Reversible Cerebral Vasoconstriction and Subarachnoid Hemorrhage following Blood Transfusion in a Pediatric Patient with Sickle Cell Disease

Discussion

We describe a pediatric patient with sickle cell disease who presented with reversible cerebral vasoconstriction syndrome about 1 week following red blood cell transfusion. He was also treated with red blood cell transfusions after presentation, the standard of care for cerebrovascular events in sickle cell disease. The patient continued to do well at follow-up 1 month after discharge.

RCVS is characterized by severe, sudden-onset headache and segmental cerebral vasoconstriction, often with cortical subarachnoid hemorrhage as well. The diagnostic criteria proposed in 2007 by Calebrese are included in Table 1.8 Our patient met these criteria as documented in our case presentation. Although RCVS has been extensively reported, the pathophysiology remains unknown. It classically presents in women in the 5th decade of life with male-to-female ratio of 1:2-4.^10,15 The most common predisposing factor is the postpartum period.¹ Pharmacologic triggers may include sympathetic and adrenergic agonists, serotonin agonists (including ergots and triptans), and illicit drugs (marijuana, cocaine). In addition, sexual activity, exercise, Valsalva maneuver, metabolic derangements (hypercalcemia, porphyria), and tumors (carcinoid, pheochromocytoma) may also trigger RCVS in susceptible individuals⁸. The typical clinical presentation has good prognosis in approximately 78-90% of cases and outcomes may range from pure cephalgia to permanent neurologic deficits. In rapid and severe cases, in-hospital death has been reported, with estimated mortality between 1 – 5%.¹⁶ Subarachnoid hemorrhage (SAH) is a known complication of RCVS, occurring frequently adult patients.¹⁰ RCVS is also a rare complication following blood transfusion.¹⁷ It has previously been reported in a teenage girl with HbSS disease, occurring about 1 week after simple packed red blood cell transfusion, similar to the case reported here.¹⁸ Although pathophysiology remains unknown, increased blood viscosity, reperfusion injury, and a lack of stored nitrous oxide in transfused red blood cells have been among the proposed mechanisms for cerebral vasospasm after blood transfusion.^17,19

Owing in part to its rarity in the pediatric population, RCVS is likely underdiagnosed in children and our case highlights some of the challenges in recognizing RCVS in children.^3,20 RCVS has similar radiologic features compared to cerebral angiitis but should be managed very differently, as steroid administration in RCVS has been associated with worse outcomes.⁴ One of the most useful diagnostic tools in distinguishing RCVS from cerebral angiitis is the history, specifically the description of the headaches.^21,22 The typical headache for RCVS is sudden, reaching peak intensity within minutes and then resolving over hours, whereas headaches associated with cerebral angiitis tend to have a more gradual onset.^8,9 Due to our patient’s age, he was unable to provide this important descriptive detail. In addition, he presented with altered mental status and a seizure, which is less common than headache in adult RCVS.⁵ A case series of 13 children with RCVS demonstrated male predominance (11 male patients, 2 female), which differs from adult presentations of RCVS. Although the exact reason for this sex discrepancy is not fully understood, androgens have a poorly understood role in cerebral vascular tone, with both vasoconstrictive and vasodilatory functions noted in animal models.⁷ Thus, it would be reasonable to speculate that an increase in androgens in prepubescent males may increase their risk for RCVS, but further studies are needed to validate this assumption. The atypical presentation and inability to provide detailed history demonstrates the importance of approaching the pediatric patient with a broad differential, consulting appropriate services for expert guidance, and maintaining a low threshold for advanced and repeat neuroimaging studies to correctly diagnose pediatric patients.

This patient also had patchy T2 FLAIR changes in the occipital-parietal regions, which is frequently seen in Posterior Reversible Encephalopathy Syndrome (PRES). There have been several reported cases of PRES in pediatric patients, including pediatric patients with sickle cell anemia after blood transfusion.^23-25 A 2017 article by Kamide, et al., presented a case of RCVS with radiographic features similar to PRES as well.²⁶ A recent review article found 5 out of 13 cases of pediatric RCVS had MRI imaging consistent with PRES.¹⁴ PRES and RCVS can have overlapping clinical features including headache and altered mental status evolving over minutes to hours.²⁷ Though the pathophysiology of both PRES and RCVS remain incompletely understood, precipitating factors such as impaired cerebral autoregulation and endothelial dysfunction are possible common pathophysiologic factors in both conditions. The authors of a pediatric patient with sickle cell disease presenting with PRES days after blood transfusion noted that a possible explanation for the association of PRES and transfusion in sickle cell disease is a rapid increase in blood viscosity (from a serum hemoglobin increase of at least 5g/dL or more) leading to acute endothelial dysfunction several days later. These mechanisms, however, remain unproven and are only speculative at the time of this publication. Given the overlap of PRES, RCVS, and known association of PRES and sickle cell disease, we feel it is reasonable for treating physicians to obtain vessel imaging in patients presenting with clinical and/or radiographic features concerning for PRES, in particular for patients with hematologic disease.

A recent review article by Maldonado-Soto and Fryer on pediatric RCVS found that 7 out of 26 documented cases of pediatric RCVS had rheumatologic or hematologic risk factors, suggesting that physicians should maintain a low threshold for imaging in pediatric patients presenting with thunderclap headache with comorbid hematologic or rheumatologic disease.14 As mentioned above, blood transfusion has been associated with PRES in sickle cell patients. Our patient had a good outcome, perhaps in part to recognition of the diagnosis of RCVS and a low threshold for reimaging. The similarity between our patient and previously reported cases indicates that this condition may be more common than previously believed, further indicating the need for future investigations.

Our case of RCVS in a pediatric patient with sickle cell disease and following blood transfusion underscores the crucial need for further research into the pathophysiology of RCVS, especially in children. Furthermore, the role that blood transfusion may play in vasospasm needs to be understood so that these complications are not overlooked. The atypical presentation also demonstrates the importance of maintaining an appropriate clinical differential diagnosis. A more comprehensive understanding of this disease could prevent serious complications, potentially permanent neurologic damage, or death in future patients.