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Stroke is defined as an acute neurological syndrome caused by occlusion of an artery or a hemorrhage with resultant ischemia and neurological signs and symptoms. Stroke occurs in about 10% of children under age 20 with sickle cell anemia. It is rarely seen under the age of one. The incidence is highest between ages 2 and 9 years. In general, hemorrhagic strokes occur in older persons while cerebral infarctions occur in younger groups. Cerebral infarctions are due to vascular occlusion. In children with sickle cell disease, the internal carotid and middle cerebral arteries are the most common areas of infarction. It is now understood that the etiology of vascular occlusion in sickle cell disease is likely a combination of accumulated sickled red blood cells in the microvasculature and vascular intimal hyperplasia. Vascular intimal hyperplasia and thrombosis may be related to the abnormal adhesive and procoagulant properties of erythrocytes containing Hb SS. Marrow or fat emboli secondary to bone marrow infarction has also been implicated in strokes among patients with sickle cell disease. Altered vascular reactivity (inability to develop compensatory vasodilatation) and vasospasm can also be contributing factors.
Children who have experienced a stroke are managed with chronic transfusion therapy to maintain a Hb S of < 30%. This significantly reduces the risk of repeated stroke. Chronic transfusion therapy ultimately requires iron chelation therapy with desferrioxamine.
Stroke prevention is now being evaluated by identifying children who have abnormally high cerebral arterial flow velocities measured by transcranial Doppler ultrasound.
Manifestations of stroke include:
- Completed stroke with neurological deficits lasting more than 24 hours.
- Transient ischemic attack (ischemia without infarction).
- Hemorrhagic infarct
- Moya-moya syndrome
- Vascular occlusions and stenosis
- Cerebral atrophy
There is now data about the incidence of stroke and risk factors from the stroke study of the (CSSCD) which included over 4000 patients. Although most patients who have strokes have Hb SS disease, it can occur in other genotypes.
Risk factors for stroke among patients with sickle cell disease include:
- Prior TIA or previous stroke
- Acute chest syndrome within the past two weeks
- Multiple episodes of acute chest syndrome
- High systolic blood pressure
- Flow velocity of > 200 cm/sec on transcranial Doppler ultrasound (TCD)
- Peripheral WBC > 11.8 k/ul
- Decrease in Hb > 1.85 g/dl from baseline
Signs and symptoms of stroke include:
- Somnolence or disorientation
- Acute severe headache
- Weakness or numbness usually on one side of the body
- Slurred speech or aphasia
- Visual or auditory changes
- Cerebral infarcts (“silent strokes”) often lead to psychometric problems and learning delays
Diagnostic Evaluation for Stroke
Transcranial Doppler ultrasound (TCD) is primarily used as a screening tool to identify children with sickle cell disease who may be at increased risk for stroke. The TCD measures the flow velocity through the cerebral arterial circulation, particularly in the internal carotid and middle cerebral arteries. An increased flow velocity (measured in cm/seconds) correlates with the presence of a narrowed vessel or segment. Flow velocities of > 200 cm/sec. are strongly associated with increased risk of stroke. These findings were the result of a large multi-center study called STOP: Stroke Prevention Trial, which examined over 2000 children with sickle cell disease. The results were published in the New England Journal of Medicine in 1998. This is the only predictive tool available to identify patients at increased risk for stroke. If two consecutive TCD studies are abnormal, the family should be offered prophylactic chronic transfusion and chelation therapy.
CAT scanning (initially without contrast) remains very important. It is readily available in most hospitals, is accurate, and can be performed rapidly when a patient presents with an acute stroke. The CT may be normal at the onset in cerebral infarction, but is helpful to rule out hemorrhage, abscess, or tumor as the causes of symptoms. The CT 2 to 7 days after an infarction may show the edematous infarcted area.
MRI/MRA studies are valuable when looking for evidence of prior vascular occlusion or infarct (“silent strokes”) and cerebral atrophy. MRI scans are performed in the axial and coronal planes. Infarcts are seen on the T2 weighted images as areas of abnormal signal. It may not be possible to distinguish between ischemia and infarction, but the size and number of lesions can be documented with precision. The lesions are classified according to the size of the areas of increased signal intensity. Angiography (MRA) is not necessary to confirm cerebral infarction demonstrated by CT or MRI, but it can be helpful in clarifying the diagnosis in a symptomatic patient with normal CT and MRI findings. Caution must be exercised in the use of hyperosmolar contrast material for angiography in patients with sickle cell disease. Adequate hydration and close monitoring are important in minimizing risks.
Click here to view the NIH suggested evaluation of neurological events in sickle cell disease.
Treatment of Acute Infarctive Stroke
Rapid evaluation and monitoring of progression of symptoms (i.e. increased intracranial pressure) are crucial. Hyperventilation therapy should be avoided. Cerebral edema should be managed pharmacologically. Mechanical ventilation may be necessary. Seizures are common and require anticonvulsant therapy. Transfusion of normal red blood cells emergently will help prevent the progression of the acute stroke. Simple transfusion (transfusing PRBC without prior or concomitant removal of the patient’s blood) is not recommended in this situation. Partial exchange transfusion or a 1-volume exchange transfusion should be used to decrease the level of Hb S to <30%.
Treatment of Hemorrhagic Stroke
Patients with intracerebral or subarachnoid hemorrhage may present with focal neuologic deficits, severe headache, increased ICP, or coma. If hemorrhage is present on initial CT or MRI, arteriography is necessary to determine if a surgically correctable lesion is present. Immediate exchange transfusion is recommended to decrease the risk of vasospasm in the area of hemorrhage which can lead to secondary cerebral edema. Hemorrhagic stroke is associated with increased mortality in the acute phase.
Treatment of Coma due to Generalized Arterial Hypoxia
This is a rare situation, but can occur in patients with sickle disorders after experiencing arterial hypoxia.
The hypoxia is usually induced by acute or chronic pulmonary disease, which impairs the capacity to exchange oxygen. It can also be induced by right-to-left shunting of blood through a patent foramen ovale due to acute pulmonary hypertension. The red cell sickling that occurs in the arterial circulation tend to lodge randomly in the terminal arterioles of the cerebral vasculature. This results in sufficient hypoxia to cause neuronal dysfunction, but usually not necrosis if the process is reversed in timely order.
The presenting symptoms may mimic embolism. There is usually a rapid, progressive, generalized neurologic deterioration without focal findings. Decorticate or even decerebrate posturing can be seen. The CT is often normal. There may be other accompanying signs of acute tissue injury from the hypoxia like renal dysfunction, acute centrilobular liver necrosis, or bone marrow necrosis. The treatment is immediate exchange transfusion, and treatment with hyperbaric oxygen for 2-3 hours at 2 atm/d. Aggressive treatment of the hypoxia with positive-end-expiratory pressure ventilation is helpful. Supportive care to other involved organs should not be overlooked. If managed promptly, the patients have the potential for complete recovery.
Correlation of Neuropsychometric Testing and MRI Findings
Data from the CSSCD stroke studies have shown that 25% of children with HbSS or HbSC disease had evidence of “silent” infarcts and cerebral atrophy. In a study of 312 children age 6-14, all 16 children with a clinical history of stroke also had abnormal MRI scans. Of the children without a history of stroke, about 10% had evidence of infarct, and 5% had evidence of atrophy.
Since the mid-1980’s studies have begun to show that some children with sickle cell disease may experience subtle neuropsychological abnormalities thought to be related to silent infarction. Most clinically apparent infarcts are in the frontal lobes. However, a majority of silent infarcts also involve the frontal lobes; 60% of infarcts are bilateral. Standard type IQ testing may not detect the type of problems encountered by children with sickle cell disease. Therefore, thorough neuropsychometric testing should include assessment of the following:
- Processing speed (this is often impaired in regards to interpretative processing rather than repetitive work)
- Memory (visual memory is more affected than verbal memory, and patterns of recall may be variable and inconsistent)
- Attention and concentration (high rates of omission errors and variable patterns in responses are seen. Periods of “spacing out” and inability to sustain attention for prolonged periods of time are common. Some impulsivity may be seen, but clinical hyperactivity is rare)
- Visual-motor integration (handwriting skills may be impaired. Essay writing and test taking may be difficult. Many find typing easier than writing)
- Mathematics (basic calculation skills can be impaired partly due to problems with memory. Application skills are less affected)
- Reading (comprehension may be good but is affected by weak decoding skills).