Migraine in children and adolescents

Abstract

This narrative review explores recent advances in the study of migraine with an emphasis on its complex polygenic aetiology, pathogenesis, clinical presentation, and the potential for new specific mechanism‐based treatments in children and adolescents. The polygenic aetiology and complex pathogenesis of migraine make its clinical presentation subject to the influences of intrinsic physiological and psychological factors as well as extrinsic environmental and lifestyle factors. In addition to variation in the clinical presentation of migraine in children, several disorders, such as abdominal migraine, cyclical vomiting syndrome, benign paroxysmal vertigo, benign paroxysmal torticollis, and infantile colic, are considered under the wide umbrella of childhood migraine syndrome. Advances in the study of migraine pathophysiology have identified the important roles of several neurotransmitters and opened the way for the development of new specific medication to treat migraine episodes and for prevention. In the absence of reliable biomarkers, clinical assessment remains the backbone for the diagnosis and assessment of migraine. With better understanding of the complexity of migraine pathophysiology comes the realization that no single drug will solve all the problems of the disease for all patients.

Abbreviations

CGRP

calcitonin gene‐related peptide

FHM

familial hemiplegic migraine

What this paper adds.

• Migraine is not just a headache; each episode consists of several clinical phases and variable symptoms.

• Several paroxysmal disorders are closely related to migraine and may share its aetiology and pathogenesis.

• Mechanism‐based treatment for migraine may soon be available for children.

• Because of the complex pathophysiology of migraine, no single drug can solve all the problems for all patients.

The first edition of the International Classification of Headache Disorders published in 1988 made population‐based studies possible and allowed better understanding of the epidemiology and impact of migraine and other related syndromes on children's quality of life. Advancement in neuroimaging, biochemical assays, and molecular genetics led to a better understanding of the pathophysiology of migraine and helped in the development of mechanism‐based medications for specific effective treatments and possibly with a better safety profile and tolerability.

The clinical presentation of migraine in a genetically predisposed individual is variable and can be influenced by intrinsic factors such as the patient's age, sex, stage of brain development, physiological changes, such as puberty, pregnancy, and menopause, and associated comorbid physical and psychological disorders, as well as extrinsic factors, including environmental, social and family factors, early life experiences, schoolwork, and peer pressure. ¹ Certain lifestyle characteristics may also have a role in the presentation of migraine, such as a sedentary lifestyle, screen time, sleep and meal routine, smoking, and alcohol and substance misuse. ²

Taking a full clinical history from children and their adult carers is an essential skill for making appropriate assessment and diagnosis of different headache disorders. ³ The clinical features of migraine may vary slightly in young children compared to adolescents and adults, while maintaining the core characteristics of the disease. Pain, nausea, vomiting, sensory impairment, visual, auditory, and vestibular disturbances, and autonomic and vasomotor changes occur in variable combinations and severity. ⁴ Full resolution of symptoms between episodes is an important characteristic feature of migraine.

EPIDEMIOLOGY AND CLASSIFICATIONS

The studies of the epidemiology of migraine and the classification of headache disorders are interdependent. Well‐defined and internationally acceptable criteria for the classification and diagnosis of headache disorders and migraine are essential for robust and reliable epidemiological studies. Also, population‐based studies with comprehensive data on the clinical features of migraine from unselected childhood populations are essential for the construction of reliable classifications and criteria for the diagnosis of migraine to capture the full spectrum of the disease free from any selection bias that may arise from the study of specialist clinics' populations. The first edition of the International Classification of Headache Disorders in 1988 started the process and the third edition in 2018 brought improvements gained from epidemiological studies in the intervening period (Table 1). ⁵ .

Table 1.

Migraine classification according to the International Classification of Headache Disorders, Third Edition. ⁷

Migraine type	Complications and associated syndromes
Migraine without aura Migraine with aura Migraine with typical aura Migraine with brainstem aura Hemiplegic migraine Retinal migraine	Complications of migraine: a Status migrainosus Persistent aura without infarction Migrainous infarction Migraine‐aura‐triggered seizure
Chronic migraine Probable migraine Probable migraine without aura Probable migraine with aura	Episodic syndromes that may be associated with migraine: Cyclical vomiting syndrome Abdominal migraine Benign paroxysmal vertigo Benign paroxysmal torticollis Infant colic

^a Rarely seen in children and adolescents (mostly in adults).

Classification based on headache frequency introduced the concept of chronic migraine, which was defined as headache occurring on at least 15 days per month, of which at least 8 days of migraine on 3 consecutive months; by default, the term episodic migraine refers to migraine occurring on less than 15 days per month. ⁵ Further subclassification of episodic migraine is proposed into high‐frequency episodic migraine (when headache occurs on ≥8 days and ≤ 14 days per month for more than 3 months, of which at least 4 days per month, has the features of migraine) and low‐frequency episodic migraine if patients have fewer than 4 migraine days per month. ⁶

The prevalence of migraine is estimated at 8% to 11% in children and adolescents across the world, increasing steadily with age from less than 2% at age 5 years to around 20% by the late teens, with a clear female preponderance in adolescents aged over 12 to 14 years. ⁷ , ⁸ Migraine is reported in all ethnic groups and socioeconomic backgrounds and it is a leading cause of disability in children and adolescents aged 5 to 19 years, as shown in the study of the Global Burden of Disease (1990–2021). ⁹

AETIOLOGY AND PATHOGENESIS

Although there are only a few studies on the pathophysiology of migraine in children, there is no reason to believe that it is different from migraine in adults. Children commonly inherit migraine from their parents, they grow up to have the same disease as adults, and they pass it on to their own children.

Population and twin studies showed a high prevalence of migraine among first‐degree relatives of patients with migraine and also a high concordance rates among monozygotic and dizygotic twins. ¹⁰ , ¹¹ Genome‐wide studies and next‐generation sequencing confirm migraine as a complex polygenic disorder in most cases, except for cases of familial hemiplegic migraine (FHM), where single‐gene mutations were identified and inherited as autosomal dominant traits. ¹¹ Patients with FHM also had first‐degree relatives with benign paroxysmal torticollis and benign paroxysmal vertigo.

Biochemical assays, functional neuroimaging, and single‐photon emission computed tomography studies helped in matching the clinical phases of the migraine episode with changes in neurotransmitters and pro‐inflammatory markers, as well as the activation of different structures in the brain. ¹²

Stimulation of the trigeminal ganglion and the trigeminal cervical complex in laboratory animals initiates migraine episodes mediated by several neurotransmitters, such as calcitonin gene‐related peptide (CGRP), pituitary adenylate cyclase‐activating polypeptide, serotonin, dopamine, glutamate, and others initiating and maintaining the clinical phases of the migraine episode. ¹³ In children, the neurotransmitters pituitary adenylate cyclase‐activating polypeptide‐38 and substance P may have a bigger role in the pathogenesis of migraine than CGRP. ¹⁴

The activated trigeminal cervical complex induces changes in the posterior hypothalamus, generating symptoms of mood change, yawning, tiredness, craving for food, sleepiness, and irritability, representing the premonitory phase, which lasts for a few hours to 2 days before the onset of headache. The aura phase follows the activation of the thalamus, the initiation of the cortical spreading depression, and a transient cerebral hypoperfusion that last for 5 to 60 minutes and are followed by the headache phase. Activation of the thalamocortical networks and dural and vascular nociceptive receptors heralds the onset of the headache phase. ¹⁵

CLINCIAL FEATURES OF MIGRAINE

Several characteristic clinical features of migraine with or without aura are present in all patients at all ages and are necessary for the diagnosis, mainly its episodic nature with resolution of symptoms between episodes. The whole episode can last from 2 hours to 3 days. There are several salient features that distinguish migraine in children from those in adults (Table 2). The clinical criteria for the diagnosis of migraine with and without aura are those of the International Classification of Headache Disorders, Third Edition (Table 3). ⁵ A diagnosis of probable migraine without aura or probable migraine with aura is made when the criteria for the diagnosis of the respective disorder are fulfilled except for one item. ⁵

Table 2.

Salient features of migraine in children.

Clinical feature	Effect of age
Short duration of episodes 2–72 hours	Less than 1 hour in about 10% of episodes. Duration of episodes increases with age
Frequency of episodes	Increases with age
Duration of episodes	Increases with age
Quality of pain	The younger the child the less able to describe the pain
Severity of pain	Assessed by the effect of migraine on child's activities
Trigger factors	Only 1 in 3 children may be able to identify a trigger
Vomiting	Slightly more common in younger children
Light and noise intolerance	Assessed by the child's behaviour; covers the eyes, avoids crowds
Mixed types of headache	10%–20% of children may also have tension‐type headache
Response to treatment	Variable, with large placebo response

Table 3.

Criteria to diagnose migraine subtypes ⁵ according to the International Classification of Headache Disorders, Third Edition.

Migraine type
Migraine without aura At least five attacks fulfilling criteria B–D Headache attacks lasting 2–72 hours (when untreated or unsuccessfully treated) Headache has at least two of the following four characteristics: unilateral location pulsating quality moderate or severe pain intensity aggravated by or cause avoiding routine physical activity (e.g. walking or climbing stairs) During headache at least one of the following: nausea and/or vomiting photophobia and phonophobia Not better accounted for by another International Classification of Headache Disorders, Third Edition diagnosis	Migraine with aura At least two attacks fulfilling criteria B and C One or more of the following fully reversible aura symptoms: (1) visual, (2) sensory, (3) speech or language, (4) motor, (5) brainstem, (6) retinal At least three of the following six characteristics: at least one aura symptom spreads gradually over ≥ 5 minutes two or more aura symptoms occur in succession each individual aura symptom lasts 5–60 minutes at least one aura symptom is unilateral at least one aura symptom is positive the aura is accompanied, or followed within 60 minutes, by headache Not better accounted for by another International Classification of Headache Disorders, Third Edition diagnosis
Hemiplegic migraine Attacks fulfilling the criteria for migraine with aura and criterion B below Aura consisting of both of the following: fully reversible motor weakness fully reversible visual, sensory, or speech and language symptoms Familial hemiplegic migraine (FHM) Attacks fulfilling the criteria for hemiplegic migraine above At least one first‐degree or second‐degree relative has had attacks fulfilling criteria for hemiplegic migraine FHM1: A mutation on the CACNA1A gene has been demonstrated FHM2: A mutation on the ATP1A2 gene has been demonstrated FHM3: A mutation on the SCN1A gene has been demonstrated FHM4: Genetic testing has demonstrated no mutation on the CACNA1A, ATP1A2, or SCN1A genes Sporadic hemiplegic migraine No first‐degree or second‐degree relative fulfils the criteria for hemiplegic migraine	Chronic migraine Headache on ≥ 15 days per month for more than 3 months, and fulfilling criteria B and C Occurs in a patient who has had ≥ 5 attacks of migraine with or without aura On ≥ 8 days per month for more than 3 months, fulfilling any of the following: criteria C and D for migraine without aura criteria B and C for migraine with aura believed by the patient to be migraine at onset and relieved by a triptan or ergot DNot better accounted for by another International Classification of Headache Disorders, Third Edition diagnosis

The episode of migraine consists of five phases: premonitory symptoms, aura, headache, postdrome, and resolution (Figure 1). Each phase can vary in duration and the number and severity of symptoms because of factors related to the stage of brain development, myelination, network maturation, and also the ability of children to express their symptoms. In the genetically predisposed child, the migraine episode may arise after exposure to specific triggers such as a stressful situation, missing a meal or missing on sleep; however, in many children, there is no apparent trigger or the trigger is subtle and unrecognized.

Figure 1.

The phases of migraine episodes.

Premonitory symptoms are reported in about 50% (42%–67%) of children and consist of mood swings, irritability, yawning, craving for food, and heightened sensory perception. ¹⁶ The premonitory symptoms precede the aura or the headache phase by 2 hours to 2 days and may not be recognized by the children and their families as part of the migraine episode. Therefore, the symptoms may not be reported spontaneously unless clinicians enquire about them.

The aura phase is reported by 25% to 30% of children with migraine, commonly as visual disturbances, including blurred vision, tunnel vision, blind spots, distorted images, and flashing lights, commonly monochromic. ¹⁷ Sensory disturbances may include unilateral abnormal sensation (pins and needles) or lack of sensation (numbness). Speech disturbances (indistinct speech or dysarthria) and motor aura (unilateral drooping of face and limb weakness) are less common. Complex aura may be generated from the brainstem and include a combination of all of these symptoms as well as confusion, dizziness, and ataxia. The typical aura phase lasts for 5 to 60 minutes and it is followed by the headache phase, although in some patients the aura symptoms may persist into part of the headache phase. Children who are unable to describe aura using words may use drawings to illustrate their experiences. ¹⁸

The headache phase starts with a gradual increase in pain severity, reaching its peak in 30 to 120 minutes. The pain is throbbing in nature, but children may refer to it as ‘beating’, ‘hammering’, ‘pounding’, ‘banging’, or ‘just sore’. The severity of the pain is best assessed by its effect on the child's routine activities; the pain is considered mild if the child continues with activities as normal, moderate if the child is unable to perform some but not all activities, and severe if the child has to stop all activities and lies down in bed. The site of maximum pain is often reported on the forehead in children under the age of 12 years and unilateral in older children (Table 2).

Headache is often associated with loss of appetite, nausea, and vomiting at a slightly higher frequency in younger children than in adolescents. ¹⁹ Light and noise intolerance are common at all ages. Light‐headedness and dizziness are more often reported by adolescents than young children, probably because of the ability to describe the symptoms using words. Children usually lie down and want to be left alone in a dark and quiet room. They resist been touched or cuddled probably because of cephalic and cutaneous allodynia.

The migraine episode does not last forever and it comes to a gradual end either spontaneously or after successful treatment. Recovery starts with the easing of pain and the lessening of nausea, vomiting, and other symptoms.

The recovery phase may run over several hours to the whole day during which the child experiences postdrome symptoms of exhaustion, tiredness, cognitive difficulties, pallor, and sleepiness. ²⁰ On waking up from sleep the child feels fresh and returns to normality with resolution of symptoms and the start of the interictal phase.

Hemiplegic migraine

Hemiplegic migraine is a specific form of migraine with motor aura. It is relatively rare and its prevalence is not known. Criteria for the diagnosis are those in Table 3.

Hemiplegic migraine is either familial (FHM), inherited as an autosomal dominant trait due to mutations on the calcium channel gene CACNA1A (FHM1), the ATP1A2 gene (FHM2), the sodium channel gene SCN1A (FHM3), PRRT2 or no identifiable gene (FHM4), or sporadic hemiplegic migraine. ⁵ , ¹¹ However, the phenotypic spectrum of mutations on these genes can also encode several neurological disorders other than FHM, including, but not exclusively, episodic ataxia, epilepsy, and intellectual disability. ¹¹ , ²¹ , ²² , ²³ , ²⁴

Hemiplegic migraine tends to be infrequent but episodes are prolonged, causing anxiety to patients and relatives. Patients present with unilateral weakness on the face followed by the ipsilateral arm and leg. Motor weakness may be associated with visual aura and is followed or accompanied by severe headache, nausea, and vomiting. Weakness should be distinguished from hemisensory aura. The episodes may last several hours to 2 days. The diagnosis of hemiplegic migraine cannot be made on first presentation and investigations are warranted to show normal brain magnetic resonance imaging and magnetic resonance arteriography to exclude an ischaemic stroke. However, cerebral perfusion studies may show transient hemispheric hypoperfusion unrelated to any arterial territory during the aura phase followed by a transient hyperperfusion. ²⁵

Chronic migraine

Chronic migraine (Table 3) affects 1% to 2% of adolescents, but it is seen in more than 50% of patients in specialist tertiary paediatric headache clinics. ²⁶ Risk factors for developing chronic migraine are female sex, untreated or poorly treated episodic migraine, physical comorbidities (obesity, other chronic pain syndromes, and medication overuse), psychological comorbidities (anxiety, sleep disorder, mood disorders, depression), and adverse lifestyle issues (sedentary lifestyle, excessive screen time, smoking, substance misuse). ²⁷

Chronic migraine is associated with a high impact on the child's quality of life, school attendance, and education. Physical and psychological comorbidities make effective treatment a challenge.

CHILDHOOD SYNDROMES CLOSELY RELATED TO MIGRAINE

Several syndromes share clinical and epidemiological features with migraine and probably a genetic background. Criteria for diagnoses are given in Table 4 and a brief description of the syndromes is given below and in Table 5. ²⁸ .

Table 4.

Criteria for the diagnosis of syndromes related to migraine. ⁵

Syndrome
Infantile colic: Recurrent episodes of irritability, fussing, or crying from birth to 4 months of age, fulfilling criterion B Both of the following: episodes last for ≥ 3 hours/day episodes occur on ≥ 3 days/week for ≥ 3 weeks CNot attributed to another disorder
Benign paroxysmal torticollis Recurrent attacks in a young child, fulfilling criteria B and C Tilt of the head to either side, with or without slight rotation, remitting spontaneously after minutes to days At least one of the following five associated symptoms or signs: (1) pallor, (2) irritability, (3) malaise, (4) vomiting, (5) ataxia Normal neurological examination between attacks Not attributed to another disorder
Benign paroxysmal vertigo: At least five attacks fulfilling criteria B and C. Vertigo occurring without warning, maximal at onset, and resolving spontaneously after minutes to hours without loss of consciousness. At least one of the following five associated symptoms or signs: (1) nystagmus, (2) ataxia, (3) vomiting, (4) pallor, (5) fearfulness Normal neurological examination and audiometric and vestibular functions between attacks Not attributed to another disorder
Cyclical vomiting syndrome At least five attacks of intense nausea and vomiting, fulfilling criteria B and C Stereotypical in the individual patient and recurring with predictable periodicity All of the following: nausea and vomiting occur at least four times per hour attacks last for 1 hour, up to 10 days attacks occur 1 week apart DComplete freedom from symptoms between attacks ENot attributed to another disorder
Abdominal migraine At least five attacks of abdominal pain, fulfilling criteria B–D Pain has at least two of the following three characteristics midline location, periumbilical or poorly localized dull or ‘just sore’ quality moderate or severe intensity At least two of the following four associated symptoms or signs: (1) anorexia, (2) nausea, (3) vomiting, (4) pallor CAttacks last 2–72 hours when untreated or unsuccessfully treated DComplete freedom from symptoms between attacks ENot attributed to another disorder

Table 5.

Key features of migraine‐related disorders.

	Migraine	IC	BPT	BPV	CVS	AM
Age at onset	> 2 years	0–3 months	1–2 years	2–5 years	4–7 years	5–10 years
Prevalence	8%–11%	15%	NK	NK	2%	1%–4%
Duration of episode	2–72 hours	2–4 hours	2–48 hours	2–12 hours	2–72 hours	2–72 hours
Photophobia	+	+	+	+	+	+
Phonophobia	+	+	+		+	+
Phonophobia	+	−	−	−	+	+
Allodynia	+	+	−	−	+	+
Dizziness	+	−	−	+	−	−
Vasomotor	Pallor	Pallor	Pallor	Pallor	Pallor	Pallor
Nausea	+	−	+	+	+	+
Vomiting	+	−	+	+	+	+
Abdominal pain	+	+	−	−	−	+
Between episodes	Normal	Normal	Normal	Normal	Normal	Normal

Abbreviations: AM, abdominal migraine; BPT, benign paroxysmal torticollis; BPV, benign paroxysmal vertigo; CVS, cyclical vomiting syndrome; IC: infantile colic; NK, not known.

Infantile colic is an episodic disorder of pain, distress, vasomotor changes, intolerance to light (photophobia), noise (phonophobia), and touch (allodynia) and a return to normality between episodes. Infants with colic are more likely to have migraine as adolescents than infants without colic, as shown in a prospective follow‐up study of 1267 infants. ²⁹ Furthermore, mothers with migraine are more likely to have a child with infant colic than mothers without migraine. ³⁰

Benign paroxysmal torticollis presents with episodes of head tilt to one side associated with distress and pallor lasting for several hours to 2 days. Children are asymptomatic between episodes and have typical growth and development. Investigations show no abnormalities. Patients with benign paroxysmal torticollis are more likely to develop cyclical vomiting syndrome and migraine later in childhood and may have first‐degree relatives with hemiplegic migraine and mutations on CACNA1A and PRRT2. ³¹

Benign paroxysmal vertigo presents with episodes of distress, unsteadiness, and feeling dizzy. Children may lie on the floor or hold on to furniture or a parent with a frightened appearance on their faces. Examination during episodes may reveal nystagmus but examination is normal between episodes. The episodes last between a few minutes and several hours with return to normality in between. Investigations are normal with no intracranial lesions and normal vestibular function tests.

Over 28% of children with benign paroxysmal vertigo grow up to have migraine in early adulthood and 57% have a family history of migraine. ³¹ Some children with benign paroxysmal vertigo have FHM‐associated mutations. ³²

Cyclical vomiting syndrome is characterized by stereotypic episodes of intense nausea and vomiting lasting from several hours to 3 days, every 6 to 8 weeks, during which the child is unwell, sleepy and pale, and may be at risk of dehydration. ²⁸ Cyclical vomiting syndrome shares many clinical features, triggers, and relieving factors with migraine as well as a family history of the two disorders. Investigations exclude other underlying causes; between episodes the child returns to normal health. Around 50% of children continue with cyclical vomiting syndrome late in adolescence and early adult life; 46% have a current or past history of migraine. ³³

Abdominal migraine presents with episodes of recurrent central abdominal pain, nausea, vomiting, pallor, and sometimes headache. Although it is primarily a childhood syndrome, abdominal migraine is increasingly recognized in adult patients. By late teenage years, around 60% of children with abdominal migraine have a current or past history of migraine with or without aura. ²⁸

ASSESSMENT OF THE CHILD WITH MIGRAINE

In the absence of any confirmatory diagnostic test for migraine, the clinical history has a central role in the classification and diagnosis of headache disorders. An appropriate and complete clinical history and physical examination can identify red flags and exclude most serious underlying neurological disorders. In young children and those with inadequate verbal skills, many symptoms can be deduced from the child's behaviour during episodes.

Investigations and neuroimaging are only necessary in a small number of cases, especially in children with a brief history of progressive headache, persistence of symptoms between episodes, associated new neurological deficits, features of raised intracranial pressure (strabismus, persistent focal deficit, seizures, papilloedema), cerebellar dysfunction (ataxia, nystagmus, intention tremors), and in patients with atypical presentation of unclassified headache disorders. Prospective headache diaries can help in confirming the diagnosis and in monitoring disease progression and response to treatment.

The impact of migraine on a child's quality of life can be assessed using the Pediatric Migraine Disability Assessment and Pediatric Quality of Life Inventory 4.0 questionnaires, especially in children with high‐frequency headache. ³⁴ Screening for psychological comorbidities using the Generalized Anxiety Disorder‐7 for anxiety and Patient Health Questionnaire for Adolescents (modified for adolescents) for depression is necessary, especially for patients with difficult‐to‐treat migraine.

MANAGEMENT OF THE CHILD WITH MIGRAINE

Migraine in children continues to be underrecognized and undertreated. The limited treatment options, the unpredictability of children's response to current medications, the lack of good clinical trials, and the high placebo response make it difficult to obtain reliable evidence of efficacy for old and sometimes new treatments, making it harder for clinicians to recommend medications with proven efficacy.

Management of migraine episodes

Management of migraine episodes starts with avoiding trigger factors, avoiding aggravating factors (exertion, noise, and bright light), and access to adequate hydration. To achieve the best chance of treatment success, medications should be taken as early as possible after the onset of symptoms, in optimum doses, formulation, and route of administration.

Paracetamol (acetaminophen) and ibuprofen are widely available, cheap, safe, and effective first‐line treatment (Table 6) in over two‐thirds of patients. ³⁵

Table 6.

Treatment of migraine episodes in children and adolescents.

Treatment	Medication	Comments
First‐line treatment (simple analgesics)	10–15 mg/kg paracetamol (OT); 7.5–10 mg/kg ibuprofen (OT)	6–8 hourly, as needed, for both
Second‐line treatment (triptans)	10 mg sumatriptan (NS); 2.5/5 mg (OT) or 5 mg (NS) zolmitriptan	Licensed for over 12 years; maximum two doses per day
Third‐line treatment (triptan + NSAID)	85/500 mg sumatriptan/naproxen (OT); 10 mg sumatriptan (NS) + 10 mg/kg ibuprofen (OT); 5 mg zolmitriptan (OT or NS) + 10 mg/kg ibuprofen (OT)	Maximum of two doses of triptans per day
Future treatment (gepants)	75 mg rimegepant (OT); 30–60 mg atogepant (OT); 10 mg zavegepant (NS)	Currently licensed for adults over 18 years

Abbreviations: NS, nasal spray; NSAID, non‐steroidal anti‐inflammatory drug; OT, oral tablet.

Triptans (5‐HT_1B and 5‐HT_1D agonists) were introduced in 1990s as specific treatment of migraine after the discovery of the role of serotonin in migraine pathophysiology. Triptans, mainly sumatriptan, are relatively inexpensive, safe, and may offer an added value as a second‐line treatment, although their efficacy in the paediatric population is modest compared to that in adults. ³⁶

A combination of a triptan and a non‐steroidal anti‐inflammatory drug may offer extra benefit as a third‐line treatment. Prokinetic antiemetic drugs taken with oral medications can improve their absorption and efficacy via improved gastric emptying and relief of nausea and vomiting.

For effective and consistent treatment, an individual migraine management plan can be formulated and implemented at home and at school.

Adverse effects of triptans are usually mild and transient; however, because of the possible, although small, risk of vasoconstriction and ischaemic stroke, triptans are best avoided in patients with hemiplegic migraine and migraine with brainstem aura.

Caution should be exercised in using acute migraine medications because medication overuse headache can result from the use of acute treatment such as paracetamol and ibuprofen (on more than 12 days per month) or the use of opiates and triptans (on more than 10 days per month) for at least 3 consecutive months. ⁵

Several CGRP receptor antagonists, collectively known as ‘gepants’, were effective and superior to placebo in the acute treatment of migraine. ³⁷ Rimegepant, atogepant, ubrogepant, and zavegepant are now available and licensed in many countries for patients older than 18 years. Trials in the paediatric population are ongoing, but off‐label use of gepants in adolescents has shown a promising response. ³⁸ Gepants have a good safety profile; unlike triptans, they lack a vasoconstrictive property, making them safe in patients with cardiovascular risk and potentially for patients with hemiplegic migraine and migraine with complex aura.

PREVENTIVE TREATMENT OF MIGRAINE

The frequency and severity of migraine episodes may be reduced by adopting the ‘SEEDS’ strategy of Sleep hygiene, Exercise, Eating regularly, Dehydration prevention, and Stress management, as well as avoiding medication overuse and managing comorbid conditions.

Non‐pharmacological treatments are generally acceptable and often the preferred initial option by some families because of concerns about the adverse effects seen with several medications.

Cognitive behavioural therapy is an effective treatment for migraine in children when used as a principal treatment or in combination with pharmacological intervention such as amitriptyline. ³⁹ Other possible psychological interventions may include individual and group sessions of biofeedback, mindfulness, relaxation exercises, and hypnosis. However, efficacy, availability, and access to such treatments can be limited.

The need for preventive medications is assessed for each patient on an individual basis and the decision to start treatment is taken jointly by clinicians, and patients and their families, based on full information on available medications, the strength of evidence of their efficacy, safety, and tolerability. Preventive medications are usually indicated for patients with at least four episodes per month, if acute treatment is unsatisfactory and migraine impacts badly on quality of life, school attendance, and education. Currently available medications are not specific for migraine and the choice of the medication depends on the patient's age, sex, weight, and the patient's own preferences (Table 7). The treatment should be taken regularly for at least 6 to 8 weeks in an optimum dose before its efficacy can be judged. The need for continuing treatment should be assessed every 6 to 12 months.

Table 7.

Preventive medications in children and adolescents.

Drug	Action	Dose and frequency	Maximum daily dose	Main side effects
Pizotifen	5‐HT2A and 5‐HT2C antagonist	0.5–1.5 mg once at bedtime	1.5 mg	Sedation, increased appetite, weight gain
Propranolol	β‐Blocker	1–2 mg/kg/day split into two doses	3 mg/kg	Sleep and mood disorders, dizziness
Flunarizine	Ca++ channel blocker	5 mg once at bedtime	10 mg	Mood disorder, weight gain
Amitriptyline	Tricyclic antidepressant	0.25–1.0 mg/kg once at bedtime	75 mg	Sedation, dry mouth, weight gain
Topiramate a	Anti‐seizure medication	1–2 mg/kg/day; 1 or split in 2 doses	200 mg	Impaired cognition, fetal abnormalities, weight loss
Candesartan	Angiotensin II receptor antagonist	4–8 mg once daily	16 mg	Pain and ache, hyperkalaemia, cough
Fremanezumab	CGRP monoclonal antibodies	225 mg subcutaneously once a month	–	Constipation, pain at injection site, Not yet licensed for children
Rimegepant	CGRP antagonist	75 mg on alternate days	–	Nausea, allergy, Not yet licensed for children

Abbreviations: CGRP; calcitonin gene‐related peptide; 5‐HT, 5‐hydroxytryptamine.

^a Topiramate: not recommended in females of child‐bearing age.

Monoclonal antibodies against CGRP (eptinezumab, fremanezumab, and galcanezumab) or CGRP receptor (erenumab) are licensed for patients older than 18 years in many countries. Clinical trials in children and adolescents showed fremanezumab to be superior to placebo in the prevention of episodic migraine. ⁴⁰ Phase 3 trials on other CGRP monoclonal antibodies (erenumab, eptinezumab, and galcanezumab) are ongoing. If these trials produce favourable results as in adults, they will open the way for more treatment options for children with migraine.

Rimegepant taken on alternate days may also be a possible option for the prevention of migraine.

Phase 2 clinical trials on pituitary adenylate cyclase‐activating polypeptide monoclonal antibodies for the prevention of migraine in adults showed promising results in reducing migraine monthly days compared to placebo. ⁴¹ Clinical trials in children may take longer to realize.

OTHER TREATMENT OPTIONS FOR CHRONIC AND DIFFICULT‐TO‐TREAT HEADACHE

Greater occipital nerve block

Greater occipital nerve block interrupts pain signal transmission and reduces peripheral sensitization. The procedure is simple to administer and is relatively well tolerated. A recent systematic review of published open observational trials showed satisfactory pain relief in two‐thirds of children and adolescents with chronic migraine. ⁴²

Other cranial nerves, including the lesser occipital nerve, and the supratrochlear and supraorbital branches of the ophthalmic branch of the trigeminal nerve, may also be potential targets for nerve block.

Botulinum neurotoxin A

In pain management, botulinum neurotoxin A probably decreases exocytosis of the primary afferent fibres that transmit pain, inhibiting sensory nerve endings, reducing pain signals to the brain, and preventing activation and sensitization of central neurons. It may also reduce the release of pro‐inflammatory and excitatory neurotransmitters. ⁴³

Treatment is carried out according to the PREEMPT trial protocol in adults, giving 155 IU at 31 different sites around the head, back of the neck, and top of the shoulders. ⁴⁴ Published open studies of the use of botulinum neurotoxin A in the treatment of children and adolescents with chronic migraine showed a meaningful reduction of migraine frequency and severity, but more and larger double‐blind, placebo‐controlled trials are needed. ⁴⁵ Treatment is generally well tolerated and safe.

DISCUSSION

Migraine is a complex polygenic brain disorder whose clinical presentation and response to treatment are influenced by the child's age, brain maturation, and stage of myelination, and follows the biopsychosocial model. Migraine is the most common and most disabling neurological disorder in children and adolescents aged between 5 years and 19 years. Recent advances in the understanding of the pathophysiology of migraine identified several neurotransmitters as possible disease biomarkers and potential targets for treatment development. However, the diagnosis of migraine continues to be based on clinical assessment and fulfilment of clinical criteria.

Current available acute and preventive treatments of migraine in children are non‐specific, lack strong evidence of efficacy, and randomized clinical trials are often plagued with an unexplained high placebo response. CGRP antagonists and CGRP monoclonal antibodies have proved to be of value in the care of adults with migraine; their roles in children and adolescents are being currently assessed with several well‐designed randomized controlled trials. Other potential therapeutic targets may include medication blocking the action of the neurotransmitter pituitary adenylate cyclase‐activating polypeptide.

Future research on childhood migraine is needed in areas of non‐pharmacological treatment, psychological interventions, and behavioural modification, as well as exploring strategies to reduce and or harness the placebo effect.

DATA AVAILABILITY STATEMENT

Data derived from public domain resources.