Mechanisms and Nonsurgical Treatment of Acquired Symptomatic Hydrocephalus
Abstract
Hydrocephalus, or “water on the brain,” describes the accumulation of cerebrospinal fluid (CSF) within the brain. Hydrocephalus can arise from many different causes and affects people across the lifespan from newborns to older adults. The most common cause of hydrocephalus that affects military Service members and Veterans is post-traumatic hydrocephalus, which typically arises a few weeks after moderate to severe traumatic brain injury. If too much CSF collects on the brain, then a person can develop symptoms from the increased pressure in the head, and even die without timely intervention. Currently, the only effective intervention for symptomatic hydrocephalus is surgical treatment. The most common form of surgical treatment is a CSF shunt to divert the excess CSF from the brain to another body cavity for absorption, such as the peritoneal cavity in the abdomen that surrounds the abdominal organs. After insertion, shunts are prone to malfunction or infection at any time over the lifespan, and additional surgery called a shunt revision is often required. Thus, an individual with a shunt must live reasonably close to a hospital with neurosurgical care at all times. Additionally, the person is always at risk for the family and job disruption caused by shunt problems and the medical comorbidities associated with urgent surgeries and prolonged hospitalizations. Thousands of people in the USA live with CSF shunts, and the need for an effective, non-surgical treatment cannot be over-emphasized. For this proposal, we have combined what we have learned from critical analyses of clinical practice with recent advances in neuroscience to develop a novel hypothesis and treatment strategy. We noticed premature babies with brain hemorrhages were at high risk of developing hydrocephalus that required surgical intervention. Surprisingly, we observed that the need for surgical treatment followed the same trend as systemic illness from infection, rather than brain bleeds. This observation implicates systemic inflammation as an important predisposing factor for the development of hydrocephalus after a brain bleed. Very preterm birth in the USA is often triggered by intrauterine infection. We made a new preclinical model that combines prenatal intrauterine infection with early postnatal brain bleeds, similar to what we observe in premature babies, and found that the animals develop progressively enlarged heads and brain ventricles, similar to babies with symptomatic hydrocephalus. We also found we could prevent hydrocephalus from developing by early and sustained treatment with high doses of naturally occurring hormones that are known to safely enhance brain repair, erythropoietin and melatonin. In addition to preventing the hydrocephalus with a non-surgical cocktail of medications, we also observed improvement in the diffuse brain damage that often accompanies hydrocephalus on neurological exam, and with sophisticated brain imaging. Here, we propose to take what we have learned about hydrocephalus in the developing brain and apply it to the adult brain, the age of our military Service members most at risk for traumatic brain injury, and subsequent hydrocephalus. Using the foundation from our model in the developing brain, we will compare how hydrocephalus precipitated by brain bleeds in the mature brain differs from the developing brain. In the mature brain, we will also investigate how hydrocephalus caused by a brain bleed differs from hydrocephalus due to traumatic brain injury, the most common cause of hydrocephalus for active military Service members. We will explore in much more detail how erythropoietin plus melatonin are able to effect repair of the processes that lead to CSF accumulation, and prevent or treat hydrocephalus. While these agents may work in selected patients, just like other areas of medicine where stronger treatments are needed in a few selected patients, specific individuals may need a more po
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810166
Entities
People
- Shenandoah Robinson
Organizations
- Johns Hopkins University
- United States Army