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When and How to Investigate the Patientwith Headache

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

ABSTRACT

The common complaint of headache usually has a benign cause, most often aprimary headache syndrome. The history and neurologic and general physical examinationsusually permit a definitive diagnosis. When in doubt, diagnostic testing is indicated.Certain historical and examination findings 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 byValsalva 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 of50; (8)neurologic findings and/or symptoms; (9) systemic signs and/or symptoms; (10) secondaryrisk factors, such as cancer or human immunodeficiency virus (HIV) infection. Less

worrisome are headaches that wake the patient from sleep at night, always occur on thesame side, or show a prominent effect of change in posture on the patients pain. Diagnosticstudies include neuroimaging, cerebrospinal fluid (CSF) examination, and blood tests,

which are selected depending on the patients history and findings. For most patients, thediagnostic test of choice is a magnetic resonance imaging (MRI) brain scan. Computedtomography (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.

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

Headache is one of the most common medicalsymptoms and reasons for neurologic consultation.Although the majority of headache disorders are benign,clinicians are faced with the crucial task of decipheringbenign variants from conditions that threaten life and

neurologic function.

1

As the potential causes of head-ache are many, and the number of randomized con-trolled studies on when and how to investigate thecomplaint of headache are few, the clinician is left withthe daunting challenge of appropriately investigating thepatient who presents with headache. A systematic ap-

proach to headache classification and diagnosis, there-fore, is paramount and serves as the focus of this review.

Headache disorders are broadly classified as pri-mary or secondary in the International Classification ofHeadache Disorders, 2nd edition (ICHD-2) (Table 1).2

Diagnosis of one of the primary headache disorders isprincipally based on historical headache features and theexclusion of other disorders. In the absence of confirma-tory diagnostic tests for primary headache disorders, theclinician is faced with the need to consider, if not ruleout, one or more secondary headache disorders that can

1Department 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 ofMedicine, Mayo Building, 8th floor, 200 First Street SW, Rochester,MN, 55905 (e-mail: [email protected]).

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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mimic a primary headache. In fact, virtually all of theprimary headache disorder diagnostic criteria include thedisclaimer not attributed to another disorder suggestedby the history, and/or physical and neurologic examina-tions, and recommend that secondary headaches beruled out by appropriate investigations, but specifictest recommendations are usually lacking.

Criteria for the primary headache disorders re-quire several attacks making it difficult to make a

diagnosis after just one or two headaches. Secondaryheadache disorders may be easily camouflaged in pre-sentations suggestive of or combined with a commonprimary headache diagnosis. Even when a patient meetscriteria for a primary headache disorder, investigationsmay be required to exclude ominous contributing causes.In fact, many of the other primary headaches (Table 1)can only be diagnosed after potential culprits responsiblefor secondary headache disorders are ruled out withappropriate testing.

The ICHD-2 classification of secondary head-ache disorders is organized by causation. In this vein,

once the suspicion of a secondary headache disorder israised, the ICHD-2 criteria recommend confirmatorytesting and/or call for improvement in the headache aftertreatment of the underlying cause. Although the ICHD-2 diagnostic criteria help guide the clinician to a specificdiagnosis, they do not provide recommendations for

when and how to investigate the individual patient

with headache.When should the patient with headache be in-

vestigated? An important strategy to identify or excludesecondary headache disorders is to search for red flags,both in the history and on general and neurologicexaminations (Table 2). The presence of any of these

worrisome features increases the likelihood that a possi-ble underlying serious medical or neurologic conditionmay contribute to the headache presentation, and shouldprompt the clinician to conduct testing.1,320 Otherconcerning symptoms that should fuel consideration ofadditional evaluation include three yellow flags

(Table 2). The evidence for these features is not asstrong as for the red flag indicators.Although the decision to obtain diagnostic tests

on the patient with headache primarily rests on historicalfeatures and examination findings, there are nonmedicalreasons that affect the decision-making process(Table 3).1,3,4,18,19

WHEN TO CONSIDER INVESTIGATING THE

PATIENT WITH HEADACHE

The accurate diagnosis of headache relies heavily on acareful history, supplemented by detailed general andneurologic examinations.21,22 Elements of the historyand physical examination enable the clinician to diag-nose primary headache disorders, and to elicit suspicionof secondary headache disorders that require promptinvestigation. A diagnostic algorithm to guide thisprocess 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 head-ache.1,3,18 Often overlooked, head or neck trauma is, ofcourse, essential for a diagnosis of posttraumatic head-ache. In addition, its presence should prompt the clini-cian to exclude hemorrhage (epidural, subdural,subarachnoid, intraparenchymal),23 and arterial dissec-tion (of a carotid or vertebral artery)24 as possible causes.Although a short interval between trauma and the onsetof headache often facilitates prompt and appropriateneuroimaging, a remote history of trauma relative toheadache onset should also raise suspicion of subduralhematoma and arterial dissection.24 Several case reports

Table 1 International Classification of HeadacheDisorders, 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 disorderHeadache 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

132 SEMINARS IN NEUROLOGY/VOLUME 30, NUMBER 2 2010


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Table 2 Headache Warning Flags

Warning Flag Considerations

Red flags

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

New level of pain (e.g., worst ever) Subarachnoid hemorrhage

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)

Primary thunderclap headache

Triggered by Valsalva maneuver or cough Chiari malformation

Mass lesion

Triggered by exertion Subarachnoid hemorrhage

Dissection

Anginal equivalent

Pheochromocytoma

Triggered by sexual activity (pre-orgasmic, orgasmic) Subarachnoid hemorrhage

Dissection

Headache during pregnancy or puerperium Cortical vein / cranial sinus thrombosis

Pituitary apoplexy

Age >50 years 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

MeningoencephalitisSystemic illness

Fever

Systemic infection

Nuchal rigidity

Meningoencephalitis

Meningeal carcinomatosis

Lyme disease

Collagen vascular disease

Weight loss Malignancy

Scalp artery tenderness Giant cell arteritis

WHEN AND HOW TO INVESTIGATE THE PATIENT WITH HEADACHE/DE LUCA, BARTLESON 133


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of dural venous thrombosis stemming from antecedenthead injury with headache being the only symptomshould also alert the clinician to this diagnostic possi-bility.25 The potential implications of trauma are in-creased in patients taking antiplatelet or anticoagulationagents or with an underlying bleeding diathesis, coagul-opathy, or connective tissue disease, wherein even trivialhead injury in the weeks and months prior to headacheonset is important. A history of chiropractic manipula-tion of the cervical spine, though not considered aninjury, should be sought given its association with bothcarotid and vertebral artery dissections.24

There has been much discussion about the diag-nostic utility of computed tomography (CT) in thesetting of head trauma. CT brain scans are very likelyto show abnormalities in the patient with signs of raisedintracranial pressure, altered mental status, skull fracture,seizures, cranial nerve abnormalities, or focal neurologicsigns, and studies have shown that up to 30% of patients

with a history of head trauma and normal neurologicexamination may have associated CT brain scan find-ings, some of which require immediate intervention.26,27

In light of the fact that subdural and even epiduralhematomas 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 patientwith evolving symptoms, increasing headache, or changein headache who initially presented with normal brainimaging.

HEADACHE FEATURES AS RED FLAGS

There are certain headache features that are consideredred flags, including new onset of headache, onset of newheadache type, change for the worse in an existingpattern of headache, new level of pain (e.g., worstever), or abrupt or split-second onset. In a prospectivestudy of patients with new or worsening headache, it wasfound 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 theauthors to conclude that a headache duration of6 months is significant.28 Rapidly increasing headachefrequency has been associated with increased frequencyof CT imaging abnormalities.13 It is evident that elicit-ing important clues in the headache history, such as newonset, new headache type, and worsening headachefeatures (i.e., severity, frequency, change in pattern), isessential to the appropriate selection of patients requir-ing further testing, usually brain imaging with CT orMRI.

Table 2 (Continued)

Warning Flag Considerations

Red flags (Continued)

Secondary risk factors

Cancer Metastatic disease

Immunocompromised host (HIV, on immunosuppressants, etc.) Opportunistic infection

Recent travel (domestic, foreign) Meningoencephalitis

Yellow flags

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 Spontaneous intracranial hypotension

Post-lumbar puncture

HIV, human immunodeficiency virus.

Table 3 Other Considerations that Influence Diagnostic Testing of the Patient with Headache

Increase Diagnostic Testing Decrease Diagnostic Testing

Need for diagnostic certainty Financial incentives

Reassure patients, families, and referring providers Lack of patient means or insurance coverage

Meet patient, relative, referring provider expectation Risk of diagnostic intervention

Financial incentives Adverse consequences of finding and pursuing

incidental abnormalitiesMedicolegal concerns

Faulty medical reasoning 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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The most worrisome headache warning sign thatshould prompt investigation is the abrupt or split-secondonset of headache.29,30 These headaches, termed thun-derclap headaches, are characterized by the very suddenonset of usually severe pain that typically reaches max-imal intensity at or very soon after onset. Thunderclapheadache is the characteristic presenting symptom ofsubarachnoid hemorrhage.29,30 An estimated 11 to 25%of patients with thunderclap headache may have bleed-ing in the subarachnoid space.31 A small subset ofpatients may present similarly in the setting of unrup-

tured cerebral aneurysm.29,30 Other important etiologiesof sudden onset headache that must be considered,include intracerebral hemorrhage, hemorrhage into amass or an arteriovenous malformation (AVM), arterialdissection, cerebral venous thrombosis, spontaneous in-tracranial hypotension, reversible cerebral vasoconstric-tion syndromes, pituitary apoplexy, acute hypertensivecrisis, and idiopathic primary thunderclap headache.2,29

Primary thunderclap headache can be associated withtransient vasospasm and can recur. The abrupt onset ofheadache obligates further evaluation, and urgent if notemergent noncontrast CT brain imaging is impera-

tive.2,29,30 As the sensitivity of CT imaging to detectsubarachnoid hemorrhage is inversely related to thetime elapsed following the bleeding event (95% within24 hours, 74% by day 3, 50% by day 7, 30% by day 14,and nearly 0% after day 21), most authors stronglyrecommend that a lumbar puncture (LP) be performed(looking for red blood cells and/or xanthochromia)after a negative CT result in patients with suspectedsubarachnoid hemorrhage.1,3,4,18,29,30,32,33 Even if theCT brain scan and cerebrospinal fluid (CSF) examina-tion are normal, the clinician evaluating thunderclap

headache should strongly consider obtaining MRI ofthe brain and MR angiography (MRA) and venography(MRV) of the intracranial and cervical vessels to ex-clude secondary headache disorders. CT angiography(CTA) and venography (CTV) are comparable toMRA and MRV in this setting.29,30,34,35

VALSALVA/COUGH HEADACHE

Headaches triggered by Valsalva maneuver, cough, orexertion often raise concern of underlying central nerv-ous system (CNS) pathology and warrant investiga-tion.36 Valsalva- and cough-induced headaches are

Figure1 Algorithm for the evaluation of headache disorders. (Copyrighted and used with permission of the Mayo Foundation

for Medical Education and Research.)



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combined into one entity by the ICHD-2, and should beviewed separately from exertion-induced headaches. Inthe absence of an underlying cause, both Valsalva/cough-induced and exertion-induced headaches can oc-cur as primary headache disorders2; only secondarycauses of these headache types will be addressed here.Valsalva/cough headache should raise suspicion of a

hindbrain malformation or mass lesion, occipitocervicaljunction disorder, or increased intracranial pressure.3638

In a large prospective series followed clinically andradiographically, 40 out of 68 participants (59%) withValsalva/cough-induced headache were found to havesecondary causes, all of which were due to structurallesions in the posterior fossa, the majority being Chiarimalformations.38 Another case series reported similarfindings, with 40% being symptomatic and most hav-ing Chiari malformation as the cause.39When compared

with primary Valsalva/cough headaches, the secondaryvariety typically began earlier (mean 40 vs. 60 years old),

lasted longer (mean 5 years vs. 11 months), were morelikely to be located posteriorly, and were associated withsymptoms/signs attributable to the posterior fossa.38 Inlight of these findings, MRI is recommended to excludeChiari malformation and other intracranial structuralcauses that are associated with Valsalva/cough headache.

EXERTIONAL HEADACHE

Exertion-induced headaches can also be attributed to astructural cause. In one case series, 12 of 28 patientspresenting with exertional headache had an underlyingstructural cause. Ten of the 12 had subarachnoid hem-orrhage, but only two of the 10 were found to have ableeding source (aneurysms).39 Exertional headaches aresimilar to headaches associated with sexual activity inthat both can occur as a primary headache disorder, andeach can be associated with migraine.2,36,39 As exertionalheadache can occur secondary to subarachnoid hemor-rhage and arterial dissection, the ICHD-2 deems itmandatory to exclude these conditions on the firstoccurrence of this type of headache.2

HEADACHE ASSOCIATED WITH SEXUAL ACTIVITY

Headache associated with sexual activity should beconsidered a red flag. This headache subtype is differ-

entiated into pre-orgasmic and orgasmic headachesbased on the time course of headache onset. Pre-orgas-mic headaches are characterized by pain that buildsgradually along with sexual excitement compared withorgasmic headaches where the pain strikes within 5seconds before or at orgasm.2,40 Although orgasmicheadache is more worrisome regarding an underlyingstructural problem such as subarachnoid hemorrhage, itis prudent to evaluate pre-orgasmic as well as orgasmicheadache before concluding they are a primary headacheassociated with sexual activity and not due to underlyingstructural disease. It is worrisome to note that 4 to 12%

of all patients with subarachnoid hemorrhage have onsetduring sexual activity.41,42 The ICHD-2 criteria specif-ically state that On first onset of orgasmic headache it ismandatory to exclude conditions such as subarachnoidhemorrhage and arterial dissection.2 If the patient isbeing seen very soon after their first attack (i.e., within48 hours), a CT brain scan followed by LP if the CT

scan is negative would be appropriate; the presence ofsubarachnoid blood would then prompt conventionalcerebral angiography. If there is no evidence of bleeding,then one would obtain an MRA or CTA of the cervicaland intracranial vessels. If days or weeks have elapsed,then an MRI brain scan with and without gadoliniumand 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) andevaluation for pheochromocytoma should be obtainedin appropriately selected cases.42

PREGNANCY AND HEADACHEHeadache during pregnancy presents a unique challengeto the clinician. Pregnancy often favorably impacts thecourse of migraine; however, pregnancy and the puer-perium predispose women to several life-threateningconditions that often manifest as headache.4346 Thecauses of secondary headache in pregnancy are numer-ous, and include preeclampsia, hemorrhagic or ischemicstroke, idiopathic intracranial hypertension, postpartumdural puncture headache, postpartum cerebral angiop-athy, pituitary apoplexy, and cerebral venous thrombo-sis.46 Pregnant women are particularly susceptible toominous headache syndromes given their relative hyper-coagulable state, especially in the postpartum period.47

Several diagnostic tools evaluate new onset headacheduring pregnancy: urinalysis, complete blood count,blood chemistries, liver function tests, CSF analysis(including xanthochromia), and coagulation studies.Brain imaging is an important complement to thesestudies. An MRI brain scan without gadolinium is safein all trimesters in pregnancy, and in fact is the preferredimaging modality to search for structural causes ofsecondary headaches in pregnancy.48 A CT head scan

without contrast is useful to rule out life-threateningconditions such as subarachnoid or intraparenchymal

hemorrhage, and is deemed to be fairly safe if radiationexposure to the fetus is less than 1 millirad.46

AGE AND HEADACHE

Age is an important factor to consider when evaluatingthe patient with headache. Several prospective observa-tional studies in the emergency room setting have

validated the notion that new onset headache after theage of50 years is associated with an increased like-lihood of intracranial pathology.4952 The data are notentirely surprising given that with increasing age there isheightened risk of many conditions that can present with



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headache, such as primary and metastatic brain tumors,cerebrovascular disease, and especially giant cell (tem-poral) arteritis. In the older patient, secondary causes fornew headache should be sought, with testing catered tothe specific clinical presentation. Brain imaging andblood work, especially erythrocyte sedimentation rate(ESR) and C-reactive protein (CRP), are reasonable

considerations. A patient of any age with a stable historyof headaches dating back decades that can be classifiedinto one of the primary headache disorders, however,need not undergo investigation.2

NEUROLOGIC SIGNS AND SYMPTOMS

There is little dispute that patients with headache whohave nonmigrainous transient or persistent neurologicsymptoms, seizures, reduced level of consciousness, orpersistent neurologic signs merit expeditious investiga-tion unless their neurologic symptoms and signs can beexplained by another static condition.1,320,53 Unex-

plained neurologic signs have a higher diagnostic imag-ing yield than do unexplained neurologic symptoms.13 Infact, many of these patients would be studied on the basisof their neurologic signs and symptoms even if they didnot have headache.

SYSTEMIC SIGNS AND SYMPTOMS

A detailed review of systems and complete generalmedical examination may provide valuable insight intothe differential diagnosis of headache. Systemic signs orsymptoms such as fever (meningitis, encephalitis, orsystemic infection), weight loss (malignancy), scalp ar-tery tenderness (giant cell arteritis), or nuchal rigidity(meningeal irritation by blood, infection, or malignancy)

warrant timely investigation that might include brainimaging possibly followed by CSF examination, bloodtests (including ESR and CRP), and general medicaltests searching for an occult malignancy, systemic in-fection, or an underlying connective tissue or anotherinflammatory disorder.1,3,4,7,18

SECONDARY RISK FACTORS

The clinician should heed and likely investigate a patientwith headache and a personal history of malignancycapable of spread to the central nervous system or at

increased risk for malignancy or opportunistic infection,such as an individual with human immunodeficiency virus(HIV) infection and anyone who is immunosuppressed. Ahistory of recent travel (domestic or foreign) should alertthe clinician to consider meningoencephalitis secondaryto infectious organisms endemic to the region visited as acause of headache. Marked elevations in blood pressurecan cause headache, or may predispose to conditionscommonly associated with headache, such as posteriorreversible encephalopathy syndrome. In the setting ofsignificant hypertension, an underlying cause of hyper-tension, such as renal dysfunction or pheochromocytoma,

should be sought and targeted therapies initiated. As inthe patient over 50 years of age, the patient with ahistory of cancer or HIV infection may not needinvestigation of headaches that are long-standing andstable with features consistent with a primary headachedisorder.

The Yellow Flags

HEADACHE THAT AWAKENS THE PATIENT FROM SLEEP

The yellow flags also warrant attention. Headaches thatwake the patient from sleep may signal a serious under-lying etiology, and the American Academy of Neurology(AAN) practice parameter recommends consideration ofbrain imaging for these patients.13 As nocturnal waken-ing is common in migraine, paroxysmal hemicrania,cluster headache, short-lasting unilateral neuralgiformheadache attacks with conjunctival injection and tearing

(SUNCT), hypnic headache, and exploding headachesyndrome, night wakening must be taken in the contextof the patients total headache picture.2,54 Sleep-relateddisorders (e.g., obstructive sleep apnea), rebound with-drawal headaches, and poorly controlled essential hyper-tension can also lead to nocturnal or morning headache,and should be considered.55,56Waking from sleep due toheadache may be more worrisome in children thanadults.16,57

NEW ONSET SIDE-LOCKED HEADACHES

New onset headaches that are side-locked (i.e., alwaysoccur on the same side) suggest an anatomically circum-scribed pathophysiologic mechanism which may be asymptom of intracranial pathology.58 A recent review ofthe literature on secondary hemicrania continua59 iden-tified several important causes including head trauma,postpartum period, internal carotid artery dissection,intracranial aneurysm, intracranial tumor, and nonmeta-static lung carcinoma.59,60 The authors noted that asecondary cause was more likely in patients with a shortduration of illness, frequent and short-lived exacerba-tions, recent head or neck trauma, miosis, older age, malegender, smoking history, and constitutional and respi-ratory symptoms.59 Patients with the new onset of

strictly unilateral headaches that do not have featuresof one of the primary unilateral headache disordersshould be investigated.

POSTURAL HEADACHES

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



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headaches occur when upright and attenuate on recum-bency. Appropriate evaluation includes MRI of the brain

with and without contrast. If the characteristic pachy-meningeal enhancement and sagging brain are seen, thena search for a CSF leak by means of radioisotopecisternography, MRI of the entire spine, and/or CT orMR 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 intra-ventricular and posterior fossa tumors.63

Medications and HeadacheHeadache is often an adverse reaction to medications. Itis 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 Drug Class Drug

Cardiovascular Calcium channel blockers Diltiazem, nicardipine, nifedipine, verapamil

Antiarrhythmics Flecainide, lorcainide, propafenone

a-2 adrenergic agonists Clonidine

a-1 adrenergic antagonists Doxazosin, prazosin

b-adrenergic antagonists Bisoprolol, carteolol

ACE inhibitors Enalapril, lisinopril, quinapril

Angiotensin II inhibitors Valsartan, tasosartan

Nitrates Nitroglycerin, isosorbide mononitrate/dinitrate

Diuretics Amiloride

Phosphodiesterase inhibitors Dipyridamole, pimobendan

Antimicrobial Antibiotics

Macrolides Dirithromycin, erythromycin, roxithromycin

Penicillins Piperacillin-tazobactam

Fluoroquinolones Levofloxacin, ofloxacin

Antifungals Fluconazole, terconazole

Antivirals Acyclovir, amantidine, ganciclovir, lamivudine, stavudine

Immunologic/antiinflammatory Immunosuppressives Cyclosporine, mycophenolate, sirolimus, tacrolimus

Interleukins Interleukin- 3, 4, 6, 10

Interferons Interferon- a2a, a2b, b1a, b1b, g1b

Corticosteroids Budesonide, fluticasone, mometasone, triamcinolone

NSAIDs Indomethacin, ketorolac, diclofenaco, naproxen, parecoxib

Gastrointestinal H2 receptor antagonists Cimetidine, famotidine, ranitidine

Proton pump inhibitors Lansoprazole, omeprazole

5HT3 antagonists Granisetron, ondansetron

Prokinetic Cisapride

Others Sulfasalazine, mesalamine

Endocrinologic Gonadotropin inhibitors Bicalutamide, danazol, droloxifene, mifepristone

Dopamine receptor agonists Bromocriptine, quinagolide

Other hormonal agents Leuprolide, octreotide, progesterone, OCP, HRT

Psychiatric Antipsychotics Clozapine, olanzapine, quetiapine, risperidone, ziprasidone

Sedative-hypnotics Clobazam, diazepam, triazolam

Antidepressants Bupropion, fluoxetine, fluvoxamine, venlafaxineStimulants Modafinil

Miscellaneous Anti-obesity Sibutramine

Smoke cessation aid Nicotine

Statins Lovastatin

Erythropoietins Epoetin-a, darbepoetin-a

Retinoid analogs Alitretinoin, tretinoin

Antineoplastic Tegafur

Prostaglandins Alprostadil, dinoprostone, enprosti l, i loprost

Agents for erectile dysfunction Sildenafil, tadalafil, vardenafil

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



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the more commonly associated drug classes are listed inTable 4. Even though headache may be a commontheme within a drug class, headache frequency can varygreatly between different agents within any given class.64

Although most drug-induced headaches occur withtherapeutic doses of a drug and are commonly dose-related, headaches may occur on medication withdrawal

instead.65

Two mechanisms of drug-induced headachehave been proposed: vasodilatation (e.g., cardiovasculardrugs) and intracranial hypertension (e.g., vitamin A orsteroid-containing compounds).66 Aseptic meningitis

with associated headache may be caused by medications.Major offending agents include nonsteroidal antiinflam-matory drugs, antimicrobials (macrolides, penicillins,fluoroquinolones, antifungals, and antivirals), and intra-

venous immunoglobulin G.6770The diagnosis is one ofexclusion. The CSF profile seen in drug-related asepticmeningitis is typically a lymphocytic pleocytosis withslightly elevated protein concentration, normal glucose

concentration, and no evidence of infectious organ-isms.64 An immunologic mechanism has been postulatedfor drug-induced aseptic meningitis.6770 A thoroughreview of medications, paying particular attention torecently added or discontinued drugs, is important inthe evaluation of a patient with headache.

HOW TO INVESTIGATE THE PATIENT

WITH HEADACHE

There are several diagnostic tests available to the clini-cian to evaluate the patient with headache. Prior tosubjecting the patient to a barrage of studies, thesuspicion of a secondary headache syndrome should besufficiently high. The red and yellow flags, as outlined inthe previous section, should serve as a guide in thisregard.

Imaging Studies

CT AND MRI

Neuroimaging is the most sensitive diagnostic tool inpatients with headache. As incidental brain findings onCT and/or MRI are common in the general nonheadache

population,71 the use of brain imaging should be limitedto patients with headache who have an appropriateindication.3,4,13,14,18,7274 Considerations that direct theclinician to order CT or MRI include (1) the need toidentify acute hemorrhage (CT preferred); (2) the need toevaluate the posterior fossa (MRI preferred); (3) generalavailability (CT more readily available); and (4) cost (CTis less expensive).4 MRI is more sensitive than CTscanning in identifying intracranial pathology. Table 5shows the relative strengths of MRI and CT in revealing

various pathologic intracranial processes. Although olderAAN practice parameters for nonacute headache (i.e.,

headache present for at least 4 weeks) could find noevidence that MRI was superior to CT,9,13 an evidence-based review from the EFNS Task Force and others

recommend MRI and not CT for appropriate patientswith nonacute headache.4,72 MRI is likely to reveal morethan CT; however, many of the abnormalities will beincidental, including nonspecific white matter lesions anddevelopmental venous anomalies.71,75

PLAIN X-RAYS

Plain x-ray films are not indicated in the routine evalua-tion of the headache patient. In the setting of head and/or neck trauma, cervical spine x-rays can be obtained,

with flexion and extension, odontoid, and pillar viewsadded to help exclude or confirm ligamentous injury,

Table 5 Imaging Modality of Choice to InvestigateCauses 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

Other

Chiari malformation

Cerebrospinal fluid hypotension with pachymeningeal

enhancement and brain sagForamen magnum and upper cervical spine lesions

Pituitary apoplexy

Rare encephalopathies with headache (CADASIL, MELAS,

SMART)

CT preferred

Fractures (calvarium)

Acute hemorrhage (subarachnoid, intracerebral)

Paranasal sinus and mastoid air cell disease

Draw between MRI and CT

MR Angiography/CT Angiography

Vasculitis (large and medium sized vessels)

Intracranial aneurysmsCarotid and vertebral artery dissections

MR Venography/CT Venography

Cerebral venous thrombosis

MRI, magnetic resonance imaging; CT, computed tomography;CADASIL, cerebral autosomal dominant arteriopathy with subcorticalinfarcts and leukoencephalopathy; MELAS, mitochondrial encepha-lomyopathy, lactic acidosis, and stroke-like episodes; SMART,stroke-like migraine attacks after radiation therapy.Copyrighted and used with permission of the Mayo Foundation forMedical Education and Research.



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instability, and fractures. Cervical x-rays can be helpful ifthere is suspicion of a cervicogenic contribution to thepatients headache, such as craniocervical or C12 sub-luxation in rheumatoid arthritis or significant mid andupper cervical spondylosis. Panoramic x-ray examinationof the temporomandibular (TMJ) joints and dental x-rays can be useful to exclude TMJ and dental pathology,

respectively, as possible causes and/or aggravators of theheadache disorder.

CEREBRAL ANGIOGRAPHY

Cerebral angiography is seldom useful for the initialinvestigation of headache. It does, however, play animportant role in nontraumatic subarachnoid hemor-rhage where it can identify intracranial aneurysms andarteriovenous malformations (AVMs), and in the diag-nosis of arterial dissection. Although MRA and CTAare useful for diagnosing CNS vasculitis of large- andmedium-sized vessels, conventional cerebral angiogra-

phy is necessary to exclude vasculitis affecting smallerarteries.

MYELOGRAPHY AND RADIOISOTOPE CISTERNOGRAPHY

CT or MR myelography and radioisotope cisternogra-phy have a key role in determining the presence andlocation of spontaneous, posttraumatic, or postoperativeCSF leaks when MRI brain findings point to a low CSFpressure syndrome.

CSF ExaminationCSF studies are a useful adjunct to neuroimaging inselect situations when investigating the patient withheadache. It has been estimated that 5% of patients

with subarachnoid hemorrhage will have a negative CTscan soon after headache onset, with the sensitivitydeclining precipitously over the subsequent days to

weeks. In this instance, examining the CSF for red bloodcells and xanthochromia is of paramount importance.Some studies suggest that xanthochromia is better de-tected by spectrophotometry than by visual inspection;nevertheless, the latter method has recently been shownto have a high positive predictive value for the presenceof aneurysm on cerebral angiography.4,32 Xanthochro-

mia is not entirely specific for antecedent hemorrhage,and can also be seen in a traumatic LP (red blood cell[RBC] count more than 100,000/mm3), hyperbiliru-binemia, elevated CSF protein (>150 mg/dL), dietaryhypercarotenemia, purulent CSF, and meningeal mela-nomatosis.4 Red blood cell and total nucleated whiteblood cell (WBC) counts should also be obtained whensuspecting subarachnoid hemorrhage, as both have beendemonstrated to be significantly elevated in patients withangiographically documented ruptured aneurysms.32 It isimportant to note that initially the ratio of WBCs toRBCs in the CSF is proportionate to the number of

WBCs to RBCs in the bloodstream. Over time, how-ever, the presence of RBCs in the CSF provokes arelative increase in the number of WBCs in the CSF.

The possibility of a traumatic LP is evaluated by per-forming cell counts on serial tubes looking for a rapidlyfalling RBC count. If the RBC count in the final tube isnot close to zero, simultaneous traumatic LP and spon-

taneous subarachnoid hemorrhage are possible.76

Inpatients whose suspected bleeding occurred greaterthan 12 hours beforehand, cell-free CSF should beexamined for xanthochromia. The presence of xantho-chromia in the absence of subarachnoid bleeding due tohead injury should influence the clinician to search for ananeurysm or AVM.

Cerebrospinal fluid examination is also helpful inevaluating for noninfectious inflammation, infectiousmeningitis or encephalitis, meningeal carcinomatosis orlymphomatosis, and confirming increased pressure (e.g.,benign intracranial hypertension) or a low CSF pressure

syndrome. To explore fully the differential diagnosis ofheadache, CSF studies should always include an openingpressure, red and white blood cell counts and white cellcount differential, protein and glucose concentrations(with coincident serum glucose determination for com-parison if there is any concern about infectious ormalignant meningitis), and possibly include cultures(bacterial, viral, and/or fungal), cytology and flow cy-tometry, condition-specific antibodies (Lyme disease,syphilis), and polymerase chain reaction testing for spe-cific infectious agents, as clinically indicated. If thesuspicion of bacterial meningitis is high, then bloodcultures should be obtained without delay and empiricintravenous antibiotics should be started soon thereafter.Lumbar puncture should be the next study completed,unless focal neurologic signs suggesting an underlyingintracranial mass lesion dictate that emergent brainimaging be obtained prior to CSF collection. The eval-uation of suspected low CSF pressure syndrome andsuspected benign intracranial hypertension should entailMRI brain with and without gadolinium prior to LP.

Electrophysiologic TestingThere is no role for electroencephalography or evoked

potentials in the evaluation of the patient with head-ache.72,77 There is no evidence to justify autonomictesting or transcranial Doppler examination in the pa-tient with headache.72 In the patient who wakes fromsleep due to headache, polysomnography can be useful tolook for a treatable sleep disturbance if there is noindication 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 carbonmonoxide poisoning, the possibility of a faulty furnaceshould be explored.



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General Medical TestsThere are several tests outside of neuroimaging andCSF analysis that are important to consider in certainpatients with headache. In a patient older than50 years who presents with headache, one must con-sider the possibility of giant cell arteritis. Corroborat-ing clinical features of this diagnosis include decreased

pulsation and/or tenderness and/or thickening of thesuperficial temporal arteries, jaw and/or tongue clau-dication, and constitutional symptoms. Elevation ofthe ESR, often to 100 mm per hour or higher, andincreased CRP are frequently encountered in giant cellarteritis. CRP is less influenced by age and genderthan is ESR.3,4,18,78 A normal ESR does not excludethe condition, as 4% of patients with positive findingson temporal artery biopsy have a normal ESR.78

Thrombocytosis is also often seen.79 Temporal arterybiopsy demonstrating characteristic vasculitic changesconfirms the diagnosis.

Other medical causes and associated tests toconsider in the patient with headache include insuli-noma (episodic headache associated with unusual be-havior or impairment of consciousness) with elevatedserum insulin and C-peptide levels and low fastingglucose level, carbon monoxide poisoning with elevatedcarboxyhemoglobin determination, drug and alcoholoveruse or abuse with positive urine or blood testing,hypothyroidism with thyroid function tests, and pheo-chromocytoma with plasma fractionated metanephrinelevels and 24-hour urine fractionated metanephrine andcatecholamine levels. Rarely, current or former smokerscan present with intractable face or head pain, oftenincluding the ear (84%), which is found to be due to anunderlying ipsilateral lung tumor without CNS in-

volvement. Seventy-seven percent of reported patientshave had an elevated ESR, and the tumor is found onchest x-ray or CT scan of the chest (20% of chest x-raysmay be unrevealing).80

Special Examinations and ConsultationsThere are certain instances in which the expertise ofsubspecialists should be considered in the evaluation ofthe patient with headache. Help from ophthalmology

may be useful to exclude glaucoma when head and/or eyepain is accompanied by conjunctival injection or cornealclouding. In this circumstance, formal visual field test-ing, tonometry, slit-lamp, and other specialized exami-nations are informative. A dentist or oral surgeon shouldbe enlisted if pain of dental or temporomandibular jointorigin is suspected. The diagnosis of tumors of thesinuses, nasopharynx, and neck, and inflammatory sinusdisease is facilitated by an otorhinolaryngologist. Inselected cases where headache may be the manifestationof a chronic pain disorder, consultation with psychiatrycan be helpful for diagnosis and management.

The Adverse Effects of InvestigationIn the evaluation of headache, the investigations to

which patients are subjected are not without risk. Asingle head CT may slightly increase the lifetime risk ofdeath from cancer attributable to exposure to radia-tion.81 In susceptible individuals, there is a risk ofanaphylaxis and renal insufficiency when iodinated

contrast material is administered. Brain MRI is alsoassociated with risk. In a Dutch population-basedstudy, brain MRI studies of 2000 asymptomatic indi-

viduals detected a substantial number of incidentalfindings including brain infarcts (7.2%), cerebral aneur-

ysms (1.8%), and benign primary tumors (1.6%).71

Incidental findings provoke worry, fear, and oftenadditional interventions, along with follow-up testingto monitor the incidental finding, none of which helpsthe patient with headache. Nephrogenic systemic fib-rosis is a noteworthy complication of MRI studies in

which a gadolinium-containing contrast agent is given

to individuals with impaired renal function.82

Diag-nostic cerebral angiography poses risks ranging fromaccess-site hematomas (4.2%), to strokes with perma-nent disability (0.14%) or even death (0.06%).83 Aprocedure as benign as LP may be complicated bypost-LP headaches, a persistent CSF leak, bleeding,low back pain, and rarely, infection. These importantcaveats serve not to deter the clinician from investigat-ing a patient with headache, but to remind the clinicianthat the selection of diagnostic tests should be tailoredto a given patients unique circumstances and justifiedby medical need.

CONCLUSIONS

Headache imposes a substantial burden on individualheadache sufferers, and is the leading reason for neuro-logic consultation. The clinician is faced with thechallenge of distinguishing between primary and sec-ondary headache disorders so that selected patientsundergo appropriate testing. A detailed clinical historyand complete general and neurologic examinations,

with special attention to the red and yellow flags, arefundamental to this process. In most instances, thesystematic selection of investigations targeted to the

specific clinical nuances surrounding the individualpatient with headache will reduce unnecessary testing,minimize the detection of clinically insignificant find-ings, and decrease extraneous costs. The mastery ofwhen and how to investigate the patient with head-ache will instill confidence and reassure the patient andprovider alike.

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