Researchers at Massachusetts General Hospital have discovered a novel molecular mechanism behind the most common forms of acquired hydrocephalus – which could lead to the first non-surgical treatments for the life-threatening disease. Research in animal models uncovered a pathway through which infection or bleeding in the brain triggers inflammation, causing increased production of cerebrospinal fluid (CSF) by the choroid plexus and lead to swelling of the brain ventricles.
“Finding a nonsurgical treatment for hydrocephalus, given the fact neurosurgery is fraught with tremendous morbidity and complications, has been the holy grail for our field,” says Kristopher Kahle, MD, PhD, a paediatric neurosurgeon at MGH and senior author of the study in the journal Cell. “We’ve identified through a genome-wide analytical approach the mechanism that underlies the swelling of the ventricles which occurs after a brain bleed or brain infection in acquired hydrocephalus. We’re hopeful these findings will pave the way for approval of an anti-inflammatory drug to treat hydrocephalus, which could be a game-changer for populations in the US and around the world that don’t have access to surgery.”
Occurring in about 0.2% of births, acquired hydrocephalus is the most common cause of brain surgery in children, though it can affect people at any age. In underdeveloped regions where bacterial infection is the most prevalent form, hydrocephalus is often deadly for children due to the lack of surgical intervention. Brain surgery, where a shunt is implanted to drain fluid from the brain, is the only known treatment. But about half of all shunts in paediatric patients fail within two years of placement, according to the Hydrocephalus Association, requiring repeat neurosurgical operations and a lifetime of brain surgeries.
Pivotal to the process is the choroid plexus, the brain structure that routinely pumps cerebrospinal fluid into the four ventricles of the brain to keep the organ buoyant and injury-free within the skull. An infection or brain bleed, however, can create a dangerous neuroinflammatory response where the choroid plexus floods the ventricles with cerebral spinal fluid and immune cells from the periphery of the brain in a cytokine storm, swelling the brain ventricles.
“Scientists in the past thought that entirely different mechanisms were involved in hydrocephalus from infection and from haemorrhage in the brain,” explains co-author Bob Carter, MD, PhD, chair of the Department of Neurosurgery at MGH. “Dr Kahle’s lab found that the same pathway was involved in both types and that it can be targeted with immunomodulators like rapamycin, a drug that’s been approved by the US Food and Drug Administration for transplant patients who need to suppress their immune system to prevent organ rejection.”
MGH researchers are continuing to explore how rapamycin and other drugs which quell the inflammation seen in acquired hydrocephalus could be repurposed. “What has me most excited is that this noninvasive therapy could provide a way to help young patients who don’t have access to neurosurgeons or shunts,” says Kahle. “No longer would a diagnosis of hydrocephalus be fatal for these children.”
Source: Massachusetts General Hospital
