Handbook of Clinical Neurology, Vol. 121 (3rd series) Neurologic Aspects of Systemic Disease Part III Jose Biller and Jose M. Ferro, Editors © 2014 Elsevier B.V. All rights reserved

Chapter 111

Reversible cerebral vasoconstriction syndrome ANNE DUCROS* Department of Neurology, Hoˆpital Gui de Chauliac, Montpellier, France

HISTORY AND TERMINOLOGY Reversible cerebral vasoconstriction syndrome is a clinical-radiologic syndrome characterized by severe headaches with or without additional neurologic symptoms, and multifocal constriction of cerebral arteries, which resolves spontaneously in 1–3 months (Headache Classification Subcommittee of the International Headache Society, 2004; Calabrese et al., 2007). The most common clinical feature is recurrent thunderclap headache – a sudden excruciating headache that peaks in less than 1 minute – over 1–2 weeks (Chen et al., 2006a; Ducros et al., 2007). The major complications are ischemic or hemorrhagic parenchymal strokes (9–39%) (Singhal et al., 2002, 2011; Ducros et al., 2007, 2010; Chen et al., 2010). Reversible cerebral vasoconstriction syndrome (RCVS) is the name proposed in 2007 by Calabrese et al. to regroup all similar cases reported over the years under many different appellations (Table 111.1) (Calabrese et al., 2007). These various eponyms each reflected the associated clinical setting or the presumed pathophysiology, for example, migrainous “vasospasm” or “angiitis” (Serdaru et al., 1984; Jackson et al., 1993), thunderclap headache with reversible vasospasm (Day and Raskin, 1986; Slivka and Philbrook, 1995; Dodick et al., 1999), postpartum cerebral angiopathy, angiitis, or vasospasm (Bogousslavsky et al., 1989; Barinagarrementeria et al., 1992; Yasuda et al., 1993), drug-induced cerebral arteritis or angiopathy (Raroque et al., 1993; Ryu and Chien, 1995; Ryu and Lin, 1995), Call or Call–Fleming syndrome(Call et al., 1988), central nervous system (CNS) pseudovasculitis (Razavi et al., 1999), and benign angiopathy of the central nervous system (Rousseaux et al., 1983; Geraud and Fabre, 1984; Calabrese et al., 1993). Indeed, RCVS has long been viewed completely differently by the various concerned specialists, most likely due to its broad clinical and radiologic spectrum, ranging from purely

cephalalgic forms to catastrophic forms with multiple strokes causing permanent sequelae, and even death (Dodick et al., 1999; Singhal et al., 2002; Singhal, 2004a; Williams et al., 2007). Cerebral vasopasm was historically thought to be the major cause of stroke, until pathologic studies from the 1950s onwards demonstrated that cerebral infarcts were mainly caused by obstructive arterial lesions such as carotid atherosclerosis, lipohyalinosis. and cardioembolism. Thereafter, “vasospasm” was forgotten by stroke specialists except for those dealing with aneurysmal subarachnoid hemorrhage. Fisher first described the phenomenon of reversible segmental cerebral vasoconstriction in the early 1970s, in a paper reporting cases of postpartum women with transient neurologic dysfunction associated with reversible cerebral arterial irregularities (Fisher, 1971). Five other similar cases were reported in France (Millikan, 1975; Rascol et al., 1979) and the entity became known as “postpartum angiopathy.” Over the next decade, similar cases were documented in association with such diverse conditions as pregnancy (Bogousslavsky et al., 1989), migraine (Jackson et al., 1993), vasoconstrictive drugs and medications (Raroque et al., 1993), neurosurgical procedures (Suwanwela and Suwanwela, 1972), hypercalcemia (Yarnell and Caplan, 1986), and even unruptured saccular aneurysms (Day and Raskin, 1986). In the early 1980s, two small series of patients were reported in the French literature (Rousseaux et al., 1983; Michel et al., 1985). In the English litterature, the first large series of 19 patients was published in 1998 (Call et al., 1988) and some authors still refer to this syndrome as “Call’s or Call–Fleming syndrome” (Dodick, 2003; Nowak et al., 2003). Meanwhile, patients with RCVS were being misinterpreted as having primary angiitis of the central nervous system (PACNS), an inflammatory condition affecting

*Correspondence to: Anne Ducros, Urgences Ce´phale´es, Hoˆpital Lariboisie`re, 2 rue Ambroise Pare´, 75475 Paris, Cedex 10, France. Tel: þ33-1-49-95-65-37, Fax: þ33-1-49-95-24-81, E-mail: [email protected]

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A. DUCROS

Table 111.1 Various names used to describe the reversible cerebral vasoconstriction syndrome Isolated benign cerebral vasculitis or angiopathy Call or Call–Fleming syndrome Central nervous system pseudovasculitis Benign angiopathy of the central nervous system (BACNS) Postpartum angiopathy Postpartum angiitis Migrainous vasospasm Migraine angiitis Idiopathic thunderclap headache with reversible vasospam Drug-induced cerebral arteritis or angiopathy Fatal vasospasm in migrainous infarction

brain arteries, because of overlapping angiographic as well as clinical features such as headache, seizures, and stroke (Snyder and McClelland, 1978; Bettoni et al., 1984). Calabrese and colleagues recognized that these patients did not exhibit the typical severe and progressive course of PACNS; instead, their angiographic abnormalities reversed promptly and clinical resolution occurred within weeks, even without immunosuppressive therapy (Calabrese et al., 1993). They suspected a transient or mild form of PACNS, and the term “benign angiopathy of the central nervous system” (BACNS) was proposed. Calabrese’s group subsequently analyzed the clinical characteristics and longterm outcomes of BACNS, and concluded that it is consistent with RCVS (Hajj-Ali et al., 2002; Hajj-Ali and Calabrese, 2009). Some years later, patients with the pure cephalalgic form of RCVS were considered as having a variety of primary headaches – i.e., headaches spontaneously produced by the activation of cerebral/cranial pain circuits without an underlying lesion (Slivka and Philbrook, 1995; Dodick et al., 1999; Dodick, 2002; Liao et al., 2003; Lu et al., 2004; Chen et al., 2006a). Indeed, many patients with RCVS have isolated recurrent thunderclap headaches over 1–2 weeks and a benign course. An entity called “primary thunderclap headaches” was even introduced in the second version of the International Classification of Headache Disorders (Headache Classification Subcommittee of the International Headache Society, 2004). During the last 5–10 years, RCVS has been increasingly recognized as a distinct syndrome due to a transient and reversible disturbance of arterial tone regulation, without inflammation of the arteries, mainly characterized by severe headaches, which are secondary and symptomatic of the underlying vascular abnormality. The recent proposal and adoption of the broad term RCVS has encouraged retrospective and prospective studies that have helped to characterize RCVS (Ducros

et al., 2007, 2010; Chen et al., 2008, 2010; Singhal et al., 2011). The now routine use of relatively noninvasive angiographic techniques such as computed tomography angiography (CTA) and magnetic resonance angiography (MRA), combined with the widespread use of illicit drugs, and serotonergic and sympathomimetic medications, makes it likely that stroke neurologists and other specialists will encounter an increasing number of patients with this syndrome. However, the debate about RCVS is not extinguished. Indeed, recent studies confirmed the “historical” observation (Rousseaux et al., 1983) that hemorrhagic manifestations, such as cortical subarachnoid hemorrhage, intracerebral and subdural hematoma, were as least as frequent as ischemic infarcts in RCVS (Nighoghossian et al., 1998; Roh and Park, 1998; Ursell et al., 1998; Veyrac et al., 2001; Geocadin et al., 2002; Edlow et al., 2007; Moskowitz et al., 2007; Moustafa et al., 2008; Santos et al., 2009; Wong et al., 2009; Ducros et al., 2010) but some are still reluctant to attribute an intracranial hemorrhage to RCVS and rather consider the arterial narrowings as a consequence of hemorrhage.

ASSOCIATED CONDITIONS RCVS may be spontaneous (so-called idiopathic RCVS). In the remaining 25–60% of cases, RCVS occurs in peculiar settings or with associated conditions (secondary RCVS), mostly after exposure to vasoactive substances and/or in the postpartum state (Table 111.2) (Hajj-Ali et al., 2002; Calabrese et al., 2007; Ducros et al., 2007; Williams et al., 2007; Singhal et al., 2011). The incriminated substances include various medications such as selective serotonin reuptake inhibitors (Singhal et al., 2002; Noskin et al., 2006) and all a-sympathomimetics (Singhal, 2004a), often used as over-the-counter nasal decongestants (Ryu and Lin, 1995; Cantu et al., 2003), some diet pills and herbal medications (Worrall et al., 2005; Ichiki et al., 2008), and most illicit drugs (Martin et al., 1995), including cannabis (Alvaro et al., 2002; Koopman et al., 2008), which is the most frequent cause in France (Ducros et al., 2007) (Table 111.2). In some patients, RCVS occurs only after a few days of exposure, while in others, the syndrome occurs after several months of either regular or irregular exposure to one or several of these substances, at normal or excessive doses. Acute alcoholic intoxication may be an additional precipitating factor (Ducros et al., 2007). Postpartum RCVS starts in two-thirds of cases during the first week after delivery, usually after a normal pregnancy (Singhal, 2004b; Singhal and Bernstein, 2005; Williams et al., 2007). In 50–70% of the cases, it is associated with the intake of vasoconstrictors, mostly

REVERSIBLE CEREBRAL VASOCONSTRICTION SYNDROME Table 111.2 Causes of reversible cerebral vasoconstriction syndrome and associated conditions Postpartum With or without exposure to vasoactive substances, eclampsia/pre-eclampsia Exposure to vasoactive substances Cannabis, cocaine, ecstasy, amphetamines, LSD, binge drinking Selective serotonin reuptake inhibitor antidepressants (SSRIs) Nasal decongestants – phenylpropanolamine, pseudoephedrine, ephedrine Acute migraine medications – ergotamine tartrate, triptans Methergine Bromocriptine, lisuride Isometheptine Nicotine patches Ginseng Catecholamine-secreting tumors Pheochromocytoma, bronchial carcinoid tumor, glomus tumors Exposure to immunosuppressants or blood products Tacrolimus (FK-506), cyclophosphamide, erythropoietin, intravenous immunoglobulin, red blood cell transfusion, interferon-a Miscellaneous Hypercalcemia, porphyria, head trauma, subdural spinal hematoma, carotid endarterectomy, neurosurgical procedures, CSF hypotension Extra- or intracranial large artery disorders Cervical dissection, unruptured intracranial aneurysm, dysplasia

ergots – bromocriptine – used to treat postpartum hemorrhage or to inhibit lactation (Williams et al., 2007). Myriads of other causes have been reported, such as catecholamine-secreting tumors (Razavi et al., 1999), head trauma (Wilkins and Odom, 1970; Suwanwela and Suwanwela, 1972; Lee et al., 1997), neurosurgical procedures (Khodadad, 1973; Hyde-Rowan et al., 1983), carotid endarterectomy (Lopez-Valdes et al., 1997; Rosenbloom and Singhal, 2007), cerebrospinal fluid (CSF) hypotension (Schievink et al., 2007) and autonomic dysreflexia (Edvardsson and Persson, 2010) (Table 111.2). RCVS may also be associated with other extra- or intracranial arterial lesions such as cervical artery dissection (Singhal, 2004b; Ducros et al., 2007; Field et al., 2010; Mawet et al., 2013) especially in women with postpartum RCVS (Arnold et al., 2008), unruptured intracranial aneurysm (Day and Raskin, 1986; Ducros et al., 2007), and arterial dysplasia (Ducros et al., 2007). The mechanism of the link between these arterial abnormalities and the vasospastic process of RCVS is unknown.

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Overlap with the posterior reversible encephalopathy syndrome RCVS has also been reported in association with a neurotoxic state called the “posterior reversible encephalopathy syndrome” or PRES. This syndrome has similar clinical features to severe RCVS with acute headache, confusion, seizures, cortical blindness (Hinchey et al., 1996; Lee et al., 2008), but a characteristic MR imaging pattern with bilateral symmetric hemispheric boundary zones of high signal on FLAIR sequences affecting the cortex, and subcortical and deep white matter to varying degrees (Bartynski and Boardman, 2008). The vasogenic edema is usually totally reversible in a few days. However, infarction or cytotoxic edema may occur in areas of severe hypoperfusion (Chen et al., 2006b; Bartynski and Boardman, 2008). PRES is recognized as a complication of many conditions including pre-eclampsia/eclampsia, immunosuppression after transplantation, autoimmune disease, high-dose chemotherapy and septic shock (Bartynski et al., 2006; Bartynski et al., 2008; Lee et al., 2008). Like RCVS, the exact pathophysiology of PRES is unknown and two hypotheses are debated (Bartynski, 2008b). In the most popular one, severe arterial hypertension leads to a failure of cerebral autoregulation with subsequent hyperperfusion and vasogenic edema. In the emerging second hypothesis, T cell and/or endothelial cell activation may trigger cerebral vasoconstriction leading to hypoperfusion with subsequent brain ischemia and vasogenic edema. Whatever the pathophysiology, recent studies have shown that first, a reversible cerebral vasoconstriction is a frequent if not a constant feature of PRES; second, 20–30% of PRES cases are normotensive; and third, normotensive cases have vasogenic edema that is more extensive than hypertensive cases which suggests that hypertension may be a reaction to the increase in cerebral blood flow in some cases (Dodick et al., 2003; Chen et al., 2006b; Bartynski, 2008a, b). Besides the association of RCVS and PRES in the setting of severe conditions, it is important to appreciate that 10% of RCVS cases are associated with PRES regardless of the cause: idiopathic, secondary to a vasoactive substance or to the postpartum state, or associated with arterial dissection (Singhal, 2004b; Ducros et al., 2007).

CLINICAL FINDINGS Demographics RCVS has been reported in patients aged from 10 to 70 years (Kirton et al., 2006; Ducros et al., 2007; Liu et al., 2010). The mean age of onset is around 45 years with a female over male preponderance ranging from

1728 A. DUCROS 2 to 10:1 (Hajj-Ali et al., 2002; Ducros et al., 2007; one trigger factor: sexual activity with orgasmic or preorChen et al., 2010). gasmic headaches, straining, sudden emotion, exertion, The exact incidence is unknown. Cases have been coughing, sneezing, urinating without effort, bathing or documented from numerous countries from the five showering, and sudden bending down (Chen et al., continents (Barinagarrementeria et al., 1992; Modi and 2006a, 2010; Calabrese et al., 2007; Ducros et al., 2007, Modi, 2000; Ichiki et al., 2008; Bouchard et al., 2009; 2010). In some patients, all thunderclap headaches are Elstner et al., 2009; Garcin et al., 2009; Saini et al., triggered by one or several of these factors, while in other 2009; Field et al., 2010) and RCVS appears to affect indipatients, some thunderclap headaches occur at rest and viduals of all races. However, RCVS is probably still others after a trigger. Some patients have a single thunderunderdiagnosed, particularly the pure cephalalgic clap headache, but in most cases thunderclap headaches forms. Only three groups have published series including recur over the ensuing 1–3 weeks, with an average of four more than 10 patients. An American group published a recurrences (Ducros et al., 2007). retrospective series of 16 patients hospitalized for susSome patients describe acute headache attacks awakpected CNS angiitis, of whom 10 had a repeat angiograing them from sleep, a situation that does not allow them phy to assess reversibility of vasoconstriction (Hajj-Ali to be sure of the thunderclap onset. Rarely, the headache et al., 2002). This series was thereafter increased to 139 is more progressive and moderate. In the presence of latpatients retrospectively recruited from a stroke unit and eral or posterior neck pain, it is important to carefully an internal medicine department (Singhal et al., 2011). look for carotid or vertebral artery dissection (Ducros A Taiwanese group extensively studied RCVS first in a et al., 2007; Arnold et al., 2008; Mawet et al., 2013). prospective series of 56 patients with recurrent thunderclap headaches of whom 22 had proven initial vasoconFocal deficits and seizures striction (Chen et al., 2006a), then in a series of 77 patients with proven RCVS who were mainly recruited The frequency of other neurologic signs and symptoms depends on how the patients are recruited into the studies, through a headache centre for thunderclap headache is higher in retrospective in-patient series, and varies from (Chen et al., 2008, 2010). A French group (to which the author belongs) studied a prospective series of 67 cases, 9% to 63% for focal deficits, and for seizures from 0% to seen in a single institution between 2004 and 2007, who 21% (Hajj-Ali et al., 2002; Calabrese et al., 2007; Ducros all had an initial demonstration of the vasoconstriction et al., 2007, 2010; Chen et al., 2010; Singhal et al., 2011). and repeat angiography showing its resolution (Ducros Indeed, the presence of such features systematically leads et al., 2007). This series was subsequently completed to extensive investigations, whereas isolated headaches reaching 89 patients (Ducros et al., 2010), than patients are often misinterpreted as “benign” and not thoroughly explored (even though for a thunderclap headache a nor(Mawet et al., 2013). mal CT scan should be followed by a lumbar puncture to look for blood in the CSF followed often by imaging of the Headache cervical and cerebral arteries and the intracranial veins). Headache is often the only symptom, as in 75% of the Whereas generalized tonic-clonic seizures are reported French series (Ducros et al., 2007). The onset is typically in up to 20% of patients at the time of presentation, recurdramatic with a thunderclap headache, a “worst-ever” rent seizures are rare. Some transient focal deficits have a headache that reaches its peak intensity in less than sudden onset, such as transient ischemic attacks (TIAs), 1 minute, often within seconds. Multiple thunderclap while others begin progressively and successively over a headaches recurring every day or so over 1–4 weeks few minutes, with positive visual and/or sensory sympare almost pathognomonic (Chen et al., 2006a, 2008; toms, mimicking migraine aura (Ducros et al., 2007). Ducros et al., 2007). Persistent focal deficits reveal a stroke (cerebral infarcThe headache is typically bilateral, with a posterior tion or intracerebral hematoma) (Hajj-Ali et al., 2002; onset followed by a diffuse pain, with a severe to very Ducros et al., 2010; Singhal et al., 2011). Visual deficits severe intensity, sometimes excruciating, with agitation, are common, including scotoma, blurring, hemianopia, shouting and yelling, often associated with nausea, vomitand cortical blindness (full or partial Balint syndrome). ing, photophobia and phonophobia. Migraineurs clearly Hemiplegia, tremor, ataxia, and aphasia have also been identify the thunderclap headaches as different from their reported. Impairment of consciousness is infrequent usual headaches (Ducros et al., 2007). Severe pain usually and usually mild. Less than 5% develop progressive ceresubsides within 1–3 hours (but ranges from a few minutes bral arterial vasoconstriction culminating in multiple to several days) and 50–75% of patients describe a permamassive strokes, brain edema, severe morbidity, or death nent mild baseline headache between two thunderclap (Hyde-Rowan et al., 1983; Geraghty et al., 1991; Marshall exacerbations. About 80% of patients report at least et al., 2007; Williams et al., 2007; Singhal et al., 2011).

REVERSIBLE CEREBRAL VASOCONSTRICTION SYNDROME

General examination The general physical examination is usually normal, except in complex conditions combining RCVS and PRES in the setting of eclampsia, septic shock, immunosuppression, and so forth. About 25–30% of the patients have blood pressure surges (Ducros et al., 2007) during the thunderclap headaches, whether from the pain, the disease itself, or the associated condition (e.g., eclampsia), and some patients also have a facial flush.

Diagnosis criteria A RCVS must be suspected in all patients with thunderclap headache, with or without other neurologic symptoms, after the exclusion of all other causes (Tables 111.3 and 111.4) (Schwedt et al., 2006). With the actual diagnosis criteria, it is impossible to diagnose RCVS in the absence of headache. However, RCVS without headache or with very minimal headache does probably exist. We had a young woman with multiple infarcts and minimal headache, smoking cannabis, with a characteristic MRA and transcranial Doppler (TCD), and a control MRA and TCD showing normalization at 2 months, and no other cause to better explain her illness. She is well now. Another middle-aged woman was seen in our institution with cortical subarachnoid hemorrhage (cSAH) and multiple cerebral hematomas, but minimal headaches. She had a huge diffuse segmental vasoconstriction on transfemoral angiography, which Table 111.3 Diagnostic criteria for RCVS adapted from the International Headache Society diagnosis criteria for “acute reversible cerebral angiopathy”* and the criteria proposed in 2007 by Calabrese et al.{ Acute and severe headache (often thunderclap headache) with or without focal neurological deficits or seizures Monophasic course without new symptoms more than 1 month after clinical onset Segmental vasoconstriction of cerebral arteries demonstrated by angiography (MRA, CTA, or catheter) Exclusion of subarachnoid hemorrhage due to a ruptured aneurysm Normal or near normal CSF (protein < 1 g/L, white cells < 15 per mm3, normal glucose) Complete or marked normalization of arteries demonstrated by a repeat angiogram (MRA, CTA or catheter) performed at 12 weeks of clinical onset, although they may be normal earlier *(Headache Classification Subcommittee of the International Headache Society, 2004) { (Calabrese et al., 2007)

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had completely resolved on the control angiogram at 2.5 months (A. Ducros, unpublished observation).

NATURAL HISTORY One of the main characteristics of RCVS is the temporal pattern of the different clinical features and the associated arterial abnormalities (Table 111.5) (Ducros et al., 2007). The first symptom is usually a thunderclap headache that recurs during the first week, with the last attack at a mean of 7–8 days after onset. Mild baseline headache may then persist in about three-quarters of the patients, and finally all significant headaches have gone by about 3 weeks (Ducros et al., 2007; Chen et al., 2008, 2010). Any intracranial hemorrhages and PRES are early complications during the first week, while ischemic complications (TIA and infarction) occur later, at the end of the second week, sometimes when the headaches have improved or even resolved (Chen et al., 2006a, 2008, 2010; Ducros et al., 2007, 2010). RCVS has a monophasic course, generally without new symptoms after 1 month. In most patients, headaches and angiographic abnormalities completely resolve within days to weeks. The long-term prognosis is determined by the occurrence of stroke and seems to be more severe in hemorrhagic forms of RCVS in the French series (Ducros et al., 2010) and in ischemic forms of RCVS in the US series (Singhal et al., 2011), but overall, less than 10% of patients are left with residual deficits (Calabrese et al., 2007; Ducros et al., 2007; Chen et al., 2010). Progressive vasoconstriction resulting in progressive symptoms or death can occur in rare cases (Buckle et al., 1964; Hyde-Rowan et al., 1983; Geraghty et al., 1991; Marshall et al., 2007; Williams et al., 2007; Singhal et al., 2009). It should be noted that “reversibility” in the appellation RCVS refers to the dynamic and reversible nature of vasoconstriction; clinical deficits from brain damage might persist and the vasoconstriction (particularly if severe and prolonged) may not fully reverse in some rare patients. During the months following the acute phase, onethird of the patients report persistent headaches with either chronic tension-type headache or exacerbation of pre-existing migraine headaches, often associated with fatigue or depression. Some patients develop a kind of post-traumatic stress-like syndrome, and live in the fear of a recurrence of thunderclap headaches. Some patients who had orgasmic thunderclap headaches as the main clinical feature of RCVS may have eventual milder sexual headaches at one time or another during follow-up, without evidence of recurrence of visible vasoconstriction (A. Ducros, unpublished observation). Whereas these milder sexual headaches have the same underlying mechanisms as thunderclap headaches

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Table 111.4 Investigation of a thunderclap headache Causes of thunderclap headaches that may be detected by this investigation

Investigation

Indications

Noncontrast CT brain scan (with visualization of sinuses if clinical symptoms suggest acute sinusitis)

All thunderclap headaches as first investigation

CSF analysis

All CT normal thunderclap headache

ESR and CRP

Age > 60 years

EKG

Thunderclap headache triggered by exertion

Complete MRI (diffusion, FLAIR, gradient-echo, sagittal T1, T1 with gadolinium, cervical FAT/SAT) þ MRA þ MRV

All thunderclap headache after normal CT and normal or near normal CSF Fewer sequences if cervical and transcranial Doppler shows abnormalities suggesting dissection or an increase in intracranial flow velocities suggesting RCVS

Catheter angiography

Gold standard for subarachnoid hemorrhage In the absence of SAH, to be performed only in case of increasing headaches, occurrence/increase of focal deficits, unexplained after CT scan, CSF analysis and complete MRI/MRA/ MRV

during RCVS or are “true” primary sexual headaches is an unresolved issue. Recurrence of an “episode” of RCVS is possible (Ursell et al., 1998), but without long-term follow-up studies, the rate is unknown. In our French series of 67 patients followed for a mean of 3.2 years (range 26–62 months), we have so far not observed any angiographically proven recurrence. However, 3 years after a severe RCVS complicated by an occipital hemorrhage, one patient had a recurrence of multiple thunderclap

Subarachnoid hemorrhage (90% within the first 24 hours) Intracerebral hematoma Intraventricular hemorrhage Subdural hematoma (rare cause of thunderclap headache) Some infarcts particularly in the cerebellum Hydrocephalus Tumors Acute sinusitis Subarachnoid hemorrhage Meningitis Giant cell arteritis (very rare cause of thunderclap headache) Cardiac cephalalgia due to myocardial ischemia (very rare cause of thunderclap headache) Intracranial venous thrombosis Dissection of cervical arteries (extra- or intracranial, carotid or vertebral) Pituitary apoplexy RCVS Unruptured but symptomatic aneurysm Acute infarct from less than 3 hours not visualized on CT scan CSF hypotension Better visualization of all abnormalities previously seen on CT scan Ruptured aneurysm in 85% of patients with subarachnoid hemorrhage Intracranial venous thrombosis Dissection (cervical, intracranial) RCVS Differential diagnosis of cerebral arteritis Unruptured but symptomatic aneurysm (Painfull palsy of the third cranial nerve)

headaches over 1 week, after smoking cannabis. He did not seek medical advice and it was thus impossible to make a firm diagnosis. In another patient not included in our first case series, who had a proven RCVS, multiple sexual thunderclap headaches recurred 6 months later, 2 days after the intake of an SSRI. He did not seek medical attention but remembered our recommendation, stopped the antidepressant, and no more thunderclap headaches occurred. In 2008, we had a woman with a first episode of RCVS characterized by multiple

REVERSIBLE CEREBRAL VASOCONSTRICTION SYNDROME Table 111.5 Mean delay from headache onset to the other features of reversible cerebral vasoconstriction syndrome Delay from headache onset to:

Mean  SD (days)

Range (days)

Diagnosis of cerebral hematoma In patients with a focal deficit In patients without focal deficit Diagnosis of subarachnoid hemorrhage Diagnosis of subdural hemorrhage First seizure Posterior reversible encephalopathy syndrome Last recurrent thunderclap headache Transient neurologic deficit Diagnosis of cerebral infarction

2.2 2.5 1.1  1.7 4  2.9

0–8 0–4 3–8

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Mild cerebrospinal fluid (CSF) abnormalities are found in more than half the patients with an excess of white blood cells (5–35/mm3), and red blood cells with or without visible subarachnoid blood on MRI, and increased protein levels up to 1 g/L (Calabrese et al., 2007; Ducros et al., 2007; Singhal et al., 2011). If the lymphocytic reaction exceeds 10 cells per mm3, it is better to repeat the lumbar puncture after a few weeks to make sure it is normal and exclude chronic meningitis.

NEUROIMAGING INVESTIGATIONS 4.6  4.3

0–20

5.5  3.5

3–8

4  1.4 4  1.5

2–5 1–6

7.4  5.6

0–28

11.6  4.9

0–23

9  6.2

2–16

(Adapted from Ducros et al., 2007, 2010.)

thunderclap headaches triggered by strong exertion, with a cortical subarachnoid hemorrhage, and a fully reversible “string and beads” aspect on cerebral angiographies. One year after, she had a proven recurrence of RCVS with multiple thunderclap headaches, again triggered by strong exertion and a reversible diffuse segmental vasoconstriction (A. Ducros, unpublished observation).

LABORATORY INVESTIGATIONS Blood counts, erythrocyte sedimentation rate, serum electrolytes, and liver and renal function tests are usually normal. In patients with oropharyngeal infections who took nasal decongestants, blood tests may show a moderate and transient inflammatory response. Rheumatoid factor, antinuclear and antinuclear cytoplasmic antibody tests, Lyme titer, and urine vanillylmandelic acid and 5hydroxyindoleacetic acid levels, are useful to rule out vasculitis and evaluate for vasoactive tumors (e.g., pheochromocytoma, carcinoid) that have been associated with RCVS (Singhal, 2004a). Serum and urine toxicology screens, in addition to a careful medication history, are important to uncover exposure to vasoactive drugs and medications (cannabis, cocaine, amfetamines, ecstasy).

Brain computed tomography and magnetic resonance imaging Patients with RCVS typically present to the emergency department for evaluation of thunderclap headaches, and appropriately undergo urgent brain and vascular imaging to rule out secondary causes. Between 30% and 70% of patients ultimately diagnosed with RCVS show no parenchymal lesion on the initial head CT or brain MRI, despite having widespread vasoconstriction on concomitant cerebral angiography (Calabrese et al., 2007; Ducros et al., 2007; Ducros et al., 2010; Singhal et al., 2011). This wide range in the frequency of abnormal brain imaging findings reflects the wide clinical spectrum of RCVS. In the French patients with purely cephalalgic RCVS, MRI showed a cortical subarachnoid hemorrhage (cSAH) in 20% and features of PRES in 10%; and in patients that presented with a persistent focal deficit, MRI showed an infarct or hematoma in 100% (Ducros et al., 2010). If abnormal, brain imaging might show a variety of lesions on initial or on follow-up studies, including cortical surface (nonaneurysmal) subarachnoid hemorrhage, intracerebral hemorrhage, subdural hemorrhage, reversible brain edema (PRES), and ischemic stroke (Singhal, 2004a; Calabrese et al., 2007; Chen et al., 2010; Ducros et al., 2010; Singhal et al., 2011). Any combination of lesions can be present and different types of lesions may successively appear. Hemorrhagic complications and brain edema are usually diagnosed during the first week after clinical onset while ischemic events occur later during the second week after headache onset. Cortical subarachnoid hemorrhage (20–30% in the French series) is usually mild, unilateral or bilateral, visible as high signal on FLAIR in a few sulci near the convexity (Fig. 111.1) (Ursell et al., 1998; Hajj-Ali et al., 2002; Singhal, 2004b; Spitzer et al., 2005; Moustafa et al., 2008; Ducros et al., 2010; Singhal et al., 2011). Convexity subarachnoid hemorrhages account for about 7% of all spontaneous subarachnoid hemorrhages, and RCVS was suggested to be the most frequent cause of cortical subarachnoid hemorrhage in patients 60 years or younger whereas amyloid angiopathy was the most frequent cause in patients over 60 (Kumar et al., 2010). Focal

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Fig. 111.1. Cortical subarachnoid hemorrhage in reversible cerebral vasoconstriction syndrome. (A) CT brain scan showing a small right frontal hemorrhage. (B) In another patient with a normal CT scan, MRI (FLAIR) shows bilateral cortical subarachnoid hemorrhage with high signal in several sulci. (Reproduced from Ducros and Bousser, 2009.)

intracerebral hemorrhage (12% in the French series) may be single or multiple, cortical or deep, of variable volume (Fig. 111.2) (Rousseaux et al., 1983; Roh and Park, 1998; Geocadin et al., 2002; Doss-Esper et al., 2005; Moskowitz et al., 2007; Santos et al., 2009; Singhal et al., 2009; Ducros et al., 2010; Singhal et al., 2011). Subdural hemorrhage has also been reported. (Santos et al., 2009; Ducros et al., 2010). It appears that hemorrhages are more common in women, and in patients with a history of migraine. Interestingly, some patients with negative initial imaging go on to develop an intracranial hemorrhage after their second or third headache exacerbation, reflecting the dynamic nature of RCVS (Ducros et al., 2010). Cerebral infarction is reported as the most frequent complication in retrospective or inpatient series, affecting 39% of the cases in the series from the USA, but is found in only 6–8% in the French and Taiwanese large prospective series (Fig. 111.3) (Calabrese et al., 2007; Chen et al., 2010; Ducros et al., 2010; Singhal et al., 2011). Infarcts are often bilateral and symmetric, and located in arterial “watershed” regions of the cerebral hemispheres. Cerebellar infarcts are also possible. Smaller infarcts are typically located in the corticalsubcortical junction, and larger infarcts are often wedge-shaped. Perfusion-weighted imaging may show areas of hypoperfusion. The presence of reversible brain edema with symmetric high signal on fluid-attenuated inversion recovery (FLAIR), in a distribution similar to the posterior reversible leukoencephalopathy syndrome, suggests an overlapping pathophysiology between these syndromes (Fig. 111.4) (Singhal, 2004b). FLAIR images may show dot or linear hyperintensities within sulcal spaces, which are distinct from subarachnoid hemorrhage and reflect

slow flow within dilated surface vessels (Iancu-Gontard et al., 2003). Finally, cervical FAT/SAT sequences are very useful to search for any associated cervical artery dissection (Ducros et al., 2007; Mawet et al., 2013).

Cerebral angiography The diagnosis of RCVS can only be considered after documenting the presence of cerebral vasoconstriction with transfemoral, CT, or MR angiography. The angiography shows segmental narrowing and dilatation (string of beads) of one or more cerebral arteries (Fig. 111.5) (Slivka and Philbrook, 1995; Calabrese et al., 2007). Caliber irregularities may affect the anterior as well as the posterior circulation, and are mostly bilateral and diffuse, and large arteries such as the basilar or the carotid siphon may also be involved (Dodick et al., 1999). The narrowings are not fixed, and a repeat angiogram after a few days may show the resolution of some with new zones of constriction often involving more proximal vessels. Noninvasive angiography (MRA or CTA) was only 75% sensitive in the French series compared with the gold standard of catheter angiography which is by definition 100% sensitive (because it defines the syndrome), although nowadays rarely necessary (Ducros et al., 2007). The first angiogram, whatever its type, may be normal if performed early, within the 4–5 days of onset of symptoms; therefore if the first MRA or CTA is normal, a second angiogram a few days later may be diagnostic (Fig. 111.6) (Ducros et al., 2010). If another condition or another lesion is very unlikely, and if the initial MRA/CTA is definitely normal, and if there is no cSAH and no stroke on MRI, we do not systematically perform a catheter angiography. But depending on the clinical state of the patient, we may repeat TCD with

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Fig. 111.2. Intracerebral hemorrhage in reversible cerebral vasoconstriction syndrome which may be single (A, C, D) or multiple (B), lobar (A, B, D) or deep (C), isolated or associated with cortical subarachnoid hemorrhage arrow please (B, right frontal cortical subarachnoid hemorrhage) or with an acute subdural hemorrhage (D, occipital subdural blood). (Reproduced from Ducros and Bousser, 2009.)

or without repeat MRA/CTA, or we simply follow up. Of course, in these patients, no definite diagnosis is possible (Ducros and Bousser, 2009). RCVS may be associated with single or multiple unruptured cerebral aneurysms (6% in our French series, which is not that much more frequent than in the general middle-aged population, but these patients had no red blood cells in the CSF and no extravasation of contrast on catheter angiography) (Day and Raskin, 1986; Ducros et al., 2007). RCVS might also be associated with vertebral or carotid dissection, more frequently in females, particularly postpartum (Singhal, 2004b; Ducros et al., 2007; Arnold et al., 2008; Field et al., 2010; Mawet et al., 2013).

Ultrasound Cervical ultrasound examination is usually normal except in the rare cases associating RCVS with cervical

arterial dissection. Transcranial Doppler, on the other hand, is very useful for monitoring the temporal evolution of cerebral vasoconstriction. Maximal mean flow velocities in the middle cerebral arteries may be normal during the first few days, then begin to increase and reach a peak ( 95%), showing an inflammatory reaction, while it is normal (40–80%) or shows only mild abnormalities in RCVS. Catheter angiography is frequently normal in PACNS, while it is by definition always abnormal in RCVS. Some aspects are suggestive of PACNS and are not observed in RCVS: irregular, eccentric, and asymmetric arterial stenoses or multiple occlusions. In the rare case of persistent uncertainty it may be best to wait a few days; RCVS should stabilize and improve quickly with regression of the vasoconstriction, while arterial irregularities in PACNS do not improve so fast. Heavy immunosuppressive treatments should be reserved for patients with biopsy-proven vasculitis. However, the anxiety awaiting the reversibility affects even the most experienced clinical teams. Intra-arterial nimodipine could serve as a differential diagnosis test because in RCVS it has been shown in a few cases to immediately normalize the arterial abnormalities (Elstner et al., 2009), whereas in PACNS it is not expected to change the lesions.

Migraine Migraine is another consideration because a prior history of migraine is frequently elicited (16–22%) by patients with a proven RCVS (Chen et al., 2006a; Ducros et al., 2007), although this frequency is not that much higher than the prevalence of migraine in the general

REVERSIBLE CEREBRAL VASOCONSTRICTION SYNDROME population. In patients with a history of migraine, attribution of any severe headache and even of stroke to migraine is a common problem, frequently leading to inappropriate treatment with antimigraine agents such as sumatriptan, which in the case of RCVS can exacerbate vasoconstriction and stroke (Meschia et al., 1998; Singhal et al., 2002). Headaches in RCVS are secondary headaches, symptomatic of the vascular disorder, that have nothing to do with migraine, which is a primary headache without any underlying causal lesion. Migraine sufferers who had a RCVS recognized the thunderclap headaches as totally different from their usual migraine attacks (Ducros et al., 2007). However, when entering the emergency room, they often complained of the “worst ever migraine attack,” which may be misleading.

Primary thunderclap headaches and headaches associated with exertion or sexual activity If imaging is negative and the patient does not prove to have vasoconstriction, primary headache disorders such as primary thunderclap headache, primary exertional headache, or orgasmic headache are usually considered (Wang and Fuh, 2010). However, a diagnosis of primary headache can be accepted only after the exclusion of all causes of secondary headaches. As presented above, sensitivity of MR or CT angiography is incomplete in RCVS and the highest load of arterial abnormalities as assessed by MRA is found only 3 weeks after headache (Chen et al., 2010). Moreover, in one study, 39% of patients presenting with thunderclap headache and normal brain MRI proved to have vasoconstriction on MRA, and those with and without vasoconstriction had similar clinical features, suggesting that RCVS and “primary thunderclap headache” belong to the same spectrum of disorders (Chen et al., 2006a). Furthermore, a recent prospective series of 30 patients complaining of headache associated with sexual activity showed that 60% had MRA features consistent with RCVS, suggesting that RCVS with thunderclap headaches triggered by sexual activity and “primary sexual headaches” also belong to the same spectrum of disorders (Yeh et al., 2010).

ETIOLOGY AND PATHOPHYSIOLOGY The cause of the prolonged but reversible arterial abnormalities with segmental vasoconstriction and vasodilatation is not known. Altered cerebral arterial tone due to abnormal vascular receptor activity or sensitivity appears critical; this may result from either a spontaneous or evoked central vascular discharge, or a variety of exogenous or endogenous factors including vasoconstrictive drugs and medications, female reproductive hormones, hypercalcemia, and others (Table 111.2). The anatomic basis to explain both the vasoconstriction

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and the headache may be the dense innervation of cerebral blood vessels with sensory afferents from the first division of the trigeminal nerve and dorsal root of C2. At the molecular level it is reasonable to postulate a role for the numerous immunologic and biochemical factors known to be involved in vasospasm associated with aneurysmal subarachnoid hemorrhage (catecholamines, endothelin-1, serotonin, nitric oxide, prostaglandins). The association of RCVS with serotonin-enhancing medications and tumors suggests that serotonin might play a pivotal role in this still mysterious condition. We previously hypothesized that arterial abnormalities first involve small distal arteries and then progresses towards medium and large-sized vessels, which could explain the high rate of normal early angiograms (up to 33%) in RCVS (Ducros et al., 2007). The finding that up to 17% of patients with hemorrhagic RCVS initially presented with isolated headaches and normal brain imaging, and only subsequently developed cSAH, intracerebral hemorrhage (ICH) and/or subdural hematoma (SDH) after a few days of recurrent severe headaches, suggests that the abnormal vascular process starts before hemorrhage (Ducros et al., 2010). Moreover, up to 17% of the patients with a cSAH due to RCVS also have a PRES. The co-occurrence of PRES, a transient vasogenic cerebral edema related to small-vessel dysfunction with acute disruption of blood–brain barrier, and cSAH suggests that the abnormal process initially affects very small cortical arteries. Serial MRA and TCD studies in a large cohort of RCVS cases showed that vasoconstriction affecting first segments of large arteries was maximal 18–22 days after headache onset, similar to the timing of headache resolution (Chen et al., 2008, 2010). Moreover, marked vasoconstriction could persist weeks after headache resolution, suggesting that vasoconstriction is not directly causing headache. Segmental vasodilatation could play an important role at the initial stage of RCVS, triggering thunderclap headaches by abrupt stretching of vessel walls, and causing hemorrhages by small vessel rupture or reperfusion injuries, whereas small vessel segmental constriction remains asymptomatic (no or rare small vessel infarction in RCVS). In a second stage, vasoconstriction of second and first segments of major cerebral arteries becomes the major problem causing mainly watershed infarction (Ducros et al., 2010).

MANAGEMENT In the absence of controlled trials, management is guided by observational data and expert opinion. For patients presenting with thunderclap headache but who have not undergone vascular imaging, empiric therapy is not justified. However, once cerebral vasoconstriction has been documented, treatment can be considered. It is

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important to note that RCVS is usually self-limited, with clinical and angiographic resolution occurring spontaneously within a few weeks. Therefore simple observation alone is reasonable in patients, especially those who show no signs of clinical progression. Calcium channel blockers such as nimodipine and verapamil (Nowak et al., 2003), and magnesium sulphate (Singhal, 2004b) have been administered in an effort to relieve the vasoconstriction. Data from two prospective case series suggest that nimodipine does not affect the time course of cerebral vasoconstriction (Chen et al., 2006a; Ducros et al., 2007; Ducros et al., 2010). However, nimodipine might relieve the number and intensity of headaches. Nimodipine may be given intravenously for a few days, in the same doses as is used in aneurysmal subarachnoid hemorrhage (1–2 mg/kg/hour with monitoring of blood pressure). More often, nimodipine is given orally, the dose varying from 60 mg every 4–8 hours for 4–12 weeks. Thunderclap headaches seem to stop within 48–72 hours, but TIAs or even infarction have been reported in patients treated for several days (Lu et al., 2004; Ducros et al., 2007). Some patients might have an increase in their background headaches on nimodipine, and rarely a thunderclap headache triggered by a nimodipine tablet. Finally, nimodipine should be avoided in patients with low blood pressure and in patients with an associated dissection with hemodynamic compromise. Short courses of glucocorticoids do not seem to prevent clinical deterioration (Singhal et al., 2011), and are even suspected to worsen sometimes the clinical course. Thus, they should be avoided. Direct intra-arterial administration of milrinone, nimodipine and prostacyclin, and balloon angioplasty, have been used with variable success (Song et al., 2004, Bouchard et al., 2009, Elstner et al., 2009, Grande et al., 2010). These interventions carry a high risk of reperfusion injury and should be reserved for patients exhibiting clear signs of clinical progression (Singhal et al., 2009). Unfortunately, there are no known clinical or imaging features that reliably predict disease progression. Symptomatic treatment includes analgesics (headache is extreme and frequently warrants round-the-clock opioid analgesic use), antiepileptic drugs for any seizures, monitoring blood pressure, hospitalization in intensive care units in severe cases, and rest for all other patients for a few days to a few weeks according to the severity of their headaches. Benzodiazepines can be used to relieve anxiety, which is common and could be an aggravating factor. Patients should be counseled to avoid sexual activity, physical exertion, the Valsalva maneuver, and other known triggers of recurrent headaches for 1 or 2 weeks. Finally, it is crucial to search for all possible vasoactive substances (repeated questioning

is sometimes necessary), eliminate all these substances immediately them and, and firmly suggest to the patient that he or she should avoid these kinds of drugs and medications in the future. Usual stroke preventive medications such as antiplatelets, anticoagulants, cholesterol-lowering agents, and others are probably not indicated.

CONCLUSIONS AND FUTURE DIRECTIONS RCVS is probably more frequent than previously thought and affects patients of both genders, with a female preponderance. It is attributed to a transient disturbance in the control of cerebral vascular tone leading to multifocal arterial constriction and dilatation. Some cases are spontaneous while others (60%) are secondary, mostly to exposure to vasoactive substances and to the postpartum state. It has a characteristic course; the onset is sudden followed by a monophasic course, generally without new events after 1 month. The main pattern is of recurrent thunderclap headaches. Cortical subarachnoid hemorrhage, intracerebral hemorrhage, seizures, and PRES are early complications, occurring mainly within the first week. Ischemic events, including TIAs and cerebral infarction, occur later than any hemorrhagic strokes, mainly during the second week. Recent results indicate that intracranial hemorrhages affect up to onethird of all RCVS cases, are far more frequent than ischemic events, and are more frequent in women and in migraineurs. RCVS should be considered as a differential diagnosis in patients with any type of spontaneous intracranial hemorrhage, and especially with localized cortical SAH. The diagnosis of RCVS may be difficult when initial brain and vascular imaging are normal, requiring repeated investigations. The definitive diagnosis is made when a later angiogram shows a resolution or at least a marked improvement of the arterial abnormalities after about 12 weeks. Nimodipine is the proposed treatment but does not seem to prevent infarctions; randomized trials are needed. Relapses do occur but are rare. Studies of cerebral blood flow at the acute stage and of cerebrovascular reactivity at a distance from RCVS could help to understand the mechanisms underlying this poorly understood syndrome.

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