Curr Pain Headache Rep (2014) 18:414 DOI 10.1007/s11916-014-0414-7
UNCOMMON HEADACHE SYNDROMES (J AILANI, SECTION EDITOR)
Reversible Cerebral Vasoconstriction Syndrome: Updates and New Perspectives Huma U. Sheikh & Paul G. Mathew
Published online: 23 March 2014 # Springer Science+Business Media New York 2014
Abstract Reversible cerebral vasoconstriction syndrome (RCVS) is an important cause of headaches that can lead to other neurological complications, including stroke, if not recognized early. Over the past few years, there has been great progress in the recognition of this entity. However, there is still much to be learned about its pathophysiology and optimal treatment strategies. RCVS occurs mostly in middle-aged adults, and there is a female preponderance with an increased incidence during the postpartum period. A consistent, predominating feature is a sudden-onset, severe headache that is frequently recurrent, usually over the span of a week. Less common presentations include seizures or focal neurological symptoms. Important causative factors include vasoactive medications, as well as illicit drugs like marijuana and cocaine. The current underlying pathophysiology is thought to be a disturbance in cerebrovascular tone leading to vasoconstriction. The diagnosis is based on history, physical examination, and cerebrovascular imaging findings that demonstrate multifocal, segmental areas of vasoconstriction in large- and medium-sized arteries. An important criterion for making the diagnosis is the eventual reversibility of symptoms and imaging findings. Keywords Reversible cerebral vasoconstriction syndrome . Thunderclap headache . Pathophysiology . Vasoconstriction . Cerebrovascular imaging This article is part of the Topical Collection on Uncommon Headache Syndromes
H. U. Sheikh (*) : P. G. Mathew Brigham and Women’s Hospital, Department of Neurology, John R. Graham Headache Center, Harvard Medical School, 1153 Centre Street, Suite 4970, Boston, MA 02130, USA e-mail: [email protected] P. G. Mathew Cambridge Health Alliance, Division of Neurology, Harvard Medical School, Cambridge, MA 02139, USA
Case Presentation A 52-year-old woman with a history of obesity and hyperlipidemia developed an acute, severe thunderclap headache during orgasm, located primarily in the frontal area. She was seen in the emergency department (ED) where a CT scan of the head was normal. She was treated symptomatically with morphine and metoclopramide, and was subsequently discharged after the headache resolved in a few hours. After four days, again while being intimate with her husband, she developed another severe thunderclap headache. She again proceeded to the ED, and again was discharged after symptomatic treatment. She had a third similar headache the next day, and was finally admitted for further evaluation. Over the course of her evaluation, she had two additional headache episodes, which were similar in presentation, occurring within eight days of her initial episode of severe headache. The last three headaches were not in the context of sexual activity. Her workup included magnetic resonance imaging (MRI) and magnetic resonance angiography (MRA), followed by a conventional angiogram that revealed diffuse segmental stenosis. She was referred to a headache clinic and reported no recurrence of headaches or other neurological symptoms. It was at the headache clinic that the diagnosis of reversible cerebral vasoconstriction syndrome (RCVS) was made, and she was started on a calcium-channel blocker. She was followed for 14 months after the first occurrence and remained asymptomatic.
Introduction/History of RCVS The above case demonstrates some important features and pitfalls that can occur in the diagnosis of reversible cerebral vasoconstriction syndrome. Although this entity has been better appreciated over the past ten years, there is still much to be learned. Call and Fleming at Massachusetts General
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Hospital first described the syndrome in 1988, in a series of four cases involving severe headache and evidence of reversible constriction of the cerebral vessels that was not attributable to a secondary cause [1••]. As such, this syndrome was initially called Call-Fleming Syndrome. An earlier case of “benign cerebral vacuities,” reported in 1978, was likely the first reported case of RCVS, but was wrongly labeled as a form of vacuities [2, 3]. Over the years, RCVS has been identified by several other names, owing to the fact that it was a poorly-recognized syndrome, and because there were no unifying diagnostic criteria [4, 5]. Other eponyms have included benign angiopathy of the CNS, post-partum angiopathy, migrainous vasospasm, and drug-induced cerebral arteritis [5]. The term RCVS was only recently proposed as a unifying term in 2007, after evidence showed that cases that fit this criteria were all likely due to the same phenomenon [6]. When Call and Fleming first described RCVS, the two suspected causes of “reversible constriction of cerebral vasculature” were vasospasm (1) after a subarachnoid hemorrhage (SAH) and (2) as a theorized mechanism of migraine. Important features of that first case series included the consistent description of healthy subjects with prominent, severe, sudden-onset headaches [1••]. In the 25 years since first being reported, there has been a concerted effort to determine the underlying pathophysiology of this entity. In a systematic review in 2010, there were around 200 reports of patients with RCVS [7]. However, these were small case studies, with most series reporting less than ten patients [8]. Since then, other larger case series have been able to better delineate the features and prognosis of RCVS [9••].
Presentation Although initial presentation can be variable, 95–100 % of cases involve a sudden-onset, severe headache that reaches peak intensity in seconds, an event that is often referred to as thunderclap headache [4, 7]. Such headaches are frequently recurrent, and usually occur over the span of a week to 10 days [7]. In terms of the features of the headache, it is most often described as bilateral and diffuse, but can less commonly be localized. RCVS is often associated migrainous features [5, 10••]. The headache is usually severe and intermittent, but can be present in conjunction with a low-grade, dull background headache, in between episodes of more severe pain [5]. A large percentage of RCVS cases have triggers, including Valsalva maneuvers like coughing or sexual activity [10••]. Other less frequent presentations include seizures (prevalence of 1–17 %) and focal neurologic symptoms, including visual loss, aphasia, or hemiparesis (prevalence of 8–43 %), based on three case studies with 305 patients [6, 7, 9••, 10••, 11].
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Among RCVS-associated focal neurologic deficits, there tends to be a higher frequency of visual symptoms, which is likely due to the occipitoparietal region being more vulnerable to the development of edema, similar to the phenomenon present in posterior reversible encephalopathy syndrome (PRES) [12].
Pathophysiology The underlying pathophysiology is thought to be a disturbance in cerebrovascular tone as the final step in the disease process, leading to the vasoconstriction. There have been a number of triggers identified, but how they lead to this final step is still unclear. It has been proposed that the vasospasm noted in RCVS may involve biochemical factors, like catecholamines, protaglandins, and nitric oxide [6]. Researchers believe there is a “vascular discharge” that transiently causes an alteration in vascular caliber that eventually reverses [6, 10••, 13]. Aberrant sympathetic activity [14••], and oxidative stress affecting vascular tone also likely play a role [13].
Risk Factors and Secondary Causes There is a female preponderance of RCVS, with case studies demonstrating a female prevalence ranging from 64–92 %. RCVS occurs mostly in middle-aged patients, with a peak incidence between 20–50 years of age, although there are reports of children with the syndrome [4, 7, 8]. The postpartum period seems to be an especially high-risk time for the development of RCVS, accounting for nearly a tenth of cases [11, 14••, 15]. It is thought that the postpartum period is a trigger for RCVS due to the levels of antiangiogenic and proangiogenic factors, including growth factors that have been correlated with eclampsia such as placental growth factor (PIGF) [14••]. There may also be a role for the soluble PIGF receptor [14••]. There is usually a history of prior headaches, including migraines, in up to 40 % of patients [3, 4, 15]. This may be due to the underlying mechanism of a migraine as well as some of the medications used in migraine treatment, including those that are vasoactive [4]. Migraines may also be associated with a higher risk of hemorrhage as a complication in patients with RCVS [9••, 16]. There are case reports of the development of RCVS with a variety of medications utilized for the treatment of migraines, including hydroxyzine and serotonergic medications [17, 18]. In patients with a history of RCVS and migraines, future prophylactic and abortive medications should be chosen wisely as to avoid taking vasoactive medications [16]. One cohort noted that vasoactive drugs were associated with 55 % of cases [10••]. Hypertension is also a
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common co-morbid condition, and many times there is an associated increase in blood pressure at the time of presentation [4]. It is unclear whether this elevated blood pressure is part of a cascade of events leading up to an episode of RCVS, or if it is a physiologic response to an episode that has already commenced. Some case studies have noted cervical dissection as a co-morbid condition, and some experts have alluded to the possibility that such dissections may have a potential causative role. As such, dissections should be actively ruled out in cases where there is a suspicion of RCVS [14••, 19]. This may be simply accomplished by including an MRA of the neck in addition to an MRI/MRA brain that is routinely performed for the evaluation of RCVS. A recent study evaluated the possible underlying genetic associations of RCVS, including alterations in brain-derived neurotrophic factor, which is a chemical associated with the regulation of vascular tone [19]. This study noted that patients with the Val allele of BDNF Val66Met polymorphism on chromosome 11 were more likely to have higher rates of vasoconstriction compared to those with Met homozygotes [19]. Although there frequently seems to be an inciting event, an identifiable cause of RCVS is only found in about 60 % of patients [7]. Secondary RCVS is differentiated from primary RCVS when a provocative factor is identified. The most common triggers are vasoactive factors, and the three most common RCVS-associated vasoactive factors are marijuana, cocaine and heroin [14••]. Other known inciting factors include immunosuppressants, cytotoxic agents, recent neurosurgical procedures, and non-aneurysmal SAH, although it is unclear whether non-aneurysmal SAH is a cause or effect of vasoconstriction [7, 10••, 14••].
Diagnosis-Imaging and Tests In 2004, the International Classification of Headache Disorders II (ICHD-II) added RCVS as a cause of secondary headaches. Outside of the ICHD-II, there are no official criteria to make the diagnosis, although it is usually done when there is a constellation of typical symptoms in conjunction with characteristic findings on imaging of the cerebral arteries [3]. In 2007, Calabrese proposed a set of criteria based on expert opinion, which is often used to help make the diagnosis [6, 14••]. This criteria includes a collection of the symptoms, most notably severe, recurrent, “thunderclap,” headaches that may be accompanied by focal neurological deficits, along with a thorough workup that rules out aneurismal SAH, usually consisting of CT and lumbar puncture. Vascular imaging, either magnetic resonance angiography (MRA), computed tomography angiography (CTA), or conventional angiogram can demonstrate multifocal,
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segmental areas of vasoconstriction in large- and mediumsized arteries. An important criterion for making the diagnosis is the eventual reversibility of symptoms and imaging findings. The amount of time that it can take for the vasoconstriction to reverse is not consistent, but most authors agree that 3 months is a reasonable upper limit for duration [6]. There is no standardized algorithm for imaging, although conventional angiogram is used as the gold standard for diagnosis. Studies looking at less invasive techniques have demonstrated that CTA and MRA are useful alternatives. They were both found to be sensitive to detect stenosis in the arteries of the circle of Willis, but may not be able to detect abnormalities in smaller caliber vessels [20]. A study by Villablanca et al. estimated that CTA can visualize about 90 % of the vessels that are visible on conventional angiogram, including vessels with a diameter of less than 0.7 mm [21]. The classic angiographic finding for RCVS is that of alternating arterial constriction and dilatation, sometimes described as “pearls on a sting,” or “beading” [4]. It affects mostly large- and medium-sized arteries [7]. Since MRA is less invasive, it is sometimes preferred over angiogram and in many cases is enough to make the diagnosis. At times, initial imaging may be negative for up to the first 2 weeks [5]. Precaution should be taken not to preemptively rule out RCVS if the initial imaging study is negative, as sometimes imaging may need to be repeated if the diagnosis is suspected clinically. Given the inherent reversibility of the disease, experts agree that an important feature is the resolution of these imaging findings [4, 7]. There are no guidelines regarding follow-up after resolution of symptoms. Although some practitioners will prefer to reassess with imaging, they will usually do so with less invasive methods, including CT angiogram or MRA. Ultrasound can also be used to follow the vasoconstriction, similar to its use in vasospasm after SAH [7]. The flow velocities are not as severe as in vasospasm, but studies have found that patients with evidence of mild vasospasm had a higher risk of PRES and infarct (P2 segment with PRES, M1 segment with infarct) [5]. Vasoconstriction can often remain present after the associated headache has resolved [5]. Most patients with a stable examination and symptoms can be followed clinically if there is no recurrence of symptoms, although some argue that the diagnosis is not confirmed if the reversibility of the arteries is not confirmed. It is also important to rule out other secondary causes of headache including subarachnoid hemorrhage with associated vasospasm. Associated subarachnoid hemorrhage is present in up to 20–34 % of cases of RCVS, although they are usually small and localized to lateral or superior portions of the cortex [5]. Aneurismal SAH can be a cause of thunderclap headache but can be distinguished from RCVS in that headaches are usually not recurrent and there may be associated nuchal rigidity [10••]. Also, the pattern of blood is usually in a
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“long-segmental,” fashion with considerable volume of blood and closely located to the area of rupture in an aneurismal hemorrhage, while it is minimal and overlying the cortex in RCVS [10••, 14••]. The subarachnoid blood in RCVS is remote from the affected arteries, and therefore not thought to be the cause of the vasoconstriction, unlike in aneurismal SAH [12]. A recent study by Muehlschlegal et al. attempted to determine the factors that could be used to differentiate between aneurismal SAH and SAH related to RCVS. The authors concluded that those with SAH related to RCVS were mostly women and younger than those with aneurismal SAH [22]. Patients with SAH related to RCVS also had lower Hunt-Hess scores, less severe neurological symptoms, as well as better outcomes. These data suggest that RCVS-associated SAH tends to have a more benign course than aneurismalassociated SAH. This study also noted that SAH associated with RCVS could be distinguished from aneurismal SAH by location. SAH related to RCVS was always located in the hemispheric convexities, while aneurismal SAH was mostly associated with blood in the sylvian fissure or basal cisterns [22]. Another important differential diagnosis to consider is vacuities. Distinguishing factors between RCVS and vacuities include the time span of symptoms and CSF findings. In vacuities, there is usually involvement of the smaller vessels compared with medium–large vessels in RCVS [10••]. In equivocal cases, brain biopsy may be needed to help differentiate these diagnoses. Isolated CNS vacuities are uncommon, occurring in 2.4 cases per million person-years [23]. They are similar to RCVS in that headache is a common symptom at onset, but it is usually insidious and subacute rather than thunderclap. Whereas in RCVS, headache can be the only symptom, in CNS vacuities there are usually other more prominent symptoms, including dementia, cognitive dysfunction, and personality changes. Both can involve stroke, which is present in primary angiitis of the CNS PACNS in 30–50 % of patients. CSF abnormalities are usually not present in RCVS, while they are present in PACNS [24]. In PACNS there can be a lymphocytic pleocytosis with occasional elevated protein, but glucose is typically within normal limits [23]. Rarely, in RCVS, CSF can show a pleocytosis or elevated protein that will usually resolve [24]. Although both vacuities and RCVS can demonstrate vasoconstriction on vessel imaging, some features suggestive of vacuities include an irregular or asymmetrical narrowing, while it is thought to be more regular and symmetric with RCVS [24]. Another distinguishing factor is the reversibility of the vasoconstriction seen on vascular imaging that is usually seen with RCVS but not with active vacuities. In both cases, imaging with MRI may reveal ischemic strokes or hemorrhage, although in up to 20 % of patients with RCVS, imaging can be normal [24]. In up to 100 % of patients with PACNS, vascular imaging will
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demonstrate some abnormalities [23]. A recent study by Mandell et al. used high-resolution vessel MRA to differentiate between the two entities. They found that there was vesselwall thickening but no wall enhancement in patients with RCVS, while those patients later diagnosed with vacuities had wall enhancement and persistent arterial narrowing at follow-up of greater than 3 months [25]. However, this was a preliminary study with a few patients, and firm conclusions were difficult to establish. It is important to differentiate between the two since the treatment and prognosis are quite different. Another important differential diagnosis is posterior reversible encephalopathy syndrome (PRES). PRES, similar to RCVS, can also present with neurological symptoms, at times with a headache. The classic findings on imaging include vasogenic edema in the occipital, parietal, and frontal lobes, although distribution can vary [20]. It may also concur with parenchymal or subarachnoid hemorrhage, and may show evidence of vasculopathy on imaging [26]. Laboratory evaluations are usually normal in PRES, including inflammatory testing [9••, 16]. Lab testing to rule out secondary causes should be done for pheochromocytoma and illicit drug use. If diagnostic evaluations are negative in the setting of a headache that occurs with sexual activity, primary sexual headaches should be considered, which is a diagnosis of exclusion [27, 28].
Treatment To date, there have been no randomized trials to determine the best treatment for RCVS. For this reason, there are no specific guidelines for treatment [5]. The obvious first step is to remove the triggering agent, if it is known [16]. It is also recommended that patients avoid possible triggering factors in the weeks after onset, including medications, illicit drugs, and Valsalva maneuvers [16]. Patients should be monitored closely in order to detect possible complications, including infarcts, hemorrhage, or worsening vasospasm that may require more aggressive treatment. Supportive measures should include treatment with analgesics, blood pressure management, and treating complications like seizures. The mainstay of treatment is calcium-channel blockers, but there have been no studies to verify or elucidate the underlying mechanism of calcium-channel blockers in RCVS [5]. Both Nimodipine and Verapamil have been found to be helpful with the symptoms and clinical outcomes [4, 5]. Nimodipine was shown to improve headaches but did not alter the course of the disease [16]. Steroids have been utilized, but a recent case series involving the use of steroids was found to be associated with poorer outcomes [11]. Other case studies looked at magnesium and even just conservative management with pain control and close monitoring, which in most cases constituted
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adequate treatment [5] Endovascular therapies are sometimes used if the patient is having major complications due to the vasoconstriction, with intra-arterial administration of vasodilators, including verapamil or milrinone. Rarely, angioplasty is used for more refractory cases [29].
Page 5 of 6, 414 Compliance with Ethics Guidelines Conflict of Interest Dr. Huma U. Sheikh and Dr. Paul G. Mathew each declare no potential conflicts of interest relevant to this article. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.
Prognosis/Complications The growing literature regarding RCVS is beginning to suggest that it is an important cause of stroke in young patients [8]. Up to one-third of patients with RCVS develop some form of vascular complication, in the form of subarachnoid hemorrhage, intraparenchymal hemorrhage (IPH) or ischemic stroke [22]. In a retrospective multi-center review, the presence of “parenchymal abnormalities at admission” was found to be an independent risk factor for poor outcome [8]. However, most patients tend to do well, as estimates report that almost all patients have little or no disability on follow-up [7]. The syndrome is thought to have a self-limited course, with most symptoms resolving within a month, although in some cases a less severe headache can linger for longer [16]. Some of the complications include subarachnoid hemorrhage, intracerebral hemorrhage, stroke, or symptoms of posterior reversible leukoencephalopathy [4, 7]. There have been rare reported cases of “fulminant” vasoconstriction leading to progressive symptoms and even death [6, 11]. Fatality has been estimated at less than 1 %, although it can happen, especially in cases that occur postpartum. One retrospective case study revealed that four out of 18 deaths in RCVS occur in the postpartum period [30]. It was noted in previous studies that SAH, ICH, seizures, and PRES usually present in the first week, while TIA and infarct occur later in the course of the disease [5]. ICH and infarct usually occur in watershed areas and, along with PRES, portend a worse prognosis [5].
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Although there has been an abundance of research on RCVS in the last few years, a complete understanding remains to be achieved. Future RCVS studies should focus on underlying pathophysiology, risk factors including genetic predisposition, the optimal time to perform diagnostic vascular imaging, the need for repeat imaging to confirm reversal of vasoconstriction, and improving treatment paradigms. With better understanding of RCVS, establishing the diagnosis early in the course of the disorder may lead to better treatment and less neurologic complications. Another important area of study in the future is the duration of treatment, including how long to continue calcium-channel blockers after initial presentation.
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•• Call GK, Fleming MC, Sealfon S, Levine H, Kistler JP, Fisher CM. Reversible cerebral segmental vasoconstriction. Stroke. 1988;19(9):1159–70. This was the first known case series of RCSV. Snyder BD, McClelland RR. Isolated benign cerebral vasculitis. Arch Neurol. 1978;35(9):612–4. Garcin B, Clouston J, Saines N. Reversible cerebral vasoconstriction syndrome. J Clin Neurosci. 2009;16(1):147–50. Velez A, McKinney JS. Reversible cerebral vasoconstriction syndrome: a review of recent research. Curr Neurol Neurosci Rep. 2013;13(1):319-012-0319-y. Yancy H, Lee-Iannotti JK, Schwedt TJ, Dodick DW. Reversible cerebral vasoconstriction syndrome. Headache. 2013;53(3):570–6. Calabrese LH, Dodick DW, Schwedt TJ, Singhal AB. Narrative review: reversible cerebral vasoconstriction syndromes. Ann Intern Med. 2007;146(1):34–44. Sattar A, Manousakis G, Jensen MB. Systematic review of reversible cerebral vasoconstriction syndrome. Expert Rev Cardiovasc Ther. 2010;8(10):1417–21. Robert T, Kawkabani Marchini A, Oumarou G, Uske A. Reversible cerebral vasoconstriction syndrome identification of prognostic factors. Clin Neurol Neurosurg. 2013;115:2351–7. •• Ducros A, Boukobza M, Porcher R, Sarov M, Valade D, Bousser MG. The clinical and radiological spectrum of reversible cerebral vasoconstriction syndrome. A prospective series of 67 patients. Brain. 2007;130(Pt 12):3091–101. Comprehensive Review. •• Chen SP, Fuh JL, Wang SJ. Reversible cerebral vasoconstriction syndrome: an under-recognized clinical emergency. Ther Adv Neurol Disord. 2010;3(3):161–71. Comprehensive Review. Singhal AB, Hajj-Ali RA, Topcuoglu MA, Fok J, Bena J, Yang D, et al. Reversible cerebral vasoconstriction syndromes: analysis of 139 cases. Arch Neurol. 2011;68(8):1005–12. Moustafa RR, Allen CM, Baron JC. Call-Fleming syndrome associated with subarachnoid haemorrhage: three new cases. BMJ Case Rep. 2009. doi:10.1136/bcr.09.2008.0989. Chen SP, Chung YT, Liu TY, Wang YF, Fuh JL, Wang SJ. Oxidative stress and increased formation of vasoconstricting F2isoprostanes in patients with reversible cerebral vasoconstriction syndrome. Free Radic Biol Med. 2013;61C:243–8. •• Chen SP, Fuh JL, Wang SJ. Reversible cerebral vasoconstriction syndrome: current and future perspectives. Expert Rev Neurother. 2011;11(9):1265–76. Important for review of recent literature. Ducros A, Fiedler U, Porcher R, Boukobza M, Stapf C, Bousser MG. Hemorrhagic manifestations of reversible cerebral vasoconstriction syndrome: frequency, features, and risk factors. Stroke. 2010;41(11):2505–11.
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Hammad TA, Hajj-Ali RA. Primary angiitis of the central nervous system and reversible cerebral vasoconstriction syndrome. Curr Atheroscler Rep. 2013;15(8):346-013-0346-4. 24. Ducros A. L37. Reversible cerebral vasoconstriction syndrome: distinction from CNS vasculitis. Presse Med. 2013;42(4 Pt 2): 602–4. 25. Mandell DM, Matouk CC, Farb RI, Krings T, Agid R, terBrugge K, et al. Vessel wall MRI to differentiate between reversible cerebral vasoconstriction syndrome and central nervous system vasculitis: preliminary results. Stroke. 2012;43(3):860–2. 26. Bartynski WS, Boardman JF. Catheter angiography, MR angiography, and MR perfusion in posterior reversible encephalopathy syndrome. AJNR Am J Neuroradiol. 2008;29(3):447–55. 27. Levin M. The International Classification of Headache Disorders, 3rd edition (ICHD III)—changes and challenges. Headache. 2013;53(8):1383–95. 28. Olesen J. ICHD-3 beta is published. Use it immediately. Cephalalgia. 2013;33(9):627–8. 29. Takis C, Kwan ES, Pessin MS, Jacobs DH, Caplan LR. Intracranial angioplasty: experience and complications. AJNR Am J Neuroradiol. 1997;18(9):1661–8. 30. Fugate JE, Ameriso SF, Ortiz G, Schottlaender LV, Wijdicks EF, Flemming KD, et al. Variable presentations of postpartum angiopathy. Stroke. 2012;43(3):670–6.
UNCOMMON HEADACHE SYNDROMES (J AILANI, SECTION EDITOR)
Reversible Cerebral Vasoconstriction Syndrome: Updates and New Perspectives Huma U. Sheikh & Paul G. Mathew
Published online: 23 March 2014 # Springer Science+Business Media New York 2014
Abstract Reversible cerebral vasoconstriction syndrome (RCVS) is an important cause of headaches that can lead to other neurological complications, including stroke, if not recognized early. Over the past few years, there has been great progress in the recognition of this entity. However, there is still much to be learned about its pathophysiology and optimal treatment strategies. RCVS occurs mostly in middle-aged adults, and there is a female preponderance with an increased incidence during the postpartum period. A consistent, predominating feature is a sudden-onset, severe headache that is frequently recurrent, usually over the span of a week. Less common presentations include seizures or focal neurological symptoms. Important causative factors include vasoactive medications, as well as illicit drugs like marijuana and cocaine. The current underlying pathophysiology is thought to be a disturbance in cerebrovascular tone leading to vasoconstriction. The diagnosis is based on history, physical examination, and cerebrovascular imaging findings that demonstrate multifocal, segmental areas of vasoconstriction in large- and medium-sized arteries. An important criterion for making the diagnosis is the eventual reversibility of symptoms and imaging findings. Keywords Reversible cerebral vasoconstriction syndrome . Thunderclap headache . Pathophysiology . Vasoconstriction . Cerebrovascular imaging This article is part of the Topical Collection on Uncommon Headache Syndromes
H. U. Sheikh (*) : P. G. Mathew Brigham and Women’s Hospital, Department of Neurology, John R. Graham Headache Center, Harvard Medical School, 1153 Centre Street, Suite 4970, Boston, MA 02130, USA e-mail: [email protected] P. G. Mathew Cambridge Health Alliance, Division of Neurology, Harvard Medical School, Cambridge, MA 02139, USA
Case Presentation A 52-year-old woman with a history of obesity and hyperlipidemia developed an acute, severe thunderclap headache during orgasm, located primarily in the frontal area. She was seen in the emergency department (ED) where a CT scan of the head was normal. She was treated symptomatically with morphine and metoclopramide, and was subsequently discharged after the headache resolved in a few hours. After four days, again while being intimate with her husband, she developed another severe thunderclap headache. She again proceeded to the ED, and again was discharged after symptomatic treatment. She had a third similar headache the next day, and was finally admitted for further evaluation. Over the course of her evaluation, she had two additional headache episodes, which were similar in presentation, occurring within eight days of her initial episode of severe headache. The last three headaches were not in the context of sexual activity. Her workup included magnetic resonance imaging (MRI) and magnetic resonance angiography (MRA), followed by a conventional angiogram that revealed diffuse segmental stenosis. She was referred to a headache clinic and reported no recurrence of headaches or other neurological symptoms. It was at the headache clinic that the diagnosis of reversible cerebral vasoconstriction syndrome (RCVS) was made, and she was started on a calcium-channel blocker. She was followed for 14 months after the first occurrence and remained asymptomatic.
Introduction/History of RCVS The above case demonstrates some important features and pitfalls that can occur in the diagnosis of reversible cerebral vasoconstriction syndrome. Although this entity has been better appreciated over the past ten years, there is still much to be learned. Call and Fleming at Massachusetts General
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Hospital first described the syndrome in 1988, in a series of four cases involving severe headache and evidence of reversible constriction of the cerebral vessels that was not attributable to a secondary cause [1••]. As such, this syndrome was initially called Call-Fleming Syndrome. An earlier case of “benign cerebral vacuities,” reported in 1978, was likely the first reported case of RCVS, but was wrongly labeled as a form of vacuities [2, 3]. Over the years, RCVS has been identified by several other names, owing to the fact that it was a poorly-recognized syndrome, and because there were no unifying diagnostic criteria [4, 5]. Other eponyms have included benign angiopathy of the CNS, post-partum angiopathy, migrainous vasospasm, and drug-induced cerebral arteritis [5]. The term RCVS was only recently proposed as a unifying term in 2007, after evidence showed that cases that fit this criteria were all likely due to the same phenomenon [6]. When Call and Fleming first described RCVS, the two suspected causes of “reversible constriction of cerebral vasculature” were vasospasm (1) after a subarachnoid hemorrhage (SAH) and (2) as a theorized mechanism of migraine. Important features of that first case series included the consistent description of healthy subjects with prominent, severe, sudden-onset headaches [1••]. In the 25 years since first being reported, there has been a concerted effort to determine the underlying pathophysiology of this entity. In a systematic review in 2010, there were around 200 reports of patients with RCVS [7]. However, these were small case studies, with most series reporting less than ten patients [8]. Since then, other larger case series have been able to better delineate the features and prognosis of RCVS [9••].
Presentation Although initial presentation can be variable, 95–100 % of cases involve a sudden-onset, severe headache that reaches peak intensity in seconds, an event that is often referred to as thunderclap headache [4, 7]. Such headaches are frequently recurrent, and usually occur over the span of a week to 10 days [7]. In terms of the features of the headache, it is most often described as bilateral and diffuse, but can less commonly be localized. RCVS is often associated migrainous features [5, 10••]. The headache is usually severe and intermittent, but can be present in conjunction with a low-grade, dull background headache, in between episodes of more severe pain [5]. A large percentage of RCVS cases have triggers, including Valsalva maneuvers like coughing or sexual activity [10••]. Other less frequent presentations include seizures (prevalence of 1–17 %) and focal neurologic symptoms, including visual loss, aphasia, or hemiparesis (prevalence of 8–43 %), based on three case studies with 305 patients [6, 7, 9••, 10••, 11].
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Among RCVS-associated focal neurologic deficits, there tends to be a higher frequency of visual symptoms, which is likely due to the occipitoparietal region being more vulnerable to the development of edema, similar to the phenomenon present in posterior reversible encephalopathy syndrome (PRES) [12].
Pathophysiology The underlying pathophysiology is thought to be a disturbance in cerebrovascular tone as the final step in the disease process, leading to the vasoconstriction. There have been a number of triggers identified, but how they lead to this final step is still unclear. It has been proposed that the vasospasm noted in RCVS may involve biochemical factors, like catecholamines, protaglandins, and nitric oxide [6]. Researchers believe there is a “vascular discharge” that transiently causes an alteration in vascular caliber that eventually reverses [6, 10••, 13]. Aberrant sympathetic activity [14••], and oxidative stress affecting vascular tone also likely play a role [13].
Risk Factors and Secondary Causes There is a female preponderance of RCVS, with case studies demonstrating a female prevalence ranging from 64–92 %. RCVS occurs mostly in middle-aged patients, with a peak incidence between 20–50 years of age, although there are reports of children with the syndrome [4, 7, 8]. The postpartum period seems to be an especially high-risk time for the development of RCVS, accounting for nearly a tenth of cases [11, 14••, 15]. It is thought that the postpartum period is a trigger for RCVS due to the levels of antiangiogenic and proangiogenic factors, including growth factors that have been correlated with eclampsia such as placental growth factor (PIGF) [14••]. There may also be a role for the soluble PIGF receptor [14••]. There is usually a history of prior headaches, including migraines, in up to 40 % of patients [3, 4, 15]. This may be due to the underlying mechanism of a migraine as well as some of the medications used in migraine treatment, including those that are vasoactive [4]. Migraines may also be associated with a higher risk of hemorrhage as a complication in patients with RCVS [9••, 16]. There are case reports of the development of RCVS with a variety of medications utilized for the treatment of migraines, including hydroxyzine and serotonergic medications [17, 18]. In patients with a history of RCVS and migraines, future prophylactic and abortive medications should be chosen wisely as to avoid taking vasoactive medications [16]. One cohort noted that vasoactive drugs were associated with 55 % of cases [10••]. Hypertension is also a
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common co-morbid condition, and many times there is an associated increase in blood pressure at the time of presentation [4]. It is unclear whether this elevated blood pressure is part of a cascade of events leading up to an episode of RCVS, or if it is a physiologic response to an episode that has already commenced. Some case studies have noted cervical dissection as a co-morbid condition, and some experts have alluded to the possibility that such dissections may have a potential causative role. As such, dissections should be actively ruled out in cases where there is a suspicion of RCVS [14••, 19]. This may be simply accomplished by including an MRA of the neck in addition to an MRI/MRA brain that is routinely performed for the evaluation of RCVS. A recent study evaluated the possible underlying genetic associations of RCVS, including alterations in brain-derived neurotrophic factor, which is a chemical associated with the regulation of vascular tone [19]. This study noted that patients with the Val allele of BDNF Val66Met polymorphism on chromosome 11 were more likely to have higher rates of vasoconstriction compared to those with Met homozygotes [19]. Although there frequently seems to be an inciting event, an identifiable cause of RCVS is only found in about 60 % of patients [7]. Secondary RCVS is differentiated from primary RCVS when a provocative factor is identified. The most common triggers are vasoactive factors, and the three most common RCVS-associated vasoactive factors are marijuana, cocaine and heroin [14••]. Other known inciting factors include immunosuppressants, cytotoxic agents, recent neurosurgical procedures, and non-aneurysmal SAH, although it is unclear whether non-aneurysmal SAH is a cause or effect of vasoconstriction [7, 10••, 14••].
Diagnosis-Imaging and Tests In 2004, the International Classification of Headache Disorders II (ICHD-II) added RCVS as a cause of secondary headaches. Outside of the ICHD-II, there are no official criteria to make the diagnosis, although it is usually done when there is a constellation of typical symptoms in conjunction with characteristic findings on imaging of the cerebral arteries [3]. In 2007, Calabrese proposed a set of criteria based on expert opinion, which is often used to help make the diagnosis [6, 14••]. This criteria includes a collection of the symptoms, most notably severe, recurrent, “thunderclap,” headaches that may be accompanied by focal neurological deficits, along with a thorough workup that rules out aneurismal SAH, usually consisting of CT and lumbar puncture. Vascular imaging, either magnetic resonance angiography (MRA), computed tomography angiography (CTA), or conventional angiogram can demonstrate multifocal,
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segmental areas of vasoconstriction in large- and mediumsized arteries. An important criterion for making the diagnosis is the eventual reversibility of symptoms and imaging findings. The amount of time that it can take for the vasoconstriction to reverse is not consistent, but most authors agree that 3 months is a reasonable upper limit for duration [6]. There is no standardized algorithm for imaging, although conventional angiogram is used as the gold standard for diagnosis. Studies looking at less invasive techniques have demonstrated that CTA and MRA are useful alternatives. They were both found to be sensitive to detect stenosis in the arteries of the circle of Willis, but may not be able to detect abnormalities in smaller caliber vessels [20]. A study by Villablanca et al. estimated that CTA can visualize about 90 % of the vessels that are visible on conventional angiogram, including vessels with a diameter of less than 0.7 mm [21]. The classic angiographic finding for RCVS is that of alternating arterial constriction and dilatation, sometimes described as “pearls on a sting,” or “beading” [4]. It affects mostly large- and medium-sized arteries [7]. Since MRA is less invasive, it is sometimes preferred over angiogram and in many cases is enough to make the diagnosis. At times, initial imaging may be negative for up to the first 2 weeks [5]. Precaution should be taken not to preemptively rule out RCVS if the initial imaging study is negative, as sometimes imaging may need to be repeated if the diagnosis is suspected clinically. Given the inherent reversibility of the disease, experts agree that an important feature is the resolution of these imaging findings [4, 7]. There are no guidelines regarding follow-up after resolution of symptoms. Although some practitioners will prefer to reassess with imaging, they will usually do so with less invasive methods, including CT angiogram or MRA. Ultrasound can also be used to follow the vasoconstriction, similar to its use in vasospasm after SAH [7]. The flow velocities are not as severe as in vasospasm, but studies have found that patients with evidence of mild vasospasm had a higher risk of PRES and infarct (P2 segment with PRES, M1 segment with infarct) [5]. Vasoconstriction can often remain present after the associated headache has resolved [5]. Most patients with a stable examination and symptoms can be followed clinically if there is no recurrence of symptoms, although some argue that the diagnosis is not confirmed if the reversibility of the arteries is not confirmed. It is also important to rule out other secondary causes of headache including subarachnoid hemorrhage with associated vasospasm. Associated subarachnoid hemorrhage is present in up to 20–34 % of cases of RCVS, although they are usually small and localized to lateral or superior portions of the cortex [5]. Aneurismal SAH can be a cause of thunderclap headache but can be distinguished from RCVS in that headaches are usually not recurrent and there may be associated nuchal rigidity [10••]. Also, the pattern of blood is usually in a
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“long-segmental,” fashion with considerable volume of blood and closely located to the area of rupture in an aneurismal hemorrhage, while it is minimal and overlying the cortex in RCVS [10••, 14••]. The subarachnoid blood in RCVS is remote from the affected arteries, and therefore not thought to be the cause of the vasoconstriction, unlike in aneurismal SAH [12]. A recent study by Muehlschlegal et al. attempted to determine the factors that could be used to differentiate between aneurismal SAH and SAH related to RCVS. The authors concluded that those with SAH related to RCVS were mostly women and younger than those with aneurismal SAH [22]. Patients with SAH related to RCVS also had lower Hunt-Hess scores, less severe neurological symptoms, as well as better outcomes. These data suggest that RCVS-associated SAH tends to have a more benign course than aneurismalassociated SAH. This study also noted that SAH associated with RCVS could be distinguished from aneurismal SAH by location. SAH related to RCVS was always located in the hemispheric convexities, while aneurismal SAH was mostly associated with blood in the sylvian fissure or basal cisterns [22]. Another important differential diagnosis to consider is vacuities. Distinguishing factors between RCVS and vacuities include the time span of symptoms and CSF findings. In vacuities, there is usually involvement of the smaller vessels compared with medium–large vessels in RCVS [10••]. In equivocal cases, brain biopsy may be needed to help differentiate these diagnoses. Isolated CNS vacuities are uncommon, occurring in 2.4 cases per million person-years [23]. They are similar to RCVS in that headache is a common symptom at onset, but it is usually insidious and subacute rather than thunderclap. Whereas in RCVS, headache can be the only symptom, in CNS vacuities there are usually other more prominent symptoms, including dementia, cognitive dysfunction, and personality changes. Both can involve stroke, which is present in primary angiitis of the CNS PACNS in 30–50 % of patients. CSF abnormalities are usually not present in RCVS, while they are present in PACNS [24]. In PACNS there can be a lymphocytic pleocytosis with occasional elevated protein, but glucose is typically within normal limits [23]. Rarely, in RCVS, CSF can show a pleocytosis or elevated protein that will usually resolve [24]. Although both vacuities and RCVS can demonstrate vasoconstriction on vessel imaging, some features suggestive of vacuities include an irregular or asymmetrical narrowing, while it is thought to be more regular and symmetric with RCVS [24]. Another distinguishing factor is the reversibility of the vasoconstriction seen on vascular imaging that is usually seen with RCVS but not with active vacuities. In both cases, imaging with MRI may reveal ischemic strokes or hemorrhage, although in up to 20 % of patients with RCVS, imaging can be normal [24]. In up to 100 % of patients with PACNS, vascular imaging will
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demonstrate some abnormalities [23]. A recent study by Mandell et al. used high-resolution vessel MRA to differentiate between the two entities. They found that there was vesselwall thickening but no wall enhancement in patients with RCVS, while those patients later diagnosed with vacuities had wall enhancement and persistent arterial narrowing at follow-up of greater than 3 months [25]. However, this was a preliminary study with a few patients, and firm conclusions were difficult to establish. It is important to differentiate between the two since the treatment and prognosis are quite different. Another important differential diagnosis is posterior reversible encephalopathy syndrome (PRES). PRES, similar to RCVS, can also present with neurological symptoms, at times with a headache. The classic findings on imaging include vasogenic edema in the occipital, parietal, and frontal lobes, although distribution can vary [20]. It may also concur with parenchymal or subarachnoid hemorrhage, and may show evidence of vasculopathy on imaging [26]. Laboratory evaluations are usually normal in PRES, including inflammatory testing [9••, 16]. Lab testing to rule out secondary causes should be done for pheochromocytoma and illicit drug use. If diagnostic evaluations are negative in the setting of a headache that occurs with sexual activity, primary sexual headaches should be considered, which is a diagnosis of exclusion [27, 28].
Treatment To date, there have been no randomized trials to determine the best treatment for RCVS. For this reason, there are no specific guidelines for treatment [5]. The obvious first step is to remove the triggering agent, if it is known [16]. It is also recommended that patients avoid possible triggering factors in the weeks after onset, including medications, illicit drugs, and Valsalva maneuvers [16]. Patients should be monitored closely in order to detect possible complications, including infarcts, hemorrhage, or worsening vasospasm that may require more aggressive treatment. Supportive measures should include treatment with analgesics, blood pressure management, and treating complications like seizures. The mainstay of treatment is calcium-channel blockers, but there have been no studies to verify or elucidate the underlying mechanism of calcium-channel blockers in RCVS [5]. Both Nimodipine and Verapamil have been found to be helpful with the symptoms and clinical outcomes [4, 5]. Nimodipine was shown to improve headaches but did not alter the course of the disease [16]. Steroids have been utilized, but a recent case series involving the use of steroids was found to be associated with poorer outcomes [11]. Other case studies looked at magnesium and even just conservative management with pain control and close monitoring, which in most cases constituted
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adequate treatment [5] Endovascular therapies are sometimes used if the patient is having major complications due to the vasoconstriction, with intra-arterial administration of vasodilators, including verapamil or milrinone. Rarely, angioplasty is used for more refractory cases [29].
Page 5 of 6, 414 Compliance with Ethics Guidelines Conflict of Interest Dr. Huma U. Sheikh and Dr. Paul G. Mathew each declare no potential conflicts of interest relevant to this article. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.
Prognosis/Complications The growing literature regarding RCVS is beginning to suggest that it is an important cause of stroke in young patients [8]. Up to one-third of patients with RCVS develop some form of vascular complication, in the form of subarachnoid hemorrhage, intraparenchymal hemorrhage (IPH) or ischemic stroke [22]. In a retrospective multi-center review, the presence of “parenchymal abnormalities at admission” was found to be an independent risk factor for poor outcome [8]. However, most patients tend to do well, as estimates report that almost all patients have little or no disability on follow-up [7]. The syndrome is thought to have a self-limited course, with most symptoms resolving within a month, although in some cases a less severe headache can linger for longer [16]. Some of the complications include subarachnoid hemorrhage, intracerebral hemorrhage, stroke, or symptoms of posterior reversible leukoencephalopathy [4, 7]. There have been rare reported cases of “fulminant” vasoconstriction leading to progressive symptoms and even death [6, 11]. Fatality has been estimated at less than 1 %, although it can happen, especially in cases that occur postpartum. One retrospective case study revealed that four out of 18 deaths in RCVS occur in the postpartum period [30]. It was noted in previous studies that SAH, ICH, seizures, and PRES usually present in the first week, while TIA and infarct occur later in the course of the disease [5]. ICH and infarct usually occur in watershed areas and, along with PRES, portend a worse prognosis [5].
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Although there has been an abundance of research on RCVS in the last few years, a complete understanding remains to be achieved. Future RCVS studies should focus on underlying pathophysiology, risk factors including genetic predisposition, the optimal time to perform diagnostic vascular imaging, the need for repeat imaging to confirm reversal of vasoconstriction, and improving treatment paradigms. With better understanding of RCVS, establishing the diagnosis early in the course of the disorder may lead to better treatment and less neurologic complications. Another important area of study in the future is the duration of treatment, including how long to continue calcium-channel blockers after initial presentation.
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