Melanie Cole, MS (Host): From new diagnostic tools and technology to advances in rare disease research, this is Pediatrica, a pediatric research and innovation podcast presented by clinicians and researchers at Children's Health of Orange County. I'm Melanie Cole. And today, to highlight finding new treatments for hydrocephalus is Dr. Leandro Castaneyra-Ruiz. He's the Senior Scientist Supervisor in CHOC's Hydrocephalus Research Laboratory at Children's Health of Orange County.

Leandro, thank you so much for joining us today. I'd like you to start by giving us a bit of an overview of hydrocephalus and the challenge that it presents in treatment.

Dr. Leandro Castaneyra-Ruiz: Hi. Thanks for having me here today. Hydrocephalus, as its own name indicates, hydro means water and cephalus means brain. It's an accumulation of water in the brain. This happens way more often than we may think. I don't know if you have noticed, but in some countries that don't have access to healthcare systems, you see sometimes that children are born and they have big heads. So, that happens here in the United States and everywhere way more often than we may think. It's around one to two births that is in patients with hydrocephalus.

The thing is we cannot notice it, because they are treated. And to treat them, they put a tube into the brain, a catheter that goes into the ventricles and the cavities inside the brain where the fluid is accumulated. That's why they have these big heads. So here, they put these catheters or tubing that release the flow and allows not having symptoms because otherwise they would have increased intracranial pressure and it's fatal. The result is almost always death if it's not treated.

The main challenge is that these shunt systems or these catheters, they fail in a really high rate. Around 50% of these catheters fail within two years of implant. And around 90% of them fail within 10 years. Every time that a neurosurgeon puts a catheter or shunt system in a pediatric patient, he knows that it's going to fail. The only thing is when it's going to fail. And this creates such an alarm for the patients, because they are always uncertain when is the treatment is going to fail. Suddenly, the patients, normally children, they start having headaches and they have to an emergency room and to get an emergency procedure to replace the shunt. Imagine how often this happened that around 50% of the workload of a pediatric neurosurgeon is replacement of catheters or shunt or catheter implantation.

Melanie Cole, MS: Wow, that's so interesting. And Leandro, as you said, the current standard treatments, such as the shunt systems you were mentioning, have these significant limitations, the risk of infection, blockage, and as you stated, the need for multiple surgeries. And given these challenges, what are the primary objectives of your research in finding new treatments? Why is it so important to conduct this type of research?

Dr. Leandro Castaneyra-Ruiz: This is fundamental to try to improve the life of these patients. We have a triple approach here in our lab. First of all, we need to understand why these catheters get obstructed, why these catheters fail. Normally, most of the failure happens in the catheter that is the proximal catheter, the catheter that isn't inside of the ventricles.

In this case, normally, they get obstructed because a foreign body reaction takes place. So, foreign body reaction means that something that doesn't belong to the body is in there, and our body reacts against that. And then, we have immune cells like microglial cells or astrocytes who migrate there. I'm trying to cover the catheter, and they end up obstructing the catheter.

Sometimes the obstruction takes place because of choroid plexus. The choroid plexus is a structure inside the ventricles, inside the brain, that produces CSF. Sometimes, the choroid plexus reacts to the catheter too, or get sucked into the catheter and end up obstructing the catheter. Our research tries to understand why all these mechanisms, how these mechanisms take place, and how can we prevent it.

For this purpose, we obtained an NIH grant in which we develop a bioreactor, where we can grow brain cells into that bioreactor in a 3D gel that allows the growth of neural stem cells who differentiate in ependymal cells and astrocytes, oligodendrocytes, and neurons. And we place catheters there and we circulate in our bioreactor, the artificial CSF cells or cell culture media to replicate the clinical conditions of this pathology. And we try to understand how this extraction take place, how the glial cells migrate to the proximal areas of the catheter and how it gets obstructed. Our bioreactor allows us to test different catheters, different materials, commercial catheters. And we have learned that there is some catheters that are less likely to get obstructed and that's super important for clinicians, for neurosurgeons to know. We work closely with neurosurgeons here at CHOC and we are really trying to improve the treatments.

We have a second approach. Since the problem in hydrocephalus is the catheter mostly, we are trying to get rid of the catheter. Here, a colleague, Dr. Lee, in our lab, he is also a PhD, he is developing a mechanism to treat hydrocephalus without using catheters. He used a valve system, we call it the thumb system, that tried to connect the areas of absorption of CSF that normally are obstructed. She tries to bypass this obstruction, it's called arachnoid corpuscula. In the arachnoid corpuscula, the CSF is collected, passed into the bloodstream in the sagittal sinus. So, with this thumb shunt system, you will connect the subarachnoid space with the blood and we can bypass the malfunctioning arachnoid corpuscula. This is very innovative. We got a little grant for this, and we are also applying for getting NIH grant fundings, because this could really improve treatment for hydrocephalus without having to use catheters.

And finally, we have a third approach to treat hydrocephalus, because these treatments right now are not a cure for real. It's just a way to kind of treat the symptoms that is accumulation of fluid in the brain. But we are really trying to understand the mechanisms that trigger hydrocephalus in the first place. So, here at CHOC, we are doing research with animal models in which we induce hydrocephalus. And our hypothesis is that hydrocephalus is a response of an acute inflammatory process. In many patients, when you have meningitis or an infection, when you're a child, you may develop hydrocephalus. Or in premature babies, when there is an interventricular hemorrhage or germinal matrix hemorrhage, these patients end up developing hydrocephalus.

Historically, we thought about scarring tissue, about certain obstructions in the pathway of the CSF that end up developing hydrocephalus, but our hypothesis is that it's more complex than that. It's an acute inflammatory process that takes place and allowed in this acute inflammatory process certain enzymes start cleaving cell junctions to allow the passage of immunological cells, so macrophages or lymphocytes, to allow them to go into the brain to fight against the infection or to clear the hemorrhage or any other injury problem. But in premature babies or newborn babies, the immunological response is not well-developed. So, these enzymes get activated and start cleaving cell junctions in a way that not only allow the immunological response cells to act, but also destroy certain brain structures like the ventricular zone, the ependymal cells.

So, they detach and fall. And in the ependymal cells, we have our ciliated cells that have a fundamental function in the movement of the cerebrospinal fluid. We are trying to treat these mice with inhibitors of these enzymes. And we have found that when we induce hydrocephalus in these mice, they end up not developing hydrocephalus, or if they develop it, it's in a really low degree. And even more importantly, when we use this, we try to replicate like an infection, right? We not only don't develop hydrocephalus, but when you have meningitis or this kind of infections, it can be lethal. In our mice, the ones that are not treated, around 50% of them die. However, when we treat them, only 10% or less die. So, we are after something really important here.

Melanie Cole, MS: Wow, that is absolutely fascinating. Thank you so much for telling us what the CHOC research team is doing to overcome some of those challenges associated with hydrocephalus and for elaborating on some of the promising therapeutic targets and strategies that your research has identified.

As we get ready to wrap up, Leandro, how do you envision these new treatments impacting the clinical management of hydrocephalus. Take us from bench to bedside. What are some of the next steps in your research and how can the broader scientific community contribute to these efforts?

Dr. Leandro Castaneyra-Ruiz: Basically, we have published part of the work. But basically, we need to publish it and make it public, so everyone can have access because this is a collective work, right? When the more people get involved, the better. We are trying to contribute as part and also try to spread the knowledge. Maybe other scientists will have even better ideas or better access to treatment.

And our second step is trying to do a clinical trial. We are in the process of publishing these important mechanisms. Our next step will be trying to create a clinical trial here at CHOC, where we can start selecting patients to treat them with these to see if are able to avoid developing hydrocephalus. And I think basically that is our main goal.

Melanie Cole, MS: Thank you so much for joining us today and for sharing your insights and the exciting progress in your research. We look forward to seeing the advancements in treating hydrocephalus. Thank you again. And to learn more about hydrocephalus research, please visit choc.org/research. Thank you for listening to Pediatrica, a pediatric research and innovation podcast presented by clinicians and researchers at Children's Health of Orange County. Please always remember to subscribe, rate, and review Pediatrica on Apple Podcast, Spotify, iHeart, and Pandora. I'm Melanie Cole.