on 29-Jun-2022 (Wed)

Patients with headache unrelated to trauma constitute approximately 2 percent of emergency department (ED) visits, though some studies suggest a rate as high as 4 percent [1-3].

This topic will discuss how to approach adults presenting to the ED with headache, with an emphasis on those components of the history and physical examination that characterize high-risk headaches. Diagnostic tables to help guide this evaluation are provided (table 1 and table 2).

While some dangerous causes of headache may present with a gradual increase in pain, any severe, persistent headache that reaches maximal intensity within a few seconds or minutes after the onset of pain warrants aggressive investigation [6-8]

Subarachnoid hemorrhage (SAH), for example, often presents with the abrupt onset of excruciating pain. Other serious etiologies of sudden-onset headache include reversible cerebral vasoconstriction syndromes, carotid and vertebral artery dissections, venous sinus thrombosis, pituitary apoplexy, acute angle-closure glaucoma, unruptured cerebral aneurysms, colloid cyst of the third ventricle, and hypertensive emergencies ( table 3).

In contrast, migraine headaches generally begin with mild to moderate pain and then gradually increase to a maximal level over one to two hours.

Cluster headache may sometimes be confused with a serious headache since the pain from a cluster headache can reach full intensity within minutes. However, cluster headache is transient (usually lasting less than one to two hours) and is associated with characteristic ipsilateral autonomic signs, such as tearing, miosis, or rhinorrhea.

Of note, many dangerous causes of headache can present with gradual-onset headache, including herpetic or Lyme meningitis, brain tumor, brain abscess, hypertensive encephalopathy, posterior reversible encephalopathy syndrome (PRES), and idiopathic intracranial hypertension.

Furthermore, dangerous causes may present with atypical timing, and symptoms may overlap. As examples, most patients with cervico-cranial artery dissections and venous sinus thrombosis present with gradual-onset headaches, and some patients with acute-angle closure glaucoma develop headaches that simulate migraine and can be intermittent [ 9]

The absence of similar headaches in the past is another finding that suggests a serious disorder. The "first" and "worst headache of my life" are descriptions that sometimes accompanies an intracranial hemorrhage or central nervous system (CNS) infection.

A new or unusual headache in a patient with acquired immunodeficiency syndrome (AIDS) or cancer is particularly worrisome, as it suggests an intracranial lesion or infection [ 10].

Infection in an extracranial location (such as the paranasal or mastoid sinuses, pharynx, or inner ear) may serve as a nidus for the development of meningitis or intracranial abscess.

Any change in mental status, personality, or fluctuation in the level of consciousness suggests a potentially serious abnormality. Syncope or near-syncope at headache onset is suggestive of SAH. Headache associated with seizure is also concerning for intracranial pathology

In the patient with a headache and altered mental status, it is important to check for hypoglycemia using a point-of-care (eg, fingerstick) glucose concentration

Preeclampsia and PRES can cause headache and seizure and may present up to six weeks following delivery.

The rapid onset of headache with exertion (eg, sexual intercourse, exercise), raises the possibility of carotid artery dissection, reversible cerebral vasoconstriction, or intracranial hemorrhage.

Patients over 50 years of age with new onset or progressively worsening headache are at significantly greater risk of a dangerous cause of their symptoms, including an intracranial mass lesion and giant cell arteritis [1,3,6,11].

HIV and other immunosuppressed patients with headache are at significant risk for intracranial disease, including toxoplasmosis, stroke, brain abscess, meningitis, and malignancy of the CNS. Clinicians should have a low threshold to perform aggressive workups on such patients, particularly if high-risk features such as new-onset seizure or altered mental status are present [10,12].

Occasionally, patients with significant ophthalmologic disease, most notably acute angle-closure glaucoma, present with a complaint of headache.

Headache may precede visual changes or eye pain in acute angle-closure glaucoma. Headache associated with visual disturbances may also be associated with giant cell arteritis, idiopathic intracranial hypertension, and PRES

Although primary headache syndromes remain the most common cause of headaches in this group, other pregnancy-related diagnoses should be considered. Preeclampsia is the most common of these; the presentation of preeclampsia can overlap with PRES [13]. Less common etiologies include venous sinus thrombosis, pituitary apoplexy, and reversible cerebral vasoconstriction [13].

Location of the pain is not particularly useful in the diagnosis. However, head pain that spreads into the lower neck (ie, occipitonuchal headache) and between the shoulders may indicate meningeal irritation due to either infection or subarachnoid blood; it is not typical of a benign process [1]

Some secondary headaches are well localized. As an example, headache from acute angle-closure glaucoma is commonly centered around the involved eye, while headache from giant cell arteritis is often, but not always, focused in a temple.

The headache patient with a family history of SAH among first- or second-degree relatives is at significantly greater risk of SAH [14]. Simultaneous headaches in multiple family members suggest carbon monoxide poisoning.

Clinicians should inquire about medication use, particularly anticoagulants, glucocorticoids, oral contraceptives, and analgesics. Use of anticoagulants or nonsteroidal antiinflammatory drugs (NSAIDs), including aspirin, increases the risk of intracranial bleeding.

All anticoagulants confer an increased bleeding risk, including bleeding into the brain. Patients on warfarin have a higher risk of intracranial hemorrhage compared with those on direct oral anticoagulants (DOACs), and patients on any oral anticoagulant plus antiplatelet agents have an increased risk compared with those not on these agents. Details pertaining to the risk of bleeding associated with particular medications are provided separately. (See "Risks and prevention of bleeding with oral anticoagulants".)

All anticoagulated patients with head trauma, even minor trauma, should undergo computed tomography (CT).

A number of illicit drugs, including cocaine, methamphetamine, and other sympathomimetic agents, increase the risk of stroke and intracranial bleeding. If the drugs are used intravenously (IV), brain abscess is another possibility, even in the absence of fever.

Headaches that involve multiple family members or coworkers and improve rapidly in the emergency department (ED) without intervention, particularly during winter months, raise the possibility of carbon monoxide poisoning.

Other historical factors to consider when investigating the cause of headache include chiropractic neck manipulation, toxic exposures (eg, carbon monoxide), and comorbidities known to put patients at higher risk for critical secondary causes of headache. Such comorbidities include malignancy with a risk of intracranial metastasis (and possibly increased intracranial pressure [ICP]) and polycystic kidney disease or connective tissue disease, both of which increase the risk of aneurysms with resultant SAH. Jaw claudication suggests giant cell arteritis as the cause of headache.

Recent rash compatible with erythema migrans (picture 1) suggests Lyme meningitis, and concurrent petechial (picture 2) or purpuric (picture 3) rash suggests bacterial meningitis.

Postural or positional headache raises concern for spontaneous intracranial hypotension or colloid cyst of the third ventricle.

Headaches that worsen upon standing are usually due to postdural puncture (eg, following a lumbar puncture [LP]) or spontaneous intracranial hypotension (if a procedure violating the dura has not been performed). These headaches are due to low ICP from cerebrospinal fluid (CSF) leaks. Headaches that worsen with cough or Valsalva suggest the possibility of brain tumor or other causes of elevated ICP.

Fever makes a diagnosis of migraine or tension-type headache highly unlikely. Fever may be due to CNS infection or inflammation and may be due to a several-day-old SAH (table 4)

Although rare, severe hypertension (diastolic blood pressure ≥120 mmHg) can manifest as headache [ 7]. Although new hypertension in a previously normotensive patient can be due to pain or anxiety, it may also be a compensatory finding from elevated ICP of any cause.

Obtundation and confusion are not seen in benign headaches and increase the likelihood of meningitis, encephalitis, SAH, or results of a space-occupying lesion.

Abnormal findings on neurologic examination remain the single best clinical predictor of intracranial pathology [1,6,15]. The findings may be quite subtle and go unnoticed by the patient (eg, slight pupillary asymmetry, unilateral pronator drift, visual field cut, or extensor plantar response) or pronounced and obvious (eg, unilateral vision loss, ataxia, or seizure).

Nonfocal alterations in mental status more commonly characterize other secondary causes of headache, including SAH, infectious processes such as meningitis or encephalitis, toxins such as carbon monoxide, and metabolic derangements such as hypoxia

In the patient with a headache and altered mental status, it is important to check for hypoglycemia using a point-of-care (eg, fingerstick) glucose concentration (hypoglycemia may cause focal neurologic deficits).

Neurologic abnormalities can also occur with migraine headaches. As an example, a visual field cut in both eyes within the same hemifield bounded by scintillations is characteristic of migraine with visual aura (see "Pathophysiology, clinical manifestations, and diagnosis of migraine in adults", section on 'Migraine aura'). However, a focal neurologic deficit should not be assumed to be related to migraine unless similar deficits have occurred with prior migraines. Any new or atypical focal neurologic deficit is considered a high-risk finding and should be investigated urgently until the cause is identified.

One concept that helps to distinguish symptoms or signs due to migraine rather than ischemia, infarct, or other destructive processes is that of "positive" versus "negative" phenomena, as described in the following table (table 5). As a general rule, positive phenomena are due to migraine and seizure whereas negative findings are found in destructive lesions.

Meningismus may indicate meningitis or SAH. It can be subtle. This sign is also less sensitive and less specific in adults older than 60 years [16].

Examination of the eye in acute angle-closure glaucoma often shows an edematous ("steamy") cornea and may reveal ciliary flush (picture 5) and sluggish pupillary light response.

Field cuts can be seen with any process that involves the optic nerve, chiasm (especially with pituitary apoplexy), optic radiations (any process), or occipital cortex (PRES or posterior cerebral artery ischemic stroke).

Abnormalities of the temporal artery (eg, diminished pulse, swelling, or tenderness) are highly suggestive of giant cell arteritis.

Nausea and vomiting can accompany increased ICP, intracranial hemorrhage, or acute angle-closure glaucoma but are also common with migraine. Vomiting in a migraineur who has never vomited with prior headaches raises concern for a secondary cause of the new headache.

A carotid bruit may accompany carotid artery dissection but is more commonly due to atherosclerotic plaque. Nasal discharge associated with sinus tenderness or signs of dental infection may reflect the cause of headache.

Approximate effective radiation dose is 2 mSv for a head CT and 4 to 5 mSv for head CTA [18,19].

In addition, the ACR Appropriateness Criteria provides general guidance for many common clinical scenarios of headache [20]. When the decision is not obvious, consultation with the radiologist is helpful to facilitate patient referral.

Patients with a history of prior headaches who present to the emergency department (ED) due to failure of their standard therapy regimen and who meet the following criteria can be considered at low-risk for dangerous headache:

● No substantial change in their typical headache pattern

● No new concerning historical features (eg, seizure, fever)

● No focal neurologic symptoms or abnormal neurologic or ophthalmologic examination findings

● No high-risk comorbidity

An extensive diagnostic workup and routine imaging in the ED are not needed in these patients [21]. However, some of these patients should be referred for evaluation for non-life-threatening but treatable causes of headache. (See "Evaluation of headache in adults".)

The yield of imaging is low if no high-risk historical feature is present and the neurologic examination is normal. As an example, a meta-analysis of published articles on the utilization of computed tomography (CT) and magnetic resonance imaging (MRI) in patients presenting with headache conducted by the Quality Standards Subcommittee of the American Academy of Neurology revealed that abnormalities were present in only 2.4 percent of patients with a normal neurologic examination [22]. The incidence of pathology was even lower (0.4 percent) in patients whose headaches were typical of migraine and whose physical examinations were normal

Another analysis of 10 years of data from the National Hospital Ambulatory Medical Care Survey (NHAMCS) reported that, of the 14 percent of ED patients with headache who had brain imaging at the discretion of the ED provider, 5.5 percent had a "pathological diagnosis" [3].

Approximately 8 percent of emergency department (ED) patients with a thunderclap headache have a subarachnoid hemorrhage [8,23]

Because the consequences of missing subarachnoid hemorrhage (SAH) are potentially dire, most guidelines state that an LP should be performed in all patients with suspected SAH in whom the CT is normal. One exception is that if a high-quality CT is obtained within six hours of the onset of symptoms and interpreted by an expert radiologist to be normal, LP is not necessary. These issues are discussed in detail separately. (See "Aneurysmal subarachnoid hemorrhage: Clinical manifestations and diagnosis", section on 'Evaluation and diagnosis'.)

Equally important to obtaining appropriate diagnostic testing are initiating actions to prevent acute complications and immediate consultation with a neurosurgeon or other cerebrovascular specialist.

Failure to evaluate patients with thunderclap headache thoroughly and expeditiously can result in misdiagnosis with resultant poor outcomes due to rebleeding, early hydrocephalus, or vasospasm. Misdiagnosed patients generally appear less ill and do not have neurologic deficits; misdiagnosis stems from a lack of appreciation of the range of possible presentations of patients with SAH and failure to do a CT or LP [14].

A dilemma sometimes confronted in the ED is determining what additional workup and disposition are appropriate for patients at risk for SAH whose head CT is unrevealing and whose initial LP is presumed to be traumatic [24]. Several approaches are available to help distinguish between a traumatic tap and true SAH.

First, finding an elevated opening pressure (greater than 20 cm of water) suggests a pathologic process.

Of note, the clearing of blood from sequential tubes of CSF is not a reliable means of excluding SAH unless a late or final collecting tube specimen is normal (ie, red blood cell count approaches zero). A useful technique to increase the likelihood of obtaining a red cell count in the last tube that approaches zero is to waste several milliliters of CSF between the first and last tubes (this is not harmful, as 10 mL of CSF are produced within 20 to 30 minutes). Another technique is to test for xanthochromia, the presence of which strongly suggests a true SAH (though this too can be falsely positive).

Another approach is to repeat the LP one intervertebral level cephalad to where the initial attempt was made (but no higher than L3/4) or under fluoroscopic guidance. The presence of blood in CSF obtained from two LPs suggests SAH, while a normal specimen from the repeat LP makes SAH less likely.

If bacterial meningitis is considered, blood cultures should be obtained, then empiric antimicrobial therapy (with or without intravenous [IV] dexamethasone) should be instituted (table 6).

After antibiotics have been given, perform a head CT without contrast to look for contraindications to LP prior to the procedure. A CT prior to a LP is mandatory in the following groups of patients (see "Clinical features and diagnosis of acute bacterial meningitis in adults", section on 'Indications for CT scan before LP'). Note that LP should not be delayed to await a head CT in the absence of these criteria:

● Immunocompromised state (eg, HIV infection, immunosuppressive therapy, solid organ or hematopoietic stem cell transplantation)

● Active CNS disease (eg, acute stroke, mass lesion, abscess) causing intracranial mass effect

● New-onset seizure (within one week of presentation)

● Papilledema

● Abnormal level of consciousness

● Focal neurologic deficit

In the absence of CT findings that would contraindicate a safe LP (eg, a mass lesion or signs of generalized cerebral edema), one can proceed with LP, measuring the opening pressure. If LP is contraindicated on the basis of concerning CT findings, the patient should be admitted to an intensive care unit (ICU), antimicrobials continued, and a neurologist consulted.

The clinical policy statement on acute headache of the American College of Emergency Physicians makes a recommendation based upon weak evidence that an LP without prior imaging may be performed in patients without signs of increased ICP (ie, papilledema, absent venous pulsations on funduscopy, altered neurologic status, or focal neurologic deficits) [21]. The presence of venous pulsations on funduscopic examination is strong evidence of normal ICP.

Headache is the primary symptom of increased ICP, which should be suspected when accompanied by papilledema, focal neurologic deficit, or repeated episodes of nausea and vomiting without another explanation.

If imaging does not reveal a structural cause or anatomical changes associated with elevated ICP, LP is performed to measure the opening pressure and to evaluate for underlying infection. Note that in patients with suspected idiopathic intracranial hypertension, most of whom will have papilledema, an LP with opening pressure is a necessary part of the evaluation, but it should follow brain imaging.

If carbon monoxide (CO) poisoning is suggested by the history (eg, multiple family members or coworkers affected simultaneously; patient brought from enclosed space with an identified source such as gasoline or kerosene generator; rapid improvement when removed from source without other intervention), high-flow oxygen should be administered immediately and the diagnosis confirmed by measuring a carboxyhemoglobin concentration with cooximetry using an arterial blood gas sample.

Standard pulse oximetry (SpO ₂) does not differentiate carboxyhemoglobin from oxyhemoglobin. In addition, the partial pressure of oxygen (PaO₂) in an arterial blood gas is normal, as it measures dissolved oxygen (which is not affected by CO), not oxygen bound to hemoglobin (which is). Chronic low-dose CO exposure may also cause headache, more often during winter months.

An acute headache accompanied by eye pain or diminished vision, typically unilateral, suggests acute angle-closure glaucoma (sometimes referred to as acute narrow-angle glaucoma). Examination typically reveals a red eye with ciliary flush and no discharge, a pupil fixed in mid-dilation, and a cornea that is edematous or "steamy" appearing (not normally translucent) (picture 5).

Headache that radiates into the neck may be the result of carotid or vertebral artery dissection. Horner syndrome is seen in approximately 39 to 47 percent of those with carotid and up to 19 percent of those with vertebral artery dissection [27,28].

Most patients with an arterial dissection do not have a thunderclap headache (3.2 percent for carotid dissection and 9 percent for vertebral dissection) [29]. Nearly 60 percent of patients have brain ischemia or infarction [29]. However, nearly 10 percent of patients present with isolated headache or neck pain [30]. In the absence of a thunderclap onset, Horner syndrome, or symptoms or signs of brain ischemia or infarction, other clues include recent (even minor) trauma and the history (given by almost all patients with migraine who describe the headache from a dissection) as different from prior headaches [30].

Because headache (and neck pain) are so common, establishing the diagnosis of arterial dissection is very difficult in patients who present with pain only (ie, without neurologic findings) and who do not have any of the clues described above. As it is neither feasible nor desirable to evaluate every such patient with cerebrovascular imaging, occasionally patients may be misdiagnosed on a first visit. This highlights the importance of giving clear, specific discharge instructions about symptoms that should prompt immediate return to the ED.

Noncontrast head CT should be followed by CT and CTA of the head and neck with IV contrast. Alternatively, MRI and MRA of the head and neck without and with IV contrast is an equivalent option. CTA or MRA of the neck extends from the carotid and vertebral artery origins at the thoracic inlet to the circle of Willis at the skull base. Reported accuracies vary somewhat but are similar for CT and MRI. Reported sensitivity ranges from 50 to 80 percent and specificity from 67 to 99 percent for both modalities [31]. (See "Cerebral and cervical artery dissection: Clinical features and diagnosis".)

A new or progressively worsening headache in a patient older than 50 years may suggest underlying tumor or hemorrhage. Head MRI without and with contrast is recommended. If MRI is not immediately available, head CT without contrast is an option to evaluate for findings associated with elevated ICP (eg, hydrocephalus, hemorrhage, and mass effect), and MRI without and with contrast is usually performed when the modality becomes available.

Infection, lymphoma, and leukemia are complications of chronic immunosuppression. Head MRI without and with contrast should be obtained to evaluate for abscess or encephalitis. If MRI is not immediately available, head CT without contrast is an option to evaluate for findings associated with elevated ICP (eg, hydrocephalus, hemorrhage, and mass effect), and MRI without and with contrast is performed when the modality becomes available.

Cancer patient with new headache — Metastases and, if the patient is immunocompromised, infection are the primary concerns in this population. Head MRI without and with contrast is recommended. If MRI is not immediately available, head CT without contrast is an option to evaluate for findings associated with elevated ICP (eg, hydrocephalus, hemorrhage, and mass effect), and MRI without and with contrast is performed when the modality becomes available.

New headache in pregnancy — Preeclampsia and eclampsia must be considered as the cause of headache in every pregnant woman over 20 weeks of gestation, in addition to the many other causes of acute headache. Preeclampsia and eclampsia can also occur up to a few weeks postpartum. Cerebral venous sinus thrombosis is another particular concern in the postpartum period

Headache with visual impairment, periorbital pain, or ophthalmoplegia could indicate acute angle-closure glaucoma, infection, inflammation, or tumor involving the orbits or cavernous sinus.

Headache of sinonasal origin usually does not require imaging for diagnosis as it is best evaluated with nasal endoscopy performed by an ear, nose, and throat (ENT) specialist as an outpatient.

Headache suspected to originate from maxillofacial conditions such as temporomandibular joint (TMJ) disorders or trigeminal neuralgia is best evaluated with head MRI without and with IV contrast, generally as an outpatient. Headache suspected of odontogenic origin is better evaluated with CT, especially in the acute setting. Dental amalgam degrades image quality with both CT and MRI, and in such cases, imaging is likely to be of limited quality.

Older adult with temporal artery abnormalities — Giant cell arteritis should be suspected in patients with temporal artery abnormalities (eg, tenderness, decreased pulsations), particularly if associated with jaw claudication, sudden monocular vision loss, or unexplained fever or anemia. The clinical manifestations, evaluation, and treatment of giant cell arteritis are discussed separately. (See "Clinical manifestations of giant cell arteritis" and "Diagnosis of giant cell arteritis" and "Treatment of giant cell arteritis".)

For many patients in whom a secondary cause was suspected but a thorough, appropriate workup was normal, symptomatic treatment and discharge with timely primary care or neurologic follow-up is reasonable.

Of note, patient response to analgesics should not be used as a diagnostic tool and should not dissuade performance of lumbar puncture (LP) when indicated by history or examination [32].

Relief of symptoms is an important part of management for patients presenting to the emergency department (ED) with severe headache, even when a thorough workup reveals no clear underlying process. The large majority of these patients will ultimately be diagnosed with either a migraine or cluster headache (table 7). Details of migraine and cluster headache treatment are discussed separately. (See "Acute treatment of migraine in adults" and "Cluster headache: Treatment and prognosis".)

For those patients with a primary headache disorder that does not clearly meet criteria for migraine or cluster headache, symptomatic treatment should be provided. Few studies are available to guide empiric management of undifferentiated headache in the ED; treatment remains symptom-based and largely nonspecific. Nevertheless, many of the treatments used for acute migraine headaches provide some relief in patients with a severe undifferentiated headache [33,34].

The authors of a systematic review of headache management in the ED propose the use of a parenterally administered nonsteroidal antiinflammatory drug (NSAID) and a dopamine antagonist [2]. Their goal is to relieve pain and allow the patient to return to baseline mental function without drowsiness. In the United States, this treatment would probably be ketorolac 15 to 30 mg intravenously (IV) and prochlorperazine 10 mg. Haloperidol 2.5 to 5 mg IV or chlorpromazine 0.1 mg/kg IV might be used in place of prochlorperazine. Pretreatment with 12.5 mg of diphenhydramine or 1 mg of benztropine is suggested to avoid akathisia.

Two small randomized trials report that low-dose haloperidol is effective for alleviating severe pain due to a benign cause of headache [ 35,36]. In a small randomized trial, prochlorperazine was shown to be as effective as subcutaneous sumatriptan [36]. Treating nausea and vomiting with a parenteral agent such as ondansetron may make the patient more comfortable while other diagnostic and therapeutic steps are occurring.

NSAIDs should be withheld in patients for whom there remains concern for a hemorrhagic cause of headache or who may require a lumbar puncture (LP)

For headaches unresponsive to treatment with a combination of NSAID and dopamine antagonist that have some migrainous features (eg, photophobia), dihydroergotamine 1 mg IV may be effective. Other medications used to treat undifferentiated headache in the ED include sumatriptan, olanzapine, metoclopramide, and droperidol [37-39]. Sumatriptan and oxygen are used to treat cluster headache.

The use of injectable opioids is strongly discouraged, but they may be necessary for patients with contraindications to NSAIDs or medications with vasoconstrictive effects (eg, dihydroergotamine), or for patients in whom prochlorperazine and diphenhydramine have not been effective.

Thunderclap headache (TCH) refers to a severe headache of sudden onset. Its explosive and unexpected nature is likened to a "clap of thunder." Multiple etiologies may cause TCH (table 1)

A TCH is a very severe headache of abrupt onset that reaches its maximum intensity within one minute or less of onset [1].

The key feature that differentiates TCH from other headaches is the rapidity with which it develops; extreme severity alone is insufficient [ 2].

Although the cause of TCH cannot be determined with certainty based upon the presentation alone, some clues to the possible etiology can be gleaned from the history and from accompanying clinical features [2,4].

TCH associated with altered consciousness, seizures, or focal neurologic symptoms and signs can be due to multiple possible causes, including subarachnoid hemorrhage, other intracranial hemorrhage, reversible cerebral vasoconstriction syndrome (RCVS), posterior reversible encephalopathy syndrome (PRES), hypertensive crisis, cerebral sinus thrombosis, cervical artery dissection, or ischemic stroke.

Other clinical presentations may suggest specific causes of TCH:

● Recurrent TCH over days to weeks suggest RCVS.

● TCH associated with orthostatic headaches suggests spontaneous intracranial hypotension.

● Postpartum setting suggests RCVS or cerebral venous thrombosis.

● Recent minor trauma suggests cervical artery dissection or spontaneous intracranial hypotension.

● Horner syndrome or pulsatile tinnitus suggests dissection of the ipsilateral internal carotid artery.

● Papilledema and visual symptoms suggest intracranial hypertension related to cerebral venous thrombosis.

● Fever or meningismus suggests meningitis.

● Facial pain, ear, nose, and throat symptoms suggest complicated sinusitis.

TCH has multiple causes (table 1). The most frequent are subarachnoid hemorrhage and reversible cerebral vasoconstriction syndromes (RCVS).

The primary symptom of aneurysmal subarachnoid hemorrhage is a sudden, severe headache. Approximately one-half of patients with subarachnoid hemorrhage present with TCH [4].

While there are no symptoms or signs that can reliably differentiate primary from secondary TCH, the following features are associated with increased odds of subarachnoid hemorrhage in a patient with TCH [ 5-7]:

● Impaired consciousness

● Neck stiffness

● Nausea, vomiting

● Exertion or Valsalva immediately preceding onset of TCH

● Elevated blood pressure

● Occipital headache

● History of smoking

Misdiagnosis occurs because of failure to recognize the spectrum of possible presentations of subarachnoid hemorrhage, lack of knowledge regarding the limitations of head computed tomography (CT), and failure to perform lumbar puncture and interpret cerebrospinal fluid tests correctly.

Initial evaluation for subarachnoid hemorrhage must include noncontrast CT of the brain (algorithm 1). Lumbar puncture is indicated when there is clinical suspicion of subarachnoid hemorrhage and the head CT is normal.

RCVS are a group of conditions characterized by reversible segmental narrowing of the cerebral arteries. The clinical presentation of RCVS is usually dramatic with sudden, severe recurrent thunderclap headaches over the span of a few days that simulate aneurysmal subarachnoid hemorrhage; however, in patients with RCVS, thunderclap headaches often recur over a span of one to four weeks, and the duration of headache in RCVS is generally shorter (ie, several hours with resolution between attacks). Headaches of RCVS are frequently triggered by diverse conditions such as sexual activity, heat or cold exposure, various therapeutic and recreational drugs, and the postpartum state [8].

Clinical suspicion for RCVS is warranted for patients who present with the following manifestations (see "Reversible cerebral vasoconstriction syndrome", section on 'Evaluation'):

● Recurrent TCH; or

● Single TCH, particularly if combined with border zone infarcts or vasogenic edema on neuroimaging; or

● No TCH but abnormal angiography and no brain lesions on neuroimaging; the absence of brain lesions virtually rules out primary angiitis of the central nervous system

Recurrent thunderclap headache and the presence of a vasoconstrictive trigger are key components of clinical scoring systems developed to help identify RCVS as the cause to TCH (table 2 and table 3) [9,10]

Despite the presence of widespread cerebral vasoconstriction, the admission brain scan is normal in 30 to 70 percent of patients with RCVS.

Cerebral angiographic abnormalities may be absent during the first days after symptom onset; the changes are dynamic and progress proximally, resulting in a "sausage on a string" appearance of the circle of Willis arteries and their branches. These abnormalities begin to resolve spontaneously (without specific therapy) over a few weeks [4].

There is no proven therapy for RCVS. Supportive care is directed toward managing blood pressure, severe headaches, and other complications such as seizures.

The clinical outcome is benign in 95 percent of patients. Rare patients develop severe irreversible deficits or death from progressive strokes or cerebral edema. Recurrence of an episode of RCVS may occur in about 5 percent of patients [11].

Conditions that are less common causes of TCH include the following:

● Cerebral infection (eg, meningitis, acute complicated sinusitis)

● Cerebral venous thrombosis

● Cervical artery dissection

● Spontaneous intracranial hypotension

● Posterior reversible encephalopathy syndrome (PRES)

● Ischemic stroke

Patients with cerebral venous thrombosis may present with TCH. Headache is the most common presenting symptom in cerebral venous thrombosis, occurring in approximately 90 percent of patients. In addition to headaches, patients with cerebral venous thrombosis usually present with some combination of papilledema, seizures, bilateral focal deficits, and/or altered level of consciousness. However, about 15 percent of patients may present with isolated headache. (See "Cerebral venous thrombosis: Etiology, clinical features, and diagnosis", section on 'Headache'.)

TCH accompanies cerebral venous thrombosis in 2 to 15 percent of patients [12-14]. Most commonly, however, the headaches of cerebral venous thrombosis have a gradual subacute onset; they may be localized or diffuse, persistent, exacerbated by Valsalva, and positional with worsening on recumbency.

Magnetic resonance imaging (MRI) with venography should be considered when cerebral venous thrombosis is suspected, as initial testing for a suspected diagnosis of subarachnoid hemorrhage with head CT and lumbar puncture will not always detect cerebral venous thrombosis.

The cerebrospinal fluid abnormalities in cerebral venous thrombosis are nonspecific, but the opening pressure is often elevated, especially when the sagittal sinus is involved. In patients with cerebral venous thrombosis who have normal neurologic exams, the head CT is normal in approximately 25 percent, whereas in patients with cerebral venous thrombosis who have focal neurologic signs, the head CT is normal in less than 10 percent [ 15,16].

Cervical artery dissection — Headache and/or neck pain is the most frequent initial symptom of cervicocephalic dissection, found in 60 to 90 percent of cases.

Although the onset of headache in cervical artery dissection is usually gradual, a minority present with TCH [17-19]. In a series of 970 consecutive patients with dissection, approximately 5 percent had a presentation consistent with a TCH (approximately 4 percent in carotid dissections and 9 percent in vertebral dissections) [19]. Diagnostic criteria from the International Classification of Headache Disorders, 3^rd edition (ICHD-3) for headache secondary to cervical artery dissection stipulate that the headache must be ipsilateral to the dissected artery [1].

Cervical artery dissection can cause ischemic stroke, transient ischemic attack, or, rarely, subarachnoid hemorrhage. In addition to neck pain and headache, other local manifestations of dissection can include a Horner syndrome, pulsatile tinnitus, an audible bruit, or cranial neuropathies. Ischemia from vertebral dissections may present with vestibular symptoms and signs that may be subtle.

Common causes of dissection include various degrees of trauma or spontaneous events, with underlying predispositions in some cases. Dissection can also result from major head and neck trauma, but most dissections occur spontaneously or after minor or trivial injury.

Infections — Bacterial and viral meningitis are most commonly associated with headaches of a gradual onset but may rarely present with TCH. A prospective analysis of 148 patients presenting to their primary care physician with TCH found four (3 percent) with infectious etiologies [20].

Headaches related to acute sinusitis may also rarely be of the thunderclap variety. Although headaches and facial pain are frequent in patients with acute rhinosinusitis, most commonly these are acute to subacute in presentation and not consistent with TCH. However, TCH may occasionally be the presenting manifestation of sinusitis when related intracranial complications have occurred, such as with extension through the sphenoid sinus [21].

Spontaneous intracranial hypotension — Patients with spontaneous intracranial hypotension usually present with orthostatic headaches and some combination of nausea/vomiting, dizziness, auditory changes, diplopia, visual blurring, interscapular pain, and/or upper extremity radicular pain. This syndrome is also known as spontaneous low cerebrospinal fluid (CSF) pressure headache.

CSF leakage from spinal meningeal defects or dural tears may be the most common causes of this syndrome [22]. The headache is caused by displacement of pain-sensitive structures due to the low CSF pressure.

A minority of patients with headache attributed to spontaneous intracranial hypotension present with TCH [23,24]. As an example, in a series of 28 patients with low CSF pressure headache due to CSF leaks from dural tears, TCH was the presenting sign in 14 percent [23].

The classic features of spontaneous intracranial hypotension are orthostatic headache, low CSF pressure, and diffuse meningeal enhancement on brain MRI. (See "Spontaneous intracranial hypotension: Pathophysiology, clinical features, and diagnosis", section on 'Introduction' and "Spontaneous intracranial hypotension: Pathophysiology, clinical features, and diagnosis", section on 'Clinical features'.)

Typical features on brain MRI include diffuse meningeal enhancement, subdural hematomas or hygromas, sagging of the brain, engorgement of cerebral venous sinuses, and pituitary enlargement. Brain MRI remains normal in up to 20 percent of patients with spontaneous intracranial hypotension.

Ischemic stroke — TCH may rarely be the presenting feature of ischemic stroke. In most cases, headaches associated with stroke are not consistent with TCH. However, several cases of ischemic stroke associated with TCH have been reported, including cases in which TCH was the primary clinical feature [5,25-27]. Neurologic exam will show a stroke-related deficit but requires careful examination for cerebellar signs.

Posterior reversible encephalopathy syndrome — The posterior reversible encephalopathy syndrome, also known as reversible posterior leukoencephalopathy syndrome (RPLS), usually presents with the insidious onset over hours to days with symptoms that may include headache, visual changes, altered mental status, seizures, or focal neurologic signs.

PRES most often occurs in the setting of hypertensive crisis, preeclampsia, or cytotoxic immunosuppressive therapy; however, it can also occur in many other clinical settings. Hypertension is frequent but not invariable. Hypertensive crisis may precede the neurologic syndrome by 24 hours or longer. (See "Reversible posterior leukoencephalopathy syndrome".)

TCH may be a rare presenting feature of acute hypertensive crisis/PRES [28]. Evaluation with head CT and lumbar puncture may miss the diagnosis of PRES. MRI is more sensitive than head CT for revealing the white matter and cortical edema associated with PRES. These changes typically involve the parietal and occipital lobes and may also involve the basal ganglia, brainstem, and cerebellum. Since the imaging changes are secondary to vasogenic edema and not ischemia or infarction, prompt treatment of the hypertension is essential and should result in correction of the associated clinical syndrome.

A number of conditions are uncommon or rare causes of TCH, including:

● Pituitary apoplexy

● Colloid cyst of the third ventricle

● Acute myocardial infarction [29]

● Anaplastic oligodendroglioma [30]

● Aortic arch dissection [31]

● Aqueductal stenosis [32]

● Giant cell arteritis [33]

● Pheochromocytoma [34,35]

● Pneumocephalus [31]

● Retroclival hematoma [36]

● Spinal epidural hematoma [37]

● Varicella zoster virus vasculopathy [38]

● Vogt-Koyanagi-Harada syndrome [39]

Pituitary apoplexy — Pituitary apoplexy is caused by hemorrhage or infarction of the pituitary gland in the setting of a pituitary adenoma [40]. The clinical presentation of pituitary apoplexy ranges from relatively mild symptoms to more severe symptoms including acute headache, ophthalmoplegia, decreased visual acuity, visual loss, change in mental status, adrenal crisis, coma, or even sudden death. TCH may be a predominant feature. (See "Causes of hypopituitarism", section on 'Pituitary apoplexy'.)

Pituitary apoplexy can present with TCH in patients who have normal physical examinations, head CT scans, and cerebrospinal fluid analyses [41,42].

Pituitary tumors that are isodense to normal brain tissue may be easily overlooked on CT studies, even if hemorrhage is present. Brain MRI has a much higher sensitivity than CT for detecting the tumor and associated blood.

Colloid cyst of the third ventricle — Patients with colloid cysts of the third ventricle may also present with TCH when the cyst, which can act like a ball valve, suddenly impedes the flow of cerebrospinal fluid, causing acute obstructive hydrocephalus. Headache is reported by 68 to 100 percent of patients with third ventricular colloid cysts, making it the most commonly associated symptom.

Typically, the headache has an acute onset and resolution, with a duration of seconds to one day [43]. The pain is often severe and may be relieved by taking the supine position. Headaches may be located in the bilateral frontal, fronto-parietal, or fronto-occipital head regions [44]. Approximately one-half of patients have associated nausea and vomiting. Loss of consciousness, mental status changes, seizures, coma, and death can occur [45].

Third ventricular colloid cysts are diagnosed via CT or MRI of the brain.

UNCERTAIN ASSOCIATION — Sentinel headache (due to an unruptured intracranial aneurysm) and primary TCH are possible causes of TCH, but supporting data are weak.

If, in the evaluation of a patient with TCH, an aneurysm is found, a neurosurgeon or other cerebrovascular specialist should be consulted. However, some experts believe that routine cerebral angiography is not necessary in patients with a single TCH who have a normal neurologic examination, normal cranial CT, and normal cerebrospinal fluid findings [8].

Primary TCH — There is controversy as to whether TCH can occur as a benign and potentially recurrent headache disorder in the absence of underlying organic intracranial pathology [2]. Reported cases of primary TCH may represent missed diagnosis of the underlying causes. Thus, it cannot be overstated that primary TCH must be a diagnosis made only after exclusion of all possible underlying causes [1,51].

Given the potentially serious nature of possible underlying intracranial etiologies, TCH must be evaluated and treated as a medical emergency, beginning with an evaluation for subarachnoid hemorrhage (algorithm 1). The clinical features, imaging characteristics, cerebrospinal fluid (CSF) findings of the more common causes of TCH (table 4) should be kept in mind.

A sudden-onset headache, though not necessarily a TCH, is characteristic of subarachnoid hemorrhage. The evaluation for subarachnoid hemorrhage is reviewed here briefly and discussed in detail elsewhere. (See "Aneurysmal subarachnoid hemorrhage: Clinical manifestations and diagnosis", section on 'Evaluation and diagnosis' and "Aneurysmal subarachnoid hemorrhage: Clinical manifestations and diagnosis", section on 'Identifying the source of bleeding'.)

All patients with TCH should have a head CT without contrast as soon as possible after the onset of TCH (algorithm 1). If the head CT does not reveal the cause, a lumbar puncture should be performed urgently to evaluate the CSF for evidence of subarachnoid hemorrhage or other causes of TCH. A negative head CT and lumbar puncture effectively eliminate the diagnosis of subarachnoid hemorrhage as long as both tests are performed within a few days of the event. In such cases, further evaluation for other possible causes of TCH is required.

Brain CT without contrast is highly sensitive and specific for the diagnosis of subarachnoid hemorrhage when performed very early after headache onset. During the first 12 hours following onset of headache, third-generation CT scanners have a sensitivity nearing 100 percent and a specificity of 98 percent [52]. Therefore, some experts believe routine lumbar puncture is not necessary if a technically adequate CT is done within six hours from headache onset is read as negative by an attending-level radiologist [8,53].

After six hours, in general practice, however, clinicians may easily overlook subtle imaging abnormalities on CT that are suggestive of subarachnoid hemorrhage. The sensitivity of head CT in subarachnoid hemorrhage declines rapidly over time, decreasing to 86 percent on day 2, 76 percent after two days, and 58 percent after five days [54]. Furthermore, head CT alone does not adequately evaluate for other causes of TCH.

Lumbar puncture should include measurement of opening pressure (which may be elevated in patients with subarachnoid hemorrhage or cerebral venous thrombosis or low in patients with spontaneous intracranial hypotension), routine CSF analyses including cell counts, and visual inspection for xanthochromia.

Some experts recommend the use of CSF spectrophotometry, if available, to measure xanthochromia, especially when a traumatic tap makes CSF interpretation difficult or when the specimen has been improperly processed. The sensitivity of spectrophotometry approaches 100 percent when lumbar puncture is performed 12 hours to two weeks after subarachnoid hemorrhage onset [55]. Despite its high sensitivity, spectrophotometry has only low to moderate specificity for the diagnosis of subarachnoid hemorrhage and is not universally recommended. As a practical matter, spectrophotometry is rarely available in North American hospitals.

Noninvasive CT angiography (CTA) of the head may be used to identify the source of subarachnoid hemorrhage, but it is less sensitive than digital subtraction angiography for identifying small (≤2 mm) aneurysms. Some experts use CTA instead of lumbar puncture in the initial evaluation of patients with TCH and a negative head CT [56,57]. However, using CTA may both miss patients with small, ruptured aneurysms and misattribute others with TCH due to another cause to surgical treatment for an unruptured cerebral aneurysm. In addition, lumbar puncture may help to diagnose other causes of TCH (eg, meningitis, spontaneous intracranial hypotension). (See "Aneurysmal subarachnoid hemorrhage: Clinical manifestations and diagnosis", section on 'Evaluation and diagnosis' and 'Infections' above and 'Spontaneous intracranial hypotension' above.)

For patients with TCH who have a negative initial work-up (ie, a nondiagnostic head CT and lumbar puncture) for subarachnoid hemorrhage or other definite cause of TCH, we suggest obtaining brain MRI with contrast and imaging of the cerebral vasculature with magnetic resonance (MR) angiography and MR venography (algorithm 1). If MR imaging is not an option, we suggest imaging the cerebral vasculature with CT angiography and CT venography.

However, some experts believe that patients who present with a single TCH but are otherwise asymptomatic and have a normal neurologic examination, normal cranial CT, and normal CSF findings on lumbar puncture do not require noninvasive angiography or additional work-up unless there is recurrent TCH [8].

An underlying cause for TCH is identified in 27 to 71 percent of patients [5,7,20,31,58].

In a multicenter study of 644 adults presenting to an emergency department with TCH, serious pathology was identified in 10.9 percent, including 3.6 percent with subarachnoid hemorrhage, 2 percent with other intracranial hemorrhage, 1.7 percent with ischemic stroke, 1.2 percent with viral meningitis, and 1.1 percent with transient ischemic attack [60].

As many as 90 percent of all primary headaches fall under a few categories, including migraine, tension-type, and cluster headache. While episodic tension-type headache (TTH) is the most frequent headache type in population-based studies, migraine is the most common diagnosis in patients presenting to primary care physicians with headache.

Cluster headache typically leads to significant disability and most of these patients will come to medical attention. However, cluster headache remains an uncommon diagnosis in primary care settings because of overall low prevalence in the general population (<1 percent).

The clinical features and diagnosis of specific primary headache syndromes are discussed separately:

● Migraine:

• (See "Pathophysiology, clinical manifestations, and diagnosis of migraine in adults".)

• (See "Chronic migraine".)

• (See "Vestibular migraine".)

• (See "Hemiplegic migraine".)

• (See "Migraine with brainstem aura (basilar-type migraine)".)

● Tension-type headache:

• (See "Tension-type headache in adults: Pathophysiology, clinical features, and diagnosis".)

● Trigeminal autonomic cephalalgias:

• (See "Cluster headache: Epidemiology, clinical features, and diagnosis".)

• (See "Paroxysmal hemicrania: Clinical features and diagnosis".)

• (See "Short-lasting unilateral neuralgiform headache attacks: Clinical features and diagnosis".)

• (See "Hemicrania continua".)

● Other primary headache disorders:

• (See "Primary cough headache".)

• (See "Exercise (exertional) headache".)

• (See

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