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Vasoconstriction and long-term headache in reversible cerebral vasoconstriction syndrome

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Neha Kumar
Neha Kumar
Neha Kumar
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Sandeep Kumar
Sandeep Kumar
Sandeep Kumar
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Eva Rocha at Universidade Federal de São Paulo
Eva Rocha
Vasileios Lioutas at Beth Israel Deaconess Medical Center
Vasileios Lioutas
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Abstract

Background: Angiographic vasoconstriction in reversible cerebral vasoconstriction syndrome (RCVS) is often undetectable at symptom onset and the diagnosis relies on clinical presentation. Although thunderclap headache is a hallmark feature of RCVS, the incidence and predictors of long-term headaches (LTH) are incompletely understood. Our study aims were twofold: to examine the sensitivity and specificity of a recently developed score (RCVS2) for vasoconstriction detection in a real-world clinical context and describe the incidence and predictors of LTH beyond the acute phase of RCVS. Methods: Retrospective analysis of consecutive patients with clinical diagnosis of RCVS in a tertiary hospital between 2017 and 2021. We examined associations between demographic factors, comorbidities, medications, imaging characteristics, and LTH (defined as at least one episode present at greater than 6-months follow-up necessitating medication). We separately examined the association between RCVS2 score and angiographic vasoconstriction and computed its sensitivity, specificity, and negative and positive predictive value based on established cutoffs (certain ≥ 5, negative ≤ 2). Results: We included 55 patients, 50.5 (± 13.7) years; 41 (75%) female. 25 (49%) patients had LTH; only prior history of headache was significantly associated with LTH [OR 4.3, 95% CI (1.1-16.2), p = 0.03]. We found a significant association between RCVS2 score and angiographic vasoconstriction [OR 1.49, 95% CI (1.18-1.88), p = 0.001]; sensitivity, specificity, and positive and negative predictive value were 64%, 94%, 95% and 58% respectively. Conclusions: Approximately 50% of RCVS patients experienced LTH; only prior headache history was associated with its incidence. The RCVS2 score had a significant association with high specificity and positive predictive value for angiographic vasoconstriction in our cohort, validating its utility in improving the accuracy of diagnosis in the clinical setting.
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Vol.:(0123456789)
1 3
Journal of Neurology (2023) 270:1647–1653
https://doi.org/10.1007/s00415-022-11511-2
ORIGINAL COMMUNICATION
Vasoconstriction andlong‑term headache inreversible cerebral
vasoconstriction syndrome
NehaKumar1,2 · SandeepKumar1,2· EvaRocha1,2· Vasileios‑ArseniosLioutas1,2
Received: 15 September 2022 / Revised: 29 November 2022 / Accepted: 30 November 2022 / Published online: 6 December 2022
© The Author(s), under exclusive licence to Springer-Verlag GmbH Germany 2022
Abstract
Background Angiographic vasoconstriction in reversible cerebral vasoconstriction syndrome (RCVS) is often undetectable
at symptom onset and the diagnosis relies on clinical presentation. Although thunderclap headache is a hallmark feature
of RCVS, the incidence and predictors of long-term headaches (LTH) are incompletely understood. Our study aims were
twofold: to examine the sensitivity and specificity of a recently developed score (RCVS2) for vasoconstriction detection in a
real-world clinical context and describe the incidence and predictors of LTH beyond the acute phase of RCVS.
Methods Retrospective analysis of consecutive patients with clinical diagnosis of RCVS in a tertiary hospital between 2017
and 2021. We examined associations between demographic factors, comorbidities, medications, imaging characteristics, and
LTH (defined as at least one episode present at greater than 6-months follow-up necessitating medication). We separately
examined the association between RCVS2 score and angiographic vasoconstriction and computed its sensitivity, specificity,
and negative and positive predictive value based on established cutoffs (certain ≥ 5, negative ≤ 2).
Results We included 55 patients, 50.5 (± 13.7) years; 41 (75%) female. 25 (49%) patients had LTH; only prior history of
headache was significantly associated with LTH [OR 4.3, 95% CI (1.1–16.2), p = 0.03]. We found a significant association
between RCVS2 score and angiographic vasoconstriction [OR 1.49, 95% CI (1.18–1.88), p = 0.001]; sensitivity, specificity,
and positive and negative predictive value were 64%, 94%, 95% and 58% respectively.
Conclusions Approximately 50% of RCVS patients experienced LTH; only prior headache history was associated with its
incidence. The RCVS2 score had a significant association with high specificity and positive predictive value for angiographic
vasoconstriction in our cohort, validating its utility in improving the accuracy of diagnosis in the clinical setting.
Keywords Reversible cerebral vasoconstriction· Headache
Introduction
Reversible vasoconstriction syndrome (RCVS) is a clinico-
imaging entity comprising a multitude of pathologies previ-
ously known with various names, including Call–Fleming
syndrome, postpartum angiitis, and others [1].
In practice, clinical judgement is often used to diag-
nose RCVS, as some of its key features, primarily angio-
graphic confirmation of vasoconstriction, are elusive, given
a temporal discrepancy between the appearance of clinical
symptoms and radiographic findings [2–4]. Thus, RCVS is
often diagnosed in the absence of demonstrable vasocon-
striction. A scoring method (RCVS2) was recently developed
to distinguish RCVS from other large and medium-vessel
intracranial arteriopathies and achieved very good specificity
and sensitivity [5].
Vasoconstriction is thought to have a central pathophysi-
ologic role in headache symptoms of RCVS. Although
recurrent thunderclap headache (TCH) is one of the most
prominent symptoms of RCVS, there is paucity of data on
whether headaches are a long-term consequence. Approxi-
mately 50% of patients are reported to have chronic head-
aches of mild-to-moderate intensity distinct from TCH [6].
Short-term post-RCVS headache is also common, affecting
approximately 50% of patients, although half of them recov-
ered within a year from RCVS. Higher anxiety levels and
* Neha Kumar
nkumar3@bidmc.harvard.edu
1 Department ofNeurology, Beth Israel Deaconess Medical
Center, Harvard Medical School, 330 Brookline Ave,
Boston, MA02215, USA
2 Department ofNeurology, Universidade Federal de São
Paulo, SãoPaulo, Brazil
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
... Around half (24/45) of the patients continued to have chronic headaches after RCVS resolution [36]. In a recent study of long-term effects, 50% of patients were found to experience long-term headaches, defined as headaches beyond 6 months from onset [39]. This chronic headache, which can be triggered by RCVS, has lately begun to be recognized and described even further. ...
... The RCVS2 score and diagnostic approach can be used to promptly diagnose and distinguish RCVS from mimics, using easily available admission variables (the presence of thunderclap headache, the absence of intracranial carotid artery involvement, the presence of a vasoconstrictive trigger, gender, and the presence of subarachnoid hemorrhage) [11]. Kumar et al. supported the usefulness of the RCVS2 score in a real-world clinical context using a cohort of 55 patients and demonstrated that the RCVS2 score had a significant association with high specificity and positive predictive value for angiographic vasoconstriction [39]. Cho et al., however, developed a new prediction model, the RCVS-TCH score, which showed high specificity and sensitivity for discriminating RCVS in patients with TCH. ...
Headache Attributed to Reversible Cerebral Vasoconstriction Syndrome (RCVS)
Article
Full-text available
  • Aug 2023
Reversible cerebral vasoconstriction syndrome (RCVS) is a condition with variable outcomes presenting a new onset thunderclap headache accompanied by focal neurological symptoms or seizures. It can be idiopathic or arise secondarily to a variety of trigger factors. The condition is increasingly recognized in clinical practice, but many facets remain poorly understood. This article aims to clarify the headache characteristics in RCVS, the temporal association of angiographic findings, the potential association of the condition with SARS-CoV-2 infection, and the clinical presentation of RCVS in children and is based on a systematic PRISMA search for published analytical or large descriptive observational studies. Data from 60 studies that fulfilled specific criteria were reviewed. Most people with RCVS exhibit a typical thunderclap, explosive, or pulsatile/throbbing headache, or a similar acute and severe headache that takes longer than 1 min to peak. Atypical presentations or absence of headaches are also reported and may be an underrecognized phenotype. In many cases, headaches may persist after resolution of RCVS. Focal deficits or seizures are attributed to associated complications including transient ischemic attacks, posterior reversible encephalopathy syndrome, ischemic stroke, cerebral edema, and intracranial hemorrhage. The peak of vasoconstriction occurs usually within two weeks after clinical onset, possibly following a pattern of centripetal propagation, and tends to resolve completely within 3 months, well after symptoms have subsided. There are a few reports of RCVS occurring in relation to SARS-CoV-2 infection, but potential underlying pathophysiologic mechanisms and etiological associations have not been confirmed. RCVS occurs in children most often in the context of an underlying disease. Overall, the available data in the literature are scattered, and large-scale prospective studies and international collaborations are needed to further characterize the clinical presentation of RCVS.
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Reversible Cerebral Vasoconstriction Syndrome:a review of pathogenesis, clinical presentation and treatment
Article
  • May 2023
  • Int J Stroke
Reversible segmental narrowing of the intracranial arteries has been described since several decades in numerous clinical settings, using variable nosology. Twenty-one years ago, we tentatively proposed the unifying concept that these entities, based on similar clinical-imaging features, represented a single cerebrovascular syndrome. This 'reversible cerebral vasoconstriction syndrome' or RCVS has now come of age. A new ICD-10 code has been established, enabling larger-scale studies. The RCVS2 scoring system provides high accuracy in confirming RCVS diagnosis and excluding mimics such as primary angiitis of the central nervous system. Several groups have characterized its clinical-imaging features. RCVS predominantly affects women. Recurrent worst-ever (thunderclap) headaches are typical at onset. While initial brain imaging is often normal, approximately one-third to half develop complications such as convexity subarachnoid hemorrhages, lobar hemorrhages, ischemic strokes located in arterial 'watershed' territories and reversible edema, alone or in combination. Vasoconstriction evolves over hours to days, first affecting distal and then the more proximal arteries. An overlap between RCVS and primary thunderclap headache, posterior reversible encephalopathy syndrome, Takotsubo cardiomyopathy, transient global amnesia, and other conditions has been recognized. The pathophysiology remains largely unknown. Management is mostly symptomatic: headache relief with analgesics and oral calcium-channel blockers, removal of vasoconstrictive factors, and avoidance of glucocorticoids which can significantly worsen outcome. Intra-arterial vasodilator infusions provide variable success. Overall, 90-95% of admitted patients achieve complete or major resolution of symptoms and clinical deficits within days to weeks. Recurrence is exceptional, although 5% can later develop isolated thunderclap headaches with or without mild cerebral vasoconstriction.
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Post-reversible cerebral vasoconstriction syndrome headache
Article
Full-text available
  • Dec 2021
  • J HEADACHE PAIN
Background Chronic headache may persist after the remission of reversible cerebral vasoconstriction syndrome (RCVS) in some patients. We aimed to investigate the prevalence, characteristics, risk factors, and the impact of post-RCVS headache. Methods We prospectively recruited patients with RCVS and collected their baseline demographics, including psychological distress measured by Hospital Anxiety and Depression scale. We evaluated whether the patients developed post-RCVS headache 3 months after RCVS onset. The manifestations of post-RCVS headache and headache-related disability measured by Migraine Disability Assessment (MIDAS) scores were recorded. Results From 2017 to 2019, 134 patients with RCVS were recruited, of whom, 123 finished follow-up interviews (response rate 91.8%). Sixty (48.8%) patients had post-RCVS headache. Migrainous features were common in post-RCVS headache. Post-RCVS headache caused moderate-to-severe headache-related disability (MIDAS score > 10) in seven (11.7%) patients. Higher anxiety level (odds ratio 1.21, p = 0.009) and a history of migraine (odds ratio 2.59, p = 0.049) are associated with post-RCVS headache. Survival analysis estimated that 50% post-RCVS headache would recover in 389 days (95% confidence interval: 198.5–579) after disease onset. Conclusions Post-RCVS headache is common, affecting half of patients and being disabling in one-tenth. Higher anxiety level and migraine history are risk factors. Half of the patients with post-RCVS headache would recover in about a year.
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Vascular wall imaging in reversible cerebral vasoconstriction syndrome - A 3-T contrast-enhanced MRI study
Article
Full-text available
  • Aug 2018
  • J HEADACHE PAIN
Background: Limited histopathology studies have suggested that reversible cerebral vasoconstriction syndromes (RCVS) does not present with vascular wall inflammation. Previous vascular imaging studies have had inconsistent vascular wall enhancement findings in RCVS patients. The aim of this study was to determine whether absence of arterial wall pathology on imaging is a universal finding in patients with RCVS. Methods: We recruited patients with RCVS from Taipei Veterans General Hospital prospectively from 2010 to 2012, with follow-up until 2017 (n = 48). We analyzed the characteristics of vascular wall enhancement in these patients without comparisons to a control group. All participants received vascular wall imaging by contrasted T1 fluid-attenuated inversion recovery with a 3-T magnetic resonance machine. The vascular wall enhancement was rated as marked, mild or absent. Results: Of 48 patients with RCVS, 22 (45.8%) had vascular wall enhancement (5 marked and 17 mild). Demographics, clinical profiles, and cerebral artery flow velocities were similar across patients with versus without vascular wall enhancement, except that patients with vascular wall enhancement had fewer headache attacks than those without (p = 0.04). Follow-up imaging completed in 14 patients (median interval, 7 months) showed reduced enhancement in 9 patients, but persistent enhancement in 5. Conclusion: Almost half of our RCVS patients exhibited imaging enhancement of diseased vessels, and it was persistent for approximately a third of those patients with follow-up imaging. Both acute and persistent vascular wall enhancement may be unhelpful for differentiating RCVS from central nervous system vasculitis or subclinical atherosclerosis.
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The International Classification of Headache Disorders, 3rd edition (ICHD-3)
Article
Full-text available
  • Jul 2018
Third edition of the International Classification of Headache Disorders
View
Transcranial Doppler findings in reversible cerebral vasoconstriction syndrome
Article
  • Nov 2021
Background and Purpose Reversible cerebral vasoconstriction syndrome (RCVS) is a syndrome characterized by reversible segmental vasoconstriction of cerebral arteries. Digital subtraction and noninvasive angiograms are typically used to detect vasospasm; however, due to the dynamic nature of RCVS these tests are often negative initially and may need to be repeated multiple times. Transcranial Doppler (TCD) offers many advantages as it is a noninvasive and nonradiating modality. Studies investigating its diagnostic utility for capturing vasospasm and studying temporal evolution of RCVS are limited. Methods We conducted a retrospective analysis on all patients admitted with suspected RCVS from 2009 to 2014 to a single center at Jackson Memorial Hospital. Results We identified 9 patients (88.9% women, age 46.6 ± 13.5 years) who met diagnostic criteria for RCVS. All patients presented with headache, 5 developed nonaneurysmal subarachnoid hemorrhage, 5 developed ischemic stroke, and 1 developed posterior reversible encephalopathy syndrome. At initial TCD, 8 patients had increased flow velocities in at least one large intracranial artery and ultimately all patients had abnormal middle cerebral artery flow velocity over the course of RCVS. We found that the number of vessels with abnormal velocities increases gradually and peaks between 13 and 14 days after first symptom onset. Finally, mean flow velocity of affected vessels also increases around the same time frame and normalizes at 60 days. Conclusions In this case series, we found TCD to be useful in detecting vasospasm and monitoring the temporal evolution of RCVS. TCD could be a helpful clinical tool to diagnose and monitor RCVS.
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Transcranial Doppler findings in a population with clinical probable reversible cerebral vasoconstriction syndrome
Article
  • Oct 2021
  • REV NEUROL-FRANCE
Objective To describe transcranial Doppler (TCD) findings in a population with clinical probable RCVS. Exploratory objectives included the study of clinical characteristics of probable RCVS patients with and without spasm detected by TCD. Methods Cross-sectional cohort study of patients with thunderclap headache (TCH) without subarachnoid hemorrhage (SAH) of our neurology and headache center between 2010 and 2019, selecting patients with clinical diagnosis of probable RCVS (negative angiography study) by ICHD-3 criteria and with at least two TCD studies. Results From 114 TCH patients, 36/114 had probable RCVS by ICHD-3 criteria and had at least two TCD studies available. The mean age at RCVS onset was 42.9 years (21–72 years); 29/36 (80.6%) were female, 7/28 (25%) had cardiovascular risk factors and 20/36 (55.6%) had history of migraine. Most common triggers were stressful emotion, drugs, valsalva maneuvers and sexual activity. Five/36 (13.9%) had complications and 3/36 (8.3%) had late recurrence. Initial TCD was performed on average of 16 (6–26) days after headache onset. Twenty-nine had vasospasm on TCD, presenting mean flow velocity of MCA (VMCA) of 135.7 ± 17.0 cm/s and mean maximum VMCA of 138.3 ± 17.2. Vasospasm was mild in 21/29 patients (72.4%) and moderate in 8/29 (27.6%). Complete VMCA normalization occurred on average 41 (30–70) days after headache onset and 24 (11–47) days after initial TCD. The group of patients with vasospasm detected by TCD had more female patients (26/29, 89.7% vs. 3/7, 42.8%, P = 0.016), and more TCH attacks (mean of 3.6 vs. 2.14, P = 0.049). Conclusion TCD may be a useful tool in the identification of vasospasm in patients with probable RCVS, supporting the diagnosis of RCVS in patients presenting with recurrent TCH without SAH.
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Vessel wall MR imaging for the detection of intracranial inflammatory vasculopathies
Article
  • Aug 2020
Intracranial vasculopathies are routinely investigated by lumen-based modalities such as magnetic resonance angiography (MRA), computed tomography angiography (CTA), and digital subtraction angiography (DSA). These techniques are useful to analyze the vessel lumen, allowing to detect vessel stenosis or occlusion. However, the primum movins of the disease, i.e., an abnormal thickening of the vessel wall, remains within the arterial wall. The vasculopathy can moreover be present without always narrowing the lumen or modifying its regularity. Hence, there is a need to detect directly and analyze vessel wall abnormalities. Development of 3D high-resolution black blood sequences for intracranial vessel wall MR imaging (VW-MRI) enabled routine clinical applications not only vasculitis, but also of intracranial atherosclerotic disease (ICAD), intracranial dissections, reversible intracranial dissections, reversible cerebral vasoconstriction syndrome (RCVS), Moyamoya disease, and intracranial aneurysms. This high-resolution intracranial VW- MRI approach is increasingly used on a clinical basis at many centers to solve diagnostic problems, especially in patients with ischemic stroke or intracranial hemorrhage. An expert consensus Guideline from the American Society of Neuroradiology provides recommendations for clinical implementation of intracranial vessel wall MRI. There are several technical aspects needed to be considered when implementing VW-MRI in intracranial vessels, including flow suppression, both in blood and cerebrospinal fluid (CSF), spatial resolution and signal-to-noise ratio (SNR). In this article, we review the technical aspects of VW-MRI, and recommend applications for vascular diseases including non-occlusive intracranial vasculopathies, Moyamoya disease, and identifying culprit plaques. We also give a focus on the utility of VW-MRI for determining stroke etiology in adults and in children and young adults.
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RCVS 2 score and diagnostic approach for reversible cerebral vasoconstriction syndrome
Article
  • Jan 2019
Objective: To develop a method to distinguish reversible cerebral vasoconstriction syndrome (RCVS) from other large/medium-vessel intracranial arteriopathies. Methods: We identified consecutive patients from our institutional databases admitted in 2013-2017 with newly diagnosed RCVS (n = 30) or non-RCVS arteriopathy (n = 80). Admission clinical and imaging features were compared. Multivariate logistic regression modeling was used to develop a discriminatory score. Score validity was tested in a separate cohort of patients with RCVS and its closest mimic, primary angiitis of the CNS (PACNS). In addition, key variables were used to develop a bedside approach to distinguish RCVS from non-RCVS arteriopathies. Results: The RCVS group had significantly more women, vasoconstrictive triggers, thunderclap headaches, normal brain imaging results, and better outcomes. Beta coefficients from the multivariate regression model yielding the best c-statistic (0.989) were used to develop the RCVS2 score (range -2 to +10; recurrent/single thunderclap headache; carotid artery involvement; vasoconstrictive trigger; sex; subarachnoid hemorrhage). Score ≥5 had 99% specificity and 90% sensitivity for diagnosing RCVS, and score ≤2 had 100% specificity and 85% sensitivity for excluding RCVS. Scores 3-4 had 86% specificity and 10% sensitivity for diagnosing RCVS. The score showed similar performance to distinguish RCVS from PACNS in the validation cohort. A clinical approach based on recurrent thunderclap headaches, trigger and normal brain scans, or convexity subarachnoid hemorrhage correctly diagnosed 25 of 37 patients with RCVS2 scores 3-4 across the derivation and validation cohorts. Conclusion: RCVS can be accurately distinguished from other intracranial arteriopathies upon admission, using widely available clinical and imaging features. Classification of evidence: This study provides Class II evidence that the RCVS2 score accurately distinguishes patients with RCVS from those with other intracranial arteriopathies.
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Primary angiitis of the CNS and reversible cerebral vasoconstriction syndrome: A comparative study
Article
  • Sep 2018
Objectives: To further improve the distinction between primary angiitis of the CNS (PACNS) and reversible cerebral vasoconstriction syndrome (RCVS). Methods: We compared 2 large French cohorts of patients with PACNS (n = 110, retrospectively and prospectively enrolled) and RCVS (n = 173, prospectively enrolled). Results: Patients with RCVS were predominantly female (p < 0.0001), with migraines (p < 0.0001), and were more often exposed to vasoactive substances (p < 0.0001) or postpartum (p = 0.002) than patients with PACNS. Headache, especially thunderclap headache, was more frequent in RCVS (both p < 0.0001). Thunderclap headache was absent in only 6% of patients with RCVS and was mainly recurrent (87%) and provoked (77%) mostly by sexual intercourse, exertion, or emotion. All other neurologic symptoms (motor deficit, seizure, cognitive disorder, or vigilance impairment, all p < 0.0001) were more frequent in PACNS. At admission, brain CT or MRI was abnormal in all patients with PACNS and in 31% of patients with RCVS (p < 0.0001). Acute ischemic stroke was more frequent in PACNS than in RCVS (p < 0.0001). Although intracerebral hemorrhage was more frequent in PACNS (p = 0.006), subarachnoid hemorrhage and vasogenic edema predominated in RCVS (p = 0.04 and p = 0.01, respectively). Multiple small deep infarcts, extensive deep white matter lesions, tumor-like lesions, or multiple gadolinium-enhanced lesions were observed only in PACNS, whereas cervical artery dissection was found only in RCVS. Conclusions: Our study confirms that careful analysis of clinical context, headache features, and patterns of brain lesions can distinguish PACNS and RCVS within the first few days of admission in most cases. However, diagnosis remains challenging in a few cases.
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