|Year : 2022 | Volume
| Issue : 2 | Page : 84-90
A retrospective study of risk factors of stroke or pathological transcranial doppler ultrasonography in Children with Sickle Cell Disease in Jeddah, Saudi Arabia
Ibrahim Al-Harbi1, Ali Algiraigri2, Sumaya Khaldi3, Rahf Albogmi4, Salha Asiri5, Wed Alogaibi5
1 Department of Pediatric Hematology Oncology, Division of Pediatric Hematology Oncology, King Fahad Armed Forces Hospital, Jeddah, Saudi Arabia
2 Department of Pediatric Hematology Oncology, Division of Pediatric Hematology Oncology, King Abdulaziz University Hospital, Jeddah, Saudi Arabia
3 Department of Pediatrics, Division of Pediatric Hematology Oncology, King Fahad General Hospital, Jeddah, Saudi Arabia
4 Department of Pediatrics, Division of Pediatric Hematology Oncology, King Fahad Armed Forces Hospital, Jeddah, Saudi Arabia
5 Department of Pediatrics, Division of Pediatric Hematology Oncology, King Abdulaziz University Hospital, Jeddah, Saudi Arabia
|Date of Submission||04-Jun-2021|
|Date of Acceptance||22-Dec-2021|
|Date of Web Publication||04-Aug-2022|
Dr. Sumaya Khaldi
King Fahad General Hospital, P. O Box 9862, Postal Code 21559 Jeddah
Source of Support: None, Conflict of Interest: None
INTRODUCTION: Sickle cell disease (SCD) is an autosomal recessive disorder characterized by hemolytic anemia with abnormal red blood cells. Stroke is a devastating complication of SCD. In Saudi Arabia, there is a high incidence of children with SCD who have had stroke. No studies have been conducted to look at the risk factors. In this review, we aim to explore these risk factors.
METHODOLOGY: In this retrospective cohort, individuals between 0 and 18 years old, diagnosed with SCD and had either a stroke, or pathological transcranial Doppler ultrasonography (TCD) result (cerebral blood velocity ≥200 cm/second or repeated borderline result >170 cm/second) were included. 38 cases were assessed. The parents were interviewed regarding patients personal, social, and family history. Medical and laboratory data were obtained from medical records.
RESULTS: Females were more affected (20/38). Most children are of an average socioeconomic status (20/38 compared to only 12/38 with poor socioeconomic status). Parental education inversely correlated with the risk of stroke/pathological TCD. The most common presentation of stroke was weakness (9/38), followed by headache (5/38). History of a prior stroke was found to be significant at 15.8%. The Cooperative Study of SCD found that leukocytosis is associated with an increased risk of stroke. In contrary, our review showed an average white blood cell count of 13.01 (+/‒5.36), HbS concentration at the onset of stroke, and/or pathological TCD of 66.23% (+/‒20.11). The most common artery involved was the middle cerebral artery.
CONCLUSION: Stroke is very prevalent in children with SCD in Saudi Arabia. A striking finding was that parental education inversely correlated with the risk; therefore, improving the awareness level of SCD among parents is crucial. Wide implementation of TCD as a screening tool and improving compliance with TCD may lead to reduce the risk. We encourage Saudi researchers to focus on central nervous system complications in children with SCD.
Keywords: Pediatric hematology/oncology, sickle cell anemia, sickle cell disease, stroke, transcranial Doppler ultrasound
|How to cite this article:|
Al-Harbi I, Algiraigri A, Khaldi S, Albogmi R, Asiri S, Alogaibi W. A retrospective study of risk factors of stroke or pathological transcranial doppler ultrasonography in Children with Sickle Cell Disease in Jeddah, Saudi Arabia. J Appl Hematol 2022;13:84-90
|How to cite this URL:|
Al-Harbi I, Algiraigri A, Khaldi S, Albogmi R, Asiri S, Alogaibi W. A retrospective study of risk factors of stroke or pathological transcranial doppler ultrasonography in Children with Sickle Cell Disease in Jeddah, Saudi Arabia. J Appl Hematol [serial online] 2022 [cited 2022 Aug 15];13:84-90. Available from: https://www.jahjournal.org/text.asp?2022/13/2/84/353279
| Introduction|| |
Sickle cell disease (SCD) is an autosomal recessive disorder characterized by a hemolytic anemia with abnormally shaped red blood cells. It is a prevalent, severe hematological disease that commonly affects children in Saudi Arabia. The traditional cultural in Saudi Arabia, which encourages consanguineous marriages, ensures autosomal recessive diseases are relatively common.
Patients with SCD suffer from different acute and chronic complications, which severely affect their lives. A previous study revealed that stroke is frequently a serious complication among children with SCD. Approximately 7% to 13% of children with SCD are affected by overt stroke, which may lead to long-term neurological impairment or even death. Stroke is defined as a neurological injury caused by the occlusion or rupture of cerebral blood vessels. Stroke can be ischemic, hemorrhagic, or both.
The Stroke Prevention Trial in Sickle Cell Anemia (STOP) study showed that transcranial Doppler ultrasonography (TCD) is a highly predictive tool for detecting children at high risk of developing stroke: by measuring the mean blood velocity in large intracranial blood vessels. Patients with abnormal flow (≥170 cm/second) are seen as being at risk of developing a stroke.
A literature search revealed a few studies that discuss the risk factors of stroke including the Cooperative Study of SCD (CSSCD) newborn cohort study. It states that the three main risk factors are dactylitis, severe anemia, and leukocytosis. It also showed that there are warning signs prior to a transit ischemic attack (TIA). These are a low status of hemoglobin (Hb), recency and an increased frequency of acute chest syndromes (ACS), and elevated systolic blood pressure. All are considered significant risk factors of having a stroke for SCD patients.
In Saudi Arabia, there is a high incidence of children with SCD who have had one or more strokes. It is astonishing, therefore, that no studies have been done there to look at the risk factors. This retrospective review aims to explore the risk factors of stroke in children with SCD in Saudi Arabia. They can then be better understood and the necessary changes to care implemented through prevention and management strategies in the hope of avoiding this devastating complication.
| Methodology|| |
This study, done in the Western Region of Saudi Arabia, Jeddah, was conducted among children with SCD who regularly received manual, partial blood transfusions in the Pediatric Hematology Oncology Department at King Fahd Army Hospital and the King Abdul-Aziz university hospital between January and June 2018. It was approved by the local research and ethical committee at both hospitals.
Eligibility criteria required individuals to be between 0 and 18 years old, diagnosed with any type of SCD and for them to have had either a history of stroke, or pathological TCD. Individuals with other coexisting neurological diseases were excluded from the study. This gave a sample of 38 cases who were assessed during their day care visit. Their parents were also interviewed regarding patient personal, social, and family history. Patients medical history and laboratory data were obtained from medical records.
Categorical variables were presented as frequencies and percentages. Continuous variables were presented as means ± standard deviations (SD). Biochemical markers and clinical history data were compared across the gender, nationality, and socioeconomic status by one-way ANOVA.
The study has no missing data, so missing data management was not required. The analysis was performed in a 95% confidence interval using the Statistical Package for the Social Sciences version 23 (IBM, Armonk, NY, USA).
| Results|| |
A total of 38 patients with SCD were included in this study. The mean age of all patient was 11.13 ± 3.95 years. Most or twenty-six (68.4%) of the patients were Saudi Arabian nationals. Almost half or twenty (52.6%) of them were from a family with average socioeconomic status. The clear majority at 92.1% of the children were living in Jeddah and with both their parents. In most of the cases (71.1%), the mother was the primary caregiver. The mean ± SD age of their father and mother was 44.47 ± 7.58 years and 36.58 ± 6.08 years, respectively. Eighteen (47.4%) of the patients had more than three siblings. Twenty-seven (71.1%) patients had at least one sibling with SCD. Three children (7.9%) were frequently absent from school and four (10.5%) had poor academic performance. The education level of their parents ranged from no formal education to university degree, more than half of the parents did not complete their higher education, only 14 (36.8%) of fathers, and 12 (31.6%) of the mothers had a university degree, as given in [Table 1].
The mean age of diagnosis of SCD was 23.65 ± 24.96 months and the mean age of the first stroke or first pathological TCD was 6.79 ± 2.85 years. 50.0% of them had pathological TCD due to receiving regular, manual partial blood transfusions. The most common first presentation of stroke was weakness in nine patients (47.3%). Six patients (15.8%) had a history of recurrent stroke. Most of them had a history of hospitalization (94.7%), whereas nearly one-third (34.2%) had a history of intensive care unit admission. Compliance with exchange blood transfusion was noted in 84.2% of patients. Five (13.2%) patients had undergone bone marrow transplantation (BMT) and three (7.9%) patients were listed for BMT [Table 2].
|Table 2: Distribution of all patients by sickle cell disease diagnosis, presentation and complication related characteristics (n=38)|
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Four main medications for the treatment of SCD, hydroxyurea, penicillin, folic acid, and iron chelating agent, were used by 78.9%, 89.5%, 100%, and 65.8% of patients, respectively, and most of the cases (73.7%) were compliant with the medications. The most frequent complication of SCD in this group of patients was painful vaso-occlusive crisis (VOC) (87.6%). The least commonly reported complication in both genders was dactylitis (31.6%). Only 2 out of 18 males suffered from priapism. The mean number of bouts of painful VOC and ACS had in the last year were 2.26 ± 1.97 and 1.61 ± 0.69 times, respectively [Table 3].
The mean Hb level of all the children, before the first stroke, or first abnormal TCD was 7.61 ± 2.87 g/dl. Among the cases with an abnormal TCD, the reticulocyte count was 9.51 ± 1.50%. The most commonly involved blood vessel was the right middle cerebral artery (MCA) (23.7%). The other pathological markers, e.g., mean corpuscular volume (MCV), leukocyte, and ferritin, are given in [Table 4].
|Table 4: Biochemical markers and lab results for all patients before their first stroke, or first abnormal transcranial doppler ultrasonography (n=38)|
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There was a statistically significant difference in HbS level in males versus females (t = 3.704, P = 0.032) and ferritin level (t = ‒3.631, P = 0.001). The first pathological TCD (t = 5.496, P < 0.001) was also significantly different in Saudi versus non-Saudi cases. Other biochemical parameters were not statistically significantly different across the gender, nationality, and socioeconomic status [Table 5].
|Table 5: Comparison of the means of biochemical markers across gender, nationality, and socioeconomic status (n=38)|
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The age of the children with an abnormal TCD was observed to be statistically significantly different across the socioeconomic status (P = 0.049). However, the age of diagnosis of SCD was not always available (P > 0.05) [Table 6].
|Table 6: Relationship between clinical history (age of diagnosis of sickle cell disease, age of diagnosis of stroke or abnormal transcranial doppler ultrasonography) and personal data (gender, nationality, and socioeconomic status) (n=38)|
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The current study also compared the personal data of the respondents (e.g., gender, nationality, and socioeconomic status) with their clinical history (e.g., compliance with medication, compliance with blood transfusion, VOC, ACS, and dactylitis). Males were found to be more compliant to the medications (odds ratio 5.33, P = 0.043). No other comparisons were found to be statistically significantly different (P > 0.05) [Table 7].
|Table 7: Relationship between clinical history (compliance with medication, compliance with blood transfusion, vaso-occlusive crisis, acute chest syndrome and dactylitis) and personal data (gender, nationality, and socioeconomic status) (n=38)|
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| Discussion|| |
SCD was given its first description by a Chicago physician named James B Herrick. He noted, in 1910, that the disease is known to cause strokes, but the exact mechanism and risk factors were still a mystery at that time. Since then, research has been actively looking into the incidence, prevalence, causes, and risk factors for both ischemic and hemorrhagic strokes in children and adults with SCD.
The CSSCD study, which was conducted between 1977 and 1995, identified for the first time, the risk factors for stroke in patients with the disease. The first thing it noticed was the fact that the peak for strokes in SCD is in cases who are only 2–5 years old. In the CSSCD study, central nervous system complications (CNS) were noticed in 17.9% of children with SCD. The prevalence of stroke among the analyzed 194 children with SCD showed 4.6% to have overt stroke. The risk factors for ischemic stroke were A prior TIA, a low steady-state Hb concentration, a recent acute chest syndrome event, and elevated systolic blood pressure. On the other hand, hemorrhagic cerebrovascular accidents (Hemorrhagic CVAs) were associated with low steady state hemoglobin and elevated leukocyte count. This was demonstrated in prior review.
Driscoll et al., 2003, suggested that there is a familial predisposition for stroke and high velocity TCD in children with SCD as demonstrated by an increased frequency of both phenomena in the siblings of those affected. Interestingly, a type of genetic mutation has been suggested too as a contributing factor for the occurrence of stroke in SCD.
Epistatic polymorphisms have been found to be an additional risk factor for stroke too in this study. Specifically, A3 and A4 alleles of the GT repeat polymorphism of the angiotensinogen gene increase the risk of stroke by 4 folds. An association of human leukocyte antigens (HLA), specifically Class-1 HLA-B and Class II HLA-DR, have both been linked to an increased susceptibility to development of strokes in children with SCD.
In terms of laboratory parameters as risk factors for ischemic strokes, previous studies showed leukocytosis as risk factors. Recent studies have shown that a specific type of T cells; the so called invariant Natural Killer T Cells are usually activated in individuals with SCD. These cells release cytokines such as IL-6 which attack endothelial cells and contribute to vasculopathy.
In the study, we found certain demographics to be linked to risk of stroke and pathological TCD. First, females seem to be more affected than males (20/38 females compared with 18/38 males affected). Second, contrary to what has been shown in other studies, poor socioeconomic status has a neutral effect on the likelihood of a stroke in children with SCD. In fact, most children in our cohort who have had a stroke or pathological TCD are of an average socioeconomic status (20/38 compared to only 12/38 with a poor socioeconomic status). Third, we found that the parental level of education inversely correlated with the risk of stroke and pathological TCD.
In terms of presenting symptoms, the most common presenting symptom of overt stroke in children with SCD in our cohort was weakness (9/38). Headaches were only found in a small number (5/38) . Dzziness, difficulty speaking (dysarthria), hallucination, seizures and personality and behavioral changes are uncommon. The history of a prior stroke was found to be significant at 15.8%.
In terms of the complications associated with the increased risk of stroke and pathological TCD, we found that the majority of children in our cohort had had at least one or more vaso-occlusive crises already, or they were concomitant with the occurrence of stroke and pathological TCD. After VOC, the second most common complication, associated with occurrence of stroke and/or pathological TCD, was shown as concurrent or recent acute chest syndrome.
When it comes to biochemical markers and laboratory findings, the average hemoglobin concentration at the time of stroke and at the time of the pathological TCD is 7.61+/‒2.87. The average MCV is 78.0 +/‒24.97. The average white cell count is 13.01+/‒5.36. The CSSCD found that leukocytosis is associated with an increased risk of stroke and especially hemorrhagic stroke. Our cohort review showed a normal white blood cell count for age (4.5–14.0). The HbS concentration at the time of the onset of the stroke and/or pathological TCD was 66.23% (+/‒20.11). The first pathological TCD velocities among those with pathological TCD were found to be 43.7% and between 180 and 200 cm/second (with at least 2 borderlines velocities defined as TCD velocity 170–200 cm/second) and 56.25% for TCD readings >200 cm/second. The most common artery involved in having pathological TCD in this cohort was the MCA (56.25). This is consistent with other studies that found the MCA and the posterior cerebral artery to be the most commonly affected.,
In terms of management, all the cases with pathological TCD and/or strokes are already on regular blood transfusion regimens to keep pretransfusion HbS below 30%. Those who have had prior strokes are at risk for subsequent strokes even though they are having regular blood transfusions. As for long-term management, all cases with pathological TCD and/or strokes do have human leukocyte antigen (HLA) typing. Five children out of thirty-eight have already undergone a successful HLA, fully match, and BMT. Three out of thirty-eight already have a full match sibling and are on their way to having a BMT. This is in accordance with international standards.
| Conclusion|| |
SCD is the most inherited disorder in Saudi Arabia. It affects about 1.5% of the population in some areas in the kingdom. Stroke is one of the most devastating complications of this disease. It affects 10%–15% of all children with SCD. Unfortunately, the peak age for the first stroke in SCD is 2–5 years of age.
Data on stroke incidence, prevalence, characteristics, and patients' demographic in Saudi Arabia are generally lacking. This pilot small cohort study looks at the unique disease-related and patient-related features surrounding stroke in children who have SCD in Saudi Arabia.
In this study, we aimed to explore the risk factors associated with stroke or pathological TCD in Saudi children with SCD. We found that the level of parental education was one of the important factors in their prevalence. It is obvious then that there is a need to improve the level of awareness of SCD complications, especially CNS ones, through the education of the parents of children with SCD. We note that this is a small study and there is lack of research dealing with CNS complications, specifically stroke in children with SCD in Saudi Arabia and we encourage researchers to focus on this aspect of the disease.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7]