45 Reversible Cerebral Vasoconstriction Syndrome
45.1 Case Description
45.1.1 Clinical Presentation
A 65-year-old female patient of Filipina-Canadian descent presented with acute-onset headache with a 10 out of 10 severity. Headache had begun acutely 4 days prior to visiting the hospital. It was characterized as diffuse and bilateral, centered at the vertex of her skull. The headache was described as different in character from the patients’ normal migraines. There were no associated symptoms such as visual symptoms, nausea or vomiting, photophobia, phonophobia, meningismus, or focal neurological deficits. The patient’s headache improved 30 to 45 minutes after taking ibuprofen, although it did not resolve completely. She continued to take ibuprofen every 4 to 6 hours over the next 4 days; however, the headache worsened. The patient went to her local hospital where a noncontrast CT of the head was performed, which showed subarachnoid hemorrhage over the left frontal convexity (Fig. 45.1). She was then transferred to a tertiary hospital and was assessed by neurology and neurosurgery; thereafter, she was admitted for treatment and further investigations. On physical examination, no focal neurological deficits were found. Laboratory investigations showed the patient to be a chronic hepatitis B carrier. Her hepatitis was not active during the course of admission. Rheumatology was consulted with working diagnosis of cerebral vasculitis versus reversible cerebral vasoconstriction syndrome (RCVS). Rheumatology blood panel was negative.
45.1.2 Imaging Workup and Investigations
Initial noncontrast CT of the head demonstrated a focal area of hyperdensity, compatible with subarachnoid hemorrhage, within a left frontal convexity sulcus. Subsequent CTA did not demonstrate a vascular cause for subarachnoid hemorrhage.
MRI of the brain exhibited sulcal hyperintensity on the fluid-attenuated inversion recovery (FLAIR) sequence and gradient echo T2 hyperintensity overlying the left frontal and parietal lobes adjacent to the central sulcus, in keeping with subarachnoid hemorrhage.
Catheter angiography was performed which exhibited multiple focal segmental areas of mild arterial narrowing, involving the pericallosal artery and distal cortical anterior cerebral artery branches, as well as the mid and distal middle cerebral artery branches. There were also similar findings in the distal posterior cerebral arteries more prominent on the left (Fig. 45.2).
Follow-up angiogram was performed four weeks after the initial catheter angiography, and there was interval resolution of the previously noted areas of arterial narrowings.
Reversible cerebral vasoconstriction syndrome.
45.1.4 Treatment and Follow-up
The patient was treated with Solu-Medrol and prednisone for the working diagnosis of vasculitis, with a tapering dose over 3 months following discharge. She was also initially treated with Nimodipine and then Verapamil for possible RCVS. Acute pain service provided supportive management for pain control. She was discharged with satisfactory resolution of her headaches and returned for follow-up catheter angiogram 4 weeks following discharge.
The patient remained asymptomatic on her last follow-up visit, 7 months after initial presentation.
RCVS is a clinicoangiographic syndrome characterized angiographically by reversible diffuse-multifocal narrowing of the cerebral arteries, and typically associated with single or recurrent episodes of sudden and severe thunderclap headaches. This may be complicated by ischemic or hemorrhagic strokes and a variety of other neurological complications. 1 , 2 , 3 , 4 , 5 , 6
It was also previously known as Call–Fleming syndrome among other names such as thunderclap headache with reversible vasospasm, postpartum cerebral angiitis, central nervous system pseudovasculitis, and benign angiopathy of the central nervous system 5 , 7 , 8 , 9 , 10
The syndrome is considered relatively rare and its exact incidence is unknown. 5 It appears to be more common in women than in men with a ratio of 2.4:1 and the mean age of presentation is 42 years (range: 10–76 years) with no clear ethnicity group specification. 2 , 3 , 4 , 5 , 11
The pathophysiology of RCVS is poorly understood. Many theories have been postulated, including sympathetic overactivity, dysregulation of vascular tone of intracranial arteries, and blood–brain barrier (BBB) breakdown. The latter was demonstrated in a study conducted by Lee et al. 12 It was based on the idea that the contrast-enhancing FLAIR MRI sequence will show gadolinium leakage into the cerebrospinal fluid (CSF) spaces and brain parenchyma secondary to a disturbed BBB. This finding was showed in two-thirds of patients with RCVS. This would suggest that the cerebral capillaries are also affected. Further studies are needed to better understand the relationship between BBB breakdown and vasoconstrictions in RCVS. 12
Dysregulation of intracranial vascular tone leading to vasoconstriction is believed to be the key pathophysiologic mechanism. It occurs secondary to spontaneous or evoked sympathetic overactivity by a release of exogenous or endogenous factors like vasoconstrictive drugs and female hormones among other immunologic and biochemical factors. This is supported by the absence of histologic changes in brain biopsy such as active inflammation or vasculitis. 1 , 2 , 3 , 8 , 13 , 14 , 15 , 16
Serotonin-producing tumors and serotonin-enhancing medication have been found to be associated with RCVS, which suggests that serotonin plays an important role in the pathophysiology of RCVS. 9
Several triggers for RCVS have been identified, including early puerperium, late pregnancy, preeclampsia, vasoactive drugs (phenylpropanolamine, pseudoephedrine, ergotamine, tartrate, methysergide, bromocriptine, lisuride, selective serotonin reuptake inhibitors, sumatriptan, and isometheptene), recreational drugs (cocaine, ecstasy, marijuana, and amphetamines), tacrolimus, cyclophosphamide, pheochromocytoma, and carcinoid. 5 , 17 , 18 , 19 , 20 , 21
RCVS is most commonly a monophasic self-limiting condition. The most prominent symptom is a severe thunderclap headache reaching its peak intensity within seconds. Up to 80% of the patients have a thunderclap headache; thus, less severe, subacute, or even absent headache is rare. In 70 to 80% of the patients, it is the only presenting symptom. The thunderclap headaches can recur up to three weeks and may occur spontaneously or be triggered by coughing, orgasm, physical exertion, acute stressful or emotional situations, straining, sneezing, bathing, or swimming. 1 , 5 , 8 , 9 , 10 , 18
Other focal neurological symptoms can be associated with RCVS. Most commonly, these are visual symptoms; however, aphasia and sensory symptoms have also been reported. They can mimic transient ischemic attacks or migraine auras. 1 , 5
The diagnostic criteria in Box 1 were proposed by Calabrese et al. 2 The new International Classification of Headache Disorders, 3rd edition (ICHD-3; beta version) has proposed the diagnostic criteria shown in Box 2 for headaches attributed to RCVS and headache probably attributed to RCVS. 6 , 14
Box 1: Diagnostic criteria of RCVS by Calabrese et al 2 :
Acute and severe headache (often thunderclap) with or without focal deficits or seizures.
Uniphasic course without new symptoms more than 1 month after clinical onset.
Segmental vasoconstriction of cerebral arteries shown by indirect (e.g., MR or CT) or direct catheter angiography.
No evidence of aneurysmal subarachnoid hemorrhage.
Normal or near-normal CSF (protein concentrations <100 mg/dL, < 15 white blood cells per μL).
Complete or substantial normalization of arteries shown by follow-up indirect or direct angiography within 12 weeks of clinical onset.
Box 2: Diagnostic criteria of RCVS in the ICHD-3b 6 :
Any new headache fulfilling criterion C.
RCVS has been diagnosed
Evidence of causation demonstrated by either or both of the following:
Headache, with or without focal deficits and/or seizures, has led to angiography (with “string of beads” appearance) and diagnosis of RCVS.
Headache has one or more of the following characteristics:
Triggered by sexual activity, exertion, Valsalva maneuvers, emotion, bathing and/or showering.
Present or recurrent during ≤ 1 month after onset, with no new significant headache after >1 month.
Either of the following:
Headache has resolved within 3 months of onset.
Headache has not yet been resolved, but 3 months from onset have not yet passed.
Not better accounted for by another ICHD-3 diagnosis.
Acute headache probably attributed to RCVS:
Any new headache fulfilling criterion C.
RCVS is suspected but cerebral angiography is normal.
Probability of causation demonstrated by all of the following:
At least two headaches within 1 month, with all three of the following characteristics:
Thunderclap onset, and peaking in <1 minute.
Lasting ≥ 5 minutes.
At least one thunderclap headache has been triggered by one of the following:
Sexual activity (just before or at orgasm).
Bathing and/or showering.
Investigations and Imaging Findings
Imaging features together with the clinical presentation are crucial in making an early diagnosis. The initial angiography (CT, MR, or conventional) can be normal, especially in the first 3 to 5 days after symptom onset. Moreover, the detection of narrowed cerebral arteries has substantial interobserver variations, especially when using noninvasive imaging modalities. Cerebral angiographic studies typically show diffuse segmental multifocal narrowing and dilatation “string of beads” appearance of multiple cerebral arteries which usually reverse within weeks. It can involve both the anterior and the posterior circulation, and are mostly bilateral and diffuse. Maximum vasoconstriction occurs at approximately 2 weeks post-onset and the constricted vessel segments are not necessarily in the area of the intracerebral or subarachnoid hemorrhage. Centripetal propagation of vasoconstriction in RCVS has been postulated in many studies with limited evidence and unclear mechanism. It showed an initial distal vasoconstriction followed by more proximal vessels’ involvement in time interval follow-up imaging. By diagnostic criteria, image evidence of vasoconstriction should be resolved by 12 weeks. 1 , 2 , 7 , 10 , 22 , 23 , 24 , 25
Vessel wall MRI: It may be used as an adjunct to differentiate between RCVS, vasculitis, and atherosclerotic plaques. It will show wall thickening with no or very mild contrast enhancement of the affected arterial wall. In case of vasculitis, it will show intense concentric contrast enhancement, and a focal contrast enhancement in case of an active atherosclerotic processes. 26 , 27
Initial CT or MR brain scans may show normal finding or spectrum of parenchymal abnormalities, including nonaneurysmal convexity subarachnoid hemorrhage, intracerebral hemorrhage, ischemic stroke, and brain edema. Contrast-enhancing FLAIR MRI assessment of BBB breakdown can be used as an adjuvant finding or a clue to support the diagnosis, as explained earlier. 1 , 12 , 23 , 24 , 28 , 29 , 30 , 31
Routine blood tests are usually normal, but other tests are useful in ruling out systemic diseases that have been associated with RCVS: rheumatoid factor, antinuclear and antinuclear cytoplasmic antibodies, Lyme disease antibodies, urine vanillylmandelic acid and 5-hydroxyindoleacetic acid, and serum and urine toxicology screens. CSF examination findings are benign in more than 85% of patients. Other than to rule out cerebral vasculitis, there is no role for brain biopsy or temporal artery biopsy. 3 , 4 , 17 , 23 , 32
45.2.5 Differential Diagnosis
The diversity of the RCVS clinical and imaging features carries a wide range of differential diagnoses. Thunderclap headaches can also indicate a variety of serious threatening conditions such as aneurysmal subarachnoid hemorrhage, parenchymal hemorrhage, cerebral artery dissection, and cerebral venous sinus thrombosis. Typical precipitants of RCVS can also trigger headache in primary (such as primary thunderclap headache, primary exertional headache, and orgasmic and migraine headache) or secondary headache disorders other than RCVS. 3 , 5 , 7 , 9 , 11
Migraine should be cautiously considered in the sitting of severe headache and migraine-related stroke, because treating it inappropriately with agents such as sumatriptan may exacerbate vasoconstriction and stroke. 4 , 13 , 18
The most challenging and difficult to exclude differential diagnosis is the primary angiitis of the central nervous system (PACNS), given the close sharing and common overlapping of the clinical and radiological features in both conditions. RCVS has the favor of stable or improving clinical course early on in comparison with continuous deterioration in PACNS. The presenting features of explosive recurrent thunderclap headaches with normal CSF findings and normal brain imaging suggest a diagnosis of RCVS. Also, the presence of history of common triggers and associated cofactors may provide clues to the diagnosis. Other characteristic radiological features that may guide the RCVS diagnosis in the appropriate clinical setting are the absence of brain lesions on initial imaging and the presence of cortical convexal subarachnoid hemorrhages as well as the angiographic findings “string of beads” appearance. 13 , 33 , 34 , 35 , 36