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Ana Recober, MD Roy J and Lucille A Carver College of Medicine University of Iowa Iowa City, IA INTRODUCTION Headache is the fifth most common complaint in the ED, representing about 2% of all ED visits in the US [McCaig, Adv Data 2006]. While the majority of the patients are found to have primary headaches (60% of them migraine), 25 % are found to have a secondary headache and 10% of the patients have a coexisting primary and secondary headache [Friedman, Ann Emerg Med 2007] The role of the physician in the ED is to rule out and treat potentially life-threatening conditions presenting as headaches and to provide headache relief. In the case of primary headaches, an accurate diagnosis of the headache disorder (migraine, tension-type headache, cluster headache, other trigeminal autonomic cephalalgias, etc) is also important to provide appropriate acute treatment. Here we will discuss the approach to diagnosis of acute non-traumatic headaches presenting to the emergency department, focusing on the identification and appropriate evaluation of potentially dangerous headaches, as well as the treatment of severe primary headaches. EVALUATION OF ACUTE NON-TRAUMATIC HEADACHES IN THE ED History: A careful history is crucial when evaluating a patient with headaches. In the ED we need to obtain a detailed description of the current headache, including: - Onset (What was the patient doing when the headache started? Did it start suddenly or slowly?) - Duration of the headache - Progression (constant, fluctuating, intermittent or progressively worsening from onset without improvement?) - Severity (current, maximum severity and time to reach maximum severity) - Quality of pain (sharp, pressure-like, throbbing, burning) - Location of pain (presence of neck pain, irradiation of pain) - Associated symptoms (autonomic symptoms, nausea, photo/phonophobia, neck pain) - Modifying factors (triggers, aggravating and ameliorating factors) In addition to obtaining a detailed description of the current headache, it is important to ask the patient about previous headaches and carefully compare them. I find very helpful to ask patients if they feel that the current headache is different from previous ones and what makes it different. Information about previously effective treatments for headaches and medications taken during the previous 24 hours for the current headache should be documented, including over-the-counter medications. A careful review of systems will guide our differential diagnosis.

Finally, we must obtain a complete past medical history, including current medications, recent medication changes, drug allergies and/or adverse reactions, as well as relevant family and social history. Physical examination: A thorough physical exam must include vital signs, cardiac exam, assessment of cranial structures (teeth, eyes, ears, sinuses, pericranial muscles, temporal arteries), neck movements to rule out signs of meningeal irritation, head and neck auscultation to rule out bruits, mental status evaluation, fundi exam to rule out papilledema, cranial nerves examination, and assessment of strength, reflexes, coordination, sensation and gait to rule out focal signs. Red Flags Features of the history or exam that raise concerns of secondary headache: New onset headache, new headache type or change in pattern of previous primary headache, especially after age 50 Progressively worsening headache New level of pain (worst headache of patients life) Abrupt onset headache (Thunderclap headache) Headache initiated by exertion or Valsalva maneuver Neurological symptoms or signs (excluding typical aura) Systemic symptoms or signs (fever, weight loss, scalp artery tenderness, nuchal rigidity) Secondary risk factors (Hx of cancer or immunosuppression)

Differential diagnosis of thunderclap headache: Thunderclap headache is an acute headache with a sudden onset and maximum severity of pain at onset [Schwedt, Lancet Neurol 2006]. Primary thunderclap headache can be recurrent and usually has a benign course, but remains a diagnosis of exclusion. The following conditions should be suspected and ruled out in any patient presenting with a thunderclap headache [Schwedt, Lancet Neurol 2006]: Subarachnoid hemorrhage Sentinel headache Cerebral venous sinus thrombosis Cervical artery dissection Spontaneous intracranial hypotension Pituitary apoplexy Retroclival hematoma Acute ischemic or hemorrhagic stroke Acute hypertensive crisis Reversible cerebral vasoconstriction syndrome Third ventricle colloid cyst Intracranial infection

Primary cough, sexual, and exertional headache Primary thunderclap headache

Testing: Routine blood tests are usually normal and may not assist much with the diagnosis except for an elevated erythrocyte sedimentation rate, which suggests giant cell arteritis or infection. A non-contrast head CT scan is usually obtained first when a secondary headache is suspected. A normal noncontrast head CT does not preclude a secondary headache. Furthermore, the sensitivity of CT to detect subarachnoid blood decreases with time (92% first 24 hours, 86% one day later, 76% two days letter, and 50% at one week) [Edlow, New Engl J Med 2000]. Even when interpreted by neuroradiologists, modern CT imaging is 97.5% sensitive [Morgenstern, Ann Emerg Med 1998] Lumbar puncture should always be performed when subarachnoid hemorrhage is suspected if non-contrast head CT scan is negative, equivocal, or technically inadequate [Edlow, New Engl J Med 2000]. CSF xanthochromia is 93% sensitive, 95% specific, and has a 72% positive predictive value, and 99% negative predictive value [Dupont, Mayo Clin Proc 2008]. Further diagnostic tests such as brain MRI with and without gadolinium, head and neck MRA, MRV, and cerebral angiography may be required based on the suspected diagnosis. The following table summarizes the most common tests used for evaluation of headache in the ED and their specific indications: Suspected diagnosis Mass lesion, SAH, stroke Mass lesion, vascular anomaly (arterial dissection, AVM, aneurysm, venous thrombosis, stroke, Chiari malformation, CSF leak) Aneurysm, AVM, vasculitis, venous thrombosis, arterial dissection Meningitis, SAH, IIH, CSF leak Acute sinusitis Giant cell arteritis Infection Hypoxemia/hypercarbia Thyroid disease Lyme disease Drugs/alcohol CT scan MRI, MRA, MRV Test


Lumbar puncture Maxillofacial CT ESR and CRP WBC and blood cultures Arterial blood gases TSH/T4 Lyme antibodies Drug/alcohol screen

TREATMENT OF SEVERE HEADACHES IN THE ED The management of secondary headaches is usually directed to treating the underlying cause of the headache. In the case of primary headaches, the goals are to: 1) provide effective, fast and sustained relieve of pain and associated symptoms, 2) restore the patients ability to function, 3) minimize the need for rescue medications, and

4) avoid adverse events. Finally, appropriate referral for definitive headache management should be arranged upon discharge from the ED. There are some general principles that apply to the acute treatment of primary headaches regardless of the type of headache: Provide a quite, cool, darkened room for the patient to rest Reassure the patient Administer IV hydration when necessary Treat nausea and vomiting aggressively and quickly Use headache-specific medications whenever possible depending on the primary headache disorder diagnosed (migraine, cluster, tension-type headaches) Use effective doses and appropriate routes of administration (usually parenteral in ED setting) Limit opioids to refractory situations or when other drugs are contraindicated Educate the patient about their condition and about future outpatient acute treatment

Acute Treatment of Migraine in the ED There are several guidelines available addressing the acute treatment of migraine: US Headache Consortium for the AAN [Silberstein, Neurology 2000] American Academy of Family Physicians and the American College of Physicians-American Society of Internal Medicine [Snow 2002] Canadian Association of Emergency Physicians [Ducharme 1999] Canadian Medical Association [Pryse-Philips 1997]

The following table summarizes the medications recommended for acute treatment of migraine by the US Headache Consortium that are more relevant to the ED setting [Silberstein, Neurology 2000]: Group 1: Proven, pronounced statistical and clinical benefit (at least 2 double-blind, placebocontrolled studies and clinical impression of effect) Group 2: Moderate statistical and clinical benefit (1 double-blind, placebo-controlled studies and clinical impression of effect) Sumatriptan SC/IN DHE (IV/IM/SC/IN) w/wo antiemetic Prochlorperazine IV Butorphanol IN Prochlorperazine IM/PR Chlorpromazine IV/IM Metoclopramide IV Ketorolac IM Lidocaine IN Meperidine IM/IV Buthorphanol IM Methadone IM Group 3: Statistically but not proven clinically or clinically but not proven statistically (conflicting or inconsistent evidence) Group 4: Proven to be statistically or clinically ineffective (failed efficacy versus placebo) Group 5: Clinical and statistical benefits unknown (insufficient evidence available) Metoclopramide IM/PR

Chlorpromazine IM Granisetron IV Lidocaine IV Dexamethasone IV Hydrocortisone IV

Despite strong evidence supporting the use of triptans, DHE and dopamine antagonists (prochlorperazine, chlorpromazine, and metoclopramide) for acute treatment of severe primary headaches in the ED, a study that included 100 million ED visits in the US (1998 National Hospital Ambulatory Medical Care Survey) revealed that the most commonly used medications were meperidine (30%), ketorolac (21%), and prochlorperazine (17%). Promethazine and hydroxyzine, which dont have anti-headache effects, were used 6 times more commonly as adjunct antiemetics of parenteral opioids than the dopamine antagonists (prochlorperazine, chlorpromazine, and metoclopramide) [Vinson, Ann Emerg Med 2002]. Triptans Sumatriptan 6 mg SC is the triptan of choice in the ED. Importantly, sumatriptan 6 mg SC has been demonstrated to be effective for the acute treatment of undifferentiated primary headaches (migraine, probable migraine and tension-type headaches) in the ED [Miner, Am J Emerg Med 2007]. Common adverse effects of triptans include chest and neck tightness, paresthesias, flushing, and dizziness. Triptans are contraindicated in patients with cardiovascular disease, uncontrolled hypertension, severe peripheral vascular disease, basilar or hemiplegic migraine, patients that have used ergots or other 5-HT1 agonists within the previous 24 hours or MAO inhibitors during the previous 2 weeks. Triptans are contraindicated in pregnancy, although registry data does not show an increase in rates of birth defects. Sumatriptan is considered compatible with lactation.

IV DHE Intravenous DHE administered every 8 hours [Raskin, Headache 1990] or as a continuous infusion [Ford, Headache 1997] are effective ways to treat transformed migraine. To avoid nausea, premedication with metoclopramide 10 mg IV, prochlorperazine 10 mg IV, or chlorpromazine 12.5 mg IV, should be used 15 min prior to DHE 0.5 mg IV. Benztropine mesylate 1 mg IV or diphenhydramine 25 mg IV may be considered prior to the antiemetic to avoid extrapyramidal symptoms. If the first dose of DHE is well tolerated, without unstable blood pressure or chest pain, then a second dose of DHE 0.5-1 mg IV can be given 1 hour later [Colman, Ann Emerg Med 2005]. The Raskin protocol (DHE 0.5 mg IV q8h) [Raskin, Headache 1999] and the Ford protocol (DHE 3 mg IV in 1 lit of normal saline continuous infusion over 24 hours) [Ford, Headache 1997] may be more convenient in the inpatient setting, but they are worth consider in some cases in the ED. Limitations to treatment with DHE include previous use of triptans within 24 hours, hypertension, intractable nausea, and pregnancy. Antiemetics Prochlorperazine is probably one of the best studied antiemetics for the treatment of migraine. A recent metaanalysis concluded that phenothiazines used for acute treatment of migraine (prochlorperazine and chlorpromazine) are superior to placebo and also clinically preferable to other agents (metoclopramide, meperidine, ketorolac, valproate, and sumatriptan) [Kelly, Headache 2009]. A randomized, double-blind, placebo controlled trial comparing a combination of prochlorperazine 10 mg IV + diphenhydramine 12.5 mg IV with sumatriptan 6 mg SC showed that prochlorperazine with diphenhydramine is more effective than subcutaneous sumatriptan in the ED setting, without differences in sedation, nausea and headache recurrence [Kostic, Ann Emerg Med 2010] A single dose of prochlorperazine 10 mg IV was more effective than Ketorolac 30 mg IV in the ED setting [Seim, Acad Emerg Med 1998]. In another randomized, double-blind clinical trial, also in the ED, prochlorperazine 10 mg IV was superior to valproate 500 mg IV infusion in reducing pain, nausea and the need for rescue treatment [Tanen, Ann Emerg Med 2003]. In this study, prochlorperazine reduced pain within 30 min and nausea within 15 min. A randomized controlled trial comparing prochlorperazine 10 mg IV with metoclopramide 20 mg IV (both in combination with diphenhydramine 25 mg IV) demonstrated that both drugs are equally effective and tolerated [Friedman, Ann Emerg Med 2008b) Metoclopramide has also been compared with sumatriptan SC for acute treatment of migraine in the ED. In a randomized, double-blind, clinical trial, patients received sumatriptan 6 mg SC once or metoclopramide 20 mg IV every 30 min for 2 hours. The group that received metoclopramide was also given diphenhydramine 25 mg with metoclopramide at 0 and 60 min, which may have some added beneficial effect on the headache. Metoclopramide and sumatriptan were comparable in pain control at 2 and 24 hours and headache recurrence although there was a trend favoring metoclopramide [Friedman, Neurology 2005]. Metoclopramide 20 mg IV every 30 min for 2 hours may represent a good alternative to sumatriptan in patients that have already used triptans prior to their visit to the ED or when triptans are contraindicated for any other reason. A recent randomized, double-blind, dose finding study did not reveal any superiority of metoclopramide 20 or 40 mg compared with 10 mg IV [Friedman, Ann Emerg Med 2011]. Chlorpromazine 0.1 mg/Kg IV was superior to placebo in a double-blind randomized trial, resulting in better control of pain and associated symptoms at 30 min and 2 h, and lower recurrence rates and need for rescue treatment. Sedation and hypotension occurred more commonly with chlorpromazine [Bigal, J Emerg Med 2002]. Another randomized, double-blinded study found that 0.1 mg/kg/dose IV of either chlorpromazine or metoclopramide were comparable and effective [Cameron, Acad Emerg Med 1995]. A small prospective, randomized, double-blind trial found no difference between ketorolac 60 mg IM and chlorpromazine 25 mg IV [Shrestha, Arch Intern Med 1996]

Meperidine In a recent meta-analysis meperidine was compared with non-opioid treatments (dihydroergotamine, antiemetic alone, or ketorolac) [Friedman, Ann Emerg Med 2008]. Meperidine (50-100 mg) was found to be less effective than dihydroergotamine, trended toward less efficacy than antiemetics (chlorpromazine, metoclopramide, droperidol, prochlorperazine, and methotrimeprazine); and was similar to ketorolac. Meperidine caused more sedation and dizziness than dihydroergotamine, similar gastrointestinal side effects and sedation as ketorolac, and less akathisia than antiemetics [Friedman, Ann Emerg Med 2008]. Despite this, meperidine was found to be the most commonly administered opioid patients treated with opioids, the majority (77%) did not receive any non-opioid ab(70%) in a study across different EDs in the US and it was also noted that among ortive headache medication [Vinson, Ann Emerg Med 2002]. Opioids should be limited to very specific circumstances where other first line headache medications are contraindicated Acute Treatment of Migraine in the Pediatric Population Sumatriptan 5 and 20 mg nasal spray have shown to have the most favorable profile (class I) based on the practice parameter for pharmacological treatment of migraine headache in children and adolescents from the American Academy of Neurology Quality standards Subcommittee and the Practice Committee of the Child Neurology Society [Lewis, Neurology 2004]. There is insufficient data regarding oral or subcutaneous sumatriptan in this population. Antiemetics remain an option for children and adolescent, but further research is needed [Walker, Curr Opin Pediatr 2008], [Bailey, Ped Emerg Care 2008]. In a randomized, double-blind trial prochlorperazine IV (0.15 mg/kg, max 10 mg) was found to be superior to ketorolac IV (0.5 mg/kg, max 30 mg) [Brousseau, Ann Emerg Med 2004]. Acute Treatment of Migraine during Pregnancy Most pregnant women report an improvement of their migraine during the second and third trimesters, but in some cases migraine may worsen during the first trimester. The lack of controlled and safety studies in pregnant women makes recommendations difficult. Because pregnancy is an exclusion criterion in most clinical trials, there is no evidence that the effective therapies discussed above for acute migraine treatment are effective or safe for pregnant women. Nevertheless, in cases of severe refractory migraine, hydration in combination with an injectable dopamine antagonist, and a triptan may be considered [Lucas, Curr Pain Headache Rep 2009]. Data from manufacturer-sponsored pregnancy registries, retrospective and observational studies suggest that sumatriptan is safe during pregnancy and breastfeeding and does not increase the risk of birth defects [Duong, Can Fam Physician 2010] [Evans, Ann Pharmacother 2008]. Opioids are frequently used during pregnancy although they should be used with caution. Dihydroergotamine and valproic acid are contraindicated in pregnancy. Acute Treatment of Cluster Headache in the ED A recent randomized trial has confirmed the efficacy of inhaled oxygen at 100%, 12 L/min, by face mask, for 15 minutes resulting in pain resolution in 15 min [Cohen, JAMA 2009] Sumatriptan 6 mg SC is the most effective medication for the acute treatment of cluster attacks [The Sumatriptan Cluster Headache Study Group, N Engl J Med 1991]. Alternatives to subcutaneous sumatriptan are intranasal sumatriptan 20 mg [van Vliet, Neurology 2003] and intranasal zolmitriptan 5 and 10 mg [Cittadini, Arch Neurol 2006], although these take longer to abort a cluster attack than sumatriptan SC. Intravenous DHE was also found effective in the acute treatment of cluster headaches [Mather, Headache 1991] and may be a good alternative to sumatriptan for those that do not respond to or cannot tolerate sumatriptan [Baron, Headache 2010].

Intranasal lidocaine 4% ipsilateral to the pain may be considered as co-adjuvant therapy but should not be used alone to abort an attack [Robbins, Headache 1995] Finally, peripheral nerve blocks and trigger point injections may have a role in the management of acute cluster attacks in the ED setting, but more research is needed to confirm this [Ashkenazi, Headache 2010], [Scattoni, Headache Pain 2006], [Ambrosini, Pain 2005]. SUMMARY Headache represents one of the more common reasons adults seek care in the emergency department (ED). The main goal when evaluating non-traumatic headaches in the ED is to distinguish between primary and secondary headaches. Secondary headaches can be benign or dangerous and occasional life-threatening. The majority of the headaches seen in the ED represent primary headaches, but an accurate diagnosis to rule out secondary headaches is crucial. One must carefully evaluate the patient with a detailed history and thorough physical examination to determine if further investigation is required. The following red flags warrant further specific diagnostic investigation: New onset headache, new headache type or change in pattern of previous primary headache, especially after age 50 Progressively worsening headache New level of pain (worst headache of patients life) Abrupt onset headache (Thunderclap headache) Headache initiated by exertion or Valsalva maneuver Neurological symptoms or signs (excluding typical aura) Systemic symptoms or signs (fever, weight loss, scalp artery tenderness, nuchal rigidity) Secondary risk factors (Hx of cancer or immunosuppression)

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