Magnetic resonance imaging/angiography and transcranial Doppler velocities in sickle cell anemia: results from the SWiTCH trial

Abstract

• Children with SCA and stroke show severe parenchymal and vascular abnormalities that can be assessed using a vasculopathy grading scale. • Results from the SWiTCHTrial support concerns about ineffectiveness of transfusion therapy in preventing cerebrovascular injury progression.The Stroke With Transfusions Changing to Hydroxyurea (SWiTCH) trial compared standard (transfusions/chelation) to alternative (hydroxyurea/phlebotomy) treatment to prevent recurrent stroke and manage iron overload in children chronically transfused over 7 years before enrollment. Standardized brain magnetic resonance imaging/magnetic resonance angiography (MRA) and transcranial Doppler (TCD) exams were performed at entry and exit, with a central blinded review. A novel MRA vasculopathy grading scale demonstrated frequent severe baseline left/right vessel stenosis (53%/41% ‡Grade 4); 31% had no vessel stenosis on either side. Baseline parenchymal injury was prevalent (85%/79% subcortical, 53%/37% cortical, 50%/35% subcortical and cortical). Most children had low or uninterpretable baseline middle cerebral artery TCD velocities, which were associated with worse stenoses (incidence risk ratio [IRR] 5 5.1, P £ .0001 and IRR 5 4.1, P < .0001) than normal velocities; only 2% to 12% had any conditional/abnormal velocity. Patients with adjudicated stroke (7) and transient ischemic attacks (19 in 11 standard/8 alternative arm subjects) had substantial parenchymal injury/vessel stenosis. At exit, 1 child (alternative arm) had a new silent infarct, and another had worse stenosis. SWiTCH neuroimaging data document severe parenchymal and vascular abnormalities in children with SCA and stroke and support concerns about chronic transfusions lacking effectiveness for preventing progressive cerebrovascular injury. The novel SWiTCH vasculopathy grading scale warrants validation testing and consideration for use in future clinical trials. This trial was registered at www.clinicaltrials.gov as #NCT00122980. (Blood. 2014;124(6):891-898)

Central nervous system complications and management in sickle cell disease

“…66,67 Among children with SCA and progressive vasculopathy, 100% had evidence of new cerebral infarct within 5.5 years. 66 Despite the routine use of TCD to identify children with SCA at risk for overt strokes, several nuances of its use exist.…”

Long-term treatment follow-up of children with sickle cell disease monitored with abnormal transcranial Doppler velocities

“…It was concluded that transfusion/chelation remains the best way to manage children with SCA and stroke. 24 The next study, TWiTCH, 32,41,42 was a multicenter noninferiority trial in patients with a history of abnormal TCD and on chronic transfusion for at least 12 months who were randomized to transfusion pursuing vs hydroxyurea treatment. Started in 2011, it was prematurely closed in November 2014 41 because the primary end point had been reached and the strength of the statistical findings was unlikely to change with the collection of additional data.…”

“…Grading for stenosis (Table 1) was as described in the Stroke with Transfusions Changing to Hydroxyurea study. 24 Silent infarcts were defined as ischemic lesions of at least 3 mm by MRI in patients without a history of cerebrovascular events.…”

Understanding sickle cell brain drain

“…1 This study, which screened 161 children with sickle cell anemia (SCA) receiving chronic transfusion therapy for prevention of recurrent strokes, is the largest SCA cohort followed prospectively with magnetic resonance imaging (MRI) and magnetic resonance angiography (MRA) published to date, giving additional insights into the relationships between strokes and cerebral vasculopathy in SCA.…”

“…3 The SWiTCH participants had a significant burden of vasculopathy: 69% of children demonstrated arterial stenosis at study entry. 1 Children with more severe vasculopathy were more likely to have low or uninterpretable transcranial Doppler ultrasound (TCD) velocities in the cerebral arteries, reinforcing that cerebral blood flow through these arterial territories is likely severely compromised. Not surprisingly, children with more severe arterial stenosis had a greater likelihood of cortical and subcortical infarctions.…”