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What is sickle cell disease?

Sickle Cell Disease (SCD) is a genetic abnormality that causes changes in the red blood cells (hemoglobin).  It is most common in people of African or Caribbean descent.  There are different subtypes of SCD.  This summary concerns Hb-SS, Hb-SC, and Hb-S beta zero thalassemia, three common subtypes that can cause serious medical complications.  (The sickle cell TRAIT, and the sickle cell disease type called Hb-S beta plus thalassemia, have not been shown to affect brain development.)

How does SCD affect the body and brain?

Sickling of blood cells: Sickle cell disease (SCD) is a recessive genetic difference in the gene for globin, part of the hemoglobin (Hb) molecule within red blood cells, which carries oxygen throughout the body.  When oxygen level within the blood cell drops, the sickle hemoglobin (HbS) forms long-chain molecules, making the blood cell more dense, less pliable, and elongated or “sickle” shaped.  These long, rigid, “stickier” cells do not move through the blood vessels as smoothly or quickly as normal cells.  The sickled cells are more likely to get stuck on the blood vessel walls, and form clumps or clots within the tiny capillaries.  A higher count of sickled blood cells, compared to normal cells, is associated with more severe complications of SCD (see below).

Chronic anemia: The body and brain do not receive sufficient oxygen from the blood.  Less oxygen is carried by each blood cell and less blood gets to some areas of the body due to narrowed vessels. More severe chronic anemia (measured by the hematocrit) is associated with lower IQ in children with SCD.  IQ in HbSS decreases slightly with age, even in children with normal MRIs, an effect not seen in children without HbSS.  This may be due to the effect of chronic anemia (hypoxia) interfering with normal brain development.

Vascular damage: The blood cell membranes are damaged by mechanical strain, and in turn cause damage, as they move through blood vessel linings.  They clump with each other and with platelets.  Blood vessel linings become narrower. More damage to the blood vessels decreases healthy blood flow to the brain and increases risk of stroke.

Increased blood volume and pressure: The body compensates for narrowed blood vessels by increasing the pressure and volume of blood flow in other vessels.  This can be visualized as increased cerebral blood flow volume (CBFV) in the carotid, middle cerebral, and anterior cerebral arteries, for example, on Transcranial Doppler (TCD) testing.  The compensatory increase in CBFV  is associated with increased risk of silent or overt ischemia/infarct (stroke).  Increased CBFV (as measured by abnormal TCD values) is associated with lower IQ even in children without evidence of strokes. Brain cells starved of oxygen do not function or develop properly, and the increased CBFV may not sufficiently compensate for needed oxygen especially given the high metabolic demands of developing brain.

Acute chest syndrome: Pain and oxygen loss due to acutely diminished blood flow in the lungs; may be associated with acute or chronic hypoxia, with brain consequences.Starving the brain of oxygen reduces energy and learning ability.

Pain crises: Pain in joints, hands, feet, or other areas of the body associated with HbSS-related vascular changes.  Can occur “out of the blue” but is most commonly triggered by dehydration, extreme temperatures, or sudden change in body temperature.  Pain crises may cause increased absences or, at least, distract children from learning and can affect mood and effort in the classroom.  Pain in the hands may affect writing and other fine motor activities.  Body pain may affect participation in PE and sports.

Other physical damage that affects learning (apart from direct effects on the brain): Diminished blood supply to the spleen makes it harder for the body to fight infections, so children with SCD become ill more easily and take longer to recover; this is especially severe in children withsplenectomy (removal of the spleen).  Frequent infectious illness may contribute to school absences even in children who do not have frequent pain.

Diminished blood supply to the bones can cause an “avascular necrosis” in which bone deteriorates, necessitating surgeries such as hip replacement, in young children.

Diminished blood supply to the tiny vessels of the eyes (retinas) can cause blindness or low vision.  In some cases, visual changes can happen suddenly, so teachers should be aware of this possibility in a child with sickle cell disease.

Diminished blood supply to the heart can cause cardiac arrhythmia, which further impair the child’s energy and blood circulation.

Normal blood cells remain in the body about 10 days, but sickled blood cells die off in 2 or 3 days, and must be constantly replaced.  The body has to work hard to make new blood cells all the time.  Therefore children with sickle cell disease may have to eat and snack more often than other children, but may not gain weight or grow normally, even when they eat a lot.

Dehydration, extreme temperatures, extreme physical exertion, and extreme emotional stress, can contribute to increased sickling and pain crises. Children need to stay very well hydrated and avoid extreme temperatures, especially temperature changes.

MRI abnormalities:  Ischemia (diminished blood flow, with diminished oxygen, glucose, and other nutrients, to certain regions of body and brain), infarct (tissue death due to severely diminished or interrupted blood flow), and atrophy (brain tissue is lost or fails to develop, so the brain is smaller than normal): In some cases, such as increases in blood flow through basilar arteries of the brain, those other vessels are fragile and not well adapted to the increased blood flow, so they can burst under the pressure, causing strokes.  Sometimes sickled cells or cell-platelet aggregates can block tiny vessels, interrupting blood supply to tissue “downstream” from the clot.  Because of the vascular anatomy of the brain, OVERT strokes with clinically obvious manifestations (changes in sensory and motor function visible on neurological exam; seizures, coma, other major changes in consciousness) tend to occur in anterior cortical regions.  SUB-CLINICAL or SILENT strokes (areas of dead tissue, visible on MRI) tend to be smaller and most likely to occur in anterior deep white matter, in the border zone of the Anterior and Middle Cerebral Artery distributions.  There may also be MICRO-INFARCTS too small to be visible on MRI scans but associated with under-development of the corpus callosum in children with HbSS.

From 10-15% of children with HbSS will have overt strokes by age 15; another 20-25% will have “silent strokes”; the rate of micro-infarcts cannot be measured with current standard neuroimaging.

Peak age for stroke appears to be ages 2 to 4 years, but recurrent stroke is common and can occur at any age.  Massive stroke (basilar artery bleeds) becomes more common in ages 10 to 14 years, associated with progressive occlusion of the anterior arteries.  Anterior infarcts (ACA/MCA border zone in particular) are more common than posterior infarcts at all ages, however it is possible for infarcts to occur anywhere.

Localization effects are uncommon except with massive strokes in older children – usually the effect is a global decrease in function.  Diminished anterior corpus callosum size is associated with lower scores on measures of attention and executive function, independent of IQ.  Greater amount of tissue loss associated with infarct is associated with lower IQ.  These changes in the brain may occur with no “gross evidence” of stroke, that is, no change in speech or movement; but they may show up as impairment of IQ, memory, or other neuropsychological test results and as a struggle to learn in school.  It is important to screen every child with SCD to assess neuropsychological function and help to determine whether more expensive and invasive medical tests, such as MRI/MRA, are needed.

Karen E. Wills, Ph.D.,

Pediatric Neuropsychologist

Children’s Hospitals and Clinics of Minnesota

Karen Wills is the Director of The Sickle Cell Disease Program for Learning Assessment and Neuropsychological Evaluation (SCD-PLANE)

This post is an excerpt from a letter sent to the Minnesota Department of Education two years ago because of misinformation found on their website regarding sickle cell disease.