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 Table of Contents  
ORIGINAL ARTICLE
Year : 2017  |  Volume : 4  |  Issue : 1  |  Page : 3-8

The management of stroke in sickle cell anemia: A single site experience in a low-income setting


Paediatrics Haematology-Oncology Unit, Department of Paediatrics, Ahmadu Bello University Teaching Hospital, Zaria, Kaduna State, Nigeria

Date of Web Publication6-Mar-2018

Correspondence Address:
Jamilu A Faruk
Department of Paediatrics, Ahmadu Bello University Teaching Hospital, P.M.B. 06, Shika - Zaria, Kaduna State
Nigeria
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DOI: 10.4103/ssajm.ssajm_42_16

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  Abstract 

Context: Stroke is a devastating complication of sickle cell anemia (SCA) and is fatal in about 5% of patients, with chronic sequelae in survivors. The occurrence of stroke is predictable and preventable. However, up to 50% of children in some low-income settings are deprived of optimal care.
Aims: The study aimed to document the presentations of stroke in sickle cell patients, and the interventions utilized.
Settings and Design: A descriptive, retrospective review was conducted.
Materials and Methods: Case records were manually retrieved of patients managed for sickle cell stroke from April 2011 to March 2016.
Statistical Analysis Used: Descriptive and analytic statistics were utilized.
Results: A total of 21 patients were analyzed, comprising 38.1% males, with a male-to-female ratio of 1:1.6. The mean age at the time of diagnosis of SCA was known to parents was 1.9 ± 1.7 years, and the chronological age of patients, at the time of first registration in the unit for sickle cell related care was 3.9 ± 2.6 years. Ten children (47.6%) were presenting for the first time on the account of the stroke, while the rest had been on follow-up visits in the unit, prior to stroke occurrence. Age at the occurrence of sickle cell stroke was 5.8 ± 2.7 years. Only 2 (9.5%) had a transcranial Doppler (TCD) examination prior to experiencing the stroke.
The symptoms of the stroke were observed 8.3 ± 19.2 days before medical care was sought. The interval between onset of stroke and medical intervention was 11.5 ± 21.3 days. Only 2 (9.5%) had intervention within 24 h of the onset of symptoms, and only 4 (19%) patients had complete recovery of stroke symptoms.
Conclusion: Although many of the participants were known to have SCA at an earlier time by parents, they were not presented for specialist care until stroke had developed. In addition, TCD was not accessible or available to majority of the patients, and there was also delay in seeking and providing medical intervention for majority of patients after stroke occurrence.

Keywords: Sickle cell anemia, sickle cell stroke, stroke


How to cite this article:
Faruk JA, Ahmad HR, Ogunrinde GO, Usman NH. The management of stroke in sickle cell anemia: A single site experience in a low-income setting. Sub-Saharan Afr J Med 2017;4:3-8

How to cite this URL:
Faruk JA, Ahmad HR, Ogunrinde GO, Usman NH. The management of stroke in sickle cell anemia: A single site experience in a low-income setting. Sub-Saharan Afr J Med [serial online] 2017 [cited 2018 Jun 19];4:3-8. Available from: http://www.ssajm.org/text.asp?2017/4/1/3/226658


  Introduction Top


Stroke is a devastating complication of sickle cell anemia (SCA) that occurs in many patients afflicted with the hemoglobinopathy.[1],[2] Sickle cell stroke is predictable and preventable through the use of current management strategies.[3],[4] Thus, transcranial Doppler (TCD) ultra-sound use for the monitoring of cerebral blood flow velocities, hydroxyurea, and judicious blood transfusions with chelation therapy have been employed successfully in reducing the morbidities associated with sickle cell stroke. However, the quality and access to care for SCA are not universal, with up to half of children in the low-income settings, of many developing countries not receiving optimum care.[5],[6],[7]

Studies have shown that patients with sickle cell stroke are preferentially treated with an exchange blood transfusion (EBT), as compared to a simple transfusion.[8] Likewise, the benefit of chronic blood transfusions in the primary and secondary prevention of stroke is very clear.[3],[9] These interventions are not always available in many low-income settings.

Stroke has been documented in 6.8% of patients with SCA in Ibadan,[6] 5.2% in Abuja,[7] and 3.6% in Sokoto.[10] The sex predilection was fairly equal, except in Ibadan where there was a 4:1 male-to-female ratio.[6],[7],[10] The mean age of stroke occurrence was between 6.3 and 6.8 years from these studies, with a mortality of at least 4.6% in one of the studies.[6] There was also a tendency for stroke to re-occur in 26.1–46.2% of the patients.[6],[7] The acceptance of chronic blood transfusion varied between 10 and 57.7%. The high cost of blood transfusions was a major determinant of its uptake and sustainability by the patients.[5],[7] In instances, where the chronic transfusions took place, patients were poorly adherent or irregular with the transfusion schedules, and at times discontinued the transfusions altogether.[5],[7] The uptake of hydroxyurea for secondary stroke prevention was equally low, at about 42% of at risk patients.[11]

The present study aimed to document the presentations of sickle cell stroke at a tertiary referral center in a low-income setting; and to describe the interventions given and mitigating factors, if any.


  Materials and methods Top


A descriptive, retrospective review of patient records was conducted at the Paediatrics Haematology-Oncology Unit, of a tertiary hospital. Case records were manually retrieved, of patients managed for a clinically diagnosed sickle cell stroke within a 5-year period, April 2011–March 2016.

General information, and timings/duration of symptoms and the time interval from onset of symptoms and commencement of therapy (intervention interval) were calculated. The time interval from commencement of therapy and the first sign or evidence of clinical improvement of stroke symptoms (resolution interval), based on the documented changes in the neurological examination findings from baseline at time of admission; and the type of intervention given were also recorded.

Stroke was defined as a neurologic deficit, lasting for more than 24 h, and or the presence of abnormal neuroimaging studies, in cases where the deficits were <24 h.[8] Patients were treated with an acute EBT, and in some selected cases, a simple top-up blood transfusion. All patients were then offered a four-weekly chronic blood transfusion regimen for prevention of stroke recurrence, in addition to routine care according to national guidelines. Data were analyzed using Epi info version 7.1.0.6 (release date 8/9/2012, CDC, Atlanta), and the results presented as figures, tables, and prose.


  Results Top


There were 2283 registered patients with SCA during the 5-year period under review. A total of 28 (1.2%) case notes were retrieved, of patients admitted with a clinical diagnosis of sickle cell stroke. There were 5–6 stroke episodes managed per year, from a pool of 575 sickle cell related admissions in the period under review. One patient declined treatment, and left against medical advice, while records of six others were incomplete, so these patients were excluded from further analysis. The remaining 21 patients were analyzed. There were 8 (38.1%) males. The male-to-female ratio was 1:1.6.

Age of patients at presentation and occurrence of stroke

Their mean age at the time diagnosis of SCA was known to parents was 1.9 ± 1.7 years (range 0.5–6 years); and as shown in [Table 1], 11 (52.4%) were aware of SCA diagnosis before 1 year of age.
Table 1: Age distribution of patients at the time of landmark events

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The mean age of patients, at the time of first registration in the unit, was 3.9 ± 2.6 years. (range 0.5–9); only 5 (23.8%) presented before their 1st birthday, although 14 (66.7%) had presented by 5 years of age. Out of the total number, 10 (47.6%) were presenting to the unit for the first time on the account of the current episode of stroke. The remaining 11 (52.4%) had been on routine follow-up visit, ranging between 0.5 and 10.3 years of hospital visits. The majority of them, that is, 9 (42.8%) were on follow-up for 1–5 years. These comprised of three patients being followed up for 12–24 months prior to the stroke; two patients followed up for 25–36 months; one each followed up for 3 and 4 years; and two being on follow-up for 5 years.

Age at occurrence of stroke was 5.8 ± 2.7 years (range 2–12 years); 10 (47.6%) had developed the stroke by 5 years of age. Only 2 (9.5%) had a TCD examination prior to experiencing the stroke. The TCD results were categorized as abnormally low, due to imperceptible velocities, suggesting very poor blood flow, but angiographic studies could not be conducted to confirm arterial stenosis.

A computerized tomography scan was obtained in 10 patients, while one patient had a magnetic resonance imaging of the brain, making a total 11 (52.4%), with a neuroimaging diagnosis. All showed features consistent with cerebral infarction, including chronic infarcts in five of them.

Out of the 21 patients studied, 3 (14.3%) were experiencing a recurrent stroke at the time of index review, while the other 18 (85.7%) were experiencing their first strokes.

Time intervals between stroke onset, interventions and clinical improvement

As shown in [Table 2], the symptoms of stroke were observed 8.3 ± 19.2 days (range 0–90 days) before seeking medical attention, with 9 (42.9%) presenting within 24 h of the onset of symptoms.
Table 2: Duration of symptoms, intervention and resolution intervals from time of occurrence of stroke

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It can also be observed from [Table 2] that, the interval between onset of stroke and blood transfusion therapy (intervention interval) was 11.5 ± 21.3 days (range 1–100 days). Only 2 (9.5%) had intervention within 24 h of onset of symptoms, while 10 (47.6%) had intervention within 5 days of developing stroke.

All the patients were empirically offered a double volume (2 × 80 ml/kg body weight) EBT, for the acute stroke treatment, due to a lack of facilities for quantification of sickle hemoglobin (HbS). The EBT was performed manually, in aliquots of 20–50 ml of blood, until the total calculated volume was exchanged over 60–90 min, through a centrally placed venous catheter.

Not all the patients’ caregivers were able to acquire the necessary blood units for the transfusions. Therefore, simple top-up transfusion alone was given to 3 (14.2%) patients, EBT alone was given to 9 (42.9%) patients, and a combination of both in the remaining 9 (42.9%) patients. Logistics for central venous access, and delays in obtaining blood for the transfusion, were major causes of treatment delay in the patients.

The first sign or evidence of clinical improvement of stroke symptoms (resolution interval), based on changes in the neurological examinations, was observed 8.0 ± 6.7 days (range 1–21 days) post-intervention, with 2 (9.5%) patients showing some improvement within 24 h, and 11 (52.4%) patients showing improvement within 5 days of the intervention. There was no correlation between intervention interval and resolution interval, with Pearson’s correlation co-efficient, r = 0.33. Likewise, there was no correlation between symptoms duration prior to presentation and resolution interval, r = 0.28.

Interventions and recovery of normal functions

Only 4 (19%) patients had complete recovery of normal functions, as at the last hospital visit, while the remaining 17 (81%) had a partial recovery of symptoms, and thus experienced chronic neurologic sequelae of stroke. Two of the patients with complete recovery had EBT, while 16 of those with partial recovery also had EBT. However, there was no statistically significant difference in terms of normal recovery with regards to EBT, Fisher’s exact P-value 0.079.

Chronic blood transfusion uptake

Following the initial hospitalization for the strokes, all patients were offered a chronic blood transfusion regimen, as secondary prophylaxis against stroke recurrence, to maintain HbS levels below 30%. There were no HbS assays available in the unit during the study period. The plan was to give a simple top-up transfusion of 15 ml/kg body weight, every 4 weeks, until the patient attained the age of 16 years. Chronic transfusion was assessed to be regular if there was adherence, and it occurred every 4 weeks, as prescribed. Transfusions at intervals >4 weeks, and or that were erratic without a discernible pattern, were termed to be irregular.

As shown in [Figure 1], 6 (28.6%) patients did not receive chronic transfusions, another 6 (28.6%) had regular transfusions while the remaining 9 (42.9%) were irregular with their transfusions. Care-giver and blood donor fatigue, as well as poor motivation were the reasons ascribed to the poor adherence.
Figure 1: Number of patients on chronic blood transfusions (CBT)

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Outcomes

There were 4 (19%) stroke recurrences among the 21 patients, while on follow-up in the unit. Incidentally, three of these patients were irregular with chronic transfusions, while the other patient had no chronic transfusion. Five of the patients who had no CBT, did not suffer stroke recurrence, but there was no statistical significant difference in the recurrence between those on CBT and those who had none. Fisher’s exact P-value 0.684. [Table 3] shows their profiles.
Table 3: Profile of patients with stroke recurrence during follow-up care

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Patients who received 10 or more CBT were offered a serum ferritin estimation to assess their iron load. Oral iron chelation, as 10–20 mg/kg of Desferraxirox was offered to patients whose serum ferritin was above 1000 ng/ml, while the CBT continued. However, only 4 (19%) of the patients who were at risk of iron overload, could afford serum ferritin estimations. Three of the patients were able to afford only two assays, while the other patient could only afford one testing. Their ferritin levels are shown in [Table 4].
Table 4: Serum ferritin levels and outcome of CBT in four patients

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Only 3 (14.3%) of the patients were able to afford oral iron chelation, which they had for 1, 7 and 4 months, respectively, then discontinued it, as they could not sustain the cost. Subsequently, due to the difficulties encountered with sustaining the CBT, concerns of iron overload, and challenges with iron chelation in particular, 4 (19%) of the total patients who were on CBT, were counseled, and they opted to switch to hydroxyurea therapy. Only 6 (28.6%) patients out of 21, continued on CBT, which was irregular. The remaining 5 (23.8%) discontinued on the CBT.

Out of 21 patients studied, 7 (33.3%) have been lost to follow-up, with the remaining 14 (66.7%) still attending follow-up clinic.


  Discussions Top


This study highlights the challenges of managing sickle cell stroke, in a resource constrained setting. Firstly, the high rate of incomplete records of 25% is distressing, and in itself very likely to hamper effective patient care and research. This further strengthens the need for electronic databases, for more robust information management.

The absence of new-born screening resulted in symptomatic presentations and diagnosis of patients starting from 6 months of age. But despite the many patients diagnosed with SCA in infancy, specialist care was not sought until complications arose. This is evident by the proportion of patients presenting for the first time to the unit, on account of a stroke. Lagunju et al.,[6] also documented a similar pattern of recurrent stroke at the time of first presentation. Unfortunately, even those patients on specialists’ follow-up care, did not have access to all the relevant care facilities they needed in the present study. This can be deduced from the low TCD rate, coupled with the lack of further radiologic angiographic studies for the two patients with abnormally low TCD values. Also, only half of the patients were able to have neuroimaging to support the diagnosis of stroke. Other studies,[6],[7] have also shown that access to these investigations may not be 100%.

Late presentation appears to be common in the present study, and other studies from the region, considering the mean times of presentation of 8 and 10 days, respectively.[10] Although, when the proportion of 66.7% that presented within 5 days of onset of stroke is considered, it may appear to be a good proportion presenting early. However, considering the consequences of a stroke, the time lag may prove consequential. Furthermore, other studies[8] have recorded up to 65% of patients presenting within 24 h. Surprisingly though, presentation was delayed for 90 days in one patient from the present study, a misdiagnosed and inappropriately referred case to another unit. Previous authors[8] have also noted delayed presentation of up to 3 months.Secondary delay in the health facility poses another challenge, as close to half of the patients in the present study, did not get appropriate intervention for more than 5 days after onset of symptoms. This contrasts with the proportion of more than half of patients receiving treatment within 24 h in other studies.[8] This should serve as a call to strengthen the healthcare system to address the issues of logistics and availability of blood transfusion services.

More than a quarter of the patients in the study did not receive CBT, and more than half of those who started CBT could not sustain it. This is not alien however, as other studies have also revealed inability to commence all eligible patients on regular CBT.[5],[7],[12],[13] In fact, the complications of iron overload in the patients on CBT in this study could not be adequately evaluated and managed due to lack of facilities and cost.


  Conclusion Top


From the fore-going, it has been shown that while a large portion of the patients with SCA were diagnosed at a relatively young age, many did not present for specialist care until the stroke had developed. For those who had been on specialist follow-up care, TCD was not accessible or available, or not performed. Majority of the patients sought care for the stroke late, and there was a further delay in providing the required intervention. The study, however, showed no correlation between the duration of symptoms or interval before intervention and first improvement in symptoms. Likewise, there was no association between resolution of symptoms and EBT.

It is, therefore, recommended, for an increase in advocacy and awareness regarding the need for early diagnosis and timely referral of patients with SCA for specialist care, while at the same time increasing access to basic investigations like TCD, with a view to offering preventive interventions to at-risk patients. This becomes even more paramount, owing to the poor rate of resolution of symptoms following sickle cell stroke, and its attendant long-term sequelae.

Acknowledgements

Our sincere gratitude goes to Mrs. Elizabeth Samaila, the Health Records Officer, who tirelessly helped in tracing and retrieving the medical records studied.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
  References Top

1.
Ohene-Frempong K, Weiner SJ, Sleeper LA, Miller ST, Embury S, Moohr JW et al. Cerebrovascular accidents in sickle cell disease: Rates and risk factors. Blood 1998;91:288-94.  Back to cited text no. 1
    
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Verduzco LA, Nathan DG. Sickle cell disease and stroke. Blood 2009;114:5117-25.  Back to cited text no. 2
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3.
Adams RJ, McKie VC, Hsu L, Files B, Vichinsky E, Pegelow C et al. Prevention of a first stroke by transfusions in children with sickle cell anaemia and abnormal results on transcranial doppler ultrasonography. N Engl J Med 1998;339:5-11.  Back to cited text no. 3
    
4.
Yawn BP, John-Sowah J. Management of sickle cell disease: Recommendations from the 2014 expert panel report. Am Fam Physcian 2015;92:1069-76.  Back to cited text no. 4
    
5.
Lagunju IA, Brown BJ, Sodeinde OO. Chronic blood transfusion for primary and secondary stroke prevention in Nigerian children with sickle cell disease: A 5 year appraisal. Pediatr Blood Cancer 2013;60:1940-5.  Back to cited text no. 5
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Lagunju IA, Brown BJ, Famosaya AA. Childhood stroke in sickle cell disease in Nigeria. J Pediatr Neurol 2011;9:49-53.  Back to cited text no. 6
    
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Oniyangi O, Ahmed P, Otuneye OT, Okon J, Aikhionbare HA, Olatunji OO et al. Strokes in children with sickle cell disease at the National Hospital, Abuja. Niger J Paediatr 2013;40:158-64.  Back to cited text no. 7
    
8.
Hulbert ML, Scothorn DJ, Panepinto JA, Scott P, Buchanan GR, Sarnaik S et al. Exchange blood transfusion compared with simple transfusion for first overt stroke is associated with a lower risk of subsequent stroke: A retrospective cohort study of 137 children with sickle cell anaemia. J Pediatr 2006;149:710-2.  Back to cited text no. 8
    
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Scothorn DJ, Price C, Schwartz D, Terrill C, Buchanan GR, Shurney W et al. Risk of recurrent stroke in children with sickle cell disease receiving blood transfusion therapy for at least five years after initial stroke. J Pediatr 2002;140:348-54.  Back to cited text no. 9
    
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Jiya NM, Ahmad MM, Baba J. Stroke in children with sickle anaemia in Sokoto: A 10 year review. Res J of Health Sci 2015;3:113-20.  Back to cited text no. 10
    
11.
Lagunju IA, Brown BJ, Sodeinde OO. Stroke recurrence in Nigerian children with sickle cell disease treated with hydroxyurea. Niger Postgrad Med J 2013;20:181-7.  Back to cited text no. 11
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12.
Lee MT, Piomelli S, Granger S, Miller ST, Harkness S, Brambilla DJ et al. Stroke prevention trial in sickle cell anemia (STOP): Extended follow-up and final results. Blood 2006;108:847-52.  Back to cited text no. 12
    
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Sarnaik S. Letter to the editor – Prevention of stroke by transfusions in children with sickle cell anaemia. N Engl J Med 1998;339:1477-8.  Back to cited text no. 13
    


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  [Table 1], [Table 2], [Table 3], [Table 4]



 

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