Reversible cerebral vasoconstriction syndrome: current and future perspectives

THEMED ARTICLE y Migraine & headache
Shih-Pin Chen1,2, Jong-Ling Fuh1,2 and Shuu-Jiun Wang†1,2
1Department of Neurology, Neurological Institute, Taipei Veterans General Hospital, Taipei, Taiwan 2Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan †Author for correspondence: Neurological Institute, Taipei Veterans General Hospital, Taipei, 112, Taiwan Tel.: +886 228 762 522 Fax: +886 228 765 215 [email protected]
Reversible cerebral vasoconstriction syndromes (RCVS) are characterized by recurrent acute severe headaches, namely thunderclap headaches, and multifocal segmental vasoconstrictions. Interest has arisen in the definitions, clinical presentations, differential diagnoses, risk factors and complications of RCVS. This article will comprehensively review the milestone monographs and the latest research work addressing these issues. Studies that have focused on the relationship between RCVS and thunderclap headache will be detailed. We will also discuss research on the enigmatic pathophysiology and potential therapeutic approaches. Up-to-date information and challenges, undergoing studies and future research directions will be deeply probed.
KEywoRDs: posterior reversible encephalopathy syndrome • reversible cerebral vasoconstriction syndromes • thunderclap headache
Reversible cerebral vasoconstriction syndrome: current and future perspectives
Expert Rev. Neurother. 11(9), 1265–1276 (2011)
Learning objectives
Upon completion of this activity, participants should be able to:
• Describe the clinical presentation and diagnosis of RCVS
• Describe the underlying pathophysiology and complications of RCVS
• Describe management and treatment strategies for RCVS
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CME
Review Chen, Fuh & Wang
Reversible cerebral vasoconstriction syndromes (RCVS) are character ized by acute-onset severe headaches, namely thunder- clap headaches, and reversible segmental cerebral vasoconstriction (Figure 1) [1]. This clinico–radiological syndrome was previously known as Call–Fleming syndrome [2], thunderclap headache (TCH) with reversible vasospasm [3,4], benign angiopathy of the CNS (BACNS) [5], postpartum angiopathy [6,7], migrainous vaso- spasm or migraine angiitis [8], or drug-induced cerebral arteritis or angiopathy [9,10], depending on whether patients present to specialists in stroke, headache, rheumatology or obstetrics. As a unifying term for a constellation of disorders [1], RCVS has attracted much more attention in recent years. It has been recog- nized that RCVS is not uncommon and still underdiagnosed [11]. With accumulating data, especially from several large series [12–17], the clinical features and temporal evolution of RCVS has become much clearer. However, several issues remain unresolved; for example, the perplexing relationship between RCVS and TCH, the appropriateness of including primary and secondary RCVS in the same diagnostic entity, the lack of gold-standard criteria and definition of typical and atypical cases, the ethnic differences in complication rates, or the therapeutic efficacy of calcium-channel blockers and so on. Besides, studies specifically focusing on the
pathophysiology of RCVS remain scarce [18]. It is still uncertain what constitutes the pathophysiological network of RCVS. To address these issues, this article offers a comprehensive review of studies to date and how they may help in better understanding this enigmatic disorder. In addition to a summary of the best available evidence, we will provide a commentary and 5-year view of the needs for future research and treatment efforts for RCVS.
The relationship between RCVS & thunderclap headache The term TCH is used to describe an unanticipated, severe head- ache reaching peak intensity within 1 min. TCH is traditionally linked to aneurysmal subarachnoid hemorrhage (SAH); however, an increasing numbers of secondary causes of TCH have been identified [19]. When a patient reports having the worst headache that he/she has ever experienced, an exhaustive investigations should be carried out to exclude all possible intracranial lesions. If no underlying cause is discovered, the TCH is considered pri- mary. Primary TCH was adopted as a diagnostic entity in the International Classification of Headache Disorders, 2nd Edition (ICHD-II; code 4.6) (Box 1) [20], but controversies exist regard- ing this diagnostic entity. For example, TCHs elicited by trig-
gers such as coughing, exertion or sexual activity could be coded separately in the ICHD-II (code 4.2–4.4) [20]. However, up to 80% of patients with recurrent TCHs have identifiable triggers, such as Valsalva-like maneuvers (exertion, defeca- tion, sexual activity or cough), bathing or emotional disturbance [12,15,21]. In addition, it is often the case that one patient can have multiple TCHs elicited by several different triggers [12]. It is illogical to code multiple headache diagnoses within one patient when the characteristics of the headaches are exactly the same. Furthermore, some patients with these TCH variants with- out identifiable causes exhibited angio- graphic findings of reversible cerebral
Financial & competing interests disclosure Editor Elisa Manzotti, Editorial Director, Future Science Group, London, UK Disclosure: Elisa Manzotti has disclosed no relevant financial relationships. CME Author Laurie Barclay, MD, Freelance writer and reviewer, Medscape, LLC Disclosure: Laurie Barclay, MD, has disclosed no relevant financial relationships. Authors Shih-Pin Chen, MD, PhD, Department of Neurology, Neurological Institute, Taipei Veterans General Hospital, Taipei, Taiwan; and Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan Disclosure: Shih-Pin Chen, MD, PhD, has disclosed no relevant financial relationships. Jong-Ling Fuh, MD, Department of Neurology, Neurological Institute, Taipei Veterans General Hospital, Taipei, Taiwan; and Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan Disclosure: Jong-Ling Fuh, MD, has disclosed no relevant financial relationships. Shuu-Jiun Wang, MD, Department of Neurology, Neurological Institute, Taipei Veterans General Hospital, Taipei, Taiwan; and Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan Disclosure: Shuu-Jiun Wang, MD, has disclosed no relevant financial relationships.
Figure 1. Characteristic angiographic findings of reversible cerebral vasoconstriction syndrome. (A) Multi-focal segmental vasoconstrictions and (B) their normalization in a patient with reversible cerebral vasoconstriction syndrome (vasoconstrictions are indicated by black arrows).
CME
ReviewReversible cerebral vasoconstriction syndrome: current & future perspectives
vasoconstriction [3,12,22,23]. A prospective study found that patients with idiopathic recurrent TCHs with or without vasoconstriction (coded separately as BACNS [code 6.7.3] or primary TCH accord- ing to the ICHD-II) (Box 1) exhibited the same clinical characteris- tics [12]. It is plausible that primary TCH and RCVS are spectra of the same disorder [12]. As vasoconstrictions might not be evident during the early stage of RCVS and some imaging modalities might not be sensitive enough to detect vasoconstrictions in distal arterioles, it is likely that some patients are diagnosed with primary TCH because they do not receive serial angiographic follow-ups.
It has been demonstrated that TCH is usually the initial symp- tom of RCVS, and up to 82–100% of patients with RCVS had repeated attacks of TCHs during the clinical course [12,15,17]. In our experience, when a patient experiences multiple TCHs within 1–2 weeks, RCVS is the most probable diagnosis. On occasion, patients with RCVS cannot be sure whether their headaches reaches the maximal intensity from the onset within 1 min, but these headaches are ubiquitously acute and severe. Sentinel head- aches, presumably due to ‘warning leak,’ stretching or dissection in the weakened walls of an aneurysm, can present as TCHs preced- ing the hemorrhage in up to 10–43% of patients with aneurysmal SAH [24]. The numbers of sentinel headaches tend to be one or two. However, as it is difficult for patients with SAH to report their prior headache history exactly, whether it is possible that one can have ‘multiple’ sentinel headaches prior to SAH is uncertain. If a patient presents with TCH and is also found to have both an unruptured aneurysm and diffuse multisegmental cerebral vasoconstriction [25], it is still controversial whether the aneurysm should be treated as a first priority, even though the diagnosis is preferably RCVS and the aneurysm may be a coincidental finding.
Some overlapping syndromes or comorbidities may provide the link between TCH and RCVS. Posterior reversible encephalo- pathy syndrome (PRES) is the leading one, which will be addressed in detail in the pathophysiology section. Arterial dissection is a recently identified one. It has been a well-known secondary cause of TCH, supposedly attributable to a distension of the artery by the mural hematoma stimulating pain-sensitive receptors [26]. However, it was recently identified that arterial dissection, either
extracranial or intracranial, could be a comorbid condition of RCVS [14–16,27,28]. It is uncertain whether there is a causal relation- ship between arterial dissection and RCVS, or whether both condi- tions could possibly be attributed to an underlying constitutional arterio pathy. Nonetheless, arterial dissection should be carefully sought in patients with suspected RCVS, and prospective stud- ies are required to investigate the prevalence of reversible cerebral vasoconstrictions in patients with arterial dissection.
Primary versus secondary RCVS Reversible cerebral vasoconstriction syndromes can be either pri- mary [12,13] or secondary to various factors [15]. An expanding list of possible etiologies of RCVS has been identified (TaBle 1) [1,12,15,17,29]. Primary RCVS is more common than previously thought. It is pos- sible that some of these patients could have certain etiologies that have remained unknown, and some could have certain unidenti- fied genetic predispositions that make them more susceptible. In this article, ‘primary RCVS’ is temporarily taken to cover all of the cryptogenic and idiopathic syndromes. In a prospective study of RCVS conducted in a hospital-based headache clinic in Taiwan, almost all of the patients have primary RCVS [12]. In another large-scale study from France, RCVS was primary in 37% of the study cohort [15]. Vasoactive substances as a group is the most com- mon incriminated secondary cause of RCVS, which accounts for half of the patients in both French and American studies [16,17]. Hence, a history of drug exposure should be sought in patients with RCVS. The three most common classes of vasoactive drugs are illicit drugs (such as cannabis, ecstasy, cocaine or amphetamine), selective serotonin-reuptake inhibitors and over-the-counter agents (nasal decongestants or diet pills) [16,17]. Postpartum state is the second common cause, which accounts for approximately 9% of the cases [16,17]. Immunosuppressants or cytotoxic agents are occa- sionally the culprits, and the diagnosis of RCVS should be kept in mind for patients who experience a sudden severe headache and are being treated with these medications.
Despite etiological heterogeneity, the clinical features of pri- mary or the various secondary RCVS are distinctively similar. Female predominance is a universal phenomenon among different
Box 1. Current diagnostic criteria of primary thunderclap headache and benign (or reversible) angiopathy of the CNS in the International Classification of Headache Disorders, 2nd Edition.
4.6 Primary thunderclap headache: A. Severe head pain fulfilling criteria B and C B. Both of the following characteristics: 1. Sudden onset, reaching maximum intensity in <1 min 2. Lasting from 1 h to 10 days C. Does not recur regularly over subsequent weeks or months D. Not attributed to another disorder 6.7.3 Headache attributed to benign (or reversible) angiopathy of the CNS: A. Diffuse, severe headache of abrupt or progressive onset, with or without focal neurological deficits and/or seizures and fulfilling criteria C and D B. ‘Strings and beads’ appearance on angiography and subarachnoid hemorrhage ruled out by appropriate investigations C. One or both of the following: 1. Headache develops simultaneously with neurological deficits and/or seizures 2. Headache leads to angiography and discovery of ‘strings and beads’ appearance D. Headache (and neurological deficits, if present) resolves spontaneously within 2 months
CME
Review Chen, Fuh & Wang
ethnic groups [12,15,17]. Most patients are middle-aged (mean age ~40–50 years), with the female patients being 10 years older than the male patients [12,15,17]. Pediatric patients are occasion- ally seen [17,30,31]. Headache characteristics were nearly identical in different studies [12,15,17]. Blood pressure surges (systolic blood pressure >160 mmHg) accompanying headache attacks were observed in more than a third of patients [12,14,15]. Despite great clinical resemblance, there are some debatable issues. It is uncertain whether those without any inciting factors have exactly the same ‘disease’ as those with known causes. It is reasonable to hypothesize that there are some shared common pathogenic pathways contrib- uting to the vasoconstrictions or TCH between those with primary and secondary ones. However, it is hard to believe that there are no specific biological effects exerted by these exposed substances [32] or humoral factors associated with puerperium [33,34] that distinguish the secondary ones from the primary ones. As knowledge evolves, we might be able to redefine or subclassify this ‘syndrome’ with mechanism- or pathophysiology-specific perspectives.
Complications of RCVS & ethnic differences Reversible cerebral vasoconstriction syndrome is not always benign. Patients with RCVS are complicated by transient ischemic attacks (up to 16%), PRES (9–14%), brain edema (38%), ischemic strokes (4–54%), cortical SAH (up to 34%), intracerebral hemorrhage (ICH; up to 20%) or subdural hemorrhage (2%) [1,12,15–17]. Figure 2 illustrates some of the complications. Patients with a mean flow velocity of greater than 120 m/s in the middle cerebral artery and a Lindegaard index of greater than 3 are associated with higher risks of PRES or ischemic stroke [13]. Female gender (odds ratio: 4.05) and history of migraine (odds ratio: 2.34) were two independent risk factors for hemorrhagic complications [16]. Seizures, either general- ized or focal, are noted in up to 21% of the patients [1,12,15,17]. Focal neurological deficits are found in 9–63% of the patients [1,12,15,17]. Permanent deficits were noted in 3–9% of patients in prospective series [14,16], and 9–29% in retrospective studies [17,35]. Mortality had been noted in a few patients [17]. Intracranial hemorrhage [16] or infarction [17] had been linked to poor outcome.
Table 1. Possible etiologies and associated conditions of reversible cerebral vasoconstriction syndrome.
General categories Specific entities
Secondary
Postpartum angiopathy (± use of vasoactive drugs) Eclampsia/preeclampsia
Vasoactive substances Illicit drugs: Cannabis, cocaine, ecstasy, amphetamines, LSD
Ergots: Ergotamine tartrate, methergine, methylergometrine, lisuride, bromocriptine
Sympathomimetics: Ephedrine, isometheptene, pseudoephedrine, diet pills, phenylpropanolamine
Serotonergic drugs: Selective serotonin-reuptake inhibitors, triptans
Immunosuppressants: Tacrolimus (FK-506), cyclophosphamide, IFN-a
Others: Nicotine patches, Ginseng, licorice, indomethacin, binge drinking, oral contraceptive pills, hormonal ovarian stimulation for intrauterine insemination
Catecholamine secreting tumors Pheochromocytoma, bronchial carcinoid tumor, glomus tumors
Extra- or intra-cranial arterial disorders or procedures
Cervical artery dissection, aortic dissection, unruptured intracranial aneurysm, fibromuscular dysplasia, postcarotid endarterectomy
Blood products Erythropoietin, intravenous immunoglobulin, massive blood transfusion
Intracranial disorders or surgery Intracranial hypotension, intracranial hemorrhage, spinal subdural hematoma, neurosurgery, head trauma
Miscellaneous Hypercalcemia, systemic lupus erythematosus, porphyria, microangiopathic hemolytic anemia, triplet cesarean delivery, ascent to high altitude, tonsillectomy, autonomic dysreflexia
LSD: Lysergic acid diethylamide.
ReviewReversible cerebral vasoconstriction syndrome: current & future perspectives
There are substantial proportional dif- ferences of complications between differ- ent series. One major factor that accounts for the differences could be the variance of patient population between institu- tions. Patients in the Taiwanese study were mostly recruited from headache clinics, and they rarely had secondary causes. The French cohort was recruited from an emergency headache center and a stroke unit. Whereas, the patients in the American study were mostly referrals and inpatients that were more likely to harbor brain lesions. Ethnic predisposi- tion could be another important issue. A recent study provided circumferential support. It was found that patients carrying the Val allele of BDNF Val66Met poly- morphism were more likely to have more severe vasoconstric- tions than Met homozygotes [18]. The frequency of the Met66 allele is considerably low in African or Caucasian populations, but higher in Asian populations [36]. Although the BDNF gene could not represent all of the genetic variance that might influ- ent severity of RCVS [18], the results of this study might indi- cate that patients in Western countries are more vulnerable to severe vasoconstrictions, and therefore more complications, than Asian patients. Nonetheless, prospective studies are required to investigate whether Caucasian or African individuals are more likely to have hemorrhagic complications than Asian individu- als after stringently controlling variables such as demographics, extent and duration of exposure to precipitating factors, disease duration and therapeutic interventions.
Diagnostic work-up & criteria for RCVS Brain magnetic resonance (MR) images, including angiography and venography, are methods of choice for studies of RCVS [14]. For differential diagnosis and the evaluation of complications, the MR sequences should include T1, T2, fluid-attenuated inversion-recovery imaging, gradient-echo (T2*) imaging, diffusion-weighted imaging and apparent diffusion coeffi- cient mapping [11]. Cervical MRI, including T1 fat-saturation sequence with contrast, should be considered if cervical artery dissection is suspected. Transcranial color-coded sonography can be used to monitor the hemodynamic changes and pre- dict risks of ischemic complications in patients with RCVS [13]. Cerebrospinal fluid (CSF) study is appropriate to exclude SAH, infection or inflammation of the CNS, but in our experience, it seldom increases diagnostic yield when a patient has experienced multiple TCHs and magnetic resonance angiography (MRA) has demonstrated multifocal segmental vasoconstrictions in the absence of neck stiffness.
An angiographic study to demonstrate cerebral vasoconstric- tions and their reversibility is the essential component for diag- nosing RCVS. Vasoconstrictions in RCVS are usually pervasive and have outlasted headache resolution [13–16], so that regular follow-up beyond remission of TCH is required. Centripetal
progression of vasoconstriction was proposed [15], but we observed this phenomenon in some, but not all, patients [14]. Conventional angiography is the gold standard [1]; however, it is invasive and not feasible for frequent follow-ups [37]. In one large series, up to 9% of patients experienced transient neurological deficits after catheter angio graphy [15]. Hence, we suggest that catheter angi- ography should only be reserved for those with diagnostic dif- ficulties. By contrast, MRA is noninvasive and valid in studying vasoconstrictions in RCVS [14]. Computed tomography angiog- raphy (CTA) could also be a useful tool in evaluating vasocon- strictions in RCVS. However, radiation exposure and potential effects of contrast medium prevent patients from undergoing frequent follow-ups.
A major radiological differential diagnosis of RCVS is primary angiitis of the CNS (PACNS). As RCVS and PACNS could both involve small and large intracranial vessels [14,38], it is difficult to differentiate these two syndromes solely by angiographic findings. The best clinical indicator to differentiate the two is that repeti- tive TCHs have never been reported in PACNS. Complications including PRES, brain infarcts and hemorrhages are typically located in watershed zones (Figure 2) [4,14,17]. On the other hand, when seeing a patient with intracranial hemorrhage distributed over the watershed zones, physicians should keep the diagnosis of RCVS in mind. The occurrence of these complications could outlast headache resolution [13,14,16]. Cortical SAH, presumably resulting from minor leaks or rupture of surface vessels, is usually minimal, overlying a few cortical sulci, with disproportionate widespread short-segmental vasoconstriction [15]. By contrast, the delayed vasospasm in aneurismal SAH is usually long-segmen- tal and has a close spatial relationship with the bleeding site [1]. Linear, serpentine or dot-like distal hyperintense vessels over the cortical sulci on fluid-attenuated inversion-recovery imaging should be differentiated from cortical SAH. These hyperintense vessels could be noted in 22% of patients in our experience and up to 70% in an American cohort [17].
Prior to the proposal of RCVS being the unifying term, the ICHD-II proposed diagnostic criteria for BACNS (code 6.7.3) (Box 1) [20]. Calabrese et al. also summarized the critical elements for the diagnosis of RCVS (Box 2) [1]. Most cases with RCVS could fulfill these criteria. However, such criteria are not
Figure 2. Complications of reversible cerebral vasoconstriction syndromes. (A) Posterior reversible encephalopathy syndrome; (B) cerebral infarction; (C) intracerebral…