Clinical manifestations

Presentation and course

The most notable symptom of childhood migraine is headache, which is accompanied by aura in about one third of patients. A key clinical feature, however, is normality between attacks. Although a unilateral, throbbing headache is typical with adult migraine, it is more common for children to complain of bilateral or midfrontal headaches. Even though the headache is often bilateral, its onset may be unilateral. If usual questioning does not disclose the location and quality of the headache, the child can be asked to point to the location of onset, and the examiner can supply several adjectives to determine the quality of the pain (eg, pounding, pressing, and burning). One measure of morbidity is how much school is missed due to migraine attacks. In a survey, 10% of children with migraine missed 1 day of school over a 2-week period, and nearly 1% missed 4 days (57). The use of a migraine disability assessment tool may help to specify the associated disabilities and can be useful for comparison at follow-up (26). A headache diary kept by a parent or child is also useful at follow-up (49). A visual aura of scintillating scotomata or flashing lights or, less commonly, a sensory or motor disturbance may precede the headache by 20 to 60 minutes in a third of migrainous children (46), but the pathognomonic fortification spectrum with its gradually expanding “C” shape with a scintillating border is rarely reported.

Visual symptoms are usually homonymous, and motor or sensory symptoms are usually unilateral. In children, gastrointestinal symptoms are especially prominent, but the headaches, sometimes lasting less than an hour or so, are usually of shorter duration than those of adults. Facial pallor commonly occurs before or with the headache, and photophobia and phonophobia may also occur. Although most children with migraine do not experience syncope, migraine is second only to vasovagal syncope as a cause of syncope in children (44), and many children report a lightheaded dizziness with the headaches. Cutaneous allodynia occurs in some children with migraine, sometimes expressed as their hair hurting, such as when combing hair, touching their head, or wearing a hat (37). Nonheadache symptoms often precede the headache and include irritability, malaise, and hyperactivity. Factors often mentioned as precipitating or exacerbating the headache include stress, light, irregular schedule (eg, meals, sleep times), menses, minor head trauma, heavy exercise, environmental heat, and weather. Medications that may increase the likelihood of headaches include adrenergic agonists (eg, for asthma or ADHD), oral contraceptives, and others. Unfavorable lifestyles (including obesity, low physical activity, and cigarette smoking) are associated with an increased prevalence of headaches. Among 112 adolescents with migraine who underwent a weight-loss program, the 40 who became migraine-free lost more weight than the 72 who continued to experience migraine (67). Dietary substances are generally less important as triggering factors (eg, chocolate, cheese, caffeine, alcohol, nitrites “hot dog headache,” and monosodium glutamate) (29).

The criteria for different headache types in the International Classification of Headache Disorders (ICHD-3) (25) may be used for children. However, if a child has not yet had five attacks or if the headaches last less than 1 hour or so, the IHS criteria may be too restrictive. As of 2016, the full headache classification can be accessed digitally: https://www.ichd-3.org.

Diagnostic criteria. Migraine has three basic types: (1) migraine without aura, (2) migraine with aura, and (3) chronic migraine (25). For all types, a criterion is that the headache is not better accounted for by an alternative diagnosis (eg, infection, mass lesion, or others).

Migraine without aura.

Migraine with aura. This diagnosis requires one or more fully reversible aura symptoms to indicate focal cerebral cortical or brainstem dysfunction. No migraine aura lasts more than 60 minutes. A typical aura may include visual, sensory, or speech symptoms and is usually followed by a typical migraine headache. Aura without headache is exceedingly rare in children and should raise suspicion for a structural lesion (eg, occipital arteriovenous malformation).

Chronic migraine. Chronic migraine is diagnosed when headaches occur for 15 days or more per month for at least 3 months, and migraine headache (with or without aura) occurs on at least 8 of those days. Tension-type headaches usually occur on the remaining headache days. The most common cause for chronic migraine is medication overuse. If medication overuse is present, diagnoses of both chronic migraine and medication-overuse headaches are appropriate. The demarcation is arbitrary between chronic migraine (15 headache days or more per month for 3 or more months) and episodic migraine (fewer than 15 days per month), and there is no biological difference between the two types (01). During some months (eg, school holidays and summer vacation), a child with chronic migraine can have fewer than 15 headache days per month, and during those months, the child has episodic migraine (69).

Subforms of migraine with aura. Please note that many of the headache types commonly referred to as “complicated migraine” are classified as subtypes of migraine with aura.

Migraine with brainstem aura (basilar-type migraine) has aura symptoms referable to brainstem dysfunction (vertigo, tinnitus, impaired hearing, ataxia, dysarthria, nystagmus, diplopia, or impaired consciousness or somnolence) and usually has typical aura symptoms as well (visual, sensory, or speech/language). Headache usually occurs within 60 minutes of the auras. There is no motor weakness, which is the key clinical feature differentiating it from hemiplegic migraine.

Hemiplegic migraine occurs both sporadically and as an inherited autosomal dominant trait. It is a migraine with aura that includes motor weakness. Fully reversible motor weakness occurs as an aura and is accompanied by reversible auras of sensory, visual, or speech/language dysfunction, with headache often occurring during or within 60 minutes of an aura. The motor weakness can last up to 72 hours (and rarely weeks), but the nonmotor auras last 5 to 60 minutes. At least one aura is typically unilateral. Symptoms of brainstem dysfunction often occur. Rarely, during an attack of hemiplegic migraine, there can be altered consciousness, confusion, fever, and CSF pleocytosis mimicking meningoencephalitis. Some of the familial patients have cerebellar signs and may have serious complications, including coma from mild head injury (14). In the familial type of hemiplegic migraine, genetic etiologies have been determined for three subtypes, with each having a mutation in a different gene: CACNA1A (calcium channel), ATP1A2 (K/Na-ATPase), and SCN1A (sodium channel).

Childhood episodic syndromes that may be associated with migraine. As mentioned above, the evaluation must determine that an alternative disorder does not account for the symptoms.

The subgroup of episodic syndromes associated with migraine are either precursors to migraine or are considered migraine equivalents. However, a clear link with migraine remains questionable. The most common of these is recurrent gastrointestinal disturbance, which comprises two disorders: abdominal migraine, with its recurrent abdominal pain, and cyclical vomiting. Other possible migraine equivalents include benign paroxysmal vertigo and benign paroxysmal torticollis, which has onset during the first year; some also consider acute confusional migraine as part of this group. These episodic syndromes are more likely to be accepted as migraine equivalents if the child also has typical episodes of migraine headache that include similar symptoms. For example, coexisting migraine headaches are most typical with abdominal migraine and cyclical vomiting and occur in 70% of the patients, whereas they are least frequent with benign paroxysmal vertigo (10%) (03). Although some children with these syndromes later develop migraine, others do not. No diagnostic marker for migraine can verify a relationship between migraine and episodic syndromes, and the existence of these disorders as forms of migraine remains uncertain.

Episodic entities of less certain status. These three entities are included in the appendix of the headache classification, indicating their uncertain status as childhood episodic syndromes that may be associated with migraine (25).

Migraine variants. (32)

Prognosis and complications

In Bille's large study, 35% to 50% of the children with migraine became asymptomatic after 4 years to 6 years of observation (09). When Bille re-evaluated his cohort near the age of 50 years, more than half of the subgroup who had “pronounced” migraine at about 6 years still had migraine at the age of 50. However, one fourth of the subgroup stopped having migraine by the age of 25 years (10). Among children who attended a neurologic clinic in 1983 because of headaches, about 80% were much improved 10 years later (16). Migraine complicated by prolonged neurologic signs has rarely been associated with a permanent neurologic deficit, and some of these cases may have been due to unrecognized metabolic diseases. Severe unilateral headaches with neurologic signs (SMART syndrome) may occur in children years after treatment for brain tumors as sequelae of cranial radiation and chemotherapy (06). Vomiting after mild head injury seems more common in children with migraine headache. Among women aged 15 to 45 years, especially those who smoked or took oral contraceptives, there was a significant association between migraine and stroke (40). Similar studies have not been performed for those under the age of 15 years.

Clinical vignette

I evaluated this boy at 12 years of age. He had headaches from the age of 7 to 8 years old, which later began worsening. The severe headaches lasted for several hours and required him to lie down and sleep twice per month. He missed 4 days of school because of the headaches. His mother could tell when a headache was coming because there was a different look in his eyes. She thought the whites of his eyes became darker, and his eyes appeared sunken. He seemed confused and dazed with the headache. The headaches were exacerbated by activity, heat, and loud noises. Sleep provided relief. The headaches were associated with abdominal pain and anorexia. There was no photophobia, nausea, vomiting, or aura. He had no history of seizures, head trauma, or loss of consciousness. Family history was positive for severe headaches in his father when he was about the same age. Physical and neurologic examinations were normal, with blood pressure 110/60 and pulse 90. He was treated with propranolol long-acting 60 mg daily. His mother telephoned a few weeks later. She was worried because she said his blood pressure and pulse were low and reported blood pressure 100/41 and pulse 52. She stopped propranolol for several days, and he had a severe headache. I reassured her that these changes in pulse and blood pressure in a child/teenager with a healthy heart were of no concern. Propranolol was restarted. When he returned 4 weeks after the initial visit, he submitted an illustration of his headaches.

He was free of headaches and asymptomatic, with a pulse of 58.

Biological basis

Etiology and pathogenesis

A large proportion of children with migraine have a family history of migraine. Furthermore, children with headaches associated with acute illnesses are more likely to have a family history of migraine (33). However, even though 72% to 89% of migrainous children have a positive family history, the relative contributions of genetics or other factors generally remain unclear. One estimate suggests 52% heritability (71). But for specific types of migraine, the role of genetics is more certain. In the familial type of hemiplegic migraine, genetic etiologies have been determined for three subtypes, with each having a mutation in a different gene: CACNA1A (calcium channel), ATP1A2 (Na/K-ATPase), and SCN1A (sodium channel). For the autosomal dominantly inherited, familial hemiplegic migraine 1, there is a mutation in a calcium-channel gene in up to 75% of cases. Surprisingly, familial hemiplegic migraine is one of three allelic disorders (ie, different alleles of the same gene) due to defects in calcium channel alpha 1A subunit gene (CACNA1A) on chromosome 19p13 the others being episodic ataxia type 2 and chronic spinocerebellar ataxia type 6. In other families with familial hemiplegic migraine 2, the chromosome 1q23 gene for sodium-potassium ATPase pump is associated with familial hemiplegic migraine, benign familial infantile convulsions, permanent mental retardation, and a family history of confusional migraine (66). A third subform of familial hemiplegic migraine is due to mutations of the sodium-channel gene SCN1A.

The exact pathogenesis of childhood migraine is unknown but is felt to represent the interaction of several factors: genetic predisposition, environmental predisposition (eg, hormonal and psychosocial influences), physiological and biochemical abnormalities, precipitating factors, and processing of pain impulses. Regarding genetic predisposition, a genome-wide study has implicated primary involvement of genes related to vascular control (23).

The trigeminovascular system, referring to the trigeminal innervation of the cranial vessels, has been linked to the pathophysiology of migraine. Activation of trigeminal nerve terminals by various triggers provokes several events, which include (1) the release into the cranial circulation of neuropeptides, including calcitonin gene-related peptide (CGRP, a vasodilator peptide), (2) vessel leakage, and (3) mast-cell degranulation. Neuropeptides are thought to play a role in several aspects of migraine, including migraine pain, lowering of the pain-response threshold, and allodynia, sensitivity to stimuli that are usually not considered uncomfortable (eg, discomfort when combing hair). In humans, sumatriptan normalizes elevated levels of CGRP and relieves the headache. Moreover, treatment with an antagonist of CGRP relieves migraine (13). Abnormalities of ion channels leading to neuronal hyperexcitability have been confirmed in familial hemiplegic migraine (66; 15).

Epidemiology

Migraine is common during childhood. Migraine affects 9.1% of children (70), as contrasted with 6% of men and 18% of women (15). Generally, boys and girls are affected equally before puberty, but girls are affected roughly three times more than boys after puberty (64). As a chronic problem, childhood headaches (migraine and other types) are more prevalent than asthma, with headaches occurring in 20% and asthma in 13% of 11-year-old children (62). Adolescents with migraine, however, have several comorbidities. They have higher rates of inflammatory conditions, such as asthma and seasonal allergies, and have higher rates of epilepsy, persistent nightmares, and motion sickness (36). Wagner and colleagues found that depression occurs at all ages, more commonly in children with either migraine or epilepsy as compared to controls with lower-leg fractures (68). However, when comparing migrainous adolescents with migrainous preadolescents, depression is more than twice as common in adolescents (68). Migraine age-of-onset influences familial clustering of migraine. If a patient has onset of migraine headaches before 16 years of age, it is more likely that other family members will have migraine (60). As mass shootings of children have become more common, morbidities in survivors are being recognized, among them a greater risk for headaches. Following a mass shooting at a camp for adolescents in the Utoya islet in Norway in 2011 that killed 69 and severely wounded 33 people, all 358 adolescent survivors participated in the study and had an increased odds ratio for both migraine (odds ratio 4.27) and tension-type headaches (odds ratio 3.39) (59).

The two basic types of migraine occur in children. Overall, 1.5% of children report migraine with aura, regardless of the criteria used, whereas the prevalence of migraine without aura varies from 2.2% to 3.4% depending on the diagnostic criteria (46). The prevalence of both migraine without aura and migraine with aura increases with increasing age (46). Thus, incidence rates for migraine in children were estimated as 9 per 100,000 person-years in 0- to 4-year-olds and 151 per 100,000 in 15- to 19-year-olds (58). Note that the age of peak incidence of migraine varies by sex; for males of all ages (including adults), the peak incidence is 246 per 100,000 person-years for 10 to 14-year-olds, whereas the peak for females is 689 per 100,000 for 20- to 24-year-olds (58). Adult migraine often starts in childhood. When adults with migraine are questioned regarding onset, half report onset before 20 years of age, whereas one fourth report onset before the age of 10 years (54). The prevalence of abdominal migraine, for which diagnostic criteria and a verifiable relationship with migraine remain controversial, peaks at the ages of 5 to 9 years (47).

Prevention

For the obese, a weight loss program will be helpful (67). Prenatal diagnosis may be available for hemiplegic migraine, for which genetic counseling is, thus, advised.

Differential diagnosis

In the presence of the following features, the diagnosis of migraine is fairly secure: (1) a positive family history of similar illness; (2) a typical history of migraine; (3) a normal examination; (4) normal health between attacks. Other combinations may suggest alternative diagnoses. For example, a structural brain lesion may be responsible if a neurologic aura lasts longer than 60 minutes or if headaches typically awaken a child from sleep. In the emergency department, about 10% of headaches in children are thought to be primary headaches, mostly migraine, and most of the remainder are due to concurrent illness or minor head trauma (30).

Confusing conditions

Disorders that may have migraine-like headaches include the following:

Chronic daily headaches. These children typically have one of three entities: chronic migraine, chronic tension-type headaches, or new daily persistent headaches. Chronic migraine and chronic tension-type headaches, which often overlap in the same child, evolve from episodic headaches to extremely frequent or even continuous daily headaches (or at least 15 or more headache days per month). New persistent daily headaches begin without a prior history of headaches. Daily or chronic headaches are sometimes associated with an infection or physical stress and uncommonly related to idiopathic intracranial hypertension without papilledema (08). The evolution to daily headaches is often related to medication overuse or to concurrent psychological problems. In adults, cutaneous allodynia can be a risk factor for chronic migraine, but allodynia is not associated with chronic migraine in children (37). Over time, the frequency of chronic migraine headaches might improve to that of episodic migraine headaches. The improvement might take years, and some patients shift over the years between episodic migraine and chronic migraine (69).

Brain tumors. Other tumor manifestations usually develop within 4 months of headache onset (27).

Vascular malformations. Headaches are always on one side, and sometimes a cranial bruit is heard.

Hydrocephalus. Check the head circumference for macrocephaly.

Idiopathic intracranial hypertension (pseudotumor cerebri). Other clinical features may include papilledema, sixth nerve palsy, and episodes of transient visual obscuration. Less commonly, there is no papilledema (08).

Posterior reversible encephalopathy syndrome. Headaches have been associated with white matter lesions and related to various disorders, including hypertension, renal disease, chemotherapeutic agents, and malignancies. More commonly in children, renal disease, extreme hypertension, and papilledema are combined with occipital edema (31).

Head trauma.

Various inflammatory disorders.

Mitochondriopathies. Including mitochondrial encephalopathy with lactic acidosis and stroke-like episodes (MELAS).

Seizures. Epilepsy is the favored diagnosis when the aura is especially brief, consciousness is altered, and there is a focal epileptiform discharge. A therapeutic trial with antimigrainous or antiepileptic drugs is rarely helpful in the differential diagnosis because many of these drugs can be used for either migraine or epilepsy (eg, valproate).

Cluster headaches or chronic paroxysmal hemicrania. These headache types are rare in children.

Abdominal disorders. Primary abdominal disorders may cause recurrent episodes of prominent vomiting and abdominal pain, whereas metabolic disorders (eg, heterozygous ornithine transcarbamylase deficiency) may add severe headaches to the abdominal symptoms.

Diagnostic workup

Indications for laboratory testing. In children with sickle cell disease, low hemoglobin is associated with headaches. However, even children with sickle cell disease and at higher risk for silent cerebral infarction do not require neuroimaging for recurrent headaches if they are neurologically normal (17). Standard CSF analysis is usually normal, even with hemiplegic migraine. However, the syndrome HaNDL might mimic hemiplegic migraine. HaNDL rarely occurs in children and can be excluded if CSF is normal (22). In general, if lumbar puncture demonstrates abnormalities, then a process other than migraine should be considered (eg, inflammatory disease, mitochondriopathy, hemorrhage). EEG is not recommended for routine evaluation of migraine (39) but may be performed if there is a clinical suspicion for seizures, realizing that abnormalities occur frequently in children with migraine and, in most cases, do not clearly define an epileptic disorder. Migraine-associated EEG abnormalities are relatively common: 10% to 75% in total (paroxysmal in 20% to 30%). For example, midtemporal or central spikes have been reported in 9% of children with migraine who did not have seizures (34). With occipital epilepsy, but not with migraine, spikes occur when the eyes are closed. In children with typical migraine (ie, migraine with or without aura) and who have normal physical and neurologic examinations, brain MRI is normal or has findings that do not require surgical treatment (39). Subsequent studies support this conclusion. Thus, brain MRIs were performed in 375 of 926 pediatric patients with migraine. Among them, 24 (6%) had nonprogressive, predominantly frontal T2/FLAIR white-matter hyperintensities, and none had stroke. Other MRI abnormalities were not clearly related to the migraine headaches (Chiari malformations, arachnoid cysts, pineal or other cysts, etc.) (43). More recently, it has been shown that T2/FLAIR white-matter hyperintensities are no more common in children with migraine than those without migraine (02). A head CT scan, eg, in the emergency department, is not helpful unless the child has acute abnormalities other than headache.

Lewis and colleagues created a practice parameter for children aged 3 to 18 years that recommends consideration of neuroimaging in children with an abnormal neurologic examination or for children with other physical findings that suggest disease of the central nervous system (39). I often perform neuroimaging in the following situations:

Management

Drug treatment

(51; 49; 50)

Acute headaches. With regard to medication management, at full dose per weight, ibuprofen, naproxen, or acetaminophen are efficacious when given rapidly, ie, during a migraine aura or as soon after headache onset as possible. However, if the individual typically has severe headaches inadequately responsive to analgesics, add a triptan to the analgesic. For analgesics the following are suggested: acetaminophen with a dosage of 15 mg/kg every 4 to 6 hours; ibuprofen 10 mg/kg every 6 to 8 hours; naproxen or aspirin 15 mg/kg every 4 to 6 hours. Do not use aspirin for pre-teenagers or those at risk for Reye syndrome. Do not use the above analgesics in combination.

The CDC does not recommend using NSAIDs or acetaminophen before vaccines, and the COVID-19 vaccine is no exception. However, these agents are indicated for postvaccination symptoms, including headache (19). The four triptans approved for pediatric use, sumatriptan plus naproxen (12 years and older), rizatriptan (6 years or older), almotriptan (12 years and older), and zolmatriptan (12 years and older), are used for severe headaches or migraine with aura. Rapid treatment with a nasal or oral triptan plus ibuprofen or naproxen is helpful for about 70% to 80% of headache episodes. Preceding the dose of a nasal triptan with a hard candy can ameliorate the side effect of bad taste. Based on the study of Linder and colleagues, the FDA in June 2009 approved oral almotriptan malate as the first triptan approved for use in adolescents aged 12 to 17 years old. The 25 mg dose showed a statistically significant decrease in headache at the 2-hour time point (41). In March 2012, rizatriptan was FDA-approved for treating headaches in children ages 6 to 17 years (5 mg once for those less than 40 kg and 10 mg once for those more than 40 kg weight). In May 2015, Treximet (sumatriptan/naproxen) was approved by the FDA for adolescents 12 years and older at a new dosage-strength recommendation of 10 mg sumatriptan and 60 mg naproxen given once per 24 hours with a maximum dose of 85 mg sumatriptan and 500 mg naproxen per 24 hours. In addition, reports have confirmed the safe use of nasal triptans, acetaminophen, and ibuprofen for children as young as 4 years of age, and oral and subcutaneous triptans are often used for children as young as 6 years of age. Experience in children is limited for intravenous dihydroergotamine, but it seems to have the same safety profile as in adults. Triptans and dihydroergotamine should not be used for hemiplegic migraine or for children who have cardiac disease or hypertension. Opioids and barbiturate-combination medications are usually avoided in outpatient treatment of pediatric headaches. In pediatric emergency departments from 2009 to 2019, opioid treatment for migraine decreased, particularly in hospitals with clinical guidelines for treating childhood migraines (20).

Chronic migraine. Chronic migraine occurs relatively infrequently in children, but an effective treatment modality is injecting the greater occipital nerve with a combination of lidocaine and methylprednisolone acetate (53).

Preventive treatment. Initiation of preventive treatment is indicated if the above measures are ineffective or if the headaches are severe or especially frequent (more than two to three per month). It can be difficult for the clinician to determine whether preventive treatment is effective due to the prominent placebo effect in childhood migraine, ie, a placebo response rate close to 60% (52; 01). Other than limited evidence supporting the preventive use of topiramate and trazodone, pediatric migraine studies have not found effective preventive treatments, but this should not be interpreted as meaning there are no effective treatments (07). However, exciting developments are on the horizon with regard to the clinical use of CGRP antagonists. Although effective in adults, CGRP antagonists are not yet approved for use in children (63; 42; 13).

More caution is now exercised with regard to potential adverse effects of medications in view of studies showing that active medications are often no more useful than placebo (07). For instance, in the Childhood and Adolescent Migraine Prevention (CHAMP) trial, children were treated for 24 weeks. Surprisingly, topiramate or amitriptyline was no more effective than a placebo for preventing migraine headaches (52). If preventive medications are chosen, propranolol or nadolol (beta blockers) can be given daily. For those weighing less than 30 kg, the dosage is 1 mg/kg per dose given three times daily. For those weighing more than 30 kg, nadolol is started at 40 or 80 mg as a single daily dose and increased every 2 weeks as limited by side effects such as fatigue, depression, or sleep disturbances. Special caution is necessary for those for whom beta-blockade could cause problems, eg, asthmatics (beta-blockers may worsen bronchospasm), allergic individuals receiving desensitization shots, children taking insulin (beta blockers can mask symptoms of anaphylaxis or hypoglycemia), or children with congestive heart failure, orthostatic hypotension, or renal insufficiency. Other oral medications might be useful when administered daily: amitriptyline or nortriptyline starting at 10 mg, verapamil, cyproheptadine (4 mg tab) starting at one-half tab once or twice daily, particularly in young children, antiepileptic agents (topiramate, divalproex, topiramate, levetiracetam, and as used more in the past, phenobarbital and phenytoin), trazodone, and naproxen sodium. Amitriptyline combined with cognitive behavioral therapy was more effective than amitriptyline alone. However, there is a Food and Drug Administration warning about suicidal thoughts and behavior for children treated with amitriptyline. In a study using divalproex sodium ER, 500 mg/day for 15 days and then 1000 mg/day, the median rate of headaches decreased by 75% when comparing the first month of therapy to the fourth month. However, the decrease in the mean rate was less than 50%. Adverse effects were like those in adults (05). In a study of topiramate in adolescents, the 100 mg dose was superior to the 50 mg dose. Topiramate not only decreased headaches but also decreased absenteeism (38). Oral chlorpromazine has not been studied for migraine in children but may be used intermittently at doses of 2.5 to 5 mg every hour for four to five doses until sleep or headache relief occurs.

Treatment with CGRP antagonists. In adults, preventive treatment using CGRP antagonists includes injectable anti-CGRP monoclonal antibodies and oral small-molecule CGRP antagonists (called gepants). At this time, post-pubertal children who have failed other treatments can be considered for treatment with a CGRP antagonist at the lowest available dose. For example, rimegepant is an orally available CGRP antagonist dosed at 75 mg orally daily that was shown to be effective in an adult trial using 75 mg every other day (13). Relative contraindications to either small-molecule CGRP antagonists or anti-CGRP monoclonal antibodies include impairment of the blood-brain barrier, severe cardiovascular conditions, stroke or risk factors for stroke, and pregnancy including planned pregnancy or breastfeeding (63). A safety trial of rimegepant treatment in children aged 6 to 17 years who have moderate-to-severe migraine is ongoing and has a completion date estimated for 2024 (clinicaltrials.gov: NCT04743141).

Nutraceuticals. One should remain cautious with use of alternative pharmacologic treatments that might have adverse side effects, particularly nutraceuticals, many of which have not been adequately studied. Nutraceuticals are often considered by parents or physicians because of purported safety or as a “natural” remedy but are not proven effective for the preventive or immediate treatment of pediatric migraine. Furthermore, these substances are not regulated by the FDA for purity, safety, or efficacy. Nutraceuticals include butterbur, riboflavin, ginkgolide B, magnesium, coenzyme Q10, polyunsaturated fatty acids, and oral melatonin (04; 12; 56; 48).

Prolonged migraine. Especially severe and prolonged migraine attacks can be treated with oral prednisone (initially 2 mg/kg per day up to 60 mg per day) for a tapering 6- to 14-day course when other agents are unsuccessful or before instituting systemic therapy.

Hospital treatment. For emergency department treatment, dopamine antagonists are often used and might include prochlorperazine, metoclopramide, or promethazine. Prochlorperazine was the most effective and promethazine the least (55). For status migrainosus, consider intravenous or intramuscular administration of a drug like valproate sodium (10 to 15 mg/kg), metoclopramide (5 to 10 mg) or prochlorperazine (2.5 to 5 mg) (55). Metoclopramide or prochlorperazine can be followed 20 minutes later by intravenous dihydroergotamine with an initial dose of 0.5 to 1 mg. In general, dihydroergotamine should not be used within 24 hours of a triptan. Status migrainosus, frequently associated with prolonged vomiting, may require hospitalization employing intravenous rehydration and treatment with metoclopramide and dihydroergotamine as above, and then dihydroergotamine every 8 hours for several days. A proportion of children whose status migrainosis has been refractory to the above treatments respond favorably to peripheral nerve blocks (21). Locations for superficial nerve blocks can include the tissue near the greater occipital nerve, lesser occipital nerve, supraorbital nerve, and auriculotemporal nerve. Morphine or intravenous chlorpromazine is sometimes added.

Nonpharmacologic treatments

Counseling. Additional aspects of counseling include the following: (1) reassurance that there is not a brain tumor or disease; (2) avoidance of triggering factors (especially stress, irregular or inadequate sleep, and irregular meal schedules); (3) the benign nature of migraine with regard to health; and (4) the importance of using analgesics early in the headache.

Lifestyle adjustments. Advice regarding the benefits of adequate rest and relaxation can provide long-lasting benefits (16). Although stress is often an unavoidable part of life, sometimes stress can be reduced, eg, the child can more completely prepare for an upcoming examination, parents and children can be counseled regarding conflict resolution, and bullies can be avoided. The headache may be exacerbated by stress related to emotional or cognitive problems resulting from or causing school failure or child abuse. Addressing these problems may reduce the frequency of these headaches. Inadequate sleep might be due to obstructive sleep apnea, among other possibilities. Factors associated with recurrent headaches in adolescents include lack of physical activity, being overweight, use of alcohol and caffeine, exposure to tobacco, and poor sleep habits (50).

Relaxation, biofeedback, psychological treatments. Cognitive-behavioral therapy, relaxation, meditation, and hypnosis have all been used with varying degrees of success. Although it is still not certain which children will benefit most from these therapies, a study that used network meta-analysis confirmed that these categories of nonpharmacologic therapies (lumped) were effective for pediatric migraine, but when categories of treatment were separated into components (split), the treatment effect was no longer statistically significant (35).

Neuromodulation. Neuromodulation devices are unproven in children. Based on the relatively good efficacy and the low rate of side effects in adults, repetitive neuromuscular magnetic stimulation for migraine prevention and remote electrical neuromodulation for acute migraine might be effective and acceptable to children (11). A 2023 study of remote electrical neuromodulation that used the device Nerivio® (FDA-authorized for the treatment of migraineurs aged 12 years and older) recruited 1,629 adolescents (average age 15.9 years, 80.6% female). For the measures 2 hours following Nerivio treatment in groups that used only the remote electrical neuromodulation without rescue medication, consistent pain relief occurred in 60.3% of 262, consistent pain freedom in 26.3% of 289, and consistent relief of functional disability in 41.2% of 255 users. Consistency was defined as the response occurring in at least 50% of treatments (18). It should be noted that this study included no control groups or sham treatments (18). The remote electrical neuromodulation Nerivio device is a nonpharmacologic abortive migraine treatment that requires a prescription. It is a battery-operated device controlled by a smartphone app. By contrast with neuromuscular magnetic stimulation and remote electrical neuromodulation, several of the other neuromodulation procedures have side effects that are unlikely to be acceptable to children, particularly transcutaneous cranial-nerve stimulation of the vagus, trigeminal, or occipital nerves. Therefore, repetitive neuromuscular magnetic stimulation and remote electrical neuromodulation are likely to undergo more studies to treat migraine in children.

Special considerations

Pregnancy

Migraine is sometimes relieved or exacerbated by pregnancy, but migraine does not have a direct adverse effect on pregnancy. However, migraine treatments are potentially harmful (eg, ergotamine may cause uterine contractions). Nondrug treatments such as biofeedback are preferred. Acetaminophen is generally safe for acute attacks. Ondansetron can help decrease the nausea and vomiting and is safe during pregnancy. Noting the potential risks of using medication during pregnancy (eg, teratogenicity), other options for treatment include a 6-day taper of prednisone (following 12 weeks’ gestation), metoclopramide, or prochlorperazine. Fluoxetine has been used as a migraine-preventive agent during pregnancy. However, because adverse pregnancy outcomes have occurred when selective serotonin reuptake inhibitors have been used to treat depression during pregnancy, caution must be exercised when treating migraine.

Anesthesia

Interactions between antimigraine therapy and anesthetic agents should be considered.