The relative rarity of neurological problems among SCD patients in the Arabian Gulf is being confirmed by multiple studies. This is especially true for patients who have an elevated HbF level and the AI haplotype, where the stroke prevalence is < 1.0%.22,29,30 Furthermore, investigations from Kuwait and other Gulf nations have repeatedly demonstrated that cerebral blood flow is scarcely hindered, with very little prevalence of abnormal or conditional TAMMV.23,24 ,25, 26,31 This shows that these patients' cerebral vasculopathy is not rapidly progressive. Interestingly, research from Oman 31,32, Iran,33 and Iraq,24 where this haplotype is not very frequent, also indicate reasonably normal TCDI indices, suggesting that this sparing of the cerebral arteries is not exclusive to patients with the AI haplotype. Consequently, this group may be immune to neurological events for other unknown reasons.
The literature has few prospective investigations of TCDI among patients with SCD.15,18,19 Also, since we do not have any patients with stenosis or stroke in our previously published studies23, 24, 25, 26, the analysis in this study focused on the relationship between TAMMV and the other individual Doppler indices in SCD patients, which was different than our recently published studies.25,26 Also, we added the initial data of the 18 patients who are not followed up due to many reasons as mentioned in the results section for comparison with 25 SCD patients group who were followed up.
Although MRI perfusion arterial spinning labelling (ASL) technique is widely used and does not require the use of contrast media and give more accurate result than TCDI, it has many disadvantages as it is time consuming, costly, and it does not provide hemodynamic of blood flow, and patient might feel claustrophic. A study concluded that TCDI and MRI modalities provide complementary resting cerebral blood flow measures, with similar effects across the whole cohort and between subgroups (age/fitness) if metrics are comparable (e.g., velocity [TCD] versus transit time [MRI]).34 Hence it was not used in the present study to detect arterial stenosis or occlusion.
This study used the TCDI approach, with one ultrasound operator blinded to initial data from the past, without angle correction, and with the patient in a stable state. The cerebral vasculature was scanned immediately while the Doppler waveform was acquired to guarantee a consistent result. Furthermore, this improves the accuracy of measuring the other vascular parameters compared to TCDNI. Furthermore, in order to identify the vessel of interest and guarantee the identification of any anomalies, TCDNI calls for a higher level of operator experience.
During TCDI, velocity recording is impacted by systemic parameters such as cardiac contractibility, heart rate, and total peripheral resistance. 35 TAMMV correlates better with perfusion and is less affected by these systemic variables, it is the vascular parameter utilized to detect stroke risk in patients with SCD. Other researchers have explored the prospect of using other indices to forecast the risk of stroke. PSV was among the metrics that shows a strong correlation with vascular stenosis or lumen diameter reduction.36 Using color Doppler imaging techniques, Seibert et al.37 computed TAMMV in several arteries, but they were unable to determine a maximum velocity that was both specific and sensitive for the diagnosis of cerebral infarction. Because of this, the STOP 10,11 trial data were re-examined in 2005 to see if another reliable, comparable vascular parameter that could be used for TCDI in the identification of arterial stenosis.
The findings in the present study are interesting in that uniformly, the TAMMV and other indices showed decreases in the follow-up group compared to the values in the initial study. The findings are in good agreement with previous studies of TAMMV.16,17 None of the patients in our study had a TAMMV exceeding 200 cm/s, which would be considered abnormal in accordance with the recommendations of Adams et al. 10,11 or exceeding 180 cm/s according to the McCarville et al.12. Moreover, we examined PSV instead of TAMMV as described previously by Jones et al.14 and applied by Naffa et al.15 Despite our results showing a direct relationship between TAMMV, PSV, and EDV, mean PSV did not reach above 140cm/s in any of the vessels in the initial study, while the lowest PSV recorded was 82 cm/s. Meanwhile, in the follow-up SCD patients, the highest PSV was 127 cm/s, and the lowest was 83 cm/s (Table 2). We attributed the normal TCDI findings in this study to several factors. Firstly, even in the normal population, TAMMV decreases with age27 and in our previous studies, 23, 24, 25, 26 we found a negative correlation between the two variables. Therefore, it was not surprising that TAMMV decreased over the 10-year interval in the patients in whom we succeeded in repeating the study. Silent brain infarcts (SBI) are rare in our children under the age of twelve. However, according to our earlier studies, they are prevalent in adult Kuwaiti patients (~ 20%).23,38,39 Contrary to reports from American patients, SBI is uncommon beyond the age of 16 and common in early childhood. We have interpreted this as effective protection from cerebral vasculopathy, which is provided by elevated HbF levels at the critical period of 2–3 years of age when vasculopathy is established. Hence, the peak incidence of ischemic stroke in susceptible patients is between the ages of 7 and 10 years.8 However, before the age of 3 years, most of our patients have HbF levels of 20 ->30%,40 thus inhibiting the development of significant vasculopathy. The relative severity of SCD among our adult patients and the higher prevalence of SBI are due to the cumulative low-level chronic inflammation.29, 39, 41
Secondly, there has been no significant vasculopathy that would produce stenosis and associated increased TAMMV because SCD among Kuwaiti patients is relatively mild, mainly because their HbS mutation is on chromosomes with the Saudi Arabia/India β-globin gene haplotype with elevated HbF levels 21,30,42. Finally, the other possible factor is the effect of hydroxyurea, which has been associated with decreasing TAMMV and is useful in preventing primary stroke as an alternative to chronic transfusion therapy. 43,44,45 Moreover, the increase in the HbF level between the 2 studies could be attributed to the hydroxyurea effect.
In the present study, the correlation between TAMMV and PSV and EDV was significant and consistent, but the correlation between TAMMV and RI and PI are not that impressive or consistent (Table 3). In addition, there was inverse relationship between PSV, EDV, and TAMMV versus RI and PI. Therefore, PSV, EDV, PI and RI could be of value in the evaluation of stroke risk in SCD patients. This might indicate an underlying intracranial vasculopathy in a patient with SCD. This is important in understanding the situation among our patients who generally have normal or low TAMMV values.
The major limitations of our study are the small sample size, given the relative underutilization of sickle cell services and the difficulty of follow-up. A larger prospective study correlating TCDI indices with magnetic resonance imaging/ angiography (MRI/MRA) findings, as well as neurological and psychological examination results, could provide or delineate the age at which evidence of cerebral ischemia/perfusion defects develops. It will also, important to determine the significance of very low TAMMV values (≤50 cm/s) as previously reported 19 since we do not have many patients with abnormally elevated values.