Continuing Education Activity

Reversible cerebral vasoconstriction syndrome (RCVS) is a medical condition in which there is multifocal arterial constriction and dilation in the cerebral vasculature and which may be associated with nonaneurysmal subarachnoid hemorrhage. This condition can correlate with pregnancy and exposure to certain drugs. This activity outlines the evaluation and management of reversible cerebral vasoconstriction syndromes and reviews the role of the interprofessional healthcare team in improving care for patients with this condition.

Objectives:

• Identify the epidemiology of reversible cerebral vasoconstriction syndrome.
• Summarize evaluation of reversible cerebral vasoconstriction syndrome.
• Outline the treatment and management options available for reversible cerebral vasoconstriction syndrome.
• Review interprofessional team strategies for improving care coordination and communication to advance reversible cerebral vasoconstriction syndrome and improve outcomes.

Introduction

Reversible cerebral vasoconstriction syndrome (RCVS) is a medical condition in which there is multifocal arterial constriction and dilation in the cerebral vasculature and which may be associated with nonaneurysmal subarachnoid hemorrhage. This condition can correlate with pregnancy and exposure to certain drugs.

RCVS has replaced previous terms, such as benign angiopathy of the central nervous system (CNS), migrainous vasospasm, migraine angiitis, drug-induced cerebral arteritis, or angiopathy, Call-Fleming and "thunderclap" headaches with reversible vasospasm to encompass multifocal arterial constriction and dilation.[1]

Etiology

A trigger for RCVS is identified in approximately 25% to 60% of cases. However, RCVS can occur spontaneously, as well. Some identified triggers include vasoactive drugs, such as over the counter sympathomimetic drugs and migraine abortive medications. The most significant contributor, accounting for approximately 50% to 60% of cases in most published series, is the postpartum state.[1][2] Onset in post-partum women is usually during the 1 to 6 weeks following an uncomplicated pregnancy. It may also have an association with the use of tetrahydrocannabinol and medications such as selective serotonin reuptake inhibitors (SSRIs).[3]

Other potential triggers of RCVS include interferon treatment, diet pills, NSAIDs, alcohol, amphetamines, cocaine, ecstasy, and nicotine. There are also reports of blood transfusions, erythropoietin, intravenous immunoglobulin, migraines, certain tumors such as pheochromocytoma and paraganglioma, trauma, head and neck surgery, carotid dissection, and other medical conditions such as HELLP syndrome, antiphospholipid antibody syndrome, and thrombotic thrombocytopenic purpura (TTP) can be potential triggers of RCVS.[3][4]

Other ubiquitous triggers have included coughing, laughing, and so forth. However, possibly, these associations may be coincidental. The onset of RCVS after exposure to triggers can be anywhere between a few days to several months.[3][4]

Epidemiology

The true incidence of reversible cerebral vasoconstriction syndrome is not known, because prompt and accurate diagnosis remains challenging. However, clinical experience suggests that RCVS is relatively common.[2] RCVS affects patients who are 20 to 50 years of age, with a mean of 42 to 45 years, although clinicians have also seen it in children and adolescents. Females are more commonly affected, with a female to male ratio of 2.4 to 1. Men who are affected present with a mean age that is a decade younger than a female presentation.[3]

Pathophysiology

Researchers hypothesize that reversible cerebral vasoconstriction syndrome possibly results from transient dysregulation of cerebral vascular tone. However, there is still uncertainty regarding the pathophysiology of RCVS; a common entity found among patients with RCVS is a dysregulation in the control of cerebrovascular tone. In many cases, there is no identifiable cause.[5]

The thinking is that there are sudden changes to vascular tone and diameter due to an evoked central vascular discharge. The cerebral vasculature receives heavy innervation from sensory fibers of both the trigeminal nerve and the dorsal root of C2. Researchers have observed a strong association with female sex hormones and fluctuations.[6]

History and Physical

Many patients diagnosed with reversible cerebral vasoconstriction syndrome have a history of migraine, pregnancy, or recent exposure to vasoactive agents.[5][7][8][9]

Commonly, patients with RCVS will present with symptoms of recurrent sudden-onset most intense headache peaking immediately to maximal intensity over seconds to minutes, medically known as a thunderclap headache. This condition may present with vomiting, photophobia, phonophobia, confusion, and blurred vision. Patients typically present with recurrent thunderclap headaches.[5][9] Other symptoms include seizures and focal neurological deficits, which usually occur after the onset of headache.[7] History of potential triggers should be sought, including a surgical history, particularly neurosurgery, recent childbirth, a thorough medication history, social history, and sexual history. Family history is also essential to identify inheritable conditions associated with RCVS, such as pheochromocytoma and porphyria.[1]

Evaluation

Clinicians should include reversible cerebral vasoconstriction syndrome as a differential in all patients presenting with a thunderclap headache, especially recurrent thunderclap headache. Other diagnoses on the differential are foremost, aneurysmal subarachnoid hemorrhage, intracerebral hemorrhage, cerebral venous thrombosis, cervical arterial or cerebral arterial dissection, and pituitary apoplexy.[5]

A common mimic of RCVS is primary angiitis of the central nervous system (PACNS). When compared to patients with PACNS, patients with RCVS were younger than those with PACNS (mean age of 43 and 51, respectively) with approximately 2.6-fold higher percentage of the female gender. Also, an exposure or trigger, such as medications or illicit drugs, as well as physiological stress, is usually identified in patients with RCVS. In patients with PACNS, a trigger rarely gets identified. Although headache is common in both diseases, the nature of the headache in patients with RCVS a dramatic onset thunderclap headache, with recurrence. In patients with PACNS, reports are that about 50% present with headache; however, only 6% report as thunderclap headaches.[2]

Diagnosis depends primarily on radiological imaging. Imaging plays a vital role in diagnosing and differentiating RCVS from PACNS. When compared, patients with RCVS had an abnormal initial CT or MRI 70% of the time, while patients with PACNS had exclusively abnormal initial CT or MRI. Infarcts are seen much more commonly in PACNS than RCVS (81% and 28%, respectively). Vasogenic edema and convexity subarachnoid hemorrhage are common features of RCVS but are rarely features of PACNS. An additional strong differentiating feature is a hyperintense artery sign on the FLAIR sequence of MRI, seen in approximately 61% of patients with RCVS and only in 7% of patients with PACNS.[2]

The diagnosis of RCVS requires the radiological findings of vasospasm on cerebral angiogram features. Research has also compared cerebral angiogram features in patients with RCVS and PACNS. Vasospasm in RCVS is more widespread, symmetric, severe and includes involvement of the proximal arteries. Findings are described as smooth, tapering arterial constriction and dilation, giving a sausage-on-a-string appearance. The middle cerebral artery (MCA), anterior cerebral artery (ACA), and posterior cerebral artery (PCA) are most commonly involved in patients with RCVS. However, RCVS can involve almost any arterial segment. In PACNS, an irregular eccentric notched appearance of the cerebral arteries is more common. Additionally, RCVS patients have a significantly higher incidence of concurrent vascular lesions, such as dissection and unruptured aneurysms.[2] 

In patients with RCVS, cerebrospinal fluid examinations and analysis do not offer much utility, as results are normal.[5] Any abnormalities identified were mild and nonspecific. These findings include mildly elevated WBC, RBC, or protein.[10]

Treatment / Management

Although no randomized controlled trials exist for the treatment of reversible cerebral vasoconstriction syndrome, empiric treatment has been suggested based on expert opinion and reported case series. There are reports that RCVS can occur after exposure to certain medications of agents such as serotonergic agents, sympathomimetics, and recreational drugs (THC). Offending agents should be discontinued.[11][12]

Calcium channel blockers, such as nimodipine, nifedipine, or verapamil, have been used as treatment with different degrees of success. Nimodipine, at a rate of 1 to 2 mg/hour, followed by an oral regimen of 30 to 60 mg every 4 hours for 4 to 8 weeks, has been commonly reported. The optimal duration is unclear.[10] Transcranial color Doppler can measure systolic velocities of intracranial arteries to assess treatment efficacy.[13] The reported treatment success is between 40 to 80%.[10]

Endovascular intervention, such as balloon angioplasty and direct intra-arterial vasodilator administration, have been used. In patients with RCVS, the use of intra-arterial vasodilators, such as nicardipine, papaverine, milrinone, and nimodipine, has shown to promptly reverse vasoconstriction in multiple intracerebral arteries. This response does not occur in patients with RCVS mimics, such as vasculitis or cerebral vessel atherosclerosis. Given that RCVS is generally self-limiting, the suggestion is that intra-arterial vasodilators serve as a diagnostic tool for patients with suspected RCVS.[14][15]

Differential Diagnosis

Reversible cerebral vasoconstriction syndrome commonly gets misdiagnosed for more common conditions such as ischemic stroke or migraine, which may be associated with vasospasm, which could be a factor as to why RCVS is under-recognized. Also contributing to misdiagnosis and under-recognition can be due to indistinguishable clinical and imaging manifestations, mimicking that of CNS arteritis and other disorders.

Prognosis

Many patients with RCVS have a full recovery without residual symptoms, given that reversibility of vasoconstriction is needed for the diagnosis. Clinical and angiographic features may not always resolve together; one may persist without the other and vice versa.[1]

Overall, the majority of patients had no evidence of disability, with less than 30% of patients having minor disabilities. In terms of cognitive function, 92% of patients reported no evidence of cognitive impairment or only minor problems. In one study, out of 214 patients reviewed who had RCVS, only one patient had relapsed.[1]

Despite the reversible nature of the disease and overall favorable long-term prognosis, patients can develop severe vasoconstriction leading to ischemic stroke and sometimes rare death. The mechanism of hemorrhage continues to be unclear, as well as the incidence of stroke in patients with RCVS. In previous studies, the reported prevalence of stroke was between 7% and 50%.[5][6][7][10]

Patients who present with thunderclap headache can have a recurrence. The average period of recurrence of thunderclap headache is approximately one week; however, it has occurred as late as 26 days after the initial presentation. A portion of patients also reports mild persistent headache. If patients develop intracranial or subarachnoid hemorrhage, it usually presents as an early complication within the first three days and ten days, respectively, after headache onset. The diagnosis of ischemic stroke was made approximately two weeks after headache onset in patients who developed this complication.[10]

Complications

The significant complications occur mostly in the first week. They include localized convexity non-aneurysmal subarachnoid hemorrhage (22%), leukoencephalopathy (9%), intracerebral hemorrhage (6%), seizure (3%), and both transient ischemic attack (TIA) and ischemic stroke (20%) with the majority of ischemic events in the second week.[7] Symptoms reported are commonly visual loss, followed by unilateral sensory symptoms, aphasia, and hemiparesis.[7][10] Complications may leave permanent residual neurological deficits.[6]

Deterrence and Patient Education

Clinicians should think of reversible cerebral vasoconstriction syndrome as a differential diagnosis in patients presenting with a thunderclap headache, especially when there is recurrent thunderclap headache.

RCVS can be seen in the postpartum state, as well as in patients who use vasoactive substances, such as over the counter sympathomimetics, serotonergic medications such as migraine-abortive medications, and SSRIs, and can get triggered by substance use such as the use of THC.

Other potential triggers of RCVS include interferon, diet pills, and NSAIDs, as well as alcohol, amphetamines, cocaine, ecstasy, and nicotine. There are also reports that blood transfusions, erythropoietin, intravenous immunoglobulin, migraines, certain tumors such as pheochromocytoma and paraganglioma, trauma, head and neck surgery, carotid dissection, and other medical conditions such as HELLP syndrome, antiphospholipid antibody syndrome and thrombotic thrombocytopenic purpura (TTP) can be potential triggers of RCVS.[3][4]

Enhancing Healthcare Team Outcomes

Reversible cerebral vasoconstriction syndrome remains underdiagnosed. Clinicians need to recognize presenting clinical and radiographic features to avoid unnecessary testing and provide a prompt diagnosis. The interprofessional team may consist of primary care, emergency medicine, neurology, radiology, pharmacists, and specialty care nurses. Cerebral vascular imaging is crucial at identifying patients with RCVS. Although RCVS is self-limiting and commonly resolves with no sequela, clinicians need to provide appropriate supportive therapy and understand the possible complications that can leave patients with permanent neurological deficits or death. Emergency and critical care nurses monitor patients, administer treatments, and provide updates to the team. Pharmacists should review medications used for acute therapy for dosage and drug-drug interactions. Nursing can assist with procedures as well as providing patient counsel on the condition and administering medication, coordinating with the ordering clinician and the pharmacist. The interprofessional team approach to reversible cerebral vasoconstriction syndrome will lead to better outcomes with fewer complications. [Level 5]