Having survived medical school anatomy and seemingly learned every part of the body down to the minutest detail, I was surprised to learn of the discovery of a lymphatic system in the brain, challenging long-held dogma that the brain does not experience classical lymphatic drainage.
While this is inherently fascinating as it demonstrates that there are still important anatomical discoveries to be made, it is even more profound in its potential to alter our understanding and treatment of neurologic disease.
Originating in the eyes, climbing up above the olfactory bulb, and then running along the sinuses, this lymphatic network is less complex with less branching than lymphatics in peripheral tissues, likely due to the high pressure of cerebrospinal fluid (CSF). These vessels carry leukocytes to draining lymph nodes and are responsible for transport of cellular and soluble constituents of CSF to deep cervical lymph nodes.
This discovery follows closely on the heels of another drainage system known as the glymphatic system which drains interstitial fluid from the brain parenchyma into the cerebrospinal fluid. If these newly discovered meningeal lymphatics drain the CSF, this creates a 2-step pathway from parenchyma to periphery, as noted by the researchers in the conclusion of their study.
With two different systems at play controlling protein egress and moderating immunologic function, there are multiple opportunities for things to go wrong. When meningeal lymphatics are ligated, CSF and T cells no longer drain to deep cervical lymph nodes. Abnormal glymphatic function has been implicated in the pathology of traumatic brain injury, stroke, and a variety of neurodegenerative disorders.
Think about the underlying pathology of neurologic diseases and you can begin to imagine the ramifications of these discoveries. In Alzheimer's disease, accumulation of amyloid-β leads to plaque formation leading to synaptotoxicity and neurotoxicity. Build-up of this soluble peptide and its subsequent formation into toxic oligomers could result from failure of glymphatic drainage of amyloid-β from the parenchyma or failure of meningeal lymphatics to drain the peptide from the CSF.
This could originate from an inherited inability to effectively clear these peptides or an acquired inability that is caused by damage to these systems from another process earlier in the disease, perhaps even years prior to plaque formation. Targeting the deficient genes or stopping the damage from occurring could effectively treat Alzheimer's years before a single plaque had formed.
Multiple sclerosis (MS) is an immune-mediated inflammatory disorder of the central nervous system characterized by demyelination, axonal loss, and gliosis. Cellular and soluble mediators of the immune system, including T cells, B cells, macrophages, microglia, cytokines, antibodies, and others, infiltrate the inflammatory lesions and resolution of the inflammation corresponds with clinical improvement.
Treatment of MS has primarily targeted immune suppression; however, this new knowledge of a pathway for immune system mediators to reach the brain from the periphery and vice versa may allow for other treatment strategies that target this pathway. Given the intrinsic risks of immunosuppressive therapies, the opportunity to potentially approach the disease in a completely different manner is extremely exciting.
These discoveries may also aid in diagnosing a range of conditions. Biomarkers of neurologic disease make their way from the parenchyma to the periphery, but to date it has been difficult to discern how they may be utilized in diagnosis, monitoring treatment response, and tracking recovery as their concentrations in the periphery fluctuate.
Understanding the pathway by which these substances make it from the parenchyma to the periphery allows researchers the opportunity to monitor them as they are drained from parenchyma to CSF and then CSF to peripheral lymphatics. Hopefully this will improve diagnosis and monitoring of conditions like traumatic brain injury and Alzheimer's disease.
The key to effective treatment and diagnosis of neurologic disease may be in understanding the connections between the brain and the rest of the body. The discovery of the brain's lymphatic system will hopefully propel this understanding and offer promise for millions of patients suffering from neurologic disease.
Joshua Cohen, MD, MPH, is a neurologist at the Headache Institute at the Icahn School of Medicine at Mount Sinai in New York City.