Role of Perinatal Inflammation in Neonatal Arterial Ischemic Stroke

Abstract

Based on the review of the literature, perinatal inflammation often induced by infection is the only consistent independent risk factor of neonatal arterial ischemic stroke (NAIS). Preclinical studies show that acute inflammatory processes take place in placenta, cerebral arterial wall of NAIS-susceptible arteries and neonatal brain. A top research priority in NAIS is to further characterize the nature and spatiotemporal features of the inflammatory processes involved in multiple levels of the pathophysiology of NAIS, to adequately design randomized control trials using targeted anti-inflammatory vasculo- and neuroprotective agents.

Cytokine production pattern of T lymphocytes in neonatal arterial ischemic stroke during the first month of life—a case study

“…Only a few case-control studies have aimed to specify risk factors; however, the number of cases was relatively low and there is little consistency in the observed maternal, obstetric, and neonatal risk factors [7,13,14]. The only independent risk factor, which appeared in all case-control studies, was perinatal inflammation, while genetic prothrombotic disorders were not found to be associated with the frequency of NAIS [3].…”

“…NAIS generally occurs in term neonates and presents a major risk for life-long motor, cognitive, and/or behavioral disabilities ranging from fine motor impairments to unilateral cerebral palsy, which develops in around 20-30% of affected neonates. Thus NAIS is a leading cause of cerebral palsy [3].…”

“…The clinical presentation of NAIS is often subtle and non-specific, the most frequent symptoms being seizures, general hypotonia, lethargy, and poor feeding, making the timely diagnosis of NAIS difficult [7]. Diagnosis of NAIS is often delayed, due to the prenatal onset or absence of specific signs; therefore, 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].…”

“…In addition, there is angiographic evidence indicating a possibility of local arterial wall defects and in situ thrombus generation [9,16]. Based on these findings, Giraud et al proposed a different pathomechanism, where maternofetal inflammation induces focal arteritis specific to the intracranial arteries developing from the carotid arterial tree, which are susceptible to NAIS [3]. Using a preclinical rat model of chorioamnionitis, they were able to demonstrate that classic prothrombotic stress applied alone to the MCA was not enough to induce NAIS; however, when combined with in utero exposure to inflammation-inducing agent (LPS), the same stress leads to the classical symptoms of NAIS and motor impairment.…”

“…[5] Based on preclinical findings, a new pathophysiological hypothesis is being raised, which considers the complex and bidirectional relationship of coagulation and inflammatory pathways [17]. It describes the development of NAIS as the result of a multiple hit mechanism, originating from both perinatal inflammation and hypoxia-ischemia (HI) [3]. Giraud et al have identified three major risk factors, the combination of which could lead to NAIS: (i) materno-fetal inflammation leading to focal arteritis of arteries susceptible to NAIS, (ii) a window of susceptibility in the development of the neonatal brain, and (iii) the physiological pro-coagulatory state of the perinatal period aggravated by the inflammatory response [5].…”