Stroke and cognitive problems are the most common permanent complications of sickle cell disease.1 Historically 10% of people who had sickle cell disease had a stoke by the time they were 20 years old. Most of those strokes occurred between the age of 6 and 10 years. There was no predictor for stroke they could occur during a severe acute problem such as acute chest syndrome and they could also occur in children who were do relatively well without any warning. By the age of 40 years 20% of people who had sickle cell anemia (SS) had suffered a stroke and 10% of those suffering from SC disease had a stroke. In a study at Howard University 4% of children who suffered a stroke died and in a California study 7% of stroke victims with a stroke died2. Children who have sickle cell disease have about 200 times the risk of stroke compared to children who do not have sickle cell disease.
- Sicklepedia: Sickle Cell Disorders (main)
Types of Strokes
There are two types of severe strokes in sickle cell disease. What are called ischemic stroke, which are caused by the blockage or narrowing of blood vessels in the brain that cause permanent damage to the area perfused by that vessel, these are the most common type of stroke. There are also hemorrhagic strokes that are caused by blood vessel rupture and cause damage by bleeding into the brain causing damage and compression and are much more likely to cause death, because many instances of “sudden death” in people who have sickle cell disease are not investigated there may be more cases than what are reported.
There are also so called “silent infarcts” that are small areas of brain damage that do not cause observable symptoms. With study it can be found that there are cognitive problems that become worse if there are more of these small lesions over time.
The prevalence of stroke is similar in countries that collect statistics. The American Cooperative Study of Sickle Cell Disease reported a prevalence of 3.75%, a Brazilian study reported 5.1%, in the United Kingdom the prevalence was 3.8% even though these studies were not done in the same time frame. The incidence is higher in Africa, in Nigeria the prevalence is between 6.8% and 8.4%. These studies may not have all used the same criteria for stroke. Stroke is common in children up to the age of about 10 years and then decreases through adolescence and young adulthood again increasing to the age of 35 to 40 years old. Hemorrhagic stroke is more common in adults.
Symptoms of Stroke
The most common symptom of stroke is paralysis, usually on one side of the body which may be just an arm or leg or may also include the face. There are also cognitive signs of stroke such as slow speech or inability to comprehend speech. Some recovery can occur with blood transfusion following the recognition of stroke, but there is never full recovery and cognitive disability remains. Even chronic blood transfusions after stroke recurrent strokes are common up to 25% in regularly transfused individuals. Without treatment the recurrence is almost 70%. Strokes are forever. There is a lifelong struggle with mobility and cognitive challenges for many people who have stroke.
In 1998 the STOP study3 changed the outlook for children (and all people who have sickle cell disease as children eventually become adults) with sickle cell disease. This study showed that with transcranial Doppler stroke could be predicted and prevented with chronic blood transfusion. Screening can be started as young as 2 years old and continues annually until the age of 16. The prevalence of stroke risk was 8% in the 1990’s leading up to the STOP study. The study was ended early when it was found that it had reached statistical significance in only 18 months. A later study, the STOP II study4, showed that you could not abruptly stop transfusion therapy without significantly increasing the risk of stroke. Transcranial Doppler screening significantly decreased the incidence of stroke in children with sickle cell disease. Unfortunately, even today not all children who have sickle cell disease have screening, there are still preventable strokes occurring in the United States. It should be noted that only ischemic strokes are prevented by transcranial Doppler screening.
The prospect of lifelong transfusions for stroke is a huge burden for people who are at risk of stroke. It requires transfusion every three to four weeks, there can be antibodies made to blood and it can be difficult to find appropriately matched blood for transfusion. If the transfusion is simple (Intravenous line that transfuses whole units of blood monthly) there is the inevitable increase in total body iron which requires daily oral therapy to remove or there can be liver damage or cardiac damage from the excess iron. The transfusion can be done by exchange (removing blood and replacing it with donate blood) which reduces the amount of iron with each transfusion. Occasionally this can prevent increased iron or make the excess iron easier to manage.
In 2016 a study was published5 that showed in children who had been transfused for a year, who did not have cerebral vascular disease could be weaned from transfusion to hydroxyurea without an increase in stroke risk. This is now standard of care, though stopping hydroxyurea could increase the risk of stroke in the future. Still a potential lifelong therapy. Though hydroxyurea has other benefits besides preventing stroke in children and adults who have sickle cell disease.
It has been shown that progenitor cell transplant can prevent stroke in children who have abnormal transcranial Doppler studies and may even improve blood flow in some patients with abnormal cerebral vessels.6
What about “silent infarcts”? In 2014 a study was published that showed silent infarcts were common in children and that they could be decreased with chronic blood transfusion.7 The blood transfusions did not completely eliminate silent infarcts, but they were decreased with five silent infarcts in the transfused group and seven in the untransfused group. It also showed that strokes occurred in children who had silent infarcts and were more common in the untransfused group than the transfused group, one stroke in the transfused group and seven strokes in the untransfused group. It has been shown that silent infarcts are not silent and there is measurable cognitive decline with increased numbers of these small infarcts.
Recently there have been developed standards of care for cerebrovascular disease in people who suffer from sickle cell disease by the American Society of Hematology.8 This is in the open journal Blood Advances and is available for free online.
- Kirkham FJ, Lagunju IA. Epidemiology of Stroke in Sickle Cell Disease. J Clin Med 2021;10(18). DOI: 10.3390/jcm10184232.
- Jordan LC, Strouse JJ. Will submandibular TCD prevent stroke in children with sickle cell anemia? Neurology 2009;73(5):340-1. (In eng). DOI: WNL.0b013e3181b1221e [pii] 10.1212/WNL.0b013e3181b1221e.
- Adams R, al. e. PREVENTION OF A FIRST STROKE BY TRANSFUSIONS IN CHILDREN WITH SICKLE CELL ANEMIA AND ABNORMAL RESULTS ON TRANSCRANIAL DOPPLER ULTRASONOGRAPHY. New England Joiurnal of Medicine 1998;339:5-11.
- Adams RJ, Brambilla D, Optimizing Primary Stroke Prevention in Sickle Cell Anemia Trial I. Discontinuing prophylactic transfusions used to prevent stroke in sickle cell disease. N Engl J Med 2005;353(26):2769-78. (In eng). DOI: 10.1056/NEJMoa050460.
- Ware RE, Davis BR, Schultz WH, et al. Hydroxycarbamide versus chronic transfusion for maintenance of transcranial doppler flow velocities in children with sickle cell anaemia-TCD With Transfusions Changing to Hydroxyurea (TWiTCH): a multicentre, open-label, phase 3, non-inferiority trial. Lancet 2016;387(10019):661-70. DOI: 10.1016/S0140-6736(15)01041-7.
- Verlhac S, Gabor F, Paillard C, et al. Improved stenosis outcome in stroke-free sickle cell anemia children after transplantation compared to chronic transfusion. Br J Haematol 2021;193(1):188-193. DOI: 10.1111/bjh.17178.
- DeBaun MR, Gordon M, McKinstry RC, et al. Controlled trial of transfusions for silent cerebral infarcts in sickle cell anemia. N Engl J Med 2014;371(8):699-710. DOI: 10.1056/NEJMoa1401731.
- DeBaun MR, Jordan LC, King AA, et al. American Society of Hematology 2020 guidelines for sickle cell disease: prevention, diagnosis, and treatment of cerebrovascular disease in children and adults. Blood Adv 2020;4(8):1554-1588. DOI: 10.1182/bloodadvances.2019001142.