ISSN 0017-8748 doi: 10.1111/head.12358 Published by Wiley Periodicals, Inc.

Headache © 2014 American Headache Society

Review Article Pediatric Headache: Where Have We Been and Where Do We Need to Be Samata Singhi, MD; Howard Jacobs, MD; Jack Gladstein, MD

In this article, we hope to summarize current understanding of pediatric headache. We discuss epidemiology, genetics, classification, diagnosis, outpatient, emergency and inpatient treatment options, prevention strategies, and behavioral approaches. For each section, we end with a series of questions for future research and consideration. Key words: pediatric headache, migraine, epidemiology, genetics, classification (Headache 2014;54:817-829)

1962 paper taught us that as children got older, the proportion of patients with nonmigrainous headaches increased. He also found that the prevalence of headache was equal in boys and girls before puberty but had a more female predominance after puberty.1 Early attempts at Classification of Pediatric Headache reflected criteria in the adult literature. Prensky2 relied upon descriptors such as throbbing and intermittent headache but did not quantify frequency. There was no account for severity or localization. As in the adult literature, it was very hard to compare groups of subjects using these criteria.3 He taught us, however, that pediatric pain is more often bilateral and short-lived. This paved the way for IHS modifications when those criteria were established. IHS I4 gave the world a uniform definition of migraine that allowed for better quantification of migraine. Criteria were for adults only, however. Using adult criteria excluded many youngsters from drug trials because headache duration had to be 4 hours, and unilateral pain was a major criterion. Maytal and others5 modified adult criteria for children and enabled us to better diagnose migraine in children.

In all fields of medicine, new discovery could not happen without the pioneering work of innovators. Pediatric headache has come a long way as Bo Bille wrote the first descriptive article on his group of Scandinavian school children. We have made strides in the fields of classification, refining International Headache Society (IHS) criteria for pediatrics, approaches to care, drug trials, emergency room (ER) management, psychiatric care, alternative medicine, and genetics. In each section of this article, we will highlight current thinking and project to the future with the hope that innovations in pediatric care for the headache patient will become a priority as we strive to improve health for our population.

HISTORIC ARTICLES Bille performed an epidemiological look at school children in Uppsala, Sweden. His oft quoted From the Pediatric Neurology, University of Maryland School of Medicine, Baltimore, MD, USA. Address all correspondence to J. Gladstein, University of Maryland School of Medicine, Pediatric Neurology, 22 South Greene Street, Room n5W69, Baltimore, MD 21201, USA. Accepted for publication February 22, 2014.

Conflict of Interest: None.

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818 Classification of chronic daily headache has been controversial in the adult literature (Silberstein et al6 vs IHS4 ). This has been reflected in the pediatric literature as well. Attempts to modify Silberstein criteria by Holden et al7 then by a multicenter approach led by Koenig et al8 showed that there was less medication overuse and a shorter period of transformation from episodic to chronic headache in children as compared with adults. Approach to care has been summarized by many of the pediatric headache experts. Excellent review articles,9-12 book chapters,13 and textbooks14 give the student, resident, and uninitiated learner the ability to provide competent care to children and teenagers who suffer with headache. Drug trials are still fraught with problems. It has been difficult to show spread between placebo and study drug. This has made it arduous to get pediatric indications for excellent medications.15 Nevertheless, almotriptan,16 rizatriptan,17,18 eletriptan, and sumatriptan nasal have jumped those hurdles.19-21 Trials of preventative medications have been mostly inconclusive, but a topiramate trial using modern classification criteria was successful.22 We have learned how to evaluate and treat children and teens who come to our ERs; thanks to the work of Li et al,23 Kabbouche and Linder,24 and Lewis and Qureshi.25 What we know in this area is summarized recently by Gelfand and Goadsby.26 We have used the work of Holyroyd and Drew27 to help us evaluate youngsters with headache and look for psychiatric co-morbidities. The works of Zeltzer and Schlank,28 and McGrath29 give us frameworks for self-efficacy and pain management. Last but not the least, Hershey30 has begun studying genetic patterns in youngsters with headache and hopes to predict who will get better based on his or her genetics.

EPIDEMIOLOGY OF PEDIATRIC HEADACHE What We Know.—The occurrence of headache increases as children age. Bigal and Lipton reported that headache prevalence rises from 3-8% of 3-yearolds, to 57-82% of 8- to 15-year-olds. They also state that in prepubertal children, the prevalence of

May 2014 migraine is higher in boys than in girls, but after puberty, this trend reverses. The peak incidence of migraine with aura in boys is 5 years of age and migraine without aura is 10-11 years of age. In girls, migraine with aura peaks at 12-13 years of age, whereas migraines without aura reaches a peak at 14-17 years of age.31 It has been well documented that one cannot adequately treat migraine without considering the comorbid psychological problems that are present in a large number of our patients. A metaanalysis by Balottin et al highlights the role of psychopathogical factors not only in migraine but also in tension-type headache (TTH) in children.32 What We Would Like to Know.—Why do some children get migraines and not others? Is it all genetics as discussed later in this article or are there other factors that need to be considered. What role does environment play? Does climate have a role? Do we need to consider housing factors, ie, environmental compounders such as mold and building materials such as insulating products? Does diet play a role not just in the cause of an acute migraine but in the tendency to get migraines? Are chronic ingestions of trace minerals or other pollutants a factor? Could this be one of the reasons migraines tend to run in families as opposed to or in addition to genetics? What is the relationship of migraine to other illnesses? We are beginning to see articles suggesting a possible relationship to gastrointestinal diseases such as inflammatory bowel disease or celiac.33 We frequently see postural orthostatic tachycardia syndrome (POTS) in our patients. Are there other illnesses that coexist in a higher frequency with migraine, and if so, why? Is this all related to a dysfunction of the autonomic nervous system? Why do some patients progress from intermittent migraine to chronic migraine while others do not? What could be mitigating this? Are pediatric migraineurs destined to have migraine as adults? Does treatment as children or adolescents have a significant effect on altering the course of migraine in adult life?

PATHOPHYSIOLOGY What We Know.—Our assumptions about the pathophysiology of headache in youngsters stems

Headache directly from what we have learned in adults. Goadsby34 categorizes the elements in understanding of headache physiology into 5 areas: 1. Anatomy of head pain. 2. Activation of the peripheral branches of the opthalmic branch of the trigeminal nerve. 3. The physiology and pharmacology of the trigeminal nucleus. 4. Central nervous system activation on association of pain in the thalamus brainstem modulation that control our perceptions of pain. Recent summaries by Peitrobon and Moskowitz,35 Sprenger and Magon,36 and Gasparini et al37 highlight general physiology, functional magnetic resonance imaging, and genetics, respectively. What We Would Like to Know.—Why do some people present in childhood while others wait until their 20s or 30s to have their headaches? Why do some children present with periodic syndromes while others present with more typical migraine? Why is migraine more bilateral in children than in adults? Why do children and adolescents with chronic daily headache evolve from episodic migraine so quickly? How does the developing brain affect this physiology? Can we alter the natural course of migraine with aggressive management? Can we prevent brain alterations that occur in the adult chronic headache sufferer if treated well in childhood?

THE GENETICS OF HEADACHE What We Know.—In 1996, Russell et al published an article confirming what had long been suspected, that migraine with and without aura tend to be inherited diseases. First-degree relatives of patients with migraine without aura had a 1.9-fold increase risk of developing migraine without aura, while spouses had a 1.5-fold risk. First-degree relatives of patients with migraine with aura had a 4-fold increased risk of migraine with aura, while spouses had no increase in risk.38 Familial hemiplegic migraine has been associated with mutations of CACNA1A on chromosome 19,39 ATP1A2 on chromosome 140 and of SCN1A on chromosome 2.41 Other gene mutations have been identi-

819 fied; the MTHFR polymorphism is increased in patients with migraine with aura but not in patients with migraine without aura,42 polymorphisms in the serotonin transporter gene (5HTTLPR), also associated with migraine with aura.43 There are others also identified.44 Amitriptyline response in depression has been linked to CYP2D6 and CYP2C19 genes,45 but this has not been studied in migraine therapy. Hershey et al showed that there was a relationship between specific blood biomarkers, which were also present in brain tissue, to medication overuse headache suggesting a genomic association. Silberstein and Dodick provide an excellent tutorial and review of genetics and the role of the genome in migraine that are highly recommended to anyone wishing to learn more on the subject.46,47 What We Would Like to Know.—There remain numerous questions whose answers could be currently hidden in the genome. Why is success of drug therapy so variable? Why are medication side effects so variable? Can genetic markers help guide what medications will be most successful in a given patient? Are there genetic polymorphisms that predispose certain patients to post-concussion headaches? Is there a genetic link between migraine and other disorders, such as POTS, inflammatory bowel disease, celiac disease, obesity, or psychological disorders?

CLASSIFICATION Primary headaches in children mainly consist of migraine, TTH, and less frequently, cluster headache. Migraines consist of acute recurrent headaches that are usually unilateral, pulsating in nature, and may be associated with autonomous symptoms such as photophobia, phonophobia, or nausea. It is important to keep in mind though that many younger children do not present with these classic symptoms and diagnosis is often made retrospectively. TTH is acute recurrent headache often described as a sense of tightness or pressure, commonly suboccipital in location, without the previously mentioned autonomic symptoms. Chronic daily headache is defined as greater than 15 headache days per month. There are 3 major categories of chronic daily headaches in children: chronic migraine, chronic TTHs, and new daily persistent headache (NDPH).48 NDPH is characterized by

820 the occurrence of a new headache that becomes daily within 3 days of onset and is not caused by another disorder. The current ICHD-II criteria/IHS 2004 International Classification Headache Disorders49 provide a detailed classification of headache; however, this classification captures only 61.9% of pediatric subjects.50,51

APPROACH TO DIAGNOSIS The approach to the youngster with headache is similar to that of adults with headache but different in a few important areas. In both adults and children, diagnosis is usually not time-consuming. Most children presenting to a primary care office with headache will end up with a diagnosis of migraine. Diagnostic criteria are different, however. Children tend to have shorter attacks and have more bilateral headache.5 Picking out the rare patient with secondary headache is again similar. Patterns of progressive headache or chronic daily headache require scanning to rule out intracranial pathology, whereas straightforward migraine does not.52 Children need to grow, and adolescents need to go through puberty. Hence, arrest in growth curves or pubertal development should alarm the practitioner into starting a work up. Similarly, secondary amenorrhea is a harbinger of possible secondary headache. Other important clues to diagnosis and management in youngsters include a different measure of disability. Whereas adults measure disability in days of work missed or inability to do housework,53 kids never do housework. Grade performance and school absenteeism may be better markers to follow.52 Triggers may be different as well. The child with an undiagnosed learning disability or the youngster being bullied may get better in the summer when stress drops precipitously. Sleep hygiene is hard to enforce upon kids who start school very early. Parents in the midst of divorce present unique challenges for the child with headaches. Physical exam is similar but focus on growth curves and pubertal development. Pediatricians may not be used to looking at fundi, which makes it difficult to evaluate chronic headache patients. Papill-

May 2014 edema, retinal hemorrhage, or focal findings on the neurological exam suggest alternate diagnosis. Symptoms of depression, which include sadness, tearfulness, and withdrawal from activities need to be checked. The presence of 1 or more of these “red flags” should make the physician consider a more extensive evaluation.

PRINCIPLES OF TREATMENT The initial approach to management of pediatric headaches includes assessing triggers, identifying comorbidities, and establishing the degree of disability.12 A headache diary is often useful in assessing characteristics of headache, associated symptoms, and possible triggers. Validated pain assessment tools or pediatric specific disability tools like the PedQL or PedMIDAS53 may be used to assess the degree of disability that can then be used to design treatment. In general, it is useful to get the family as well as the patient involved, set up realistic expectations, and ensure consistent follow-up. The evidence supporting the effectiveness of any intervention – pharmacological or nonpharmacological – is confounded by the fact that migraines in children are of shorter duration and have a higher rate of spontaneous remission than that in adults; hence, making it difficult to distinguish effectiveness of treatment from the natural course of the migraine.54,55 Moreover, a high placebo response rate in children, up to 55% for prophylactic drugs and up to 69% for symptomatic treatment, has been demonstrated in children.12 OUTPATIENT ACUTE MANAGEMENT What We Know.—Initial symptomatic therapy for pediatric migraine primarily consists of acetamenophen and ibuprofen.56,57 A randomized, controlled trial in 88 children aged 4-16 years comparing acetaminophen 15 mg/kg, ibuprofen 10 mg/kg, and placebo during 3 migraine attacks demonstrated that acetaminophen and ibuprofen were more effective than placebo at 2 hours in reduction of headache.58 Although multiple triptans have been studied in the treatment of pediatric migraine,59 only almotriptan and rizatriptan are approved for use in acute treatment of migraine headache in adolescents

Headache and children aged 6-17 years, respectively. In adolescents aged 12 and above, sumatriptan nasal spray 5, 10, and 20 mg has been found to be effective for acute migraine over placebo in the symptomatic treatment of intensity and duration of pediatric migraine.60-64 However, nasal sumatriptan has been found to be associated with bad taste, nausea, vomiting, burning/ stinging sensations, or paresthesia and lightheadedness. Oral or nasal zolmitriptan has also been found to be effective in treatment of migraine attacks in children aged 5-15 years.65-67 There are insufficient data to support the efficacy of other oral triptans in the treatment of pediatric migraine.56,65,68,69 Most TTH is managed by primary care physician and commonly used agents include acetaminophen, ibuprofen, and aspirin.12,70,71 It has been widely postulated that medication should be taken shortly after onset of headache to maximize effectiveness,48 although there is no scientific evidence to support this.12 Moreover, migraine is often complicated by concomitant gastroparesis, which may necessitate higher than normal doses of medications to achieve desired effect. Expert opinion suggests addition of caffeine (in soda, tea, or coffee) to an Non-steroidal Anti-inflammatory drug (NSAID) less than 9 days a month for severe headache, although there are no trials demonstrating the efficacy of this.48 What We Would Like to Know.—We need larger scale, well-designed, randomized, controlled trials in children to establish the effectiveness of triptans as abortive agents. How do we design trials that reduce the high placebo rate? Are there combinations that work better than one preparation alone? What are the potential long-term effects of routine use of these medications on children? Do they develop tolerance as they advance into adulthood?

ER AND INPATIENT MANAGEMENT What We Know.—Headache is one of the most common presentations to the pediatrics ER.25 Most of the time, one can ferret out who has tumor, bleed, or other serious secondary headache disorder from those with exacerbation of migraine or chronic daily headache. We therefore do not advocate routine ER imaging for those patients at low risk for secondary headache when they present.72

821 There have been multiple papers describing successful approaches to treatment of status migraine in both the emergency setting, as well as the inpatient setting.73,74 Careful sequential use of medications used in the adult setting has been tried in children without a systemic prospective study.75,76 In patients naïve to triptans, triptans may serve as good first-line agents after analgesics.65 As with adults who utilize the ER for their headache exacerbations, pediatric headache experts have shied away from the prescribing of narcotics.77,78 Judicial use of Intravenous fluids, NSAIDs, dopaminergic agents, magnesium, valproate, and Dihydroergotamine (DHE) have been used successfully.24,65,79-83 Steroids are used as anti-inflammatory agents, and their roles in the ER settting have been summarized well for adults.26,76 There is much experience treating adults as inpatients.84 There is one long-term inpatient unit at Cleveland Clinic where children and adolescents with chronic headache are shown a multidisciplinary approach. Programs in Michigan, Chicago, and Philadelphia incorporate teens into their adult inpatient headache units on a regular basis. Criteria to enter these units mirror those in the adult literature. What We Would Like to Know.—In the future, we would like to see a more rigorous approach with prospective trials of both individual agents and cocktails to look for safety, efficacy, and ER efficiency. What role does each of the components in a sequential cocktail have? Do steroids help? What about magnesium? Does DHE early in the pathway get people out quicker? What about IV valproate? Should youngsters be sent home on steroids and/or long-acting triptans? How different is treating status migraine in an episodic migraineur compared with a patient with chronic daily headache and acute exacerbation? Should the approach be different? Does frequent ER use predict debilitation as an adult?

PROPHYLAXIS Pharmaco-prophylaxis is usually indicated if migraines occur at least 3-4 times a month and cause significant impairment in the patient’s daily function or quality of life and if lifestyle modification and nonpharmacological measures have not been effective. The goal is usually to reduce frequency of migraines

822 to less than 1-2 attacks a month. The general approach to pharmaco-prophylaxis is to start at the lowest dose and titrate upwards as needed. Before beginning any preventive therapy, it is important to set realistic expectations with the patient and the family because any preventive therapy typically takes at least 8-12 weeks to cause a recognizable effect.12,48 What We Know.—Various agents have been tried in the prophylaxis of pediatric migraines including tricyclic antidepressants (amitryptiline and nortriptyline), trazodone, beta blockers (propranolol), calciumchannel blockers (verapamil and flunarizine), antiserotonergics (cyproheptadine), gabapentin, and anti-epileptics.67 Based on Cochrane systematic review of 20 randomized trials, flunarizine has demonstrated efficacy in the prophylaxis of chronic pediatric migraine. This compound is not available in the USA, however.67,85-88 It is associated with daytime sedation and weight gain. Administering it in early evening can avert daytime sleepiness.12 Anti-epileptics such as topiramate at 2 mg/kg have been shown to be effective for reduction of headache frequency, severity, and duration.89 Most common side effects cognitive and weight loss.12,90,91 Divalproate 15-45 mg/kg/day has shown to be effective in reducing frequency as well as severity of pediatric migraine with 50% headache reduction seen; side effects were dizziness, drowsiness, and increase in appetite.92,93 Amitryptiline,94,95 cyproheptadine,12,91 levetiracetam,96 and zonisamide97 have been trialed successfully in pediatric migraine, but further evidence is needed to establish efficacy. Conflicting data exist for the efficacy of propranolol.12,98-101 Trials have not established efficacy of nimodipine,102 timolol, papaverine, pizotifen,103 trazodone,104 clonidine,105,106 metoclopramide,67 and domperidone.67 Further research is needed on all other agents before making any conclusive recommendations regarding their use for management of pediatric migraine. Before starting therapy, care must be taken to identify potential side effects of these medications that may affect certain groups of children more than others. For instance, valproic acid may be teratogenic and have other toxic effects and therefore may not be suited for teenage girls. Beta-blockers may not be

May 2014 ideal agents for children with asthma, atopy, or a history of depression. At the same time, antiserotonergics such as cyproheptadine may be particulary useful in children with comorbid environmental allergies.48 What We Would Like to Know.—What is different in the pathophysiology of migraine in children requiring pharmacoprophylaxis from those who respond to abortive treatment? Is there something fundamental to the perception of pain that can be addressed with psychotherapy rather than pharmacotherapy, thereby reducing the need for medication? What specific criteria based on disability and risk of relapse should we use for starting prophylactic therapy weighing it against the potential long-term effects of pharmacoprophylaxis (much like the asthma severity assessment tool used in many canters)? Prospective studies are needed to assess what is the long-term evolution of migraine (into adulthood) of children who are on pharmaco-prophylaxis compared with those who are not.

BEHAVIORAL AND NUTRACEUTICAL THERAPY In addition to the pharmaceuticals used for migraine therapy, other modalities are often called upon. Behavioral therapies, such as biofeedback and relaxation therapy/self-hypnosis, are often suggested to the pediatric and adolescent migraineur, and there continues to be a large and possibly increasing interest in nutraceutical products for migraine therapy. Pistola, Sacco, and Carolei’s review (2012) state that in the case of chronic migraine, at least, “The highest level of care is achieved when behavioral therapies are integrated with other treatments, including physical and pharmacological interventions.”107 What We Know.—In 2000, the US Headache consortium evaluated Biofeedback and graded the evidence supporting its use in migraine as “Grade A.”108 This evidence is often quoted in more recent articles supporting its use.109,110 Mullally et al, however, came to a different conclusion: Biofeedback is an extremely costly and timeconsuming modality that, in our study, provided no additional benefit when compared to simple

Headache relaxation techniques alone, in the treatment of migraine and tension type headaches in adults.111 One can find many pediatric reports supporting the use of biofeedback,54,112-116 but the overall evidence is inconclusive.117-119 This begs the question, why is biofeedback not in more widespread use? Is there a lack of qualified practitioners? Is it, as suggested earlier, not cost-effective? Many of the studies that support the use of biofeedback in pediatrics also make a strong case for relaxation therapy.12,54 Psychotherapeutic approaches such as relaxation techniques and cognitive behavioral therapy have been shown to reduce frequency and intensity of headache in children and adolescents.54,120-122 However, the overall effectiveness of psychotherapy needs further investigation.123 In addition, music therapy has also shown promise in the prevention of pediatric migraine.11 Finally, there is some evidence to support prophylaxis with lifestyle modification such as intake of adequate amount of fluids, regular meals, maintenance of sleep hygiene, and exercise.12,124 There is conflicting use for the role of diet modification such as adoption of oligo-antigenic diet.12 What We Would Like to Know.—Why is biofeedback not a routine part of migraine care? Is biofeedback in the pediatric population cost-effective? In the pediatric population, is biofeedback superior to relaxation therapy or vice versa, and how do either compare with acupuncture? How do they compare with more accepted pharmaceutical therapies? How can they best be used to augment pharmaceutical therapy?

NEUTRACEUTICALS What We Know.—Nutraceuticals such as herbals and vitamins have always taken a back seat to pharmaceuticals in the eyes of most practitioners. However, many patients and parents are drawn to the promise of migraine therapy with less, if any, side effects suggested in the nutraceutical aisle at the pharmacy. Two excellent review articles were published in Headache in March 2011. Sun-Edelstein and Mauskop’s article on alternative headache therapy125 and Taylor’s discussion of the biological basis of

823 nutraceutical therapy126 are excellent sources of information on the why’s and how’s of nutraceutical therapy. Magnesium, coenzyme Q10, butterbur, feverfew, riboflavin, and others have a biological basis to expect them to be efficacious in the treatment of migraine, and combinations such as Migravent® (Vita Sciences, Airmont, NY, USA) (magnesium, riboflavin, butterbur, coenzyme Q10) and MigreLief® (Akeso Health Sciences LLC, Westlake Village, CA, USA) (magnesium, riboflavin and feverfew), and others should, in theory, be helpful for our pediatric migraineuers. But good double-blinded studies do not exist. Magnesium oxide has been studied in children and adolescents with some evidence that it might reduce headache severity; however, the effect on headache frequency remains unclear.127,128 The typical adolescent dose of elemental magnesium is 350-500 mg/day. The most common side effect of oral magnesium is diarrhea. Coenzyme Q10 was found to be more effective than placebo in 1 small randomized clinical trial.129 Riboflavin 25-400 mg/day has been shown to be effective in the prevention of adult migraine130,131 but has not been proven to be effective in migraine prophylaxis in children. What We Would Like to Know.—High-quality studies are needed comparing the various nutraceuticals, comparing the combination products and finally comparing nutraceuticals to more established pharmaceutical therapies, in terms of efficacy, adverse effects, and cost.

CONCLUSION In this review, we hope to have summarized current knowledge and approaches for the youngster with headache. If we have missed key literature citations, we owe an apology to those that have worked so hard to render care and grow the field of pediatric headache. We hope to stimulate conversation and research collaboration as we seek answers to the challenges that lie ahead. It is our sincere wish that attention to pediatric headache can lessen the burden of headache for the youngsters that suffer now and prevent further disability down the line as these youngsters grow into adulthood.

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STATEMENT OF AUTHORSHIP Category 1 (a) Conception and Design Jack Gladstein; Howard Jacobs; Samata Singhi (b) Acquisition of Data Jack Gladstein; Howard Jacobs; Samata Singhi (c) Analysis and Interpretation of Data Jack Gladstein; Howard Jacobs; Samata Singhi

9. 10. 11.

Category 2 (a) Drafting the Manuscript Jack Gladstein; Howard Jacobs; Samata Singhi (b) Revising It for Intellectual Content Jack Gladstein; Howard Jacobs; Samata Singhi

12.

Category 3 (a) Final Approval of the Completed Manuscript Jack Gladstein; Howard Jacobs; Samata Singhi

14.

13.

15.

REFERENCES 1. Bille B. Migraine in pediatric school children. Acta Paediatric Scand. 1962;51(Suppl. 136):1-151. 2. Prensky AL. Migraine and migraine variants in pediatric patients. Ped Clin North America. 1976; 23:3461-3471. 3. Ad Hoc Committee on Classification of Headache. National Institute of Neurologic Diseases and Blindness. Classification of Headache. Neurology. 1962;12:378-380. 4. Headache Classification Committee of the International Headache Society. Classification and diagnostic criteria for headache disorders, cranial neuralgias and facial pain. Cephalalgia. 1988;8 (Suppl. 7):1-96. 5. Maytal J, Young M, Shechter A, Lipton RB. Pediatric migraine and the IHS criteria. Neurology. 1997;48:602-607. 6. Silberstein SD, Lipton RL, Solomon S, Mathew NT. Classification of daily and near daily headaches. Proposed revisions to the IHS criteria. Headache. 1994;34:1-7. 7. Holden EW, Gladstein J, Trulsen MA, Wall MA. Chronic daily headache in children and adolescents. Headache. 1994;34:508-514. 8. Koenig MA, Gladstein J, McCarter RJ, Hershey AD, Wasiewski W. Chronic daily headache in children and adolescents presenting to tertiary head-

16.

17.

18.

19.

20.

21.

22.

ache clinics. Pediatric Committee of the American Headache Society. Headache. 2002;42:491-500. Jacobs H, Gladstein J. Pediatric headache: A clinical review. Headache. 2012;52:333-339. Seshia SS. Chronic daily headache in children and adolescents. Curr Pain Headache Rep. 2012;16:60-72. Ozge A, Termine C, Antonaci F, Natriashvili S, Guidetti V, Wober-Bingol C. Overview of diagnosis and management of pediatric headache part 1. J Headache Pain. 2011;12:13-23. Termine C, Ozge A, Antonaci F, Natriashvili S, Guidetti V, Wober-Bingol C. Overview of diagnosis and management of paediatric headache part 2. J Headache Pain. 2011;12:25-34. Lewis DW. Pediatric migraine. Neurol Clin. 2009; 27:481-501. Winner P, Lewis DW, Rothner AD, eds. Headache in Children and Adolescents. Hamilton, Ontario: Dekker; 2008. Lewis DW, Winner P, Wasiewski W. The placebo responder rate in children and adolescents. Headache. 2005;45:232-239. Linder SL, Mathew NT, Cady RK. Efficacy and tolerability of almotriptan in adolescents: A randomized double blind placebo controlled trial. Headache 2008;48:1326-1336. Fraser IP, Han L, Tae H, et al. Pharmacokinetics and tolerability of rizatriptan in pediatric migraineurs in a randomized study. Headache. 2012; 52:4625-4635. Hewitt DJ, Pearlman E, Hamalainen M. Long term open label safety study of rizatriptan in the acute treatment of pediatric migraine. Headache. 2013;53:104-117. Winner P, Linder SL, Lipton RB, et al. Eletriptan for the acute treatment of migraine in adolescents: Results of a double blind placebo controlled trial. Headache. 2007;47:4511-4518. Winner P, Rothner AD, Saper J, et al. A double blind placebo controlled study of sumatriptan nasal spray in acute migraine in adolescents. Pediatrics. 2000;106:989-997. Hershey AD, Powers SW, LeCates S, et al. Efficacy of nasal sumatriptan in 5-12 year old children. Headache. 2001;41:693-697. Brandes JL, Saper JR, Diamond M, et al.; MIGR002 Study Group. Topiramate for migraine prevention. A randomized controlled trial. JAMA. 2004; 291:965-973.

Headache 23. Li K, Nagelberg J, Maytal J. Headaches in a pediatric emergency department: Etiology, imaging, and treatment. Headache. 2000;40:25-30. 24. Kabbouche MA, Linder SL. Acute treatment of pediatric headache in the emergency department and inpatient setting. Pediatr Ann. 2005;34:466471. 25. Lewis DW, Qureshi F. Acute headache in children and adolescents presenting to the emergency department. Headache. 2000;40:200-203. 26. Gelfand AA, Goadsby PJ. Treatment of pediatric migraine in the emergency room. Pediatr Neurol. 2012;47:4233-4241. 27. Holroyd KA, Drew JB. Behavioral approaches to the treatment of migraine. Semin Neurol. 2006;26: 199-207. 28. Zeltzer JK, Schlank CB. Conquering Your Child’s Chronic Pain. New York: Harper Collins; 2005. 29. McGrath PA. Pain in Children. Nature, Assessment and Treatment. New York: Harper Collins; 1990. 30. Hershey AD. Genetics of headache in children: Where are we headed? Curr Pain & Headache Rep. 2008;12:367-372. 31. Bigal ME, Lipton RB. The epidemiology, burden and comorbidities of migraine. Neurol Clin. 2009; 27:321-334. 32. Balottin U, Poli PF, Termine C, Molteni S, Galli F. Psychopathological symptoms in child and adolescent migraine and tension-type headache: A metaanalysis. Cephalalgia. 2012;33:112-122. 33. Dimitrova AK, Ungaro RC, Lebwohl B, et al. Prevalence of migraine in patients with celiac disease and inflammatory bowel disease. Headache. 2013;53:344-355. 34. Goadsby PJ. Pathophysiology of migraine and other headaches. In: Ishaq A-A, ed. Childhood Headache, 2nd edn. London: Mac Keith Press; 2013. 35. Pietrobon D, Moskowitz MA. Pathophysiology of migraine. Annu Rev Physiol. 2013;75:365-391. 36. Sprenger T, Magon S. Can functional MRI at rest shed light on the pathophysiology of migraine? Headache. 2013;53:5723-5725. 37. Gasparini CF, Sutherland HG, Griffith LR. Studies on the pathophysiology and genetic basis of migraine. Curr Genomics. 2013;14:5300-5315. 38. Russell MB, Iselius L, Olesen J. Migraine without aura and migraine with aura are inherited disorders. Cephalalgia. 1996;16:305-309.

825 39. Ophoff RA, Terwindt GM, Vergouwe MN, et al. Familial hemiplegic migraine and episodic ataxia type-2 are caused by mutations in the Ca2+ channel gene CACNL1A4. Cell. 1996;87:544552. 40. de Fusco M, Marconi R, Silvestri L, et al. Haploinsufficiency of ATP1A2 encoding the Na+/ K + pump alpha2 subunit associated with familial hemiplegic migraine type 2. Nat Genet. 2003;33:192196. 41. Dichgans M, Freilinger T, Dreier JP, et al. Mutation in the neuronal voltage-gated sodium channel SCN1A in familial hemiplegic migraine. Lancet. 2005;366:371-377. 42. Scher A, Terwindt GM, Verschuren WM, et al. Migraine and MTHFR C677T genotype in population-based sample. Ann Neurol. 2006;59: 372-375. 43. Szikagyi A, Boor K, Orosz I, et al. Contribution of serotonin transporter gene polymorphisms to pediatric migraine. Headache. 2006;46:478-485. 44. Hershey A, Burdine D, Kabbouche M, Powers S. Genomic expression patterns in medication overuse headaches. Cephalalgia. 2006;31:161171. 45. Steimer W, Zopf K, von Amelunxen S, et al. Amitritpyline or not, that is the question: Pharmacogenetic testing of CYP2D6 and CYP2C19 identifies patients with low or high risk for side effects in amitriptyline therapy. Clin Chem. 2005;51:376385. 46. Silberstein S, Dodick D. Migraine genetics – A review: Part 1. Headache. 2013;53:1207-1217. 47. Silberstein S, Dodick D. Migraine genetics: Part 2. Headache. 2013;53:1218-1229. 48. Blume HK. Pediatric headache: A review. Pediatr Rev. 2012;33:562-576. 49. Headache Classification Subcommittee of the International Headache Society. The International Classification of Headache Disorders: 2nd edition. Cephalalgia. 2004;24(Suppl. 1):9-160. 50. Hershey AD. Pediatric headache: Update on recent research. Headache. 2012;52:327-332. 51. Hershey A, Winner P, Kabbouche MA. Use of the ICHD-II criteria in the diagnosis of pediatric migraine. Headache. 2005;45:1288-1298. 52. Lewis DW, Ashwal S, Dahl G, et al. Quality Standards Subcommittee of the American Academy of Neurology. Practice Committee of the Child

826

53.

54.

55.

56.

57.

58.

59.

60.

61.

62.

63.

May 2014 Neurology Society. Practice parameter: Evaluation of children and adolescents with recurrent headache: Report of the quality standard subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society. Neurology. 2002;59:490-498. Hershey AD, Powers SW, Vockell AL, LeCates S, Kabbouche MA, Maynard MK. PedMIDAS: Development of a questionnaire to assess disability of migraines in children. Neurology. 2001;57:20342039. Damen L, Bruijn J, Verhagen AP, Berger MY, Passchier J, Koes BW. Prophylactic treatment of migraine in children – Part 1. A systematic review of non-pharmacological trials. Cephalalgia. 2006;26:373-383. Baumann RJ. Behavioral treatment of migraine in children and adolescents. Paediatr Drugs. 2002;4: 555-561. Lewis DW, Kellstein D, Dahl G. Children’s ibuprofen suspension for the acute treatment of pediatric migraine. Headache. 2002;42:780-786. Damen L, Bruijn J, Verhagen AP, Berger MY, Passchier J, Koes BW. Symptomatic treatment of migraine in children: A systematic review of medication trials. Pediatrics. 2005;116:e295-e302. Hamalainen ML, Hoppu K, Valkeila E, Santavuori P. Ibuprofen or acetaminophen for the acute treatment of migraine in children: A double-blind, randomized, placebo-controlled, crossover study. Neurology. 1997;48:103-107. Evers S. Efficacy of triptans in childhood and adolescent migraine. Curr Pain Headache Rep. 2013; 17:1-6. Winner P, Rothner AD, Saper J. A randomized, double-blind, placebo-controlled study of sumatriptan nasal spray in the treatment of acute migraine in adolescents. Pediatric. 2000;106:989997. Major PW, Grubisa HS, Thie NM. Triptans for treatment of acute pediatric migraine: A systematic literature review. Pediatr Neurol. 2003;29:425-429. MacDonald JT. Treatment of juvenile migraine with subcutaneous sumatriptan. Headache. 1994;34: 581-582. Linder SL. Subcutaneous sumatriptan in the clinical setting: The first 50 consecutive patients with acute migraine in a pediatric neurology office practice. Headache. 1996;36:419-422.

64. Ahonen K, Hamalainen ML, Rantala H, Hoppu K. Nasal sumatriptan is effective in treatment of migraine attacks in children: A randomized trial. Neurology. 2004;62:883-887. 65. Bonfert M, Strauber A, Schroeder AS, Reilich P, Ebinger F, Heinen F. Primary headache in children and adolescents: Update on pharmacotherapy of migraine and tension type headache. Neuropediatrics. 2013;44:3-19. 66. Linder SL, Dowson AJ. Zolmitriptan provides effective migraine relief in adolescents. Int J Clin Pract. 2000;54:466-469. 67. Evers S, Rahman A, Kraemer C, et al. Treatment of childhood migraine attacks with oral zolmitriptan and ibuprofen. Neurology. 2006;67:497-499. 68. Lewis DW. Headaches in children and adolescents. Curr Probl Pediatr Adolesc Health Care. 2007;37: 207-246. 69. Victor S, Ryan SW. Drugs for preventing migraine headaches in children. Cochrane Database Syst Rev. 2003;CD002761. 70. Anttila P. Tension-type headache in childhood and adolescence. Lancet Neurol. 2006;5:268-274. 71. Steiner TJ, Lange R, Voelker M. Aspirin in episodic tension-type headache: Placebo-controlled doseranging comparison with paracetamol. Cephalalgia. 2003;23:59-66. 72. Lateef TM, Grewal M, McClintock W, Chamberlain J, Kaulas H, Nelson KB. Headache in young children in the emergency department: Use of computed tomography. Pediatrics. 2009;124:e12e17. 73. Richer LP, Laycock K, Millar K, et al. Pediatric Emergency Research Canada Emergency Department Migraine Group. Treatment of children with migraine in the emergency department: A national practice variation study. Pediatrics. 2010;126:e150e155. 74. Szyszkowicz M, Kaplan GG, Grafstein E, Rowe BH. Emergency department visits for migraine and headache: A multi-city study. Int J Occup Med Environ Health. 2009;22:235-242. 75. Bailey B, McManus BC. Treatment of children with migraine in the Emergency department: A qualitative review. Pediatr Emerg Care. 2008;24:321330. 76. Conicella E, Raucci U, Vanacore N, et al. The child with headache in a pediatric emergency department. Headache. 2008;48:1005-1011.

Headache 77. Kabbouche MA, Cleves C. Evaluation and management of children and adolescents presenting within an acute setting. Semin Pediatr Neurol. 2010;17:105-108. 78. Kelley NE, Tepper DE. Rescue therapy for acute migraine. Part 3: Opioids, nsaids, steroids and post discharge medications. Headache. 2012;52:467-482. 79. Kelley NE, Tepper DE. Rescue treatment of acute migraine, part 1: Triptans, DHE, and magnesium. Headache. 2012;52:114-128. 80. Kelley NE, Tepper DE. Rescue treatment for acute migraine, part 2: Neuroleptics, antihistamines and others. Headache. 2012;52:292-306. 81. Callahan N, Raskin N. A controlled study of dihydoergotamine in the treatment of acute headache. Headache. 1986;26:168-171. 82. Mathew NT, Kailasam J, Meadors L, Chernyschev O, Gentry P. Intravenous valproate sodium (depacon) aborts migraine rapidly. Headache. 2000;40:720-723. 83. Kabbouche MA, Powers SW, Segers A, et al. Inpatient treatment of status migraine with dihydroergotamine in children and adolescents. Headache. 2009;49:106-109. 84. Freitag FG, Lake A 3rd, Lipton R, Cady R, Diamond S, Silberstein S. US headache guidelines consortium, section on inpatient treatment chairpersons. Inpateint treatment of headache. An evidence based assessment. Headache. 2004;44: 342-360. 85. Lewis D, Ashwal S, Hershey A, Hirtz D, Yonker M, Silberstein S. American Academy of Neurology Quality Standards Subcommittee of the Child Neurology Society. Practice parameter: Pharmacological treatment of migraine headache in children and adolescents: Report of the American Academy of Neurology Quality Standards Subcommittee and the Practice Committee of the Child Neurology Society. Neurology. 2004;63:2215-2224. 86. Sorge F, De Simone R, Marana E, Nolano M, Orefice G, Carrieri P. Flunarizine in prophylaxis of childhood migraine. A double-blind, placebocontrolled, crossover study. Cephalalgia. 1988;8:1-6. 87. Lutschg J, Vassella F. The treatment of juvenile migraine using flunarizine or propranolol. Schweiz Med Wochenschr. 1990;120:1731-1736. 88. Sorge F, Marano E. Flunarizine v. placebo in childhood migraine. A double-blind study. Cephalalgia. 1985;5(Suppl. 2):145-148.

827 89. Hershey AD, Powers SW, Vockell AL, LeCates S, Kabbouche M. Effectiveness of topiramate in the prevention of childhood headaches. Headache. 2002;42:810-818. 90. Lewis D, Winner P, Saper J, et al. Randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of topiramate for migraine prevention in pediatric subjects 12 to 17 years of age. Pediatrics. 2009;123:924-934. 91. Lakshmi CV, Singhi P, Malhi P, Ray M. Topiramate in the prophylaxis of pediatric migraine: A doubleblind placebo-controlled trial. J Child Neurol. 2007;22:829-835. 92. Caruso JM, Brown WD, Exil G, Gascon GG. The efficacy of divalproex sodium in the prophylactic treatment of children with migraine. Headache. 2000;40:672-676. 93. Serdaroglu G, Erhan E, Tekgul H, et al. Sodium valproate prophylaxis in childhood migraine. Headache. 2002;42:819-822. 94. Lewis DW, Diamond S, Scott D, Jones V. Prophylactic treatment of pediatric migraine. Headache. 2004;44:230-237. 95. Hershey AD, Powers SW, Bentti AL, Degrauw TJ. Effectiveness of amitriptyline in the prophylactic management of childhood headaches. Headache. 2000;40:539-549. 96. Miller GS. Efficacy and safety of levetiracetam in pediatric migraine. Headache. 2004;44:238243. 97. Pakalnis A, Kring D. Zonisamide prophylaxis in refractory pediatric headache. Headache. 2006;46: 804-807. 98. Forsythe WI, Gillies D, Sills MA. Propanolol (“Inderal”) in the treatment of childhood migraine. Dev Med Child Neurol. 1984;26:737741. 99. Ludvigsson J. Propranolol used in prophylaxis of migraine in children. Acta Neurol Scand. 1974;50: 109-115. 100. Damen L, Bruijn J, Verhagen AP, Berger MY, Passchier J, Koes BW. Prophylactic treatment of migraine in children. Part 2. A systematic review of pharmacological trials. Cephalalgia. 2006;26:497505. 101. Olness K, MacDonald JT, Uden DL. Comparison of self-hypnosis and propranolol in the treatment of juvenile classic migraine. Pediatrics. 1987;79:593597.

828 102. Battistella PA, Ruffilli R, Moro R, et al. A placebocontrolled crossover trial of nimodipine in pediatric migraine. Headache. 1990;30:264-268. 103. Gillies D, Sills M, Forsythe I. Pizotifen (Sanomigran) in childhood migraine. A doubleblind controlled trial. Eur Neurol. 1986;25:32-35. 104. Battistella PA, Ruffilli R, Cernetti R, Pettenazzo A, et al. A placebo-controlled crossover trial using trazodone in pediatric migraine. Headache. 1993;33:36-39. 105. Sillanpaa M. Clonidine prophylaxis of childhood migraine and other vascular headache. A double blind study of 57 children. Headache. 1977;17:2831. 106. Sills M, Congdon P, Forsythe I. Clonidine and childhood migraine: A pilot and double-blind study. Dev Med Child Neurol. 1982;24:837-841. 107. Pisiola JF, Sacco S, Carolei A. Behavioral therapy for chronic migraine. Curr Pain Headache Rep. 2013;17:1-8. 108. Campbell JK, Penzien DB, Wall EM. Evidencebased guidelines for migraine headache: Behavioral and physical treatments. US Headache Consortium. 2000. Available at: https://www.aan .com/Guidelines/home/GetguidelineContent/68 (accessed May 2013). 109. Andrasik F. Biofeedback in headache: An overview of approaches and evidence. Cleve Clin J Med. 2010;3(Suppl. 77):S72-s76. 110. Buse D, Andrasik F. Behavioral medicine for migraine. Neurol Clin. 2009;27:445-465. 111. Mullally W, Hall K, Goldstein R. Efficacy of biofeedback in the treatment of migraine and tension type headaches. Pain Physician. 2009;12: 1005-1011. 112. Sartory G, Muller B, Metsch J, Pothmann R. A comparison of psychological and pharmalogical treatment of pediatric migraine. Behaviour Research & Therapy. 1998;36:1155-1170. 113. Scharff L, Marcus DA, Masek BJ. A controlled study of minimal-contact thermal biofeedback treatment in children with migraine. J Pediatr Psychol. 2002;27:109-119. 114. Larsson B, Carlsson J, Fichtell A. Relaxation treatment of adolescent headache sufferers: Results from a school-based replication series. Headache. 2005;45:692-704. 115. Arndorfer RE, Allen KD. Extending the efficacy of a thermal biofeedback treatment package to the

May 2014

116.

117.

118.

119.

120.

121.

122.

123.

124.

125.

126. 127.

management of tension-type headaches in children. Headache. 2001;41:183-192. Larsson B, Melin L, Doberl A. Recurrent tension headache in adolescents treated with self-help relaxation training and a muscle relaxant drug. Headache. 1990;30:665-671. Sarafino EP, Goehring P. Age comparisons in acquiring biofeedback control and success in reducing headache pain. Ann Behav Med. 2000;22: 10-16. Andrasik F, Grazzi L, Usai S, D′Amico D, Leone M, Bussone G. Brief neurologist-administered behavioral treatment of pediatric episodic tensiontype headache. Neurology. 2003;60:1215-1216. Grazzi L, Andrasik F, D′Amico D, Leone M, Moschiano F, Bussone G. Electromyographic biofeedback-assisted relaxation training in juvenile episodic tension-type headache: Clinical outcome at three-year follow-up. Cephalalgia. 2001;21:798803. Kazdin AE. The state of child and adolescent psychotherapy research. Child and Adolescent Mental Health. 2002;7:53-59. Eccleston C, Palermo TM, de C Williams AC, et al. Psychological therapies for the management of chronic and recurrent pain in children and adolescents. Cochrane Database Syst Rev. 2003; CD003968. Eccleston C, Morley S, Williams A, Yorke L, Mastroyannopoulou K. Systematic review of randomised controlled trials of psychological therapy for chronic pain in children and adolescents, with a subset meta-analysis of pain relief. Pain. 2002;99:157-165. Trautmann E, Lackschewitz H, Kroner-Herwig B. Psychological treatment of recurrent headache in children and adolescents – A meta-analysis. Cephalalgia. 2006;26:1411-1426. Bruni O, Galli F, Guidetti V. Sleep hygiene and migraine in children and adolescents. Cephalalgia. 1999;19(Suppl. 25):57-59. Sun-Edelstein C, Mauskop A. Alternative headache treatments: Nutraceuticals, behavioral and physical treatments. Headache. 2011;51:469483. Taylor F. Nutraceuticals and headache:The biological basis. Headache. 2011;51:484-501. Wang F, Van Den Eeden SK, Ackerson LM, Salk SE, Reince RH, Elin RJ. Oral magnesium oxide

Headache prophylaxis of frequent migrainous headache in children: A randomized, double-blind, placebocontrolled trial. Headache. 2003;43:601-610. 128. Grazzi L, Andrasik F, Usai S, Bussone G. Magnesium as a treatment for paediatric tension-type headache: A clinical replication series. Neurol Sci. 2005;25:338-341. 129. Oelkers-Ax R, Leins A, Parzer P, et al. Butterbur root extract and music therapy in the prevention of childhood migraine: An explorative study. Eur J Pain. 2008;12:301-313.

829 130. Schoenen J, Jacquy J, Lenaerts M. Effectiveness of high-dose riboflavin in migraine prophylaxis. A randomized controlled trial. Neurology. 1998;50: 466-470. 131. Maizels M, Blumenfeld A, Burchette R. A combination of riboflavin, magnesium, and feverfew for migraine prophylaxis: A randomized trial. Headache. 2004;44:885-890.