Abstract
BackgroundThe perinatal period carries the highest risk for stroke in childhood; however, the pathophysiology is poorly understood and preventive, prognostic, and therapeutic strategies are not available. A new pathophysiological model describes the development of neonatal arterial ischemic stroke (NAIS) as the combined result of prenatal inflammation and hypoxic–ischemic insult. Neuroinflammation and a systemic inflammatory response are also important features of NAIS. Identifying key players of the inflammatory system is in the limelight of current research.Case presentationWe present four NAIS cases, in whom detailed analysis of intracellular and plasma cytokine levels are available from the first month of life. All neonates were admitted with the initial diagnosis of hypoxic ischemic encephalopathy (HIE); however, early MRI examination revealed NAIS. Blood samples were collected between 3 and 6 h of life, at 24 h, 72 h, 1 week, and 1 month of life. Peripheral blood mononuclear cells were assessed with flow cytometry and plasma cytokine levels were measured. Pooled data from the cohort of four NAIS patients were compared to infants with HIE.At 6 and 72 h of age, the prevalence of IL10+ CD8+ lymphocytes remained lower in NAIS. At 6 h, CD8+ lymphocytes in NAIS produced more IL-17. At 72 h, CD8+ cells produced more IL-6 in severe HIE than in NAIS, but IL-6 production remained elevated in CD8 cells at 1 month in NAIS, while it decreased in HIE. At 1 week, the prevalence of TGF-β + lymphocytes prone to enter the CNS was elevated in NAIS. On the other hand, by 1 month of age, the prevalence of TGF-β + CD4+ lymphocytes decreased in NAIS compared to HIE. At 72 h, we found elevated plasma levels of IL-5, MCP-1, and IL-17 in NAIS. By 1 month, plasma levels of IL-4, IL-12, and IL-17 decreased in NAIS but remained elevated in HIE.ConclusionsDifferences in the cytokine network are present between NAIS and HIE. CD8 lymphocytes appear to shift towards the pro-inflammatory direction in NAIS. The inflammatory response appears to be more pronounced at 72 h in NAIS but decreases faster, reaching lower plasma levels of inflammatory markers at 1 month.
Highlights
The perinatal period carries the highest risk for stroke in childhood; the pathophysiology is poorly understood and preventive, prognostic, and therapeutic strategies are not available
Differences in the cytokine network are present between neonatal arterial ischemic stroke (NAIS) and hypoxic ischemic encephalopathy (HIE)
The inflammatory response appears to be more pronounced at 72 h in NAIS but decreases faster, reaching lower plasma levels of inflammatory markers at 1 month
Summary
The perinatal period carries the highest risk for stroke in childhood; the pathophysiology is poorly understood and preventive, prognostic, and therapeutic strategies are not available. By 1 month, plasma levels of IL-4, IL-12, and IL-17 decreased in NAIS but remained elevated in HIE. Diagnosis of NAIS is often delayed, due to the prenatal onset or absence of specific signs; the primary focus regarding therapeutic interventions is focused on prevention and post-insult anti-inflammatory mechanisms [3]. Another challenge regarding the diagnosis of NAIS is the fact that the risk factors and clinical signs of global hypoxic-ischemic encephalopathy (HIE) due to perinatal asphyxia show a significant overlap with NAIS and the two often co-occur [7,8,9]. Differentiating between the two syndromes is a complex question, some studies list perinatal asphyxia as an independent risk factor for NAIS [10], while neuroinflammation following ischemia appears to be a common feature of the two
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