This patient, with symptoms of gastroenteritis, SCD-related pain, and no clinical evidence of neurologic injury, had a markedly elevated GFAP prior to developing clinical evidence of stroke. This initial elevation was followed by a peak GFAP at the time of clinical stroke diagnosis and a decline to normal levels 4 weeks later after 2 red cell exchanges. Elevated GFAP prior to the onset of overt stroke may arise from several causes. There was evidence of prior silent cerebral infarcts on the initial MRI, and elevated GFAP prior to overt stroke may represent elevation from a prior ischemic event. Another possibility is that in the evolution of stroke in SCD, GFAP is an early indicator of brain injury.
The pattern of GFAP levels peaking at the time of stroke and decreasing exponentially immediately after suggests that GFAP tracked the evolution and resolution of stroke. The acute decline in GFAP after red cell exchange may be attributed to treatment efficacy, plasma dilution, a decreased release of GFAP into circulation, or enhanced clearance via renal or proteolytic pathways. Certainly, red cell exchange must dilute plasma GFAP concentrations to some degree because manual red cell exchanges remove whole blood; however, the red cell exchanges reduced GFAP by a disproportionately low amount. The first red cell exchange reduced HbS by 63% and GFAP by 42%, and the second exchange reduced HbS by 46% and GFAP by 13%. Thus, the change in GFAP cannot be entirely explained by plasma dilution. It is likely that an ongoing release of GFAP into the circulation mitigates the dilutive effect of red cell exchange. The elevation of plasma GFAP after effective transfusion and before surgery is more difficult to interpret but is highly suggestive of continuing or recurrent subclinical brain injury.
Despite the reduction in GFAP after the stroke in this child, GFAP became elevated again and remained elevated for a year after his stroke. Chronic elevation of a brain-specific protein may reflect chronic ischemic injury, even though this child had stable disease on serial brain MRIs. Indeed, the presence of moyamoya implies chronic ischemia, even if the regions of infarct on MRI are stable. Thus, elevated GFAP may be a more sensitive marker of subtle brain injury than MRI alone under select circumstances.
GFAP expression is highly restricted to the brain [11
], and several studies have taken advantage of this fact to use GFAP as a biomarker of brain injury in other high risk settings, including traumatic brain injury [12
], hypoxic ischemic encephalopathy [13
], sepsis [14
], and brain tumor diagnosis [15
]. What is clear from these studies is that GFAP is highly specific for diagnosing brain injury and, therefore, a good measure for ruling in brain injury. Thus, the observation of elevated levels of GFAP that correlate with clinical findings of overt stroke and brain imaging in this patient make it likely that the GFAP levels reflect brain injury.
The elevation of plasma GFAP in this HbSS patient before the diagnosis of overt stroke raises the possibility that GFAP can detect subclinical brain injury and could be used as a screening test in ill patients with SCD as approximately 19% of strokes in pediatric SCD patients are associated with antecedent conditions [16
]. Transcranial Doppler has been an effective tool for identifying children at risk of stroke, and initiating transfusion therapy in these children leads to a profound reduction in stroke risk [17
]. Studies to test whether a blood biomarker can predict stroke risk would be a useful adjunct to current screening because blood is easy to obtain frequently, especially during times of increased risk for stroke. Patients identified at a higher risk could be triaged to brain MRI evaluation or close clinical follow-up.
Brain injury biomarkers could also be used potentially to track treatment efficacy. There is evidence in this report that exchange transfusion is associated with a decrease in GFAP. There are too few GFAP measurements after pial synangiosis to make reasonable conclusions about how well GFAP may track the benefits of this procedure, although the GFAP decreased after the surgery. Future studies to correlate posttreatment GFAP levels with neurologic and neurovascular outcomes could yield important prognostic information. Evaluation of GFAP and other potential biomarkers of brain injury in SCD are worthy of further study.