g-Lymphatic System
There is increasing insight into the role of the production and absorption of CSF and interstitial fluids into the lymphatic system. This in part attributed to the developmental understanding of the g-lymphatic (glial-lymphatic) system. More interesting from an osteopaths perspective is the interplay of this system with other physiological systems and biomechanics.
Traditionally the cranium has been viewed as a rigid box, unyielding, and enclosing the brain and all its fluids. When studied in relation to the body’s physiology, the movement of these fluids is at least partially dependent upon the systemic functioning of the body.
This is true of fluid movement all over the body. However from a mechanical perspective the fluids in the head and brain are placed under unique circumstances as they are encased in the relatively unyielding cranium. Because the casing of the head doesn’t move much if a lot of fluid was to flow into and out of the head in an uncoordinated manner intracranial pressure would dangerously rise and drop. If the skull lacked any compliance to accommodate these fluctuations in pressure from the ebb and flow of fluid into and out of the cranium there could be the potential of physiological discord. For this reason a degree of cranial compliance (Seimetz et al 2012) is essential to help maintain a controlled fluctuation of intracranial pressure. This is the basis of the Monro-Kellie hypothesis.
Brief introduction to the g-lymphatic system
The g-lymphatic system is discussed in more detail under 'g-lymphatic system'. This is a brief introduction to the concepts of this system. Essentially the g-lymphatic system delivers CSF into the brain where it mixes with the interstitial fluid (ISF). This mix of CSF-ISF then returns to and gets drained away by the lymphatic system.
CSF gets pumped along arterial perivascular pathways into the brain parenchyma.
This creates a mix of ISF-CSF in the brain parenchyma that gets drained away along venous perivascular pathways.
The ISF-CSF mix then gets emptied into the subarachnoid space. From here it gets drains into the lymphatic vessels of (i) perineural spaces of the cranial nerves and (ii) the lymphatics of the dural venous sinuses (superior sagittal sinus, transverse sinus & sigmoid sinus), diploic veins (Tsutsumi et al 2014) and middle meningeal artery.
These lymphatic vessels in turn drain into the deep cervical lymphatic vessels and nodes.
Production, movement and drainage of the CSF - EXCLUDING the g-lymphatic system
Production of CSF
Traditionally the CSF is thought to be solely produced from the choroid plexus in the ventricles of the brain.
Miyajima and Arai (2015) reviewed the literature on CSF being produced by the capillaries in the CNS. It seems to be a concept that has kept reoccurring over the last 100 years and has been widely reported in other mammals. Bulat & Klarica (2011) attributed the mechanism of the capillaries in producing CSF to the filtering out of water across the walls of arterial capillaries. This process sieves out the plasma osmolytes. Whilst this is typically a mechanism of producing ISF Yiming et al (2017) found 20% of all CSF originates from the brain's ISF.
The intimate relationship of the ISF and CSF is discussed further in the g-lymphatic system.
Movement of CSF from the ventricles --> subarachnoid spaces
The CSF moves through the ventricles ending in the fourth ventricle. At the fourth ventricle the CSF passes through three small foramina into the subarachnoid spaces. These foramina are the two lateral apertures (of Luschka) and one median aperture (of Magendie). The subarachnoid space is formed between the outer arachnoid mater and inner pia mater.
As well as exiting the fourth ventricle via its apertures CSF also exits the ventricles by the parenchymal (cerebral) capillaries. These capillaries directly absorbs CSF from the ventricular walls into the brain parenchyma (Miyajima & Arai 2015).
In the spinal canal the capillaries absorbs CSF into the subarachnoid space. Arachnoid granulations have been shown to exist in the spinal subarachnoid space (Miyajima & Arai 2015).
Movement of CSF from the subarachnoid spaces --> veins & lymphatics
The CSF moves through the subarachnoid spaces accumulating in the subarachnoid cisterns. These cisterns are dilations of the subarachnoid space where the arachnoid mater and pia mater are not in close approximation. These cisterns are all interconnected and transmit cranial nerves and intracranial vessels.
Flanagan (2015) found the cisterns strategically located to provide extra protection and buoyancy for the brain, especially the brainstem due to its location above the base of the skull and foramen magnum.
For example:
The lower cisterns e.g. cisterna magna, premedullary, and prepontine cisterns, help to prevent the cerebellum from sinking into the foramen magnum. This prevents cerebellar tonsillar ectopia similar to Chiari malformations.
Cisterna magna may function as a shock absorber against the pulsatile CSF pressure waves emanating from within the brain. These pressure waves are determined by fluctuating CSF volume and pressure in the cranial vault. This loss of buffering capacity of the cisterna magna can shift pressure to the central canal. This increase in pulsatility in the central canal could lead to a syrinx formation.
Increase in CSF volume in the cisterns compromises their compliance and reduces their shock absorbing function. This may cause potentially destructive increases in not only CSF but also arterial pulsatility and pressure waves surrounding the brainstem. This can cause or contribute to atrophy of the brainstem.
A similar action can be attributed to the veins in the subarachnoid space. A loss of compliance in the veins decreases their buffering capacity. Consequently, high pulsatile arterial pressure waves can be transmitted from the subarachnoid space to the delicate tissues of the brain parenchyma, as well as the walls of the ventricles.
Movement of CSF from the subarachnoid spaces --> dural venous sinus
Projections from the arachnoid mater, the arachnoid villi, protrude into the dura mater and dural venous sinuses (as well as the diploic veins, Tsutsumi et al 2014). This allows absorption of the CSF into the dural venous sinuses (superior sagittal sinus, transverse sinus & sigmoid sinus) and possibly their lymphatic vessels (refer movement of CSF from the subarachnoid space --> lymphatics).
Movement of CSF from the subarachnoid spaces --> lymphatics
1. Lymphatics in the perineural space
As the cranial nerves cross the subarachnoid space the lymphatics in the perineural spaces drain the CSF into the nasal mucosa and deep lymph nodes in the neck.
2. Dural lymphatics (refer movement of the CSF from the subarachnoid spaces --> dural venous sinuses)
The arachnoid villi projects into the dura mater and the dural venous sinuses as well as the diploic veins. This not only allows absorption of the CSF into the venous sinuses (superior sagittal sinus, transverse sinus & sigmoid sinus) but also possibly their lymphatic vessels (Simon & Iliff 2016).
Tsutsumi et al (2019) found a vein between the olfactory fossa and nasal vestibule. This vein drained into the lower limit of the superior sagittal sinus. They proposed this maybe an extracranial route of cerebrospinal fluid drainage.
The lymphatic system in absorbing CSF
The main drainage route of CSF is into the lymphatic circulation. Some CSF can be drained from the Arachnoid Villi and granulations into the walls of the venous sinus and diploe veins (Lachkar et al 2019). However Miyajima and Arai (2015) attributed absorption of CSF into the venous sinuses as a secondary pathway when there is an increased CSF hydrostatic pressure.
These authors concluded this as the arachnoid villi do not exist prenatally in humans but occur postpartum, increasing in number with age. In some mammals it is estimated that at least 50% of CSF drains into the lymphatics but the proportion in humans is still unknown. These lymphatic pathways include:
1. Nasal lymphatics: via the cribriform plate of the ethmoid, channels connect the subarachnoid space with lymphatic vessels in the nasal mucosa (Engelhardt 2016). Engelhardt et al (2016) found in the mouse lymphatic drainage along the sagittal sinus continued through the cribiform plate into the nasal mucosa. In human studies Visanji et al (2017) found dural lymphatics in the sagittal sinus.
2. Dural lymphatics: Benveniste et al (2019) described lymphatic vesels along the venous sinuses (e.g. superior sagittal sinus, transverse sinus, sigmoid sinus) and middle meningeal artery. CSF runs in the subarachnoid spaces. Dilations in this space (subarachnoid cisterns) are filled with CSF. The subarachnoid cisterns directly associated with the dural sinuses, for example quadrigeminal cistern with the great cerebral vein, could give access to sinus-associated lymphatic vessels (Simon & Iliff 2016).
3. Lymphatic vessels around the perineural spaces of the cranial nerves I, II, V, VIII (acoustic), X, XII (Koh et al 2005). The cranial nerves are bathed in CSF as they pass through the subarachnoid space and subarachnoid cisterns. The olfactory nerve (CNI) exits the skull via the cribriform plate into the nasal mucosa draining into the deep cervical lymph nodes. Although the eye doesn’t contain any lymphatics Hasuo and colleagues proposed CSF drainage from the subarachnoid space of the optic nerve through arachnoid granulations into the orbital connective tissue from which lymphatics were believed to transfer the fluid to the cervical lymph nodes.
4. Engelhardt et al (2016) identified lymphatic drainage along spinal nerve roots.
g-lymphatic system
The g-lymphatic system both integrates and adds a new component to this model. It comes into play after the CSF has left the ventricles to enter the subarachnoid spaces:
Movement of the CSF from the subarachnoid spaces --> periarterial spaces
Benveniste et al (2019) identified CSF being driven from the subarachnoid space to the periarterial spaces. This was driven from pressure gradients derived from arterial pulsations (bulk flow).
Movement of CSF from the periarterial spaces --> interstitial fluid spaces
CSF is propelled from the periarterial compartments into the interstitial fluid spaces. The interstitial spaces is the space between the neural cells and capillaries and is filled with interstitial fluid. This fluid facilitates communication between the nerves in the brain.
This movement of CSF from the periarterial spaces to the interstitial fluid spaces is facilitated by aquaporin 4 (AQP4). These are water channels on the perivascular endfeet of astrocytes (glial cells) (O'Donnell et al 2015). Brinker et al (2014) found AQP4 allowed for a continuous to and fro flow of bi-directional fluid exchange.
In the interstitial fluid spaces the CSF and ISF mix
Movement of CSF-ISF mix from the interstitial fluid spaces --> perivenous spaces
CSF-ISF fluid mixed with interstitial waste solutes is subsequently transported towards the perivenous spaces of the larger central veins.
Movement of CSF-ISF from the perivenous spaces --> subarachnoid spaces:
Once transported along the perivenous spaces the CSF-ISF mix drains into the subarachnoid spaces (and cisterns).
This creates a continuous space from the brain parenchyma along the perivascular pathways to the subarachnoid spaces.
Movement of CSF-ISF from the subarachnoid spaces --> lymphatics
Once in the subarachnoid space the CSF-ISF mix drains into the lymphatic circulation as identified previously. However there is another potential route of spread into the lymphatics of the dural sinuses.
Simon & Iliff (2015) found the drainage of interstitial solutes along perivenous routes conceivably provides direct access to the most distal segments of these sinus-associated lymphatic structures. For example, the internal cerebral veins merge to form the Great Vein of Galen, which in turn joins the inferior sagittal sinus to form the straight sinus. Therefore could the perivenous flow through the internal cerebral vein eventually give access to the lymphatic vessels of the inferior sagittal and straight sinus?
Factors influencing movement in the g-lymphatic system
Lee et al (2015) experimented on rats and mice to identify different influences that affect movement of the g-lymphatic system. Some of the mechanical influences may differ for humans due to the dimensional differences. These authors found the movement of the g-lymphatic system to be dependent upon:
Sleep. During sleep the brain's interstitial space volume expands by 60% (Xie etal 2013). This expansion lowers the overall resistance to periarterial inflow of CSF into the brain parenchyma. In turn this increases CSF-ISF exchange and drainage along perivenous spaces and ultimately the lymphatic vessels.
Body position. The most effective positions for encouraging the g-lymphatic system is firstly lying in a right lateral position, then supine and lastly prone.
This could give an evolutionary explanation as to why the most popular sleep posture is in a lateral position as it optimises waste removal during sleep.
Arterial pulsatility. Arterial pulsatility drives g-lymphatic influx. Greitz et al (1992) found an influx of arterial blood leads to an outflow of CSF.
Movement of the brain. In systole the arteries expand. This expansion creates a piston like effect squashing the CSF out of the brain and into the spinal cord (Greitz et al 1992). This venting of CSF into the spinal cord during systole may explain the funnel-shaped movement of the brain as if it were being pulled down by the spinal cord (Greitz et al 1992).
Forced inspiration. Forced inspiration leads to an increase venous flow out of the head and an increase CSF flow into the head. This upward movement of CSF on inspiration was noted from the middle thoracic spine all the way up to aqueduct in the ventricular system (Kulaczewski et al 2017).
Increased intracranial pressure decreases CSF production (Miyajima and Arai 2015).
Body position (CSF influx): there is a reduced CSF influx into the brain in the prone position. But conversely an increase influx into the spinal cord.
Body position (CSF efflux): Lee et al (2015) tested the effect of body position on CSF efflux pathways of CNVIII (auditory nerve–cochlea complex), CNX (point of exit of the vagus), superior sagittal sinus and the periarterial space along the internal carotid arteries.
The vagus nerve is the most prominent CSF efflux pathway compared with the other routes.
The only route affected by body position was along the internal carotid artery. Here efflux was more pronounced in rats when in a prone position compared with a right lateral position.
Reciprocal movement of CSF into the brain and spinal cord
There seems to be a reciprocal relationship with CSF flow into the brain and spinal cord. This reciprocal relationship seems to be dependent on body posture, arterial pulsations and respiration.
Body posture
Lee et al (2015) found being in the prone position reduces influx of CSF into the head, slows the influx of CSF in the g-lymphatic system and increases an efflux of CSF along the internal carotid artery pathway. In contrast being prone increases CSF flow to the spinal cord.
Arterial pulsations
In systole the arteries expand. Greitz et al (1992) found this expansion created a piston like effect squashing the CSF out of the brain and into the spinal cord. These authors attributed this venting of CSF into the spinal cord to creating the funnel-shaped movement of the brain as if it were being pulled down by the spinal cord.
Respiration
Forced inspiration leads to an increase venous flow out of the head and an increase CSF flow into the head. This upward movement of CSF on inspiration was noted from the middle thoracic spine all the way up to aqueduct in the ventricular system (Kulaczewski et al 2017).
Neurological and physiological influences on g-lymphatic transport
Lee et al (2015) asked why does g-lymphatic transport improve when placing anesthetised rats in the right lateral position and get worse when prone.
They concluded the answer is likely a function of complex physiological adjustments to different head and body positions inducing a stretch on different nerves and vessels.
When prone the slight thoracic compression of venous return volume decreases stroke volume, with little impact on the heart rate. In other words less coming in the heart = less coming out the heart. This reduction in stroke volume will reduce arterial pulsatility, which is an important driver of g-lymphatic influx.
Also it would be expected that overall sympathetic tone in the prone position would be higher as a natural response to the decrease in cardiac stroke volume from compression of venous return. Conversely sympathetic tone lowers when lying in the right rather than in the left lateral position. The sympathetic nervous system effects the g-lymphatic system.
The effect of norepinephrine in inhibiting g-lymphatic influx is though to be because norepinephrine triggers rapid changes in neural activity that can reduce interstitial space volume (Xie et al 2013). This constriction increases the overall resistance to the periarterial inflow of CSF into the brain parenchyma.
Not only does lowering sympathetic tone increase the efficiency of the g-lymphatic system but so does stimulating the vagus nerve (Cheng et al 2019).
Whilst acknowledging the limitations of their research these authors proposed the effects of vagal nerve stimulation maybe partially or completely independent of systemic cardio and respiratory responses and more dependent upon (1) regionalised brain reflexes. For example the synaptic connections of the vagus nerve to the facial nerve which in turn innervates the cerebral artery. (2) Altering the neurotransmitter and metabolite content of CSF which could possibly interact with the astrocytic (glial) endfeet lining the paravascular spaces.
Lee et al (2015) thought the effect of body position may also effect systemic lymphatic circulation via the effects on the autonomic nervous system. They attributed the prone position to increasing sympathetic tone to the lymphatic vessels which would slow g-lymphatic transport. Conversely right sidelying reduces sympathetic tone concomitantly with an increase in vagal tone which speeds up g-lymphatic transport. However Le & Sloan (2016) found norepinephrine significantly increased lymph flow.
One other possible reason for the advantage of the right lateral position is that the heart is positioned higher when lying on the right side.
This slight elevation of the heart facilitates the pumping of blood and with greater venous return may increase cardiac stroke volume; also, the sympathetic tone is reduced, reducing norepinephrine which improves g-lymphatic influx.
References
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Regulation of cerebrospinal fluid (CSF) flow in neurodegenerative, neurovascular and neuroinflammatory disease (2016). Matthew J. Simon and Jeffrey J. Iliff
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