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Migraine Headache – Update on Diagnosis & Treatment Herbert L. Muncie, Jr., M.D.

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Presentation on theme: "Migraine Headache – Update on Diagnosis & Treatment Herbert L. Muncie, Jr., M.D."— Presentation transcript:

1 Migraine Headache – Update on Diagnosis & Treatment Herbert L. Muncie, Jr., M.D.

2 What is the diagnosis? Sarah, a previously very healthy 14 year old female complains of a severe headache & nausea. It is the start of the Thanksgiving holiday and all she wants to do is lay on the sofa.  PMH H. flu meningitis age 7 months Car motion sickness as a child  Family history positive for migraines – maternal grandmother & mother

3 Diagnosing Migraine Headache Any severe or recurrent headache most likely is a form of migraine Almost all patients will have family history of migraines or at least “sick” headaches Only 15% have preceded or accompanied focal neurologic symptoms  Usually visual Vision loss or distortion in one eye – ‘ocular migraine’  “Classic migraine”

4 Sarah Spent most of Thanksgiving holiday resting on the sofa Diagnosed with onset of migraine headaches

5 Recurrent Headaches Primary  Migraine  Tension  Cluster  Other benign – cough, cold temperature, post coital, exertion

6 Recurrent Headaches Secondary (pain from complications)  Intracranial tumor  Intracranial aneurysm  Intracranial A-V malformation  Temporal arteritis

7 Migraine with aura – Criteria* At least 2 attacks with 3 of the following:  Fully reversible aura symptoms  At least 1 aura symptom develops gradually during more than 4 minutes or 2 symptoms occur in succession  Any aura symptom lasts less than 60 minutes  Headache follows the aura within 60 minutes *International Headache Society

8 Migraine with aura Visual aura common  Slowly evolving scintillating scotoma that moves or passes through visual field  Duration of aura – 22 minutes  Should not be called ocular migraine if bilateral eye involvement Just call them migraine with aura

9 Visual aura rating scale (VARS) Visual SymptomRisk Score Duration minutes3 Develops gradually over 5 min2 Scotoma2 Zigzag line (fortification)2 Unilateral (homonymous)1 MIGRAINE with AURA DIAGNOSIS≥ 5

10 Migraine with aura – vascular risk? Migraine with aura is associated with 2 fold risk of ischemic stroke & cardiovascular event  Absolute risk is low (4 per women years)  May be indication for aggressive treatment of other risk factors  Unclear if more intense treatment & prevention of migraines will alter the risk

11 Migraine without aura – Criteria* At least 5 attacks (bunch of them) Lasting 4-72 hours untreated or unsuccessfully treated (didn’t just go away quickly) Must have one of these to be migraine:  Nausea or vomiting  Photophobia  Phonophobia *International Headache Society

12 Migraine without aura – Criteria* Then usually have at least 2 of these:  Unilateral pain  Throbbing/pulsating  Aggravation on movement  Moderate or severe intensity And of course to be sure not something else:  H & P does not suggest organic disorder  H & P suggests an organic disorder which is then ruled out  An organic disorder is present but attacks do not occur for the 1 st time in close time to the disorder *International Headache Society

13 Diagnosing the acute headache The classification criteria are best suited for a between-attack assessment of their typical headache  However, they are often used for the acute attack  Once acute pain relieved, take time to make an accurate diagnosis Up to 1/3 of ED patients cannot be assigned a diagnosis  Despite a through questionnaire-based assessment

14 ER Clinical Decision Rule “ID Migraine” – three features  Sensitivity to light  Nausea or vomiting  Disabling intensity of headache positive - low probability If 2 positive higher probability of migraine  Criteria focus on typical attacks not the current acute attack

15 Epidemiology - Migraine Can start at any age, however,  Peak incidence of onset is mid-adolescence (age 13-16)  History of colic or motion sickness support Dx Median frequency - 1.5/month Greater increase in prevalence with aging in women  Females - 6.4% age ; 17.3% age  Males - 4.0% age ; 5.0% age 18 – 29  Usually more severe in women

16 Pathophysiology Migraine is a primary neural event  Something lowers threshold for a cortical spreading depression (CSD) Which causes regional hypoperfusion (aura) Release of proinflammatory neurochemicals  Neural event results in vasodilation  Which leads to pain & more nerve activation Migraine headache is not a primary vascular event

17 Why does it hurt? Substance of brain is largely insensate Pain could come from:  Cranial blood vessels  Trigeminal innervations of vessels  Reflex connection of trigeminal system with cranial parasympathetic flow No clear explanation for why it hurts

18 Testing Indications* Laboratory tests not helpful or needed to make the diagnosis EEG not indicated as routine evaluation Neuroimaging guidelines  Typical migraine with normal neurologic exam Neuroimaging not warranted (SOR-B)  Insufficient evidence regarding imaging in presence of neurologic symptoms (SOR-C) *U.S. Headache Consortium (2000)

19 Neuroimaging - EBM For non-acute HA with unexplained abnormal finding on neurologic examination – obtain neuro image (SOR-B) If atypical features or headache does not fulfill definition of migraine – lower the threshold for obtaining imaging (SOR-C) CT vs. MRI?  Insufficient data to recommend MRI compared to CT in evaluation of migraine or other nonacute headache (Grade C)

20 Red Flags! Strongly consider neuroimaging if  New onset > age 50  Thunderclap onset  Focal and nonfocal symptoms  Abnormal signs  Headache with change in posture  Valsalva headache  HIV or cancer diagnosis

21 Prodrome (before headache) Some patients experience symptoms hours to days before the headache (prodrome)  Fatigue  Inattentiveness/confusion  Restlessness, elation, +/- irritability  Insomnia +/- depression  Joint pain  Hunger or food craving  Yawning

22 Treatment Goals of treatment  Reduce frequency, severity, & duration of headaches  Improve quality of life (QOL)  Avoid acute medication escalation Treatment Guidelines are based upon having a specific diagnosis  Often difficult initially to make specific Dx  Therefore, significant uncertainty about ‘best’ initial treatment

23 Treatment - Migraine The brain of patients with migraines does not tolerate peaks or troughs of life Patients should get:  Regular sleep Go to bed and awaken same time every day  Regular meals Eat same time every day Never skip meals – fasting associated with precipitating headache  Regular exercise  Avoid peaks of stress, troughs of relaxation  Avoid unique dietary triggers

24 Migraine & Diet - EBM Frequency, duration & severity are NOT increased by dietary choices (SOR-A)  Cheese, alcohol, chocolate, citrus are not universal triggers Low-fat diet reduced frequency of migraines (SOR-B)

25 Migraine & Supplements - EBM Supplements reduced frequency & intensity  Riboflavin – 400 mg qd Effect begins at 1 month, 3 months  Magnesium – 600 mg qd Diarrhea common - almost 20% 360 mg qd during luteal phase reduced menstrual migraine  Others Butterbur mg/d CoQ mg/d Feverfew mg/d National Guideline Clearing House  SOR – A 

26 22 yo female presents with throbbing headache, nausea, photophobia for 5 hours. BP 116/76, P 86. Which of these treatments would be appropriate for her? Question a.Ketorolac (Toradol ® ) 60 mg IM b.Metoclopramide (Reglan ® ) 20 mg IV c.Prochlorperazine (Compazine ® ) 10 mg IV d.D.H.E mg IV e.Sumatriptan (Imitrex ® ) 6 mg SQ

27 Treatment of Acute Pain NSAID (SOR-A) Ketorolac (Toradol ® ) – 10 mg oral, 60 mg IM, or 30 mg IV(SOR-C) Combinations  Isometheptene mucate, dichloralphenazone and acetaminophen (Midrin ® )  Butalbital has not been effective in controlled trials (butalbital/acetaminophen/caffeine- 50/325/40 Fioricet ®, butalbital/ASA/caffeine-50/325/40 Fiorinal ® )

28 Treatment of Acute Pain NSAIDs – more effective when:  Taken early  With adequate initial dose  Combined with antiemetic ASA 1000 mg  Combined with metoclopramide IM (Reglan ® ) reduces nausea/vomiting but not better pain control

29 Treatment of Acute Pain IV fluids may benefit patients, although benefit is not well established  Unlikely to be harmful especially in patients with persistent GI symptoms  Parenteral therapy preferred due to gastric stasis & delayed absorption of oral medications

30 Treatment of Acute Pain Droperidol (Inapsine ® ) probably most effective of dopamine agonists  Pain relief at 2 hours approaching 100%  Ideal dose – 2.5 mg IV  FDA warning about QT prolongation

31 Treatment of Acute Pain Prochlorperazine (Compazine ® ) 10 mg IV  Effective with diphenhydramine (Benadryl ® ) – 25 mg IV [Friedman 2008]  Superior to SC sumatriptan in ED setting [Kostic 2010]  Children 0.15 mg/kg IV over 15 minutes (max 10 mg) If EPS develop give diphenhydramine 1mg/kg (max 50 mg)

32 Treatment of Acute Pain Metoclopramide* (Reglan ® )  IV – monotherapy mg IV  IM – 10 mg adjunct to other therapies (SOR-C) * FDA boxed warning 2/26/09 –Long-term or high-dose use of metoclopramide has been linked to tardive dyskinesia.

33 Treatment of Acute Pain Ergot alkaloids  Dihydroergotamine (D.H.E. 45 ® ) – 1 mg IM/IV/SC Since it may cause nausea, more effective with metoclopramide (Reglan ® ) to reduce nausea Nasal spray effective  Ergotamine/caffeine (1/100) (Cafergot ® ) Little evidence effective alone High risk of overuse & rebound headache

34 Treatment of Acute Pain Sodium valproate (Depacon ® )  500 – 1000 mg in 10 ml normal saline IV over 30 min  May be effective but less than prochlorperazine (Compazine ® )

35 Treatment of Acute Pain Complementary medicine  Topical menthol 10% was more effective at complete pain relief than placebo at 2 hours (38.3% vs 12.1%) [Haghighi 2010] 10% solution of menthol crystals in ethanol Forehead and the temporal area most painful are washed with tap water After drying 1 ml is applied with sponge on a surface area of 5 x 5 cm Can be reapplied in 30 min

36 Treatment of Acute Pain - EBM Patients with substantial disability will benefit from serotonin 5-HT 1B/1D agonists (‘triptans’)  SOR – A  Clinical Evidence ns/nud/1208/1208.jsp

37 Triptan Efficacy No one triptan is superior in all pain relief parameters Use one triptan for 2-3 attacks before abandoning that medication If one does not work try another one

38 How is pain relief measured? 1)Was pain better within 2 hours? 2)Did the pain go away at 2 hours? 3)Did the pain stay away for at least 24 hours? (No immediate recurrence) 4)Did the patient consistently obtain pain relief from that medication?

39 Oral Triptan Efficacy Was pain better within 2 hours?  55-65% of patients experience improvement at 2 hours  Can be repeated in 1 – 2 hours if partial response

40 Oral Triptan Efficacy Did pain go away within 2 hours?  25-35% of patients are pain free at 2 hours

41 Oral Triptan Efficacy Did pain stay away for 24 hours?  Freedom from pain at 2 hours, no rescue medication, no recurrence of pain in 24 hours % of patients have sustained freedom from pain

42 Oral Triptan Efficacy Intra-patient Consistency?  The same patient experiences pain relief with the same medication Rizatriptan (Maxalt ® ) has highest intra- patient consistency of the oral medications

43 Sumatriptan (Imitrex ® ) – Parenteral 6 mg SC  Pain decreased within 2 hours - 76%  Pain gone within 2 hours - 48%  Consistent pain relief for that patient - 90%  In ER best candidates are those with previous response to this treatment  Adverse events more frequent than with oral medication And more intense

44 Sumatriptan (Imitrex ® ) – Parenteral Cutaneous allodynia - sensation of pain in response to normally non-toxic touch stimuli (e.g. brushing hair, taking shower, putting hair in ponytail)  Presence of cutaneous allodynia associated with reduced response to SC sumatriptan Needle-free injection available (Sumavel ® DosePro ™ )  Causes as much pain as needle & more swelling, bruising & bleeding at site

45 Triptans (Medical Letter 2008) Onset of actionElimination half-life Almotriptan (Axert ® ) min3 - 4 hours Eletriptan (Relpax ® ) min3 - 4 hours Frovatriptan (Frova ® )~ 2 hrs~ 25 hrs Naratriptan (Amerge ® )1 - 3 hrs~ 6 hrs Rizatriptan (Maxalt ® ) min2 - 3 hrs Sumatriptan (Imitrex ® )~ 2 hrs tablets min nasal spray min SC injection~ 10 min Zolmitriptan (Zomig ® )2 - 3 hrs tablets min nasal spray min

46 22 yo female presents with throbbing headache, nausea, photophobia for 5 hours. BP 116/76, P 86. Which of these treatments would be appropriate for her? Question a.Ketorolac (Toradol ® ) 60 mg IM b.Metoclopramide (Reglan ® ) 20 mg IV c.Prochlorperazine (Compazine ® ) 10 mg IV d.D.H.E mg IV e.Sumatriptan (Imitrex ® ) 6 mg SQ

47 Triptans – Side Effects Tingling Paresthesias Warmth head, neck, chest & limbs Nasal spray associated with taste disturbance

48 Triptans – Cautions Contraindicated with CAD, uncontrolled hypertension or cerebrovascular disease, hemiplegic migraine Should not be taken within 24 hrs of another triptan or ergotamine- containing/ergot-type medication Taking them with an SSRI or SNRI can cause life-threatening serotonin syndrome

49 Combining Medications Sumatriptan 85 mg & Naproxen 500 mg (Treximet ® ) more effective than either alone for acute pain relief  Unknown effect of taking 2 separate pills (not tested)  The combination may have some increased benefit in mild/moderate pain but no evidence of need for fixed dose combination (Medical Letter 2008)

50 Early Recurrence Up to 75% of patients will experience a recurrence of pain within 48 hours  Naproxen (500 mg) or sumatriptan (100 mg) equally effective treating the recurrence [Friedman 2010]  Naproxen prophylactically can prevent recurrence (NNT – 3)  Triptans should not be used prophylacticly

51 Preventing Early Recurrence Parenteral dexamethasone (10-25 mg IV)  Produced 26% relative reduction in recurrence within 72 hours [Colman 2008]  Modest benefit in the ED – prevented 1 in 10 patients from experiencing moderate or severe recurrence [Singh 2008]  Later trials failed to find benefit with oral dexamethasone or prednisone

52 Acute Pain & Parenteral Opioids Should not be used as 1 st line therapy  International Headache Consortium  Canadian Association of Emergency Physicians  American Academy of Neurology Meperidine (Demerol ® ) less effective than DHE and there is an:  Increased risk of sedation  Toxic metabolite with repetitive use

53 New Treatments Acute Pain Diclofenac oral solution (Cambia ® ) – dissolve contents in water Sumatriptan patch (Zelrix ™ ) – similar levels to SC

54 New Treatments Acute Pain DHE inhaled (Levadex ® ) – patients not responding to triptans or more than 6 hours into headache? Calcitonin gene-related peptide (CGRP) antagonist (telcagepant) – as effective as zolmitriptan 5 mg oral Single-pulse transcranial magnetic stimulation (sTMS)  More effective than placebo in pain-free at 2 hours (39% vs 22%)

55 After the Migraine - Postdrome Some patients may have:  Mood changes  “Hangover”  Tired  Weak  Disoriented  “Not right”

56 Chronic Migraine (CM) or Medication Overuse Headache (MOH) Chronic migraine previously called ‘transformed migraine’ Consider medication overuse if ≥ 2 days/week for > 3 months analgesic use Over period of time (months to years) can become almost daily headache  Resembles mixture of tension & migraine  Occasionally called ‘tension-vascular’  Hint – if awaken with headache consider medication overuse

57 CM Modifiable Risk Factors Risk factor associated with increased risk of developing CM  Stressful life events  Sleep disturbance (i.e. Snoring/sleep apnea)  Obesity  Baseline headache frequency  Medication overuse

58 CM & MOH Treatment  Must stop acute medication to determine Headaches will go away in a few days if medication overuse is etiology  No controlled trials of medication withdrawal  May get severe withdrawal headache Severe withdrawal headache can be treated with short course of prednisone Randomized trial found no difference with steroid compared to placebo

59 Preventive Medication Candidates:  Unresponsive to acute attack medication & disabling headache  ≥ 2 attacks/month  Increasing frequency of attacks  Migraines with potential neurological sequelae  Patient preference (just wants to use medication to prevent headaches)

60 Audience Question 23 y. o. female with recurrent migraine headaches. You advise starting preventive therapy. Which medication would be appropriate? a)Anticonvulsant medication b)Bipolar/anticonvulsant medication c)Beta-blocker medication d)Tricyclic medication

61 Prevention therapy - EBM First line treatment should be:  Propranolol (Inderal ® ) 20 – 240 mg/day  Timolol 10 – 30 mg/day Less evidence to support other beta-blockers  Amitriptyline 10 – 150 mg/day

62 Prevention therapy - EBM First line treatment should be:  Divalproex sodium (Depakote ® ) 125 – 500 mg BID  Topiramate (Topamax ® ) mg BID May be as good as propranolol Anti-epileptic drugs had greater suicidal ideation vs. placebo (0.43% vs 0.22%)

63 Prevention therapy Second line (SOR-B)  Gabapentin - pregnancy category D  Carbamazepine* - pregnancy category D * FDA Alert 12/12/07 –Dangerous or even fatal skin reactions can be caused by Carbamazepine therapy in patients with a particular HLA-B*1502 allele.

64 Prevention Therapies - EBM Relaxation training (SOR-A)  Progressive muscular relaxation  Breathing exercises  Directed imagery Cognitive-behavioral (SOR-A)  Combined with medication (SOR-B) Acupuncture appears to be effective (SOR-A)  Sham acupuncture just as effective as real [Linde 2009] Thermal biofeedback with relaxation training

65 Audience Question 23 y. o. female with recurrent migraine headaches. You advise starting preventive therapy. Which medication would be appropriate? a)Anticonvulsant medication b)Bipolar/anticonvulsant medication c)Beta-blocker medication d)Tricyclic medication

66 Menstrual Migraine – two classes A.Pure menstrual migraine without aura  Migraine without aura on days -2 to +3 of cycle  During at least 2 of 3 cycles B.Menstrual related migraine without aura  Migraine without aura as above and  At other times of the month

67 Menstrual Migraine Strongly associated with estrogen  Steep drop in estrogen just prior to menses may trigger headache  Peak incidence is 1 st day and preceding day of cycle Other clinical features  Greater severity of pain  Increased risk of nausea & vomiting  Less responsive to acute treatment

68 Menstrual Migraine Acute therapy the same as other migraines Short-term prevention  NSAID on days -7 to +6 helped Naproxen sodium (Anaprox ® ) & mefenamic acid (Ponstel ® ) orally have been studied  Triptans starting day -2 for 5-6 days helped Frovatriptan (Frova ® ), naratriptan (Amerge ® ) & sumatriptan (Imitrex ® ) orally have been studied

69 Prognosis of Migraines Study with 10 year follow-up of year olds at onset of migraines  40% no longer had headache  20% had episodic tension headache  20% had migraine type that was different from the original diagnosed headache Frequency & intensity usually decreases after menopause Two fold increased risk of CVA [Spector 2010]  May influence how aggressive to be with other therapies to reduce risk of CVA

70 Areas of Uncertainty Causal relationship between patent foramen ovale (PFO) & migraine postulated  Closure of PFO suggested for treatment  Relationship remains uncertain & treatment of unselected patients is questionable Intranasal lidocaine provided no relief of migraine pain in ED

71 Tension Type Headache (TTH) - Criteria First  No vomiting – if vomiting probably a migraine  Not worsened by routine physical activity  But can have one of these clinical features Photophobia Phonophobia

72 TTH - Criteria If no vomiting & only 1 other symptom - then need 2 of the following:  Pressing, tightening or non-pulsatile pain  Mild to moderate intensity of pain  Bilateral  No aggravation with movement Diagnosis best made with use of headache diary for 4 weeks

73 TTH Underlying cause uncertain Muscle tenderness & psychological tension associated with aggravating them  But are not clearly the cause Susceptibility influenced by genetic factors

74 TTH Gender ration female:male 5:4 Age of onset – years old Peak prevalence – years old Prevalence increases with higher educational level

75 TTH – Treatment OTC analgesic medications NSAID (prescription) May be augmented with:  Promethazine (Phenergan ® )  Diphenhydramine (Benadryl ® )  Metoclopramide (Reglan ® ) Efficacy tends to decrease with increasing frequency of headaches

76 Chronic Tension Headache Tension headache that occurs  15 or more days a month  For at least 6 months

77 Treatment of Chronic Tension Headache – EBM Beneficial (1 st choice)  Amitriptyline (Start 10 – 25/day; increase up to 150 mg daily)  If no effect in 4 weeks, change therapy Other effective therapies (second choice)  Mirtazapine (Remeron ® )  Venlafaxine (Effexor ® ) Likely to be beneficial  Cognitive behavioral therapy

78 Treatment of Chronic Tension Headache – Clinical Evidence Unknown effectiveness  Acupuncture  Indian head massage  Relaxation or EMG biofeedback  SSRI  Tricyclics other than amitriptyline Likely to be ineffective or harmful  Benzodiazepines  Regular acute pain medication  Botulism toxin

79 Cluster Headaches - Criteria Severe unilateral, bilateral, supraorbital or temporal pain lasting minutes (untreated) and one of following on same side  Lacrimation  Rhinorrhea  Forehead or facial swelling  Ptosis  Miosis  Eyelid edema

80 Cluster Headaches - Criteria Sense of restlessness (93% patients) or agitation  Prefer to be erect & move about 5 attacks with frequency of 1-8 on any given day from no other cause  75% of attacks last < 60 minutes

81 Cluster Headaches Male : female – 2.1 : 1 Peak onset in 40’s 60% right sided Probably most severe pain known to humans  Female patients describe attacks as worse than childbirth

82 Episodic cluster ≥ 2 cluster periods lasting days & separated by pain-free remission ≥ 1 month Absence of aura, nausea, vomiting  Distinguishes it from migraine

83 Cluster Headache Treatment Acute  Sumatriptan 6 mg SC – relief in 15 min  Intranasal spray sumatriptan or zolmitriptan – relief in 30 min  Triptans limits on daily usage Limit to 2 SC or 3 nasal sprays per day to prevent tachyphylaxis or rebound  High flow O 2 effective & safe [Cohen 2009] O 2 – L/min with loose fitting nonrebreathing facial mask for 15 min

84 Cluster Headache Treatment Acute  DHE mg IM or IV useful as abortive agent  Octreotide (Sandostatin ® ) 100 mcg SC can abort an attack NNT 5 for complete relief in 30 min  Prednisone mg – short course

85 Cluster Headache Treatment Prophylactic  Verapamil mg/day

86 Daily Headache When chronic daily headache is strictly unilateral, same side, consider diagnosis to be:  Hemicrania continua Ipsilateral side one or more autonomic symptoms (ptosis, lacrimation, etc.)  Defined by absolute response to indomethacin (25 – 300 mg daily, must be continued indefinitely) If intolerant of indomethacin conside COX2 inhibitor

87 Key Points Diagnosis of migraine headache is clinical  Almost always positive family history Triptans are preferred treatment for frequent migraines Discuss preventive therapy with all patients Provide treatment plan for breakthrough pain

88 What Questions do you have?

89 References 1.Cohen AS et al. High-flow oxygen for treatment of cluster headache. JAMA 2009;302: Colman I et al. Parenteral dexamethasone for acute severe migraine headache: meat-analysis of randomized controlled trials for preventing recurrence. BMJ 2008;336: Friedman BW et al. The relative efficacy of meperidine for the treatment of acute migraine: a meta-analysis of randomized controlled trials. Ann Emerg Med 2008;52: Friedman BW et al. A randomized controlled trial of prochlorperazine versus metoclopramide for treatment of acute migraine. Ann Emerg Med 2008;52: Friedman BW et al. Treating headache recurrence after emergency department discharge: A randomized controlled trial of naproxen versus sumatriptan. Ann Emerg Med 2010;

90 References 6.Haghighi AB et al. Cutaneous application of menthol 10% solution as an abortive treatment of migraine without aura: a randomised, double-blind, placebo-controlled, crossed-over study. Int J Clin Pract 2010;64: Kostic MA et al. A prospective, randomized trial of intravenous prochlorperazine versus subcutaneous sumatriptan in acute migraine therapy in the Emergency Department. Ann Emerg Med 2010;56: Linde K et al. Acupuncture for migraine prophylaxis. Cochrane Database Syst Rev 2009;(1):CD Schurks M et al. Migraine and cardiovascular disease: systematic review and meta-analysis. BMJ 2009;339:b3914.

91 References 10.Singh A et al. Does the addition of dexamethasone to standard therapy for acute migraine headache decrease the incidence of recurrent headache for patient treated in the emergency department. Acad Emerg Med 2008;15: Spector JT et al. Migraine headache and ischemic stroke risk: an updated meta-analysis. Am J Med 2010;123:


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