Scenario 1: Headache + Sudden/Severe Onset

The quintessential dangerous headache presentation is that of the patient with severe, sudden onset of symptoms. Although cases of “thunderclap headache” may ultimately be attributed to primary or benign causes, emergent causes must be considered. A patient presenting with the new onset of a severe and sudden headache will require neuroimaging in the ED to detect hemorrhagic stroke, including SAH. Best practices for ruling out SAH in this clinical setting continue to evolve as new data emerge. Cranial computed tomography (CT) without intravenous (IV) contrast does not demonstrate bleeding in all cases and a complete workup currently includes a lumbar puncture (LP) to detect the presence of xanthochromia or red blood cells.

Although SAH is a critical to identify, a broader differential of life-threatening diagnoses exists in these patients. In addition to hemorrhagic stroke, any vascular origin of headache in the arterial or venous system can cause a sudden onset of symptoms. For example, other potential underlying pathologies, such as CeAD and cerebral venous thrombosis (CVT), may present with a thunderclap, and may be clinically indistinguishable from SAH. Severe unilateral symptoms in the head and neck, particularly when accompanied by neurologic deficits, raise concern for CeAD. Although CVT more often presents as a gradual-onset headache with other associated visual or neurologic symptoms, a significant proportion (2%–13%) also can present with a thunderclap.

The patient with severe-onset headache, ocular pain, and visual complaints should alert the physician to the possibility of acute angle closure glaucoma (AACG), prompting a more thorough ophthalmologic examination that includes visual acuity and intraocular pressure measurement. Careful inspection of the patient’s eyes may reveal a mid-fixed dilated pupil along with conjunctival injection. An intraocular pressure measurement greater than 21 mm Hg is considered abnormal and any pressure greater than 30 mm Hg is highly concerning for AACG. Other important diagnoses in this category include pituitary apoplexy, spontaneous intracranial hypotension, reversible cerebral vasoconstriction syndrome (RCVS), and hypertensive encephalopathy. Although it is important to maintain high vigilance for SAH in the patient with headache of sudden onset, simple awareness and consideration of these other secondary causes can help avoid misdiagnoses.

Scenario 2: Headache + Focal Neurologic Deficits and Altered Mental Status

There should be no hesitation to obtain neuroimaging in patients with headache and new neurologic deficits, including any alteration in mental status. The presence of focal neurologic findings has the single highest predictive value for intracranial pathology.

Neurologic findings can result from a variety of dangerous secondary causes, including malignancies, trauma, infection, and any disease state resulting in increased intracranial pressure (ICP). Vascular causes should also be considered, such as CeAD and CVT. Toxic/metabolic causes, notably carbon monoxide (CO) poisoning, may also manifest with neurologic deficits. All such clinical presentations require further diagnostic evaluation.

Headache is a primary feature of acute cerebrovascular disease, most commonly in patients with hemorrhagic stroke or SAH. However, patients with ischemic stroke also may present with headache at time of onset. The frequency of headache in ischemic stroke is higher in women, younger patients, and those with posterior circulation ischemia and infarction. It is important, therefore, to avoid making a diagnosis of hemiplegic migraine in young patients without a complete and thorough evaluation.

Anterior circulation stroke symptoms in the setting of unilateral headache, facial pain, or neck pain should prompt consideration of carotid artery dissection, particularly if seen in the setting of sudden onset retinal ischemic symptoms or Horner syndrome. Posterior circulation stroke symptoms with unilateral head, face, or neck pain should similarly prompt suspicion for vertebral artery dissection. It should be emphasized that in both carotid and vertebral dissection, there may be a significant time interval between the onset of headache and any focal neurologic findings, often several days. Although the diagnosis may be a difficult one at this stage, this presents an important opportunity to prevent potentially devastating complications that may ensue.

Finally, specific cranial nerve deficits in the setting of headache should trigger alarm. A cranial nerve II (optic nerve) palsy may indicate cerebral ischemia, temporal arteritis, or primary ocular pathology. A cranial nerve III (oculomotor nerve) palsy in the setting of headache has several potential dangerous and benign causes, but is most concerning for a posterior communicating aneurysm in the subarachnoid space. More than 90% of patients with SAH with a posterior communicating aneurysm will present with a cranial nerve III palsy. In the setting of severe head trauma, a cranial nerve III palsy also can indicate uncal (transtentorial) herniation. Cranial nerve VI (abducens nerve) has a long intracranial course before exiting the skull and is sensitive to any pathology that causes an increase or decrease in ICP. Moreover, any involvement of a combination of cranial nerves III, IV, and VI can indicate serious pathology of the cavernous sinus. Finally, the involvement of multiple cranial nerves may also indicate the presence of brainstem disease. Thus, the presence of new neurologic deficits in the setting of headache is a true “red flag” for serious pathology and neuroimaging should be pursued without delay.

Scenario 3: Headache + Human Immunodeficiency Virus or Other Immunocompromised State

Patients with a history of immunosuppression and headache should immediately raise suspicion for intracranial pathology. Patients with human immunodeficiency virus (HIV) and headaches have substantially higher rates of intracranial disease when compared with the general population, 24% to 36% in 2 separate studies. Key considerations of headache in patients with HIV include infectious causes, such as cryptococcal meningitis and toxoplasmosis, and noninfectious causes, most notably lymphomas.

Similarly, patients on immunosuppressive therapy, such as those on posttransplantation medications, have a broad range of potential complications. Bacterial, fungal, viral, and parasitic infections of the brain or meninges account for 4% to 29% of central nervous system (CNS) lesions in organ transplant recipients and are associated with high mortality. After transplantation, patients can similarly develop several other noninfectious neurotoxic complications, including de novo CNS malignancies and posterior reversible encephalopathy (PRES). The increased prevalence of both infectious and noninfectious neurologic complications in immunosuppressed patients underscores the importance of a more comprehensive workup in this patient subgroup.

Scenario 4: Headache + Advanced Age

The ACEP specifically advocates for advanced imaging in patients older than 50 years with a new-type headache (Level C Recommendation, see Table 2 ). Elderly patients are at higher risk for several concerning secondary causes of headache, such as intracranial hemorrhage, occult trauma, giant cell arteritis, and malignancy. One review of patients with headache revealed a 15% incidence of dangerous secondary headaches in patients older than 65 years. Another large study examining all available risk factors for headache found that patients older than 50 years demonstrated 4 times the rate of pathology compared with younger patients. Given the increased likelihood of secondary headache in this age population, further diagnostic testing should be strongly considered in the elderly patient with new headache. In patients older than 60 years with a new headache, especially if accompanied by polymyalgia rheumatic (PMR) or symptoms such as scalp tenderness, jaw claudication, or visual symptoms, consider giant cell arteritis (see later in this article).

Scenario 5: Headache + Pregnancy

The most likely etiologies of headache in patients who are pregnant or postpartum are similar to the general population with primary headaches, such as tension-type and migraines, being most common.

However, patients are at increased risk for secondary headaches during pregnancy, warranting a meticulous evaluation for etiologies such as preeclampsia, cerebral venous thrombosis, and pituitary apoplexy. A particularly high index of suspicion should be maintained for the diagnoses of preeclampsia and eclampsia. These etiologies must be considered in pregnant women at greater than 20 weeks’ gestation up through 6 weeks postpartum, with the highest risk in the first week postdelivery. Patients with eclampsia are often found to have had headaches preceding their seizures by more than a day, thus a low threshold for initiating diagnostic workup is necessary even in the absence of symptoms beyond headache.

The prothrombotic state associated with pregnancy also increases the risk for stroke and CVT, particularly in the third trimester and postpartum period. From an endocrine perspective, pregnancy may cause a 139% size increase of the pituitary gland, increasing the risk for pituitary apoplexy.

Postpuncture dural headaches and RCVS should also be considered in the postpartum patient. Postpuncture dural headaches can occur in patients receiving epidural injections. Postpartum RCVS is a rare but potentially serious cause of headache that occurs in the early postpartum period and is characterized by acute-onset, severe headaches due to prolonged vasoconstriction of medium and large cerebral arteries. Recurrent episodes of a thunderclap headache are highly suggestive of RCVS. The symptoms of RCVS are often recurrent and can lead to life-threatening emergencies, such as intracranial hemorrhage, cerebral infarction, and vasogenic brain edema.

Other causes of secondary headache in pregnancy occur with approximately similar prevalence as the general population and workup should be guided by the patient’s clinical presentation.

Scenario 6: Headache + Coagulopathy

Any patient with hematologic disturbances due to hypercoagulability or an anticoagulated state has an increased likelihood of serious pathology associated with his or her headache. Prothrombotic disorders can be inherited or acquired and account for approximately 34% of patients diagnosed with CVT. Patients with antithrombin deficiency, protein C/S deficiency, factor V Leiden mutations, use of oral contraceptives, and hyperhomocysteinemia all have increased risk for CVT.

On the other hand, in patients with bleeding disorders, several risk factors can lead to an increased probability of spontaneous intracranial hemorrhage. Patients with both acquired and congenital disorders, such as hemophilia A/B and von Willebrand disease, are at higher risk for intracranial hemorrhage, particularly after trauma. Patients on anticoagulant medications are of particular concern, as they account for 12% to 20% of patients with intracranial hemorrhage. Hematoma expansion also can occur more aggressively in these patients with rapid neurologic deterioration, further emphasizing the importance of expedited diagnosis, workup, and intervention.

Scenario 7: Headache + Malignancy

Headache in the patient with history of malignancy can occur from a variety of causes, including the mass effect of the tumor itself or as a result of the therapy. Although traditional teaching holds that a morning or nocturnal headache can be suggestive of intracranial malignancy, this pattern is actually uncommon in adult patients, with nausea, vomiting, and neurologic abnormalities being far more common. Both primary and metastatic tumors are equally likely to cause headache at a rate of approximately 60%. The most common primary sites for metastases to the brain are as follows: lung (19.9%), melanoma (6.9%), renal (6.5%), breast (5.1%), and colorectal (1.8%). It is important to note that brain cancer rarely presents with headache as its sole presenting feature, occurring in only 2% to 8% of patients. Most patients with primary or metastatic disease will demonstrate concomitant neurologic deficits, neuropsychiatric disorders, or seizures.

In addition to pain caused by the tumor itself, patients with intracranial malignancy are at risk for intracranial hemorrhage. Approximately 1% to 11% of intracranial hemorrhage cases are secondary to malignancy, most commonly from metastatic solid tumors. Therefore, new headaches in patients with identified tumors should be further investigated. Finally, patients receiving chemotherapeutic agents or radiation therapy and those who have received a craniotomy can all present with the onset of a new type of headache. In such patients, the clinician should first evaluate the possibility of other more serious causes before attributing the symptoms to therapeutic interventions.

Scenario 8: Headache + Fever

Fever in the setting of headache can occur secondary to a CNS infection as well as systemic disease. In the toxic patient with fever and altered mental status, it can be particularly difficult to differentiate CNS infection from other systemic causes, such as septicemia, serotonin syndrome, or other potential pathologies. If other systemic etiologies are not readily apparent, the diagnostic study of choice to evaluate for meningitis or meningoencephalitis is an LP; however, certain patient subsets are at increased risk for elevated ICP, and these patients should likely undergo neuroimaging before LP (ACEP Level C Recommendation, see Table 2 ). Specifically, cranial CT prior to LP should be considered in any patient with any of the following features: 60 years or older, immune-compromised, history of CNS disease, recent seizures, altered mental status, focal neurologic deficit, or papilledema, as these patients may have a higher potential risk of brain herniation with LP.

Brain abscess is another uncommon but important primary CNS infection to be considered. It is very rarely associated with meningitis. Potential mechanisms for development of brain abscess include contiguous spread from surrounding structures, hematogenous spread, and after neurosurgical manipulation. The most common is via direct spread from surrounding sinusitis, otitis media, or dental infections. Alternatively, hematogenous seeding from sources such as lung abscess or infective endocarditis can also lead to brain abscess. Approximately 70% of patients with brain abscess will report headache, but only 50% are febrile. In fact, the triad of headache, fever, and focal neurologic deficits occurs in only 20% of patients; the only clue may be a new headache in an at-risk patient (eg, recent neurosurgical instrumentation). Lastly, brain abscess should be a special consideration in patients who are immunosuppressed from acquired immune deficiency syndrome (AIDS) or posttransplantation.

Other important noninfectious causes of headache that may present with fever include SAH, pituitary apoplexy, and giant cell arteritis (GCA). Fever in the setting of SAH tends to occur in the days following the event and is associated with increased mortality and functional disability. Fever in SAH can be attributed to both a systemic inflammatory reaction and a loss of central thermoregulatory control. Pituitary apoplexy also can pose a diagnostic challenge with a meningitis/encephalitis-type clinical presentation. Of 12 patients examined in a case series of pituitary apoplexy, 33% presented with fever and 83% had signs of meningeal irritation. Further complicating matters, cerebrospinal fluid (CSF) samples can show inflammatory changes resembling meningitis. Finally, vasculitic diseases, such as GCA, may lead to various systemic manifestations, including febrile illness, and should remain in the provider’s differential diagnosis.

The spectrum of severity in patients with headache and fever can range from benign to high risk with increased mortality. A patient with fever and headache will therefore require a careful and thorough evaluation for systemic pathology as well as consideration of primary CNS infectious and noninfectious causes.

Scenario 9: Headache + Visual Deficits

Patients with a clinical presentation of headache and visual complaints warrant further consideration for the possibility of secondary etiologies. Clarifying the nature of the patient’s visual symptoms is paramount in determining the likelihood of serious disease. For example, a migraine headache commonly presents with a visual aura that is clinically distinct from visual symptoms due to dangerous causes such as vascular disease. Patients with migraine classically describe visual complaints involving colors, scintillations, and scotomata. The aura in migraine will usually develop gradually over 5 to 20 minutes and resolve within 60 minutes, often preceding the onset of headache. Distinguishing these more benign features in the setting of the patient’s typical headaches from concerning new visual features such as sudden-onset monocular visual loss or visual field defects can prevent misidentification of more concerning pathology.

Patients presenting with headache and transient monocular vision loss should undergo evaluation for underlying secondary headache. Carotid artery dissection can result in retinal ischemia but this presentation occurs in only 2% of patients. Other causes of monocular vision loss include optic neuritis, GCA, and AACG. Rarely, “retinal migraines” have been described with transient monocular vision loss, although this diagnosis should be considered only in consultation and only after all other dangerous causes have been ruled out. In the case of headache and binocular visual loss, idiopathic intracranial hypertension and intracranial masses should be strongly considered.

A visual field examination should be conducted on all patients with headache and visual complaints. The presence of headache with visual field disturbance, such as homonymous hemianopsia, is highly concerning for a dangerous underlying cause. Most cases of hemianopsia in adults are secondary to vascular pathology, including cerebral infarction and intracranial hemorrhage, followed by trauma and brain tumor. A fundoscopic examination is another key component of evaluation. The presence of papilledema suggests increased ICP from any cause, including idiopathic intracranial hypertension, cerebral venous thrombosis, malignancy, or infection. Patients with headache and papilledema require expedited workup to prevent ischemia and subsequent permanent optic nerve damage.

Scenario 10: Headache + Loss of Consciousness

A headache associated with loss of consciousness is worrisome. In some cases, it can be difficult to discern whether the patient experienced a syncopal episode or a seizure. Both scenarios, however, justify further investigation. In the case of loss of consciousness with headache, vascular etiologies should be considered primarily and ruled out. Subarachnoid hemorrhage can present with syncope in 5% of cases and should be a leading consideration. Another consideration of note for patients presenting with headache and syncope is an intracranial mass obstructing the third ventricle, such as a colloid cyst. A presentation of headache and seizure may indicate dangerous disease including eclampsia, CNS infection, intracranial hemorrhage, CNS malignancy, and increased ICP. In subarachnoid hemorrhage, the presence of seizures alone predicts worsening clinical disability. Regardless of the underlying cause for unconsciousness, patients with a headache in this setting merit a thorough diagnostic evaluation.