Migraine Headache in Childhood

Etiology

Migraine is a primary headache disorder and a common, recurrent, disabling condition affecting an estimated 18% of women and 6% of men. There are commonly reported triggers that can induce migraine, namely stress, fatigue, various foods, alcohol, drugs, smoking, weather changes, and odors. Recent studies also provide new insights into the underlying pathophysiology and genetics of migraine that would provide novel pharmacotherapies for management and prevention.[7] Children with migraine have a genetic predisposition activated by an environmental or physiological stimulus. These stimuli include exposure to drugs, diet, stress, or puberty. Most children with a history of migraines seem to have a positive family history.[8] Some studies have shown genetic contributions.[9] However, it is not fully proven yet. Genetic etiology is certain for certain types of migraines, such as hemiplegic migraine. Mutations have been reported in CACNA1A (calcium channel), ATP1A2 (Na/K-ATPase), and SCN1A (sodium channel) genes resulting in the development of hemiplegic migraine.

Migraine is considered a strongly heritable disorder. Studies investigated the age of onset of migraine between successive generations. The age of migraine onset was significantly lower in the children with a history of maternal or paternal migraine than in their parents. Findings revealed that parental history of migraine showed that children with migraine were significantly younger at the first appearance of migraine than their affected parents.[10] Migraine is perceived to affect the relationship between the parent and child. A parent with migraines increases a child's risk of having a more severe migraine disease. However, children with migraine whose parent also has migraine seem to receive more early and aggressive treatment. The effect of migraine goes beyond the parent with migraine and influences children across biological, psychological, and social domains.[10]

Epidemiology

Migraine is 1 of the most burdensome primary headache disorders in the pediatric population.[11] Epidemiologic data can help us to understand its scope and distribution. Knowing the sociodemographic and environmental risk factors usually helps us to know which groups are at risk of migraine. Prevalence ranges from 5% to 40% in the pediatric population. In the United States, migraine is diagnosed in 5% of children by age 10, with an estimated prevalence rate of 10%.[12] The prevalence increases with age and reaches 80% when they transfer to adult neurologic care. Before puberty, no sex differences exist, but in later adolescence, females predominate.[13] Another study showed that migraine prevalence estimates vary from 1% to 3% at 7 years and 4% to 11% at 7 to 15 years. Before puberty, there is an equal prevalence in girls and boys, but after puberty, the prevalence is 2 to 3 times more common in girls.[14] 

Data from ∼1.2 million children and adolescents in Germany revealed that the incidence of migraine increased with age, reaching about 1% per year around the age of 10 for both sexes, 3.49% per year in females, and 1.72% per year in males at the age of 19. Incidences in males and females were the same until 13 years of age but higher in females.[7] Pooled data from China, Japan, and South Korea revealed that the overall prevalence of migraine increased with age. There were reports on the significant association of migraine with high levels of disability and negative effects on quality of life. Studies suggested low levels of disease awareness/diagnosis within each country studied. Moreover, findings showed that over-the-counter medication use was high and prescription medication use was low in each country, which suggested that there are unmet needs for migraine in terms of sufficient and appropriate diagnosis and better management and therapies for the treatment of migraine in East Asia. There is also a need to conduct population-based studies assessing disease burden and clinical management of migraine to confirm unmet needs across East Asia.[15]

Migraine in children below 7 years of age is challenging for clinicians. As there are only a few studies in this age group, we have shown that migraines in this age group affect up to 4% of the general population. This is most likely underestimated due to the lack of specific diagnostic markers, the frequent difficulty of describing pain in childhood, and the necessity of reliable parental reports. Recent findings showed that migraines have some differences, especially in clinical and therapeutic terms, in this age group compared to subsequent ages. Current literature also showed that the onset of migraine in younger children might play an unfavorable role in its natural history; therefore, early identification and management of migraine is vital to the point of considering the factors of prenatal and perinatal development in the predisposition and anticipation of migraine onset.[16]

A study for the association between preterm categories and migraine in Finland revealed no evidence for a greater risk of migraine among individuals born preterm. Migraine was predicted by parental migraine, lower socioeconomic position, maternal hypertensive disorder, and maternal smoking during pregnancy.[17] Migraine and epilepsy comorbidity are also being studied since they represent prevalent chronic childhood neurological disorders. Both diseases rely on the common pathophysiologic and genetic mechanisms of paroxysmal disorders, the similarity of their precipitating factors, clinical manifestations, and therapeutic approaches. Numerous genetic diseases accompanied by migraine and epilepsy could lean towards the shared pathogenetic mechanisms of these paroxysmal disorders in which genetically determined channelopathies may play a vital part. The efficacy of antiepileptic drugs has been proven as the prophylactic treatment of migraine in pediatric patients, as well as the advantages of levetiracetam as the prophylactic treatment for migraine and epilepsy comorbidity in children.[18]

Another study evaluated the prevalence of headache subtypes, epilepsy, atopic disorders, motion sickness, and recurrent abdominal pain among ADHD children and their parents. Findings showed that migraines were significantly common among children with ADHD and their mothers. This means that migraine is a vital part of ADHD comorbidity, not only for children but also for mothers.[19] Another study perceived that the security of attachment to the mother and the father mediated the association between migraine and anxiety and concluded that insecure parental attachment might exacerbate anxiety in children with migraine and points to the importance of multimodal interventions, especially family relationships.[20]

Other migraine comorbidities are atopic disorders such as allergic rhinitis, allergic rhinoconjunctivitis, and seasonal allergic rhinitis, as well as the disability caused by headache (ISAAC - International Study of Asthma and Allergies in Childhood; CARATkids - Control of Allergic Rhinitis and Asthma Test for Children; PedMIDAS - Pediatric Migraine Disability Assessment). Results showed higher scores on the PedMIDAS than those patients without atopy for children with current allergic rhinoconjunctivitis. There was also a significant positive correlation between CARATkids scores and PedMIDAS scores. Therefore, allergic rhinoconjunctivitis is correlated to enhanced disability caused by headaches among children with migraine.[21] Migraine was observed in 29% of 96 patients with sarcoidosis in another study. Among those with sarcoidosis, only the female sex was predictive of having migraine. There was no association between migraine and age, depression, dyspnea, immunosuppression use, or ESR.[22] 

Pathophysiology

Migraine is now considered a brain disease. In the past, it was thought of as a vascular disease. This new theory requires the brain to be genetically sensitive to migraine-inducing neurochemical changes that result in premonitory symptoms. Migraine consists of trigeminal vascular system activation wherein nociceptive neurons that innervate the dura release various vasoactive peptides, including the most active calcitonin gene-related peptide.[16] These neurochemical changes lead to trigeminovascular activation and, eventually, neurogenic inflammation.[23] This inflammation drops the threshold for trigeminal input entering the nucleus caudalis of the trigeminal nerve in the brain stem. These sensory changes from C1 and C2 dermatomes eventually synapse in the somatosensory and limbic cortices where conscious awareness of headache occurs.[24][25] 

The possible reason why children have more severe and cyclic vomiting compared to adults is related to their reduced cholinergic function. Centrally, the area postrema is considered the trigger zone and responds to circulating neuronal and chemical emetic stimuli. Peripherally, vagal pathways are involved in emetic stimulation. Emesis is coordinated via abdominal vagal nerve afferents that terminate in the tractus solitaries nucleus. Signals are mediated by multiple cholinergic and adrenergic neurotransmitters, mainly 5-HT, 5-hydroxytryptamine, which binds to the 5-HT3 receptor, and substance P, which binds to the neurokinin-1 receptor.

Copeptin is a hypothalamic stress hormone synthesized in the hypothalamus with arginine-vasopressin and circulated from the neurohypophysis in equimolar amounts and can indicate the individual stress level. Studies revealed that copeptin levels were significantly higher in patients with childhood migraine. The specificity and sensitivity of copeptin for 249.5 pg/dL cut-off value predicting the diagnosis of migraine were 67% and 64%, respectively. Plasma copeptin levels tend to increase in childhood migraine due to increased oxidative stress.[26]  

In line with an imbalance in cortical excitability, GABA-edited Magnetic resonance spectroscopy (MRS) studies revealed that children (7 to 13 years) with migraine and aura had significantly lower glutamate levels in the visual cortex. Also, higher GABA levels were correlated to a higher migraine burden and higher glutamate in the thalamus. Higher GABA/Glx ratios in the sensorimotor cortex were related to longer migraine attacks. Lower GABA levels in the sensorimotor cortex were connected with being closer to their next migraine attack. Overall, this implied that GABA and glutamate disturbances occur early in migraine pathophysiology and emphasizes that adult migraine cannot be immediately correlated with pediatric patients.[27]

The most common comorbidity with migraine in childhood is sleep disorders. There is a greater prevalence of parasomnias, obstructive sleep apnea, and sleep-related movement disorders in children migraineurs. This can be attributed to the bidirectional relationship between migraine and sleep disorders based on their shared pathophysiology. The structures and networks of the cerebral and neurochemical systems involved in migraine are closely related to those responsible for sleep regulation, particularly adenosine, melatonin, orexin, and calcitonin gene-related peptides.[16] A study evaluated the potential correlation between migraine and sleep disorders in children, as reflected by sleep architecture and electroencephalographic patterns. All children had inpatient full-night polysomnographic recordings. Those in the migraine group had decreased REM sleep, increased N1 sleep percentages, more arousal, and lower sleep latency, thereby establishing the significant relationship between migraine and sleep disorders using polysomnography.[28]

The function of the insula, the hypothalamic-pituitary-adrenal axis, the serotonergic system, and the unstable hyperactivated neural networks may trigger the pathophysiology of both migraine and its psychiatric comorbidities. It is unclear whether the symptoms of anxiety and depression are comorbid with migraine in children due to the overlap between migraine symptomatology and that assessed by many screening tools. However, functional neurologic disorders such as psychogenic non-epileptic seizures (PNES) and other functional movement disorders are not common but can be comorbid with migraine in children and tend to improve with migraine treatment. A study revealed that a child's exposure to adverse childhood experiences (ACEs) appears to be near-linearly associated with the risk of migraine but not with tension-type headaches (TTH). The findings stressed the importance of choosing the appropriate screening methodologies for identifying psychiatric disorders in children with migraine.[29] 

An evaluation of hypertension in children with migraine by performing ambulatory blood pressure monitoring (ABPM) showed that although the frequency of hypertension was not higher, abnormal ABPM patterns were significantly more frequent in the migraine group (migraine, 45.9%; control, 16.7%; p, 0.018). At the same time, nighttime means arterial blood pressure, nighttime diastolic blood pressure, and the non-dipping pattern was greater in children with migraine than those in the control group (p < 0.05).[30] 

Some studies evaluated the clinical interdependency of myofascial trigger points and migraine in children, which would support an interaction of spinal and trigeminal afferents in the trigeminal-cervical complex as a contributing factor in migraine. Trapezius muscle trigger points were determined by palpation, and the threshold of pressure pain at the trigger points was obtained. Findings revealed an association between trapezius muscle myofascial trigger points and migraine, but in children, it can be induced by pressure to myofascial trigger points but not by pressure to non-trigger points in the trapezius muscle. Therefore, this supports the trigeminal-cervical-complex's involvement in migraine's pathophysiology, which might have implications for innovative treatment.[31]

History and Physical

The most common symptom in children is headache; therefore, a detailed history and a thorough physical examination are vital in diagnosing.[2] The patient must have at least 5 attacks that fulfill the criteria of migraine, which include duration of at least an hour to 72 hours, unilateral location, pulsating quality, moderate to severe in intensity, aggravated by activity, and at least 1 of the following: nausea or vomiting or photophobia and photophobia. There is a slight difference in migraine among children compared to adults because the latter is mainly frontal rather than temporal/occipital and bilateral rather than unilateral.[32]

A thorough physical examination is needed, including blood pressure measurement and palpation of the head in search of sinus tenderness and nuchal rigidity. A funduscopic examination is necessary for papilledema, hemorrhage, or other signs of increased intracranial pressure. A visual field examination should be done.[33] Head circumference is also a must despite the age of the child. Examine the skin for any neurocutaneous finding that could indicate possible neurofibromatosis and tuberous sclerosis, which are highly associated with resulting intracranial neoplasms and headaches. Vomiting is more prominent in the pediatric migraine population. A study by Barlow showed recurrent vomiting during their first 2 years in toddlers before migraine headaches start and other associated migraine symptoms. It is essential to administer the standard International Headache Society (IHS) questionnaire routinely for the child and the parents to complete.[34]

Evaluation

While the diagnosis of pediatric migraine is primarily clinical, lab testing and neuroimaging may be needed in certain circumstances.

Indications for Lab Testing

• Children with sickle cell disease may present with headaches in case of low Hgb. Blood work may be warranted for such patients.[35]
• A lumbar puncture may be performed if an inflammatory process or mitochondriopathy is considered the cause of the headache. Caution is advised while performing lumbar punctures as it can worsen the headaches by causing intracranial hypotension.[36]
• EEG may be performed in patients if there is clinical suspicion of seizures. Migraine-associated EEG abnormalities are relatively common: 10% to 75% in total (paroxysmal in 20% to 30%).[37]

Neuroimaging for Patients with Migraine Indications

• Any neurological deficits, including but not limited to seizures, reduced visual acuity, altered consciousness, and deterioration of motor skills.
• Enlarged head in an infant or toddler.
• Abnormal ophthalmological evaluation, such as visual field cuts, disconjugate gaze, or abnormal fundus.
• Headaches that always occur on 1 side (fixed unilaterally).
• Refractory headaches that last several days and are not responsive to treatment.

Treatment / Management

Migraine treatment is warranted in children if the headaches prevent the child from going through daily activities like going to school, playing, etc. Since migraine is prevalent in children and impacts the cause of their disability, effective treatment is likely to result in improved outcomes. Previous studies suggested that a biopsychosocial approach that applies interdisciplinary multimodal care is most effective for treating pediatric migraines. Key elements are effective and timely acute pharmacological interventions (such as NSAIDs or triptans), education of patients regarding self-management techniques, psychological interventions such as biofeedback, relaxation, and cognitive-behavioral therapy.[38](B3)

The treatment regimen can be both non-pharmacologic and pharmacologic. Non-pharmacologic measures include sleep hygiene patterns, diet, managing stress, exercise, and avoiding triggers. On the other hand, Pharmacologic treatment includes beta-blockers, calcium channel antagonists, serotonin antagonists, antidepressants, and antiepileptics.[32] Amitriptyline manifested a suitable effect on controlling headaches as well as adverse side effects. At the same time, nutraceuticals are found to be promising as effective drugs with fewer side effects. Coenzyme Q10 was observed to have promising therapeutic effects, especially in long-term use, with fewer side effects; however, amitriptyline presented a more rapid response.[39] Moreover, observational studies, randomized controlled trials, systematic reviews, and meta-analyses showed the efficacy and safety of single-compound nutraceuticals for managing migraine in children. The following nutraceuticals were reviewed: vitamin D, riboflavin, coenzyme Q10, magnesium, butterbur, and polyunsaturated fatty acids. However, due to low-quality evidence and limited studies, there were no definite conclusions on the efficacy of nutraceuticals for treating pediatric migraine.[40](B2)

Prophylaxis should be considered when migraine symptoms cause frequent school absenteeism, poor quality of life, recurring emergency room visits, and frequent analgesic use. Since the majority of the patients can be treated with lifestyle changes and acute attack prophylaxis, a study was conducted to compare the efficacy and side effects of drugs used in migraine prophylaxis, such as propranolol, topiramate, flunarizine, and cyproheptadine. There was a significant improvement in all drug groups, but topiramate was found to be the most effective drug in reducing the frequency of attacks. All 4 drugs in this study may be utilized for migraine prophylaxis in terms of effectiveness and safety, with palpitations as the most common side effect.[41] 

Triptans plus non-steroidal anti-inflammatory drugs (NSAIDs) reinforce triptan's effectiveness. lmotriptan and rizatriptan are effective as oral formulations. Meanwhile, sumatriptan and zolmitriptan are effective as both oral and nasal spray formulations. There are suggestions for considering dopamine receptor antagonists in cases of severe migraines.[42] A study evaluated the efficacy and safety of zolmitriptan nasal spray (ZNS) in treating migraine headaches in patients aged 6 to 11 years. Though the effect of high-dose ZNS on the primary endpoint of pain-free status at 2 hours was not statistically significant, ZNS was safe and well tolerated in this pediatric population.[43] In addition, ZNS is rapidly absorbed from the nasal mucosa and can contribute to the fast onset of action. ZNS with a 5 mg dose was more effective in relieving headache pain, photophobia, and phonophobia and was associated with a more rapid return to normal daily activities. Findings showed that ZNS was generally well tolerated, with no serious adverse events, and may benefit patients with nausea or who cannot easily swallow tablets.[44] (A1)

On the other hand, another study revealed that sumatriptan and zolmitriptan nasal spray are above placebo in the 2 efficacy outcomes, but almotriptan, rizatriptan, sumatriptan with naproxen sodium, ibuprofen, and ibuprofen suspension were on top of placebo only in 1 of the efficacy outcomes. In addition, the findings showed that the best treatments for achieving pain-free effects are ibuprofen suspension, ibuprofen, and rizatriptan. In conclusion, most triptans and NSAIDs are effective in terms of pain-free or pain-relief. The most effective pain-free solution is sumatriptan with naproxen sodium, while for pain relief, the most effective solution is ibuprofen and ibuprofen suspension.[45] This was supported by other evidence from small trials, which showed that ibuprofen improved pain freedom for the acute treatment of children with migraines. In general, triptans are also associated with higher rates of minimal adverse events.[46](A1)

Topiramate (TPM) decreases the frequency of headaches, and studies revealed that topiramate is effective and safe for migraine prophylaxis among children. The following are observed after TPM treatment: reduced headache frequency, severity, and duration.[47] Prophylactic vitamin B12 therapy is used on migraine patients in adults, but limited studies were done regarding vitamin B12 and folic acid levels in pediatric patients diagnosed with migraine. Data showed a statistically significant difference between migraine patients and the control group regarding vitamin B12 and folic acid levels. The results indicated the requirement for routine evaluation of vitamin B12 and folic acid levels in pediatric patients diagnosed with migraine.[48] 

Strategies for Migraine Management

• Counsel patients about the possible trigger factors and subsequent avoidance. Maintaining a headache diary may help identify such triggers.
• Relaxation and biofeedback techniques with counseling about diet and proper sleep
• Analgesics for intermittent headaches
• Antinausea agents such as promethazine and metoclopramide
• Prophylaxis with a daily preventive medication

Recommended Abortive Treatment

Abortive treatment may be required for children with migraine headache attacks. In a study conducted in Israel, about 87.5% of children, during the first recorded migraine attack, reported intake of only 1 type of medication for each headache episode, particularly ibuprofen or acetaminophen, and less than 25% used dipyrone (metamizole). After 2 hours of treatment, the rate of improvement was 65.4% ± 27 for ibuprofen, 59.8 ± 35.3 for acetaminophen, and 50.9 ± 27.4 for dipyrone without statistical difference. It was also noted that male children responded significantly better to acetaminophen than ibuprofen (95% ± 28 vs. 75 ± 20). Although the most common abortive treatment is ibuprofen, the 1 that showed a better response was acetaminophen.[49]

Studies compared the efficacy of oral paracetamol and oral ibuprofen for managing acute headaches in children with migraines without aura in India. There was no significant difference between the Paracetamol and Ibuprofen groups. This means that both paracetamol and ibuprofen are effective and safe for treating acute migraine attacks in children.[50] At the same time, ibuprofen and paracetamol are included in the World Health Organization Essential Medicines List (WHO EML) as the 2 analgesics for treating acute migraine attacks in children. Meta-analysis and evidence assessments indicated that ibuprofen was superior to placebo for pain-free at 2 hours or pain relief at 2 hours, without difference in adverse events. At the same time, there were no differences between ibuprofen and paracetamol.[51] For mild headaches - acetaminophen with a dosage of 15 mg/kg every 4 to 6 hours; ibuprofen 10 mg/kg every 6 to 8 hours; naproxen 15 mg/kg every 4 to 6 hours. For moderate to severe headaches, adding a triptan may be necessary. Rizatriptan and sumatriptan, along with a combination of analgesics, have been FDA-approved for use in children. Based on clinical studies, sumatriptan is an effective and well-tolerated treatment when administered intravenously, subcutaneously, or orally. Sumatriptan also relieves photophobia, nausea, headache, and functional disability.[52](A1)

The protocol involves a non-opioid analgesic and dopamine receptor antagonist for emergency department treatment. Meanwhile, treatment with valproic acid is used as a continuous infusion. Administration of ketamine or propofol and peripheral nerve blocks could accelerate the treatment of pediatric migraine. Although there is an increasing variety of abortive treatments for pediatric migraine, there Is still a need for further research to validate these approaches.[37] A study compared pediatric migraine treatment efficacy in the emergency department before and after implementing a comprehensive migraine initiative in terms of standardized treatment protocol, provider educational series, and standardized physician documentation template. Results showed improvement in the efficacy and efficiency of migraine through a standardized treatment protocol, improved provider education, and ease of documentation.[53] 

Recommended Preventive Treatment

Preventive treatment is needed during frequent migraine attacks, an impairment of the quality of life, severe accompanying or aura symptoms, and the failure of acute drug treatment. Below is a list of recommended pharmacological classes:

• Antidepressants
• Antiepileptics
• Antihistamines
• Beta-adrenergic receptor blockers
• Calcium ion channel antagonists, as well as onabotulinum toxin A and nutraceuticals (butterbur) [54] 

If preventive medications are chosen, propranolol or nadolol (beta-blockers) can be given daily. Caution is advised in patients where beta-blockers are contraindicated, such as asthmatics, etc. Other medications that have proven useful include amitriptyline or nortriptyline, verapamil, antiepileptic agents (divalproex, topiramate, levetiracetam, and as used more in the past, phenobarbital and phenytoin), trazodone, and naproxen sodium. Studies are conducted to update evidence-based recommendations for migraine prevention using pharmacologic treatment with or without cognitive behavioral therapy in the pediatric population using the American Academy of Neurology 2011 process, as amended. Children with migraines who receive propranolol have at least a 50% reduction in headache frequency. Children receiving topiramate and cinnarizine have a decrease in headache frequency. Children with migraine receiving amitriptyline with cognitive behavioral therapy have a reduction in headache frequency. Other recommendations include counseling on lifestyle and behavioral factors influencing headache frequency and assessing and managing comorbidities related to persistent headaches.[55] Moreover, previous studies also evaluated the efficacy and safety of topiramate (TPM) for migraine prophylaxis. They found that TPM could be considered a safe and effective drug in pediatric migraine prophylaxis.[56] In line with TPM, plasma calcitonin gene-related peptide (CGRP) level may be used as a therapeutic strategy since it is higher in patients needing migraine prevention and responsive to short-term topiramate treatment. CGRP can also differentiate migraine from non-migraine headaches. These findings are clinically significant among young children who cannot identify their headache symptoms.[57] (A1)

Another study found that serum magnesium levels were significantly lower among children with migraine compared to those without migraine. Therefore, natural remedies such as magnesium, CoQ-10, ginkgolide B butterbur, riboflavin, polyunsaturated fatty acids, and oral melatonin have proven efficient and have a lower side effect profile.[58] Since most preventive migraine treatments modify the brain's excitation/inhibition balance or serotonin metabolism, they most likely produce unfavorable side effects. Biological therapies blocking CGRP transmission are effective and better tolerated; however, they are expensive and may not influence brain dysfunctions upstream in the pathophysiological cascade of migraine, including premonitory and aura symptoms. On the other hand, biochemical and clinical studies mentioned a complementary treatment strategy focusing on migraine pathophysiology's metabolic facet. Findings revealed that riboflavin and coenzyme Q10 are effective for migraine prevention and quasi-devoid of adverse effects. Their response rates are similar to those of topiramate, propranolol, and CGRP/CGRPrec mAbs but are weaker for thioctic acid. Therefore, metabolic treatments of migraine demonstrated an effective, well-tolerated, inexpensive, and evidence-supported therapeutic option for migraine prophylaxis and may be used as the first treatment line among children.[59] (B2)

Moreover, another study evaluated the efficacy of riboflavin treatment among pediatric patients. Findings revealed that children treated with riboflavin had reduced frequency of headaches, acute medication usage, and absences in school. Riboflavin prophylaxis also demonstrated a reduction in migraine intensity and duration. Therefore, riboflavin is recommended as a safe, inexpensive, and effective nutraceutical in pediatric migraine treatment.[60] Recent findings on phytomedicines, or plant-based medicinal formulations, appear promising in identifying therapeutic targets in migraines as clinical and preclinical evidence of efficacy increases. Studied reviewed the mechanisms of action of the phytomedicines potentially useful for migraine, namely treatment-feverfew (Tanacetum parthenium), butterbur (Petasites hybridus), marijuana (Cannabis spp.), Saint John's Wort (Hypericum perforatum) and the Damask rose (Rosa × Damascena). Findings for feverfew are mixed; butterbur is effective with potential risks of hepatotoxicity related to preparation; marijuana has limited data and mostly did not show effectivity in migraine treatment; Saint John's Wort shows relevant physiological activity but is a hepatic enzyme inducer; the Damask rose when used in topical preparations did not show efficacy in 1 clinical trial.[61](B2)

Several studies showed that melatonin is effective for adult migraine prevention and has been used acutely for procedural pain in children. For acute treatment of pediatric migraine, both low and high doses of melatonin are involved with pain reduction; however, higher doses and napping after treatment predicted greater benefit.[62] Natural remedies such as ginkgolide B butterbur, riboflavin, magnesium, CoQ-10, polyunsaturated fatty acids, and oral melatonin have also proven efficient and have a lower side effect profile. 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). Previous studies mentioned that the majority of pediatric migraine patients are successfully discharged, and findings revealed that prochlorperazine appeared to be superior to metoclopramide in preventing a revisit. Diphenhydramineuse is associated with increased rates of return.[63] . Furthermore, ibuprofen, prochlorperazine, and other triptan medications are the most effective and safe treatments for the acute management of migraine and other benign headache disorders in the pediatric group.[64](B2)

A study assessed the efficacy and safety of a common monotherapy (intravenous [IV] metoclopramide) versus a combination strategy (adding IV ketorolac to metoclopramide) in children with acute treatment of migraine headaches in the emergency department. Findings revealed that the combination of IV metoclopramide and ketorolac failed to improve pain scores compared to metoclopramide monotherapy. Most of the patients were discharged with residual pain. The study also recommended counseling in terms of the following: reassurance of prognosis to the parents. trigger avoidance, the importance of lifestyle modification like proper sleep and water intake, and the importance of using analgesics at the early onset of headache.[65] However, some studies characterize the dystonic reactions to metoclopramide and prochlorperazine in children. It was revealed that dystonic reactions are rare among pediatric patients treated for acute headaches, but they are more common with prochlorperazine than metoclopramide.[66] (A1)

Other studies mentioned that migraine is a response to a cerebral energy deficiency or oxidative stress levels that exceed antioxidant capacity. The ketogenic diet, which causes the elevation of ketone bodies (KBs), targets cerebral metabolism and has recently shown great potential in preventing migraines. Ketone bodies are an alternative fuel source for the brain and are thus likely able to bypass some of the abnormalities in glucose metabolism and transport found in migraine. Recent findings revealed that KBs-D-β-hydroxybutyrate could potentially influence other pathways believed to be part of migraine pathophysiologies, such as mitochondrial functioning, oxidative stress, cerebral excitability, inflammation, and the gut microbiome. However, further studies are suggested to check whether the absence/restriction of dietary carbohydrates, the presence of KBs, or both are significant for the migraine protective effects of KD.[67] 

Recent studies have been conducted to review the following treatment use in children, namely angiotensin antagonists such as candesartan, more selective 5-HT1F agonists like lasmiditan, new calcitonin gene-related peptide (CGRP) antibodies and antagonists, peripheral nerve blocks and botulinum toxin and electroceuticals which are therapeutic electric devices such as external trigeminal nerve stimulator (e-TNS), a non-invasive vagal nerve stimulator (nVNS), a single-pulse transcranial magnetic stimulator (sTMS) and a remote electrical neuromodulation device (REN). However, there is still a lack of evidence for their effectiveness in children.[68] Counseling- Additional aspects of counseling include the following: reassurance to the parents about the prognosis, avoidance of triggers, the importance of lifestyle adjustments such as proper sleep and water intake, and the importance of using analgesics early in the headache. Addressing these issues may reduce the frequency and severity of headaches. Inadequate sleep might be due to obstructive sleep apnea, among other possibilities.

Differential Diagnosis

Several other health conditions may present, like a pediatric migraine.

• Chronic daily headaches
• Brain tumors
• Vascular malformations
• Hydrocephalus
• Head trauma
• Mitochondriopathies
• Cluster headaches

Headaches manifested in pseudotumor cerebri (pseudotumor; idiopathic intracranial hypertension) are nonspecific and are difficult to distinguish clinically from migraine. Children's headaches have a high predictive value for migraine versus nonmigraine headaches. Pseudotumor symptoms were similar to migraine except for the presence of diplopia in pseudotumor.[69]

Prognosis

Early onset of migraine seems predictive for a less favorable outcome in later ages; however, follow-up studies are very limited and mostly with a short-term prospective period, of which the longest follow-up study is in a population of children with migraine under the age of 6. Some studies suggest that the onset of migraine at a very young age represents an unfavorable prognostic factor for the persistence of migraine at later ages. Some clinical features may change during the clinical course, and the active persistence of migraine may lead to an increase in allodynia.[70] Studies showed that cephalic cutaneous allodynia might appear in children and adolescents in the first 6 months of migraine onset. Contrary to adult studies, allodynia is not associated with migraine frequency or long disease duration but is significantly associated with migraine with aura, female gender, and awakening pain. A genetic tendency may be attributed to the appearance of allodynia in the pediatric age group.[71] In 1 of the published studies, 25% of patients stopped having migraines by the age of 25 years.[72] Another study reported an 80% improvement in migraines by the age of 10 years.[73] Lidegaard et al reported a significant association between migraine and stroke in women aged 15 to 45 years who smoked or were on oral contraceptives.[74]

Complications

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.