Childhood primary headaches as a neurologic health problem

Childhood primary headaches are increasingly being recognized as a significant neurologic health problem. Migraine remains under-recognized, under-diagnosed, and ultimately under- or inappropriately treated in the pediatric population. This has potential long-term consequences regarding disease progression. The underlying pathophysiology is presumably the same as in adults, but the presenting symptoms in a developing brain are often different, especially in children. Early effective intervention may prevent progression and lifelong consequences, including the development of comorbidities. The prevalence of migraine in children age 11 to 13 is estimated to be between 6.1 and 13.6 per 100 and for tension-type headache between 9.8 and 24.7 per 100 (85). These common disorders are often accompanied by significant disability, impacting the child's life and school performance. Early diagnosis and an integrative treatment approach are essential to minimize the impact on a child's quality of life. In addition, differentiating primary headaches from those caused by underlying, perhaps life-threatening pathology is critical to expedient establishment of appropriate treatment and, potentially, cure.

Epidemiology and classification

In a metaanalysis of 64 cross-sectional studies on headaches in children and adolescents performed over a 25-year period with an aggregate population of 227,249 children from 32 different countries, the estimated mean prevalence of headache was 54.4%, and the estimated mean prevalence of migraine was 9.1% (92). In a study performed on 7643 school children in Austria, 44.3% of whom filled out the study questionnaires, prevalence and attributable burden of all headache, undifferentiated headache, migraine, tension-type headache and headache on greater than or equal to 15 days per month (chronic headache) were assessed using the Headache-Attributed Restriction, Disability, Social Handicap and Impaired Participation questionnaire for children and adolescents and the KIDSCREEN questionnaire for health-related quality of life (55). The 1-year prevalence of headache was 75.7%, increasing with age and higher in girls (82.1%) than in boys (67.7%; p < 0.001). Undifferentiated headache, migraine, tension-type headache, and chronic headache were reported by 26.1%, 24.2%, 21.6%, and 3.0% of participants, respectively. Attributable burden was high, with 42% of those with headache experiencing restrictions in daily activities. Medication use (50% overall) was highest in chronic headache (67%) and still considerable in undifferentiated headache (29%). Health-related quality of life was reduced for all headache types except undifferentiated headache. Participants in single parent or blended families had a higher probability of migraine (respectively, OR 1.5, p < 0.001; OR 1.5, p < 0.01).

Using the Pediatric Migraine Disability Assessment (PedMIDAS) questionnaire, an analogous school-based study performed in Norway on 493 adolescents (12 to 18 years of age) revealed the 1-year prevalence of any headache, migraine, probably migraine, and tension-type headache was 88%, 23%, 15%, and 58%, respectively (33). Interestingly, 9% of participants had more than one type of headache, and the duration, rather than the frequency, of individual headaches correlated best with the magnitude of the burden perceived by the participants. Participants with headaches lost up to nine days of activity each year due to their headaches. A study of 7361 children (age 7 to 18 years) in Hungary revealed the 1-year prevalence of migraine to be 12.5%, but requiring a headache duration of four hours in 15- to 18-year-olds, and 1 hour below 15 years of age lowered the 1-year prevalence to 9.1% (30). Another study of 2466 children (ages 3 to 18) presenting to a single hospital in South Korea demonstrated an apparent 3-fold increase in the number of children presenting to the hospital with headache between 2005 and 2016 (27). However, over that period, classification criteria transitioned from International Classification of Headache Disorders-2 (ICHD-) to ICHD-3, and it is not clear what role this transition, differential patient and family reporting bias, and/or changes in hospital utilization and outpatient census may have played in this increase. Interestingly, all of the increase was accounted for by changes in frequency of nonmigraine, nontension-type headaches.

The American Migraine Prevalence and Prevention study (AMPP) used a validated headache questionnaire that was mailed to 120,000 households representative of the United States population. The headache questionnaire was developed to investigate the epidemiology of migraine and the medical treatments utilized (87; 09; 71). This study included 162,576 participants with a migraine prevalence of 5.6% in males and 17.1% in females. Of the 18,968 individuals that met the ICHD-2 criteria for migraine, 823 were between the ages of 12 and 17 years. A subanalysis of AMPP restricted to adolescents found a 1-year ICHD-2 migraine prevalence of 6.3% to 5% in boys and 7.7% in girls (87; 04). For acute treatment, they found that 49.0% used over-the-counter remedies, 20.1% used prescription remedies, and 28.8% used both. The adolescents were more likely to use over-the-counter remedies (59.3%) compared to prescription medications (16.5%) or a combination (22.1%) (87; 04). The majority of adolescents (63.7%) never used preventative medication for migraine, with just 10.6% reporting current use. One of the many observations in this study was the effect of the socioeconomic status and the familial pattern of migraine. If there was a family history of migraine, there was no effect on the prevalence due to the socioeconomic status. However, when there was not a family history, the odds ratio of having migraine increased with a lower socioeconomic status. Further analysis is needed to explain the balance between the genetic and environmental components of migraine.

The relationship of female gender, particularly after puberty, to increased incidence of migraine is long-established. The associated symptom profile also differs significantly between female and male adolescents with migraine, with adolescent girls having non-headache migraine-associated symptoms of all kinds more frequently than adolescent boys (06). Studies also suggest an association between obesity and migraine and provide less robust evidence for an association between obesity and tension-type headache (51).

International Classification of Headache Disorders (ICHD-1) criteria were initially developed to advance the clinical and scientific study of headache but were criticized for a lack of sensitivity and specificity in diagnosing pediatric headaches, especially migraine. Some of the suggested modifications were adopted in the footnotes to the criteria for migraine in the second edition of the International Classification of Headache Disorders (ICHD-2) (19). This improved the sensitivity from the ICHD-1, yet it remained incomplete (24).

A subsequent iteration of this classification system, ICHD-3, is currently in use, and Table 1 presents its diagnostic criteria for migraine without aura (1.1) and migraine with aura (1.2). Note that, in section 1.1, footnote 3 and the comments that follow it, ICHD-3 has addressed the concerns raised with regard to the short duration, the higher likelihood of a bilateral location, and the difficulty in describing the headache features and associated symptoms seen in pediatric migraines (84).

In a study evaluating the sensitivity of ICHD-2 criteria for pediatric migraine, headache characteristics in 260 patients aged 18 years and younger diagnosed with migraine were summarized from standard intake questionnaires, and physician-assigned clinical diagnoses were used as the gold standard for assessing the validity of ICHD-2 criteria (24; 03). Among the 260 patients clinically diagnosed with migraine, 70.4% met ICHD-1 criteria, and 61.9% met ICHD-2 criteria, including the 4- to 72-hour headache duration. When a 1- to 72-hour duration specified in the ICHD-3 footnote is used, 71.9% met the criteria. The most common reasons that patients’ headaches did not meet the standard criteria were the requirements for unilateral location, headache duration, and number of associated symptoms. When the ICHD-2 criteria were modified to the criteria now found in ICHD-3 (Table 1), including bilateral headache, headache duration of 1 to 72 hours, and nausea and/or vomiting plus two of five other associated symptoms (photophobia, phonophobia, difficulty thinking, lightheadedness, or fatigue), the sensitivity for diagnosing migraine improved to 84.4% (24; 70; 03). The suggestion has been made that childhood syndromes associated with a family history of migraine, like neck-tongue syndrome, be brought to the attention of the neurology community (01).

New tools and biomarkers need to be developed and integrated into the diagnostic process. Researchers have begun to examine additional tools for children to augment these criteria and include the use of drawings for the pediatric population (75; 74; 34; 09). Advanced imaging techniques can distinguish migraine from tension headache in children in the mechanistic research setting. For example, children with either tension-type or migraine headache demonstrate increased ADC signal in the hippocampus and brainstem on diffusion-weighted MRI scans relative to age-matched controls, whereas only children with migraine demonstrate increased ADC signal in the thalamus (65). However, imaging is not recommended for children with uncomplicated, primary headache. Symptoms and/or signs indicative of secondary headache (eg, papilledema, headache with cough or Valsalva, nocturnal or early morning headache) should trigger performance of imaging studies (07).

Tension-type headaches are generally considered mild, recurrent headaches, and many features of tension-type headaches are the opposite of migraine. Epidemiology studies have varied on the prevalence of these headaches in children due to the present criteria. One study in which 466 of 4812 children and adolescents in Shanghai, China had experienced at least one headache in the three months preceding the study indicated that 29.1% of the participants with headache had tension-type headache (28).

Cluster headaches can begin at any age, but the mean age of onset is approximately the late twenties. Childhood and adolescent onset of cluster headaches has been reported, but these early-onset cases appear to be rare. Only 18% of patients had their onset of cluster headaches prior to 18 years of age, and 2% began before 10 years of age (49). In the study in China reported by Jin and colleagues, only 6.2% of the 466 children with recent headache met ICHD-2 criteria for cluster headache (28).

With the first occurrence of headache in a child, differential diagnosis includes secondary (ie, symptomatic) headaches for which making the diagnosis depends critically on a high index of suspicion and discovery and treatment of the underlying primary cause (Table 2).

Table 1. Migraine Without and With Aura (ICHD-3 – 1.1, 1.2)

Comments

Migraine headache in children and adolescents (aged under 18 years) is more often bilateral than is the case in adults; unilateral pain usually emerges in late adolescence or early adult life. Migraine headache is usually frontotemporal. Occipital headache in children is rare and calls for diagnostic caution. A subset of otherwise typical patients have facial location of pain, which is called “facial migraine” in the literature; there is no evidence that these patients form a separate subgroup of migraine patients. In young children, photophobia and phonophobia may be inferred from their behavior. Migraine attacks can be associated with cranial autonomic symptoms and symptoms of cutaneous allodynia.

Migraine without aura often has a menstrual relationship. ICHD-3 (beta) offers criteria for A1.1.1 Pure menstrual migraine and A1.1.2 Menstrually-related migraine, but in the Appendix because of uncertainty over whether they should be regarded as separate entities.

Very frequent migraine attacks are now distinguished as 1.3 Chronic migraine. When there is associated medication overuse, both diagnoses, 1.3 Chronic migraine and 8.2 Medication-overuse headache, should be applied. 1.1 Migraine without aura is the disease most prone to accelerate with frequent use of symptomatic medication.

Regional cerebral blood flow imaging shows no changes suggestive of cortical spreading depression (CSD) during attacks of migraine without aura, although blood flow changes in the brainstem may occur, as may cortical changes secondary to pain activation. This contrasts with the pathognomonic spreading oligemia of migraine with aura. Although the bulk of the literature suggests that CSD does not occur in migraine without aura, some recent studies disagree. Furthermore, it has been suggested that glial waves or other cortical phenomena may be involved in migraine without aura. The messenger molecules nitric oxide (NO), 5-hydroxytryptamine (5-HT) and calcitonin gene-related peptide (CGRP) are involved. Although the disease was previously regarded as primarily vascular, the importance of sensitization of pain pathways, and the possibility that attacks may originate in the central nervous system, have gained increasing attention over the last decades. At the same time, the circuitry of migraine pain, the trigeminovascular system, and several aspects of its neurotransmission peripherally and in the trigeminal nucleus caudalis, the central mesencephalic grey and the thalamus, have been recognized. New highly receptor-specific acute medications such as the triptans, which are 5HT1B/D receptor agonists, 5-HT1F receptor agonists and CGRP receptor antagonists have demonstrated efficacy in the acute treatment of attacks. Because of their high receptor-specificity, their mechanism of action provides new insight into migraine mechanisms. It is now clear that migraine without aura is a neurobiological disorder; clinical as well as basic neuroscience has advanced our knowledge of migraine mechanisms, and continues to do so.

Table 2. Differentiating Characteristics of Common Primary and Secondary Headache Syndromes

Impact

Pediatric migraines can have a significant impact in the lives of children and their parents. The impact of a migraine can be measured by both the disability to participate desired in activities and the effect on the individual’s quality of life. Several tools have been developed to evaluate the disability of migraine. In adults, this can be addressed by using the MIDAS (Migraine Disability Assessment) tool (78; 77; 76; 43). The MIDAS was not adequate for pediatrics due to the differences in lifestyles of children; subsequently, the PedMIDAS was developed (21). The scoring system was centered on patient-based disability and has a higher scoring range than the MIDAS because children are likely to miss out on school, home, and social activities more frequently than adults (23). PedMIDAS can be used clinically to identify the impact of migraine in the individual pediatric patient as well as their response to treatment. For example, a study from Izmir, Turkey used the PedMIDAS effectively to evaluate and compare prophylactic treatment of migraine in children with topiramate, propranolol, and flunarizine (81).

The impact of headache can also be assessed by measuring an individual’s quality of life. The Short Form-20 has been used for assessing quality of life in adults (53). In pediatric headache patients, a useful tool is the PedsQL 4.0 (83). PedsQL is a 23-question tool with separate, developmentally appropriate versions for age with opportunity for parent and child response. PedsQL is able to identify a significant impact of the quality of life for pediatric headache patients aged 5 to 17 years (60). When the PedsQL was used to compare rheumatologic diseases, oncologic diseases, cardiac diseases, and migraine, it demonstrated an impact on quality of life similar in all disease states as related to emotional and school development. Some studies have raised the question of whether recurrent migraines have negative effects on specific aspects of cognition and metacognition or the ability to monitor and control one’s own cognitive processes (13; 45; 79).

One study utilized the Strengths and Difficulties Questionnaire to discern and compare emotional and behavioral comorbidities in children with migraine or tension headache (68). Children with migraine had higher levels of emotional difficulties than strengths and higher emotional difficulties scores than children with tension headache. Scores for behavioral difficulties were not significantly different between children with migraine and children with tension headache. In children with migraine, the magnitude of the emotional difficulties score correlated with the duration of treatment (whether pharmacological or non-pharmacological) required to achieve 50% reduction in headache frequency.

Treatment

A comprehensive integrative treatment plan for pediatric headaches includes acute, preventative, and bio-behavioral therapy. A practice parameter reviewed the available evidence for both acute and preventative therapies in detail as related to the pediatric population (36; 26). Advances in this area have included acute treatments with several triptans, preventative treatment with topiramate (88) and levetiracetam (26), and the use of supplements including CoQ10 (22) and butterbur root extract (52).

Ginkgolide B and a mixture of feverfew, magnesium, and an extract of the plant Andrographis paniculata have been purported to have preventive value in childhood headache (11; 47).

Acute treatment. An effective acute treatment plan should end the episodic headache and return the child to normal functioning in 1 to 2 hours. The ultimate goal of this treatment should be a quick response with return to normal activity and without relapse. In the pediatric population, the nonspecific medications including NSAIDs (ibuprofen, naproxen sodium) and general pain relievers (acetaminophen) are frequently used. Two studies have evaluated the efficacy of ibuprofen in children. Hämäläinen reported a comparative, double-blinded, placebo-controlled, crossover study of placebo versus ibuprofen versus acetaminophen (18); the study indicated that ibuprofen was superior to both placebo and acetaminophen at both the 1- and 2-hour time point. Lewis performed a similar study on a group of children using a dose of ibuprofen at 7.5 mg/kg versus placebo; again, ibuprofen was more beneficial (40). The proper use of ibuprofen and other NSIADs includes: (1) early treatment, (2) effective doses (7.5 to 10.0 mg/kg), and (3) avoidance of overuse (limited to one to two headaches treated per week).

If this initial strategy of using over-the-counter medications is ineffective or not completely effective, migraine-specific therapy is often required. Children often report that the NSAIDs will work for the majority of their headaches, but they occasionally will have a moderate to severe migraine during which the response is incomplete or the treatment completely ineffective. When needed, triptans (migraine-specific medications) may be added to the treatment plan. Seven triptans are currently approved for adult migraine in the United States. Almotriptan (12.5 mg tablet) has been approved for the treatment of migraine pain in the adolescent population aged 12 to 17 years (42); it has been demonstrated to be statistically beneficial over placebo in adolescents. In Europe, several triptans, including nasal sumatriptan, have been approved for the use of adolescent migraine. Double-blinded, placebo-controlled studies have been performed in adolescents using almotriptan, eletriptan, rizatriptan, sumatriptan, and zolmitriptan. In six crossover and 11 parallel group trials, significant efficacy in children and adolescents was found for sumatriptan (10 to 20 mg nasal spray), zolmitriptan (2.5 to 5 mg tablet), rizatriptan (5 to 10 mg tablet), and almotriptan (12.5 to 25 mg tablet). Although the trials were heterogenous with respect to the triptans and the dosage, the pooled responder rate of triptans for two hours pain-free was 36.0% in crossover trials and 32.5% in parallel group trials, both significantly better than placebo in each case. Triptans also showed a significantly higher pain reduction rate at two hours than placebo both in crossover and parallel group trials. The rate of adverse events was significantly higher after triptans than after placebo. However, triptans were well tolerated in all trials (37; 12). Efficacy in children and adolescents in several placebo-controlled trials has also been noted for intranasal sumatriptan (16).

In an early intervention, open-labeled study with sumatriptan RT 100 mg tablet formulation in 35 adolescent migraine patients, 32 reported control of at least one migraine attack, and 23 reported control of four migraine attacks over a 6-month period. The adolescents were instructed to administer sumatriptan RT 100 mg tablet within 30 minutes of attack onset while pain was still mild. Pain-free response two hours postdose (primary endpoint) was reported in 71% of the 112 attacks treated. Migraine-free response (ie, no pain, nausea, vomiting, photophobia, or phonophobia and no use of rescue medication) two hours postdose was reported in 69% of attacks. Response rates were consistent from attack to attack. Rescue medication was used in 19% of migraine attacks. In 112 attacks, a total of 25 adverse events (none serious) were reported in nine patients. The most common adverse events were worsening of symptoms (n=5), neck pain (n=4), and chest tightening (n=4). Early intervention with sumatriptan RT 100 mg tablets constitutes a promising approach to treating migraine in adolescents and warrants further assessment in controlled clinical trials (91). One study has been conducted to examine efficacy and safety of the combination drug sumatriptan RT 85 mg and naproxen sodium 500 mg in adolescents. In this study, 94 subjects treated 347 attacks in total, treating 277 with sumatriptan/naproxen sodium and 70 with placebo. Compared with placebo, sumatriptan/naproxen sodium produced significantly higher 2-hour pain-free rates (sumatriptan/naproxen sodium 37%, placebo 18%; P <  .004). Compared with placebo, 24 hour pain-free rates were higher with sumatriptan/naproxen sodium than placebo, but this difference was not statistically significant (89), perhaps reflecting the shorter timeframe without treatment of pediatric migraine relative to its adult counterpart.

A few placebo-controlled clinical trials for acute treatment, or for that matter preventative treatment, agents among adolescents have consistently shown statistically significant superiority. This is often explained by the high placebo response rates in adolescent migraineurs. Many other factors may play a contributory role: the choice of efficacy endpoints, timing of assessments, and time to treatment initiation. In order to fully determine the clinical benefit of migraine-specific therapies in the setting of adolescent migraine, innovative study designs are needed. A study design built around an initial placebo challenge before patients are randomized to active therapy with an acute treatment agent may be one approach by which this could be achieved. Although these studies are being designed and preformed, we presently must use the results of the available studies (despite their limitations) to determine how to manage childhood headache in routine practice (88).

One new therapy for acute migraine in adults is a specific antagonist at the 5HT(1F) receptor. This specificity of ditans make them nonvasoactive and safer than triptans for those with cardiovascular disease. An open-label, phase I study in children indicates that ditans are safe in children; a placebo-controlled efficacy study is underway (82).

Patients and their parents should be advised to avoid the overuse of acute medications. Medication overuse or analgesic rebound headaches can frequently lead to an increase in headache frequency and require cessation of acute therapy for recovery. Any patient having at least one headache per week should be considered a candidate for preventative medication with a “rescue” option for breakthrough headaches.

Treatment aimed at reduction in headache frequency. Strategies for reduction in headache frequency and resultant disability include lifestyle changes (eg, institution of more regular eating and sleeping habits, reduction in modifiable social and environmental exposures), preventative medication, and bio-behavioral treatment (58) have demonstrated that amitriptyline (1 mg per kilogram of body weight per day), topiramate (2 mg per kilogram per day), and placebo had equivalent (50% to 60%) efficacy in reduction of headache frequency by 50% in children and adolescents 8 to 17 years of age with migraine. Adverse effects were more frequent with amitriptyline or topiramate than with placebo. For children with chronic migraine (15 more headache days per month), addition of cognitive behavioral therapy to amitriptyline was more effective in reduction of headache frequency than addition of headache education to amitriptyline (31). Compliance was equivalent in the two alternative regimens (32). Injection of lidocaine and methylprednisolone into the greater occipital nerve appears to be both safe and effective in children with primary headache that is chronic and refractory to other therapies (62). At the present time, antibodies against calcitonin gene‐related peptide or its receptor are not recommended for use in children, as neither their efficacy nor their safety have been demonstrated (73). However, preliminary results of ongoing randomized, controlled trials in children and adolescents are promising (26; 54). Choice of treatment modality for a given child involves multifactorial consideration, discussion with the child and family, and flexibility as the disorder and circumstances evolve over time.

OnabotulinumtoxinA has been used in adults for frequent and chronic migraine. Although there are no definitive studies in children and adolescents, what studies exist have been promising, with statistically significant reduction in frequency and severity of headaches over that seen with placebo (82).

When the frequency increases to three to four migraines per month, with increased disability, a preventative therapy plan should be developed in the adolescent patient. Two to three migraines per month should be considered the threshold for considering preventative treatment in young children. Implementation of this approach often falls to the neurologist, as in a study of 106 consecutive patients seen in a headache clinic, although 62% met published criteria (39) for needing prophylaxis, prophylaxis was initiated by the referring physician in only 30% of the patients (67).

A comprehensive integrative approach may need to include, at least temporarily, preventative medication as well as incorporation of bio-behavioral management. The impact of migraine on the pediatric patient should be routinely measured by increased use of assessment tools such as PedMIDAS and the PedsQL (21; 23; 60).

The goal of preventative treatment is to reduce headache frequency and decrease headache disability. Ultimately, the goal is to maintain this reduction at an acceptable level for a long enough period of time so the preventative medication can be discontinued and the bio-behavioral therapy alone can sustain this response. Again, there are no absolutes as to what this frequency must be nor for how long, but in general most patients can be successfully weaned off of their preventative medication once they are at one to two headaches per month for 3 to 6 months. This time period may be altered based on the school year. Children typically experience decreases in headache frequency over the summer when they are out of school. Early summer provides an opportunity to reduce medication. Headaches often worsen in the fall with the start of the school year as well as in late spring. Thus, these are less desirable times to discontinue preventative medication.

Presently, in the United States only topiramate is FDA-approved as a preventative medication for the treatment of migraine in children age 12 and over (29). As in adults, preventative medications are grouped into: antiseizure medications, antidepressant medications (especially the tricyclic antidepressants), anti-serotonergic medications, and antihypertensive medications, including both beta-blockers and calcium channel blockers (36). The antiseizure medications currently being used include divalproate sodium and topiramate (both approved by the FDA for the prevention of migraine in adults) (46; 69) as well as gabapentin, levetiracetam, and zonisamide. Although a Cochrane review concluded that there was no evidence for efficacy of pregabalin or gabapentin in adults with migraine (41), a randomized comparative effectiveness study of propranolol and pregabalin for prophylaxis of childhood migraine suggested that pregabalin is superior to propranolol in this regard (02).

For children, the effective doses for most preventative anti-seizure medications have not been established, but in general the doses should be slowly increased, typically increasing the dose as tolerated over 6 to 8 weeks to the lower dosages used for epilepsy (90).

Lewis and colleagues completed a randomized, double-blind, placebo-controlled, multicenter, 16-week study evaluated the efficacy and safety of topiramate for the prevention of pediatric migraine (38). The primary efficacy measure was the percent reduction in the monthly migraine attack rate compared with baseline. The percent reductions in the monthly rates of migraine days, headache days, migraine attacks, migraine days with rescue medication, and the 50% responder rate were also evaluated. A total of 106 pediatric subjects with migraine with a mean (±SD) age of 14.2 (±1.6) years were randomized to topiramate 50 mg/day, topiramate 100 mg/day, or placebo. Topiramate 100 mg/day, but not 50 mg/day, resulted in a statistically significant reduction from baseline compared with placebo in the monthly migraine attack rate (72.2% vs. 44.4%) during the last 12 weeks of double-blind treatment. In addition, topiramate 100 mg/day, but not 50 mg/day, resulted in statistically significant percent reductions from baseline compared with placebo in the monthly rates of migraine days, headache days, and migraine attacks (24-hour rule; 48-hour rule). The 50% responder rate was statistically significantly higher for the topiramate 100 mg/day treatment group compared with placebo. Topiramate 100 mg/day for preventive treatment of migraine was both effective and well tolerated in pediatric migraine subjects.

For antidepressant medications, amitriptyline is the most widely used tricyclic antidepressant for headache prevention. In the pediatric population, the efficacy data are limited by open-labeled or small sample studies (35; 20). Other antidepressants have been used to a lesser degree with mixed results.

Antihypertensive agents have also been used for headache prevention and include beta-blockers (44; 93) and calcium channel blockers with flunarizine, available in Europe for migraine prevention (17; 72) with grade I evidence of its effectiveness (36).

New approaches to frequent and chronic migraine in adults include anti-CGRP monoclonal antibodies and small molecule CGRP receptor antagonists (termed “gepants”), for both of which there are ongoing pediatric trials (82).

Additional prevention agents may include some nonpharmaceutical treatments and supplements including: riboflavin (66; 05), coenzyme Q10 (63; 64), butterbur extract (57), melatonin (14), feverfew with Andrographis paniculata, and magnesium (47). Their effectiveness and usefulness in children has yet to be rigorously demonstrated.

When pharmacologic treatment is chosen to reduce headache frequency, the key to successful use of preventative medications is to slowly titrate the dose to an effective level. This requires an understanding by the patient and parent that it may take several weeks to months before an effective level and, thus, an effective response, is achieved. The most effective levels have yet to be established in children although adult guidelines may be useful for adolescents. Nearly one third of adolescent migraineurs met criteria for preventative therapy whereas only 19% have received it. Prospective studies are needed to fully evaluate the efficacy of preventative management in this population and to establish whether early intervention might slow this disease progression (87).

Several different devices that modulate the activity of the brain, spinal cord, or peripheral nerves, called neuromodulatory devices, have been approved in the U.S. and Europe for use in adults with acute or chronic migraine and have been proposed for prevention of episodic primary headache in children and adolescents. Towards the standardization of and the application of rigorous methods to the clinical evaluation of these devices, the International Headache Society has published guidelines for these clinical trials in adults and children with migraine (80). The challenge is that most of these have not been adequately tested in children, although there are some data suggestive of both efficacy and safety in adolescents. At present, most insurance companies will not pay for these devices for use in children and adolescents and their long-term cost can be prohibitive for many families (82).

Bio-behavioral treatment. The third component of a comprehensive integrative treatment plan is bio-behavioral therapy. This incorporates normalizing a pediatric patient’s lifestyle as well as establishing long-term healthy goals. In addition, attention to the contribution of adverse psychosocial circumstances and events to the origin of childhood headache is critical to treating underlying precipitants (54; 56; 94). Bio-behavioral therapy can roughly be divided into treatment adherence, lifestyle management, and psychological intervention including biofeedback-assisted relaxation training and cognitive behavioral therapy. Treatment adherence involves educating the patient and parent about the importance of compliance with their treatment plan and identifying obstacles that may limit the effectiveness of the plan. Adjustment of lifestyle habits includes identification of triggers for pediatric headaches, such as inadequate nutrition, skipping meals, and altered sleep patterns. This discussion includes the importance of adequate fluid hydration with limited use of caffeine, regular exercise, and adequate nutrition (25; 10). Additional psychological intervention can include biofeedback-assisted relaxation therapy, which has been shown to be effective in the pediatric population (08; 86; 61; 59), and cognitive behavioral therapy, which demonstrated sustained effectiveness for at least three months after initiation (50; 15).

Conclusion

The impact of headache in children is under-appreciated, with children experiencing substantial disability. Present advances in the study of pediatric migraine have led to improved recognition of this condition. Given the high prevalence, incidence, and disability of migraine, this recognition needs to be increased in order to attain improved outcomes and to potentially prevent lifelong impact and disease progression (48). Further research is needed to expand our biological, mechanistic classification, and treatment options, and to develop biomarkers, therapeutic targets, better long-term outcome measurement tools. A user-friendly, clinically relevant grading system for headache management is also needed. Finally, and perhaps most important, development and approval of treatments for children and adolescents with frequent or chronic migraine in whom currently approved preventive strategies have failed are critically needed (82).