Reversible Cerebral Vasoconstriction Syndromes

Etiology

The relationship between recurrent TCHs and dynamic cerebral artery narrowing in RCVS is poorly understood. Some theories suggest the involvement of trigeminovascular or serotonergic pathways connecting the cerebral vessels and the brainstem as the underlying culprits.[2]

Systemic hypertension may contribute to the blood-brain barrier breakdown commonly observed in cerebral dysregulation syndrome.

Numerous RCVS triggers have been identified, many of which feature increased sympathetic tone. Prominent among them are primary headache disorders, especially those of the exertional variety. Women are vulnerable to RCVS during late pregnancy and in the puerperium; eclampsia and pre-eclampsia are additional risk factors. Many drugs—both licit and illicit—have been associated with RCVS. Illicit drugs such as cocaine, ecstasy, amphetamines, cannabis, and LSD are reportedly known triggers. The list of licit drugs is legion and includes anticholinergic agents, antimigraine medications, cough and cold suppressants, antidepressants, adrenergic agents, blood products, chemotherapeutic and immune-modulatory agents, hormonal agents, and anti-protozoal medications. Common substances such as coffee, eucalyptus, and licorice can also precipitate RCVS.

Other potential triggers of RCVS include tumors such as pheochromocytoma and paraganglioma, trauma, head and neck surgery, and carotid dissection. Medical conditions, including antiphospholipid antibody syndrome and thrombotic thrombocytopenic purpura (TTP), can also be potential triggers of RCVS.[3][4] The onset of RCVS after exposure to triggers can range between a few days to several months.[5][6]

Although definitive genetic risk factors for RCVS have not been conclusively identified, occasionally, this condition has been observed in patients with underlying genetic diseases, such as adult-onset Leigh syndrome.[7] A single study reported that the Val66Met polymorphism in brain-derived neurotrophic factors may influence RCVS, with patients carrying the Val allele showing higher mean vasoconstriction scores across all arterial segments than MetMet homozygotes.[8]

Epidemiology

Although RCVS is considered a rare condition, it has received growing attention in peer-reviewed medical literature over the past 20 years. In 2003, 3 published studies focused on RCVS; by 2023, this number had risen to 80. However, due to the absence of large-scale epidemiological studies, the actual incidence and prevalence of RCVS remain poorly understood. The incidence is likely increasing due to a combination of increased awareness of the condition among clinicians and the widespread use of vascular and magnetic resonance imaging (MRI).[9] A 2019 study published in the journal Stroke estimated the incidence to range widely from 7% to 54%, highlighting significant variability in reported cases.[10] 

RCVS predominantly affects adult women with female-to-male ratios ranging from 2:1 to 10:1, even after accounting for postpartum cases. Interestingly, male predominance is observed in children. The age range of RCVS patients is vast—ranging from infancy to the early 80s—but in reported cohort studies, the mean age of onset was in the fifth decade of life.[2]

As our understanding of cerebral dysregulation has improved over the past 2 decades, the term "RCVS" has replaced many previous terms, including benign angiopathy of the CNS; cerebral vasoconstriction associated with drugs, chemotherapeutic agents, and immune modulators; Call syndrome; Call-Fleming syndrome; postpartum cerebral angiopathy; migraine angiitis; and CNS pseudovasculitis.[10][2]

Pathophysiology

The underlying pathophysiology of RCVS remains enigmatic and poorly understood, similar to its incidence and prevalence. An emerging consensus suggests that transient dysregulation of cerebral vascular tone leads to the multifocal vasoconstriction and dilatation seen in the syndrome. Endothelial dysfunction, sympathetic hyperstimulation, and oxidative stress are prominent factors and pathogenic mechanisms implicated in RCVS.[11][12] Recent pathophysiological studies have increasingly highlighted disruptions to the blood-brain barrier as a consequence of endothelial dysfunction.[1]

History and Physical

Commonly, patients with RCVS present with symptoms of an explosive headache that reaches peak intensity within 1 minute of onset, known as a TCH. The TCH recurs in up to 85% to 90% of patients, typically occurring roughly weekly for up to 4 weeks, with a decrease in intensity and frequency during that time span.[2] Clinicians should suspect RCVS in any patient presenting with a TCH. A thorough headache history should be obtained, with particular attention to any prior history of migraine headaches and any reported changes in the pattern of headaches.

Seizures and neurological focality may emerge within the first 10 days of recurrent headaches, and such a history should always be sought. Focal symptoms such as aphasia and hemiparesis may indicate an underlying brain injury, typically ischemic or hemorrhagic complications. Visual symptoms are common, including blurriness, cortical blindness, and scotomas.

Indicators of generalized neurological dysfunction include seizures and encephalopathy. The latter is likely a consequence of intolerable headache pain, as it tends to be mild and of limited duration. When present, seizures are typically generalized with tonic-clonic features and are usually self-limited. Seizures occur less frequently in RCVS compared to PRES, another well-characterized syndrome of cerebrovascular dysregulation.  

A history of potential triggers must always be sought, including a surgical history, particularly neurosurgery, recent childbirth, a thorough medication history, social history, and sexual history. Regarding medications, it is essential to inquire about the use of vasoactive substances, particularly adrenergic agonists and serotonergic agents.[13] Similarly, inquiring about the use of recreational substances, both licit (eg, cannabis) and illicit (eg, cocaine and amphetamines) is mandatory. Although RCVS has not been linked to causative underlying genetic mechanisms to date, family history should always be sought, as RCVS has been associated with other heritable conditions, such as pheochromocytoma and porphyria.[14]

A 2019 study, based on a retrospective analysis of 202 consecutive patients with arteriopathy in the Massachusetts General Hospital's Research Patient Database Repository, described an RCVS₂ score. With a maximal score of 10 (range -2 to 10), the RCVS₂ score includes the following 5 factors:

• The presence of TCH
• Involvement of the intracranial carotid artery
• Female sex
• An identified vasoactive trigger
• The presence of subarachnoid hemorrhage.

TCH alone engenders a score of 5. Scores of 5 or higher showed 90% sensitivity and 99% specificity for diagnosing RCVS.[15]

Evaluation

After obtaining a history focused on possible triggers of the TCH, recent use of medications and substances, and any history of recent confusion or seizures, a thorough neurological examination must be performed, assuming the patient is hemodynamically stable. This examination should focus particularly on determining the level of consciousness and mental acuity, the presence of visual signs, and other localizing findings such as aphasia, neglect, hemiparesis, and hemisensory loss. Diffuse hyperreflexia is common and likely reflects a combination of underlying serotonergic activity and autonomic dysregulation.[16]

Over 70% of RCVS patients have normal structural brain imaging at presentation. Within the ensuing 2 weeks, approximately 70% of hospitalized patients will develop either subarachnoid or parenchymal hemorrhage, ischemic stroke, or vasogenic edema, with hemorrhagic insults generally occurring earlier than the ischemic variety. Edema and ischemia are seen preferentially in the posterior watershed regions, the cerebellum, and the cortical-subcortical regions of the parietooccipital and frontal lobes, while deep structures are rarely affected.

The nature of the TCH can effectively guide the initial steps in a workup. When the TCH is recurrent—as tabulated by the RCVS₂ score—the pretest probability of RCVS is functionally 100%, essentially obviating the need for additional invasive diagnostic procedures such as lumbar puncture or brain biopsy.[15]

In cases of a single TCH, potentially fatal underlying conditions must be ruled out. These conditions include aneurysmal subarachnoid hemorrhage, pituitary apoplexy, cervical artery dissection, meningitis, and cerebral venous sinus thrombosis. Emergent brain and cerebrovascular imaging must be performed; if imaging is negative for subarachnoid hemorrhage, lumbar puncture can be conducted to definitively exclude subarachnoid hemorrhage or meningitis. In cases of recurrent TCH, brain imaging is still indicated, primarily to investigate for RCVS sequelae, such as convexity (non-aneurysmal) bleeding, lobar hemorrhage, or ischemic stroke.

The angiographic appearance of affected arteries in RCVS is classically a combination of smoothly tapered narrowing alternating with dilatation, producing the characteristic "sausage on a string" appearance.[17] Lesions tend to progress centripetally and are primarily seen in medium to large arteries. While correlations are often modest, transcranial ultrasound can reveal elevated blood flow velocities.[2]

Treatment / Management

Current treatment approaches to RCVS are predicated on recognizing it as a predominantly benign and self-limited condition. The goal is to avoid misdiagnosis that could lead to unnecessarily invasive investigations, favoring symptomatic treatment over empiric approaches. If triggers are identified, it is crucial to remove them whenever possible until clinical symptoms and imaging findings are resolved.

The use of long-term antiepileptic agents is generally unwarranted in the absence of irreversible brain injury, even when structural brain lesions are present. Symptomatic management of headaches and hyperglycemia, which can worsen outcomes, if present, is important. Patients exposed to glucocorticoids should be admitted to a higher level of acuity, such as a step-down unit or ICU. Additionally, the use of laxatives, bed rest, and temporary avoidance of sexual activity may be beneficial.

Management missteps in the treatment of RCVS include administering vasoconstrictive migraine medications (ie, triptans or ergots) for headaches, empiric use of glucocorticoids for suspected PACNS, and proceeding to brain biopsy or intra-arterial vasodilators to rule out non-RCVS arteriopathies such as vasculitis. Intra-arterial vasodilators only have temporary effects, and their use can cause reperfusion injury; thus, their use is best avoided.[2]

Differential Diagnosis

When cerebral angiography reveals a new diagnosis of intracranial arteriopathy, the differential diagnoses include moyamoya disease, intracranial arteriosclerosis, infectious vasculitis, and PACNS.

PACNS commonly mimics RCVS. Compared to patients with PACNS, those with RCVS are younger (mean age 43 versus 51) and have an approximately 2.6-fold higher percentage of females. Furthermore, 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 is rarely identified. Although headaches are common in both diseases, the nature of the headache differs. In RCVS, the headache typically has a dramatic onset with recurrent TCH. In PACNS, about 50% of patients present with headaches, but only 6% report TCHs.[18]

Imaging is crucial for diagnosing and differentiating RCVS from PACNS. When compared, patients with RCVS showed abnormalities in initial computed tomography (CT) or MRI scans 70% of the time, whereas patients with PACNS had exclusively abnormal initial CT or MRI. Infarcts are significantly more frequent in PACNS than in RCVS, occurring in 81% and 28% of cases, respectively. Vasogenic edema and convexity subarachnoid hemorrhage are typical features of RCVS but are seldom observed in PACNS. Another notable distinguishing feature is the hyperintense artery sign on the FLAIR sequence of MRI, which appears in approximately 61% of RCVS patients compared to only 7% of PACNS patients.[18]

Prognosis

Patients with RCVS precipitated by trauma or surgical procedures, as well as those presenting with focal cortical deficits, are at higher risk of residual neurological deficits. Therefore, close monitoring of these patients is essential.[19]

A portion of patients with RCVS reports mild persistent headaches. Intracranial or subarachnoid hemorrhages typically manifest as early complications, occurring within the first 3 days of headache onset for intracranial bleeds and within 10 days for subarachnoid bleeding. Ischemic stroke most commonly occurs approximately 2 weeks after the onset of headaches in patients who develop this complication.[20]

Many patients with RCVS recover fully without residual symptoms, as vasoconstriction often resolves spontaneously. Clinical and angiographic features may not always resolve concurrently; one may persist without the other and vice versa.[14] By definition, the duration of symptoms and vasoconstrictor changes in RCVS does not exceed 3 months and typically resolves within a few weeks.

Despite the reversible nature of the disease and its generally favorable long-term prognosis, patients can occasionally develop severe vasoconstriction, which may lead to ischemic stroke and, rarely, death.

Complications

Significant complications primarily occur within the first week after headache onset in RCVS. These include localized convexity (non-aneurysmal) subarachnoid hemorrhage (22%), leukoencephalopathy (9%), intracerebral hemorrhage (6%), seizure (3%), and transient ischemic attack or ischemic stroke (20%), with the majority of ischemic events occurring in the second week.[21] These complications can potentially result in permanent residual neurological deficits.[22]