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Published on: November 20, 2015
Modeling Posthemorrhagic Hydrocephalus of Prematurity in Rats
Shenandoah Robinson1, Timothy Heck2, Riddhi Patel2
1Division of Pediatric Neurosurgery, Department of Neurosurgery, Johns Hopkins University School of Medicine; Department of Neurology, Johns Hopkins University School of Medicine; Division of Neonatal-Perinatal Medicine, Johns Hopkins University School of Medicine; Neurosciences Intensive Care Nursery, Johns Hopkins Children's Center; Kennedy Krieger Institute; Srobin81@jhmi.edu.
Insights
Researchers developed a rat model for posthemorrhagic hydrocephalus of prematurity (PHHP), a condition affecting preterm infants. This model mimics key features of PHHP, aiding in the study of treatments for this serious brain condition.
Area of Science:
- Neuroscience
- Developmental Biology
- Pediatric Medicine
Background:
- Posthemorrhagic hydrocephalus of prematurity (PHHP) is a severe complication in preterm infants (<32 weeks gestational age) following intraventricular hemorrhage (IVH).
- PHHP involves cerebrospinal fluid (CSF) accumulation, elevated intracranial pressure (ICP), and often lifelong shunt dependence, with high rates of reoperation.
- Systemic inflammation, suggested by chorioamnionitis and neonatal sepsis, appears integral to PHHP pathophysiology.
Purpose of the Study:
- To establish a preclinical rat model that accurately recapitulates the clinical and pathological features of PHHP.
- To provide a platform for investigating the pathophysiology of PHHP and evaluating potential therapeutic interventions.
Main Methods:
- Induction of PHHP in rats by combining in utero chorioamnionitis with postnatal intraventricular hemorrhage using lysed red blood cells.
- Assessment of hydrocephalus using magnetic resonance imaging (MRI) and microscopy to detect macrocephaly, domed craniums, elevated ICP, and ventriculomegaly.
- Evaluation of long-term functional outcomes, including cognitive delay and functional disability in adult rats.
Main Results:
- The established rat model demonstrated progressive macrocephaly, elevated ICP, and ventriculomegaly, mirroring human PHHP.
- The model exhibited sustained disruption of CSF dynamics and resulted in cognitive and functional deficits into adulthood.
- The model allows for comprehensive analysis of choroid plexus, ependymal cilia, and glymphatic system function.
Conclusions:
- This novel preclinical model effectively replicates key aspects of PHHP in rats, offering a valuable tool for translational research.
- The model supports investigation into the molecular, cellular, and functional mechanisms underlying PHHP.
- It serves as a platform for testing novel surgical and non-surgical therapeutic strategies for hydrocephalus treatment.
Abstract:
Posthemorrhagic hydrocephalus of prematurity (PHHP) is a serious sequela of severe intraventricular hemorrhage (IVH) in very preterm infants less than 32 weeks gestational age (GA). PHHP is defined by the accumulation of cerebrospinal fluid (CSF) associated with clinical symptoms of elevated intracranial pressure (ICP). Infants with PHHP suffer lifelong shunt dependence, with half requiring repeat surgery in the first year of life and many requiring multiple additional surgeries throughout the lifespan. Prenatal chorioamnionitis predisposes preterm infants to severe IVH and the need for surgical treatment of PHHP trends with neonatal sepsis. These clinical features suggest that systemic inflammation is an integral component of PHHP pathophysiology. Here, we define an animal model that recapitulates all clinical aspects and essential features of PHHP in rats. The goal of this protocol is to illustrate how in utero chorioamnionitis and postnatal IVH using lysed red blood cells can be combined to yield PHHP. This preclinical approach yields progressive macrocephaly and domed craniums, elevated intracranial pressure, and ventriculomegaly that can be detected via magnetic resonance imaging (MRI) or via microscopy. In addition to sustained disruption in CSF dynamics, rats also have cognitive delay and functional disability into adulthood. Accordingly, this preclinical platform facilitates unique and unparalleled translational studies of PHHP that can incorporate molecular, cellular, biochemical, histologic, imaging, and functional outcome measures. It can also be used for rigorous analysis of the choroid plexus, ependymal motile cilia, and glymphatic system in parallel. Last, it can also be an invaluable preclinical tool for the investigation of novel surgical intervention strategies and non-surgical therapeutic approaches for the treatment of hydrocephalus.
