corresponding author had full access to the data for all patients from each institute under conditions of anonymity. Mann–Whitney test was used for comparison of onset/medical referral ages between the MA, MO and suspected MO groups, and chi-square tests were used for comparison of other points in these groups and groups with/without developmental disorders, as well as demographic data of younger and older patient groups. 3. Results 3.1. Patients’ demographic characteristics Retrospective data for 154 patients (76 males and 78 females) were collected. Clinical diagnoses based on the ICHD-3 beta (Tables 1 and 2) for these patients were: migraine with aura (MA; n = 49), MO (n = 65), clinical MO not fulfilling the ICHD-3 beta criteria (suspected MO; n = 38), and hemiplegic migraine (n = 2). Coexistence of tension-type headaches were reported in 15 out of 154 patients. In the suspected MO group, 21 patients did not fulfill one of the criteria B, C, or D (probable MO in Table 1), and 16 and 1 patients did not fulfill two and all of them, respectively. The MA group included three patients with headache duration shorter than 2 h. Onset age (mean ± standard deviation) of recurrent headaches was 9.34 ± 3.09 years, and the age of first referral to the study hospitals was 11.1 ± 2.8 years (Suppl. Fig. 1). Family history of headaches/migraine was present in 99 patients (64%), including mother (n = 66), father (n = 26), siblings (n = 22), and grandmother (n = 8). Five patients had a family history of febrile convulsion and four of epilepsy. Patients’ past history included rhinitis/sinusitis (n = 13), bronchial asthma (n = 13), epilepsy (n = 10), febrile convulsion (n = 7), and cyclic vomiting (n = 4). In addition, comorbid developmental disorders were reported in 33 subjects, including mild ID with intelligence quotient 50–73 or learning disability (n = 13), ASD (n = 17), and attention deficient hyperactivity disorder (n = 7; overlap with ASD in 4). Three patients had a history of febrile acute encephalopathy (Suppl. Table 1). EEG findings (n = 44) were normal for 25 patients, but showed epileptiform discharges in 18 patients and background laterality in one patient. MRI findings were available for 87 patients: 72 were normal, six showed non-specific high signal spots in the cerebral white matter (Suppl. Fig. 2, Suppl. Table 2), five showed sinusitis,
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one showed laterality of posterior horn, one showed cerebellar vascular anomaly, one showed hypoplastic vermis, and one showed chordoma in the clivus. These findings were not thought to be responsible for the headaches. Amelioration of the white matter spots in signal intensity and/or number was observed in one patient on follow-up imaging after headache resolution (Suppl. Fig. 2C and 2D). 3.2. Characteristics of headaches and comorbidities For the delineation of headache characteristics, we tentatively divided the 154 patients into those younger than 12 years (n = 76, male:female = 42:34), and those aged 12 years or older (n = 78, male:female = 34:44) at the first referral. The proportion of daily headache emergence at the first referral was higher, and the duration tended to be longer in the older group. Distribution of headache pain was more predominant in the frontal and parietal areas in the younger group and in the temporal areas in the older group. Children in both groups were susceptible to headache in the morning, followed by evening and/or night, with fewer headaches in the daytime (Suppl. Fig. 3). Vomiting was significantly (p = 0.029) more common in the younger group, while OD was significantly (p = 0.046) more common in the older group (Fig. 1). Limb pain tended to be common in the older group, but this did not reach a statistical significance (p = 0.051). The proportion of MA, MO, and
suspected MO was comparable in both groups (Suppl. Fig. 3F). In addition, the suspected MO group showed a family history of headache or seizure, and comorbidity of developmental disorders comparable with the MA and MO groups. Psychosocial problems were less common, and EEG abnormality was more common in the suspected MO group (Table 3). Accompanying gastrointestinal symptoms and history of seizure disorders were significantly higher in patients with developmental disorders compared with other patients (Table 4). 3.3. Effects of medication Among the 154 patients, abortive medicine showed excellent to moderate effects in 74 of 97 treated patients, and preventive medicine showed excellent to moderate effects 61 of 84 treated patients. Commonly used drugs with higher efficacy were acetaminophen (assessed as excellent or good in 51% of treated patients) and ibuprofen (77%) for abortive therapy, and cyproheptadine (77%), amitriptyline (59%), lomerizine (48%), and propranolol (70%) for preventive therapy. Among the triptans used in the older group, sumatriptan and rizatriptan were effective on some occasions. Valproate sodium appeared less supportive (11%) in this series of patients (Fig. 2). These trends were also common in the MO and suspected MO groups (Fig. 3), as well as in those with developmental disorders (Suppl. Fig.4). The degree of efficacy of acetaminophen, ibuprofen, amitriptyline, lomerizine,
Fig. 1. Accompanying symptoms and past history of patients younger than 12 years of age (gray column) and aged 12 years or older (black column). Asterisks (*) represent statistical significance of p < 0.05.
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MA MO MO susp
Onset age
Age at medical referreal
9.3 ± 3.3 9.4 ± 2.5 9.3 ± 3.3
11.3 ± 2.5 11.0 ± 2.6 11.0 ± 3.6
Familial Hx
Personal Hx
Developmental disorders
Headache
FC/epilepsy
FC/epilepsy
ADHD
ASD
ID
LD
Total
34/49 39/65 25/38
4/49 3/65 4/38
6/49 6/65 5/38
0/49 3/65 0/38
3/49 12/65 2/38
5/49 4/65 3/38
1/49 0/65 0/38
9/49 17/65 5/38
Psychosocial factors 12/49 22/65 4/38
EEG abnormality
p < 0.01
5/21 4/15 8/11
p < 0.05
ADHD: attention-deficit hyperactivity disorder, ASD: autism spectrum disorder, EEG: electroencephalography, FC: febrile convulsion ID: intellectual disorder, Hx: history, LD: learning disorder.
Table 4 Characteristics of children with migraine, with and without developmental disorders.
Developmental disorders (+) (n = 33) Developmental disorders ( ) (n = 141)
Familial history of headache
Frequency (d/w/m/y)
Duration (～1/1–3/ 3–6/6～) (hours)
Limbs pain
OD
19/33
13/13/5/2
2/8/7/14
5/33
7/33
80/141
49/31/33/5
8/35/28/41
13/141
35/141
FC/ epilepsy 3 8/33 5 9/141
Vertig 6/33 p < 0.01 30/141
Abdominal pain 3 8/33 5 14/141
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Diarrhea 4/33 p < 0.05
3 5
p < 0.05
4/141
FC: febrile convulsion, OD: orthostatic dysregulation.
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Table 3 Characteristics of children in groups of migraine with aura, migraine without aura, and suspected migraine without aura.
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Fig. 2. Effects of abortive (A) and preventive (B) medication for headache in 154 patients. White, light gray, dark gray, and black columns represent excellent (100% resolution), moderate (50% or more but less than 100% resolution), fair (amelioration less than 50%), and poor (no effect) responses, respectively.
propranolol, and valproate was not significantly different between the MA, MO and suspected MO groups. No abortive or preventive medication was effective in six patients (M:F = 4:2, MA 2 and MO 4; age at medical referral 13.0 ± 1.5 years, trial of 4–9 abortive/preventive agents). All of them presented with daily headaches at the referral, which were occurring on 30 or more consecutive days in four of them.
3.4. Childhood migraine with duration of less than 2 h (Suppl. Table 3) Seven of nine subjects with headache duration shorter than 2 h were younger than 12 years at their first referral. Five patients manifested with daily headaches at referral, and four (three with daily and one with weekly headaches) were treated with preventive medication. Cyproheptadine
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Fig. 3. Effects of medication for headache in the migraine without aura (A) and the suspected migraine without aura (B) groups. White, light gray, dark gray, and black columns represent excellent (100% resolution), moderate (50% or more but less than 100% resolution), fair (amelioration less than 50%), and poor (no effect) responses, respectively.
and lomerizine showed excellent effects in one daily patient, and lomerizine showed a moderate effect in another. Amitriptyline showed an excellent effect in the patient with weekly headaches. Valproate was ineffective in the remaining patient with daily headaches. 3.5. Characteristics of children with daily headaches Chronic daily headache (CDH) is defined as a headache frequency of 15 or more days per month over a period of 3 consecutive months, in the absence of organic pathology [12,13]. However, given our clinical concern of a high-morbidity group in childhood migraine, we collected and analyzed data from patients with daily headaches occurring on 30 or more consecutive days. Of the 62 subjects who presented with headaches of daily emergence at referral, daily headaches had lasted for more than one month in 33 patients (1–12 months). Epileptiform discharges were noted in two of six examined patients, and white matter spots on MRI were found in three of 14 patients. Diagnoses for these 33 patients were MA (n = 6), MO (n = 26), and suspected MO (n = 1). The onset of headache was at an age of
10.1 ± 2.9 years, and the first referral was at an age of 11.5 ± 2.3 years. Family history of headache was present in 18 patients (55%). Only one patient had a history of epilepsy. Comorbid OD was noted in 15 patients. In total, 24 of the 33 patients had a background of developmental disorders (n = 9: 6 ASD and 3 ID) and/or psychosocial problems (n = 18). Medication overuse was reported in one patient without such a background. Psychosocial problems included school phobia (n = 9), perfectionism, anxiety, and nervous traits (n = 3), transfer to foreign countries from Japan (n = 2), parental psychological/psychiatric problems (n = 2), death of parent, and traffic accident. Twelve patients suffered from persistent daily headaches during the waking period. Of these, 11 had psychosocial problems (n = 9) and/or developmental disorders (n = 3). OD was reported in six patients. Abortive medication benefited 10 of these 33 patients, and preventive medication benefited 15. Moderate effects were reported for acetaminophen (4 of 12 patients), ibuprofen (5/7), cyproheptadine (2/5), lomerizine (5/11), propranolol (2/9), valproate (5/9), gosyuyuto (5/7), and paroxetine (2/2).
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Psychotherapy/counseling (n = 4), treatment for OD (n = 4), and elimination of stressors (n = 3) markedly alleviated the headaches in 11 patients with daily headache. 4. Discussion A limitation of this study is selection bias due to the retrospective data collection from tertiary medical centers, which, for example, might have resulted in a high proportion of patients with epilepsy. Assessment of the effects after treatment was dependent on medical charts. However, even with these limitations, the demographic characteristics of the patients were consistent with those in the childhood migraine literature described to date. In addition, the assumed efficacy of acetaminophen, ibuprofen, cyproheptadine, amitriptyline, and propranolol is comparable with previous prospective and case-controlled studies [14–17]. As mentioned, there is controversy regarding the minimum duration of headache in MO in the international criteria. The revision from 1 h in the IHS-R and ICHD-II to 2 h in the ICHD-3 beta has also been criticized [18]. Indeed, a duration of 0.5 h was accepted in childhood migraine in classical studies [10], and the proportion of children with headaches of a duration 61 h has been reported as 14–27% [19,20]. We tentatively enrolled 154 children with headaches of any duration with a clinical diagnosis of migraine by specialists, and found nine with such headache duration; at least three of these benefited from preventive medication. Antimigraine medication is effective for many children whose headaches do not fulfill ICHD-3 beta criteria; amitriptyline showed an excellent effect for children with repeated headaches, including 25.1% who were not classified by IHS criteria [17]. Broadening IHS-R and other criteria for childhood MO criteria not only for the duration of headache but also for laterality and the manifestations of vomiting/nausea/photophobia/phonophobia, could increase the sensitivity for clinically diagnosed migraine [1,2]. To our knowledge, this is the first study focused on the effect of anti-migraine drugs in children included in the MO population by these loose criteria. The efficacy in the suspected MO group was comparable with that in the MA and MO groups, which may support a practical attitude of accepting that ‘‘all recurrent paroxysmal (primary) headache in childhood is likely to be migraine” [21]. Among other drugs, the low efficacy of valproate contradicted the results of studies that proved its efficacy [11,22]. One explanation is that valproate is usually used in Japan as an antiepileptic at a dose 620 mg/kg/d, lower than the dosage of 30–40 mg/kg/d in these trials [11,22]. In contrast, valproate was fairly effective in the daily headache group. This might suggest a pathophysiology of this group distinct from usual childhood migraine.
In the daily headache group, prevalence of psychosocial stressors (55%; 68% in [23]), the proportion of certain benefit from medication (21 of 33, 63%; 68% in [23]), and the recovery not by medication (11 of 33, 33%; 21% in [23]) were comparable with previous results for childhood CDH. In particular, we want to emphasize the comorbidity of OD and ASD in this group. Although not scrutinized in this study, symptoms of OD are often markedly aggravated and persist for weeks after a bout of severe migraine headache, possibly with a similar pathophysiology to the complication of syncope in those who suffer from migraines [24]. A psychosomatic approach is often effective in the management of OD, for which a promising option is the addition of treatment for co-existing migraine. Eight of the nine patients with ASD/ID in the daily headache group did not have comorbid OD, which could be regarded as a distinct feature of this group. This point has not been discussed in the literature, but may suggest that children with ASD/ID are catastrophizing their headache pain and could be easily sensitized. Serotonin reuptake inhibitors [25], as well as elimination of stressors, may be worth trialing in such a situation. Defects in the serotonergic system are also hypothesized as a common pathology in migraine and autism [26,27], which requires further clarification. Lastly, the prevalence (6.9%, six of 86 cases examined with MRI) and distribution of high signal dots in the cerebral white matter was consistent with a report showing a prevalence of 2.9% and the distribution of small (multiple in some cases) high signal dots at the centrum semiovale and frontal white matter, and other areas of deep white matter [28]. We found one case where evolution of lesions supported the statement ‘‘although not proven, prevention and treatment of headaches may reduce the rate of accumulation of white matter lesions” [28]. In conclusion, patients with suspected MO not filling the ICHD diagnostic criteria should not be missed for treatment for migraine. In this study, experts clinically diagnosed essentially all of the childhood MO when the headache met one or more of the three criteria B, C, and D in ICHD-3 beta in addition to A and E (Table 1). This strategy was proven to be practically effective in the view of medication for these headaches. Treatment should be also targeted to comorbid developmental disorders, OD, and psychosocial problems in patients with refractory daily headaches. Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10. 1016/j.braindev.2016.11.011.
Please cite this article in press as: Saito Y et al. Reconsideration of the diagnosis and treatment of childhood migraine: A practical review of clinical experiences. Brain Dev (2016), http://dx.doi.org/10.1016/j.braindev.2016.11.011
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Please cite this article in press as: Saito Y et al. Reconsideration of the diagnosis and treatment of childhood migraine: A practical review of clinical experiences. Brain Dev (2016), http://dx.doi.org/10.1016/j.braindev.2016.11.011