According to The International Classification of Headache Disorders, 3rd edition, RCVS is characterized by a severe, diffuse, sudden-onset, TCH-like headache that reaches its maximum intensity within less than one minute and lasts for 5 to 10 minutes. It recurs for one month and usually resolves within three months of its onset. It can also be associated with focal neurological deficits and seizures (1). It mostly affects middle aged women (13) and is believed to be more prevalent than what is reported in the literature (5). Therefore, it is commonly underdiagnosed (5, 14, 15). Several precipitating factors including exertion (1, 3), coughing (3), sexual activity (1, 3), bathing (3), and Valsalva maneuver (1), a number of underlying causes such as pregnancy related conditions (3, 4), postpartum (1, 3-5), exposure to vasoactive drugs (1, 3-5), use of licit or illicit drugs (1, 4, 5), catecholamine excess (3-5), head and neck related disorders including trauma, head and neck surgery, carotid endarterectomy, and cervical artery dissection (3, 4), and various medical conditions such as exposure to immunosuppressant drugs or blood products (3, 4) have been implicated in RCVS.
As mentioned earlier, any new TCH is a medical emergency prompting further investigations (1, 2, 16), including careful physical and neurologic examination, a brain CT scan without contrast as soon as possible, and a lumbar puncture in case of an inconclusive CT scan to evaluate SAH. Further radiological evaluations are needed if SAH is ruled out (2, 17, 18).
Diagnosis of RCVS is based on clinical manifestations and radiological findings including the “string of beads” appearance on angiography (1). Lab tests are usually normal in RCVS (2). Similarly, radiologic studies can be normal in a number of cases (19), especially during the first week of symptoms. However, any new headache fulfilling the criteria of RCVS with normal imaging and lab test results can be regarded as an “Acute Headache Probably Attributed to RCVS” (1). If the clinical and radiological findings are inconclusive or the underlying cause is still missing, routine blood tests, urinalysis, urine vanillylmandelic acid and 5-hydroxyindoleacetic acid levels, serum and urine toxicology screens, ESR, CRP, infectious and rheumatological panel tests, and CSF examination are indicated (6).
Repeated headache attacks can be triggered by the Valsalva maneuver or exertion in RCVS (20). These factors also triggered headache attacks in our patient. Therefore, such headache episodes do not preclude RCVS.
Management of RCVS includes treatment of the underlying cause(s) and avoidance of triggers and precipitants. Calcium channel blockers such as nimodipine and verapamil are used to relieve the headache and acute symptoms. They can also prevent further problems (3, 5-7).
Headache may persist after the resolution of RCVS signs and symptoms; however, there are limited studies in this regard and the headache frequency and type are not well defined yet. Our patient had mild persistent headaches after the second bout of RCVS.
Complications of RCVS include ischemic stroke and intracranial hemorrhages (3, 5, 14). However, the long-term outcome of RCVS is usually excellent (6, 13, 14). A number of studies have reported a low risk of recurrence for RCVS in the long term (20), which is usually due to re-exposure to RCVS triggers (6, 15, 21). Nonetheless, some authors believe that the risk of recurrence is underestimated. In case of RCVS recurrence, a comprehensive evaluation is necessary for RCVS, as explained earlier in detail, to find the underlying cause for appropriate management (15).
Vasoactive substances and catecholamine excess have been categorized as the most important precipitants of RCVS (3, 4), and diagnostic evaluation of RCVS includes these entities (6). In our case, recurrence of thunderclap headaches after 3 years and repeated investigations suggested that pheochromocytoma was the underlying cause of RCVS, and the signs and symptoms completely resolved with proper management of pheochromocytoma.
According to the literature and our case, functional pheochromocytomas have diverse manifestations, such as hypertension, orthostatic hypotension, hyperhidrosis, palpitation, tachycardia, facial pallor and rarely flushing, fever, anxiety and panic attacks, severe constipation, etc., which are caused by excessive amounts of catecholamine release (8, 22, 23). It is important for clinicians to keep pheochromocytoma in mind as a differential diagnosis for such diverse manifestations. Measurement of 24-hour urine vanillylmandelic acid is the most sensitive initial test for diagnosis of pheochromocytoma (24). CT scan and MRI are used for localization and further assessment of tumor characteristics. Further investigations such as metaiodobenzylguanidine (MIBG) scintigraphy might be used depending on the case. The best cure for pheochromocytomas, especially functional and non-metastasized ones, is to remove them surgically (8, 11, 12).
Patients should receive α1-blockers such as phenoxybezamine for 10-14 days prior to surgery to avoid hypertensive crisis. Calcium channel blockers and β-blockers can be used as alternatives or adjunct treatments to prevent tachycardia and disrhythmias. In our case, verapamil and phenoxybenzamine were administered prior to surgery. Laboratory tests (1 month later, 6 months later, 1 year later, and then annually) and imaging studies (1 year after the operation) are necessary postoperatively (11, 12). About 10% of pheochromocytomas metastasize to other organs requiring different, case-based diagnostic and therapeutic approaches (8).
Pre-syncope attacks were associated with pheochromocytoma in our patient, which has been reported in previous studies. Some studies have attributed it to the effects of dopamine produced by some pheochromocytomas and paragangliomas (25-27). Another study attributed hypotension and syncope in pheochromocytoma to excess epinephrine secretion and volume depletion (28). Accordingly, several studies have reported that pre-syncope attacks might occur because of transient autonomic dysregulations caused by intermittent excessive secretion of catecholamines (29) or due to altered sympathetic vascular modulation (30). Another suggested hypothesis is that chronic norepinephrine secretion from phaochromocytoma downregulates the vascular adrenergic receptors causing orthostatic hypotension. Then, it results in reflex stimulation of central sympathetic discharge and causes a further rise in plasma norepinephrine, which aggravates the adrenergic receptor downregulation (31).
Another interesting finding in our patient, in line with previous case reports, was the association of intracranial hemorrhages and ischemic events with pheochromocytoma (32-34).
To the best of our knowledge, three cases of TCH associated with pheochromocytoma (35-37) and four cases of RCVS accompanied by pheochromocytoma (35, 38-40) have been reported in the literature. This emphasizes the need of further investigation of the relationship of RCVS and TCH with pheochromocytoma and excessive catecholamine production indicating the importance of including pheochromocytoma in the differential diagnosis of the underlying causes of RCVS or thunderclap headache, especially in case of recurrence, even if the initial investigations are unremarkable.