Transcranial Doppler Ultrasound in Children with sickle cell disease
By Soundrie Padayachee, Consultant Clinical Scientist, Ultrasonic Angiology Department, Guy’s & St Thomas’s NHS Trust, and Baba Inusa, Professor, Kings College London, UK & International Medical Vice President.
Keywords: Transcranial Doppler, Sickle Cell Disease, Stroke
Sickle cell disease (SCD) is one of the most commonly inherited disorders worldwide in which an abnormal haemoglobin is inherited. Children affected are predominantly of sub-Saharan origin but also include Indian, Arab and some Mediterranean populations and with migration more than 14,000 people in the UK are affected. The disease is characterised by a range of occlusive vascular events including stroke, which is one of the most devastating complications occurring in 11% of patients under the age of 20.1 The rate of stroke is most frequent in children with the sickle cell anaemia form HbSS. Vascular occlusion is thought to occur due to endothelial damage by irregular sickle blood cells triggering an inflammatory response, which produces a hyperplastic lesion that narrows blood vessels.2 There is compelling evidence that the cause of stroke in SCD is by obstruction of the larger basal cerebral arteries caused by this proliferative intimal hyperplasia.
Ultrasound has played a significant and important role in improving the quality of life of children affected by SCD. The first report of using Transcranial Doppler ultrasound (TCD) to monitor blood flow in children with SCD, was published by Robert Adams in 1988.3 Several studies underpinned the ultrasound protocol in the landmark Stroke Prevention Trial in Sickle Cell Anaemia (STOP).4 This included reports that the time-averaged mean of the maximum (TAMMV) blood velocity in the middle cerebral artery (MCA) of neurologically asymptomatic children with SCD was between 100-130 cm/sec, MCA TAMMV between 140-190 cm/s was associated with early evidence of stenosis, significant stenosis was identified by a TAMMV of ≥170cm/s and clinical follow-up indicated that a threshold of ≥200cm/s TAMMV identified children at the highest risk of stroke.5-7
The STOP trial focussed on children at the highest risk of stroke. Non-imaging TCD was used to assess the TAMMV in the MCA), terminal internal carotid (TICA) and anterior cerebral (ACA) arteries. The STOP trial randomised children with high TCD velocities (≥200cm/s) into either chronic transfusion therapy or standard of care treatment. The trial reported a 92% reduction in stroke by intention-to-treat analysis in the chronic transfusion patients. The results were significant and unequivocal leading to the trial being halted and TCD screening being recommended for all children with SCD. Despite reducing the risk of stroke, transfusions are associated with adverse effects such as iron overload and alloimmunisation, hence the STOP II trial was conducted to determine whether transfusions could be halted safely when the TAMMV dropped to normal levels. STOP II results demonstrated that halting transfusion resulted in reversion to high TCD velocities and stroke, hence it is recommended that transfusion should be delivered indefinitely.8
The TCD screening programme is recommended for all children between the ages of 2 to 16 years with HbSS and HbSβ0 thalassaemia genotypes. The highest TAMMV from either the right or left MCA or TICA or ACA is used to classify stroke risk (Table). Normal STOP TAMMV is below 170cm/s and annual surveillance is recommended. The conditional STOP category has an increased stroke risk where 3 monthly surveillance is recommended. When the TAMMV is ≥ 200cm/s, the STOP category is abnormal and transfusion therapy is indicated. Elevated ACA velocity (>170cm/s) was added to the risk assessment when an increased risk of stroke (OR = 2.9) was found, after adjusting for ICA/MCA velocity (Figure). The strokes in these patients were not in the ACA distribution, but were thought to be due to collateral flow effects.
Successful delivery of TCD screening is limited by the number of qualified practitioners performing TCD in SCD.9 Diagnostic vascular ultrasound is highly operator-dependant; hence training and competency validation are essential in producing skilled TCD operators. Training in the UK has been delivered through a modular training programme instructing practitioners from a range of professional backgrounds and competency.10 Although non-imaging TCD was used in the STOP trial, equipment availability led to sites using imaging TCD for screening. Non-imaging TCD and imaging TCD (duplex ultrasound) are both effective methods to examine children with SCD. Some early studies reported that imaging TCD velocities were lower than those measured by non-imaging TCD, however there is sufficient evidence that with proper technique, optimisation and measurement, the same velocity thresholds can be applied using either method.11
TCD is an important technique for predicting stroke in children with sickle cell disease. TCD can be continued when children are on chronic transfusion to monitor the impact on TAMMV. It can also monitor the impact of other treatments such as Hydroxyurea which can reduce sickling of red blood cells and reduces TCD velocities, and is an important alternative or adjunct to transfusion.