NEW YORK CITY—Most headaches do not signify serious disease, but when a patient with a headache syndrome does not respond to conventional therapy, a high index of suspicion for a neurologic emergency is warranted. According to Casilda Balmaceda, MD, Assistant Professor of Neurology at Columbia University College of Physicians and Surgeons in New York City, more than one third of headaches seen in general office practices are attributable to serious underlying neurologic disease. In addition, approximately 10% to 37% of headaches encountered in emergency departments are due to secondary causes.

"These are headaches we don't want to miss in our practices," said Dr. Balmaceda, who is also an Assistant Attending Neurologist at New York-Presbyterian Hospital. Speaking at a symposium on Advances and Innovations in Headache Management (held at Columbia Presbyterian Medical Center), she outlined the key points and caveats in the diagnosis of potentially serious head pain syndromes—ranging from headaches associated with subarachnoid hemorrhage, stroke, and vascular problems to those signifying brain tumors, infections, ophthalmologic emergencies, and rheumatologic disorders.

SUBARACHNOID HEMORRHAGE

Responsible for about 18,000 deaths per year in the United States, subarachnoid hemorrhage (SAH) has a usual presentation of sudden, violent headache. But not every patient presents this way, according to Dr. Balmaceda. Fewer than half of patients with this condition have headache, she stated, and two thirds have impairment of consciousness and meningismus. Moreover, treatment with nonsteroidal anti-inflammatory drugs may afford temporary pain relief, removing the sense of urgency. "Not every headache that responds to medications is benign," she noted.

She also urged that the so-called sentinel headache be heeded. "A headache caused by a warning leak is often erroneously diagnosed as migraine, sinusitis, or a cervical spine disorder," she noted. "Almost half of the patients with unruptured aneurysms are symptomatic," she said, "and the risk of aneurysm rupture is at least 1% per year." The mean interval between a sentinel headache and a subarachnoid hemorrhage is 11 days.

Dr. Balmaceda pointed out two potential causes for confusion in the early recognition of SAH. First, patients can display confusion and be combative. Second, backache and stiffness may be severe. "These manifestations may be enough to distract attention from the cranial origin of the symptoms," she said.

The precise nature of the clinical syndrome can vary according to the site of the aneurysm, Dr. Balmaceda explained. With carotid artery involvement, patients may have localized headache, facial palsy, and tinnitus. "Aneurysms of the cavernous carotid, however, may cause trigeminal neuralgia, exophthalmos, and retro-orbital pain," she cautioned. Patients with aneurysms of the posterior communicating artery can have third-nerve palsy and ipsilateral orbital pain. Sudden monocular blindness may result when the site is the ophthalmic artery.

The first diagnostic modality to use in suspected SAH is computed tomography (CT). According to Dr. Balmaceda, it will detect acute SAH in 90% of patients—and 85% of CT scans will be abnormal for five days following the hemorrhage. "The longer imaging is delayed, the greater the likelihood that CT will miss the hemorrhage," she noted. Areas deserving special attention during CT scanning, she said, include the prepontine cisterns and the skull base—because artifacts may obscure collected blood.

Is lumbar puncture still recommended after a normal CT scan when clinical suspicion of SAH is high? "Yes, absolutely," Dr. Balmaceda said, because "about 3% of patients with subarachnoid hemorrhage and normal CT findings have xanthochromatic cerebrospinal fluid."

The idiopathic thunderclap headache, which is intense but benign, can be difficult to distinguish clinically from the headache of SAH. Onset is hyperacute—sometimes within 30 seconds—and cerebral angiography may be required to rule out SAH. "The angiogram may be normal or show focal cerebral vasoconstriction," according to Dr. Balmaceda, "and most patients with thunderclap headache never have a second episode, nor are they at higher risk for hemorrhage."

Subarachnoid hemorrhage can occur in the absence of an aneurysm. According to Dr. Balmaceda, "trauma, angiopathy, blood diseases, tumors, and anticoagulant therapy increase the risk of subarachnoid hemorrhage." On the flip side, there are several conditions besides SAH to keep in mind when a patient has a sudden, painful headache. "Headache from hemorrhage within a pituitary tumor and a first migraine in an elderly patient can be sudden and intense," she said. She added that "a benign orgasmic headache can also be frightening, but usually there is no meningismus."

VASCULAR DISSECTION

Dissection of the carotid or vertebral arteries may lead to stroke, either from local compressive effect or thromboembolism. "The goal of early recognition of vascular dissection," Dr. Balmaceda observed, "is to prevent ischemic symptoms and stroke with timely anticoagulation therapy." The risk factors for dissection, she pointed out, are atherosclerosis, fibromuscular dysplasia, and trauma, which can be minor. "Chiropractic manipulation, trivial trauma, and unusual head positions can trigger a dissection," she said.

With internal carotid artery dissection, headache is present in 90% of patients and severe in 75%. "Onset may not be as acute as in subarachnoid hemorrhage," Dr. Balmaceda said, "although 15% of patients have a thunderclap headache." Headache is the initial symptom in almost half of patients, and the delay between the headache and other signs and symptoms can be a week or longer. Only 19% of patients have neck pain exclusively, she explained, and look-alike syndromes include cluster headache, migraine, and carotodynia.

Dr. Balmaceda explained that the most important findings associated with carotid dissection are ischemic signs in the carotid distribution and Horner's syndrome (oculosympathetic paresis), although Horner's syndrome alone occurs in only 12% of patients. "Look for Horner's syndrome and unilateral headache, or hemicrania with delayed ischemic events," she said, noting that up to 46% of patients have a history of migraine and 51% have had muscle contraction headaches. "Twenty-five percent of patients say their headache is similar to their usual migraines," Dr. Balmaceda reported. In addition, 25% of patients have transient monocular blindness and 27% experience pulsatile tinnitus.

The presentation of vertebral artery dissection is similar to that of other causes of brainstem ischemia. Tip-offs include age and history. "Vertebral artery dissection usually presents in young men," Dr. Balmaceda said, "and I have seen it following chiropractic manipulation, yoga practice, boating accidents, and bungee jumping."

The most serious consequence of vertebral artery dissection is stroke. "Magnetic resonance imaging reveals infarcts in the vertebrobasilar territory in 85% of patients," according to Dr. Balmaceda. A majority of patients have cranial nerve findings and ataxia, she said, and many have Wallenberg's syndrome—dysphagia, dysarthria, Horner's syndrome, nystagmus, ipsilateral loss of facial pain and temperature sensation, and contralateral loss of pain and temperature sensation on the trunk and extremities. An important diagnostic clue: Cervical symptomatology—neck muscle tenderness or restricted neck movement—is almost invariably absent.

CEREBRAL SINUS THROMBOSIS

According to the International Headache Society, patients with cerebral sinus thrombosis will have seizures, raised intracranial pressure, or a focal neurologic deficit in addition to headache. "The clinical picture can begin with a vague headache or ear pain," Dr. Balmaceda explained, "but eventually papilledema and other evidence of elevated intracranial pressure will be apparent."

Cerebral sinus thrombosis is associated with numerous clinical conditions. In children, Dr. Balmaceda said, precipitating causes are dehydration, infection, and mastoiditis. In adults, it is associated with trauma, glomus tumors, iatrogenic sinus occlusion (during brain tumor surgery), meningioma, hypercoagulable states (including cancer, disseminated intravascular coagulopathy, oral contraceptive use, and pregnancy), and rheumatologic conditions (especially Behçet's syndrome and systemic lupus erythematosus).

Most frequently, the superior sagittal and lateral sinuses are affected. According to Dr. Balmaceda, the typical diagnostic finding is the "empty delta sign" on CT—absence of contrast surrounding a thrombus at the confluence of the sinuses. CT with contrast is diagnostic in up to 80% of patients. Magnetic resonance venography (MRV), however, is more sensitive than CT and is the preferred diagnostic modality when it is available.

Headache occurs in approximately 50% of patients with cerebral sinus thrombosis, but the headache is more likely related to vascular events in the sinuses than to brain damage. Dr. Balmaceda suggested that cerebral sinus thrombosis be considered in two settings. "The triad of new-onset headache, seizures, and focal neurologic deficit suggests the diagnosis," she stated, "and when a patient with a thunderclap headache has normal CT findings, the cerebrospinal fluid pressure should be measured."

The history is also important. Dr. Balmaceda described a patient whose history and risk factors, in combination with worsening clinical findings, pointed to cerebral sinus thrombosis. "A 31-year-old woman who had been using oral contraceptives for 10 years and who had what were thought to be migraines began having severe left temporal and ear pain but no fever. It turned out that she had cerebral sinus thrombosis," Dr. Balmaceda said. The patient's CT scan showed mastoiditis; MRV, however, revealed lateral sinus thrombosis.

BRAIN TUMORS

"The 'classic' brain tumor headache—early morning pain, dull and aching quality, nausea, vomiting, and aggravated by body position—does not really exist," stated Dr. Balmaceda, who is also a member of the Brain Tumor Center at Columbia Presbyterian Medical Center. Moreover, while the majority of patients with brain tumors experience headaches at some point in their illness, only about 8% of patients have headache as a first and isolated symptom. More often, brain tumors manifest themselves through focal signs or symptoms, altered mentation, or seizures. In addition, metastatic brain lesions are more frequently associated with headache than are primary tumors.

Dr. Balmaceda said that the location of the headache corresponds roughly to the site of the tumor. Correlation is better for supratentorial tumors than for infratentorial tumors, and there is no correlation at all between headache severity and tumor size. There is, however, a correlation between cerebral edema and headache progression. "Isolated headaches recurring for longer than 10 weeks are not likely to be caused by a brain tumor," she said.

Brain tumors in children pose a unique diagnostic challenge, according to Dr. Balmaceda, who pointed out that diagnosis is often delayed because it is difficult to get beyond psychologic factors. "The likelihood of a brain tumor is increased by sleep-related headaches, headaches that occur immediately on awakening, and an absence of a family history of migraine or other serious headaches," she said. In this setting, neuroimaging should be done sooner rather than later. In some series of children with brain tumors, the duration of symptoms before diagnosis has been as long as five months, Dr. Balmaceda noted.

STROKE

"There is no correlation between headache and either the severity or the size of a stroke," Dr. Balmaceda said. Nor is headache a typical presenting symptom in the stroke patient. According to Dr. Balmaceda, however, stroke patients with headache tend to be younger than stroke patients without headache. There is no relation between stroke-related headache and traditional vascular risk factors such as hypertension, heart disease, or diabetes.

She referred to the Copenhagen Stroke Study, which followed 867 stroke patients prospectively. The incidence of headache at the onset of the stroke was low—28%. "Half of the patients with hemorrhagic stroke had headaches, but only 25% of those with infarctions had headaches," Dr. Balmaceda said. She noted that the headache was ipsilateral to the stroke in 68% of patients and was described as a pressing pain by 73% of patients, throbbing pain by 18%, and stabbing pain by 9%.

INFECTION

"Rapid-onset generalized headaches that precede fever, confusion, meningismus, and seizures suggest acute viral encephalitis," according to Dr. Balmaceda. The diagnosis of acute herpes simplex virus (HSV) encephalitis may be made by detection of elevated levels of white blood cells and red blood cells in cerebrospinal fluid, as well as a polymerase chain reaction assay for the virus. "Magnetic resonance imaging will demonstrate necrosis or damage in both temporal lobes," Dr. Balmaceda said. Early diagnosis is essential, she added, because appropriate treatment cuts mortality of HSV encephalitis from 70% to 10%.

Bacterial meningitis produces headache and neck stiffness in 88% of patients, Dr. Balmaceda said. Other signs and symptoms include altered consciousness (in 80%) and fever (95%). In 90% of patients, cerebrospinal fluid analysis is diagnostic: The white blood cell count exceeds 100/mm3, and the concentration of protein exceeds 45 mg/dL.

Significant causes of headache in patients with human immunodeficiency virus (HIV) infection include cryptococcal meningitis, toxoplasmosis, progressive multifocal leukoencephalopathy, HIV encephalitis, mass lesions, and drug reactions. According to Dr. Balmaceda, new-onset headache brings 20% of HIV-positive patients to emergency departments.

PSEUDOTUMOR CEREBRI

This intracranial hypertensive condition must be diagnosed and treated early to preserve vision. "Normal imaging studies and cerebrospinal fluid chemistry in the presence of intracranial hypertension suggests pseudotumor cerebri when there is no space-occupying lesion," Dr. Balmaceda said. Additional physical findings include papilledema, an enlarged blind spot, and unilateral or bilateral sixth nerve palsies.

Pseudotumor cerebri and idiopathic intracranial hypertension appear to be associated with a number of general medical conditions, Dr. Balmaceda noted. These include cystic fibrosis, HIV infection, systemic lupus erythematosus, sarcoidosis, and renal failure. "It is more likely in patients taking vitamin A or corticosteroids," she observed.

Differentiation from migraine may be problematic. According to Dr. Balmaceda, unexplained daily headaches in migraineurs may be secondary to idiopathic intracranial hypertension. "A normal magnetic resonance imaging scan or response to migraine therapy does not exclude the diagnosis," she said, "and if migraine therapy fails to relieve frequent headaches, especially when the patient is obese, a lumbar puncture may be appropriate."

OTHER CAUSES TO CONSIDER

Intracranial hematomas are usually posttraumatic, although the injury may not seem significant; the clinical picture may be slow to evolve relative to subarachnoid hemorrhage or vascular dissection. Subdural hematomas, Dr. Balmaceda explained, usually result from bridging veins and cause diffuse headache without focal signs and symptoms. "Keep a high index of suspicion when patients with recent head trauma or anticoagulation therapy are drowsy or display changes in behavior," she suggested. Epidural hematomas, on the other hand, develop after rupture of the meningeal arteries after skull fracture and progress more rapidly than do subdurals. Diagnosis typically requires CT.

Temporal arteritis is important to recognize in elderly patients with headache. "In 40% of untreated patients, temporal arteritis progresses to visual loss," warned Dr. Balmaceda. The presentation may be vague (with fever, anorexia, and anemia) she explained; but usually there is tenderness on temporal artery palpation. The erythrocyte sedimentation rate is usually elevated above 50 mm/h, she continued, and biopsy of the temporal artery will show vasculitis.

Dr. Balmaceda warned that temporal arteritis occasionally occurs as part of a polymyalgia rheumatica syndrome. "This is important because the treatment of both is corticosteroids, but the dosage and duration of therapy for treating temporal arteritis are much greater than those typically used in polymyalgia rheumatica."

Posterior leukoencephalopathy, which subsumes hypertensive encephalopathy, is characterized by headaches, increased intracranial pressure, seizures, and eventually blindness. According to Dr. Balmaceda, the syndrome was formerly thought to be secondary to small-vessel cerebrovascular disease but involves both gray and white matter. It has been reported in association with hypertension, renal disease, pheochromocytoma, and use of immunosuppressive drugs or amphetamines—but Dr. Balmaceda cautioned that it can occur without hypertension. Typically, she explained, the constellation of symptoms comprises headache, visual disturbance, seizures, confusion, and coma. "Look for focal neurologic deficits, especially retinal hemorrhages and papilledema, and evidence of other end-organ damage," she said.

When headaches occur in association with deficits involving the third, fourth, fifth, or sixth cranial nerves, Dr. Balmaceda urged physicians to consider cavernous sinus lesions. Although isolated headache is a possible presentation, she said, headache in conjunction with chemosis, exophthalmos, and painful ophthalmoplegia is more common, she said.

Dr. Balmaceda reminded her audience not to overlook acute angle-closure glaucoma as a cause of severe headache with nausea and vomiting. "This can mimic cluster headache, with unilateral eye pain and scotomata," she said. The diagnosis should be considered when onset of symptoms coincides with entry into a dark environment or the use of an anticholinergic medication. "Examination usually shows a red eye and a fixed, mid-dilated pupil," she added.

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