Reversible cerebral vasoconstriction syndrome in paediatric patients with systemic lupus erythematosus: implications for management.

Preeclampsia and Cerebrovascular Disease.

Reversible cerebral vasoconstriction syndrome (RCVS) is an increasingly recognized clinical emergency characterized by acute onset of severe headaches (usually multiple thunderclap headaches) and reversible segmental stenosis of cerebral arteries (1). RCVS is associated with several potentially devastating complications or comorbidities, such as posterior reversible encephalopathy syndrome (PRES) (9%–38%), ischemic stroke (4%–54%), intracerebral hemorrhage (12%–20%), cortical subarachnoid hemorrhage (SAH) (22%–34%), or cervical artery dissection (1%–12%) and even death (2– 7). The prevalence of RCVS is unknown, but it could be higher than that of its most important differential diagnosis—aneurismal SAH when patients complain of thunderclap headaches. Although the clinical features of RCVS are distinct, the diagnosis could sometimes be difficult in the lack of awareness or alertness about the dynamic nature of the disease. This is especially the case in the very early stage of the disease, when cerebral vasoconstrictions might be insignificant on the initial angiographic studies (3,4), and ischemic or hemorrhagic complications might not have occurred. In this issue of Cephalalgia, Kameda et al. report on a case of a 30-year-old woman who developed thunderclap headaches and seizure one week post-partum (8). Magnetic resonance imaging disclosed hyperintense vessel signs and PRES on the initial fluid-attenuated inversion recovery (FLAIR) imaging in the absence of significant vasoconstriction on magnetic resonance angiography (MRA). The hyperintense vessels disappeared one week later, but vasoconstrictions of major cerebral arteries became apparent (8). Although this case is not the first one to report hyperintense vessel sign in patients with RCVS (9,10), the unique finding that hyperintense vessels predated the occurrence of cerebral vasoconstrictions raised several important questions: 1.) Could hyperintense vessel sign help diagnose RCVS in the very early stage of disease? 2.) Does this finding support the centripetal propagation theory? and 3.) How to differentiate hyperintense vessels from cortical SAH, the early complication of RCVS? Hyperintense vessels on FLAIR imaging are hypothesized to be distal branches of the cerebral arteries or their leptomeningeal anastomotic collateral vessels with very low-flow velocities attributed to severe stenosis or occlusion of proximal cerebral arteries (11). In RCVS, FLAIR hyperintense vessels could be noted in up to 22% of patients (10). The presence of hyperintense vessels in RCVS is associated with more severe vasoconstrictions and cerebral hemodynamic derangements, and could herald the occurrence of ischemic stroke or PRES (10). In the case reported by Kameda et al. (8), hyperintense vessels were noted concomitantly with PRES two days after the onset of thunderclap headaches, in the absence of MRA vasoconstrictions. If these FLAIR hyperintense vessels also came from the failure of cerebrospinal fluid (CSF) nulling effect due to stagnant or retrograde flow of distal arterioles or leptomeningeal networks, this rare observation might have serendipitously captured the point when severe vasoconstrictions were still restricted to distal arteries beyond the resolution of routine MRA. In our previous study, MRA vasoconstrictions were not at its worse point until 11–20 days after headache onset (4). In another large series, it was reported that up to 33% of the patients with RCVS had a normal early angiogram (3). In other words, in one-third of the patients,

Introduction: Posterior reversible encephalopathy syndrome (PRES) and reversible cerebral vasoconstriction syndrome (RCVS) are diagnoses that have a clinical and radiographic overlap. One particular overlap includes the presence of hemorrhage, which we studied in each population to determine its effect on outcomes. Objective: To compare characteristics and outcomes of hemorrhagic PRES and hemorrhagic RCVS populations. Methods: We conducted a review of the electronic health record at a single tertiary center from January 2008 to December 2018. Inclusion criteria were 18 years or older with clinical and radiographic evidence of PRES or RCVS. Patient demographics, presenting symptoms, imaging findings, and outcomes were compared between PRES and RCVS groups. Poor outcome was defined as discharge to skilled nursing facility or death. Analysis was performed using Pearson’s Chi-Square test. Results: Among 281 PRES and 98 RCVS cases, intracranial hemorrhage was seen on imaging in 51 PRES cases (18%) and 34 RCVS cases (35%). Headache was present in all patients with hemorrhagic RCVS but only seen in 40% of hemorrhagic PRES. Use of antidepressants or drugs of abuse was more frequent with hemorrhagic RCVS (53%) as compared to hemorrhagic PRES (7%, p <0.05). Among hemorrhagic PRES, presence of intraparenchymal hemorrhage but not subarachnoid hemorrhage was associated with vasoconstriction on arterial imaging (p<0.05). Length of stay was longer for both hemorrhagic PRES and hemorrhagic RCVS (p<0.001) compared those without hemorrhage. Presence of focal neurological deficits, motor and sensory, was associated with poor outcomes in hemorrhagic RCVS patients (p<0.05). Discharge to a rehabilitation facility was associated with hemorrhagic PRES (p<0.05), no association in those without hemorrhage. There is no evidence that discharge location is significantly different between RCVS hemorrhage and non-hemorrhage groups. Conclusion: Hemorrhage in PRES and RCVS is associated with more clinical deficits at presentation and longer hospital stays. Underlying vasoconstriction is frequent and associated with hemorrhagic PRES.

Introduction: Reversible cerebral vasoconstriction syndrome (RCVS) may co-occur with brain MRI T2/FLAIR sequence changes, and posterior reversible encephalopathy syndrome (PRES) may be associated with cerebral vasoconstriction. Both entities with overlapping features may be considered as a single group. We compared the isolated RCVS group to the overlapping group to investigate clinical and radiological features, with a focus on vessel involvement. Methods: We performed a retrospective study of adult patients admitted to a tertiary medical center from February 2008 until February 2018 and who were diagnosed with PRES or RCVS. Overlap cases consisting of PRES with vasoconstriction and RCVS with reversible MRI T2/FLAIR changes were compared to isolated RCVS cases. Clinical and radiological features of both groups were compared with each other. Involved vessel segments were classified as internal carotid artery, M1 and M2 middle cerebral artery, A1 and A2 anterior cerebral artery, P1 and P2 posterior cerebral artery, vertebral artery, and basilar artery. Severity was also graded (1-49% or >49%). Appropriate statistical tests were used to compare the variables and significant findings reported. Results: There were 86 cases with isolated RCVS and 44 cases of overlap. Seizures (19, 43%) and encephalopathy (13, 30%) were common in the overlap group, whereas headache was common in the isolated RCVS group (79, 92%). Immunosuppressant use was more often present in the overlap group (9, 20%), but there were no differences in antidepressant, cocaine, or marijuana use. Intracerebral hemorrhage was more common in the overlap group (12/44, p=0.003), but there were similar numbers of ischemic strokes and subarachnoid hemorrhages. There were no differences in the number or location of segments involved or stenosis severity between the groups. Home discharge was more frequent among pure RCVS (73, 85%) than among overlap patients (27, 61%, p=0.004). Conclusion: Clinical presentations and short-term prognosis differed among isolated RCVS and group with PRES-RCVS overlap characteristics. There was no difference in vascular involvement between the groups.

Rituximab‐associated posterior reversible encephalopathy syndrome

Introduction: Posterior reversible encephalopathy syndrome (PRES) is a clinical syndrome with typical neuroimaging findings of vasogenic cerebral edema in posterior brain regions. Reversible cerebral vasoconstriction syndrome (RCVS) is diagnosed when there is reversible cerebral vessel narrowing and often with thunderclap headache. The two diseases have overlap in clinical and radiographic features. Objective: To compare clinical presentation, vascular abnormalities and imaging findings among PRES and RCVS. Methods: We searched patients in electronic health record at a single tertiary center from January 2008 to December 2018. Inclusion criteria was 18 years or older with clinical and radiographic evidence of PRES or RCVS. PRES was diagnosed by clinical presentation and presence of vasogenic edema on radiographic imaging. RCVS was determined by clinical presentation and transient arterial stenosis. Patient demographics, presenting symptoms, comorbid conditions, and imaging findings were compared between PRES and RCVS populations. Analysis was performed using Fisher’s exact test Results: Seventy-four patients with PRES and 24 patients with RCVS met inclusion criteria. The median age and presenting blood pressure did not differ between PRES and RCVS groups. PRES population consisted of fewer females (70%) compared to RCVS (92%, p=0.05). There was no significant difference in frequency of DWI lesions in PRES (37%) and RCVS (24%, p=0.308). Among patients who had arterial imaging, arterial stenosis was seen in 28% (13/46) of PRES. The occurrence of > 50% FLAIR reversibility was more common in PRES (67%) and seen less frequently in RCVS (27%, p=0.008). Conclusion: There is radiographic overlap between PRES and RCVS. About a quarter of PRES have arterial stenosis, while about a quarter of the RCVS group had FLAIR reversibility.

Introduction: Nontraumatic convexity subarachnoid hemorrhage (cSAH) is a non-aneurysmal variant associated with various etiologies. Methods: We performed retrospective review of consecutive cSAH admitted to a large comprehensive stroke center, from 8/1/06-1/1/16. We abstracted data on demographics, neuroimaging, and clinical presentation; trauma was excluded. Cases were categorized: cryptogenic (negative work-up), susceptibility-weighted imaging-confirmed amyloid angiopathy (AA), posterior reversible encephalopathy syndrome (PRES), imaging-confirmed reversible cerebral vasoconstriction syndrome (RCVS), cerebral venous thrombosis (CVT), large artery occlusion (LA), or other known cause (sepsis, endocarditis, cerebral infarcts, or malignancy). Results: We identified 84 cases of cSAH occurring in 83 patients. Etiology subgroups were: 25% cryptogenic (N=21), 16% AA (N=13), 13% PRES (N=11), 13% RCVS (N=11), 11% CVT (N=9), 8% LA (N=7), and 14% other (N=12). Among cryptogenic patients, 8 had suspected clinical RCVS and 1 had suspected AA. There were significant differences in age, gender, and clinical presentation among etiology subgroups. AA patients were the oldest (mean 75.6 years), while RCVS patients were the youngest (45.6 years, p<0.0001). The majority of AA cohort was male (61%), whereas PRES and RCVS cohorts were exclusively female (100%, p=0.0002). Transient neurologic symptoms were common in AA (69%) but rare in RCVS (0%, p=0.01); headache was common in RCVS (80%) but unusual in AA (15%, p=0.001). Among 11 patients with confirmed RCVS, initial vascular imaging was negative in 6 (55%); repeat vascular imaging was necessary to diagnosis vasoconstriction (mean delay 5 days, range 3 -16 days). Conclusions: To our knowledge, this is the largest case series of cSAH patients. Convexity SAH has a broad range of etiologies, with the most common being cryptogenic, RCVS, PRES, and AA. In our cohort, cSAH due to AA most typically presented as older males with transient neurological symptoms; cSAH due to RCVS presented as younger females with headache. Over half of patients with cSAH due to RCVS required repeat vascular imaging to confirm vasoconstriction. Further research is warranted to clinically characterize this complex variant of SAH.

Introduction: Posterior reversible encephalopathy syndrome (PRES) and reversible cerebral vasoconstriction syndrome (RCVS) might represent a pathophysiological spectrum. They are commonly diagnosed separately, based on prominent clinical features. We aimed to compare clinical and radiographic findings of PRES and RCVS. Methods: We performed a retrospective study of adult patients admitted to a tertiary medical center from February 2008 until February 2018 and were diagnosed with PRES or RCVS. Patient demographics, risk factors, clinical features, imaging, and outcomes were compared. Appropriate statistical tests were used to compare the variables and significant findings are reported. Results: There were 281 PRES and 98 RCVS cases meeting diagnostic criteria. Seizures, encephalopathy, and hypertension were more common with PRES, whereas headache was more common with RCVS (p <0.001). Hypertension and transplant recipient or immunocompromised status were associated with PRES (p <0.001), as did diabetes mellitus (p <0.05). Marijuana use, smoking, and obesity were associated with RCVS (p <0.05). ). Intraparenchymal or subarachnoid hemorrhage was found in 51 PRES cases and 34 RCVS cases. Arterial stenosis was present in 19 % of PRES cases. Brain FLAIR MRI hyperintensity that was reversible on follow-up was present in 26% of RCVS cases. Conclusion: PRES and RCVS share common clinical characteristics and might represent a pathophysiological spectrum, though distinct clinical features were noted in our retrospective analysis.

Guillain-Barré syndrome is an immune-mediated inflammatory polyneuritis characterised by rapidly progressive flaccid paralysis. Guillain-Barré syndrome may present with posterior reversible encephalopathy syndrome or reversible cerebral vasoconstriction syndrome in rare cases. A woman in her 60s with a history of follicular lymphoma presented with a one-week history of difficulty walking and thunderclap headaches. The patient was diagnosed with Guillain-Barré syndrome based on neurological examination, cerebrospinal fluid analysis and nerve conduction findings. Further diagnosis of posterior reversible encephalopathy and reversible cerebral vasoconstriction syndromes was based on imaging findings and headache history. The patient was treated with intravenous immunoglobulin and amlodipine, and symptoms improved. We reviewed the literature on Guillain-Barré syndrome associated with posterior reversible encephalopathy and/or reversible cerebral vasoconstriction syndrome. The underlying pathophysiology may involve dysautonomia resulting in unstable blood pressure, and hyponatraemia causing endothelial dysfunction. The SNOOP mnemonic highlights the 'red flags'. This SNOOP mnemonic suggests the possibility of secondary headaches that require imaging studies. In this case, the patient exhibited three SNOOP symptoms: S (history of malignancy: follicular lymphoma), O (sudden-onset headache) and O (over 50 years old). This case highlights the importance of considering coexisting central neurological disorders in patients with Guillain-Barré syndrome. Guillain-Barré syndrome (GBS) alone rarely causes headaches; therefore, when GBS patients complain of severe headaches, especially when the headache is associated with 'red flags', other complications and differential diagnosis should be considered.Posterior reversible encephalopathy syndrome (PRES) and reversible cerebral vasoconstriction syndrome (RCVS) can be triggered by GBS.Hyponatraemia, age over 50 years and female gender may be risk factors for developing PRES and RCVS in GBS patients.

Reversible cerebral vasoconstriction syndrome (RCVS) is characterized by transient constriction of cerebral arteries, leading to severe headache and potential complications. The association between RCVS and Guillain-Barre syndrome (GBS) is rare and poorly understood and warrants further investigation. A detailed case of RCVS in a patient with GBS was presented, followed by a comprehensive literature review. PubMed, Embase, and Google Scholar were searched for relevant cases and studies. The case involved a 62-year-old woman with GBS who developed RCVS. The literature review identified three additional reported cases. RCVS in GBS primarily affected middle-aged women and presented with a variety of neurological symptoms. Neuroimaging showed reversible vasoconstriction in the cerebral arteries, along with other complications such as posterior reversible encephalopathy syndrome, subarachnoid hemorrhage, and infarcts. While the treatment for GBS consisted mainly of intravenous immunoglobulin, specific treatments for RCVS remain unclear. The coexistence of RCVS and GBS is a rare occurrence. RCVS in GBS may result from the disruption of cerebral vascular tone regulation, possibly influenced by GBS-related dysautonomia and consequent high blood pressure. Recognizing RCVS in GBS patients is critical for appropriate management.

We read with interest the recent article by Pugliese et al. [1] concerning a case of intracranial hypotension and PRES and the debate that followed [2, 3]. The authors reported a rare patient who presented worsening of headache and seizures at 7 days after spinal anesthesia. Brain MRI showed signs of intracranial hypotension (IH) and posterior reversible encephalopathy syndrome (PRES). Therefore, the authors diagnosed the patient as PRES caused by IH, secondary to spinal anesthesia. We wish to provide further comment. Reversible cerebral vasoconstriction syndrome (RCVS) is characterized by severe acute headache and constriction of cerebral arteries [4, 6]. IH is also a cause of RCVS [5, 7]. RCVS should not be confused with PRES although there is overlap in both the presumed underlying mechanisms and the predisposing factors [5]. Indeed, some patients can actually exhibit RCVS with PRES [4, 5]. The authors ruled out RCVS, mainly because of the subacute and progressive onset of the clinical symptoms and normal MRA findings. However, it is possible that the characteristics of headache may be changed by anesthesia. Further, Ducros et al. [6] described that, in some patients who had an initial normal MRA at a mean of 5.5 days (range 2–9 days) after headache onset, a repeat MRA showed visible narrowings at a mean of 13.6 days (range 9–20 days). In contrast, a repeat MRA was not performed in the cases presented by Pugliese et al., suggesting that the authors cannot rule out the possibility of RCVS.

Charles Bonnet syndrome (CBS) was first described by a Swiss philosopher named Charles Bonnet in 1760. For a long time, this syndrome was considered to be rare; however, in 1996, Teunisse et al. [1] reported psychopathological characteristics of 60 patients with CBS and questioned the rarity of CBS. CBS is diagnosed if the following criteria are fulfilled: (a) the presence of formed and complex, persistent, or repetitive visual hallucinations; (b) full or partial retention of insight; (c) the absence of delusions; (d) and the absence of hallucinations in other modalities [2]. Reversible cerebral vasoconstriction syndrome (RCVS) is a disorder characterized with reversible segmental and multifocal vasoconstriction of cerebral arteries and severe headaches with or without focal neurological deficits or seizures. Calabrese et al. described the following features for RCVS: (a) transfemoral angiography or indirect [computed tomography (CT) or magnetic resonance (MR)) angiography showing segmental cerebral artery vasoconstriction; (b) no evidence for aneurysmal subarachnoid hemorrhage; (c) normal or near-normal findings for cerebrospinal fluid analysis (protein level \80 mg/dL, white blood cell count\10 cells/lL, normal glucose level); (d) severe, acute headache with or without additional neurological signs or symptoms; and (e) the diagnosis cannot be confirmed until reversibility of the angiographic abnormalities is documented within 12 weeks after onset and if death occurs before the follow-up examinations are completed, the autopsy rules out conditions such as vasculitis, intracranial atherosclerosis, and aneurysmal subarachnoid hemorrhage, which can also manifest with headache and stroke [3]. Here, we report transient visual hallucinations resembling the ones in CBS in a patient with RCVS. A 64-year-old woman experienced severe thunderclap headache when she was skiing. CT and MR imaging (MRI) of her brain performed at that time revealed no abnormality. MRI and magnetic resonance angiography (MRA) conducted about 3 weeks later revealed convexity subarachnoid hemorrhage in the right frontal lobe and multiple segmental cerebral artery vasoconstrictions (Fig. 1). Her blood pressure was 130/96 mmHg, her body temperature was 36.2 C, and she was alert. She had no visual loss but experienced formed and complex visual hallucination such as ‘‘people walking down the street’’ or ‘‘people acting in a theater’’ only when she closed her eyes, and she had full retention of insight. Her visual hallucinations began about 3 weeks after the onset of headache, and lasted for about a week. 99mTc-ECD single-photon emission computed tomography showed diminished blood flow in both the occipital lobes (Fig. 2). Her headache eventually resolved without any neurological deficit. MRA performed at about 5 weeks after the onset of headache showed more cerebral artery vasoconstrictions, but the vasoconstrictions resolved 2 weeks after that, and the patient was diagnosed with RCVS. Y. Yagi (&) Y. Watanabe H. Yokote T. Amino T. Kamata Department of Neurology, Musashino Red Cross Hospital, Kyonancho 1-26-1, Musashino, Tokyo 180-8610, Japan e-mail: yyagi-tmd@umin.ac.jp

Posterior reversible encephalopathy syndrome (PRES) and reversible cerebral vasoconstriction syndrome (RCVS) are relatively uncommon neurological disorders, but their detection has been increasing mainly due to clinical awareness and spreading of magnetic resonance imaging (MRI). Because these syndromes share some common clinical and radiologic features and occasionally occur in the same patient, misdiagnosis may occur. PRES is characterized by varied neurological symptoms including headache, impaired visual acuity or visual field deficit, confusion, disorders of consciousness, seizures, and motor deficits often associated to peculiar neuroradiological pattern even if uncommon localization and ischemic or hemorrhagic lesions were described. RCVS is a group of diseases typically associated with severe headaches and reversible segmental vasoconstriction of cerebral arteries, often complicated by ischemic or hemorrhagic stroke. Pathophysiological basis of PRES and RCVS are still debated but, because they share some risk factors and clinical features, a possible common origin has been supposed. Clinical course is usually self-limiting, but prognosis may fluctuate from complete recovery to death due to complications of ischemic stroke or intracranial hemorrhage. Neuroradiological techniques such as digital angiography and MRI are helpful in the diagnostic pathway and a possible prognostic role of MRI has been suggested. This review will serve to summarize clinical, neuroradiological features and controversies underlying both syndromes that may mislead the diagnostic pathway and their possible relationship with pathophysiology, clinical course, and prognosis.

We thank Dr Satoru Takeuchi and his colleagues for their comments [1] about our article on the probable causal association between intracranial hypotension (IH) and posterior reversible encephalopathy syndrome (PRES) [2]. They ask us to further debate the possible role of reversible cerebral vasoconstriction syndrome (RCVS) in the clinical history of our patient. RCVS is a group of disorders characterized by the reversible segmental and the multifocal vasoconstriction of cerebral arteries at angiography and severe “thunderclap” headache with or without focal neurological deficits or seizures [3]. In our patient, RCVS was mainly ruled out because of normal MRA findings. As described by Ducros et al. [4], some patients (only 9% of the cases) even with an initial normal MRA could have a repeated MRA showing vessels narrowing, but we did not suspected RCVS because of the headache clinical features and the neurological signs. In fact, our patient presented a bilateral headache, pressure-like, with a postural component, different from the thunderclap headache, typical of RCVS. It is possible that the mild headache onset was consequent to the epidural anesthesia, but the headache did not change in severity until the patient discharge, some days after the end of anesthesia effect. Moreover, the MR findings were typical of PRES, showing multiple symmetric and bilateral hypertintensities on T2-weighted images in the posterior territories, with high signal on DWI, as well as on ADC maps. It has been described that a post-partum RCVS could cause PRES [5, 6], but we supposed that the demonstrated intra-cranial hypotension (IH), subsequent to the inadvertent dural puncture, was the leading cause of PRES. This hypothesis is mainly supported by the prompt resolution of the neurological symptoms and the radiological alterations of both IH and PRES, only after the treatment of IH with a blood patch. This would be difficult to be expected in case of RCVS. Finally, we know that the association between IH and PRES is only a presumption and that there are some limitations of our single experience and of the proofs provided. We look forward to further contributions that could eventually clarify the relationship between IH and PRES.

Background: Reversible cerebral vasoconstriction syndrome (RCVS), also known as Call-Fleming syndrome, is characterized by thunderclap headaches, non-aneurysmal segmental cerebral vasoconstriction seen on arteriogram, and spontaneously resolves within 12 weeks. Fingolimod has been reported to cause posterior reversible encephalopathy syndrome (PRES) and one case of RCVS. Objective: We report a case of RCVS possibly related to fingolimod use, and compare to cases of adverse outcomes in fingolimod use. Methods: This is a single observational study without controls; therefore, level of evidence is IV. A literature review in pubmed with keywords, fingolimod, vasospasm, RCVS, Call-Fleming, stroke, PRES and hemorrhage. Results: One case of RCVS on fingolimod in the post-partum period. Two other cases in the literature were found one with hemorrhagic encephalitis and the other critical vasospasm in the upper extremity associated with fingolimod 1.25 mg daily in the FREEDOMS II trial and TRANSFORMS study, respectively. Additionally, Novartis reports nine cases of PRES related to fingolimod use. Conclusion: Fingolimod has the potential to cause vasoconstriction however appears to be rare and more likely on doses higher than 0.5 mg daily. Fingolimod may be associated in RCVS and should be considered in patients with severe headache on fingolimod.