Doctors practicing today have been taught that there are no lymphatic vessels inside the skull. Those deep-purple vessels were seen for the first time in images published this week by researchers at the U.S. National Institute of Neurological Disorders and Stroke.In the rest of the body, the lymphatic system collects and drains the fluid that bathes our cells, in the process exporting their waste. It also serves as a conduit for immune cells, which go out into the body looking for adversaries and learning how to distinguish self from other, and then travel back to lymph nodes and organs through lymphatic vessels.
So how was it even conceivable that this process wasn’t happening in our brains?Lead researcher Daniel Reich trained as both a neurologist and radiologist, and his expertise is in inflammatory brain disease. The connection between the immune system and the brain is at the core of what he says he spends most of his time thinking about: multiple sclerosis. The immune system appears to modulate or even underlie many neurologic diseases, and the cells of the central nervous system produce waste that needs to be washed away just like other metabolically active cells. This discovery should make it possible to study how the brain does that, how it circulates white blood cells, and how these processes may go awry in diseases or play a role in aging.Reich started his search in 2015, after a major study in Nature reported a similar conduit for lymph in mice. The University of Virginia team wrote at the time, “The discovery of the central-nervous-system lymphatic system may call for a reassessment of basic assumptions in neuroimmunology.” The study was regarded as a potential breakthrough in understanding how neurodegenerative disease is associated with the immune system.
Around the same time, researchers discovered fluid in the brains of mice and humans that would become known as the “glymphatic system.” It was described by a team at the University of Rochester in 2015 as not just the brain’s “waste-clearance system,” but as potentially being involved in fueling the brain by transporting glucose, lipids, amino acids, and neurotransmitters. It remained unclear how the fluid communicated with the rest of the body. Reich reasoned that since this fluid exists in human brains, and the conduits exist in mice brains, the conduits likely exist in humans, too.After two years of work and inordinately complex physics calculations, Reich’s team found the vessels. When Reich started telling colleagues what his team found, he got two reactions: “No way, it’s not true,” and “Yeah, we’ve known that.”There are occasional references to the idea of a lymphatic system in the brain in historic literature. Two centuries ago, the anatomist Paolo Mascagni made full-body models of the lymphatic system that included the brain, though this was dismissed as an error. A historical account in The Lancet in 2003 read: “Mascagni was probably so impressed with the lymphatic system that he saw lymph vessels even where they did not exist—in the brain.”
No one had published definitive evidence of lymph vessels in any brain until the Virginia mouse study and a concordant Helsinki one in 2015. “You could say that was the discovery,” Reich said. “Did Newton discover gravity? I mean—not to equate these two discoveries—but obviously people knew that things fell before Newton’s apple.”
His team’s discovery, though, not only shows that the vessels exist in people, but just how elaborate the system is.
Daniel Reich / National Institute of Neurological Disorders and Stroke
Wouldn’t neurosurgeons, at some point in their meticulous down-to-the-millimeter dissecting of brains, have stopped and said, “Hey … what’s this thing?”
The lymph vessels probably escaped detection because they’re inside a thick membrane, the dura mater, which is the consistency of leather. They run alongside blood vessels that are much larger, and on MRI the signal that creates the images is dominated by the blood vessels.Reich adds the other obvious but important factor: “And, I mean, no one was looking for them.”The assumption was never that the brain doesn’t drain waste. The major pathway taught in medical school is that waste around cells goes into cerebrospinal fluid—the clear fluid that bathes the brain and spinal cord—and from there gets absorbed directly into the blood through structures called arachnoid granulations. Reich also explained that some fluid is understood to drain through tiny pores in our skulls, mostly at the top of our noses, and then get absorbed into the lymphatic system through the mucous membranes of the nose, and then, from there, go down into the lymph nodes of the neck.
It now seems clear that there is a third pathway through which byproducts get out of the brain—and it may be the most important—through these specialized vessels in the dura mater.
“Looking back, those other two really seem insufficient,” said Reich.
It remains a mystery exactly how that lymph fluid gets into these vessels. There are a lot of open questions that show how far we are from fully understanding many neurologic disorders—or even basic day-to-day functioning of the nervous system.
But this pathway appears crucial to life and health. A 2013 study in Science found that glymphatic flow seems to increase by almost double during sleep (in mice). Sleep disturbances are a common feature in Alzheimer’s and other neurologic disorders, and it’s possible that inadequate clearing of the brain’s waste products is related to exacerbating or even causing the disease. In a 2016 study, also in mice, glymphatic dysfunction appeared to cause accumulation of Alzheimer-related amyloid proteins.The flow of glymphatic fluid can change based on a person’s intake of omega-3 fatty acids, a study showed earlier this year. Preliminary findings like these together suggest a pathway through which nutrition and sleep can be related to neurologic disorders. Optimizing this glymphatic flow could become a central theme for the future of neurologic health.“If all of this is true, there probably is a connection between these two systems, glymphatic and lymphatic,” Reich said. “And that would be one of the major functions of cerebrospinal fluid.”
This is all interesting to scientists and anatomy enthusiasts—both in terms of highlighting the potential for future work and highlighting how little we really know about what happens inside our skulls. But beyond the academic, what does it mean for the millions of people with neurologic diseases that are linked to the immune system?
Reich wants to be careful not to overpromise on what this all means, because he spends a lot of his time fielding questions from people with MS who are desparate for a breakthrough.
“The study shows that these vessels exist. We haven’t shown that they’re involved in any disease process,” he said in the careful hedge-based language of a scientist, “but it’s reasonable to think that they might be.”