REVIEW ARTICLE
Paediatr Drugs 2001; 3 (6): 421-432 1174-5878/01/0006-0421/$22.00/0 © Adis International Limited. All rights reserved.
Stroke in Children With Sickle Cell Anaemia Aetiology and Treatment Charles H. Pegelow University of Miami School of Medicine, Miami, Florida, USA
Contents Abstract . . . . . . . . . . . . . . . . . . . 1. Incidence of Stroke in Sickle Cell Disease 2. Pathophysiology . . . . . . . . . . . . . . . 3. Clinical and Laboratory Associations . . . 4. Clinical Management . . . . . . . . . . . . 5. Risk for Recurrence . . . . . . . . . . . . . 6. Duration of Transfusion Therapy . . . . . . 7. Marrow Transplantation . . . . . . . . . . . 8. Silent Infarcts . . . . . . . . . . . . . . . . . 9. Primary Stroke Prevention . . . . . . . . . 10. Intracranial Haemorrhage . . . . . . . . . 11. Conclusions . . . . . . . . . . . . . . . . . .
Abstract
. . . . . . . . . . . .
. . . . . . . . . . . .
. . . . . . . . . . . .
. . . . . . . . . . . .
. . . . . . . . . . . .
. . . . . . . . . . . .
. . . . . . . . . . . .
. . . . . . . . . . . .
. . . . . . . . . . . .
. . . . . . . . . . . .
. . . . . . . . . . . .
. . . . . . . . . . . .
. . . . . . . . . . . .
. . . . . . . . . . . .
. . . . . . . . . . . .
. . . . . . . . . . . .
. . . . . . . . . . . .
. . . . . . . . . . . .
. . . . . . . . . . . .
. . . . . . . . . . . .
. . . . . . . . . . . .
. . . . . . . . . . . .
. . . . . . . . . . . .
. . . . . . . . . . . .
. . . . . . . . . . . .
. . . . . . . . . . . .
. . . . . . . . . . . .
. . . . . . . . . . . .
. . . . . . . . . . . .
. . . . . . . . . . . .
. . . . . . . . . . . .
. . . . . . . . . . . .
421 422 422 423 425 425 427 428 428 429 429 430
Cerebral infarction is a frequent, severe complication of sickle cell anaemia. During childhood, most strokes are due to infarction with the majority resulting from occlusion of the large cerebral arteries. Risk factors include transient ischaemic attacks, acute chest syndrome, severe anaemia and elevated blood pressure. Less certain is the association with leucocytosis, or protection provided by αthalassaemia or fetal haemoglobin. Children who have one stroke are at significant risk for having subsequent events that can be substantially reduced by maintaining haemoglobin S below 30%. It has not yet been possible to identify individuals for whom transfusion can be safely stopped. Haemosiderosis is a consequence of intensive and long term transfusion therapy, which requires chelation with deferoxamine. Iron accumulation can be minimised using erythrocytapheresis but this is technically difficult in children, expensive and results in increased donor exposure. In addition to lesions associated with strokes, an additional 17% of patients can be shown to have clinically silent cerebral infarcts. Although these are termed ‘silent’, those affected have mild neuropsychological deficits. Their relationship to stroke or risk for recurrence is unknown. Transfusion therapy has been shown to provide primary stroke prevention for children who have elevated cerebral artery velocity. Finally, intracranial haemorrhages, more commonly found in adults, also affect children. Subarachnoid haemorrhage is frequently found to result from cerebral artery aneurysms. A condition that mimics the moyamoya syndrome radiographically, as well as for its risk of haemorrhage, can be found in children with partly occluded cerebral arteries either as a result of stroke or silent infarct.
422
Sickle cell anaemia (HbSS) is a complex medical disorder caused by an abnormal haemoglobin that forms aggregates when deoxygenated.[1] This haemoglobin and its behaviour result from a nucleic acid point mutation[2] that in turn causes a single amino acid substitution at position 6 of the βglobin chain.[3] The formation of haemoglobin S aggregates is believed to be the primary cause of the intermittent vascular obstruction that underlies most, if not all, of the clinical abnormalities typical of this disease. Stroke was described as a complication of HbSS shortly after the first clinical description of the disease process.[4] While other manifestations are more likely to be fatal, the frequency, long term consequences, and risk for recurrence of cerebral infarction result in this being a major adverse clinical manifestation of the disease. 1. Incidence of Stroke in Sickle Cell Disease Stroke is an uncommon event during childhood. A recent report providing data on the incidence of stroke in children less than 14 years of age[5] indicates an incidence of 0.58 per 100 000 patientyears observation for normal children compared with 285 per 100 000 patient-years for those who have sickle cell disease. The prevalence of stroke in sickle cell disease has been reported from several institutions.[6-11] These reports indicate that strokes occur primarily, but not exclusively, in children and that the usual event is cerebral infarction. However, infarction can occur in older individuals and haemorrhage, which is more frequently found in adults, also occurs in children. The data suggest an equal sex distribution. The Cooperative Study of Sickle Cell Disease (CSSCD) was a multi-institution natural history study that collected and analysed data on 4082 individuals over a 10-year period.[12] Several haematological diagnoses were included but the majority of the findings were in those who had HbSS. The age-adjusted prevalence for stroke in individuals with HbSS was 4.01%. In haemoglobin SC disease, © Adis International Limited. All rights reserved.
Pegelow
haemoglobin S-β plus thalassaemia and haemoglobin S-β zero thalassaemia, the prevalence was 0.84, 1.29 and 2.43%, respectively. Prevalence increased with age. For individuals with HbSS, the chances of having a stroke by 20, 30 and 45 years of age were estimated to be 11, 15 and 24%. The risk for stroke varies by age. While the incidence is elevated at all ages, it is highest between 2 and 5 years. Stroke incidence was calculated on data obtained during the study’s 10-year observation period (table I). As the frequency in haematological diagnoses other than HbSS was low, incidence estimates were made only for individuals who had HbSS. Males and females were equally affected. There was minimal risk before 2 years of age. The highest risk for infarction was between 2 and 5 years, whereas haemorrhage was most frequently encountered between the ages of 20 and 29 years. Although infarction was most common in children and haemorrhage in adults, both were seen in all age groups. 2. Pathophysiology Although the pathology of the first report of stroke in sickle cell disease indicated obliteration of the middle cerebral arteries, it was initially believed that small vessel occlusion was responsible.[13] Some reports demonstrated diffuse abnormalities in small vessels,[10,14] while other investigators reported that large blood vessels were involved.[15,16] In 1972, angiographic studies provided conclusive Table I. Stroke incidence for individuals with sickle cell anaemia (HbSS) in each age category expressed as number of episodes per 100 patient-years observation (modified from Ohene-Frempong et al.[12]) Age (y)
Type of stroke infarctive
haemorrhagic
<2
0.13
0.00
2-5
0.70
0.15
6-9
0.51
0.25
10-19
0.24
0.14
20-29
0.04
0.44
30-39
0.37
0.07
40-49
0.24
0.24
≥50
0.62
0.00
Paediatr Drugs 2001; 3 (6)
Stroke in Sickle Cell Anaemia
evidence that strokes in sickle cell disease result from large vessel abnormalities.[17] These investigators speculated that the abnormalities of vessels were the result of occlusive disease in the vasa vasorum. Subsequent pathology reports confirmed the presence of endothelial abnormalities and proliferation in the large intracerebral arteries[18] (fig. 1). These vessels were shown to become partly or completely occluded by abnormal proliferation of the endothelium and occasionally by thrombus formation. There have been no reports of similar arterial abnormalities in other parts of the body. The process involved the anterior vessels almost exclusively. No evidence of involvement of the vasa vasorum could be identified and other studies indicate that vasa vasorum do not supply the portions of the intracranial vessels responsible for the majority of stroke in sickle cell disease.[19] The strokes evaluated involved the areas of the brain primarily served by the middle and anterior cerebral arteries.[18] Their occlusion was shown to result in the expected infarction and necrosis of the areas of brain for which they provide blood. Smaller areas of infarction were also noted with speculation that they might have resulted from emboli from the abnormal proximal portion of the vessel in question or from a more distant location. The concept of borderzone infarction described for haematologically normal individuals appears to be operative in sickle cell disease. This concept relates to the decreased perfusion that exists at the edge of the area of brain served by a given artery.[20] The major arteries provide blood supply to a volume of tissue through multiple, progressively smaller branches. Tissue nearer the centre of this volume is supplied by a number of branches. Toward the periphery this redundancy decreases. The location where the peripheral areas of 2 major arterial systems abut is called a borderzone. Infarction in these areas does not even require the occlusion of one of the vessels. If the blood flow from the major artery is compromised by partial occlusion, tissue is subject to inadequate blood supply that can result in infarction if hypotension or hypox© Adis International Limited. All rights reserved.
423
aemia is encountered. Investigators have found a concentration of cerebral infarction in these borderzones, particularly in the anterior-middle cerebral artery and middle-posterior cerebral artery borderzones. As more pathology and radiographic reports have been published, it has become clear that large vessel disease accounts for most, but not all cerebral infarctions.[21,22] Infarcts are described in individuals who have normal vascular structure and appearance on angiography. It is suggested that the vessels involved are the small distal penetrating arterioles with the mechanism related to the abnormal physical characteristics of the sickled red cell in the small vessels.[22] Currently accepted theories for the vascular occlusion that occurs in sickle cell disease suggest neutrophil involvement which, upon activation, produces cytokines that increase the display of receptors on the endothelial surface.[23] Neutrophils are thought to adhere, as do passing red cells, which have similar exposed receptors. Once the red cells adhere, haemoglobin S polymerises, causing shape change and altered blood flow characteristics. As the process develops, the coagulation mechanism appears to be activated,[24] at least in part as a result of exteriorised phospholipids[25-27] abnormally exposed on the haemoglobin S-containing red cell. This exposure may initiate thrombus formation. 3. Clinical and Laboratory Associations Efforts to better characterise those who are at risk for stroke have led investigators to search for clinical and laboratory associations. Transient ischaemic attacks have been reported to be a strong predictor of stroke as has acute chest syndrome.[12] Acute anaemia, as a result of aplastic crisis, has been associated with stroke.[9] Both acute chest syndrome and aplastic crisis can result in a sudden, substantial decrease in oxygen-carrying capacity and possibly a degree of hypotension, either of which could result in ischaemia in a circulatory system compromised by partial occlusion of the arterial blood supply. More recently, a possible role for parvovirus has been suggested with respect Paediatr Drugs 2001; 3 (6)
424
Pegelow
Fig. 1. Cerebral artery from a patient with sickle cell anaemia (HbSS) who suffered a stroke. The black arrows indicate artifactual clefts in the thrombus. The thickened intima is the paler tissue between the thrombus and the dark, undulating elastic lamina. (Image provided by Dr E. Manci, of the Centralized Pathology Unit for Sickle Cell Disease, University of Mississippi, Jackson, MI, USA.)
to aplastic crisis.[28] The unexpected frequency with which this virus is associated with acute chest syndrome raises an interesting possible connection.[29] Bone marrow embolism has been associated with stroke,[30] an association also strengthened by the recently demonstrated association between marrow embolism and chest syndrome.[29] An association has also been noted between priapism and stroke, seemingly when exchange transfusion was used in its treatment.[31] There have been many efforts to characterise laboratory abnormalities associated with stroke. Some were unable to be supported by the data from CSSCD,[12] the participants of which were selected to represent the population at large. A high fetal haemoglobin level was said to have a protective effect against stroke,[32] but no such protection was demonstrated in the CSSCD cohort. α-Thalassaemia has been shown to be protective.[33-35] The data from CSSCD showed a strong inverse relationship © Adis International Limited. All rights reserved.
between strokes and haemoglobin level. The relationship between α-thalassaemia and stroke was confounded by the fact that individuals with thalassaemia had a milder degree of anaemia. Elevated leucocyte counts have been shown in one report to be significantly associated with stroke.[9] In the CSSCD cohort, leucocytosis was associated with haemorrhagic but not infarctive stroke. That study also showed blood pressure elevation to be a weak but significant predictor of infarctive stroke. Since blood pressure is generally lower than that found in normal individuals, its elevation must be determined by comparison with normal values established in individuals who have sickle cell disease.[36] Some investigators have observed an apparent increased risk for stroke in affected siblings, an association that can be explored further to determine if gene markers can identify individuals at increased risk. Paediatr Drugs 2001; 3 (6)
Stroke in Sickle Cell Anaemia
4. Clinical Management Hemiplegia is the most common clinical presentation of stroke in sickle cell disease, although symptoms are dependent on the location of the infarct. In sickle cell disease, the anterior circulation is primarily involved,[18] so bulbar symptoms are seldom encountered. Neurological abnormalities may at times be obscured by the symptoms of an associated sickle cell disease complication such as meningitis or severe chest syndrome and not appreciated until after recovery from that complication. If stroke is due to subarachnoid haemorrhage, headache, photophobia and nuchal rigidity will be prominent features of the presentation. Although common in sickle cell disease, headache is seldom associated with an infarctive stroke. Appropriate supportive care must be provided. Standard practice calls for transfusion to lower the haemoglobin S level to 30% or less.[37] Care must be taken to avoid increasing total haemoglobin to levels above 12 g/dl before the haemoglobin S reduction is accomplished.[38] Exchange transfusion is the preferable modality. Automated exchange transfusion or erythrocytapheresis is becoming widely used where available.[39-41] Imaging studies should be done to determine the location, type and extent of the stroke. Computed tomographic brain scans can be obtained if haemorrhagic stroke is suspected. They are of little help for cerebral infarcts, since contrast must be avoided until the haemoglobin S level has been reduced, as it may be sufficiently hypertonic to promote sickling and cause worsening of the process.[42] If the cerebral artery circulation is compromised by significant stenosis, any further formation of irreversibly sickled cells may lead to stroke extension. Magnetic resonance imaging studies have been shown to be the preferable imaging modality, providing considerably better resolution of the pathology.[21] For children who have sustained intracranial haemorrhage, herniation is possible, since the extravasated blood occupies space. Neurosurgical therapy may be required, since aneurysms are fre© Adis International Limited. All rights reserved.
425
quently the cause of the haemorrhage.[43-45] Alternatively, haemorrhage might occur as a complication of prior stroke[3] or vascular occlusion, resulting in the moyamoya phenomenon.[46] Supportive care is critical. The mortality rate for such individuals is high in the period immediately following the event.[47] 5. Risk for Recurrence The primary feature of stroke in sickle cell disease is its high risk for recurrence. That risk has been variably reported to range from 50 to 90%.[8,9,48] Early reports indicated that transfusion therapy, designed to maintain the haemoglobin S at levels comparable to that found in sickle trait, would prevent recurrence.[49-51] Chronic transfusion therapy provided to 13 patients with stroke showed stabilisation of angiographic abnormalities in 12 patients and complete resolution in 1.[52] After cessation of transfusion therapy, these lesions recurred and presumably placed the child at risk for stroke recurrence. Differing maximum levels of haemoglobin S were allowed in these programmes but ultimately a level of 30% was accepted as standard practice.[37] Transfusion therapy does not guarantee freedom from recurrent stroke, although it dramatically lowers the risk. Most children whose haemoglobin S levels are maintained below 30% will be stroke free (fig. 2). A small but significant percentage of children will have recurrent events even when haemoglobin S is maintained below 30%.[53,55,56] An incidental benefit of transfusion therapy is the reversal of the typical symptoms and complications associated with HbSS. Pain and chest syndrome are almost completely avoided and growth is improved. While transfusion therapy provides protection from stroke recurrence it has several disadvantages. In addition to the risk of infection, exposure to blood products can be minimised and sometimes avoided if leucocyte-depleted red cell products are used. More importantly, alloimmunisation is frequently encountered in individuals with sickle cell disease, particularly in the US, where those affected are predominantly of African heritage while Paediatr Drugs 2001; 3 (6)
426
Pegelow
1
0.9
Probability of no recurrence
0.8
0.7
0.6
No trans Trans HU
0.5
0.4
0.3
0.2 0
10
20
30
40
50
60
70
Time to second stroke (mo) Fig. 2. Comparison of stroke recurrence with time. Probability
for stroke recurrence is displayed for children managed with long term transfusion therapy (Trans),[53] those changed from transfusion to hydroxycarbamide (hydroxyurea) after a period of transfusion therapy (HU)[54] and historical controls managed without either treatment (No trans).[8,48] Follow-up for hydroxycarbamide was reported for 22 ± 14 months. That for transfusion and historical controls was censored at 62 months.
the blood donor pool is not. It has been reported that 19% of individuals receiving sporadic blood transfusion are sensitised.[57] This value would be expected to be much higher in those receiving regular transfusions over an extended period. Typing donor blood for several antigens beyond the usual ABO and Rh typing can substantially reduce the frequency of this problem.[58] Iron overload is a natural consequence of any long term red cell transfusion regimen and is associated with heart, endocrine and hepatic toxicity.[59] At present, deferoxamine is the only agent available to remove the iron so infused. Unfortunately, the drug must be given parenterally, the usual and most practical approach being to administer it by a nightly continuous subcutaneous infu© Adis International Limited. All rights reserved.
sion.[60] Because of its inconvenience, compliance with this therapy is poor. In general, therapy is satisfactory when the child is young and parents can enforce its regular administration. Once the child reaches adolescence, compliance often deteriorates, with a dramatic increase in iron burden. Alternative approaches have been suggested, including high dose intravenous administration and twice daily subcutaneous injections.[61,62] Neither is sufficiently more convenient to substantially overcome the poor compliance. Toxicity has been described in association with the use of deferoxamine. Vision loss and deafness have both been described.[63] These may be avoided if high deferoxamine doses are avoided at times when iron stores are not excessively high. Growth failure has been reported in thalassaemic patients treated with high daily doses.[64] A formula has been proposed, the use of which is said to prevent ototoxicity and possibly other toxicities as well. It suggests that daily deferoxamine dose in milligrams per kilogram divided by the serum ferritin value expressed in micrograms per litre should be less than 0.025.[65] Ascorbic acid has been shown to facilitate iron removal when chelating with deferoxamine but can be associated with increased toxicity as well. Little information is available to guide its use in sickle cell disease, but its cautious use has been advised in certain circumstances in thalassaemia with a low dose given just before beginning the deferoxamine infusion.[59] Deferiprone, an oral iron-chelating agent has been in development for several years. There has been considerable variability in reports of its efficacy and safety. Both were recently called into question in a controversial report of a clinical trial in which individuals received deferiprone.[66] Other toxicities have been reported, specifically severe neutropenia, agranulocytosis, arthritis and teratogenicity.[67-70] Providing exchange rather than simple red cell transfusions can reduce iron accumulation. Automated exchange transfusion has become an accepted approach in many centres.[39-41] Because red Paediatr Drugs 2001; 3 (6)
Stroke in Sickle Cell Anaemia
cells are removed with each procedure, the amount of iron accumulation is substantially less than that associated with simple transfusion. It has been suggested that if erythrocytapheresis is initiated early in the course of long term transfusion, the need for deferoxamine may be avoided.[39,41] Problems associated with erythrocytapheresis include need for stable venous access, increased exposure to blood products and expense. In view of the expense associated with deferoxamine, estimated to be 50% of the $US10 000 to $50 000 annual cost of long term transfusion therapy,[71] the ability to avoid chelation may make erythrocytapheresis financially competitive. The greater donor exposure creates an increased risk for alloimmunisation but typing the blood products used beyond the ABO and Rh loci can minimise this risk.[58] In view of the present level of blood product safety, the infectious risk that results from increased donor exposure may be considered by some to be minimally important. The potential risk for contamination of the blood supply as happened with the human immunodeficiency virus is an argument in favour of minimising donor exposure to whatever degree is possible and is the problem most difficult to address in this approach. 6. Duration of Transfusion Therapy Several attempts have been made to determine the necessity for transfusion therapy. A trial to determine if transfusion could be safely discontinued after 2 years demonstrated a prompt recurrence in 7 of the 10 participants.[56] A subsequent study that included 10 individuals who had been transfused for 5 to 12 years resulted in recurrent stroke or haemorrhage in 5 participants and unexplained death in a sixth.[72] One individual safely resumed transfusion therapy. Three others, all of whom were aged over 17 years, declined further transfusions and were stroke free 18 to 20 months later. Two groups of investigators report that less intensive transfusion therapy can be used in patients who have remained stroke free for an extended period.[73,74] Participants had been receiving transfusions sufficient to maintain haemoglobin S below © Adis International Limited. All rights reserved.
427
30% for at least 4 years. Haemoglobin S levels were then allowed to rise to 50[73] or 60%.[74] No stroke recurrence was reported in the combined total of 29 patients. Two had fatal intracranial haemorrhages, which would in all likelihood have occurred even if transfusion therapy had continued. Two others died of complications of transfusional haemochromatosis. From these data, it appears that it may be safe to decrease the intensity of transfusion therapy after some arbitrary period. Doing so substantially decreases the rate of iron accumulation and donor exposure. In response to problems that made further transfusion therapy difficult or impossible, 2 patients were treated with the regular administration of hydroxycarbamide (hydroxyurea) and without transfusion.[75] No neurological complications were encountered over the course of 31 and 35 months, respectively. In fact, total haemoglobin increased sufficiently that regular phlebotomy was performed and iron burden was substantially decreased. Based on those data, hydroxycarbamide was started for 16 patients, all of whom were receiving transfusion for infarctive stroke,[54] with a reported mean follow-up of 22 months. Three had neurological events consistent with stroke recurrence and returned to transfusion therapy. No haemorrhagic complications were encountered. Caution has been suggested in using hydroxycarbamide for patients susceptible to stroke on the basis of a report of 2 patients who sustained intracranial haemorrhage while being treated with the drug.[76] In another report a 15-year-old boy died as the result of an acute intracranial haemorrhage[77] while taking hydroxycarbamide. In contrast, no such haemorrhagic complications were observed in major studies involving adults[78] and children.[79] While conclusions cannot be drawn from these reports, they suggest caution be exercised when considering the risks associated with the replacement of long term transfusion with hydroxycarbamide, especially in a population well known to have a high risk of haemorrhage.[80] A recent report documented results when transfusion therapy was simply discontinued.[81] Data Paediatr Drugs 2001; 3 (6)
428
were reported on 9 patients whose transfusion therapy had been discontinued at various ages. No new strokes occurred and patients remained neurologically stable. Imaging studies were not performed, so no information was provided on the possibility of new, subclinical infarcts. While the authors report it is their practice to stop transfusion at age 18 if it has been given for at least 3 years, the report included 2 children whose transfusion had been stopped at age 8 and 9 years. Their inclusion dramatically inflated the stroke-free survival reported for the remaining 7 patients. Hydroxycarbamide was given to 6 individuals, making it uncertain if the results simply indicated no further need for transfusion or resulted from protection provided by that drug. However, these data, taken together with those from the 3 previously reported,[72-74] suggest that cautious discontinuance of transfusion might be safely accomplished when the patient reaches 18 years of age. This question is sufficiently important to warrant a controlled trial to determine its safety, since at present most paediatric programmes continue transfusion indefinitely. 7. Marrow Transplantation Bone marrow transplantation has the potential to cure sickle cell disease. In the US it was decided that transplantation should be provided only for children with certain severe disease manifestations, with stroke being one of the complications for which it was considered appropriate. In the early stages of a study designed to explore the safety and efficacy of transplantation, 2 such patients developed intracranial haemorrhage and 1 died.[82] After protocol modification to ensure an adequate platelet count and more stringent efforts to control blood pressure elevation, there was no further mortality.[83] A later report of 26 individuals with a median post-transplant observation of 57 months included 13 who had qualified for transplantation by virtue of having had a stroke. Three had graft rejection, 1 of whom had a recurrent stroke when haemoglobin S rose to 60%. The other 2 resumed long term transfusion therapy. The 10 with stable grafts are not receiving transfusion © Adis International Limited. All rights reserved.
Pegelow
therapy and have had no stroke recurrence. One of these had persistent donor-host haematopoietic chimerism and had progression of neurologically silent brain infarcts lesions 5 years after transplantation.[84] Unfortunately, if HLA-matched siblings are required for marrow transplantation, donors are available for only 18% of patients with sickle cell disease.[85] 8. Silent Infarcts When magnetic resonance brain imaging became available and was applied to individuals with sickle cell disease, it revealed a subset of individuals who had abnormalities consistent with cerebral infarction but no history or clinical evidence of stroke.[21,22,86] The cause of these lesions was uncertain but there was speculation that some could result from small rather than large vessel disease.[21] Other authors have also documented the occurrence of these silent infarcts. Such lesions are not confined to sickle cell disease. Similar imaging abnormalities have been reported in thalassaemia,[87] migraine headaches,[88] haemophilia,[89] autism[90] and leukaemia.[91] A silent infarct prevalence of 17% was reported for a group of 199 children with HbSS who constituted a newborn cohort in a natural history study. All had magnetic resonance imaging done at or after 6 years of age.[92] The prevalence in concomitantly studied children with haemoglobin SC disease was 3%. Lesions were generally smaller than infarcts associated with strokes and differed in their location. Although they occurred in the anterior portion of the brain, they were much more likely to be found in white rather than grey matter. Subsequent studies have demonstrated that such children have neuropsychological abnormalities.[93-96] While these lesions are relatively mild, they argue against their continued designation as silent. Since the neuropsychological deficits appear to be of a severity intermediate between those found in children who have strokes and those who are neurologically normal, and in view of the fact that children with HbSS who have strokes are susceptible to having further lesions, there has been conPaediatr Drugs 2001; 3 (6)
Stroke in Sickle Cell Anaemia
siderable interest in determining if the presence of silent infarcts is associated with or predicts strokes. Data from the primary stroke prevention trial suggested that children who had silent infarcts were more likely to have a stroke than those who had initially normal magnetic resonance studies.[97] However, all had abnormal cerebral artery velocities and when analysed together, only the transcranial Doppler ultrasonography (TCD) velocity was significant. Preliminary longitudinal data from that study indicate that individuals who had silent infarcts when randomised to standard care were more likely to develop more lesions than those whose initial magnetic resonance examinations were normal.[98] Although the numbers are small, these individuals also appeared to be more likely to develop stroke. Data from the second 5 years of the CSSCD suggest that individuals who had silent infarcts were more likely to develop stroke than those who were without lesions,[99] a relationship that is difficult to interpret, since the TCD status of these children is not known. This makes it impossible to determine which abnormality might be responsible for the strokes that occurred. Data obtained from a subset of the children who made up the newborn cohort indicate that 25% of children with silent infarcts had TCD velocities greater than 200 cm/sec.[100] 9. Primary Stroke Prevention TCD performed in children with HbSS has identified a group of children who are at particularly high risk for stroke.[101] The basis for this finding is that increased arterial velocity indicates partial obstruction of the artery in question. The risk was shown to increase with increasing velocity. For velocities over 200 cm/sec it reached 40% over a 3-year period. A clinical trial was designed in which children with HbSS who were found to have velocities greater than 200 cm/sec were randomised to receive standard sickle cell disease medical care or long term transfusion therapy designed to maintain their haemoglobin S below 30%.[97] Of the 130 children randomised, 67 received standard care. The study was terminated © Adis International Limited. All rights reserved.
429
early when it was discovered that 10 strokes had occurred in the standard care arm and only 1 in the group receiving transfusion therapy. Practical application of these results is problematic. The TCD technique used is difficult to reproduce and differs from that generally used by radiologists. Velocities obtained by the 2 methods vary in a somewhat unpredictable manner, making difficult any comparison with values used in the trial. The risk for stroke observed during the Stroke Prevention Trial in Sickle Cell Disease (STOP) trial was somewhat lower than that reported originally, but this may have been affected by the need for early closure due to the dramatic degree of protection provided by transfusion.[97] Some have expressed concern about the wisdom of transfusion exposure for children whose risk for stroke may be lower than 40% considering the iron accumulation, risk for infection and potential alloimmunisation. The sequel to that study will begin shortly. Designed to learn if transfusion therapy can be safely stopped, it will study children given transfusion therapy for at least 3 years for elevated TCD velocity. Those whose TCD velocities are below 200 cm/sec will be offered randomisation to continued transfusion or standard sickle cell disease medical care. TCD velocity will be monitored, with the end-point being an increase to a level above 200 cm/sec. If it can be shown that increased risk for stroke can be altered by transfusion given for a limited time, the potential disadvantages of that therapy may become more acceptable. This is particularly true considering the current low risk for infection transmission by blood products, the potential for limiting iron accumulation using erythrocytapheresis and minimising alloimmunisation by using phenotypically matched red cells. Alternatively, the potential devastation resulting from stroke suggests this approach be carefully considered for children with HbSS. 10. Intracranial Haemorrhage Adults aged between 22 and 29 years are at highest risk for intracranial haemorrhage.[12] There are multiple causes, which include arterial aneurysms.[43-45,102-104] Angiography often reveals multiPaediatr Drugs 2001; 3 (6)
430
Pegelow
ple lesions, and women appear to be somewhat more frequently affected. Lesions are frequently found in the posterior circulation.[45] Haemorrhage is also found in young adults who had strokes as children.[80] Affected children can often be shown to have abnormal vasculature similar to that found in the moyamoya phenomenon.[46] While transfusion therapy clearly reduces the risk for recurrent infarctive stroke, it does not appear to provide protection from recurrent intracranial haemorrhage. In fact, care must be taken when providing transfusion for any child suspected to have abnormal cerebral vasculature, as increased viscosity or pressure might cause vascular rupture and haemorrhage. The mortality rate is high whether the haemorrhages occur in adults or children.[47] Those who survive the immediate insult and whose aneurysms can be managed surgically will often be free of recurrent bleeding episodes. 11. Conclusions In summary, stroke is a frequently encountered, severe complication of sickle cell disease. Some events can be prevented. The potential severity and considerable disability involved argue in favour of efforts for primary prevention as well as improved management modalities for those affected. References 1. Harris JW. Studies on the destruction of red blood cells, VII: molecular orientation in sickle-cell hemoglobin solutions. Proc Soc Exp Biol Med 1950; 75: 197-201 2. Marotta CA, Wilson JT, Forget BG, et al. Human β-globin messenger RNA: nucleotide sequences derived from complementary DNA. J Biol Chem 1977; 252: 5040-51 3. Ingram VM. Gene mutation in human hemoglobin: the chemical difference between normal and sickle cell hemoglobin. Nature 1957; 180: 326-9 4. Syndstricker VP, Mulherin WA, Houseal RW. Sickle cell anemia. Am J Dis Child 1923: 26: 132-54 5. Early C, Kittner SJ, Feeser BR, et al. Stroke in children and sickle cell disease: Baltimore-Washington cooperative young stroke study. Neurology 1998; 51: 169-76 6. Greer M, Schotland D. Abnormal hemoglobin as a cause of neurologic disease. Neurology 1962; 12: 114-23 7. Portnoy BA, Herion JC. Neurological manifestations in sickle cell disease. Ann Intern Med 1972; 76: 643-52 8. Powars DR, Wilson B, Imbus C, et al. The natural history of stroke in sickle cell disease. Am J Med 1978; 65: 461-71 9. Balkaran B, Char G, Morris JS, et al. Stroke in a cohort of patients with homozygous sickle cell disease. J Pediatr 1992; 120: 360-6
© Adis International Limited. All rights reserved.
10. Hughes JG, Diggs LW, Gillespie CE. The involvement of the nervous system in sickle cell anemia. J Pediatr 1940; 17: 166-84 11. Huttenlocher PR, Moohr JW, Johns L, et al. Cerebral blood flow in sickle cell cerebrovascular disease. Pediatrics 1984; 73: 615-21 12. Ohene-Frempong K, Weiner SJ, Sleeper LA, et al. Cerebrovascular accidents in sickle cell disease: Rates and risk factors. Blood 1998; 91: 288-94 13. Bridgers WH. Cerebrovascular disease accompanying sickle cell anemia. Am J Pathol 1939; 15: 353-61 14. Baird RL, Weiss DL, Ferguson AD, et al. Studies in sickle cell anemia: XXI. Clinicopathological aspects of neurological manifestations. Pediatrics 1964; 34: 92-100 15. Boros L, Thomas C, Weiner WJ. Large cerebral vessel disease in sickle cell anemia. J Neurol Neurosurg Psychiatry 1976; 39: 1236-9 16. Merkel KH, Ginsberg PL, Parker JC, et al. Cerebrovascular disease in sickle cell anemia: a clinical, pathological and radiological correlation. Stroke 1978; 9: 45-52 17. Stockman JA, Nigro MA, Mishkin MM, et al. Occlusion of large cerebral vessels in sickle cell anemia. N Engl J Med 1972; 287: 846-9 18. Rothman SM, Fulling KH, Nelson JS. Sickle cell anemia and central nervous system infarction: a neuropathological study. Ann Neurol 1986; 20: 684-90 19. Clower BR, Sullivan DM, Smith RR. Intracranial vessels lack vasa vasorum. J Neurosurg 1984; 61: 44-8 20. Torvik A. The pathogenesis of watershed infarcts in the brain. Stroke 1984; 15: 221-3 21. Adams RJ, Nichols FT, McKie V, et al. Cerebral infarction in sickle cell anemia: mechanism based on CT and MRI. Neurology 1988; 38: 1012-7 22. Pavlakis SG, Bello J, Prohovnik I, et al. Brain infarction in sickle cell anemia: magnetic resonance imaging correlates. Ann Neurol 1988; 23: 125-30 23. Platt O. Easing the suffering caused by sickle cell disease. N Engl J Med 1994; 330: 783-4 24. Liesner R, Mackie I, Cookson J, et al. Prothrombotic changes in children with sickle cell disease: relationships to cerebrovascular disease and transfusion. Br J Haematol 1998; 103: 1037-44 25. Chiu D, Lubin B, Roelofsen B, et al. Sickled erythrocytes accelerate clotting in vitro: an effect of abnormal membrane lipid asymmetry. Blood 1981; 58: 398-401 26. Lane PA, O’Connell JL, Marlar RA. Erythrocyte membrane vesicles and irreversibly sickled cells bind protein S. Am J Hematol 1994; 47: 295-300 27. Helley D, Eldor A, Girot R, et al. Increased procoagulant activity of red blood cells from patients with homozygous sickle cell disease and β thalassaemia. Thromb Hemost 1996; 76: 322-7 28. Wierenga KJJ, Serjeant BE, Serjeant GR. Parvovirus B19 infection and cerebrovascular complications in homozygous sickle cell disease. Proc Natl Sickle Cell Dis Prog 2000; 24: 29a 29. Vichinsky EP, Neumayr LD, Earles AN, et al. Causes and outcomes of the acute chest syndrome in sickle cell disease. N Engl J Med 2000; 342: 1855-65 30. Horton DP, Ferriero DM, Mentzer WC. Nontraumatic fat embolism syndrome in sickle cell anemia. Pediatr Neurol 1995; 12: 77-80 31. Rackoff WR, Ohene-Frempong K, Month S, et al. Neurologic events after partial exchange transfusion for priapism in sickle cell disease. J Pediatr 1992; 120: 882-5
Paediatr Drugs 2001; 3 (6)
Stroke in Sickle Cell Anaemia
32. Powars DR, Weiss JN, Chan LS, et al. Is there a threshold level of fetal hemoglobin that ameliorates morbidity in sickle cell anemia? Blood 1984; 63: 921-6 33. Adams RJ, Kutlar A, McKie V, et al. Alpha thalassaemia and stroke risk in sickle cell anemia. Am J Hematol 1994; 45: 279-82 34. Miller ST, Rieder RF, Rao SP, et al. Cerebrovascular accidents in children with sickle cell disease and alpha thalassaemia. J Pediatr 1988; 113: 847-9 35. Piomelli S, Seaman C, Cirella B, et al. Does alpha thalassaemia protect from early stroke in sickle cell anemia? Pediatr Res 1986; 10: 285a 36. Pegelow CH, Colangelo L, Steinberg M, et al. Natural history of blood pressure in sickle cell disease: risks for stroke and death associated with relative hypertension in sickle cell anemia. Am J Med 1997; 102: 171-7 37. Reid C, Charache S, Lubin B, et al. Management and therapy of sickle cell disease. 3rd ed. Bethesda (MD): US Department of Health and Human Services, 1995: 53-8. NIH Publication No 96-2117 38. Jan K, Usami S, Smit JA. Effects of transfusion on rheological properties of blood in sickle cell anemia. Transfusion 1982; 22: 17-20 39. Kim HC, Dugan NP, Silber JH, et al. Erythrocytapheresis therapy to reduce iron overload in chronically transfused patients with sickle cell disease. Blood 1994; 83: 1136-42 40. Hilliard LM, Williams BF, Lounsbury AE, et al. Erythrocytapheresis limits iron accumulation in chronically transfused sickle cell patients. Am J Hematol 1998; 59; 28-35 41. Adams DM, Schultz WH, Ware RE, et al. Erythrocytapheresis can reduce iron overload and prevent the need for chelation therapy in chronically transfused pediatric patients. J Pediatr Hematol Oncol 1996; 18: 46-50 42. Imbus C, Powars D, Pegelow C, et al. Computerized tomography complications [letter]. Arch Neurol 1978; 35: 620 43. Anson JA, Koshy M, Ferguson L, et al. Subarachnoid hemorrhage in sickle cell disease. J Neurosurg 1991; 75: 552-8 44. Overby MC, Rothman AS. Multiple intracranial aneurysms in sickle cell anemia. Report of two cases. J Neurosurg 1985; 62: 430-4 45. Oyesiku NM, Barrow DL, Eckman JR, et al. Intracranial aneurysms in sickle cell anemia: clinical features and pathogenesis. J Neurosurg 1991; 75: 356-63 46. Seeler RA, Royal JE, Powe L, et al. Moyamoya in children with sickle cell anemia and cerebrovascular occlusion. J Pediatr 1978; 93: 808-10 47. Van Hoff J, Ritchey AK, Shaywitz BA. Intracranial hemorrhage in children with sickle cell disease. Am J Dis Child 1985; 139: 1120-3 48. Moohr JW, Wilson H, Pang EJ-M. Strokes and their management in sickle cell disease. In: Fried W, editor. Comparative clinical aspects of sickle cell disease. Amsterdam: Elsevier North Holland, 1982: 101-1 49. Lusher JM, Haghighat H, Khalifa AS. A prophylactic transfusion program for children with sickle cell anemia complicated by CNS infarction. Am J Hematol 1976; 1: 265-73 50. Sarnaik S, Soorya D, Kim J, et al. Periodic transfusions for sickle cell anemia and CNS infarction. Am J Dis Child 1979; 133: 1254-7 51. Russell MO, Goldberg HI, Reis L, et al. Transfusion therapy for cerebrovascular abnormalities in sickle cell disease. J Pediatr 1976; 88: 382-7
© Adis International Limited. All rights reserved.
431
52. Russell MO, Goldberg HI, Hodson A, et al. Effect of transfusion therapy on arteriographic abnormalities and on recurrence of stroke in sickle cell disease. Blood 1984; 63: 162-9 53. Pegelow CH, Adams RJ, McKie V, et al. Risk of recurrent stroke in patients with sickle cell disease treated with erythrocyte transfusions. J Pediatr 1995; 126: 896-9 54. Ware RE, Zimmerman SA, Schultz WH. Hydroxyurea as an alternative to blood transfusions for the prevention of recurrent stroke in children with sickle cell disease. Blood 1999; 94: 3022-6 55. Buchanan GR, Bowman P, Smith SJ. Recurrent cerebral ischemia during hypertransfusion therapy in sickle cell anemia. J Pediatr 1983; 103: 921-2 56. Willimas J, Goff JR, Anderson HR, et al. Efficacy of transfusion therapy for one to two years in patients with sickle cell disease and cerebrovascular accidents. J Pediatr 1980; 96: 205-8 57. Rosse WF, Gallagher D, Kinney TR, et al. Transfusion and alloimmunization in sickle cell disease. Blood 1990; 76: 1431-7 58. Vichinsky EP, Earles A, Johnson RA, et al. Alloimmunization in sickle cell anemia and transfusion of racially unmatched blood. N Engl J Med 1990; 322: 1617-21 59. Olivieri NF, Brittenham GM. Iron-chelating therapy and the treatment of thalassaemia. Blood 1997; 89: 739-61 60. Propper RD, Shurin SB, Nathan DG. Reassessment of the use of desferrioxamine B in iron overload. N Engl J Med 1976; 294: 1421-3 61. Cohen AR, Mizanin J, Schwartz E. Rapid removal of excessive iron with daily, high dose intravenous chelation therapy. J Pediatr 1989; 115: 151-5 62. Borgna-Pignatti C, Cohen A. Evaluation of a new method of administration of the iron chelating agent deferoxamine. J Pediatr 1997; 130: 86-8 63. Olivieri NF, Buncic JR, Chew E, et al. Visual and auditory neurotoxicity in patients receiving subcutaneous deferoxamine infusions. N Engl J Med 1986; 314: 869-73 64. De Virgiliis S, Congia M, Frau F, et al. Deferoxamine-induced growth retardation in patients with thalassaemia major. J Pediatr 1988; 113: 661-9 65. Porter JB, Jaswon MS, Huehns ER, et al. Desferrioxamine ototoxicity: evaluation of risk factors in thalassaemic patients and guidelines for safe dosage. Br J Haematol 1989; 73: 403-9 66. Olivieri NF, Brittenham GM, McLaren CE, et al. Long-term safety and effectiveness of iron chelation therapy with deferiprone for thalassaemia major. N Engl J Med 1998; 339: 417-23 67. Al-Refaie FN, Wonke B, Hoffbrand AV, et al. Efficacy and possible adverse effects of the oral iron chelator 1,2-dimethyl-3-hydroxypyrid-4-one (L1) in thalassaemia major. Blood 1992; 80: 593-9 68. Kontoghiorghes GJ, Bartlett AN, Hoffbrand AV, et al. Long term trial with the oral iron chelator 1,2-dimethyl-3hydroxypyrid-4-one (L1) I. Iron chelation and metabolic studies. Br J Haematol 1990; 76: 295-300 69. Bartlett AN, Hoffbrand AV, Kontoghiorghes GJ. Long-term trial with the oral iron chelator 1,2-dimethyl-3-hydroxypyrid4-one (L1). II Clinical observations. Br J Haematol 1990; 76: 301-4 70. Al-Refaie FN, Hershko C, Hoffbrand AV, et al. Results of long term deferiprone (L1) therapy: a report by the international study group on oral iron chelators. Br J Haematol 1995; 91: 224-9
Paediatr Drugs 2001; 3 (6)
432
71. Wayne AS, Scheonike SE, Pegelow CH. Financial analysis of chronic transfusion for stroke prevention in sickle cell disease. Blood 2000; 96: 2369-72 72. Wang WC, Kovnar EH, Tonkin IL, et al. High risk of recurrent stroke after discontinuance of five to twelve years of transfusion therapy in patients with sickle cell disease. J Pediatr 1991; 118: 377-82 73. Cohen AR, Martin MB, Silber JH, et al. A modified transfusion program for prevention of stroke in sickle cell disease. Blood 992; 79: 1657-61 74. Miller ST, Jensen D, Rao SP. Less intensive long-term transfusion therapy for sickle cell anemia and cerebrovascular accident. J Pediatr 1992; 120: 54-7 75. Ware RE, Steinberg MH, Kinney TR. Hydroxyurea: an alternative to transfusion therapy for stroke in sickle cell anemia. Am J Hematol 1995; 50: 140-3 76. Vichinsky EP, Lubin BH. A cautionary note regarding hydroxyurea in sickle cell disease. Blood 1994; 83: 1124-8 77. Scott JP, Hillery CA, Brown ER, et al. Hydroxyurea therapy in children severely affected with sickle cell disease. J Pediatr 1996; 128: 820-8 78. Charache S, Terrin ML, Moore RD, et al. Effect of hydroxyurea on the frequency of painful crises in sickle cell anemia. N Engl J Med 1995; 332: 1317-22 79. Kinney TR, Helms RW, O’Branski EE, et al. Safety of hydroxyurea in children with sickle cell anemia: results of the HUG-KIDS study, a phase I/II trial. Pediatric Hydroxyurea Group. Blood 1999; 94: 1550-4 80. Powars D, Adams RJ, Nichols FT, et al. Delayed intracranial hemorrhage following cerebral infarction in sickle cell anemia. J Assoc Acad Minor Phys 1990; 1: 79-82 81. Rana S, Houston PE, Surana N, et al. Discontinuation of longterm transfusion therapy in patients with sickle cell disease and stroke. J Pediatr 1997; 131: 757-60 82. Walters MC, Sullivan KM, Bernaudin F, et al. Neurologic complications after allogenic marrow transplantation for sickle cell anemia. Blood 1995; 85: 879-84 83. Walters MC, Patience M, Leisenring W, et al. Bone marrow transplantation for sickle cell disease. N Engl J Med 1996; 335: 369-76 84. Walters MC, Storb R, Patience M, et al. Impact of bone marrow transplantation for symptomatic sickle cell disease: an interim report. Blood 2000; 95: 1918-24 85. Mentzer WC, Heller S, Pearle PR, et al. Availability of related donors for bone marrow transplantation in sickle cell anemia. Am J Pediatr Hematol Oncol 1994; 16: 27-9 86. Seibert JJ, Miller SF, Kirby RS, et al. Cerebrovascular disease in symptomatic and asymptomatic patients with sickle cell anemia: screening with duplex transcranial Doppler US: correlation with MR imaging and MR angiography. Radiology 1993; 189: 457-66 87. Manfre L, Giarratano E, Maggio A, et al. MR imaging of the brain: findings in asymptomatic patients with thalassaemia intermedia and sickle cell-thalassaemia disease. Am J Roentgenol 1999; 173: 1477-80 88. Osborn RE, Alder DC, Mitchell CS. MR imaging of the brain in patients with migraine headaches. Am J Neuroradiol 1991; 12: 521-4 89. Wilson DA, Nelson MD, Fenstermacher MJ, et al. Brain abnormalities in male children and adolescents with hemophilia: detection with MR imaging. Radiology 1992; 185: 553-8
© Adis International Limited. All rights reserved.
Pegelow
90. Nowell MA, Hackney DB, Muraki AS, et al. Varied MR appearance of autism: fifty-three pediatric patients having the full autistic syndrome. Magn Reson Imaging 1990; 8: 811-6 91. Wilson DA, Nitschke R, Bowman ME, et al. Transient white matter changes on MR images in children undergoing chemotherapy for acute lymphocytic leukemia: correlation with neuropsychologic deficiencies. Radiology 1991; 180: 205-9 92. Moser FG, Miller ST, Bello JA, et al. The spectrum of brain MR abnormalities in sickle cell disease: a report from the cooperative study of sickle cell disease. Am J Neuroradiol 1996; 17: 965-72 93. Armstrong FD, Thompson RJ, Wang W, et al. Cognitive functioning and brain magnetic resonance imaging in children with sickle cell disease. Pediatrics 1996; 97: 864-70 94. Bernaudin F, Verlhac S, Freard F, et al. Multicenter prospective study of children with sickle cell disease: radiographic and psychometric correlation. J Child Neurol 2000; 15: 333-43 95. Craft S, Schatz J, Glauser TA, et al. Neuropsychologic effects of stroke in children with sickle cell anemia. J Pediatr 1993; 123: 712-7 96. DeBaun MR, Schatz J, Siegel MJ, et al. Cognitive screening examinations for silent cerebral infarcts in sickle cell disease. Neurology 1998; 50: 1678-82 97. Adams RJ, McKie VC, Hsu L, et al. Prevention of a first stroke by transfusions in children with sickle cell anemia and abnormal results on transcranial Doppler ultrasonography. N Engl J Med 1998; 339: 5-11 98. Pegelow CH, Adams R, Hsu L, et al. Children with silent infarct and elevated transcranial Doppler ultrasonography velocity are at increased risk of subsequent infarctive events. Proc Natl Sickle Cell Dis Prog 1999; 23: 137 99. Miller ST, Macklin E, Sleeper L, et al. Risk factors for stroke in children with sickle cell disease: a report from the CSSCD. Proc Natl Sickle Cell Dis Prog 2000; 24: 25a 100. Wang WC, Gallagher D, Pegelow CH, et al. A multi-center comparison of magnetic resonance imaging and transcranial Doppler ultrasonography in the evaluation of the central nervous system in children with sickle cell disease. Am J Pediatr Hematol Oncol. In press 101. Adams R, McKie V, Nichols F, et al. The use of transcranial ultrasonography to predict stroke in sickle cell disease. N Engl J Med 1992; 326: 605-10 102. Batjer HH, Adamson TE, Bowman GW. Sickle cell disease and aneurismal subarachnoid hemorrhage. Surg Neurol 1991; 36: 145-9 103. Preul MC, Cendes F, Just N, et al. Intracranial aneurysms and sickle cell anemia: multiplicity and propensity for the vertebrobasilar territory. Neurosurgery 1998; 42: 971-8 104. Wiznitzer M, Berman B. Subarachnoid hemorrhage in sickle cell anemia: evaluation using parenchymal and vascular magnetic resonance imaging. Neurology 1991; 41: 1521-2
Correspondence and offprints: Dr Charles H. Pegelow, MD, Department of Pediatrics (R-131), University of Miami School of Medicine, Post Office Box 016960, Miami, FL 33101, USA. E-mail:
[email protected]
Paediatr Drugs 2001; 3 (6)