Rudolph's Pediatrics, 22nd Ed.

CHAPTER 565. Migraine and Headache Disorders

Alyssa Ann LeBel and Anna Minster

Primary headaches, including migraine headaches and tension-type headaches, are common during childhood, often occur together in an individual, and are most frequently reported during adolescence. The reported prevalence for migraine headache is estimated at 3% for ages 3 to 7 years (males > females), 4% to 11% for 7 to 11 years (males = females), and 8% to 23% for 11 to greater than 15 years (females > males).¹ Children less than 3 years of age may have a forme fruste of migraine which presents as periodic irritability, head-banging or holding, change in sleep and behavioral patterns, abdominal pain, recurrent vomiting, and pallor. Reports of non-specific headache pain are even more common. By age 5 years, 20% of children report experiencing a headache, 40% by age 7 years, and 100% by age 16 years.²Most of these episodes are benign. However, recurrent headaches may present with severe pain, decreased academic performance and school absence, anxiety, depressed mood, family disruption, and high health care costs.

CLASSIFICATION/DIAGNOSIS

The criteria for the diagnosis of migraine vary, but most children have 2 or more of the following features: unilateral; throbbing quality; associated aura; abdominal pain, nausea, or vomiting; relief after sleep; and a positive family history. Unique features in children include shorter duration with sleep included as part of the duration, the increased incidence of bilateral location, especially frontal and bitemporal, and ability to include parental observation of photo- and phonophobia. Migraine without aura is most prevalent. For migraine with aura, visual symptoms are the most typical auras. An aura generally develops over > 5 minutes, may precede or accompany the head pain, or may occur without headache. It lasts no more than 60 minutes. Visual aura may be reported as brightly colored or moving lights, distorted images of the environment, scotomata, visual field defects, or fortification spectra.¹ Tension-type headache is classified based on adult criteria.³

The formal diagnosis of primary headache in children is based on clinical criteria modified in 2004 by the International Headache Society.^4,5

The criteria for migraine with and without aura are shown in Table 565-1.

Criteria for tension-type headache for children are still evolving but are based on description in adults^3,6 (see Table 565-2).

HEADACHE ASSESSMENT

The clinical interview is essential and includes both open-ended and structured questions about headache duration, location, frequency, intensity, quality, triggers (puberty, diet, worries) associated affect (“How did you feel when you had your last headache?”) and accompanying symptoms. Such a symptom checklist may include the following:

• Aches or pins and needles in arms and legs

• Dizziness: spinning, near-fainting

• Soreness in neck and shoulders

• Feeling of light bothering the eyes

• Seeing bright white or colored spots, flashes, wavy lines, or dark/black spots

• Feeling that sounds bother you

• Feeling tired, wanting to sleep

• Feeling sick to your stomach or throwing up

• Feeling hot and sweaty

• Feeling the heart beat very fast

These symptoms may variably accompany the pain or may occasionally occur independent of the headache. For chronic pain problems, data related to childhood disability are elicited, such as pain interfering with sports, homework, going out with friends or to parties, doing chores, watching television, playing video games, and attending school.^1,7

DIFFERENTIAL DIAGNOSIS

Most headaches in children are primary disorders, differentiated by history and examination from secondary headaches that may be associated with systemic or CNS infection, toxins, postictal period, hypertension, hypoglycemia, trauma, vascular thrombosis, intracranial hemorrhage, tumor, pseudotumor, hydrocephalus, Chiari malformation, and craniofacial disorders. The use of electroencephalogram (EEG), head computerized tomography (CT), and magnetic resonance imaging (MRI) in the evaluation of children with a normal or stable neurological examination and normal optic fundi is rarely useful.¹

Table 565-1. Criteria for Migraine with and without Aura

Migraine in children generally presents without aura (prevalence of 70% versus 15% for migraine with aura). Some migraine syndromes are common in children, including ophthalmoplegic migraine (third nerve paresis/palsy); complex migraine (transient neurological abnormalities); basilar-type migraine (Bickerstaff migraine)⁸; confusional migraine (most common in adolescence; with aphasia); and Alice-in-Wonderland syndrome (headache with visual illusion and spatial distortions).

Epilepsy and migraine headaches, 2 paroxysmal disorders, may coexist in an individual. However, nonepileptiform EEG abnormalities are also common in patients with migraine and do not establish a seizure diagnosis. As in adults and especially in female adolescents, visual symptoms may not be associated with headache—migraine sine hemicrania. Acute confusional migraine, which may present with unexpected stroke-like symptoms (dysphasia and aphasia), is a benign migraine variant but always prompts a neurological evaluation.^1,5,6

Table 565-2. Criteria for Tension-Type Headache

Migraine variants or “childhood periodic syndromes” are much more prevalent in children, may precede the development of common migraine, and may occur in a patient with a family history of migraine; initially headache may not be a prominent feature. Such disorders are benign and include paroxysmal vertigo (brief episodes presenting before 6 years of age with transient instability with or without nystagmus), paroxysmal torticollis (recurrent head tilt with nausea and vomiting; rare), abdominal migraine (recurrent abdominal pain and nausea and vomiting without headache with negative gastrointestinal and metabolic evaluations), and cyclic vomiting (stereotypical, frequent episodes with mean age of onset of 5 years, with severe vomiting and dehydration; no headache).⁶ In one recent report of 5848 children seen over an 8-year period, 1106 were identified with migraine, of which 108 (9.8%) had migraine equivalents.

A separate primary headache category is chronic daily headache (CDH), which includes tension-type and persistent migraine headaches. CDH is present for more than 15 days per month for 3 consecutive months. Chronic tension-type headache may be concurrent with infection, head trauma, or environmental stress or begin without any precipitating factors. Chronic migraine usually evolves from episodic migraine and may be exacerbated by medication overuse, defined as symptomatic agents used for more than 10 to 15 days per month. The appropriate approach to this problem is abrupt discontinuation of the overused medication, with anticipation of improvement within 2 months. Status migrainosus refers to severe migraine symptoms for more than 72 hours.

Headaches may also be classified as 1 of 4 temporal patterns: acute, acute recurrent (usually migraine), chronic progressive, and chronic nonprogressive (usually tension type). Chronic progressive headache is often due to a secondary etiology, with concern for changes in intracranial pressure, or infection.^5,6 Secondary causes may be suggested by the following historical red flags:

• New headache less than 1 year history or headache in a child 5 years or longer

• Sudden onset, high intensity

• Headache that wakens child in middle of night and not relieved by sleep

• Change in established pattern of headache

• Headache with new neurologic deficit

• Headache triggered by cough, squatting, valsalva, exertion

• Unexplained headache with fever

• Absence of family history

• Headache in immunocompromised child¹

One rare genetic pediatric headache syndrome, familial hemiplegic migraine (FHM), is a possible window into the still enigmatic molecular and cellular origins of migraine headache. It is discussed below.

PATHOPHYSIOLOGY OF MIGRAINE

The current model of migraine is the neurovascular theory, best supported clinically by patients with migraine with aura. Increasing evidence supports the concept that cortical spreading depression (CSD) is associated with migraine aura. CSD is a brief depolarization wave that moves across the cortex at a rate of 3 to 5 mm/minute, followed by nerve cell depression, accompanied by a loss of neuronal and glial membrane resistance, disruption of ionic gradients, and release of glutamate and other excitatory neurotransmitters. Alteration in neocortical function with CSD most frequently begins in the occipital region with subsequent activation of trigeminal afferents, trigeminovascular neurogenic inflammation, and neuronal excitation in the trigeminal brain stem nuclear complex (TBNC). Sensory information is subsequently transmitted to the thalamus and multiple diencephalic, limbic, and brain stem areas, including the periaqueductal gray, nucleus raphe magnus, and reticular formation. These areas are involved in the regulation of autonomic, endocrine, affective, and motor functions, and their activation may result in familiar symptoms such as photophobia, nausea, vertigo, fatigue, and dysphoria. Cortical activity ultimately determines and modulates pain perception. Dysfunction of the trigeminal system, peripheral and central, results in central neuronal sensitization, which may then persist for hours as well as for several months in the case of chronic daily headache. A possible clinical correlate of central sensitization is cutaneous allodynia of the scalp and face. If peripheral and central neuronal activation of the trigeminal system is prolonged, psychologic and pharmacologic therapies are less effective.⁶

Migraine susceptibility is believed to be inherited, with its presentation modified by both internal and environmental factors, although specific generic loci are not readily identified in most families with migraine headaches. However, in FHM, at least 3 loci have been documented by linkage analysis. FHA is an autosomal dominant form of migraine with aura, with a variable presentation of hemiparesis, ataxia, and nystagmus. Some headache episodes may resemble confusional migraine. Cerebellar atrophy may be seen on MRI. The first gene identified with FHM was CACNAlA on chromosome 19p13 (FHM1). It encodes for the alpha-1A subunit of the PIQ-type voltage-gated calcium channel. Mutations in the CACNAlA gene may also be associated with other autosomal dominant neurological disorders, such as episodic ataxia type-2 and spinocerebellar atrophy type-6. Some affected family members within this evolving spectrum show seizures, mental retardation, and severe cerebral edema following mild head trauma. Another specific FHM polymorphism involves ATP 1A2 (FHM2) on chromosome lq23, which encodes the alpha-2 subunit of the NA+/K+ pump. FHM 3 is associated with the SCN1A gene on chromosome 2q24, which encodes the alpha-1 subunit of a neuronal voltage-gated sodium channel. Further FHM linkage studies have excluded these 3 loci, suggesting additional heterogeneity of this disorder.⁹ The calcium channels implicated in FHM are known to regulate glutamate and other neurotransmitter release in the regulation of the cortical neuronal hyperexcit-ability, possibly contributing to the phenomenon of cortical spreading depression. These channels also control the release of calcitonin-gene-related polypeptide from trigeminovascular afferents and are localized to the descending nucleus of the trigeminal nerve in the medulla and upper cervical spine. They are well positioned for modulation of head and neck pain. However, their precise pathophysiologic contribution to headache is still under investigation. Clinically, nonspecific calcium channel blocking agents have currently been of some benefit for patients with FHM.¹⁰

TREATMENT OPTIONS

Treatment of all primary headaches includes both pharmacologic and nonpharmacologic therapies. It is initiated with patient and family education, removal of identified triggers, and modification of disruptions in lifestyle, such as decreased school attendance, physical inactivity, and nonrestorative sleep. Education includes reassurance that a serious secondary pathology is absent and explanation of the basic physiology of migraine and tension-type headache as it relates to individual symptoms. For example, often disturbing phenomena, such as visual and sensory aura, vertigo, photophobia, and cutaneous allodynia, may be demystified. Adjustment of unrealistic expectations for immediate and complete pain relief, especially for patients with chronic daily headaches, may be useful, as well as discouraging sole reliance on medications. Overuse of symptomatic analgesics is as prevalent in pediatrics as in the adult population, and analgesic rebound headache may contribute to a chronic pain disorder. However, prophylactic medications will be ineffective if not taken daily, whether or not headache symptoms are present. In general, attention to good health habits is the primary therapy.

• Hydration: Children and adolescents need at least 4 to 8 glasses of fluid per day. During a headache or increased activity, sports drinks with glucose and electrolytes are recommended. Beverages with low-dose caffeine (30 to 100 mg) may also be used for regular hydration.

• Diet: Children do best with regular and balanced meals. Foods that trigger headache are individual, and general exclusionary diets are not indicated.

• Sleep: Fatigue and overexertion may trigger headaches. Most children require 8 to 10 hours of uninterrupted sleep per night and a regular sleep schedule.

• Activity: Sensible child activity schedules, without overcrowding or exposure to stressful situations, are reasonable.

• Counseling: Although all children with recurrent headaches may benefit from psychological counseling or cognitive-biobehavioral therapy, an early referral is considered for those driven to excel at school or extracurricular activities, those with interpersonal challenges, or those with preexisting psychological disorders, such as depression and/or anxiety.^11,12

ACUTE MANAGEMENT

The goals of acute treatment are to reduce immediate pain and accompanying symptoms and to prevent recurrence or rebound. The pharmacologic agents with the most established efficacy are ibuprofen and acetaminophen. In a recent practice parameter published by the American Academy of Neurology (AAN), authors reviewed 166 articles from 1980 to 2003 with an age qualifier of 3 to 18 years and a 4-tiered scheme of evidence classification (Class I to IV) and recommendation (Levels A through C, U). The recommendations were

• Ibuprofen effective (Level A)

• Acetaminophen probably effective (Level B)

• Sumatriptan nasal spray effective for adolescents (Level A)

• No data for oral triptans (Level U)

• Inadequate data for subcutaneous sumatriptan (Level U)¹¹

This review highlighted the need for “multi-centered, placebo-controlled clinical trials to assess the safety, tolerability, and efficacy of medications” used for the treatment of pediatric migraine, an often cited deficiency in general pediatric pharmacology. Therefore, choices of acute medications are still, in part, based on adult patient guidelines, although there are increasing numbers of controlled, blinded, and open-label pediatric trials showing safety and efficacy of triptans in children 12 years or older.^12,13 There are no trials comparing the efficacy among the various triptans available. As in most pediatric headache studies, placebo effects may be as high as 50%, necessitating a large sample size to confirm efficacy.

For mild to moderate pain and minimal nausea, preferred agents are nonsteroidal anti-inflammatory drugs (NSAIDs) and acetaminophen. For severe pain, opioids may be judiciously used as well as nasal sumatriptan. Oral triptans and adult combination medications such as Fiorinal® (butalbital, acetaminophen, and caffeine) and Midrin® (isometheptene, acetaminophen, and dichloralphenazone), although not FDA approved, are potential options for children over 12 years.¹⁴ For nausea and vomiting associated with headache, diphenhydramine and hydroxyzine are least likely to be associated with adverse effects, such as the mood changes and dystonia potentially noted with chloropromazine, metaclopromide, and ondansetron. If the patient has intractable and severe pain or nausea and vomiting, intravenous (IV) administration of promethezine, 0.25 to 0.5 mg/kg/dose (max 25 mg), or ondansetron 0.15 mg/kg (max 4 mg), added to a bolus of IV fluids, may be effective and repeated every 6 to 8 hours over a 24- to 48-hour period. Intravenous ketorolac tromethamine, although not studied in controlled trials in pediatric migraine, is used effectively for postoperative pain in children weighing more than 8 kg at a dose of approximately 0.5 mg/kg or 30 mg for an adolescent weighing more than 50 kg. This NSAID is now the preferred analgesic for the emergency treatment of adult migraine patients¹⁵ (Table 565-3).

CHRONIC MANAGEMENT

Prophylactic and daily medical therapy are indicated for children with a minimum of 2 to 3 severe headaches per month associated with functional disability, such as school absence or withdrawal from desirable activities. The choice of appropriate agent, as previously described with symptomatic medications, is currently supported primarily by adult studies and the use of the same agents for nonpainful conditions, such as seizures. All prophylactic medications have potential adverse effects, some of which may be useful, such as sedation or appetite suppression/stimulation. These agents require slow titration, frequent monitoring, anticipation of side effects, and delay of patient and family gratification.¹²

Table 565-3. Acute Treatment of Migraine

In the AAN practice parameter described earlier, evidence for preventive treatment of headaches is limited:

• Flunarizine probably effective (Level B) but not available in the United States

• Insufficient evidence to recommend cyproheptadine, amitriptyline, divalproex sodium, topiramate, or levitiracetum (Level U)

• Pizotizem, nimodipine, and clonidine showed no efficacy (Level B) and not recommended

• Propranol and trazadone with conflicting evidence (Level U)¹¹

Current adult literature supports beta-blockers, amitriptyline, and valproic acid as the most effective agents. Second-tier agents include other antidepressants and antiseizure medications and calcium channel blocking drugs. Selective serotonin-reuptake inhibitors, such as fluoxetine, sertraline, citalopram, escitalopram, venlafaxine, and trazadone, are best used for associated symptoms, such as anxiety, sleep disturbance, and mood disorder. The data for analgesic efficacy are anecdotal, as is the benefit of cyproheptadine in prepubertal patients. Trazadone has shown some efficacy in pediatric trials^6,16,17 (Table 565-4).

Table 565-4. Chronic Treatment of Headache

Although data are currently limited regarding the efficacy of these modalities, the use of occipital nerve blockade, acupuncture, and botulinum toxin injection for intractable headaches is reported in a few open-label and case-controlled trials. There is controlled-trail data for the use of some supplements and herbs: magnesium 300 to 600 mg/day; riboflavin 25 to 400 mg/day; feverfew (tenacetum parthenium) 10 to 100 mg/day; butterbur (pestasites hybridus) 25 to 75 mg/day; coenzyme Q10 25 to 300 mg/day.^18-22

Nonpharmacologic therapies, such as cognitive biobehavioral therapy, biofeedback, relaxation techniques, and self-hypnosis, have robust controlled-trial support, are unencumbered by side effects, and are the primary recommendation for patients with acute severe and chronic intractable headaches. These modalities modify the multiple factors that trigger migraine attacks, exacerbate pain, prolong disability, and maintain the cycle of repetitive headache episodes. Biobehavioral therapy is clearly indicated for all patients with severe pain disorders, as these problems are often associated with reactive anger, frustration, anxiety, and functional impairment. Family therapy may also aid caretakers in discouraging pain/illness behaviors, reinforce healthy lifestyle choices, and understand the spectrum of pain treatment modalities. Finally, physical therapy may address a musculoskeletal contribution to tension-type headache and improve patient posture and conditioning.⁷

SUMMARY

Recurrent primary headaches are a common pediatric disorder, generally manifest as either migraine or tension-type head pain but also sometimes presenting as gastrointestinal, vestibular, and focal neurologic symptoms, currently described as migraine variants. Accurate diagnosis eliminates the concern for secondary etiologies and facilitates rapid treatment, balanced between biobehavioral and pharmacologic therapies. Family education and support are essential to reduce analgesic overuse, delay in acute treatments, and functional disability. Increasing numbers of controlled pediatric trials in headache therapy will inform our current therapeutic choices and reduce dependence on adult data.