B. Neurologic Complications

1. Inverse correlation between cerebral blood flow measured by continuous arterial spin-labeling (CASL) MRI and neurocognitive function in children with sickle cell anemia (SCA). Strouse JJ, Cox CS, Melhem ER, Lu H, Kraut MA, Razumovsky A, Yohay K, van Zijl PC, Casella JF. Blood. 2006;108:379-81.

Neurologic complications are common in children with sickle cell anemia (SCA); by age 18, 11% will have had an overt stoke and an additional 15% to 22% will have a silent cerebral infarct (SCI). On average, children with SCA and magnetic resonance imaging (MRI)-confirmed SCI have lower intelligence quotients (IQs) than those with a normal MRI. Furthermore, even those with normal MRIs perform worse on neuropsychologic testing than their unaffected siblings.

Cerebral blood flow (CBF) may be affect neurcognitive function. In this study, the investigators examined the relationship between CBF and neurocognitive function in children with SCA and a normal transcranial Doppler ultrasound (TCD). They hypothesized that measuring CBF by MRI could identify children at increased risk for neurocognitive impairment and SCI. These children could then be targeted for educational and other specific interventions.

They evaluated 24 children with SCA with a neurologic exam, complete blood count, TCD, measurement of IQ, and MRI with measurement of CBF using continuous arterial spin-labeling (CASL) MRI. Average CBF to gray matter was 112 +/- 36 mL/100 g/min. They identified a strong inverse relationship between performance IQ and CBF (-1.5 points per 10 mL/100 g/min increase in CBF, P = .013). Elevated steady-state white blood cell count (> or = 14 x 10(9)/L [14,000/microL]) was associated with lower full scale IQ (86 +/- 9 vs 99 +/- 10, P = .005).

The authors concluded that CASL MRI may identify children with neurocognitive impairment, before damage is evident by structural MRI or TCD.

2. Overt and incomplete (silent) cerebral infarction in sickle cell anemia: diagnosis and management. Wong WY, Powars DR. Hematol Oncol Clin North Am. 2005;19:839-55.

This is an extensive and comprehensive review of the problem of overt and silent cerebral infarction in sickle cell anemia. The authors review the incidence, risk factors, clinical diagnosis, neuroimaging, prevention, acute management, transfusion therapy, hydroxyurea therapy and neurorehabilitation.

The accumulative overall risk for cerebral infarction during a patient's lifetime, in sickle cell anemia has been estimated to be as high as 30%. This percentage rises even further if one uses improved MRI techniques, particularly fluid-attenuated inversion recovery (FLAIR). 44% of patients demonstrated infarction, ischemia, or atrophy on MRI (FLAIR) and 49% had abnormal findings on MR angiography.

During the last decade, a changing prevalence pattern has been observed, with an increasing frequency of first identified clinical neurologic events at 20 to 25 years of age. Using definitive neuroimaging techniques it is clear that these patients have "silent" stroke (incomplete infarctions) before overt clinical stroke becomes apparent. In the authors' series, children observed from 1980-1995 had evidence of incomplete infarctions based on positron-emission tomography (PET) technology, but were not placed on transfusion therapy or hydorxyurea. They now appear with identified neurologic events during the third decade of life.

Regional complete infarctions in children with sickle cell anemia are often associated with stenosis of the large intracranial arteries and result in lifetime disability. Incomplete infarction occurs more frequently than previously recognized and has far-reaching effects on neurocognitive development and the risk for overt secondary strokes into adulthood. The recognition of an emerging "second peak" incidence in the third decade of life is worrisome and warrants more intense scrutiny and diagnosis of subtle findings of stroke in this young adult population.

(Comment: Once again the high frequency and clinical significance of silent and overt strokes is emphasized. As pointed out by these and other others, incomplete infarction has far-reaching effects on neurocognitive development and the risk for overt secondary strokes into adulthood. One continues to wonder why there is not more enthusiasm for cure of sickle cell anemia by hematopoietic cell transplantation at a young age before such complications arise, even considering the important side effects of that therapy.)

3. Defining stroke risk in children with sickle cell anaemia. Hoppe C. Br J Haematol. 2005;128:751-66.

The authors point out that children with sickle cell anemia (SCA) carry a 300-fold increased risk for stroke. By 20 years of age, 11% of children with SCA will have experienced a clinical stroke syndrome, and a further 17-22% will have subclinical evidence of cerebral infarction on brain magnetic resonance imaging (MRI). Children with silent infarcts identified by MRI may appear asymptomatic, but these subclinical lesions on MRI correlate with significant neuropsychological deficits, and almost half of the children with silent infarcts will eventually require life-long support or custodial care.

The use of hydroxyurea to prevent silent infarcts has not been investigated. While transfusion therapy may reduce the risk of acute ischemic stroke, it may not prevent the development of subclinical small vessel disease associated with subtle neuropsychologic deficits. There are presently no published evidence-based data on the prevention of silent infarction and associated cognitive disability.

In this comprehensive article, the author reviews in depth the following aspects of stroke in SCA: epidemiology, phenotypes, pathogenesis, risk factors and genetic modifiers. Data concerning transcranial Doppler (TCD) ultrasound are reviewed thoroughly as are preventive therapies. She points out that hematopoietic stem cell transplantation has proven curative in young patients with severe SCA and has resulted in stabilization of cerebral vasculopathy as documented by MRI. Currently, the event-free survival rate after allogeneic-matched sibling hematopoietic cell transplantation for SCA is 82%, and novel conditioning regimens and alternative stem cell sources show promise for the wider application of this mode of therapy in SCA.

4. Magnetic resonance angiography in children with sickle cell disease and abnormal transcranial Doppler ultrasonography findings enrolled in the STOP study. Abboud MR, Cure J, Granger S, Gallagher D, Hsu L, Wang W, Woods G, Berman B, Brambilla D, Pegelow C, Lewin J, Zimmermann RA, Adams RJ; STOP study. Blood 2004;103:2822-6.

The authors point out that ischemic strokes are more frequent among patients younger than 20 years of age, whereas older patients experience hemorrhagic strokes. The incidence of ischemic strokes is highest in patients with homozygous sickle cell anemia between 1 and 9 years of age. Patients who have ischemic strokes are at high risk for recurrence unless they are placed on a regimen of chronic transfusions.

Until recently there were no reliable means of prospectively identifying patients at higher risk for stroke with sufficient certainty to warrant intervention. As part of the stroke prevention study in sickle cell disease (STOP), a study was performed of magnetic resonance angiograms (MRAs) and time-averaged mean cerebral blood velocity as measured by transcranial Doppler (TCD). The authors found that patients with abnormal MRA findings and higher TCD velocities are at higher risk for stroke. They suggested that TCD is the optimal screening test for stroke risk and it is reasonable to suggest that MRA be performed in all patients in whom TCD indicates risk and in children in whom TCD cannot be obtained. TCD measurements in STOP patients were likely to remain abnormal over time, regardless of treatment in patients who had abnormal MRA findings. On the other hand, TCD measurements reverted to normal in many patients with normal MRA findings, mostly with treatment. This suggests that children who have established MRA lesions may need long-term or indefinite treatment.

5. Stroke and conversion to high risk in children screened with transcranial Doppler ultrasound during the STOP study. Adams RJ, Brambilla DJ, Granger S, et al., for the STOP Study. Blood. 2004;103:3689-94.

The authors point out that cerebrovascular disease is one of the most serious complications of sickle cell anemia, and elevated blood flow velocity measured by transcranial Doppler (TCD) is a powerful predictor of stroke due to sickle cell disease. The Stroke Prevention Trial in Sickle Cell Anemia (STOP) was a randomized multi-center controlled trial comparing prophylactic blood transfusion to standard care in SCD children aged 2 to 16 years selected for high stroke risk by TCD. A total of 5,613 TCD studies from 2,324 children were evaluated. The authors describe the changes in TCD with repeat testing and report the outcome without transfusion in the STOP screened cohort. Risk of stroke was higher with abnormal TCD than with normal or conditional or inadequate TCD. Repeat TCD in 1215 children showed that 9.4% of children became abnormal during observation. Younger patients and those with higher initial flow velocities were most likely to convert to abnormal. Screening in STOP confirmed the predictive value of TCD for stroke. Substantial differences in probability of conversion to abnormal TCD were observed, with younger children and those with higher velocity more likely to have an abnormal TCD with re-screening.

6.Stroke Prevention Trial in Sickle Cell Anemia (STOP): Extended Follow-up and Final Results. Lee MT, Piomelli S, Granger S, Miller ST, Harkness S, Brambilla DJ, Adams RJ. Blood 2006;108:847-852.

Stroke is a devastating complication of sickle cell disease (SCD) particularly during childhood, with an estimated 11% of patients with homozygous SCD having stroke by the age of 20 years. The use of transcranial Doppler (TCD) ultrasonography identifies children with SCD who are at high risk for stroke.

The Stroke Prevention Trial in Sickle Cell Anemia (STOP) was a randomized trial to evaluate whether chronic transfusion could prevent initial stroke in sickle cell children at high risk as determined by TCD. The trial demonstrated a large benefit of transfusion and was halted early.

After termination of the trial, patients participated in a Post-Trial Follow-up Study. More patients in the Transfusion group (70%) elected transfusion for primary stroke prevention compared to those on Standard Care (45%). Six patients with persistently abnormal TCD developed stroke. A minority with initially abnormal TCD remained stroke-free without transfusion. Except for lower baseline and follow-up TCD velocities compared to those with stroke, no predictive features of this apparent lower risk subgroup could be determined. TCD results at last testing in 108 that did not have stroke were: normal (44.4%), abnormal (22.2%) and inadequate (6.5%). Patients on transfusion were more likely to have normal TCD. Transfusion resulted in iron overload and alloimmunization but no infection. The potential morbidity from long-term transfusion, particularly iron overload, has deterred its universal acceptance among clinicans and patients. Overall, only about 70% of patients from the original transfusion group and 45% from the standard care group were on transfusion for primary prevention of stroke in the Follow-up Study.

The study provides new information on acceptance rates and long-term effects of transfusion. Persistent TCD elevation signals ongoing stroke risk. Reduction in TCD over time without transfusion is observed in some cases and requires further study.

7. Pathophysiology of stroke in sickle cell disease. Hillery CA, Panepinto JA. Microcirculation. 2004;11:195-208.

The authors point out that stroke is a major cause of morbidity and mortality in SCD, and affects both motor and cognitive function. Overt stroke occurs in 11% of those with homozygous SCD by 20 years of age and in 24% by 45 years of age. Without treatment, there is a 70% chance for recurrent stroke. A chronic RBC transfusion regimen decreases the rate of recurrent stroke to 10-22%. However, long-term use of monthly RBC transfusions almost universally results in iron overload, despite chelation therapy with deferoxamine.

Silent stroke, defined as cerebral infarction in the absence of overt clinical neurologic symptoms, occurs in 22% of children with homozygous SCD. Such strokes are often due to microinfarcts suggestive of microvascular disease. While chronic RBC transfusions are sometimes used, there is no proven treatment to prevent progression of silent stroke.

Both overt and silent stroke in SCD are associated with significant cognitive deficits that may progress over time. Silent stroke is associated with significant neuropsycological impairment which worsens with advancing age, and it is not clear whether treatment significantly changes performance.

The authors point out that, while the natural history of stroke in SCD is well described, the pathophysiology remains poorly understood and probably varies with the site of vascular injury. Increased red cell adhesion, oxidative injury of the vessel wall, inflammation, abnormal vasomotor tone regulation, and increased activity of the coagulation system all may contribute to cerebral vasopathology in SCD.

8. Declining stroke rates in Californian children with sickle cell disease. HJ Fullerton, RJ Adams, SJ Zhao, SC Johnston. Blood 2004;104:336-339.

Although the Stroke Prevention Trial in Sickle Cell Anemia (STOP) demonstrated the efficacy of blood transfusions for primary stroke prevention in high-risk children with sickle cell disease in 1998, the impact of this trial on public health has not been studied. Our objective was to determine whether stroke rates in Californian children with sickle cell disease have declined since 1998. Using a California-wide hospital discharge database, we identified all first admissions for stroke in children with sickle cell disease from 1991 through 2000. Annual stroke incidence rates were calculated as the number of admissions divided by the estimated population of Californian children with sickle cell disease in that year. From 1991-2000, 93 children with sickle cell disease were admitted to Californian hospitals with a first stroke during 12,030 person-years of follow-up; 92.5% were ischemic, 7.5% hemorrhagic. Overall, the rate of first stroke was 0.77 per 100 person-years. For the study years 1991-1998, the first-stroke rate was 0.88 per 100 person-years, compared to 0.50 in 1999 and 0.17 in 2000 (p<0.005 for trend). Since the publication of the STOP study in 1998, annual rates of first-stroke admissions for Californian children with sickle cell disease have declined.

9. Gene interactions and stroke risk in children with sickle cell anemia. Hoppe C, Klitz W, Cheng S, et al. Blood. 2004;103:2391-6.

The authors state that stroke is a devastating complication of sickle cell anemia, affecting up to 30% of children with the disease. They genotyped 230 children with sickle cell anemia for 104 polymorphisms among 65 candidate vascular genes to identify risk associations with stroke. They identified several candidate genes. For example, a combination of TNF(-308)GG homozygosity and the IL4R 503P variant carrier status was associated with a particularly strong predisposition to large vessel stroke (odds ratio – 5.5; 95% confidence interval = 2.3-13.1). They suggest that their results provide evidence for the involvement of multiple candidate genes predisposing to stroke in children with sickle cell anemia. Both single gene effects and gene-gene interactions appear to influence the risk of specific vascular subtypes of stroke. Such results may provide a basis for population screening and targeted intervention in sickle cell anemia.