The Journal of Emergency Medicine, Vol. -, No. -, pp. 1–6, 2015 Copyright Ó 2015 Elsevier Inc. Printed in the USA. All rights reserved 0736-4679/$ - see front matter http://dx.doi.org/10.1016/j.jemermed.2015.01.012 Selected Topics: Neurological Emergencies REVERSIBLE CEREBRAL VASOCONSTRICTION SYNDROME Kenneth R. L. Bernard, MD, MBA* and Morris Rivera, MD† *Harvard Affiliated Emergency Medicine Program, Department of Emergency Medicine, Brigham and Womens/Massachusetts General Hospital, Boston, Massachusetts and †Partners Healthcare, Martha’s Vineyard Hospital, Oak Bluffs, Massachusetts Reprint Address: Kenneth R. L. Bernard, MD, MBA, Harvard Affiliated Emergency Medicine Progam, Department of Emergency Medicine, Brigham and Womens/Massachusetts General Hospital, 75 Francis Street, Neville House, Boston, MA 02115 , Abstract—Background: Reversible cerebral vasoconstriction syndrome (RCVS) is an underappreciated and poorly understood cause of thunderclap headache (TCH). Although self-limited in the majority of patients, incidence is increasing, with presentations overlapping considerably with life-threatening conditions, such as aneurysmal subarachnoid hemorrhage and stroke. In addition, radiographic findings seen in RCVS are also present in primary angiitis of the central nervous system (PACNS). Misdiagnosis of RCVS might subject patients to unnecessary invasive testing and immunosuppressive therapy. Furthermore, the recommended treatment of glucocorticoids used in PACNS can be harmful in RCVS. RCVS is not a benign condition, as patients can have ischemic or hemorrhagic complications leading to persistent neurologic deficits and even death. Current treatments, guided only by expert consensus, have no proven effect on these complications, which argues the need for accurate identification of patients with RCVS and prospective studies to validate treatment and inform prognoses. Case Report: We describe a previously healthy male who presented to the emergency department after 2 episodes of TCH and angiography consistent with RCVS. Why Should An Emergency Physician Be Aware of This?: RCVS is a common but underappreciated cause of TCH. The likelihood of misdiagnosing RCVS following the accepted diagnostic algorithm of acute headache in the emergency department is high due to a lack of clinical awareness and common features shared with other headache syndromes. Emergency department physicians must broaden the differential in patients presenting to the emergency department with TCH to include RCVS and be familiar with the accepted treatments and appropriate follow-up. Elsevier Inc. Ó 2015 , Keywords—headache; thunderclap; subarachnoid hemorrhage; reversible cerebrovasconstriction syndrome INTRODUCTION Headache is a common presenting symptom to the emergency department (ED), prompting >2 million ED visits per year and contributing to 2.2% of yearly ED visits (1). A subset of these headaches is described as thunderclap headaches (TCH), a testament to both the abrupt onset as well as the severity of the discomfort that patients experience. The differential of TCH is broad and includes intracranial aneurysm, subarachnoid hemorrhage (SAH), cerebral venous thrombosis, caudocervical artery dissection, ischemic stroke, and hypertensive crisis (2). An underappreciated cause of TCH is the recently clinically defined reversible cerebral vasospasm syndrome (RCVS), which now unifies a spectrum of conditions previously referred to as Call-Fleming syndrome, migraine angiitis, postpartum angiopathy, or drug-induced vasospasm (3). The exact prevalence is unknown and mortality is <1% (3–5). However, in the largest retrospective case series, complications such as seizure, stroke, SAH, intracerebral hemorrhage, and posterior reversible encephalopathy syndrome (PRES) had an incidence of RECEIVED: 28 May 2014; FINAL SUBMISSION RECEIVED: 21 December 2014; ACCEPTED: 11 January 2015 1 2 K. R. L. Bernard and M. Rivera 17%, 39%, 34%, 20%, 38%, respectively. In this same study, 20% percent of patients experienced persistent neurologic deficits (4). In this case, we describe a healthy 41-year-old male who presented after 2 episodes of TCH associated with mild nausea and right-hand paresthesias with segmental vasoconstriction present on cerebral angiography consistent with RCVS. To the authors’ knowledge, this is the first case report of RCVS in the United States emergency medicine literature. sedimentation rate, C-reactive protein, and lumbar puncture were performed, given concerns for Lyme meningitis or vasculitis. His inflammatory markers were normal and his cerebrospinal fluid (CSF) was bland, including negative Lyme polymerase chain reaction. The patient was admitted to the neurology service with presumed diagnosis of RCVS for observation and magnetic resonance imaging, which revealed no additional findings. He was discharged on a 1-month course of 240 mg verapamil daily without recurrence of his symptoms. CASE REPORT DISCUSSION A 41-year-old male, nonsmoker, taking no medications and with no history of headaches presented to the ED after two episodes of sudden-onset and severe headache associated with mild nausea and transient right-hand paresthesias. The first episode occurred a week before presentation, during a road race at a time when the patient fully exerted himself to the finish line. At that time, he reported feeling like he had been, ‘‘hit with a ton of bricks,’’ describing a holocephalic, 10 out of 10, throbbing headache associated with a tingling or twitching sensation in his right hand. Notably, he finished the race with no other neurologic symptoms. The paresthesias abated within minutes and the headache resolved over a few hours without intervention. The next episode occurred 6 days later while on a boat when, without provocation or prodrome, he experienced another severe, sharp, 10 out of 10, holocephalic headache. After this second episode, he presented to a local ED, where his physical examination was normal as were basic laboratory results. A noncontrast head CT (NCHCT) and CT angiography (CTA) were performed to rule out SAH, and revealed multiple areas of segmental narrowing of the anterior cerebral vasculature without evidence of infarction or hemorrhage consistent with diagnosis of RCVS (Figure 1). Notably, his only recent medical history included an empiric course of doxycycline after a deer tick exposure a month before his presentation. Given this additional history erythrocyte RCVS is a syndrome that presents clinically with acuteonset, severe headaches that reach peak intensity within 1 min and can recur over 1 to 3 weeks. Patients frequently endorse nausea, vomiting, photophobia, and phonophobia. In addition, neurologic deficits, such as encephalopathy, visual changes, dysarthria, ataxia, or focal numbness or weakness, might be present and can persist (5). Recently, diagnostic criteria based on clinical, laboratory, and radiographic findings have been proposed (Figure 2) (6). Recent prospective cohort studies have estimated incidence of RCVS among patients presenting with TCH and no obvious secondary cause of headache to be between 8.8% and 45.8% (7,8). Although angiography might be normal on initial evaluation, the key to diagnosis is the presence of a characteristic ‘‘string and beads’’ or ‘‘sausage on a string’’ appearance of cerebral arteries, which describes the alternating pattern of severe vasoconstriction and dilatation seen exclusively in the intradural vessels (9). The exact pathogenesis of RCVS is unknown, and the headaches are thought to be secondary to an as of yet unidentified vascular pathology and need not correlate with presence of vasospasm. Prior studies have shown that early angiographic evaluation in patients with RCVS may be negative in up to 20% of patients (9). In one study by Ducros et al., vasoconstriction was detected at a mean Figure 1. Patient’s computed tomography angiography images showing segmental vasoconstriction. ACOM = anterior communicating artery. Reversible Cerebral Vasoconstriction Syndrome 3 Figure 2. Diagnostic criteria for reversible cerebral vasoconstriction syndrome. CSF = cerebrospinal fluid; RCVS = reversible cerebral vasoconstriction syndrome; SAH = subarachnoid hemorrhage; TCH, thunderclap headache; TP = total protein. of 8 days after headache onset and up to 14 days in some patients (9). Several potential precipitants and predisposing conditions have been postulated (Figure 3) (3). The largest studies suggest that up to 60% to 80% of patients will have a secondary cause. Of these, a large proportion occurs in the setting of drugs possessing vasoactive properties (10). The incidence peaks at around 40 years of age and is more common in women than men, with incident ratios of 2.6:1 to 10:1 (11). Only a small number of cases have been reported in the pediatric literature (3). Presentations of RCVS share considerable overlap with other life-threatening conditions, such as SAH, PACNS, and caudocervical dissection, however, clinical and laboratory findings can help narrow this differential (Table 1) (3). Patients with RCVS can have recurrent TCH with normal NCHCT compared to SAH, in which the majority will have abnormal NCHCT in the acute presentation. Even in patients with normal mental status and nonfocal neurologic examination, >90% of patients with SAH can be identified with NCHCT (sensitivity 91%; 95% confidence Figure 3. Secondary causes of reversible cerebral vasoconstriction syndrome. EtOH = alcohol; IVIG = intravenous immunoglobulin; RBC = red blood cells. Adapted from Tan and Flower (11), with permission. Calcium channel blocker, magnesium, analgesia, avoid triggers Treatment Embolization, coiling, surgery Reversible, diffuse segmental stenosis and adjacent dilatation of intradural vessels Angiographic characteristics CSF CT/MRI findings AVM = arteriovenous malformation; CSF = cerebrospinal fluid; CT/MRI = computed tomography/magnetic resonance imaging; ICH = intracerebral hemorrhage; PACNS = primary angiitis of the central nervous system; PRES, posterior reversible encephalopathy syndrome; RBCs = red blood cells; RCVS = reversible cerebral vasoconstriction syndrome; SAH = subarachnoid hemorrhage; TCH, thunderclap headache. Anticoagulation, antiplatelet therapy, angioplasty with stenting, surgery Segmental stenosis of intra- and extradural vessels, intimal flaps/ hematoma, pseudoaneurysm Normal Majority abnormal—diffuse infarcts, ICH Majority abnormal—pleocytosis, elevated total protein Irreversible ‘‘string and bead’’ appearance, majority small vessel changes (confirmed by biopsy) Glucocorticoids, immunosuppression 40–60 Males > females Insidious, progressive, dull 50–60 Females/males = 2/1 TCH Family history, polycystic kidney disease, connective tissue disorder Majority abnormal—SAH, edema, hydrocephalus Majority abnormal—elevated RBCs, xanthochromia Aneurysm, AVMs, local vasospasm 40–60 Females >> males TCH, recurrent Vasoactive drugs, puerperium, eclampsia, brain injury, immunosuppression Majority normal, cortical SAH, ICH, PRES, infarct Normal Median age of presentation, y Sex Character of headache Risk factors PACNS SAH RCVS Majority normal—infarct, edema Table 1. Differentiating Reversible Cerebral Vasoconstriction Syndrome and Overlapping Conditions (3,8,9) interval [CI] 82% to 97%) (12). The sensitivity of NCHCT within the first 6 h is even higher, at 100% (95% CI 97% to 100%) (13). The remaining patients with SAH can be identified by abnormal CSF findings, including xanthochromia or elevated red blood cell count (14). The vasospasm seen in SAH is typically localized to the vascular territory involving the aneurysm, as opposed to the diffuse pattern seen in RCVS. The headache of PACNS is insidious and progressive course, and the CSF often exhibits pleocytosis, elevated protein, and occasionally oligoclonal bands. Finally, dissection usually presents with head or neck pain due to involvement of extradural vessels, which are not affected in RCVS (3,11). The key feature that distinguishes RCVS from other causes of TCH is reversible vasoconstriction, which warrants serial imaging to confirm the diagnosis and usually resolves over 2 to 3 months (3,11). The authors note that the sequence of tests performed in this case deviated from the standard diagnostic approach to acute headache in the ED, which includes NCHCT followed by lumbar puncture (LP) if imaging is nondiagnostic (15). The initial intent had been to follow a minimally invasive pathway for exclusion of SAH or symptomatic cerebral aneurysm with CT angiography following a nondiagnostic NCHCT, a suggested diagnostic course in select patients (16). After the CTA results were obtained, there was lingering concern for a falsenegative CT result in the setting of SAH, as well as, Lyme meningitis or vasculitis, so an LP was performed in addition to inflammatory markers. The authors note that if the current American College of Emergency Physicians guidelines for diagnostic approach to acute headache in the adult were followed in this patient, the diagnosis would have been missed (15). At this point, we cannot recommend that angiography be performed in all patients presenting to the ED with TCH, but at some institutions this is standard practice (9). However, given the incidence of RCVS and known risk factors, such as recurrent TCHs, female sex, use of vasoactive substances, peripartum state, or headaches triggered by bathing or exertion, it may be prudent to obtain cerebral angiography in patients with normal NCHCT and CSF studies (Figure 4). Prognosis is favorable compared to aneurysmal SAH or PACNS, with the majority of patients experiencing no or minor disability (10). Even in the absence of treatment, a majority of patients will have significant resolution of angiographic abnormalities on the order of weeks or months (2). Despite potential complications, <6% of patients go on to develop persistent neurologic deficits and mortality reported from the largest case studies is <1% (5,13). The presence of infarction, hemorrhage, or neurologic deficits portends a worse prognosis (4). 40–50 Males = females Acute head and neck pain Atherosclerosis, neck trauma, connective tissue disorder K. R. L. Bernard and M. Rivera Caudocervical Dissection 4 Reversible Cerebral Vasoconstriction Syndrome 5 Figure 4. Proposed approach to presentation of thunderclap headache (TCH) and suspicion for reversible cerebral vasoconstriction syndrome (RCVS). *Patients with very high risk of aneurysm should also undergo vascular imaging if noncontrast head computed tomography (NCHCT) and cerebrospinal fluid (CSF) results are negative (14). PACNS = primary angiitis of the central nervous system; SAH = subarachnoid hemorrhage. Adapted from Tan and Flower (11), with permission. Presently, there are no randomized controlled or comparative trials available to guide treatment or prevent complications arising as a result of RCVS. Expert consensus and case reports recommend that all patients receive symptomatic treatment with multimodal analgesia, calcium channel blocker (CCB), antiepileptics in the presence of seizures, antiemetics as needed, and discontinuation of any offending agent. Intravenous and oral nimodipine is the best described CCB therapy and has been efficacious at symptomatic control (3,10,11). However, nimodipine has not been shown to improve long-term outcomes or prevent complications of RCVS. Other less well-described treatments include alternative CCBs, such as verapamil or nicardipine (6). Magnesium sulfate has been used largely in the setting of preeclampsia and eclampsia, and there are few data to show efficacy in other populations but, also, there is little downside to this treatment (3). Case reports have described intra-arterial delivered vasodilatory agents or angioplasty for the most severe cases, but experience with these modalities is limited and benefit is unclear (3,10,11). As opposed to PACNS, glucocorticoids are not recommend and may be associated with poorer outcomes (5). It is out of the scope of this report to provide exhaustive review of management of RCVS complications such as stroke, SAH, and PRES. However, these conditions should be managed per local standards and neuroprotective protocols (e.g., reversal of coagulopathy, seizure prophylaxis, avoidance of hypoxia, hypotension and hyperthermia, and management if elevated intracranial pressure). At this time there are no recommendations with regard to blood-pressure control in patients with RCVS, but prior studies have shown that a majority are normotensive (9). As mentioned in our case, the patient was treated in the ED with intravenous analgesia, antiemetics, and CCB. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS? RCVS remains an underappreciated cause of headache in the emergency medicine literature, owing in part to the narrow diagnostic scope of the typical algorithm for TCH involving noncontrast head CT and LP. Although the prognosis for patients with RCVS is generally favorable and intuitive therapies remain unproven, accurate diagnosis can target precipitating conditions and guide management. At this time, the goal in the evaluation is to rule out other causes such as SAH, PACNS, and dissection, which overlap considerably with RCVS. Distinction of RCVS from PACNS is particularly important as glucocorticoids may lead to poorer outcomes in patient with RCVS. 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