Robert J. Adams

Sickle cell disease is associated with a high risk of stroke in the early years of childhood. The risk of a secondary stroke can be significantly reduced through chronic blood transfusions. Prevention of the first stroke (primary prevention) was made possible through the use of transcranial Doppler (TCD) US and demonstrated in a randomized clinical trial called the stroke prevention trial in sickle cell anemia (STOP). TCD results were classified as normal, conditional, abnormal or inadequate based on velocity readings in specific arterial segments. The MCA and ICA were carefully searched to find the highest velocity, and this was used to stratify patients as to stroke risk. Those with abnormal or high-risk TCD received either monthly blood transfusions or no transfusions, and those randomized to transfusion had a much better outcome in terms of stroke (one stroke, versus ten in the control group) and also fewer other medical problems while transfused. TCD screening is recommended for SCD patients to begin at 24 months of age and should be repeated every 6–12 months during early childhood. Transcranial Doppler imaging (TCDI) can be easier to use and learn and with a few adjustments can provide equivalent predictive power. Currently, TCD is the only recommended method for treatment selection for primary-stroke prevention. MRI and MRA can provide important information on the status of the brain and the blood vessels and, when abnormal, indicate greater risk. Although TCD cannot predict all strokes, TCD and TCDI offer an opportunity to apply an effective therapy for patients in this risk group and reduce many first-time strokes.

Ischemic stroke occurs in at least 11% of patients with homozygous sickle cell anemia (SCD) by the time they turn 20 years old. High risk associated with distal intracranial internal carotid (ICA) and proximal middle cerebral artery (MCA) stenosis can be detected by transcranial Doppler (TCD). TCD screening offers the possibility of reducing the risk of first stroke significantly based on a paradigm tested and proven to be effective in a stroke prevention trial in sickle cell anemia (STOP). Children with high flow velocity in the ICA and MCA of 200 cm/s time average mean of the maximum (TAMM) or higher had a 10% per year risk of first stroke that was reduced to r=0.94). The multivariate model for prediction indicated that TAMM velocity was a better predictor than EDV, and PSV and TAMM were approximately equivalent. PSV cutpoints defining the two relevant STOP risk categories—“conditional,” which should lead to increased TCD surveillance, and “abnormal,” which should lead to strong consideration for treatment according to STOP—were derived taking into consideration known differences in measurements between the dedicated Doppler systems (TCD) used in STOP and the transcranial Doppler imaging (TCDI) systems commonly used in clinical practice. The recommended PSV cutpoint for conditional TCD is 200 cm/s, and for abnormal TCD triggering consideration for treatment is 250 cm/s. Assuming TCDI equipment is used and the STOP protocol is applied, a PSV cutpoint of 200 cm/s is recommended as the threshold for increased TCD surveillance (comparable to a TCD TAMM of 170 cm/s in STOP); a PSV of 250 cm/s is recommended as the cutpoint at which, if confirmed in a second examination, chronic transfusion should be considered. Assuming the STOP scanning protocol is used, PSV is at least as good as TAMM and can be used to select children with SCD for treatment or increased surveillance to prevent first stroke.

The Stroke Prevention Trial in Sickle Cell Anemia (STOP) was a randomized multicenter controlled trial comparing prophylactic blood transfusion with standard care in sickle cell anemia (SCA) children aged 2 to 16 years selected for high stroke risk by transcranial Doppler (TCD). More than 2000 children were screened with TCD to identify the 130 high-risk children who entered the randomized trial. A total of 5613 TCD studies from 2324 children were evaluated. We also collected information on stroke. We describe the changes in TCD with repeated testing and report the outcome without transfusion in the STOP screened cohort. Risk of stroke was higher with abnormal TCD than with normal or conditional TCD (P < .001) or inadequate TCD (P = .002), and risk with conditional TCD was higher than with normal TCD (P < .001). Repeated TCD in 1215 children showed that the condition of 9.4% of children became abnormal during observation. Younger patients and those with higher initial flow velocities were most likely to convert to abnormal TCDs. Screening in STOP confirmed the predictive value of TCD for stroke. Substantial differences in the probability of conversion to abnormal TCD were observed, with younger children and those with higher velocity more likely to have an abnormal TCD with rescreening.