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Mayo Clin Proc. 2010 July; 85(7): e44–e47.
PMCID: PMC2894724

55-Year-Old Man With Thunderclap Headache

A 55-year-old man who was in his usual state of good health jogged a short distance to his car as he was leaving a restaurant. As he sat down in the driver's seat, he experienced the sudden onset of a severe left occipital headache that was at maximal severity at onset and was associated with nausea and an episode of emesis. He experienced no photophobia, phonophobia, neck stiffness, or focal neurologic symptoms or signs. He had no history of headache. He presented to the emergency department at an outside institution about 20 minutes after onset. Findings on neurologic examination were normal, and he was not hypertensive.

  1. Which one of the following is the least likely cause of this patient's thunderclap headache (TCH)?
    1. Aneurysmal subarachnoid hemorrhage (SAH)
    2. Pituitary apoplexy
    3. Cerebral venous sinus thrombosis (CVST)
    4. Reversible cerebral vasoconstriction syndrome (RCVS)
    5. Migraine headache
    International Classification of Headache Disorders, 2nd edition (ICHD-2) criteria for a TCH include the sudden onset of severe head pain that reaches a maximum intensity in less than 1 minute and lasts for 1 hour to 10 days.1 The differential diagnosis of TCH includes vascular and nonvascular causes. Vascular causes include SAH, intracerebral hemorrhage, CVST, internal carotid and vertebral artery dissection, pituitary apoplexy, severe paroxysmal arterial hypertension, acute cerebral ischemia, and RCVS. Nonvascular intracranial disorders that can cause TCH include spontaneous intracranial hypotension, third ventricle colloid cyst, and intracranial infections.2
    Aneurysmal SAH is the most common cause of secondary TCH. Patients can present solely with a headache or with additional symptoms such as loss of consciousness, seizures, delirium, focal neurologic deficits, visual disturbances, neck stiffness, and photophobia. The most common cause of SAH is ruptured intracranial aneurysms. If findings on noncontrast computed tomography (CT) of the head are negative for blood and the clinical suspicion is high, then a lumbar puncture must be performed.2
    Pituitary apoplexy (hemorrhage or infarction of the pituitary gland) occurs most commonly in patients with pituitary macroadenomas; it can also occur in the setting of pregnancy, general anesthesia, bromocriptine therapy, and pituitary irradiation. Thunderclap headache can be associated with ophthalmoplegia, diminished visual acuity, reduction in visual fields, altered mental status, and pituitary dysfunction. Patients with pituitary apoplexy can have normal findings on physical examination, CT, and cerebrospinal fluid (CSF) analysis. The preferred investigative tool is magnetic resonance imaging (MRI) of the brain, with a particular focus on the pituitary gland.2
    Headache occurs in 80% of patients with CVST. Headache can be the only symptom in 15% to 30% of patients, with 10% of the patients having a TCH. Cerebral venous sinus thrombosis can also be associated with seizures, papilledema, an altered level of consciousness, and focal neurologic deficits. Etiologies for CVST, including hypercoagulable disorder, dehydration, and infection, need to be sought. Because CT and CSF analysis may not reveal abnormalities, magnetic resonance venography is the preferred investigative tool.2
    Reversible cerebral vasoconstriction syndrome is characterized by a reversible, segmental, cerebral vasospasm. Patients typically present with TCH when they are aged 20 to 50 years. Exertional triggers (eg, sexual intercourse, coughing, straining) are common, and appropriate imaging must be performed before making a diagnosis of a primary headache disorder (eg, primary sexual headache). Findings on CSF analysis are normal or near normal in most patients, with some having a mild elevation in CSF protein and a lymphocytic pleocytosis (white blood cells, <10/μL). Imaging provides no evidence of aneurysmal SAH; however, up to 20% of patients can have focal cortical SAHs. Angiography shows segmental cerebral vasospasm of medium and large vessels. Reversibility of vasospasm is documented within 12 weeks after onset.3
    Other potential causes of TCH include pituitary apoplexy, CVST, and RCVS. Migraine headache is not a common cause of TCH and is highly unlikely in this patient, especially in the absence of a history of headache. A diagnosis of migraine requires at least 5 attacks that meet ICHD-2 criteria for migraine headache.1 Migraine headaches also do not reach maximal intensity at onset or within 1 minute. Noncontrast CT of the head showed a left parietal-occipital cortical SAH.
    The patient was admitted to the hospital for further evaluation. On day 7 after the onset of headache, the patient underwent angiography, which showed alternating narrowing and dilation of multiple intracranial vessels of all sizes in all intracranial vascular distributions. No aneurysms were identified. The findings were thought to be consistent with central nervous system (CNS) vasculitis. A 5-day course of intravenous corticosteroids was initiated, followed by 60 mg/d of oral prednisone with a taper. On day 9, a lumbar puncture was performed, showing 1023/μL red blood cells, 1/μL white blood cells, a protein level of 31 g/L, and a glucose level of 95 g/L.
    The patient had no history of fevers, chills, weight loss, petechiae, purpura, mononeuritis multiplex symptoms, inflammatory arthritis, rhinosinusitis, eye or ear inflammation, hearing loss, stomatitis, pulmonary symptoms, or renal involvement. Blood tests, which were done after prednisone was started, included antineutrophil cytoplasmic antibody, antinuclear antibody, extractable nuclear antigen antibody, rheumatic factor, and coagulation (including anticardiolipin antibodies) panels; complete blood cell count; sedimentation rate; and measurement of C-reactive protein levels. Findings on blood tests were unremarkable.
    The patient underwent follow-up cerebral angiography 22 days after the onset of his TCH. Initial angiography had shown alternating narrowing and dilation of multiple intracranial vessels of all sizes in all intracranial vascular distributions. On follow-up angiography, these abnormalities had completely resolved.
  2. With which one of the following diagnoses are the results of the patient's evaluations most consistent?
    1. RCVS
    2. Primary CNS vasculitis
    3. Pituitary apoplexy
    4. Ruptured cerebral aneurysm
    5. Primary TCH
    Our patient presented with a TCH and was found to have a nonaneurysmal cortical SAH. He had no preceding illness, and findings on his neurologic examination were normal. His CSF showed increased red blood cells from the hemorrhage but did not show any inflammatory changes. Follow-up angiography performed 22 days after the initial symptoms showed substantial improvement.
    The patient's TCH, vasospasm on angiography, absence of inflammatory changes on CSF examination, normal brain parenchyma on MRI, and near-complete resolution of angiographic abnormalities are consistent with RCVS. Diagnosis of RCVS should include imaging with conventional angiography, CT angiography, or magnetic resonance angiography. Computed tomography should reveal no evidence of an aneurysmal SAH. Findings on CSF analysis should be essentially normal. Angiographic abnormalities should reverse within 12 weeks after onset of symptoms.3
    Primary CNS vasculitis, a subset of vasculitis confined to the vessels of the CNS, occurs in all age groups, with a male predominance. It is an inflammatory process that affects the small and medium leptomeningeal and intracranial arteries. Primary CNS vasculitis presents with insidious, subacute, and progressive headaches rather than TCH. Other presenting symptoms can be confusion, stroke, seizures, and focal neurologic deficits. In 80% to 90% of patients, findings on CSF analysis will be abnormal, with lymphocytic pleocytosis and elevated protein levels. Findings on MRI are typically abnormal, with multifocal ischemic lesions and both cortical and subcortical infarctions in different vascular territories. Brain biopsy is the criterion standard for diagnosis and will often demonstrate an inflammatory granulomatous process. Patients with primary CNS vasculitis are treated with long-term immunosuppressive agents and have a poor prognosis; therefore, distinguishing primary CNS vasculitis from RCVS is critical.4 Abnormalities on cerebral angiography often do not reverse completely in patients with primary CNS vasculitis.
    Vascular imaging revealed no evidence of a ruptured cerebral aneurysm or of a pituitary hemorrhage, infarction, or enlargement, making aneurysmal SAH and pituitary apoplexy unlikely causes of this patient's headache. The diagnosis of primary TCH is a diagnosis of exclusion and, by definition, must not have imaging abnormalities. The presence of cortical SAH and changes on vascular imaging ruled out primary TCH.
    Three months after his TCH, the patient presented to our institution with a persistent, moderate to severe, daily headache. The headache was located mainly in the left occipital region, with occasional pain felt in the bilateral frontal regions. The headache was associated with substantial phonophobia and was exacerbated by bending. He had been taking an average of 2 g/d of acetaminophen, along with occasional hydrocodone-acetaminophen for pain control. He had been tapered off prednisone. He had not had recurrent TCH.
    The patient's medical history and family history were noncontributory. He had never smoked or used recreational drugs and drank alcohol only occasionally. He was also taking verapamil for hypertension, atorvastatin, and metaxalone. Approximately 5 to 6 weeks before his headache, he took citalopram for 1 week, discontinued it, and then restarted it 6 to 7 days before the TCH.
  3. Which one of the following medications being taken by the patient could have precipitated his original TCH?
    1. Statin
    2. Selective serotonin reuptake inhibitor (SSRI)
    3. Proton pump inhibitor
    4. Corticosteroid
    5. Calcium channel blocker (CCB)
    Medications that have been associated with RCVS include SSRIs, cannabis, ecstasy, and vasoactive drugs such as diet pills, exercise stimulants, nasal decongestants, amphetamines, and cocaine. Other associated substances are red blood cell products, intravenous immune globulin, erythropoietin, cyclophosphamide, tacrolimus, and interferon. Reversible cerebral vasoconstriction syndrome has also been associated with pregnancy in the peripartum period, hypercalcemia, porphyria, and pheochromocytoma. Such headache disorders as migraine, primary exertional headache, primary sexual headache, and primary cough headache can also be associated with RCVS.2
    While RCVS can occur spontaneously, it is associated with a trigger in most patients. At the time of presentation, hypertension is present in 50% of patients; vasoactive substances, in 36%; and a postpartum state, in 33%.5 About 84% of patients will have more than one trigger, including cough, the Valsalva maneuver, singing, hot baths, sexual intercourse, and exertion.
    The patient was counseled to avoid SSRIs in addition to sympathomimetic drugs, including over-the-counter decongestants with phenylpropanolamine or pseudoephedrine. He was also counseled to avoid triptans, ergots, and other vasoactive drugs.
  4. Which one of the following is the most appropriate treatment for this patient's headache?
    1. Triptan
    2. Interferon
    3. Oral CCB
    4. Observation
    5. Tricyclic antidepressant
    Triptans are contraindicated in patients with RCVS and have been known to precipitate episodes of vasospasm. Interferon has also been implicated in RCVS and therefore cannot be used as a treatment.
    In patients with RCVS, cerebral vasoconstriction and symptoms such as headache have been treated successfully with CCBs, including nimodipine, verapamil, and nicardipine.6 However, no randomized controlled trials have evaluated the use of any CCB for the treatment of this disorder.
    Patients should be admitted for inpatient management if they have focal neurologic deficits, recurrent TCHs, or positive findings on vessel imaging. In the setting of severe hypertension, transient ischemic attacks (TIAs), cerebral infarction, or posterior reversible encephalopathy syndrome (PRES), a parenteral CCB should be initiated. Intravenous nimodipine has been used successfully in this setting.7,8 If parenteral CCBs are used, the patient should be treated until angiographic abnormalities resolve. If oral CCBs are used, the patient should continue to receive therapy until 4 weeks after angiographic abnormalities and/or symptoms have resolved because elevated transcranial Doppler velocities have been shown to persist and peak up to 3 weeks after the last TCH.9
    In cases in which clinical suspicion for RCVS is still low, careful observation with no initiation of treatment may be appropriate. If findings on neurovascular imaging are negative, close outpatient observation is warranted. In our patient, findings on imaging were positive and RCVS was strongly suspected, making outpatient observation a less than ideal option.
    Tricyclic antidepressants have not been shown to be effective in the management of RCVS.
    This patient has not experienced a TIA or stroke, and findings on MRI of the brain are normal. In the 3 months since the onset of TCH, he has not experienced a recurrent TCH. Therefore, inpatient admission and parenteral CCB are not required. However, because he still has a headache and cerebral vasoconstriction has been documented, outpatient treatment should be considered.
    Our patient was treated with a larger daily dose of verapamil, which he had been taking previously for hypertension.
  5. Which one of the following clinical courses is most likely in this patient?
    1. Recurrent TCH
    2. Ischemic stroke
    3. Seizures
    4. Vasculitis
    5. No neurologic sequelae
    The clinical outcome of RCVS is varied. More than 90% of patients experience recurrent TCH, most commonly within several days to weeks after the first TCH. Patients may be completely asymptomatic after 1 episode of headache, have a persistent residual headache, or go on to have disabling or fatal ischemic strokes that are often posterior in location and watershed in distribution. Ischemic stroke usually occurs within the first week after the initial presentation, highlighting the importance of making the diagnosis at presentation. Intracerebral hemorrhage, which occurs in approximately 6% of patients, often occurs in the second week after presentation. By definition, however, the vasoconstriction is reversible, and most patients will fully recover without residual deficits.10
    If RCVS is complicated by PRES or stroke, the risk of seizures may be higher. However, a diagnosis of RCVS in itself does not put the patient at increased risk of seizure. Reversible cerebral vasoconstriction syndrome is not a risk factor for vasculitis.
    The syndrome is usually self-limiting with a benign outcome. In a study of 67 patients with RCVS, 36% of the 61 patients treated with nimodipine had recurrent TCHs at 12-month follow-up, 7% had TIAs, 1 had multiple infarctions, and none experienced relapse.10 Of the patients taking nimodipine, 83% had resolution of headache within 48 hours and 45% had residual, less severe headaches. The average time to headache resolution was 16 days, with a range of 7 to 32 days. No improvement was seen in 17% of patients taking nimodipine.10
    A benign clinical course is likely in this patient. Seizures, ischemic stroke, and recurrent TCH occur in less than 20% of patients, typically within the first 2 weeks after onset. Vasculitis is not a recognized complication of RCVS. With resolution of the angiographic changes and no evidence of ischemic stroke, this patient is unlikely to experience recurrent TCH or RCVS. However, because this can occur on rare occasion, necessary precautions, particularly regarding the avoidance of medications known to trigger this syndrome, should be taken.


Reversible cerebral vasoconstriction syndrome encompasses a number of different headache syndromes, including Call-Fleming syndrome, isolated benign cerebral vasculitis, benign acute cerebral angiopathy, CNS pseudovasculitis, benign angiopathy of the CNS, postpartum angiopathy, migrainous vasospasm, migraine angiitis, TCH with reversible vasospasm, and drug-induced cerebral vasculopathy or angiopathy.2 It is characterized by recurrent TCHs within a 7- to 14-day period and multifocal areas of cerebral vasoconstriction that often normalize within 12 weeks. Patients may have TCH with or without neurologic symptoms or signs.

Diagnostic criteria for RCVS include the following: (1) documentation by transfemoral angiography, CTA, or MRA of multifocal segmental cerebral artery vasoconstriction; (2) no evidence of aneurysmal SAH; (3) normal or near-normal findings on CSF analysis (protein level, <80 mg/dL; white blood cells, <10/μL; normal glucose level); (4) severe, acute headaches, with or without additional neurologic signs or symptoms; and (5) reversibility of angiographic abnormalities within 12 weeks after onset.

If death occurs before the follow-up studies are completed, autopsy rules out such conditions as vasculitis, intracranial atherosclerosis, and aneurysmal SAH, which can also manifest with headache and stroke.

In addition to diffuse, multifocal, segmental vasoconstriction on neurovascular imaging, other imaging abnormalities can be present. Changes consistent with PRES may be evident on MRI of the brain.11 Symmetric posterior watershed infarctions and multifocal intracerebral hemorrhages can also be seen.2 Ischemic stroke and TIAs usually occur within a week of the first TCH, whereas intracerebral hemorrhages most often occur in the second week. Cortical SAHs, such as that seen in this patient, have also been reported. In a study of 67 patients, 22% were found to have a cortical SAH, and 6% were found to have an intracerebral hemorrhage.10 Cortical SAHs were not implicated in causing diffuse vasoconstriction in any of these cases. The vascular constriction that occurs after an aneurysmal hemorrhage is typically delayed, occurring 1 to 2 weeks after the ictus, and most often involves the major cerebral arteries at the base of the brain.

Thunderclap headache can be the presenting symptom of numerous conditions. Often underdiagnosed, RCVS should be considered in patients presenting with recurrent TCH, PRES, a cortical SAH, or posterior watershed infarctions. Prompt noninvasive cerebrovascular imaging is required, and rapid diagnosis is of paramount importance because of the risk of ischemic stroke and intracerebral hemorrhage within the first 2 weeks after onset. Because up to 20% of cases may escape detection on initial noninvasive vascular imaging, catheter-based angiography may be considered in patients with recurrent TCH within a 7- to 14-day period when a high index of suspicion exists. Although the outcome of RCVS is benign in most patients, serious neurologic injury can occur. Recognizing triggers and initiating appropriate treatment can prevent serious complications.


We thank Dr Timothy Ingall for his help and guidance in preparing the submitted manuscript.


See end of article for correct answers to questions.

Correct answers: 1. e, 2. a, 3. b, 4. d, 5. e


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9. Chen SP, Fuh JL, Chang FC, Lirng JF, Shia BC, Wang SJ. Transcranial color doppler study for reversible cerebral vasoconstriction syndromes. Ann NeUrol. 2008;63:751-757 [PubMed]
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