When and How to Investigate the Patient with Headache

G.C. De Luca, M.D., Ph.D.,1 and J.D. Bartleson, M.D.1

ABSTRACT

KEYWORDS: Headache, diagnostic testing, investigation, neuroimaging, guidelines

eadache is one of the most common medical symptoms and reasons for neurologic consultation. Although the majority of headache disorders are benign, clinicians are faced with the crucial task of deciphering benign variants from conditions that threaten life and neurologic function.1 As the potential causes of headache are many, and the number of randomized controlled studies on when and how to investigate the complaint of headache are few, the clinician is left with the daunting challenge of appropriately investigating the patient who presents with headache. A systematic apDepartment of Neurology, Mayo Clinic College of Medicine, Rochester, Minnesota. Address for correspondence and reprint requests: J.D. Bartleson, M.D., Associate Professor of Neurology, Mayo Clinic College of Medicine, Mayo Building, 8th oor, 200 First Street SW, Rochester, MN, 55905 (e-mail: bartleson.john@mayo.edu).
1

proach to headache classication and diagnosis, therefore, is paramount and serves as the focus of this review. Headache disorders are broadly classied as primary or secondary in the International Classication of Headache Disorders, 2nd edition (ICHD-2) (Table 1).2 Diagnosis of one of the primary headache disorders is principally based on historical headache features and the exclusion of other disorders. In the absence of conrmatory diagnostic tests for primary headache disorders, the clinician is faced with the need to consider, if not rule out, one or more secondary headache disorders that can
Headache; Guest Editor, Jerry W. Swanson, M.D., F.A.C.P. Semin Neurol 2010;30:131144. Copyright # 2010 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel: +1(212) 584-4662. DOI: http://dx.doi.org/10.1055/s-0030-1249221. ISSN 0271-8235.

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The common complaint of headache usually has a benign cause, most often a primary headache syndrome. The history and neurologic and general physical examinations usually permit a denitive diagnosis. When in doubt, diagnostic testing is indicated. Certain historical and examination ndings increase the likelihood of a secondary headache disorder and the need for diagnostic testing. These include (1) recent head or neck injury; (2) a new, worse, worsening, or abrupt onset headache; (3) headache brought on by Valsalva maneuver or cough; (4) headache brought on by exertion; (5) headache associated with sexual activity; (6) pregnancy; (7) headache in the patient over the age of 50; (8) neurologic ndings and/or symptoms; (9) systemic signs and/or symptoms; (10) secondary risk factors, such as cancer or human immunodeciency virus (HIV) infection. Less worrisome are headaches that wake the patient from sleep at night, always occur on the same side, or show a prominent effect of change in posture on the patients pain. Diagnostic studies include neuroimaging, cerebrospinal uid (CSF) examination, and blood tests, which are selected depending on the patients history and ndings. For most patients, the diagnostic test of choice is a magnetic resonance imaging (MRI) brain scan. Computed tomography (CT) of the brain is usually obtained in the setting of trauma or the abrupt onset of headache. CSF examination is useful in diagnosing subarachnoid bleeding, infection, and high and low CSF pressure syndromes.

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Table 1 International Classification of Headache Disorders, 2nd Edition2

The primary headaches Migraine Tension-type headache Cluster headache and other trigeminal autonomic cephalalgias Other primary headaches Primary stabbing headache Primary cough headache Primary exertional headache Primary headache associated with sexual activity Pre-orgasmic headache Orgasmic headache Hypnic headache Primary thunderclap headache Hemicrania continua New daily persistent headache The secondary headaches Headache attributed to head and/or neck trauma Headache attributed to cranial or cervical vascular disorder Headache attributed nonvascular intracranial disorder Headache attributed to a substance or its withdrawal Headache attributed to infection Headache attributed to disorder of homeostasis Headache or facial pain attributed to disorder of cranium, neck, eyes, ears, nose, sinuses, teeth, mouth, or other facial or cranial structures Headache attributed to psychiatric disorder Cranial neuralgias, central and primary facial pain, and other headaches Cranial neuralgias and central causes of facial pain Other headache, cranial neuralgia, central or primary facial pain

mimic a primary headache. In fact, virtually all of the primary headache disorder diagnostic criteria include the disclaimer not attributed to another disorder suggested by the history, and/or physical and neurologic examinations, and recommend that secondary headaches be ruled out by appropriate investigations, but specic test recommendations are usually lacking. Criteria for the primary headache disorders require several attacks making it difcult to make a diagnosis after just one or two headaches. Secondary headache disorders may be easily camouaged in presentations suggestive of or combined with a common primary headache diagnosis. Even when a patient meets criteria for a primary headache disorder, investigations may be required to exclude ominous contributing causes. In fact, many of the other primary headaches (Table 1) can only be diagnosed after potential culprits responsible for secondary headache disorders are ruled out with appropriate testing. The ICHD-2 classication of secondary headache disorders is organized by causation. In this vein,

WHEN TO CONSIDER INVESTIGATING THE PATIENT WITH HEADACHE The accurate diagnosis of headache relies heavily on a careful history, supplemented by detailed general and neurologic examinations.21,22 Elements of the history and physical examination enable the clinician to diagnose primary headache disorders, and to elicit suspicion of secondary headache disorders that require prompt investigation. A diagnostic algorithm to guide this process is given in Fig. 1.

The Red Flags

TRAUMA AND HEADACHE

It is important to extract a history of recent and remote head or neck injury in evaluating the patient with headache.1,3,18 Often overlooked, head or neck trauma is, of course, essential for a diagnosis of posttraumatic headache. In addition, its presence should prompt the clinician to exclude hemorrhage (epidural, subdural, subarachnoid, intraparenchymal),23 and arterial dissection (of a carotid or vertebral artery)24 as possible causes. Although a short interval between trauma and the onset of headache often facilitates prompt and appropriate neuroimaging, a remote history of trauma relative to headache onset should also raise suspicion of subdural hematoma and arterial dissection.24 Several case reports

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once the suspicion of a secondary headache disorder is raised, the ICHD-2 criteria recommend conrmatory testing and/or call for improvement in the headache after treatment of the underlying cause. Although the ICHD2 diagnostic criteria help guide the clinician to a specic diagnosis, they do not provide recommendations for when and how to investigate the individual patient with headache. When should the patient with headache be investigated? An important strategy to identify or exclude secondary headache disorders is to search for red ags, both in the history and on general and neurologic examinations (Table 2). The presence of any of these worrisome features increases the likelihood that a possible underlying serious medical or neurologic condition may contribute to the headache presentation, and should prompt the clinician to conduct testing.1,320 Other concerning symptoms that should fuel consideration of additional evaluation include three yellow ags (Table 2). The evidence for these features is not as strong as for the red ag indicators. Although the decision to obtain diagnostic tests on the patient with headache primarily rests on historical features and examination ndings, there are nonmedical reasons that affect the decision-making process (Table 3).1,3,4,18,19

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Table 2 Headache Warning Flags

Warning Flag Red ags Head or neck injury Hemorrhage Epidural Subdural Subarachnoid Intraparenchymal Dissection Carotid Vertebral New onset or new type or worsening pattern of existing headache Mass lesion Subdural hematoma Medication overuse Meningoencephalitis Abrupt or split-second onset Intraparenchymal hemorrhage Bleed into a mass or arteriovenous malformation Dissection Cerebral venous thrombosis Pituitary apoplexy Spontaneous intracranial hypotension Reversible cerebral vasoconstriction syndrome Acute hypertensive crisis Mass lesion (especially posterior fossa) Triggered by Valsalva maneuver or cough Triggered by exertion Primary thunderclap headache Chiari malformation Mass lesion Subarachnoid hemorrhage Dissection Anginal equivalent Pheochromocytoma Triggered by sexual activity (pre-orgasmic, orgasmic) Headache during pregnancy or puerperium Age >50 years Subarachnoid hemorrhage Dissection Cortical vein / cranial sinus thrombosis Pituitary apoplexy Brain tumor (primary, metastatic) Cerebrovascular disease Giant cell arteritis Neurologic signs or symptoms (seizures, confusion, impaired alertness, weakness, papilledema, etc.) Mass lesion Arteriovenous malformation Connective tissue disease Benign intracranial hypertension Meningoencephalitis Systemic illness Fever Nuchal rigidity Systemic infection Meningoencephalitis Meningeal carcinomatosis Lyme disease Collagen vascular disease Weight loss Scalp artery tenderness Malignancy Giant cell arteritis New level of pain (e.g., worst ever) Subarachnoid hemorrhage Considerations

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Table 2 (Continued )
Warning Flag Red ags (Continued ) Secondary risk factors Cancer Immunocompromised host (HIV, on immunosuppressants, etc.) Recent travel (domestic, foreign) Yellow ags Wakes patient from sleep at night Sleep-related disorders (e.g., obstructive sleep apnea) Rebound withdrawal headaches Poorly controlled hypertension New onset side-locked headaches Head trauma Dissection Intracranial aneurysm Lung carcinoma Postural headaches
HIV, human immunodeficiency virus.

Considerations

Metastatic disease Opportunistic infection Meningoencephalitis

Spontaneous intracranial hypotension Post-lumbar puncture

of dural venous thrombosis stemming from antecedent head injury with headache being the only symptom should also alert the clinician to this diagnostic possibility.25 The potential implications of trauma are increased in patients taking antiplatelet or anticoagulation agents or with an underlying bleeding diathesis, coagulopathy, or connective tissue disease, wherein even trivial head injury in the weeks and months prior to headache onset is important. A history of chiropractic manipulation of the cervical spine, though not considered an injury, should be sought given its association with both carotid and vertebral artery dissections.24 There has been much discussion about the diagnostic utility of computed tomography (CT) in the setting of head trauma. CT brain scans are very likely to show abnormalities in the patient with signs of raised intracranial pressure, altered mental status, skull fracture, seizures, cranial nerve abnormalities, or focal neurologic signs, and studies have shown that up to 30% of patients with a history of head trauma and normal neurologic examination may have associated CT brain scan ndings, some of which require immediate intervention.26,27 In light of the fact that subdural and even epidural hematomas may develop some time after head injury, it is not unreasonable to consider repeat CT or magnetic

resonance imaging (MRI) of the brain in any patient with evolving symptoms, increasing headache, or change in headache who initially presented with normal brain imaging.
HEADACHE FEATURES AS RED FLAGS

There are certain headache features that are considered red ags, including new onset of headache, onset of new headache type, change for the worse in an existing pattern of headache, new level of pain (e.g., worst ever), or abrupt or split-second onset. In a prospective study of patients with new or worsening headache, it was found that headaches of organic origin (39% of the total) had a shorter mean duration (2.9 months) compared with nonorganic headaches (8.2 months) leading the authors to conclude that a headache duration of 6 months is signicant.28 Rapidly increasing headache frequency has been associated with increased frequency of CT imaging abnormalities.13 It is evident that eliciting important clues in the headache history, such as new onset, new headache type, and worsening headache features (i.e., severity, frequency, change in pattern), is essential to the appropriate selection of patients requiring further testing, usually brain imaging with CT or MRI.

Table 3 Other Considerations that Influence Diagnostic Testing of the Patient with Headache
Increase Diagnostic Testing Need for diagnostic certainty Reassure patients, families, and referring providers Meet patient, relative, referring provider expectation Financial incentives Medicolegal concerns Faulty medical reasoning Decrease Diagnostic Testing Financial incentives Lack of patient means or insurance coverage Risk of diagnostic intervention Adverse consequences of nding and pursuing incidental abnormalities Faulty medical reasoning

Reprinted with permission from Bartleson JD. When and how to investigate the patient with headache. Semin Neurol 2006;26:165.

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Figure 1 Algorithm for the evaluation of headache disorders. (Copyrighted and used with permission of the Mayo Foundation for Medical Education and Research.)

The most worrisome headache warning sign that should prompt investigation is the abrupt or split-second onset of headache.29,30 These headaches, termed thunderclap headaches, are characterized by the very sudden onset of usually severe pain that typically reaches maximal intensity at or very soon after onset. Thunderclap headache is the characteristic presenting symptom of subarachnoid hemorrhage.29,30 An estimated 11 to 25% of patients with thunderclap headache may have bleeding in the subarachnoid space.31 A small subset of patients may present similarly in the setting of unruptured cerebral aneurysm.29,30 Other important etiologies of sudden onset headache that must be considered, include intracerebral hemorrhage, hemorrhage into a mass or an arteriovenous malformation (AVM), arterial dissection, cerebral venous thrombosis, spontaneous intracranial hypotension, reversible cerebral vasoconstriction syndromes, pituitary apoplexy, acute hypertensive crisis, and idiopathic primary thunderclap headache.2,29 Primary thunderclap headache can be associated with transient vasospasm and can recur. The abrupt onset of headache obligates further evaluation, and urgent if not emergent noncontrast CT brain imaging is impera-

tive.2,29,30 As the sensitivity of CT imaging to detect subarachnoid hemorrhage is inversely related to the time elapsed following the bleeding event (95% within 24 hours, 74% by day 3, 50% by day 7, 30% by day 14, and nearly 0% after day 21), most authors strongly recommend that a lumbar puncture (LP) be performed (looking for red blood cells and/or xanthochromia) after a negative CT result in patients with suspected subarachnoid hemorrhage.1,3,4,18,29,30,32,33 Even if the CT brain scan and cerebrospinal uid (CSF) examination are normal, the clinician evaluating thunderclap headache should strongly consider obtaining MRI of the brain and MR angiography (MRA) and venography (MRV) of the intracranial and cervical vessels to exclude secondary headache disorders. CT angiography (CTA) and venography (CTV) are comparable to MRA and MRV in this setting.29,30,34,35
VALSALVA/COUGH HEADACHE

Headaches triggered by Valsalva maneuver, cough, or exertion often raise concern of underlying central nervous system (CNS) pathology and warrant investigation.36 Valsalva- and cough-induced headaches are

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PREGNANCY AND HEADACHE

EXERTIONAL HEADACHE

Exertion-induced headaches can also be attributed to a structural cause. In one case series, 12 of 28 patients presenting with exertional headache had an underlying structural cause. Ten of the 12 had subarachnoid hemorrhage, but only two of the 10 were found to have a bleeding source (aneurysms).39 Exertional headaches are similar to headaches associated with sexual activity in that both can occur as a primary headache disorder, and each can be associated with migraine.2,36,39 As exertional headache can occur secondary to subarachnoid hemorrhage and arterial dissection, the ICHD-2 deems it mandatory to exclude these conditions on the rst occurrence of this type of headache.2
HEADACHE ASSOCIATED WITH SEXUAL ACTIVITY

Headache associated with sexual activity should be considered a red ag. This headache subtype is differentiated into pre-orgasmic and orgasmic headaches based on the time course of headache onset. Pre-orgasmic headaches are characterized by pain that builds gradually along with sexual excitement compared with orgasmic headaches where the pain strikes within 5 seconds before or at orgasm.2,40 Although orgasmic headache is more worrisome regarding an underlying structural problem such as subarachnoid hemorrhage, it is prudent to evaluate pre-orgasmic as well as orgasmic headache before concluding they are a primary headache associated with sexual activity and not due to underlying structural disease. It is worrisome to note that 4 to 12%

Headache during pregnancy presents a unique challenge to the clinician. Pregnancy often favorably impacts the course of migraine; however, pregnancy and the puerperium predispose women to several life-threatening conditions that often manifest as headache.4346 The causes of secondary headache in pregnancy are numerous, and include preeclampsia, hemorrhagic or ischemic stroke, idiopathic intracranial hypertension, postpartum dural puncture headache, postpartum cerebral angiopathy, pituitary apoplexy, and cerebral venous thrombosis.46 Pregnant women are particularly susceptible to ominous headache syndromes given their relative hypercoagulable state, especially in the postpartum period.47 Several diagnostic tools evaluate new onset headache during pregnancy: urinalysis, complete blood count, blood chemistries, liver function tests, CSF analysis (including xanthochromia), and coagulation studies. Brain imaging is an important complement to these studies. An MRI brain scan without gadolinium is safe in all trimesters in pregnancy, and in fact is the preferred imaging modality to search for structural causes of secondary headaches in pregnancy.48 A CT head scan without contrast is useful to rule out life-threatening conditions such as subarachnoid or intraparenchymal hemorrhage, and is deemed to be fairly safe if radiation exposure to the fetus is less than 1 millirad.46
AGE AND HEADACHE

Age is an important factor to consider when evaluating the patient with headache. Several prospective observational studies in the emergency room setting have validated the notion that new onset headache after the age of 50 years is associated with an increased likelihood of intracranial pathology.4952 The data are not entirely surprising given that with increasing age there is heightened risk of many conditions that can present with

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combined into one entity by the ICHD-2, and should be viewed separately from exertion-induced headaches. In the absence of an underlying cause, both Valsalva/ cough-induced and exertion-induced headaches can occur as primary headache disorders2; only secondary causes of these headache types will be addressed here. Valsalva/cough headache should raise suspicion of a hindbrain malformation or mass lesion, occipitocervical junction disorder, or increased intracranial pressure.3638 In a large prospective series followed clinically and radiographically, 40 out of 68 participants (59%) with Valsalva/cough-induced headache were found to have secondary causes, all of which were due to structural lesions in the posterior fossa, the majority being Chiari malformations.38 Another case series reported similar ndings, with 40% being symptomatic and most having Chiari malformation as the cause.39 When compared with primary Valsalva/cough headaches, the secondary variety typically began earlier (mean 40 vs. 60 years old), lasted longer (mean 5 years vs. 11 months), were more likely to be located posteriorly, and were associated with symptoms/signs attributable to the posterior fossa.38 In light of these ndings, MRI is recommended to exclude Chiari malformation and other intracranial structural causes that are associated with Valsalva/cough headache.

of all patients with subarachnoid hemorrhage have onset during sexual activity.41,42 The ICHD-2 criteria specifically state that On rst onset of orgasmic headache it is mandatory to exclude conditions such as subarachnoid hemorrhage and arterial dissection.2 If the patient is being seen very soon after their rst attack (i.e., within 48 hours), a CT brain scan followed by LP if the CT scan is negative would be appropriate; the presence of subarachnoid blood would then prompt conventional cerebral angiography. If there is no evidence of bleeding, then one would obtain an MRA or CTA of the cervical and intracranial vessels. If days or weeks have elapsed, then an MRI brain scan with and without gadolinium and MRA or CTA of the cervical and intracranial vessels would be appropriate. Evaluation of the coronary arteries (to rule out headache as an anginal equivalent) and evaluation for pheochromocytoma should be obtained in appropriately selected cases.42

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headache, such as primary and metastatic brain tumors, cerebrovascular disease, and especially giant cell (temporal) arteritis. In the older patient, secondary causes for new headache should be sought, with testing catered to the specic clinical presentation. Brain imaging and blood work, especially erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP), are reasonable considerations. A patient of any age with a stable history of headaches dating back decades that can be classied into one of the primary headache disorders, however, need not undergo investigation.2
NEUROLOGIC SIGNS AND SYMPTOMS

should be sought and targeted therapies initiated. As in the patient over 50 years of age, the patient with a history of cancer or HIV infection may not need investigation of headaches that are long-standing and stable with features consistent with a primary headache disorder.

The Yellow Flags

HEADACHE THAT AWAKENS THE PATIENT FROM SLEEP

SYSTEMIC SIGNS AND SYMPTOMS

A detailed review of systems and complete general medical examination may provide valuable insight into the differential diagnosis of headache. Systemic signs or symptoms such as fever (meningitis, encephalitis, or systemic infection), weight loss (malignancy), scalp artery tenderness (giant cell arteritis), or nuchal rigidity (meningeal irritation by blood, infection, or malignancy) warrant timely investigation that might include brain imaging possibly followed by CSF examination, blood tests (including ESR and CRP), and general medical tests searching for an occult malignancy, systemic infection, or an underlying connective tissue or another inammatory disorder.1,3,4,7,18
SECONDARY RISK FACTORS

NEW ONSET SIDE-LOCKED HEADACHES

The clinician should heed and likely investigate a patient with headache and a personal history of malignancy capable of spread to the central nervous system or at increased risk for malignancy or opportunistic infection, such as an individual with human immunodeciency virus (HIV) infection and anyone who is immunosuppressed. A history of recent travel (domestic or foreign) should alert the clinician to consider meningoencephalitis secondary to infectious organisms endemic to the region visited as a cause of headache. Marked elevations in blood pressure can cause headache, or may predispose to conditions commonly associated with headache, such as posterior reversible encephalopathy syndrome. In the setting of signicant hypertension, an underlying cause of hypertension, such as renal dysfunction or pheochromocytoma,

New onset headaches that are side-locked (i.e., always occur on the same side) suggest an anatomically circumscribed pathophysiologic mechanism which may be a symptom of intracranial pathology.58 A recent review of the literature on secondary hemicrania continua59 identied several important causes including head trauma, postpartum period, internal carotid artery dissection, intracranial aneurysm, intracranial tumor, and nonmetastatic lung carcinoma.59,60 The authors noted that a secondary cause was more likely in patients with a short duration of illness, frequent and short-lived exacerbations, recent head or neck trauma, miosis, older age, male gender, smoking history, and constitutional and respiratory symptoms.59 Patients with the new onset of strictly unilateral headaches that do not have features of one of the primary unilateral headache disorders should be investigated.
POSTURAL HEADACHES

Postural headaches should be considered as a yellow ag for the possibility of an underlying intracranial problem. Headache is the most common clinical manifestation of spontaneous intracranial hypotension, which in the majority of cases stems from a CSF leak.61 Even in the absence of a recent LP, low CSF pressure syndrome should be highly suspected in any patient whose

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There is little dispute that patients with headache who have nonmigrainous transient or persistent neurologic symptoms, seizures, reduced level of consciousness, or persistent neurologic signs merit expeditious investigation unless their neurologic symptoms and signs can be explained by another static condition.1,320,53 Unexplained neurologic signs have a higher diagnostic imaging yield than do unexplained neurologic symptoms.13 In fact, many of these patients would be studied on the basis of their neurologic signs and symptoms even if they did not have headache.

The yellow ags also warrant attention. Headaches that wake the patient from sleep may signal a serious underlying etiology, and the American Academy of Neurology (AAN) practice parameter recommends consideration of brain imaging for these patients.13 As nocturnal wakening is common in migraine, paroxysmal hemicrania, cluster headache, short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT), hypnic headache, and exploding headache syndrome, night wakening must be taken in the context of the patients total headache picture.2,54 Sleep-related disorders (e.g., obstructive sleep apnea), rebound withdrawal headaches, and poorly controlled essential hypertension can also lead to nocturnal or morning headache, and should be considered.55,56 Waking from sleep due to headache may be more worrisome in children than adults.16,57

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headaches occur when upright and attenuate on recumbency. Appropriate evaluation includes MRI of the brain with and without contrast. If the characteristic pachymeningeal enhancement and sagging brain are seen, then a search for a CSF leak by means of radioisotope cisternography, MRI of the entire spine, and/or CT or MR myelography is appropriate. A CSF leak is not always found, however.62 Brain imaging can also exclude

other rare causes of positional headache such as intraventricular and posterior fossa tumors.63

Medications and Headache Headache is often an adverse reaction to medications. It is has been estimated that over 1,000 drugs with diverse mechanisms of action can induce headache.64 Some of

Table 4 Medications that Can Cause Headache

System Cardiovascular Drug Class Calcium channel blockers Antiarrhythmics a-2 adrenergic agonists a-1 adrenergic antagonists b-adrenergic antagonists ACE inhibitors Angiotensin II inhibitors Nitrates Diuretics Phosphodiesterase inhibitors Antimicrobial Antibiotics Macrolides Penicillins Fluoroquinolones Antifungals Antivirals Immunologic/antiinammatory Immunosuppressives Interleukins Interferons Corticosteroids NSAIDs Gastrointestinal H2 receptor antagonists Proton pump inhibitors 5HT3 antagonists Prokinetic Others Endocrinologic Gonadotropin inhibitors Dopamine receptor agonists Other hormonal agents Psychiatric Antipsychotics Sedative-hypnotics Antidepressants Stimulants Miscellaneous Anti-obesity Smoke cessation aid Statins Erythropoietins Retinoid analogs Antineoplastic Prostaglandins Agents for erectile dysfunction Dirithromycin, erythromycin, roxithromycin Piperacillin-tazobactam Levooxacin, ooxacin Fluconazole, terconazole Acyclovir, amantidine, ganciclovir, lamivudine, stavudine Cyclosporine, mycophenolate, sirolimus, tacrolimus Interleukin- 3, 4, 6, 10 Interferon- a2a, a2b, b1a, b1b, g1b Budesonide, uticasone, mometasone, triamcinolone Indomethacin, ketorolac, diclofenaco, naproxen, parecoxib Cimetidine, famotidine, ranitidine Lansoprazole, omeprazole Granisetron, ondansetron Cisapride Sulfasalazine, mesalamine Bicalutamide, danazol, droloxifene, mifepristone Bromocriptine, quinagolide Leuprolide, octreotide, progesterone, OCP, HRT Clozapine, olanzapine, quetiapine, risperidone, ziprasidone Clobazam, diazepam, triazolam Bupropion, uoxetine, uvoxamine, venlafaxine Modanil Sibutramine Nicotine Lovastatin Epoetin-a, darbepoetin-a Alitretinoin, tretinoin Tegafur Alprostadil, dinoprostone, enprostil, iloprost Sildenal, tadalal, vardenal Drug Diltiazem, nicardipine, nifedipine, verapamil Flecainide, lorcainide, propafenone Clonidine Bisoprolol, carteolol Enalapril, lisinopril, quinapril Valsartan, tasosartan Nitroglycerin, isosorbide mononitrate/dinitrate Amiloride Dipyridamole, pimobendan Doxazosin, prazosin

NSAIDs, nonsteroidal antiinflammatory drugs; OCP, oral contraceptive pill; HRT, hormone replacement therapy.

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Other Chiari malformation Cerebrospinal uid hypotension with pachymeningeal enhancement and brain sag Foramen magnum and upper cervical spine lesions Pituitary apoplexy Rare encephalopathies with headache (CADASIL, MELAS, SMART) CT preferred Fractures (calvarium) Acute hemorrhage (subarachnoid, intracerebral)

HOW TO INVESTIGATE THE PATIENT WITH HEADACHE There are several diagnostic tests available to the clinician to evaluate the patient with headache. Prior to subjecting the patient to a barrage of studies, the suspicion of a secondary headache syndrome should be sufciently high. The red and yellow ags, as outlined in the previous section, should serve as a guide in this regard.

Paranasal sinus and mastoid air cell disease Draw between MRI and CT MR Angiography/CT Angiography Vasculitis (large and medium sized vessels) Intracranial aneurysms Carotid and vertebral artery dissections MR Venography/CT Venography Cerebral venous thrombosis
MRI, magnetic resonance imaging; CT, computed tomography; CADASIL, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy; MELAS, mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes; SMART, stroke-like migraine attacks after radiation therapy. Copyrighted and used with permission of the Mayo Foundation for Medical Education and Research.

Imaging Studies
CT AND MRI

Neuroimaging is the most sensitive diagnostic tool in patients with headache. As incidental brain ndings on CT and/or MRI are common in the general nonheadache population,71 the use of brain imaging should be limited to patients with headache who have an appropriate indication.3,4,13,14,18,7274 Considerations that direct the clinician to order CT or MRI include (1) the need to identify acute hemorrhage (CT preferred); (2) the need to evaluate the posterior fossa (MRI preferred); (3) general availability (CT more readily available); and (4) cost (CT is less expensive).4 MRI is more sensitive than CT scanning in identifying intracranial pathology. Table 5 shows the relative strengths of MRI and CT in revealing various pathologic intracranial processes. Although older AAN practice parameters for nonacute headache (i.e.,

headache present for at least 4 weeks) could nd no evidence that MRI was superior to CT,9,13 an evidencebased review from the EFNS Task Force and others recommend MRI and not CT for appropriate patients with nonacute headache.4,72 MRI is likely to reveal more than CT; however, many of the abnormalities will be incidental, including nonspecic white matter lesions and developmental venous anomalies.71,75
PLAIN X-RAYS

Plain x-ray lms are not indicated in the routine evaluation of the headache patient. In the setting of head and/ or neck trauma, cervical spine x-rays can be obtained, with exion and extension, odontoid, and pillar views added to help exclude or conrm ligamentous injury,

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the more commonly associated drug classes are listed in Table 4. Even though headache may be a common theme within a drug class, headache frequency can vary greatly between different agents within any given class.64 Although most drug-induced headaches occur with therapeutic doses of a drug and are commonly doserelated, headaches may occur on medication withdrawal instead.65 Two mechanisms of drug-induced headache have been proposed: vasodilatation (e.g., cardiovascular drugs) and intracranial hypertension (e.g., vitamin A or steroid-containing compounds).66 Aseptic meningitis with associated headache may be caused by medications. Major offending agents include nonsteroidal antiinammatory drugs, antimicrobials (macrolides, penicillins, uoroquinolones, antifungals, and antivirals), and intravenous immunoglobulin G.6770 The diagnosis is one of exclusion. The CSF prole seen in drug-related aseptic meningitis is typically a lymphocytic pleocytosis with slightly elevated protein concentration, normal glucose concentration, and no evidence of infectious organisms.64 An immunologic mechanism has been postulated for drug-induced aseptic meningitis.6770 A thorough review of medications, paying particular attention to recently added or discontinued drugs, is important in the evaluation of a patient with headache.

Table 5 Imaging Modality of Choice to Investigate Causes of Headache

MRI preferred Vascular disease Cerebral infarction Venous infarction Neoplastic disease Primary and secondary brain tumors (especially in posterior fossa) Skull base tumors Meningeal carcinomatosis and lymphomatosis Pituitary tumors Infections Cerebritis and brain abscess Meningitis Encephalitis

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instability, and fractures. Cervical x-rays can be helpful if there is suspicion of a cervicogenic contribution to the patients headache, such as craniocervical or C12 subluxation in rheumatoid arthritis or signicant mid and upper cervical spondylosis. Panoramic x-ray examination of the temporomandibular (TMJ) joints and dental xrays can be useful to exclude TMJ and dental pathology, respectively, as possible causes and/or aggravators of the headache disorder.
CEREBRAL ANGIOGRAPHY

MYELOGRAPHY AND RADIOISOTOPE CISTERNOGRAPHY

CT or MR myelography and radioisotope cisternography have a key role in determining the presence and location of spontaneous, posttraumatic, or postoperative CSF leaks when MRI brain ndings point to a low CSF pressure syndrome.

CSF Examination CSF studies are a useful adjunct to neuroimaging in select situations when investigating the patient with headache. It has been estimated that 5% of patients with subarachnoid hemorrhage will have a negative CT scan soon after headache onset, with the sensitivity declining precipitously over the subsequent days to weeks. In this instance, examining the CSF for red blood cells and xanthochromia is of paramount importance. Some studies suggest that xanthochromia is better detected by spectrophotometry than by visual inspection; nevertheless, the latter method has recently been shown to have a high positive predictive value for the presence of aneurysm on cerebral angiography.4,32 Xanthochromia is not entirely specic for antecedent hemorrhage, and can also be seen in a traumatic LP (red blood cell [RBC] count more than 100,000/mm3), hyperbilirubinemia, elevated CSF protein (>150 mg/dL), dietary hypercarotenemia, purulent CSF, and meningeal melanomatosis.4 Red blood cell and total nucleated white blood cell (WBC) counts should also be obtained when suspecting subarachnoid hemorrhage, as both have been demonstrated to be signicantly elevated in patients with angiographically documented ruptured aneurysms.32 It is important to note that initially the ratio of WBCs to RBCs in the CSF is proportionate to the number of

Electrophysiologic Testing There is no role for electroencephalography or evoked potentials in the evaluation of the patient with headache.72,77 There is no evidence to justify autonomic testing or transcranial Doppler examination in the patient with headache.72 In the patient who wakes from sleep due to headache, polysomnography can be useful to look for a treatable sleep disturbance if there is no indication of a primary headache disorder associated with nocturnal wakening, depression, or medication/ caffeine rebound withdrawal headaches.55 As nocturnal wakening from headache can also result from carbon monoxide poisoning, the possibility of a faulty furnace should be explored.

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Cerebral angiography is seldom useful for the initial investigation of headache. It does, however, play an important role in nontraumatic subarachnoid hemorrhage where it can identify intracranial aneurysms and arteriovenous malformations (AVMs), and in the diagnosis of arterial dissection. Although MRA and CTA are useful for diagnosing CNS vasculitis of large- and medium-sized vessels, conventional cerebral angiography is necessary to exclude vasculitis affecting smaller arteries.

WBCs to RBCs in the bloodstream. Over time, however, the presence of RBCs in the CSF provokes a relative increase in the number of WBCs in the CSF. The possibility of a traumatic LP is evaluated by performing cell counts on serial tubes looking for a rapidly falling RBC count. If the RBC count in the nal tube is not close to zero, simultaneous traumatic LP and spontaneous subarachnoid hemorrhage are possible.76 In patients whose suspected bleeding occurred greater than 12 hours beforehand, cell-free CSF should be examined for xanthochromia. The presence of xanthochromia in the absence of subarachnoid bleeding due to head injury should inuence the clinician to search for an aneurysm or AVM. Cerebrospinal uid examination is also helpful in evaluating for noninfectious inammation, infectious meningitis or encephalitis, meningeal carcinomatosis or lymphomatosis, and conrming increased pressure (e.g., benign intracranial hypertension) or a low CSF pressure syndrome. To explore fully the differential diagnosis of headache, CSF studies should always include an opening pressure, red and white blood cell counts and white cell count differential, protein and glucose concentrations (with coincident serum glucose determination for comparison if there is any concern about infectious or malignant meningitis), and possibly include cultures (bacterial, viral, and/or fungal), cytology and ow cytometry, condition-specic antibodies (Lyme disease, syphilis), and polymerase chain reaction testing for specic infectious agents, as clinically indicated. If the suspicion of bacterial meningitis is high, then blood cultures should be obtained without delay and empiric intravenous antibiotics should be started soon thereafter. Lumbar puncture should be the next study completed, unless focal neurologic signs suggesting an underlying intracranial mass lesion dictate that emergent brain imaging be obtained prior to CSF collection. The evaluation of suspected low CSF pressure syndrome and suspected benign intracranial hypertension should entail MRI brain with and without gadolinium prior to LP.

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Special Examinations and Consultations There are certain instances in which the expertise of subspecialists should be considered in the evaluation of the patient with headache. Help from ophthalmology may be useful to exclude glaucoma when head and/or eye pain is accompanied by conjunctival injection or corneal clouding. In this circumstance, formal visual eld testing, tonometry, slit-lamp, and other specialized examinations are informative. A dentist or oral surgeon should be enlisted if pain of dental or temporomandibular joint origin is suspected. The diagnosis of tumors of the sinuses, nasopharynx, and neck, and inammatory sinus disease is facilitated by an otorhinolaryngologist. In selected cases where headache may be the manifestation of a chronic pain disorder, consultation with psychiatry can be helpful for diagnosis and management.

CONCLUSIONS Headache imposes a substantial burden on individual headache sufferers, and is the leading reason for neurologic consultation. The clinician is faced with the challenge of distinguishing between primary and secondary headache disorders so that selected patients undergo appropriate testing. A detailed clinical history and complete general and neurologic examinations, with special attention to the red and yellow ags, are fundamental to this process. In most instances, the systematic selection of investigations targeted to the specic clinical nuances surrounding the individual patient with headache will reduce unnecessary testing, minimize the detection of clinically insignicant ndings, and decrease extraneous costs. The mastery of when and how to investigate the patient with headache will instill condence and reassure the patient and provider alike.
REFERENCES
1. Evans RW. Diagnostic testing for the evaluation of headaches. Neurol Clin 1996;14(1):126

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General Medical Tests There are several tests outside of neuroimaging and CSF analysis that are important to consider in certain patients with headache. In a patient older than 50 years who presents with headache, one must consider the possibility of giant cell arteritis. Corroborating clinical features of this diagnosis include decreased pulsation and/or tenderness and/or thickening of the supercial temporal arteries, jaw and/or tongue claudication, and constitutional symptoms. Elevation of the ESR, often to 100 mm per hour or higher, and increased CRP are frequently encountered in giant cell arteritis. CRP is less inuenced by age and gender than is ESR.3,4,18,78 A normal ESR does not exclude the condition, as 4% of patients with positive ndings on temporal artery biopsy have a normal ESR.78 Thrombocytosis is also often seen.79 Temporal artery biopsy demonstrating characteristic vasculitic changes conrms the diagnosis. Other medical causes and associated tests to consider in the patient with headache include insulinoma (episodic headache associated with unusual behavior or impairment of consciousness) with elevated serum insulin and C-peptide levels and low fasting glucose level, carbon monoxide poisoning with elevated carboxyhemoglobin determination, drug and alcohol overuse or abuse with positive urine or blood testing, hypothyroidism with thyroid function tests, and pheochromocytoma with plasma fractionated metanephrine levels and 24-hour urine fractionated metanephrine and catecholamine levels. Rarely, current or former smokers can present with intractable face or head pain, often including the ear (84%), which is found to be due to an underlying ipsilateral lung tumor without CNS involvement. Seventy-seven percent of reported patients have had an elevated ESR, and the tumor is found on chest x-ray or CT scan of the chest (20% of chest x-rays may be unrevealing).80

The Adverse Effects of Investigation In the evaluation of headache, the investigations to which patients are subjected are not without risk. A single head CT may slightly increase the lifetime risk of death from cancer attributable to exposure to radiation.81 In susceptible individuals, there is a risk of anaphylaxis and renal insufciency when iodinated contrast material is administered. Brain MRI is also associated with risk. In a Dutch population-based study, brain MRI studies of 2000 asymptomatic individuals detected a substantial number of incidental ndings including brain infarcts (7.2%), cerebral aneurysms (1.8%), and benign primary tumors (1.6%).71 Incidental ndings provoke worry, fear, and often additional interventions, along with follow-up testing to monitor the incidental nding, none of which helps the patient with headache. Nephrogenic systemic brosis is a noteworthy complication of MRI studies in which a gadolinium-containing contrast agent is given to individuals with impaired renal function.82 Diagnostic cerebral angiography poses risks ranging from access-site hematomas (4.2%), to strokes with permanent disability (0.14%) or even death (0.06%).83 A procedure as benign as LP may be complicated by post-LP headaches, a persistent CSF leak, bleeding, low back pain, and rarely, infection. These important caveats serve not to deter the clinician from investigating a patient with headache, but to remind the clinician that the selection of diagnostic tests should be tailored to a given patients unique circumstances and justied by medical need.

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2. Headache Classication Subcommittee of the International Headache Society. The international classication of headache disorders, 2nd edition. Cephalalgia 2004; 24(Suppl 1):1160 3. Bartleson JD. When and how to investigate the patient with headache. Semin Neurol 2006;26(2):163170 4. Evans RW. Diagnostic testing for headache. Med Clin North Am 2001;85(4):865885 5. Frishberg BM. The utility of neuroimaging in the evaluation of headache in patients with normal neurologic examinations. Neurology 1994;44(7):11911197 6. Danish Neurological Society and the Danish Headache Society. Guidelines for the management of headache. Cephalalgia 1998;18(1):922 7. Field AG, Wang E. Evaluation of the patient with nontraumatic headache: an evidence based approach. Emerg Med Clin North Am 1999;17(1):127152, ix 8. Locker TE, Thompson C, Rylance J, Mason SM. The utility of clinical features in patients presenting with nontraumatic headache: an investigation of adult patients attending an emergency department. Headache 2006;46(6): 954961 9. Report of the Quality Standards Subcommittee of the American Academy of Neurology. Practice parameter: the utility of neuroimaging in the evaluation of headache in patients with normal neurologic examinations (summary statement). Neurology 1994;44(7):13531354 10. Bartleson JD. Treatment of migraine headaches. Mayo Clin Proc 1999;74(7):702708 11. Masdeu JC, Drayer BP, Anderson RE, et al. Atraumatic isolated headachewhen to image. American College of Radiology. ACR Appropriateness Criteria. Radiology 2000; 215(Suppl):487493 12. Frishberg BM. Neuroimaging in presumed primary headache disorders. Semin Neurol 1997;17(4):373382 13. Silberstein SD. Practice parameter: evidence-based guidelines for migraine headache (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2000;55(6): 754762 14. Jamieson DG, Hargreaves R. The role of neuroimaging in headache. J Neuroimaging 2002;12(1):4251 15. American College of Emergency Physicians. Clinical policy: critical issues in the evaluation and management of patients presenting to the emergency department with acute headache. Ann Emerg Med 2002;39(1):108 122 16. Medina LS, DSouza B, Vasconcellos E. Adults and children with headache: evidence-based diagnostic evaluation. Neuroimaging Clin N Am 2003;13(2):225235 17. Cortelli P, Cevoli S, Nonino F, et al; Multidisciplinary Group for Nontraumatic Headache in the Emergency Department. Evidence-based diagnosis of nontraumatic headache in the emergency department: a consensus statement on four clinical scenarios. Headache 2004;44(6):587595 18. Evans RW. Headaches. In: Evans RW, ed. Diagnostic Testing in Neurology. Philadelphia: WB Saunders Company; 1999:119 19. Sudlow C. US guidelines on neuroimaging in patients with non-acute headache: a commentary. J Neurol Neurosurg Psychiatry 2002;72(Suppl 2):ii16ii18 20. Lewis DW, Ashwal S, Dahl G, et al; Quality Standards Subcommittee of the American Academy of Neurology

21.

22.

23. 24.

25.

26.

27.

28.

29. 30. 31.

32.

33.

34.

35. 36. 37.

38.

Practice Committee of the Child Neurology Society. Practice parameter: evaluation of children and adolescents with recurrent headaches: report of the Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society. Neurology 2002;59(4):490498 ska-Czerlunczakiewicz H, Tynecka-Turowska M, Krasin Mitosek-Szewczyk K, Stelmasiak Z. The use of instrumental examinations in the diagnosis of headaches. Neurol Sci 2003; 24(4):305307 Bartleson JD, Black DF, Swanson JW. Cranial and facial pain. In: Bradley WG, Daroff RB, Fenichel GM, Jankovic J, eds. Neurology in Clinical Practice: Principles of Diagnosis and Management. Vol. 1. Philadelphia: Butterworth-Heinemann; 2008:263269 Milo R, Razon N, Schiffer J. Delayed epidural hematoma. A review. Acta Neurochir (Wien) 1987;84(1-2):1323 ger B, et al. Cervical artery Dziewas R, Konrad C, Dra dissectionclinical features, risk factors, therapy and outcome in 126 patients. J Neurol 2003;250(10):1179 1184 Caplan JM, Khalpey Z, Gates J. Closed traumatic head injury: dural sinus and internal jugular vein thrombosis. Emerg Med J 2008;25(11):777778 Mills ML, Russo LS, Vines FS, Ross BA. High-yield criteria for urgent cranial computed tomography scans. Ann Emerg Med 1986;15(10):11671172 Bordignon KC, Arruda WO. CT scan ndings in mild head trauma: a series of 2,000 patients. Arq Neuropsiquiatr 2002; 60(2-A, 2-A):204210 Duarte J, Sempere AP, Delgado JA, Naranjo G, Sevillano a LE. Headache of recent onset in adults: a MD, Claver prospective population-based study. Acta Neurol Scand 1996; 94(1):6770 Dodick DW. Thunderclap headache. J Neurol Neurosurg Psychiatry 2002;72(1):611 Dodick DW. Thunderclap headache. Headache 2002;42(4): 309315 Landtblom AM, Fridriksson S, Boivie J, Hillman J, Johansson G, Johansson I. Sudden onset headache: a prospective study of features, incidence and causes. Cephalalgia 2002;22(5):354 360 Dupont SA, Wijdicks EF, Manno EM, Rabinstein AA. Thunderclap headache and normal computed tomographic results: value of cerebrospinal uid analysis. Mayo Clin Proc 2008;83(12):13261331 Edlow JA, Caplan LR. Avoiding pitfalls in the diagnosis of subarachnoid hemorrhage. N Engl J Med 2000;342(1): 2936 Matharu MS, Schwedt TJ, Dodick DW. Thunderclap headache: an approach to a neurologic emergency. Curr Neurol Neurosci Rep 2007;7(2):101109 Schwedt TJ, Matharu MS, Dodick DW. Thunderclap headache. Lancet Neurol 2006;5(7):621631 Cutrer FM, Boes CJ. Cough, exertional, and sex headaches. Neurol Clin 2004;22(1):133149 Sands GH, Newman L, Lipton R. Cough, exertional, and other miscellaneous headaches. Med Clin North Am 1991; 75(3):733747 lez-Mandly A, Mart n R, Oterino A. Pascual J, Gonza Headaches precipitated by cough, prolonged exercise or sexual activity: a prospective etiological and clinical study. J Headache Pain 2008;9(5):259266

Downloaded by: Banner Good Samaritan Medical Center. Copyrighted material.

WHEN AND HOW TO INVESTIGATE THE PATIENT WITH HEADACHE/DE LUCA, BARTLESON

143

zquez-Barquero A, 39. Pascual J, Iglesias F, Oterino A, Va Berciano J. Cough, exertional, and sexual headaches: an analysis of 72 benign and symptomatic cases. Neurology 1996;46(6):15201524 40. Evers S, Lance JW. Primary headache attributed to sexual activity. In: Olesen J, Goadsby PJ, Ramadan NM et al, eds. The Headaches. 3rd Ed. Philadelphia: Lippincott Williams & Wilkins; 2006:841845 41. Locksley HB. Natural history of subarachnoid hemorrhage, intracranial aneurysms, and arteriovenous malformations. In: Sahs AL, Perret GE, Locksley HB et al, eds. Intracranial Aneurysms and Subarachnoid Hemorrhage. Philadelphia: Lippincott; 1969:3757 42. Lundberg PO, Osterman PO. The benign and malignant forms of orgasmic cephalgia. Headache 1974;14(3):164 165 43. Lance JW, Anthony M. Some clinical aspects of migraine. A prospective survey of 500 patients. Arch Neurol 1966;15(4): 356361 44. Somerville BW. A study of migraine in pregnancy. Neurology 1972;22(8):824828 45. Chen TC, Leviton A. Headache recurrence in pregnant women with migraine. Headache 1994;34(2):107110 46. Menon R, Bushnell CD. Headache and pregnancy. Neurologist 2008;14(2):108119 47. Bousser MG, Barnett HJ. Cerebral venous thrombosis. In: Mohr JP, Choi DW, Grotta JC et al, eds. Stroke: Pathophysiology, Diagnosis, and Management. Philadelphia: Churchill Livingstone; 2004:301325 48. Standards ACR. MRI safety and sedation. Available at www://http.acr.org. Accessed June 30, 2009 49. Bigal ME, Lipton RB. The differential diagnosis of chronic daily headaches: an algorithm-based approach. J Headache Pain 2007;8(5):263272 50. Harris JE, Draper HL, Rhodes AI, Stevens JM. High yield criteria for emergency cranial computed tomography in adult patients with no history of head injury. J Accid Emerg Med 2000;17(1):1517 51. Kahn CE Jr, Sanders GD, Lyons EA, Kostelic JK, MacEwan DW, Gordon WL. Computed tomography for nontraumatic headache: current utilization and cost-effectiveness. Can Assoc Radiol J 1993;44(3):189193 52. Edmeads J. Headaches in older people. How are they different in this age-group? Postgrad Med 1997;101(5):91 94, 98100 53. Mitchell CS, Osborn RE, Grosskreutz SR. Computed tomography in the headache patient: is routine evaluation really necessary? Headache 1993;33(2):8286 54. Cohen AS, Kaube H. Rare nocturnal headaches. Curr Opin Neurol 2004;17(3):295299 55. Dodick DW, Eross EJ, Parish JM, Silber M. Clinical, anatomical, and physiologic relationship between sleep and headache. Headache 2003;43(3):282292 56. Gil-Gouveia R, Goadsby PJ. Secondary hypnic headache. J Neurol 2007;254(5):646654 57. Medina LS, Pinter JD, Zurakowski D, Davis RG, Kuban K, Barnes PD. Children with headache: clinical predictors of surgical space-occupying lesions and the role of neuroimaging. Radiology 1997;202(3):819 824 58. Leone M, Cecchini AP, Mea E, Tullo V, Bussone G. Epidemiology of xed unilateral headaches. Cephalalgia 2008;28(Suppl 1):811

59. Prakash S, Shah ND, Soni RK. Secondary hemicrania continua: case reports and a literature review. J Neurol Sci 2009;280(1-2):2934 60. Evans RW. Hemicrania continua-like headache due to nonmetastatic lung cancera vagal cephalalgia. Headache 2007;47(9):13491351 61. Mokri B. Low cerebrospinal uid pressure syndromes. Neurol Clin 2004;22(1):5574, vi vi 62. Leep Hunderfund AN, Mokri B. Orthostatic headache without CSF leak. Neurology 2008;71(23):19021906 63. Ropper AH, Samuels MA. Headache and other craniofacial pains. In: Principles of Neurology. New York: McGraw-Hill; 2009:178 64. Ferrari A. Headache: one of the most common and troublesome adverse reactions to drugs. Curr Drug Saf 2006;1(1): 4358 65. Karachalios GN, Charalabopoulos A, Papalimneou V, et al. Withdrawal syndrome following cessation of antihypertensive drug therapy. Int J Clin Pract 2005;59(5):562 570 66. Askmark H, Lundberg PO, Olsson S. Drug-related headache. Headache 1989;29(7):441444 67. Hopkins S, Jolles S. Drug-induced aseptic meningitis. Expert Opin Drug Saf 2005;4(2):285297 68. Jolles S, Sewell WA, Leighton C. Drug-induced aseptic meningitis: diagnosis and management. Drug Saf 2000;22(3): 215226 69. stensen M, Villiger PM. Nonsteroidal anti-inammatory drugs in systemic lupus erythematosus. Lupus 2001;10(3): 135139 70. Nettis E, Calogiuri G, Colanardi MC, Ferrannini A, Tursi A. Drug-induced aseptic meningitis. Curr Drug Targets Immune Endocr Metabol Disord 2003;3(2):143149 71. Vernooij MW, Ikram MA, Tanghe HL, et al. Incidental ndings on brain MRI in the general population. N Engl J Med 2007;357(18):18211828 nig W, et al. Neurophysiological 72. Sandrini G, Friberg L, Ja tests and neuroimaging procedures in non-acute headache: guidelines and recommendations. Eur J Neurol 2004;11(4): 217224 73. Detsky ME, McDonald DR, Baerlocher MO, Tomlinson GA, McCrory DC, Booth CM. Does this patient with headache have a migraine or need neuroimaging? JAMA 2006;296(10):12741283 74. Rothrock SG, Buchanan C, Green SM, Bullard T, Falk JL, Langen M. Cranial computed tomography in the emergency evaluation of adult patients without a recent history of head trauma: a prospective analysis. Acad Emerg Med 1997;4(7): 654661 75. Sempere AP, Porta-Etessam J, Medrano V, et al. Neuroimaging in the evaluation of patients with non-acute headache. Cephalalgia 2005;25(1):3035 76. Edlow JA. Diagnosis of subarachnoid hemorrhage in the emergency department. Emerg Med Clin North Am 2003; 21(1):7387 77. Report of the Quality Standards Subcommittee of the American Academy of Neurology. Practice parameter: the electroencephalogram in the evaluation of headache (summary statement). Neurology 1995;45(7):14111413 78. Smetana GW, Shmerling RH. Does this patient have temporal arteritis? JAMA 2002;287(1):92101 79. Costello F, Zimmerman MB, Podhajsky PA, Hayreh SS. Role of thrombocytosis in diagnosis of giant cell arteritis and

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differentiation of arteritic from non-arteritic anterior ischemic optic neuropathy. Eur J Ophthalmol 2004;14(3):245257 80. Eross EJ, Dodick DW, Swanson JW, Capobianco DJ. A review of intractable facial pain secondary to underlying lung neoplasms. Cephalalgia 2003;23(1):25 81. Brenner DJ, Hall EJ. Computed tomographyan increasing source of radiation exposure. N Engl J Med 2007;357(22): 22772284

82. Perez-Rodriguez J, Lai S, Ehst BD, Fine DM, Bluemke DA. Nephrogenic systemic brosis: incidence, associations, and effect of risk factor assessmentreport of 33 cases. Radiology 2009;250(2):371377 83. Kaufmann TJ, Huston J III, Mandrekar JN, Schleck CD, Thielen KR, Kallmes DF. Complications of diagnostic cerebral angiography: evaluation of 19,826 consecutive patients. Radiology 2007;243(3):812819

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