Reversible cerebral vasoconstriction syndrome: current and ...migrainequebec.com/wp-content/uploads/2016/05/PDFs_chen_rcvs_thunderclap_2011.pdfReversible cerebral vasoconstriction

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www.expert-reviews.com ISSN 1473-7175© 2011 Expert Reviews Ltd10.1586/ERN.11.112

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)

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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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Expert Rev. Neurother. 11(9), (2011)1266

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 headacheThe 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 disclosureEditorElisa Manzotti, Editorial Director, Future Science Group, London, UK Disclosure: Elisa Manzotti has disclosed no relevant financial relationships.CME AuthorLaurie Barclay, MD, Freelance writer and reviewer, Medscape, LLCDisclosure: Laurie Barclay, MD, has disclosed no relevant financial relationships.AuthorsShih-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, TaiwanDisclosure: 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, TaiwanDisclosure: 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, TaiwanDisclosure: 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).

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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 RCVSReversible 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 CB. Both of the following characteristics: 1. Sudden onset, reaching maximum intensity in <1 min 2. Lasting from 1 h to 10 daysC. Does not recur regularly over subsequent weeks or monthsD. Not attributed to another disorder6.7.3 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 DB. ‘Strings and beads’ appearance on angiography and subarachnoid hemorrhage ruled out by appropriate investigationsC. 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’ appearanceD. Headache (and neurological deficits, if present) resolves spontaneously within 2 months

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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

Primary

Spontaneous or evoked by triggers Primary thunderclap headache Exertional headacheHeadache associated with sexual activity Cough headache Bath-related thunderclap headache

Secondary

Pregnancy and the postpartum period

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.

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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 RCVSBrain 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 hemorrhage.

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yet satisfactory and inclusive enough. Based on our experiences, we proposed that CSF studies might not be a requisite element if the patient has experienced multiple TCHs and had character-istic angiographic findings. In addition, the duration criterion of reversibility needs to be modified. Vasoconstrictions in most patients normalized within 3 months; however, we have noticed that some patients ran a more protracted course. If the vaso-constrictions had improved greatly by 3 months, even though not completely normalized, ‘reversibility’ could still be claimed. There are also some patients with atypical presentation, such as those without recallable ‘acute severe headaches’ [17] or with relapse dur-ing follow-up [14,39]. Further elaboration to cover these cases is necessary when revising the criteria in the future.

Pathophysiology of RCVSThe exact pathophysiology of RCVS remains unknown. As the etiologies of RCVS are heterogeneous, the underlying mecha-nisms are probably multifactorial. With accumulating data, there are some proposed pathophysiological mechanisms (briefly summarized in Figure 3).

Dysfunctional regulation of cerebral vascular tone might be the central element in the pathogenesis of RCVS. A sud-den alteration of central vascular tone may lead to segmental vasoconstriction and vasodilatation in small vessels and trigger TCH by abruptly stretching vessel walls at the initial stage of RCVS [16]. Aberrant sympathetic response of cerebral vascula-ture is a preferred hypothesis [37]. Blood pressure surge [12,15], triggers with elevated sympathetic tone [12,15], ingestion of sym-pathomimetic vasoactive substances [10,14,15,17], pheochromo-cytoma [40–42] and acute hypertensive crises [43] all support the role of sympathetic overactivity. In addition, it is hypothesized that some of the immunologic and biochemical factors known to regulate vascular tone in the delayed vasospasm in SAH might also be important in the pathophysio logy of vasocon-striction in RCVS [44–46], although direct evidences are lacking. Recently, the BDNF Val66Met polymorphism has been linked to vaso constriction in patients with RCVS [18]. In animal stud-ies, BDNF is found to cause perivascular inflammation and vasoconstriction under circumstances of sympathetic overactiv-ity [47]. BDNF could also upregulate neuropeptide Y, a vasocon-strictive sympathetic cotransmitter [48]. Furthermore, we have recently noticed that urine levels of 8-iso-PGF2a were higher in patients with RCVS than patients with other severe headache

or normal control [49]. A role of oxidative stress and endothelial dysfunction in the pathogenesis of vascular tone regulation in RCVS is highly plausible.

Posterior reversible encephalopathy syndrome is found in a sub-stantial proportion of patients with RCVS [4,13,14,16,17], and up to 87% of patients with PRES were found to have diffuse vaso-constriction, focal vasculopathy or vessel pruning [50]. Besides, acute severe headaches are not uncommon in patients with PRES. Immunosuppressive or cytotoxic agents that might cause RCVS are frequently reported in PRES [51]. A shared pathophysiology between these two overlapping syndromes is highly probable. Blood pressure surge is observed in nearly half of patients with RCVS [14], which might result from underlying sympathetic over-activity or a stress response to the excruciating headaches. As hypertensive encephalopathy constitutes a substantial proportion of PRES [51], it is also possible that the abrupt blood pressure elevation could be an active player in the pathogenesis of PRES in RCVS. It is hypothesized that in PRES, the autoregulation is impaired. The endothelial control of arteriolar vascular tone is overwhelmed, which leads to a vicious cycle of homeostatic failure and progressive increase in vascular resistance. Increased vascular permeability ensues, which contributes to the vasogenic edema in PRES [50,51]. The progressive increase of vascular resistance results in diffuse vasoconstriction. When vasoconstrictions become severe and involve more proximal vessels, irreversible ischemic change over the watershed zones develops [4,50]. In line with this concept, we recently found that severe vasoconstrictions in the M1 segment of middle cerebral artery and P2 segment of posterior cerebral artery were associated with a higher risk of PRES and ischemic stroke in patients with RCVS [14].

Postpartum angiopathy, one of the secondary RCVS, has many overlapping clinical, laboratory and radiographical features with eclampsia and preeclampsia. These disorders might belong to the same disease spectrum and have some shared pathophysio logical mechanisms [29,52,53]. It was demonstrated that placental growth factor (PlGF), soluble PlGF receptor (sFlt-1) [33,34] and a soluble TGF-b1 receptor (soluble endoglin) [54] correlate with the presence of eclampsia. The ratio of sFlt-1 to PLGF could also be used to pre-dict the occurrence of preeclampsia [34]. A recent case report sug-gested that the balance of these antiangiogenic and proangiogenic factors could also play a role in the pathogenesis of postpartum angiopathy [55]. However, these mechanisms maynot be applicable to those who are not pregnant or being in the puerperium.

Box 2. Summary of critical elements for the diagnosis of reversible cerebral vasoconstriction syndromes proposed by Calabrese et al.

A. Transfemoral angiography or indirect computed tomography angiography or magnetic resonance angiography documenting multifocal segmental cerebral artery vasoconstrictionB. No evidence for aneurysmal subarachnoid hemorrhageC. Normal or near-normal cerebrospinal fluid ana lysis (protein level <80 mg/dl, leukocytes <10 mm3 and normal glucose level)D. Severe, acute headaches, with or without additional neurologic signs or symptomsE. 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 subarachnoid hemorrhage, which can also manifest with headache and stroke

Taken from [1].

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A recent retrospective study reported that up to 17% of the studied patients received open-brain biopsy or full autopsy [17]. Extensive histological studies demonstrated no evidence of arte-rial inflammation or infection. One case report that detailed both histological and electron-microscopical examinations showed that major cerebral arteries were normal except for a patch of sub-endothelial thickening in the posterior cerebral artery [55]. No specific morphologic abnormalities were found to correlate with the vasoconstrictions.

Therapeutic strategies Reversible cerebral vasoconstriction syndromes should be treated as an emergent condition. Neuroimaging studies or lumbar puncture should be carried out as soon as possible. Withdrawal of secondary causes and avoidance of triggers are the first things to enact. No pharmacological treatment has gained enough evi-dence. Glucocorticoids were recently shown to be independent predictors of a poor outcome [17], and thus their use is not recom-mended. A recent case report demonstrated that indomethacin might cause reversible cerebral vasoconstriction phenomena, and should be used with caution in acute treatment of head-ache [56]. The calcium-channel blocker nimodipine has been shown to be effective in aborting the headaches in 64–83% of patients in open-label series [12,15,57]. A recent retrospective study demonstrated that monotherapy with calcium-channel

blockers is associated with good outcome [17]. In our clinical practice, most patients were given oral nimodipine (30–60 mg every 4 h) or intravenous nimodipine (0.5–2 mg/h), based on the effectiveness of headache abortion, severity or progression of vasoconstrictions, or presence of PRES or ischemic stroke. A suggested diagnostic and therapeutic workflow is illustrated in Figure 4. However, it should be stressed that not every patient can benefit from nimodipine and dose escalation may worsen the condition in some patients [15]. In our practice, we monitored blood pressure every 2 to 4 h when parenteral treatment was required. If hypotension (systolic blood pressure <100 mmHg) occurred, it should be corrected immediately by dose tapering or normal saline hydration. None of our patients had experienced complications from this practice.

Other calcium-channel blockers, such as nicardipine [31] or verapmil [58], have been shown effective in case reports. Magnesium sulfate has been attempted in a small subset of patients with post-partum angiography, with acceptable outcomes [59]. Intravenous prostacyclin is effective in one case report [60]. Intra-arterial nimodipine [61–63], verapamil [64] or the phosphodiesterase inhibi-tor milrinone [58] had been employed in some cases with refractory vasoconstrictions, with satisfactory outcomes. However, risk of reperfusion injury after intra-arterial intervention should be con-sidered [55]. It is uncertain how long the therapy should be main-tained. As the risks of ischemic stroke or PRES outlast headache

Predisposition

Genes (Val66 BDNF),female gender

Precipitating factorsVasoactive substances,pregnancy/pospartum,

triggers

Catecholamines, vasoconstrictive prostaglandins,proangiogenic factors, proinflammatory cytokines

Cerebral vascular tone dysregulation

TCHVasoconstriction

Vasodilatation

Borderzone hypoperfusionIschemic infarct

PRESICH

cSAH

Autoregulation failureBBB breakdown

Sympathetic overactivity Endothelial dysfunction Oxidative stress

Figure 3. Proposed pathophysiology of reversible cerebral vasoconstriction syndromes. cSAH: Cortical subarachnoid hemorrhage, ICH: Intracerebral hemorrhage; PRES: Posterior reversible encephalopathy syndrome; TCH: Thunderclap headache.

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resolution [13,14], maintenance therapy beyond headache resolu-tion is warranted. In our practice, we continue to treat the patient until complete or nearly complete normalization of vasoconstric-tions were observed. To explore the actual efficacy of these drugs, prospective randomized placebo-controlled trials are required. Study efficacy end points may reasonably include the number and frequency of thunderclap headaches, severity of vasoconstrictions (by flow velocity or MRA vasoconstriction scores) and incidences of ischemic and hemorrhagic complications.

ConclusionReversible cerebral vasoconstriction syndrome is a potentially devastating syndrome that has been increasingly recognized in recent years. The clinical features and angiographic findings of this clinical emergency are distinctive. When encountering a patient with the clinical hallmark of ‘recurrent TCHs’, looking for its counterpart ‘reversible cerebral vasoconstrictions’ is manda-tory. Primary TCH and RCVS are considered spectra of the same disorder; even if there is no initial vasoconstriction, a follow-up angiographic study should be performed. Vasoconstrictions tend to outlast headache resolutions, and contribute to risks of ischemic complications. Complications including PRES, ischemic strokes or intracranial hemorrhage are highly prevalent and associated with poor prognosis. The diagnostic criteria are not yet satisfac-tory and require further refinement. Possible pathophysiology includes sympathetic overactivity, oxidative stress, endothelial dysfunction and imbalance of proangiogenic and antiangiogenic factors. Nimodipine might be effective for TCHs in RCVS, but randomized placebo-controlled trials are still required to establish optimal treatment strategies.

Expert commentaryIt was only less than 5 years since the proposal of RCVS as a unifying term for a group of syndromes. Many physicians still have limited knowledge about this clinco–radiological syndrome, even though this syndrome can actually be encountered in multiple specialties. RCVS is still in the process of being defined, but large series from different countries supported that this syndrome is globally prevalent [12–18]. The clinical presentation of RCVS has been better characterized, but it is still under-recognized. The etiological heterogeneity and controversies of spectral or overlapping disorders make it difficult to establish gold-standard criteria. Using the contemporary term RCVS is appropriate to improve the recognition of this syndrome and to iden-tify more patients. However, we propose that an etiol ogy-specific subgrouping from the seemingly unrelated and diverse range of causes might be more reasonable to understand the essence of disease nature and explore disease-targeting therapy.

Dividing the patients into primary and secondary RCVS is the very initial thing that we can do at the present time.

Prospective randomized placebo-controlled trials to evaluate the efficacy of nimodipine is important, since it is currently the most commonly employed treatment. Because the complication rate of RCVS is considerably high, putting patients into clini-cal trials, obtaining consents, choice of study end points and criteria for drop-outs and unblinding all involve tough ethical issues. Collaboration studies from multiple centers are preferred to increase study power and generalizability. This can serve as a platform for exploring the safety and efficacy of future disease-targeting therapy.

Five-year viewTo date, research on the complications of RCVS has shown large interpopulation variability, and those regarding the pathophysiol-ogy and treatment are still in paucity. We propose several avenues for study in the next 5 years.

Biomarkers in establishing the diagnosis & monitoring the courseReversible cerebral vasoconstriction syndromes are conditions where diagnosis cannot definitively be made in the acute stage (awaiting for reversibility of vasoconstrictions), but treatment should be implemented as soon as possible. The diagnostic criteria should also be refined to clarify the significance and necessity of ‘reversibility’. An expert committee is required to reach a consensus. On the other hand, identifying disease-specific biomarkers that can help diagnose the syndrome as early as possible, such as in the early stage, is imperative. The difficulty in identifying a disease-specific

Thunderclap headache

Mildvasoconstrictions

First attack

Brain CT±CSF studies

SAHRCVS

Oral CCB iv. or ia. CCB

Avoid triggers/precipitating factors

Worsened TCH/vasoconstrictions

Severe vasoconstrictionsor hypertensive crisis

Other intracranial disorders:• Intracerebral hemorrhage• Carotid/vertebral artery dissection• Unruptured aneurysm• Venous sinus thrombosis• Intracranial hypotension• Pituitary apoplexy

Multipleattacks

Brain MRI + MRA + MRV ± TCCS ± CSF studies

Figure 4. Algorithm of diagnosis and treatment of thunderclap headache.CCB: Calcium-channel blockers; CSF: Cerebrospinal fluid; CT: Computed tomography; ia.: Intra-arterial; iv.: Intravenous; MRA: Magnetic resonance angiography; MRV: Magnetic resonance venography; RCVS: Reversible cerebral vasoconstriction syndromes; SAH: Subarachnoid hemorrhage; TCCS: Transcranial color-coded sonography; TCH: Thunderclap headache.

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biomarker and exploring the complex pathophysiology in such an enigmatic syndrome is that it is like searching for a needle in the haystack. Future research using system biology techniques, such as genomics, proteomics or metabolomics, are probably more effi-cient and holistic than hypothesis-driven approach. Analyzing the pattern differences will also be helpful for mechanism-based sub-grouping of this syndrome. Based on the study results, it might be possible to develop animal models of this syndrome.

Distribution & evolution of the vasoconstrictionA goal of future investigations could also be the ana lysis of the distribution and evolution of segmental vasoconstrictions using high-field MR equipment. Whether there is really a centripetal evolution is of interest. Investigating the more distal arteries and even arterioles in the early stage of disease is crucial to answer this question and important in elucidating the pathogenesis of the disease. In addition, whether patients with RCVS also have an increased risk of extracranial or systemic vasoconstrictions remains unexplored. A systematic investigation is required.

Hemorrhagic complicationsProspective studies on hemorrhagic complications are required to explore whether the discrepancy of complication rate is intrinsi-cally owing to the difference of study population or ethnic pre-disposition. Future studies might examine the prevalence of vasoconstrictions among intracranial hemorrhages in the general population and analyze the pattern of hemorrhage between those with and without vasoconstrictions.

Risk factorsThe association of drugs with RCVS requires further elabora-tion. To date, most of the associations are derived from obser-vational studies. Case–control or prospective trials are needed to evaluate whether these drug associations hold up in com-parison to female predominant populations with other forms of headaches. Some pathological mechanisms, such as genetic polymorphism or external triggers, still need to be identified in patients with RCVS with unknown etiologies. BDNF Val66Met polymorphism may affect the degree of vasoconstrictions, but is not associated with the risks of developing RCVS [18], suggest-ing that there could be some other genetic or epigenetic factors contributing to disease susceptibility. Although the phenotype is distinct, RCVS is more likely to be a complex disease than a monogenic disorder following Mendenlian inheritance. A genome-wide approach is a more appropriate method, but the required case number to reach adequate statistical power is a great concern.

Potential therapeutic agentsA last issue for research concerns potential trials of therapeu-tic agents. Therapies that are tailored to the underlying causes, mechanisms or genetic predisposition will be a trend. Whether these approaches can effectively reduce the ischemic or hemor-rhagic complications should be proved by well-designed clini-cal trials. Based on currently available information, we speculate that therapies targeting on the restoration of endothelial function might be promising and deserves further explorations.

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Key issues

• Reversible cerebral vasoconstriction syndromes (RCVS) are comprised of diverse conditions characterized by repetitive thunderclap headaches and reversible cerebral vasoconstrictions.

• Primary thunderclap headache and RCVS belong to the same disease spectrum.

• RCVS can be either primary or evoked by various factors, such as puerperium or exposure to vasoactive substances.

• Up to 80% of sufferers have identifiable triggers, such as Valsalva-like maneuvers (exertion, defecation and sex), bathing and emotional disturbance.

• Thunderclap headaches recur for a period of approximately 2 weeks, while the vasoconstrictions are pervasive and may last for months.

• Complications include posterior reversible encephalopathy syndrome, ischemic stroke and intracranial hemorrhage (intracerebral hemorrhage, cortical subarachnoid hemorrhage and subdural hemorrhage).

• The severity of vasoconstrictions determines the risk of ischemic complications. Migraine and female gender are risk factors for hemorrhagic complications.

• Dysregulation of cerebral vascular tone is central to the pathophysiology. Overlapping syndromes, such as posterior reversible encephalopathy syndrome and eclampsia, suggest possible pathogenic mechanisms.

• Treatment is empirical and includes calcium-channel blockers. Glucocorticoids may be harmful.

• Most patients recover well. Cerebral infarction and hemorrhagic complications are predictive of permanent neurological deficits.

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Reversible cerebral vasoconstriction syndrome: current and future perspectives

1. Your patient is a 53-year-old man seen in the emergency department for what he describes as “the worst headache of his life,” which came on suddenly and without apparent trigger. On the basis of the above review by Dr. Chen and colleagues, which of the following statements about the presentation and diagnosis is most likely correct?

£ A The headache reaching maximal intensity within 1 hour would be characteristic of thunderclap headache (TCH)

£ B If his presentation is consistent with TCH, a neuroimaging study is not necessary

£ C Primary TCH and reversible cerebral vasoconstriction syndrome (RCVS) are considered spectra of the same disorder

£ D For primary TCH without initial vasoconstriction, follow-up angiography is unnecessary

3. The patient described in question 1 is diagnosed with RCVS. Per the review by Dr. Chen and colleagues, which of the following statements is most likely to apply to his treatment?

£ A Treatment is empiric and includes calcium-channel blockers

£ B Optimal dosing regimen and duration of treatment with nimodipine are well defined according to randomized, placebo-controlled trials

£ C Glucocorticoids have been proven to be effective in RCVS

£ D Blood pressure monitoring is not necessary with intravenous nimodipine

2. On the basis of the review by Dr. Chen and colleagues, which of the following statements about the pathophysiology and complications of RCVS is most likely correct?

£ A Vasoconstriction typically resolves spontaneously in a few hours

£ B Most patients with RCVS have no identifiable triggers

£ C Complications of posterior reversible encephalopathy syndrome (PRES), ischemic stroke, and intracranial hemorrhage are rare

£ D Possible pathophysiology includes sympathetic overactivity, oxidative stress, endothelial dysfunction, and imbalance of proangiogenic and antiangiogenic factors

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