Ep. 212: Reversible Cerebral Vasoconstriction Syndrome

00:00:00: Welcome to EANcast, your weekly source for education, research, and updates from the European Academy of Neurology.

00:00:16: Hello and welcome to EANcast Weekly Neurology. My name is Jurgita Valaikienė. I am a clinical neurologist and neurosonologist at Vilnius University Center of Neurology.

00:00:28: The topic today is neurosonology, and in today's episode, we are going to be talking about reversible cerebral vasoconstriction syndrome, or RCVS.

00:00:38: My guest today is Theodoros Mavridis.

00:00:41: He is a consultant neurologist, stroke and headache specialist at the Department of Neurology, Tallaght University Hospital, the Adelaide and Meath Hospital, Dublin, Ireland.

00:00:53: He is also a scientific research associate at the First Neurology Department, Aeginition Hospital, Medical School, National and Kapodistrian University of Athens, Greece, and Chair of the Irish Headache Society and Migraine Ireland.

00:01:10: Welcome, Theodoros. Thank you for joining us today.

00:01:14: Thank you. Thank you, Jurgita, for the kind introduction, and thank you for having me here to discuss this really interesting topic.

00:01:24: Many clinicians might still be confused by the various names this condition has had over the years. Would you clarify what RCVS is and how the terminology has evolved?

00:01:37: Thank you, Jurgita, for a nice question. Let's start with the basics.

00:01:43: RCVS is basically a clinical-radiological syndrome that was classically defined by recurrent thunderclap headaches, which we'll talk more about—when they appear and when they do not appear—multifocal segmental vasoconstriction of the intracranial arteries, and, as the name suggests, reversibility of these changes within approximately 12 weeks, perhaps a little longer or a little shorter.

00:02:18: It has had many names previously, including Call-Fleming syndrome, and, when occurring after pregnancy, postpartum angiopathy.

00:02:29: Other names include migrainous vasospasm and benign angiopathy of the CNS.

00:02:36: But in 2007, it was proposed that these entities should be unified under a single umbrella term, basically reversible cerebral vasoconstriction syndrome, or RCVS, because they share the same clinical course and imaging patterns.

00:02:56: Today, it even has its own ICD-10 and ICD-11 codes, and we know that it is an entity in its own right.

00:03:06: This is very, very important because this is the basis of the pathophysiology underlying this problem.

00:03:12: Basically, it involves a transient, multifocal dysregulation of cerebrovascular tone, mainly affecting the medium and small vessels.

00:03:20: We think this is likely driven by sympathetic overactivity and a temporary impairment of the blood-brain barrier.

00:03:27: It is important at this stage to say that, regarding the pathophysiology, it is not primarily inflammatory and not atherosclerotic.

00:03:36: It is a functional disturbance of vascular tone rather than a structural or inflammatory disease, such as vasculitis.

00:03:43: This dysregulation of vascular tone leads to what we know as the “string-of-beads” appearance, where some segments are constricting and other segments are dilating.

00:03:54: Usually, this involves the distal vessels, but in severe forms, the vasoconstriction can migrate to more proximal segments over several weeks.

00:04:03: Okay, thank you. RCVS, as you explained, is a relatively benign condition, but recent data from the REVERSE network suggest a more complex picture, especially here in Europe.

00:04:28: What did that data reveal?

00:04:32: Yes, this is something I think is a bit of a misunderstanding. We think that RCVS is benign, but it's not exactly what the term says: reversible.

00:04:44: The latest findings from the REVERSE network suggest that it is not always a benign condition.

00:04:52: In large pooled cohorts, specifically from European populations, we see high rates of brain lesions, specifically ischemic stroke, intracranial hemorrhage, or even PRES.

00:05:07: We're going to talk more about that. There is also a difference between European and Asian populations.

00:05:15: Brain parenchymal lesions appear in around 29–30% of European patients, compared with around 6% in Asian populations.

00:05:26: Now, another thing is that in the European population, secondary or triggered RCVS is far more frequent in Europe and appears in more than 50% of cases.

00:05:37: So we have some trigger factors, which is not as typical in the Asian population.

00:05:44: Another thing that needs to be said regarding the classical presentation of RCVS being thunderclap headache is that it is not very typical for Europeans.

00:05:56: Around 30–32% of European patients can actually present without the classical thunderclap headache, which makes the diagnosis even more difficult.

00:06:07: We have to know that there are also differences in outcomes between European and Asian populations. The unfavorable three-month outcome is more frequent in the European population.

00:06:22: And if the presentation can be atypical, how can we reliably distinguish RCVS from other serious conditions, such as primary angiitis of the CNS, or Moyamoya disease or syndrome?

00:06:45: Yeah, this is something very, very important.

00:06:48: As we discussed before, there are other presentations, specifically in European populations, that don't have the classical thunderclap headache.

00:07:00: We can have focal neurological signs, seizures, and visual disturbances.

00:07:06: We know that patients who present without thunderclap headache may even have a worse outcome than those who present with thunderclap headache.

00:07:17: That's why there was a tool developed to help us distinguish RCVS from other mimics, such as primary angiitis of the CNS or Moyamoya disease. This is the RCVS2 score.

00:07:31: This is basically a clinical score that adds or subtracts points. For example, recurrent thunderclap headaches give up to five points.

00:07:42: Carotid artery involvement subtracts two points.

00:07:45: The presence of a vasoconstrictive trigger gives three points, female sex gives one point, and the presence of a subarachnoid hemorrhage gives one point.

00:07:58: Basically, you calculate a total score. We know from several cohorts that a score of 5 or higher gives us a specificity of around 99% for RCVS.

00:08:09: If we have a score of 2 or less, then the specificity for excluding RCVS is very high, with a sensitivity of around 85%.

00:08:19: The problem lies when we have a score of three or four, which is indeterminate. In this situation, the specificity drops and the sensitivity is much lower.

00:08:32: That's why you need further investigation and more imaging data to make sure that you have RCVS.

00:08:40: Keep in mind that the RCVS2 score is very useful in clinical practice, but you have to be very careful because it was originally developed from a single retrospective study.

00:08:53: If you have a score of five or more, RCVS is very likely. If you have a score of two or less, RCVS is unlikely.

00:09:01: But with scores of three or four, you have to be very careful and use additional tools, particularly imaging.

00:09:10: Agreed, that's very important. We have several modalities at our disposal: CT, MRI, DSA, and ultrasound. How should we navigate these for diagnosis and monitoring?

00:09:23: We need those tools, and we need to know all the advantages and disadvantages of each. Let's start with CT and CTA.

00:09:32: CT is not very specific for parenchymal lesions, but CTA is very useful for assessing the “string-of-beads” appearance.

00:09:41: We can also use it very often in the emergency department to determine whether there is an aneurysmal subarachnoid hemorrhage or other pathology.

00:09:53: MRI is much better for detecting parenchymal lesions. For example, if we have PRES or watershed infarcts, MRI is much more sensitive.

00:10:04: In terms of MRA and CTA, it is very important to remember that if you perform the examination very early, you might miss the “string-of-beads” appearance because this is something that evolves over a period of two to three weeks.

00:10:20: So, if you do the imaging too early, you might miss those changes, even though you have a strong clinical suspicion of RCVS. You may therefore need to repeat the imaging.

00:10:33: Digital subtraction angiography (DSA) is the gold standard for vessel resolution, but it is invasive.

00:10:40: We don't usually use it too often; we use it when there is doubt about whether this is RCVS or another condition.

00:10:48: And again, if you perform it too early, you might miss the changes, so timing is important.

00:10:55: Of course, as you know, Jurgita, you're a neurosonologist, and transcranial Doppler (TCD) and transcranial color-coded sonography (TCCS) can be very useful, specifically in the hands of experienced physicians.

00:11:10: We can see the evolution of the vessels with TCD. We can assess how the vasoconstriction evolves because it is non-invasive and can be performed at the bedside.

00:11:21: You can measure velocities and ratios to see whether the condition is getting worse or better and how the medication is working.

00:11:31: Which ratios have you mentioned? Which ratios do you calculate?

00:11:58: This is very important. We personally do two things. First of all, I don't do just one measurement.

00:12:04: I perform a series of measurements because, as we discussed before, RCVS is something that evolves. I do measurements and try to be more specific around weeks two and four.

00:12:15: First of all, I measure the middle cerebral artery (MCA) velocities.

00:12:20: We know that if the MCA velocities are higher than approximately 120 cm/s, this may indicate an evolution toward increased arterial stenosis.

00:12:29: The other ratio we discuss is the Lindegaard index, which is basically the ratio between the MCA velocity and the extracranial internal carotid artery (ICA) velocity.

00:12:40: If it is below three, then you don't have significant vasospasm.

00:12:45: If it is between three and 4.5, this may indicate moderate vasospasm, while values above 4.5 suggest moderate to severe vasospasm. A value above six points toward severe vasospasm.

00:12:57: This is very interesting because it is a bedside investigation. You can monitor the patient and also assess what we call hemodynamic trends.

00:13:05: If you give the patient specific treatment, such as calcium channel blockers, we can see whether there is an improvement.

00:13:13: I wouldn't say that they are the best treatment we have, but they are among the main treatments we use for RCVS, specifically for headache.

00:13:22: For example, we can see the resolution with nimodipine.

00:13:26: I think it's a very useful tool.

00:13:30: I wouldn't say that it's the best one, but it is something that you can do at the bedside, and if the physician is trained and knows how to perform it, it can be very useful.

00:13:55: That's very interesting. You mentioned the Lindegaard index, and sometimes it is difficult to differentiate subarachnoid hemorrhage in a case of CT-negative subarachnoid hemorrhage.

00:14:19: Have you had such cases?

00:14:23: Yes, this is very, very difficult because, you know, we go back to what we call the “chicken and egg” problem.

00:14:26: Sometimes in severe RCVS, you can have convexity subarachnoid hemorrhage, specifically in the cortical areas, and it is not always certain whether RCVS caused the subarachnoid hemorrhage or the subarachnoid hemorrhage caused the vasoconstriction, because we know that in severe subarachnoid hemorrhage, we can have vasoconstriction.

00:14:36: It's very, very difficult. To be honest, I had two of those cases, and I needed to put all the tools together and see how the condition evolved.

00:14:40: What I did—and I don't say that this is what everyone should do—was to treat for the worst-case scenario, which was subarachnoid hemorrhage, and try to find whether there was an aneurysm.

00:14:46: When I didn't find an aneurysm, then I relaxed and searched for RCVS, the triggers, and everything else.

00:14:49: I don't know if you have had a similar experience, but I was struggling with it as well.

00:14:52: I totally agree with you. That is a problem. We should collaborate and should have more examples and more cases to find the exact answer to this question. That's difficult.

00:15:21: Also, I find the role of ultrasound particularly useful. How can we use POCUS, specifically in the management of these patients?

00:15:52: Yes, this is what we discussed, and I think it's very, very useful. It's accessible and a non-invasive tool that you can use as many times as you want.

00:16:00: You don't need to worry about radiation or about being invasive, as with DSA. It's not only advantages, though; it also has limitations.

00:16:07: For example, it's not a standalone diagnostic test. It also has segmental coverage, so you cannot see the whole spectrum of the MCA if you want to identify those changes.

00:16:16: As we discussed before, it is a “string of beads,” so it is not really easy to identify all the segmental narrowings and corresponding high velocities.

00:16:24: Of course, it is also operator- and acoustic-window-dependent. If the patient doesn't have a good acoustic window, you cannot find anything.

00:16:32: And if you are not a trained operator, you reduce the reliability of the examination.

00:16:36: But it is very useful because you can see clinical improvement and changes in vascular velocities, for example, after treatment with extended-release verapamil or nimodipine.

00:16:46: You can see the resolution of those vascular changes, even if treatment is administered intravenously or, in very severe cases, intra-arterially.

00:16:53: I haven't done it myself, but I know from the literature that in severe refractory cases, ultrasound can also be used to guide a stellate ganglion block as a rescue therapy.

00:17:03: I think it's a very useful tool.

00:17:04: I think neurologists should be trained in transcranial ultrasound because, as we discussed before, it is an accessible, non-invasive bedside tool that you can use repeatedly.

00:17:14: Of course, it is not a standalone diagnostic test.

00:17:17: That's perfect. Thank you. We must also discuss the triggers. What should we be looking for, particularly regarding pregnancy and medications?

00:17:44: As we discussed before, Europeans have more trigger-associated RCVS than Asians. There are some vasoactive substances that have been recognized in more than 60% of cases.

00:17:57: The most common ones are serotonergic antidepressants, either SNRIs or SSRIs; triptans are also very common, as are over-the-counter decongestants, such as nasal decongestants.

00:18:11: Illicit drugs such as cocaine and cannabis are also major triggers, among others.

00:18:17: Then there is the postpartum period, which is a major trigger and accounts for approximately 7–21% of cases, often peaking around two weeks after delivery.

00:18:30: Among postpartum RCVS cases, hemorrhagic presentations are common.

00:18:35: About 53% are hemorrhagic and around 50% are non-hemorrhagic, with intracerebral hemorrhage being more frequent than subarachnoid hemorrhage.

00:18:46: There is also a very tight overlap between postpartum RCVS, preeclampsia, eclampsia, and PRES, likely due to a shared mechanism involving endothelial dysfunction and impaired vascular tone.

00:19:01: A case-control study of 40 pregnancy-related RCVS cases versus 120 controls found preeclampsia/eclampsia in 73% of the cases versus 10% of the controls, with 55% of the RCVS cases having intracranial complications such as hemorrhage, infarction, or PRES.

00:19:21: We also have other drugs. Immunosuppressants and some hormonal agents have also been implicated.

00:19:29: And, of course, we must not forget glucocorticoids, which are also important when differentiating RCVS from primary angiitis of the CNS.

00:19:39: It is very important to differentiate these conditions because glucocorticoids are a treatment for primary angiitis of the CNS.

00:19:49: However, if you give glucocorticoids in RCVS or in a missed RCVS case, they may exacerbate or worsen RCVS because glucocorticoids have also been suspected as a possible trigger.

00:20:04: Exactly. Thank you.

00:20:30: RCVS and PRES—are they actually the same thing, or are they separate diseases? This is a very nice question.

00:20:34: Many studies suggest that there is a shared mechanism between RCVS and PRES.

00:20:38: Basically, if I can answer with one sentence, I would say that they are distinct clinical-radiological syndromes, but they are on the same spectrum.

00:20:45: I would say that they have shared pathophysiological mechanisms, but they are considered different diseases.

00:20:49: If we go from the RCVS point of view, we would say it is more of a vasoconstriction problem, so it primarily involves the vessels, whereas in PRES we have more of a problem within the parenchyma, with vasogenic edema.

00:20:59: But in fact, around 38–40% of RCVS cases have PRES-like findings on their scans.

00:21:03: On the other hand, around 85% of PRES cases show some degree of vasoconstriction on angiography, even though they don't have the full “string-of-beads” appearance.

00:21:10: We see patients with RCVS having PRES imaging, and we see many PRES patients who have features of RCVS.

00:21:15: So I would say that they may be two sides of the same coin, with one emphasizing the vessels and the other emphasizing the consequence of endothelial dysfunction, which is essentially the brain parenchymal edema.

00:21:25: That's interesting. And now, just a practical question for these patients: are you doing transorbital POCUS? Are you looking at the optic nerve sheath diameter?

00:21:55: Yeah, this is very, very interesting because, as we know, the brain has a direct connection with the optic nerve, and we see in other conditions, such as idiopathic intracranial hypertension and other types of cerebral edema, that the optic nerve sheath diameter can increase.

00:22:13: I don't do it routinely in RCVS cases, but in cases that have PRES, I'm more interested in finding out whether there is dilation and an increase in the diameter, which could point to higher intracranial pressure.

00:22:27: I'm not sure how I can use it in future treatment decisions because we don't have much treatment for RCVS and PRES apart from removing the trigger or giving a calcium channel blocker, such as nimodipine, in RCVS.

00:22:42: But it's a useful tool. At the moment, I don't know how to fully utilize it. I don't know if you have any more thoughts about that.

00:22:51: Theodoros, sometimes I have found enlargement of the optic nerve sheath diameter, and I think we should continue our research and look at that.

00:23:13: It is an interesting question for the future.

00:23:20: Yeah, I think so. If we can utilize it, it would be great in the future. I think research is needed on the optic nerve sheath diameter.

00:23:45: To wrap up, where is the field heading? What are the future directions for RCVS research? As we have mentioned before, there are significant gaps.

00:23:53: One of them is, as you mentioned before, the optic nerve sheath diameter and how we can utilize it.

00:23:59: We need biomarkers that can reliably distinguish RCVS from its mimics, as we said before, specifically when imaging is inconclusive—for example, in subarachnoid hemorrhage, primary angiitis of the central nervous system, or Moyamoya disease.

00:24:14: We also lack randomized controlled trials to confirm whether early initiation of, for example, calcium channel blockers, actually alters long-term outcomes or simply manages symptoms.

00:24:25: So we're not quite sure whether nimodipine improves future outcomes.

00:24:29: We also use it because previous physicians were using it, and we have some evidence that it helps with symptoms, but we don't know whether it changes long-term outcomes.

00:24:39: The other thing that I would like to mention, which is very interesting in this case, is that there is a difference between European and Asian populations.

00:24:48: We might need more research into genetic and environmental factors to explain why Europeans seem to experience more severe disease or worse outcomes and why they have more trigger-associated RCVS than Asian populations.

00:25:01: I think it would be very interesting to conduct a really good genetic study on that.

00:25:07: And you have summarized our talk.

00:25:09: I think after our talk, the listeners will remember that reversible cerebral vasoconstriction syndrome, or RCVS, is a potentially serious but reversible condition characterized classically by recurrent thunderclap headaches and transient segmental vasoconstriction of cerebral arteries, typically affecting younger individuals, usually younger than 60 years, with a mean age of around 40 years.

00:25:36: The vascular abnormalities typically resolve within three months.

00:25:41: However, in approximately 30% of cases, it may present without typical thunderclap headache and may be complicated by stroke and other intracranial complications, with potentially worse outcomes reported particularly in European cohorts.

00:25:57: And you also summarized the triggers and associated conditions.

00:26:02: We can thank our listeners for listening to this episode of EANcast. We hope that these insights help you in your clinical practice. And I would like to say goodbye.

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