Natural History of Pediatric Patients with Sickle Cell Disease and Concurrent Cerebral Vasculopathies: Report of 62 Cases from a Single Institution

Introduction Children with sickle cell disease (SCD) may develop cerebral vasculopathies, increasing their risk of stroke. Some vasculopathies involve altered hemodynamics and may respond to medical interventions, while others, such as moyamoya disease, have been shown to achieve particular stroke reduction with revascularization surgery. Characterization of this spectrum of vasculopathies is well-defined with neuroimaging; however, comparisons of the semiology and laboratory findings are less detailed.

Objective To compare the temporal pattern of radiographic, clinical, and laboratory findings in SCD-associated vasculopathy treated with medical and neurosurgical therapies.

Methods Pediatric patients diagnosed with homozygous SCD and at least one cerebral vasculopathy: moyamoya, cerebral vessel stenosis, stroke or transient ischemic attack (TIA), ivy sign, or elevated transcranial doppler (TCD) velocities were retrospectively reviewed at a single institution. Patients lacking significant follow-up (<3 clinic visits) were excluded. Children who underwent revascularization were classified as "surgical;" those who did not were classified as "medical."

Results Sixty-two children were identified between 1994 and 2021. The mean age at vasculopathy diagnosis was 7.0 and 7.8 years for the surgical and medical cohorts, respectively.

Thirty (48.4%) patients had at least one vasculopathy medically managed with chronic transfusion, hydroxyurea, and/or stem cell therapy. Among these patients, 4 (13.3%) were diagnosed with moyamoya, 22 (73.2%) had stroke or TIA, 6 (20%) had other vessel stenosis, 15 (50%) had elevated TCD velocities, and a single patient (3.3%) had ivy sign [20 (66.6%) patients had multiple vasculopathies].

Thirty-two (51.6%) patients underwent a pial synangiosis revascularization surgery, all of whom had moyamoya. Sixteen (50%) were also found to have elevated TCD velocities, and 17 (53.1%) were noted to have ivy sign.

Preoperatively, 27 (84.4%) surgical patients were found to have radiographic evidence of stroke. When comparing preoperative and postoperative stroke rates (1.5 and 0.076 strokes per year) following revascularization surgery, this stroke rate significantly improved (p<0.001), with only 8 patients experiencing postoperative strokes. Three of these occurred during the immediate (<10 days) postoperative period, characterizing a 9.4% (3/32) risk of perioperative stroke in this cohort. Surgery was also found to significantly reduce long-term stroke risk in these patients when compared to the long-term stroke risk of the medical cohort (0.076 and 0.22 strokes per year, p<0.05).

Patients with subclinical strokes detected on interval imaging were mainly in the medical cohort and had higher maximum TCD MCA velocities than patients with symptomatic strokes, who were primarily surgical moyamoya patients (p<0.05 on the right, a not significant trend on the left). The maximum concentration of HbF before the first stroke was also found to be significantly lower in patients who experienced subclinical strokes rather than symptomatic acute strokes (on average 11.1% versus 20.2%, p<0.05).

Conclusions Children with SCD have an increased risk of stroke, further exacerbated by cerebral vasculopathies. Clinical, laboratory, and radiological evaluation may distinguish different stroke risk phenotypes: elevated MCA velocities and lower HbF concentrations were identified in patients who experienced subclinical stroke events and tended not to have moyamoya, whereas clinically evident acute strokes were largely identified in moyamoya vasculopathy. For patients with SCD and moyamoya, revascularization improves long-term stroke outcomes compared to medical management; however, surgery for children with SCD is associated with a perioperative stroke risk that is slightly higher than non-SCD moyamoya patients, likely attributed to the relevant comorbidities.

Heeney:FORMA Therapeutics: Consultancy; Novartis: Consultancy; Oric Pharmaceuticals: Consultancy; Vertex/ Crisper Therapeutics: Consultancy; Bluebird Bio: Consultancy. Archer:Global Blood Therapeutics: Research Funding; Novartis: Research Funding; Haemonetics: Other: Stocks are provided to my husband as part of his compensation as an employee of the company.