The clinical spectrum of reversible cerebral vasoconstriction syndrome: The Italian Project on Stroke at Young Age (IPSYS)

Abstract

Introduction

To describe clinical, neuroimaging, and laboratory features of a large cohort of Italian patients with reversible cerebral vasoconstriction syndrome.

Methods

In the setting of the multicenter Italian Project on Stroke at Young Age (IPSYS), we retrospectively enrolled patients with a diagnosis of definite reversible cerebral vasoconstriction syndrome according to the International Classification of Headache Disorders (ICHD)-3 beta criteria (6.7.3 Headache attributed to reversible cerebral vasoconstriction syndrome, imaging-proven). Clinical manifestations, neuroimaging, treatment, and clinical outcomes were evaluated in all patients. Characteristics of reversible cerebral vasoconstriction syndrome without typical causes (“idiopathic reversible cerebral vasoconstriction syndrome”) were compared with those of reversible cerebral vasoconstriction syndrome related to putative causative factors (“secondary reversible cerebral vasoconstriction syndrome”).

Results

A total of 102 patients (mean age, 47.2 ± 13.9 years; females, 85 [83.3%]) qualified for the analysis. Thunderclap headache at presentation was reported in 69 (67.6%) patients, and it typically recurred in 42 (60.9%). Compared to reversible cerebral vasoconstriction syndrome cases related to putative etiologic conditions (n = 21 [20.6%]), patients with idiopathic reversible cerebral vasoconstriction syndrome (n = 81 [79.4%]) were significantly older (49.2 ± 13.9 vs. 39.5 ± 11.4 years), had more frequently typical thunderclap headache (77.8% vs. 28.6%) and less frequently neurological complications (epileptic seizures, 11.1% vs. 38.1%; cerebral infarction, 6.1% vs. 33.3%), as well as concomitant reversible brain edema (25.9% vs. 47.6%).

Conclusions

Clinical manifestations and putative etiologies of reversible cerebral vasoconstriction syndrome in our series are slightly different from those observed in previous cohorts. This variability might be partly related to the coexistence of precipitating conditions with a putative etiologic role on disease occurrence.

Keywords

Reversible cerebral vasoconstriction syndrome (RCVS)thunderclap headache stroke

Introduction

Reversible vasoconstriction syndrome (RCVS) is a clinical and radiological entity characterized by recurrent severe thunderclap headaches (TCHs) with or without other neurological deficits and diffuse segmental vasoconstrictions of the cerebral arteries which resolve spontaneously within 3 months (1,2). Although the disease is increasingly recognized as a medical condition in the literature, mostly because of the routine availability of non-invasive imaging including computed tomography angiography (CTA), magnetic resonance angiography (MRA), and transcranial Doppler (TCD) (1,3,4), the reports from large case series remain limited and are predominantly from sparse main groups in France, the US, Taiwan, and Korea (5 –11). Furthermore, since the clinical and radiological features of the disease derived from the series reported to date are far from being homogeneous, there is a clear need for more detailed data from large patient cohorts. Therefore, in the present study, we sought to determine the clinical characteristics, risk factors, triggering conditions, as well as detailed neuroimaging and laboratory features of RCVS from a large series of Italian patients recruited in the setting of the Italian Project on Stroke at Young Age (IPSYS).

Methods

Study design and study population

The IPSYS is a countrywide network of neurological centers with special interest in cerebral vascular disease at young age across Italy, aimed at recruiting Caucasian patients with first-ever acute vascular events in the setting of a hospital-based, multi-center, observational study (12). For the purpose of the present study, we retrospectively identified consecutive patients with RCVS regardless of whether they had a stroke or not, at institutions included in the IPSYS network, which serve as referral centers for acute neurological diseases. The recruitment period was January 2011 through January 2018. We diagnosed RCVS patients among those who visited the outpatient headache clinic or the emergency unit, were admitted to the stroke unit or the neurology ward or underwent in-patient consultation in each center. The performance of noninvasive brain vascular imaging investigations (TCD, CTA, or MRA) or conventional cerebral angiography was left to the discretion of the investigator in charge of the patient, when the latter presented with TCH or any acute, severe, persistent or recurrent headache of recent onset not fulfilling the criteria for primary headaches, regardless of concomitant focal neurologic deficit and/or other neurologic manifestation, or cryptogenic stroke. In those cases where imaging findings prompted suspicion of RCVS, a follow-up visit and MRA or CTA to determine the reversibility of intracranial vasoconstriction were scheduled at 3 months after onset. In the present analysis, we included only patients who met the criteria for definite RCVS according to the third edition of the International Classification of Headache Disorders, beta version (ICHD-3 beta)(13). Cases of probable RCVS, that is, patients who had had recurrent, triggered TCHs typical of RCVS but with normal cerebral angiography, did not qualify for the analysis. The study complies with the Declaration of Helsinki. All aspects of the study were approved by the Ethics Committee of the coordinating Center (University of Brescia) and of each study site. Written informed consent was obtained from all patients (or next of kin).

Risk factor definition

Hypertension was defined as systolic blood pressure ≥140 mm Hg and diastolic pressure ≥90 mm Hg in two separate measurements after the acute phase or use of antihypertensive drugs before recruitment. Diabetes mellitus was defined as a history of diabetes mellitus, use of hypoglycemic agent or insulin, or fasting glucose ≥7.0 mmol/L. Smoking history was defined as “current smoking”, including former smokers who had quit smoking for 6 months before the index event, versus “ever smoking” or “never smoking”. Hypercholesterolemia was defined as cholesterol serum levels ≥5.7 mmol/L or use of cholesterol-lowering drugs. Current use of oral contraceptives included current users as well as former users who had quit taking these medications for 1 month before the index event. We also collected information on alcohol consumption, personal history of coronary artery disease (history of physician-diagnosed angina or myocardial infarction) or other heart disease, as well as any vascular disease before the index event. Personal history of migraine was assessed in all patients by study physicians during a face-to-face interview in both the acute phase and follow-up evaluations, according to the diagnostic criteria of the International Headache Society (12,14).

Trigger factors

Based on the individual history of specific precipitating factors with a clear temporal association with the disease occurrence, in agreement with previous reports (7), RCVS was qualified as secondary or idiopathic. Secondary RCVS were cases in whom any conditions that have been reported in the literature as accepted causes of RCVS (i.e. postpartum status or use of serotonergic or adrenergic medications) were identified, while idiopathic RCVS were those in whom the above-mentioned conditions could not be detected.

Clinical features

We collected the following data: recent pregnancy and delivery, use of vasoactive and serotonergic medications or any other medication taken within 15 days before disease occurrence, and detailed characteristics of present headaches and any neurological symptoms. In particular, headache intensity was evaluated by using a verbal scale ranging from 0 (no pain) to 10 (the maximum pain that you can ever imagine). Headaches reaching a maximum intensity above 7/10 in less than 1 min qualified as TCH. Information on duration of symptoms prior to establishment of diagnosis, date of established diagnosis, presence of neurological complications (i.e. seizures, ischemic stroke, intracranial hemorrhage, or posterior reversible encephalopathy syndrome (PRES)) or clinical worsening after diagnosis, and treatments were also collected. Any recurrence of TCH or development of new neurological deficits after treatment and timing of these events were recorded at three-month follow-up.

Radiological and laboratory data

Brain imaging findings and non-invasive and conventional angiography imaging results on diagnosis and on eventual clinical worsening, as well as time to angiography, were also collected. Biological data included results from cerebrospinal fluid (CSF) analysis.

Statistical analyses

Descriptive statistics are presented as mean ± standard deviation or number (percentage). We compared patients’ characteristics by subgroups defined by presumed etiology (idiopathic vs. secondary RCVS) as well as by personal history of TCH at disease onset (RCVS with TCH vs. RCVS without TCH) using the χ² test and Fisher’s exact test for categorical variables and the Student’s t-test for continuous variables. p ≤ 0.01 on two-sided test was considered significant. Data were analyzed using the SPSS (version 21.0) software package (www.spss.com).

Results

The study group was composed of 102 patients with definite RCVS (mean age, 47.2 ± 13.9 years). As expected, there was a female preponderance (female:male ratio, 5:1). The other baseline demographic and clinical characteristics of these subjects are summarized in Table 1.

Table 1.

Baseline demographic characteristics of the study group.

	All (n = 102)	Idiopathic RCVS (n = 81)	Secondary RCVS (n = 21)	p-value	RCVS with TCH (n = 69)	RCVS without TCH (n = 33)	p-value
Age, yrs ± SD	47.2 ± 13.9	49.2 ± 13.9	39.5 ± 11.4	0.004	47.6 ± 13.7	46.3 ± 14.6	0.679
Sex, females	85 (83.3)	67 (82.7)	18 (85.7)	0.743	56 (81.2)	29 (87.9)	0.571
Body mass index, Kg/m²	25.1 ± 4.2	25.0 ± 3.9	25.2 ± 5.1	0.920	25.0 ± 3.7	25.1 ± 5.1	0.917
Coronary artery disease	2 (2.0)	2 (2.4)	0 (0.0)	0.768	2 (2.8)	0 (0.0)	1.000
Previous atrial fibrillation	1 (1.0)	1 (1.2)	0 (0.0)	1.000	1 (1.4)	0 (0.0)	1.000
Previous cerebrovascular disease				0.845			0.233
TIA	1 (1.0)	1 (1.2)	0 (0.0)		0 (0.0)	1 (3.0)
Ischemic stroke	3 (2.9)	2 (2.5)	1 (4.8)		2 (2.9)	1 (3.0)
Hemorrhagic stroke	1 (1.0)	1 (1.2)	0 (0.0)		0 (0.0)	1 (3.0)
Peripheral arterial disease	1 (1.0)	1 (1.2)	0 (0.0)	1.000	1 (1.4)	0 (0.0)	1.000
Hypertension				0.240			0.215
Non-hypertensive	68 (66.7)	51 (63.0)	17 (81.0)		47 (68.1)	21 (63.6)
Hypertensive under treatment	15 (14.7)	14 (17.2)	1 (4.8)		12 (17.4)	3 (9.1)
Hypertensive not under treatment	19 (18.6)	16 (19.8)	3 (14.3)		10 (14.5)	9 (27.3)
Diabetes				0.529			0.367
Non-diabetic	91 (89.2)	73 (90.1)	18 (85.7)		63 (91.3)	28 (84.8)
Diabetic under treatment	10 (9.8)	7 (8.7)	3 (14.3)		5 (7.2)	5 (15.2)
Diabetic not under treatment	1 (1.0)	1 (1.2)	0 (0.0)		1 (1.4)	0 (0.0)
Hypercholesterolemia				0.833
Non-hypercholesterolemic	77 (75.5)	62 (76.5)	15 (71.4)		56 (81.2)	21 (63.6)	0.023
Hypercholesterolemic under treatment with statins	14 (13.7)	11 (13.6)	3 (14.3)		5 (7.2)	9 (27.3)
Hypercholesterolemic not under treatment	11 (10.8)	8 (9.9)	3 (14.3)		8 (11.6)	3 (9.1)
Smoking				0.087			0.140
Never smoking	61 (59.8)	45 (55.6)	16 (76.2)		41 (59.4)	20 (60.6)
Ex smoking	6 (5.9)	4 (4.9)	3 (14.3)		2 (2.9)	4 (12.1)
Current smoking	35 (34.3)	32 (39.5)	2 (9.5)		26 (37.7)	9 (27.3)
Alcohol*				0.431			0.743
Never use	73 (71.5)	56 (69.1)	17 (81.0)		50 (72.5)	23 (69.7)
Low intake	25 (25.4)	21 (25.9)	4 (19.0)		17 (24.6)	8 (24.2)
Moderate intake	4 (3.9)	4 (4.9)	0 (0.0)		2 (2.9)	2 (6.1)
Heavy intake	0 (0.0)	0 (0.0)	0 (0.0)		0 (0.0)	0 (0.0)
Antiplatelet agents	10 (9.8)	7 (8.6)	3 (14.3)	0.426	5 (7.2)	5 (15.2)	0.286
Oral anticoagulants	1 (1.0)	1 (1.2)	0 (0.0)	1.000	0 (0.0)	1 (3.0)	0.324
Migraine
Any migraine	22 (21.6)	12 (14.8)	10 (47.6)	0.002	14 (20.3)	8 (24.2)	0.797
Migraine without aura	17 (16.7)	8 (66.7)	9 (90.0)	0.323	11 (78.6)	6 (75.0)	1.000
Migraine with aura	5 (4.9)	4 (33.4)	1 (10.0)	0.323	3 (21.4)	2 (25.0)	1.000
Other headaches				0.599			0.361
Episodic tension-type headache	6 (6.3)	4 (5.3)	2 (9.5)		5 (7.9)	1 (3.0)
Other headache	2 (2.1)	2 (2.7)	0 (0.0)		2 (3.2)	0 (0.0)

Low alcohol intake was defined as up to seven drinks per week, moderate intake as 7–14 drinks per week for women or 7–21 drinks per week for men, and high intake as more than 14 drinks per week for women or more than 21 drinks per week for men.

TCH: thunderclap headache.

Precipitating factors

Overall, at least one precipitating condition was detected in 57 (55.8%) cases. In particular, RCVS occurred during the postpartum state in six (5.8%) patients, and it co-occurred with a complication of pregnancy (pre-eclampsia) in two (2.0%). Two (2.0%) patients were regular cannabis smokers, while four (3.9%) had used vasoactive substances, including recreational drugs (cocaine, n = 3) the night before the onset of symptoms, and diet pills (n = 1) for less than 2 weeks. Nine (8.8%) patients had been using serotoninergic medications (n = 6, selective serotonin-reuptake inhibitors (SSRI) as anti-depressant medications [n = 3, escitalopram; n = 2, paroxetine; n = 1, sertraline]; n = 3, triptans) on a regular basis for more than 3 months. In three (2.9%) patients, RCVS occurred with the use of blood products, including blood transfusions (n = 1) and use of intravenous immunoglobulin (n = 2), while in two (2.0%) other patients symptoms occurred soon after a carotid endovascular procedure. Other potential triggers were detected in 29 (28.4%) patients and included sexual intercourse (n = 9), major head trauma (n = 1), coughing (n = 1), showering (n = 4), emotional surge (n = 5), or other medical conditions (n = 9) (see Table 2).

Table 2.

Precipitating conditions associated with RCVS.

Any trigger	57 (55.8)
Use of cannabis	2 (2.0)
Postpartum	6 (5.8)
Pregnancy complications	2 (2.0)
Antidepressant medications	6 (5.9)
Vasoactive substances	4 (3.9)
Triptans	3 (2.9)
Carotid endovascular procedures	2 (2.0)
Blood products	3 (2.9)
Other	29 (28.4)

Headaches

Headache was the presenting symptom in all patients. However, TCH was documented at disease onset only in 69 (67.6%), and it typically recurred only in 42 (60.9%) of these cases. Pain location was mainly bilateral (n = 63; 91.3%), and nausea/vomiting were the most frequently reported associated symptoms (n = 56; 81.2%). Severe headache of gradual onset was reported by 15 (14.7%) patients, while eight (7.8%) patients had throbbing headache. The remaining patients reported other varieties of pain, including persistent headaches of variable severity and acute headache episodes peaking in more than 1 minute. Most patients with episodic pain also had lingering headache of mild severity between their acute headaches.

Brain imaging

The most frequent abnormality detected at brain imaging was cortical subarachnoid hemorrhage (cSAH; n = 16 [15.7%]), followed by acute cerebral infarction (n = 12 [11.7%]) and intracerebral hemorrhage (ICH; n = 3 [2.9%]). Fourteen of these patients showed persistent neurological deficits.

Vascular imaging

The diagnosis of vasospasm was made by cerebral magnetic resonance angiography (MRA) in the majority of cases (n = 47 [46.1%]), followed by conventional digital subtraction angiography (n = 42 [41.2%]), computed tomographic angiography (CTA, n = 12 [11.8%]), and transcranial Doppler sonography (n = 1 [1.0%]). Overall, the first vascular imaging procedure was performed at a mean of 5.9 ± 7.4 days after symptom onset. In 36 (35.3%) cases, however, cerebral vasospasm was not detectable on the first investigation and it was visualized on a second angiogram (MRA in 28 cases, CTA in eight) performed at a mean of 15.4 ± 14.8 days following symptom occurrence.

Cerebrospinal fluid analysis

Lumbar puncture was performed in 45 (44.1%) patients. Nine had slightly elevated CSF WBC (mean, 7.8/mm³; range, 5–16) and six (5.9%) slightly elevated CSF protein levels (mean 93 mg/l, range 67–111).

Treatment

Eighty (78.4%) patients were treated with nimodipine, by intravenous infusion (1–2 mg/hours) followed by oral administration (n = 10) or by direct oral administration (n = 70; 30–60 mg every 4 hours) for 4 to 8 weeks; 10 (9.8%) patients received glucocorticoids, while in the remaining 12 (11.8%) cases no specific therapy was used because of the spontaneous improvement of symptoms.

Idiopathic versus secondary RCVS

RCVS was classified idiopathic in 81 (79.4%) subjects and secondary in 21 (20.6%). Patients with idiopathic disease were older, more often non-migraineurs, and more frequently had the typical TCH at disease onset. The course of the disease in these cases was less frequently complicated by seizures and cerebral infarction, but more often by cortical subarachnoid hemorrhage, compared to patients with secondary RCVS (Tables 1 and 3).

Table 3.

Clinical features of the study group according to RCVS etiology.

	All (n = 102)	Idiopathic RCVS (n = 81)	Secondary RCVS (n = 21)	p-value	RCVS with TCH (n = 69)	RCVS without TCH (n = 33)	p-value
Headache
Thunderclap headache	69 (67.6)	63 (77.8)	6 (28.6)	≤0.001
Severe headache of gradual onset	15 (14.7)	8 (9.9)	7 (33.7)	0.013
Throbbing headache	8 (7.8)	2 (2.5)	6 (28.6)	0.001
Other headache	10 (9.8)	8 (9.9)	2 (9.5)	1.000
Recurrent headaches	62 (60.7)	48 (59.3)	14 (66.7)	0.536
Seizures
Any seizures	17 (16.7)	9 (11.1)	8 (38.1)	0.007	9 (13.0)	8 (24.2)	0.167
Generalized tonic-clonic seizures	12 (11.8)	7 (8.6)	5 (23.8)	0.120	6 (8.7)	6 (18.2)	0.195
Focal seizures	4 (3.9)	1 (1.2)	3 (14.3)	0.027	2 (2.9)	2 (6.1)	0.593
Non-convulsive status epilepticus	1 (1.0)	1 (1.2)	0 (0.0)	1.000	1 (1.4)	0 (0.0)	1.000
Stroke
Cerebral infarction	12 (11.7)	5 (6.1)	7 (33.3)	0.002	6 (8.7)	6 (18.2)	0.195
Intracerebral hemorrhage	3 (2.9)	1 (1.2)	2 (9.5)	0.107	1 (1.4)	2 (6.1)	0.244
Cortical subarachnoid hemorrhage	16 (15.7)	16 (19.8)	0 (0.0)	0.038	13 (18.8)	3 (9.1)	0.255
PRES	31 (39.4)	21 (25.9)	10 (47.6)	0.066	22 (31.9)	9 (27.3)	0.818
Cervical artery dissection	2 (2.0)	2 (2.0)	0 (0.0)	1.000	2 (2.9)	0 (0.0)	1.000

PRES: posterior reversible encephalopathy syndrome; TCH: thunderclap headache.

RCVS with TCH versus RCVS without TCH

Apart from a higher prevalence of hypercholesterolemia in the subgroup of RCVS patients without typical TCH, we did not detect any difference in both predisposing conditions and clinical features between the two groups defined by headache characteristics (Tables 1 and 3).

Discussion

The main findings from the analysis of this large series of Italian patients with definite RCVS were a) confirmation that the disease targets middle-aged women in most of the cases; b) the evidence, consistent with the literature, that precipitating conditions or potential triggers with putative impact on cerebral arterial tone are a frequent finding in these patients; c) the relatively high rate of RCVS related to putative etiologic conditions, which occurred in approximately one out of five cases. These patients were, furthermore, younger than those with idiopathic RCVS, more frequently had a personal history of migraine, and more likely had atypical clinical manifestations, with TCH as presenting symptom in less than one-third of cases and a relatively high rate of neurological complications leading to incomplete recovery; d) the difficulty in making the correct diagnosis in a non-negligible proportion of cases, about one-third of the patients having a normal cerebral vasculature at initial angiogram.

In the context of the current literature

Baseline demographic characteristics of the patients included in the present case series are in line with those from other cohorts, regarding, in particular, the mean age of subjects at the time of disease occurrence and the obvious female preponderance. Conversely, some findings might appear different from those reported in the literature. First, our patients seem to have a worse cardiovascular risk profile compared to patients from other cohorts, especially regarding the prevalence of hypertension, which was diagnosed in about one case out of three in our data set. Second, although TCH was the presenting symptom in most of our patients, it was less frequently detected than in previous reports, more than one-third of cases complaining of a headache other than thunderclap. When present, however, TCH tended to recur over a mean period of one week following symptom onset in most of the patients, which, as already noticed, can be considered the distinctive clinical feature of RCVS. Third, neurological complications, especially seizures and cerebral infarction, were more prevalent in our series than in most RCVS cohorts (Table 4) (5 –11). This finding, in addition to the unexpectedly high prevalence of PRES, puts into question the prevailing conception that RCVS has a benign course with self-limited syndrome in the majority of cases, makes an appropriate level of clinical and instrumental monitoring mandatory in these patients, and warrants further studies aimed at identifying those cases at increased risk of complications. Although such differences are noteworthy, they are likely the unavoidable consequence of the specific design of each study and, in particular, of the target group from which cases of RCVS were identified. Referrals and inpatients are more likely to have an increased burden of traditional cardiovascular risk factors and are more prone to harbor brain lesions than patients recruited from those who complain of TCHs. Since our patients were recruited from both outpatient headache clinic and emergency unit-stroke unit as well as from in-patient consultation, a selection bias is likely to be less relevant. Similarly, the extensive use of cerebral vascular imaging as routine diagnostic work-up in the IPSYS centers provides a plausible explanation for the relatively high rate of RCVS with atypical presentation, such as the cases with non-specific persistent headache we observed in our setting and, indirectly, underscores the need for a validated imaging algorithm to prevent the disease from being underdiagnosed. Overall, taking into account all the considerations mentioned above, the RCVS profile derived from our data is only slightly different from that emerging from the few other hospital-based cohorts reported so far. Our findings prompt emphasis of the wide variability in the manifestation of the disease and, going a step further, underscore that increased disease awareness might affect the likelihood of RCVS diagnosis, particularly in patients with subtle, atypical symptoms or cryptogenic stroke.

Table 4.

Summary of selected studies including large series of RCVS patients.

	Katz et al., 2014 (n = 59)(5)	de Boysson et al., 2018 (n = 173)(6)	Choi et al., 2017 (n = 138)(7)	Singhal et al., 2016 (n = 159)(8)	Chen et al., 2018 (n = 65)(9)	Chen et al., 2010 (n = 77)(10)	Lee et al., 2017 (n = 41)(11)	Present study (n = 102)
Recruitment	Retrospective, from two centers with emergency unit	Prospective, from a single center with emergency headache center and stroke unit	Prospective, from a single center with headache clinic, emergency unit, stroke unit, and in-patient consultation	Retrospective, from a single center with emergency unit and stroke unit	Prospective, from a single center with headache clinic and emergency department	Prospective, from a headache clinic	Prospective, from a single center emergency unit, outpatient headache clinic, and inpatient consultation	Retrospective, from a network of neurological centers with emergency unit, outpatient headache clinic, and inpatient consultation
Duration	US, 2004–2012 Argentina, 2009–2012	2004–2018	2012–2016	1998–2015	2010–2012	2002–2009	2015–2016	2011–2018
Country	US, Argentina	France	Korea	US	Taiwan	Taiwan	Korea	Italy
Age, yrs	47 (15–75)	44.0 (17–85)	50.2 ± 12.1, definite RCVS 52.0 ± 12.6, probable RCVS	43.5 ± 13.0	50.1 (26–67)	47.7 ± 11.6	51 (45–59)	47.2 ± 13.9 only definite RCVS
Sex, females	88.1	70.5	81.8	72.0	89.2	89.6	87.8	83.3
Hypertension	22.0	15.0	20.2	37.0	10.8	24.7		33.3
Current smoking	21.1	36	6.5					34.3
Migraine	27.1	32.0	16.6	42.0	24.6	16.9	9.8	21.6
Clinical features
Headache
Thunderclap headache		94.0	89.8	89.0		100.0	80.5	67.6
Severe headache of gradual onset			7.9					14.7
Seizures		5.0	2.1	15.0		1.2	4.9	16.7
Cerebral infarction	1.6	8.0	4.3	33.0	1.5	7.7	7.3	11.7
Intracerebral hemorrhage	10.1	9.0		13.0	1.5	0.0		2.9
Cortical subarachnoid hemorrhage	25.4	27.0	5.0	39.0	1.5	0.0	4.9	15.7
PRES	6.7	8.0	3.6	28.0	4.6	9.1	9.8	39.4
Cervical artery dissection		12.0			1.5			2.0

PRES: posterior reversible encephalopathy syndrome.

Finally, in agreement with findings from prior cohorts, the first angiogram was normal in more than one third of our cases when performed within the first week of symptom onset, and it became diagnostic at a mean of two weeks (15). These observations underline the importance of repeated vascular imaging investigations in the diagnostic workup of RCVS, even in those cases with persistent non-TCH.

Strengths and limitations

One of the strengths of the present study relies on the thoroughness of case ascertainment, which allowed unbiased diagnosis and comprehensive evaluation. In this regard, our decision to include only patients who met the criteria for definite RCVS was taken in order to reduce the risk of misdiagnosis as much as possible. Nevertheless, several limitations should also be considered. Although this is one of the largest series reported thus far, the number of patients included might have been too small and the analysis underpowered to identify subtle correlations with specific risk factors and comorbid conditions. Therefore, estimates, especially for subgroups that contain only a few patients, might be unstable and should, therefore, be interpreted with caution. In addition, the criteria we adopted for the definition of specific subgroups, such as those of idiopathic RCVS and secondary RCVS, is another issue. Our results were, actually, derived on the basis of a non-validated etiologic classification of the disease, which potentially limits their generalizability. However, in the absence of standardized classification criteria, any other way of subcategorizing the disease based on the presumed etiology would have been equally arbitrary. Obviously, because the study was designed as a multicenter registry for epidemiologic purposes, any exhaustive investigation of pathogenic determinants was beyond the scope of the present analysis. Finally, inaccurate capture of the incident cases cannot be excluded. This, in addition to the fact that the present cohort is not population-based, implicates that our study group could be similar to a convenience sample. However, this is an unavoidable feature of all hospital-based registries even when all consecutive cases diagnosed at the participating centers are included.

Conclusions

In conclusion, the present study showed that the clinical manifestations of RCVS are slightly different from and more heterogeneous than those observed in some previous cohorts and suggests, in particular, that such variability might be partly related to coexistent precipitating conditions with a putative etiologic role in disease occurrence. Whether this depends on different biologic processes underlying the disease is beyond the scope of our analysis and warrants further investigations. Our results also confirmed the difficulty in making a diagnosis in selected cases, especially when the angiogram performed within a week of symptom onset is normal, which implies that a high level of clinical suspicion is needed in these circumstances and that the opportunity for repeated vascular investigations about two weeks later should be considered, even in case of persistent non-TCH. Finally, neurological complications leading to persistent deficits are all but uncommon. Formal randomized trials on the management of RCVS and its impact on patient outcome or prognosis are, therefore, urgently needed.

Footnotes

Clinical implications

Reversible cerebral vasoconstriction syndrome (RCVS) targets middle-aged women in most of the cases, is frequently preceded by precipitating conditions with putative impact on cerebral arterial tone, and about one-third of the patients have a normal cerebral vasculature at initial angiogram.

Patients with RCVS related to putative etiologic conditions are more likely to have atypical manifestations with a relatively high rate of neurological complications. This suggests that the biologic process underlying the disease might partly vary according to the causative mechanisms.

The first angiogram, irrespective of type, is negative in more than one third of cases if it is performed within a week of symptom onset. The opportunity for performing a second angiogram at two weeks should be considered in the event of persistent, though atypical, headache.

Author contributions

Filomena Caria: Manuscript drafting/revising, study design, data analysis and interpretation, data acquisition. Alessandro Pezzini: Statistical analysis, manuscript drafting/revising, study design, data analysis and interpretation, data acquisition, statistical analysis, study supervision. All authors: Manuscript drafting/revising, data acquisition.

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. The sponsor had no role in the design and conduct of the study; the collection, management, analysis, and interpretation of the data; the preparation, review or approval of the manuscript; or the decision to submit the manuscript for publication. Alessandro Pezzini had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: The Italian Project on Stroke in Young Adults (IPSYS) is supported by a grant from the Associazione per la Lotta alla Trombosi e alle Malattie Cardiovascolari (ALT).

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