BEST PRACTICE MIGRAINE. NPBarnes,SJayawant. ep53

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1 H BEST PRACTICE MIGRAINE NPBarnes,SJayawant Arh Dis Child Edu Prat Ed 2005; 90:ep53 ep57. doi: /ad eadahes in hildren are ommon, with around 70% of shool hildren experiening at least one per year and 25% more frequently. 1 They are a ause of onsiderable morbidity, with shool absene and aademi underahievement ommon sequelae in older hildren. Studies from developed ountries indiate that migraine is the most ommon diagnosis among hildren with headahe who present to a medial pratitioner. This artile fouses on the diagnosis, epidemiology, differential diagnosis, and management of migraine, and inludes a review of the evidene base for urrently used treatment. DIAGNOSIS AND CLASSIFICATION In 1988 the International Headahe Soiety (IHS) published omplex diagnosti riteria for lassifying headahes in general. 2 For young hildren these riteria were too restritive, and a reently published revision inludes an extensive lassifiation of migraine headahe (table 1) as well as more developmentally sensitive riteria for use in hildren (table 2). 3 Diagnosti riteria for hildren are broader than those for adults, and allow for a broader range of duration and a broader loalisation of the pain. In essene, migraine an be defined as a reurrent headahe that ours with or without aura and lasts 1 72 hours. It is usually unilateral, of moderate or severe intensity, pulsating in quality and aggravated by routine physial ativity. Nausea, vomiting, phonophobia, and photophobia are ommon aompanying symptoms (table 2). EPIDEMIOLOGY AND AETIOLOGY Migraine affets 3 10% of hildren, a figure whih equates to 50/1000 shool age hildren in the UK and an estimated 7.8 million hildren in the European Union. 7 The mean age at onset is 7.2 years for boys and 10.9 years for girls, with 20% of hildren experiening their first attak before the age of 5 years. 8 9 The symptom based definition preludes diagnosis in very young hildren. The inidene inreases steadily with age, affeting girls and boys equally before puberty but girls more ommonly thereafter The ause of migraine is unknown, and there are few reliable data that have identified risk fators or quantified their effets in hildren. A family history is ommon. Proposed preipitants in genetially predisposed hildren and adolesents inlude hunger, fasting, menses, exerise, stress (for example, sleep deprivation), and foodstuffs (for example, hoolate) Reently, a link between dominantly inherited migraine with aura and atrial septal defet/patent foramen ovale has been proposed. 12 This is supported by one study of 215 adult patients in whih losure of a patent foramen ovale in known migraineurs signifiantly redued the frequeny of subsequent migraine attaks. 13 ep53 Arh Dis Child Edu Prat Ed: first published as /ad on 21 September Downloaded from See end of artile for authors affiliations Correspondene to: Dr Sandeep Jayawant, Department of Paediatris, John Radliffe Hospital, Headington, Oxford OX3 9DU, UK; sandeep.jayawant@ orh.nhs.uk PATHOGENESIS Migraine is urrently thought to be a primary neural proess. In the milieu of a hyperexitable ortex, various stimuli probably produe disturbanes in neuronal ion hannel ativity, resulting in a lowered threshold for external or internal fators to trigger ortial spreading dysfuntion (CSD). This slowly propagating wave of neuronal depolarisation is most likely responsible for the migraine aura and ativation of the trigemino-vasular system. 14 The pereption of pain assoiated with migraine probably begins with ativation of trigeminal vasular afferents, whih in turn sensitise other peripheral and entral afferent iruits to mehanial, thermal, and hemial stimuli. Stimulation of these iruits is painful. 15 An abnormal erebrovasular response to visual stimuli may also be ontributory; when ompared with headahe-free subjets, migraineurs with aura exhibit a signifiantly higher erebral blood flow in response to repetitive visual stimulation. 16 Furthermore, migraineurs signifiantly lak habituation of this vasular response, suggesting that a redued adaptation to environmental stimuli (inluding light) may be part of the pathogeni proess. 16 on 2 July 2018 by guest. Proteted by opyright.

2 ep54 DIFFERENTIAL DIAGNOSIS A detailed history and metiulous examination is essential in identifying those hildren that require further investigation. Unless the history is typial of migraine or one of its variants, other auses of headahe must be onsidered (table 3). This initial assessment also provides an insight into the level of patient and family anxiety that might be ontributing to symptom pereption, failitating the setting of realisti expetations of management. Although it is beyond the sope of this artile to elaborate on the entire differential diagnosis, a few onditions merit speial mention. Episodi tension-type headahes are usually bilateral, last from 30 minutes to seven days, have a pressing or tightening quality, and are not aggravated by physial ativity. Nausea, vomiting, photophobia, and phonophobia are not typial aompaniments. Cluster headahes are lassially severe in nature, unilateral, orbital, supra-orbital, and/or temporal and last minutes. Conjuntival injetion, larimation, nasal ongestion, rhinorrhoea, forehead and faial sweating, miosis, ptosis, and eyelid oedema on the side of the headahe are all ommonly assoiated. CHRONIC DAILY HEADACHE Complex proposed riteria exist for diagnosis of this ondition, whih may be divided into a number of ategories on the basis of speifi linial features and the pattern of headahe evolution: Transformed migraine Affeted hildren initially suffer from migraine, but then develop a hroni headahe in whih isolated migraine attaks may or may not persist. Chroni tension-type headahe Episodes our on average 15 days per month for six months, with the linial features of episodi tension-type headahes. Table International Headahe Soiety (IHS) lassifiation of migraine 3 Migraine without aura Migraine with aura typial aura with migraine headahe typial aura with non-migraine headahe typial aura without headahe familial hemiplegi migraine sporadi hemiplegi migraine basilar type migraine Childhood periodi syndromes (ommonly migraine preursors) ylial vomiting abdominal migraine benign paroxysmal vertigo of hildhood Retinal migraine Compliations of migraine hroni migraine status migraine persistent aura without infartion migrainous infartion Probable migraine New persistent headahes Headahes last over four hours per day, more than one per month, with no history of episodi migraine or tension-type headahe. Hemirania ontinua Charaterised by a low level baseline hemiranial headahe with superimposed exaerbations of more severe pain. Exaerbations last from minutes to days Table 2 aura 3 IHS riteria for paediatri migraine without A. At least five attaks fulfilling riteria B D B. Headahe attaks lasting 1 72 hours C. Headahe with at least two of the following features: 1. Unilateral/bilateral/fronto-temporal loation, but not oipital 2. Pulsating quality 3. Moderate to severe intensity 4. Aggravation by/or ausing avoidane of routine physial ativity D. During the headahe at least one of the following: 1. Nausea and/or vomiting 2. Photophobia and phonophobia E. Not attributable to another disorder and may be assoiated with ipsilateral autonomi features suh as miosis, ptosis, larimation, onjuntival injetion, and rhinorrhoea; when present, these features tend to be less pronouned than those seen with luster headahe. Co-morbid/mixed headahe Affeted hildren have two different headahe patterns, whih exist independent of eah other. This lassifiation is useful in distinguishing this group of onditions from the other types of migrainous and nonmigrainous headahe. Obstrutive sleep apnoea may manifest as early morning headahes with aompanying nausea and anorexia, in a hild who snores at night with noturnal arousals and daytime somnolene. The possibility of environmental exposure to arbon monoxide or non-pharmaologial drug use should also be onsidered when the aetiology of headahe is not otherwise obvious. Clinial findings suggestive of raised intraranial pressure inlude reent onset headahes worsened by lying down, noturnal vomiting, altered onsious level, papilloedema, hypertension, and inreasing head irumferene with/without sun setting. Further pointers to signifiant intraranial Table 3 Differential diagnosis of migraine Organi headahe Post-traumati Infetions for example, otitis media, dental infetions, meningitis, sinusitis Post-seizure Pharmaologial for example, analgesis, affeine, food additives Toxi (substane abuse for example, marijuana and oaine, arbon monoxide poisoning) Ophthalmologial (refration errors) Arthritis of the temporo-mandibular joint Vasulitis for example, systemi lupus erythematosus Hypertension Tumours and other spae oupying lesions Raised intraranial pressure for example, benign intraranial hypertension, hydroephalus, Chiari malformation Low intraranial pressure (post-lumbar punture, dural tear) Vasular headahe Cluster headahe Intraranial bleed for example post-traumati, ruptured arteriovenous malformations, aneurysmal bleeding Venous sinus thrombosis Non-organi headahe Chroni episodi tension-type headahe Chroni daily headahe Depression

3 Table 4 Clinial signs suggestive of an alternative diagnosis to migraine inlude Altered onsious level Inappropriate behaviour (espeially if reent onset) Inreasing head irumferene, sun setting eyes, and prominent salp veins Papilloedema New or worsening squint Hypertension with or without bradyardia Cranial nerve palsies or motor defiits Cerebellar signs Hepatosplenomegaly pathology for example, brain tumours (whih aount for less than 1% of the lifetime prevalene of headahes 17 ) inlude a hange in personality or deline in shool performane, and foal neurologial signs suh as ophthalmoplegia, weakness, ataxia, nystagmus, dysarthria, and hypotonia. The presene of any of the signs in table 4 suggests an alternative diagnosis. For the hild with longstanding headahes and a normal physial examination, no investigation is required. Routine laboratory studies, lumbar punture, and eletroenephalogram (EEG) are not reommended. It is easy to make the assertion that routine brain omputed tomography (CT) or magneti resonane imaging (MRI) is not indiated; realistially there are individual ases where it is essential to allay extreme levels of anxiety. Suh imaging may prove therapeuti, although there remains a risk of deteting an inidental anxiety enhaning (and asymptomati) abnormality for example, an Arnold-Chiari malformation. 18 MANAGEMENT The emphasis in a treatment plan should be on reduing headahe frequeny, duration, severity, and assoiated disability, and should be tailored to eah individual. Most available literature deals with pharmaologial and biobehavioural interventions in the treatment of migraine and its variants. There is a pauity of ontrolled data to support the use of any drug in the management of paediatri migraine. This has led to a tendeny to extrapolate data from adult trials or to use anedotal personal experiene when onsidering any drug for use. Treatment of aute attaks Paraetamol and ibuprofen Using simple analgesis (for example, paraetamol, nonsteroidal anti-inflammatory drugs) is an appropriate initial therapeuti step, although only limited supportive data are available. Both drugs have been shown to be more effetive than plaebo in providing redution of headahe pain by two grades (p, 0.05) ; in one study 19 ibuprofen (10 mg/kg) was twie as likely as paraetamol (15 mg/kg) to abort migraine within two hours (odds ratio 2.2, 95% onfidene interval 1.1 to 4.0). In this study paraetamol was observed to have a faster onset of ation than ibuprofen. However, the results of both studies should be interpreted with aution. Both had high dropout rates (17% 19 and 40%, 20 respetively) and the first study 19 did not report results before rossover. This is a potential soure of bias aused by ontinued potential effets after rossover and unequal withdrawals among groups. Codeine phosphate There is virtually no published data on the use of odeine phosphate autely, and the known adverse effets (whih inlude nausea, vomiting, drowsiness, onstipation, and a dry mouth) mediate against it for use as a first line agent. Ergot derivatives A number of studies have evaluated ergotamine derivatives for use in paediatri pratie, but methodologial limitations of eah make objetive onlusions diffiult and their use unommon. They are ontraindiated with the triptan lass of drugs and in ompliated migraine. Triptans (5-hydroxytryptamine reeptor agonists) Three randomised ontrolled trials (RCTs) have demonstrated nasal sumatriptan to be both safe and effetive in adolesents with migraine. The first study (n = 14, age 6 14 years) found that 20 mg nasal sumatriptan was more effetive than plaebo in providing headahe relief by two hours (p = 0.03). 23 A seond RCT (n = 510, age years) ompared 5 mg, 10 mg, and 20 mg sumatriptan nasal spray to plaebo. Signifiant relief was noted at one hour with the 5 mg and 20 mg dose (p, 0.05). The 20 mg dose was also more effetive than plaebo at ahieving a pain-free state after two hours and in reduing phonophobia and photophobia (p, 0.05). Taste disturbane with sumatriptan was reported by 26% of hildren. 24 A third study (n = 83, age 8 17 years) also suggested nasal sumatriptan to be superior to plaebo, with signifiantly more hildren experiening some relief of symptoms at two hours (p = 0.003). Taste disturbane was again the most ommonly reported side effet (29%). 25 Oral sumatriptan has not been found to be any more effetive than plaebo, 26 and the subutaneous formulation has only been evaluated in open label studies. Limited data exist for other agents in this lass (for example, rizatriptan, zolmitriptan), and there are little data urrently available to support their use. Prophylaxis In the UK propranolol and pizotifen are widely presribed as prophylati agents, though in the absene of onvining RCT derived evidene suggesting a benefit. Propranolol Three studies have evaluated the use of propranolol, and eah differs in its onlusion; the first suggested a benefit, a seond suggested no benefit, and a third onluded that it may atually worsen symptoms. In a very small double blind rossover RCT of 32 hildren (aged 7 16 years) with IHS ongruent migraine, Ludviggson demonstrated that propranolol ( mg daily divided in three doses) produed a signifiant inrease in the pereption of benefit ompared with plaebo over a three month period. The reliability of these results is limited beause of the small size of this trial, oupled with a 13% dropout rate. 31 In ontrast, Forsythe et al showed that propranolol ( mg daily over a 30 week period) atually inreased headahe duration ompared with plaebo in 53 hildren ep55

4 ep56 aged 9 15 years. Again, the reliability of these results is limited beause of a 26% dropout rate. 32 Finally, in a trial of 33 hildren aged 6 12 years Olness ompared propranolol (3 mg/kg per day) with plaebo for migraine prophylaxis. This RCT found no signifiant differene between propranolol and plaebo when the number of migraine attaks was taken as the primary end point. 33 Pizotifen Only two trials have evaluated pizotifen for use as prophylaxis, and both have methodologial flaws that onsiderably limit the interpretation of their results. In a double blind rossover RCT of 47 hildren aged 7 14 years Gillies 34 found no benefit for pizotifen (twie or three times daily dosing, dose range mg per dose) over plaebo in reduing the number of attaks, total duration of attaks, duration of the longest attak, or mean duration of attak. This study (1986) predated the IHS diagnosti riteria for migraine, and partiipants would not all fulfil the urrent IHS definition for migraine. The reliability of these results is also limited by the fat that 17% of hildren did not omplete the study. The only other study to have ompared pizotifen with plaebo was never published in full and so its methodology is not open to srutiny. In this study Salmon 35 evaluated 40 hildren (aged 6 15 years) with headahe, only some of whom had migraine. The results were published only in abstrat form and did not inlude numerial data. Other prophylati agents A number of other agents have been evaluated. Flunarizine has been shown to be more effetive than plaebo, 36 though awaits further study. Nimodipine, 37 trazodone, 38 L-5-hydroxytryptophan, lonidine, and anti-emetis (for example, domperidone, metolopramide) 43 have all been used in small plaebo ontrolled studies, though none were shown to signifiantly redue headahe frequeny or duration. The herbal remedy feverfew (Tanaetum parthenium L), shown in RCTs in adults to be of potential benefit, 44 is still to be effetively evaluated for use in hildren, as are phenobarbitone, phenytoin, amitriptyline, arbamazepine, metoprolol, topiramate, piraetam, and yproheptadine. 43 In onlusion, only very limited data on paediatri migraine urrently exist to support the use of drugs to relieve aute symptoms or provide prophylaxis. There remains an urgent need for methodologially sound RCTs to determine whih agents are therapeuti. Suh studies would ideally be large, multientre, parallel group without rossover, with stringent monitoring of ompliane and a low dropout rate. The use of headahe frequeny as a primary outome is preferable to headahe indies. Psyhologial and behavioural therapy A number of approahes have been evaluated, though few in suitably blinded large RCTs with a low dropout rate. There are no reliable data on the effiay of speifi dietary exlusion. One small RCT (whih pre-dated the IHS riteria for migraine) attempted to investigate the effets of exluding dietary amines in 39 hildren, but its onlusions are unreliable given that 33% of eligible hildren were exluded before randomisation. 45 Though some preliminary evidene is available to suggest that progressive musle relaxation and self administered stress management programmes are of potential benefit as prophylaxis, these and other psyhologial therapies for example, thermal biofeedbak await more stringent further evaluation PROGNOSIS There are no reliable data regarding the prognosis of paediatri migraine diagnosed by IHS riteria. Spontaneous remission after puberty may our, and this is supported in part by one 40 year longitudinal study from Sweden (73 hildren with migraine, mean age onset 6 years). 50 It found that migraine headahes had eased before the age of 25 years in 23% of people, although by the age of 50 years more than 50% of people remained affeted. This study predated the IHS diagnosti riteria. CONCLUSIONS Careful onsideration of the broad differential diagnosis is important when evaluating a hild with headahe. Migraine remains a signifiant soure of morbidity in hildren; despite reent advanes an understanding of its pathophysiology remains inomplete. The expetations for the suess of treatment should take aount of the level to whih psyhologial fators are ontributing to symptoms. Ibuprofen and nasal sumatriptan should be onsidered for the treatment of aute attaks; paraetamol is also probably effetive. Limited evidene exists to support the use of any speifi prophylati agent; further evaluation is required in methodologially sound RCTs. ACKNOWLEDGEMENTS We thank Clinial Evidene for the use of data from a searh arried out by them in Authors affiliations N P Barnes, S Jayawant, John Radliffe Hospital, Oxford, UK Competing interests: none REFERENCES 1 Abu-Arefeh I, Russell G. Prevalene of headahe and migraine in shoolhildren. 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5 17 Rasmussen BK. Epidemiology of headahe. Cephalalgia 1995;15: Goadsby PJ. To san or not to san in headahe. BMJ 2004;329: Hamalainen ML, Hoppu K, Valkeila E, et al. Ibuprofen or aetaminophen for the aute treatment of migraine in hildren. Neurology 1997;48: Lewis DW, Kellstein D, Dahl G, et al. Children s ibuprofen suspension for the aute treatment of pediatri migraine. Headahe 2002;42: Linder SL. Treatment of hildhood headahe with dihydro-ergotamine mesylate. Headahe 1994;34: Hamalainen ML, Hoppu K, Santavuori P. Oral dihydroergotamine for therapy-resistant migraine attaks in hildren. Pediatri Neurology 1997;16: Ueberall MA, Wenzel D. Intranasal sumatriptan for the aute treatment of migraine. Neurology 1999;53: Winner P, Rothner AD, Saper J, et al. A randomized, double-blind, plaeboontrolled study of sumatriptan nasal spray in the treatment of aute migraine in adolesents. Pediatris 2000;106: Ahonen K, Hamalainen ML, Rantala H, et al. 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Propranolol in the treatment of hildhood migraine. Dev Med Child Neurol 1984;26: Olness K, Madonald JT, Uden DL. Comparison of self-hypnosis and propranolol in the treatment of juvenile lassi migraine. Pediatris 1987;79: Gillies D, Sills M, Forsythe I. Pizotifen (Sanomigran) in hildhood migraine. A double-blind ontrolled trial. Eur Neurol 1986;25: Salmon MA. Pizotifen (BC.105. Sanomigran) in the prophylaxis of hildhood migraine [abstrat]. Cephalalgia 1985;5(suppl 3): Sorge F, De Simone R, Marano E, et al. Effiay of flunarizine in the prophylaxis of migraine in hildren: a double blind, ross over, ontrolled study. Cephalalgia 1985;5(suppl 3): Battistella PA, Ruffilli R, Moro R, et al. A plaebo-ontrolled rossover trial of nimodipine in paediatri migraine. Headahe 1990;30: Battistella PA, Ruffilli R, Cernetti R, et al. A plaebo-ontrolled rossover trail using trazodone in pediatri migraine. Headahe 1993;33: Longo G, Rudoi I, Ianunuelli M, et al. Treatment of essential headahe in developmental age with L-5-HTP (ross over double-blind study versus plaebo). Pediatria Media e Chirurgia 1984;6: Santui M, Cortelli P, Rossi PG, et al. L-5-hydroxytrytophan versus plaebo in hildhood migraine prophylaxis: a double-blind rossover study. Cephalalgia 1986;6: Sillanpaa M. Clonidine prophylaxis of hildhood migraine and other vasular headahe. A double blind study of 57 hildren. Headahe 1977;17: Sills M, Congdon P, Forsythe I. Clonidine and hildhood migraine: a pilot and double-blind study. Dev Med Child Neurol 1982;24: Vitor S, Ryan SW. Drugs for preventing migraine headahe in hildren (Cohrane Review). In: The Cohrane Library, Issue 3, Chihester, UK: John Wiley and Sons, Ltd. 44 Ersnt E, Pitter MH. The effiay and safety of feverfew (Tanaetum parthenium L.): an update of a systemati review. Publi Health Nutr 2000;3: Salfield SAW, Wardley BL, Houlsby WT, et al. Controlled study of exlusion of dietary vasoative amines in migraine. Arh Dis Child 1987;62: Labbe EL, Williamson DA. Treatment of hildhood migraine using autogeni feedbak training. J Consult Clin Psyhol 1984;52: Andrasik F, Attanasio V, Blanhard EB, et al. Behavioural treatment of pediatri migraine headahe. In: Andrasik F (Chair). Reent developments in the assessment and treatment of headahe. Symposium onduted at the annual meeting of the Assoiation for Advanement of Behaviour Therapy, Philadelphia, MGrath PJ, Humphreys P, Goodman JT, et al. Relaxation prophylaxis for hildhood migraine: a randomised plaebo-ontrolled trial. Dev Med Child Neurol 1988;30: MGrath PJ, Humphreys P, Keene D, et al. The effiay of a self-administered treatment for adolesent migraine. Pain 1992;49: Bille B. A 40-year follow-up of shool hildren with migraine. Cephalalgia 1997;17: ARCHIVIST... Primary adrenal insuffiieny P rimary adrenal insuffiieny (PAI) is unommon in hildren. The most ommon diagnoses are ongenital adrenal hyperplasia (CAH) and autoimmune Addison s disease. A series of 103 patients has been desribed from Montreal (Rebea Perry and olleagues. Journal of Clinial Endorinology and Metabolism 2005;90: ). The study inluded all 55 girls and 48 boys who attended one hospital department with PAI between September 1981 and September The diagnosis was 21-hydroxylase defiieny CAH for 41 girls and 31 boys (70% of the whole series). Among these, 30 girls and 29 boys had the lassi form and 11 girls and two boys had the non-lassi form. Of the 59 patients with the lassi form 53 had salt-wasting CAH. The average age at diagnosis of the six hildren with simple virilising CAH was 5.8 years. One patient of eah sex had 3-bhydroxysteroid dehydrogenase defiieny. Thirteen patients had autoimmune adrenal failure and five of these had a diagnosis of autoimmune polyendorinopathy-andidiasis-etodermal dystrophy syndrome (APECED). Four of the five had mutations at the AIRE lous (the fifth was not tested). Gluoortioid or mineraloortioid defiieny was diagnosed at between 5.4 and 13.6 years in patients with APECED and at between 7.8 and 16.3 years in patients with non-apeced autoimmune PAI. Other diagnoses inluded adrenoleukodystrophy (4 boys), Wolman disease (3), triple A syndrome (1), Zellweger disease (1), X-linked CAH (1), and unexplained PAI (6). An algorithm for the diagnosis of hildren with PAI is inluded in the paper. ep57