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14 Articles in Volume 15, Issue #6
Antihistamine for G-CSF–Induced Bone Pain
Book Review: Advanced Headache Therapy
Brain Drain: Lymphatic Drainage System Discovered in the Brain
Case History of Chronic Migraine: Update 2015 Part 2
Disturbed Sleep: Causes and Treatments
Is Topical Ketamine Ready For Prime Time?
Letters to the Editor: Central Sensitization, Microglia Modulators, Supplements
New App Helps Interpret Urine Drug Test Results
Osteoarthritis Update: 2015
Pain Catastrophizing: What Clinicians Need to Know
PPM Editorial Board: Tips for Treating Osteoarthritis
Practical Overview of Osteoarthritis
Status Report on Role of Stimulants in Chronic Pain Management
Treatment of Osteoarthritis

Brain Drain: Lymphatic Drainage System Discovered in the Brain

August 5, 2015
Editor's Memo from July/August 2015

In a study published in Nature, a research team at the University of Virginia, Charlottesville, provides new insights into the anatomy of the brain, specifically, a lymphatic drainage system within the meninges.1

A new discovery involving human tissue is, indeed, a rare occurrence because anatomists have, over the centuries, pretty well dissected the body! This makes the discovery of lymphatic vessels in the brain a most remarkable and unexpected finding, which has significant relevance to pain management.

Until now, it was believed that the brain was the only organ in the body that did not have a classical lymphatic drainage system that transports and eliminates cellular waste products. This newly discovered meningeal lymphatic system is a novel path for cerebrospinal fluid (CSF) drainage and represents a more conventional path for immune cells and degradation products of neural activity, including neuroinflammation, to egress the central nervous system (CNS).

Through immunohistochemical techniques, the researchers demonstrate that the meningeal lymphatic system drains into the deep cervical lymph nodes, which then deliver the waste into the general peripheral circulation to exit the body by the urine, bile, and sweat routes. Prior to this finding, it was believed that CSF drained from the subarachnoid space into nasal lymphatics or did not drain at all.2

The researchers discovered that the found structures were not blood vessels, but rather lymphatic vessels that carried leukocytes (T-lymphocytes). Further imaging studies confirmed that the meningeal lymphatic vessels provided a drainage route from the CSF. “We knew that the brain drains to deep cervical lymph nodes, but we did not know how. Now we know that lymphatic vessels exist in the brain, and that they drain immune cells and macromolecules from the CSF to the draining lymph nodes,” noted Jonathan Kipnis, a coauthor of the study in an interview in Nature.3

This step may be the second step in the drainage of interstitial fluid from the brain parenchyna. The first is the recently discovered perivascular pathway known as the glymphatic system.4 The term glymphatic derives from the system’s reliance on glial cells and its resemblance to the lymphatic system.3 The glymphatic system works as a “macroscopic waste clearance system that utilizes a unique system of perivascular tunnels, formed by astroglial cells, to promote efficient elimination of soluble proteins and metabolites from the CNS.”4 Besides waste elimination, the glymphatic system also enhances the distribution of several compounds in the brain, including glucose, lipids, amino acids, growth factors, and neuromodulators.4

Relevance to Pain Management

The relevance to pain management of the discovery of glymphatic and lymphatic systems is big, if not huge. To date, the entire discussion of brain drainage and CSF flow has been missing in pain management journals, conferences, and seminars. One thing is clear; this memo is a signal to “start your engines.”

Here are some of my initial thoughts. Recently, we learned the pain that initially arises from a peripheral nervous system injury may become imprinted or “embedded” in the CNS, activate microglial cells, and produce neuroinflammation. This phenomenon is called “central sensitization,” and the resulting state is centralized pain.5-7 Phantom limb pain is the classic example. Other examples include neuropathies, including complex regional pain syndrome and diabetic neuropathies. Disorders that originate in the CNS, such as trauma, stroke, infections, and arachnoiditis, also cause significant neuroinflammation.

We now believe that these immunologic, toxic, and antigenic degradation products of painful neuroinflammation may be exiting the CNS and CSF through the newly discovered meningeal lymphatic system. This understanding gives us a scientific explanation for the peripheral, autoimmune symptoms, and syndromes we commonly see with chronic pain conditions. We now can explain to patients and families how neuroinflammatory, painful conditions in the CNS may cause chronic pain.

Now that we know that there are glymphatic and lymphatic drainage systems in the brain, are there therapeutic opportunities? Since waste products from neuroinflammation are toxic and antigenic to peripheral tissues, the question is reasonably raised as to whether increased or more rapid lymphatic drainage from the brain is necessarily a good thing. While the answer to this question is unknown, it seems clinically prudent to simultaneously increase peripheral clearance with exercise and movement at the same time measures may be executed to increase CNS drainage. In my own work, I have found neuroinflammatory biomarkers in the serum to be distressingly high in centralized pain patients. I now know why I am able to find these markers in serum. They simply drain out of the CNS through the meningeal lymphatic system.

Here is my new dogma—rapid drainage begets rapid healing. For example, all pain practitioners know that those patients who walk, swim, and exercise do better. Movement and physical activity undoubtedly accelerates lymphatic brain drainage, which would explain why Dr. Janet Travell’s rocking chair therapy did President John F. Kennedy some good. Rocking likely accelerates CNS lymphatic drainage.

Sleep: The Brain’s Housekeeper

As clinicians, we have to ask if there is a treatment that may enhance the sweeping out of toxin through the newly discovered lymphatic drainage system. The most obvious question is how can we control neuroinflammation and decrease antigenic and toxic byproducts, which we now know are egressing the CNS and entering the peripheral circulation to set up autoimmune reactions that damage peripheral tissue.

In researching for this memo, I came across a dynamite, but obscure, study showing that a major function of sleep, if not its most critical function, is to clear toxic substances from the brain’s interstitial spaces and CSF fluid.8 The authors found that “natural sleep or anesthesia are associated with a 60% increase in the interstitial space, resulting in a striking increase in convective exchange of cerebrospinal fluid with interstitial fluid. In turn, convective fluxes of interstitial fluid increased the rate of beta-amyloid clearance during sleep. Thus, the restorative function of sleep may be a consequence of the enhanced removal of potentially neurotoxic waste products that accumulate in the awake central nervous system.”8

As noted above, drainage from brain tissue into the CSF occurs through a microchannel system now called the glymphatic system. Since sleep promotes glymphatic drainage, you can bet that I will be more aggressive in promoting good sleep hygiene practices and, when necessary, prescribing sleep medication for pain patients. A most interesting finding from the study was that mice given a cocktail of adrenergic receptor antagonists (prazosin [Minipress, others], atipamezole [Antisedan], and propranolol [Inderal, others]) increased drainage of cellular waste products from brain parenchyma.8 Anyone prescribed an adrenergic receptor antagonist to pain patients lately? Is this why propranolol may prevent migraines?

Drainage of toxic waste from body tissue is as old as medicine itself. We drain abscesses, bladders, and blood. In pain management, we now know to “drain the brain.”

Last updated on: September 14, 2015
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