This chapter tries to address Section K1(iii) of the 2017 CICM Primary Syllabus, which asks the exam candidates to "describe the physiology of cerebrospinal fluid". Somehow, out of all the possible options, this relatively narrow subject matter has commanded the CICM First Part examiners' attention the most; in the sense that there are more questions about CSF physiology then virtually anything else. Historical examples of CSF questions are listed here as a reference:
- Cerebrospinal fluid (CSF) is an ultrafiltrate of plasma contained within the ventricles of the brain and the subarachnoid spaces of the cranium and spine.
- Amount: Approximately 400-600ml/day, or 25ml/hr;
- At any given time, a normal adult has about 150ml
- About 25ml is in the ventricles, and a further 30 ml in the spinal canal
- The rest is in the subarachnoid space
- Site: three main sources:
- Choroid plexus within the ventricles (mainly lateral ventricles)
- Brain interstitial fluid (minor source)
- Circumventricular organs (very minor source)
- Mechanism: By highly regulated ultrafiltration and active secretion
- Ultrafiltrate of plasma is formed by the fenestrated choroidal capillaries
- It collects in the choroid interstitial space
- Ions are actively transported out of this ultrafiltarte, and into the CSF:
- Sodium is actively secreted from the apical membrane (Na/K/ATPase)
- Carbonic anhydrase also provides H+ to power Na/H+ exchange at the basal membrane
- The sodium gradient created and maintained in this way is then used to co-transport HCO3- and CL- into CSF
- This creates an osmotic gradient which pulls water across the membrane through aquaporin channels
- This process is disconnected from ultrafiltration, i.e. CSF production is constant and is not pressure-dependent (though at low CPP, <55 mmHg, CSF prodction decreases)
- CSF contains minimal protein (~0.2g/L)
- CSF sodium potassium and calcium are slightly lower than plasma
- CSF chloride CO2 and bicarbonate are higher than plasma
- CSF glucose is about 2/3rds of the plasma value
- Barrier function (the blood-CSF barrier)
- Chemical stability and waste removal
- Buoyancy and mechanical cushioning of the CNS
- Hydraulic pressure buffering of ICP with arterial pulse and respiration
- Out of the choroid plexus on the floor of the lateral ventricles
- Through the foramen of Munro into the third ventricle
- Through the Aqueduct of Sylvius, into the fourth ventricle
- From the fourth ventricle, into the cisterna magna via the lateral foramina of Luschka and then up to the basilar cisterns around the pons, and then to the rest of the cortex
- Or, from the fourth ventricle, via the medial foramen of Magendie, down to the spinal subarachnoid space
- It is then reabsorbed from the subarachnoid space
- The motor force driving this flow comes from:
- Constant production at the choroid plexus
- Arterial pulsation of the central nervous system structures
- Venous pulsation of the CNS related to the respiratory cycle
- Constant reabsorption by the arachnoid granulations
- Reabsorbed at 25ml/hr (CSF secretion rate = reabsorption rate) into the dural venous blood
- Main sites are arachnoid granulations
- Driving force is hydrostatic gradient between CSF and venous blood
- Thus, CSF reabsorption stops when CSF pressure is less than ~ 7 cm H2O
For a paying reader of Springer journals, Segal (2000) covers this topic nicely, but the dumpster-diving freegan can get exactly the same information from Telano & Baker (2020), Sakka et al (2011), and literally a thousand other papers. If you really want to pay for something, you could pay for Herndon & Brumback's The Cerebrospinal Fluid (1989), or Desenheimer's Cerebrospinal Fluid in Clinical Neurology (2015). The CICM First Part candidate is warned against embarking on any 442-page journey just for the purpose of exam preparation, but the casual reader could potentially derive some sort of joy from it, and potentially the Tumani chapter on Physiology and Constituents of CSF (p 25-34) could be recommended on its own as a solid summary.
This (usually) crystal-clear liquid is typically introduced to a reader by means of some kind of short sentence that pithily summarises the reasons for why it is interesting and how it is distinct from any other random fluid collecting in the human body. For shortness and pithiness, nothing beats Telano & Baker (2020):
"Cerebrospinal fluid (CSF) is an ultrafiltrate of plasma contained within the ventricles of the brain and the subarachnoid spaces of the cranium and spine."
That, reader, is exactly what and where it is. Most authors also follow these introductory statements with some blurb to the effect of "vitally important", "cushioning", "nourishment and protection" etc. These are not pointless motherhood statements, and could benefit with some supportive explanations. The presence of cerebrospinal fluid and some sort of system of ventricles and meningeal CSF cavities appears to be the precondition for even a very basic central nervous system. It is present in all vertebrates, all the way down to the level of a hagfish (whose vertebrate passport looks pretty fake, in all honesty, as they do not have a vertebral column per se). Myxine glutinosa do not appear to have a choroid plexus and their blood-brain barrier looks very abnormal (Murray et al, 1975), suggesting that they secrete CSF directly out of their brain, but they do still have a system of cerebrospinal fluid spaces. Invertebrates don't seem to need them, but then they also often seem to lack a blood-brain barrier, and in many of them the fluid bathing major neural structures is basically the same gross toilet water that sloshes around everywhere in whatever passes for a circulatory system in those animals. In short, CSF seems to be an essential part of being a neurologically complex organism.
The "amount, site and mechanism" were important to the examiners in the answer to Question 15 from the second paper of 2018. Thus:
"Ultrafiltration and active secretion" here is an oversimplification which might make a person think about some sort of crude glomerulus-like sieving mechanism. Sure, ultrafiltration does take place, and the fenestrated capillaries are often compared to those of the glomerulus, but "ultrafiltration" does not even begin to describe what the choroid plexus does, and it would be offended by the comparison. The formation of a filtered plasma is just the first part. The ultrafiltrate in the choroidal interstitial compartment is then processed by the choroidal epithelium and some of it is secreted into the ventricular cavity by a series of carefully controlled active processes. Additionally, there is contribution to CSF formation from the extracellular fluid of the brain, with which it mingles passively, and from the various other circumventricular organs where the blood-brain barrier is broken (which are small, and their contribution minimal).
Thomas H. Milhorat (1976) offers perhaps the best description of this structure in a style that is largely missing from modern scientific literature:
"When visualized directly at surgery, or viewed through a ventriculoscope, the human choroid plexus appears as a velvety vascular membrane which floats lazily in the CSF. Gross pulsations are not apparent, but the ventricular pulse, reflecting transmitted cardiac and respiratory influences, causes the plexus to bounce to and fro like an anchored boat at sea. When the choroid plexus is excised and fixed in Formalin, it loses its gossamer appearance and becomes rather polypoid and villiform."
No high-resolution images or videos are easily available, but if one wanted to have a look at what this gossamer appearance looks like under the hot lights of an endoscope, Tamburrini (2017) offer some images snapped during endoscopic third ventriculostomy:
When people say "the choroid plexuses are the main interface between the blood and CSF", they usually mean this in terms of raw surface area as well as fluid output. The plexuses on the blood side are highly vascular structures, furnished with a vast number of fenestrated capillaries, and their ventricular side they are covered in an epithelium bristling with microvilli. Here's some SEM photographs of vascular casts by Zagórska-Świeży et al (2008), to demonstrate the rich choroidal blood supply. As you can see, the capillaries form almost glomerulus-like basket shaped structures.
The whole thing is only about 2g of tissue, sitting on the floor of the lateral ventricle, measuring no more than 4mm in thickness in the normal adult (İmamoğlu et al, 2013). Fortunately, the carpet of microvilli massively increase its surface area, such that the adolescent rat has about 75m2 of it (Keep & Jones, 1990). This microvillous layer is separated from the capillaries by an interstitial space where ultrafiltrate collects. There do not seem to be a lot of images of this structure out in the easily available Googleable spaces, but one nice picture could be sourced and altered from Damkier & Praetorius (2020):
Those capillaries lack tight junctions. That interstitial space under the basal lamina of the choroidal epithelial cells is full of fluid which has extruded through the fenestrated capillaries, and is probably similar to glomerular ultrafiltrate, but in all honesty nobody knows - this is a difficult space to access. To say with a straight face that "an ultrafiltrate forms here" would require the measurement of protein and pressure, and both would be challenging in vitro, let alone while it "bounce to and fro like an anchored boat at sea". If you did have those measurements, you could plug them into the standard Starling equation (or some kind of computer model). Fortunately, it is not essential to consider this compartment in any great detail, as all the magic happens at the choroidal cells themselves, and so the entire capillary-interstitial-cellular complex can be consider en masse, as the choroidal secretory surface.
The most important upshot of this information is that the rate of ultrafiltration (dependent on things like pressure of the blood and the protein oncotic pressure) is disconnected from the rate of CSF secretion, which is independent of pressure. Only with very low cerebral perfusion pressure (where the choroid plexus becomes relatively underperfused) does the rate of production become affected. Experiments by Weiss & Wertman (1978) determined the range of pressures where this is likely to happen, and concluded that a CPP of less than 55mmHg will decrease the rate of CSF production. Conversely, if the CPP remains over 70mmHg, CSF will continue to be secreted at the same rate, irrespective of how high the ICP is.
How is the fluid actively transformed from a dumb soupy ultrafiltrate to the pristine aqua vita in the ventricular cistern? There are a ton of different ionic mechanisms, and the real trick for the CICM trainee is not to get bogged down in detail. To get an appreciation for the size and viscosity of that bog, the trainee is invited to peek at the likes of Brown et al (2004) or Speake et al (2001). It is not essential to become a master of this content; broad brushstrokes would be enough. For example:
Or, in an even shorter form,
Or, in the form of a horrific ion channel diagram:
So: with all these ions being actively moved into the CSF, and other ions and proteins being selected out, it sounds like the CSF would be rather biochemically different from plasma.
This brings us to:
At one stage, it was believed that there is actually nothing particularly special about the chemical composition of the CSF, and that it was a pure crystalloid ultrafiltrate of the plasma. A series of experiments had proved this theory wrong, such as the 1964 exploration by Adelbert Ames III et al. Here, their cat data are arrayed illustratively:
It would be logical for us to think that modern intensive care trainees should be expected to know human values, but interestingly, if you dig deep, you will find that most textbooks produce a table of comparison values which is mainly based on animal data from as far back as the 1930s (eg. Merritt et al, 1937) Here, a representative set is borrowed from Brown et al (2004), which is mainly dog and some cat:
|Protein (g/L)||65 g/L||0.25 g/L|
Again, wherever you look, slightly different values are found, as everybody drained the CSF of different dogs and used different techniques. Those differences do not matter. They depend on how the blood and the CSF were collected, how the animal was anaesthetised, and whether the experiment was performed in the 1930s using some sort of brass-valved steampunk apparatus to analyse the samples. From the perspective of the modern CICM trainee, the most important things to remember are that in CSF,
To memorise this list of differences is probably a good enough strategy if some sort of naked tooth-and-claw exam survival is the goal. Each of these differences is clearly important and has some sort of reason behind it, as CSF ions are all secreted actively and therefore their concentration is some sort of deliberate choice by the choroid plexus. Even though the reasons for these differences in concentration are not always well established, let us try to muddle through them anyway:
Salty. According to patients with post-operative dural tears (classically following a transsphenoidal resection of a pituitary tumour) the post-nasal drip of CSF has a slightly metallic salty taste, similar to tears. This is sufficiently commonplace that highly respected publically available patient information material from centres of excellence include this as one of the things about which you should "ask your healthcare provider".
Like everything in the history of early medicine, where the most sensitive chemical apparatus available to the physician was often their tongue, CSF sampling by taste seems to have been carried out routinely. Schwab & Green, in A Case of Cerebrospinal Rhinorrhoea" (1905), casually drop the information that "many specimens of the fluid were examined, [and were] clear, odorless, and tasteless".
As was already mentioned in a series of highly alarming remarks, CSF appears to be a mandatory part of having a complex central nervous system. So: let's answer the question, what exactly does it do? For exam purposes, you could summarise this as:
More detail is available below, but is really not essential.
The CSF bathes the brain tissue and penetrates widely, communicating with the extracellular interstitial fluid of the brain through fenestrations in the pia mater. From this, it should follow that its composition should be tightly controlled, because it would make no sense to have a highly sophisticated blood-brain barrier control every exit and entrance from the bloodstream, and then to bathe the brain in some random liquid of uncontrolled composition. The control of the composition of CSF is therefore carefully regulated to be as benign as possible. As already mentioned, the filtration of plasma which takes place at the choroid plexus is a very deliberate process that excludes various troublemakers (large proteins, bacteria and virus particles, neurotransmitters, hormones, metabolic toxins, etc). In this sense, the organs which secrete CSF can be thought of as barrier organs, and the secretory surface can be thought of as a "blood-CSF barrier".
The effect of CSF can be viewed as similar to the effect of dialysate fluid. Having a constantly flowing liquid of a controlled concentration circulate around your brain is beneficial because it constantly exposes regions of the brain to this controlled concentration, maintaining the concentration gradient for the removal of waste products and weird electrolytes. Consider what might happen if this was not going on. The brain has no lymphatics, and needs to rely on the flow of interstitial fluid through perivascular spaces for the clearance of metabolic byproducts (which ultimately washes into CSF, with which is its basically continuous, barring a few steps). If CSF was motionless and stagnant, these spaces would become regionally highly concentrated pools of cellular wastes and electrolytes, like the bottom of an aquarium when the pump has failed for a week. Moving CSF however acts as a sink into which these wastes can easily diffuse, and the rate of its circulation is sufficiently fast to always present the perivascular spaces with a ready supply of fresh fluid.
The term used to describe this waste clearance system is "glymphatics", a term coined by Maiken Nedergaard to incorporate the contribution of the (g)lial cells to the process. Iliff et al (2013) were actually able to visualise this glymphatic system in action by the use of contrast-enhanced MRI, and confirmed that yes, it does in fact flush the perivascular spaces (and in fact that there is some retrograde reflux, were CSF from the subarachnoid space washed down along those perivascular channels, deep into the brain tissue). For the purposes of CICM exams, it would not be essential to become a master of this material; but in case more detail is called for, this "beginner's guide" by Jessen et al (2015) would be a good starting point.
The words "cushion"or "buffer" are often seen in medical textbooks which try to explain the reasons for the physical presence of the CSF. Others refer to "a buoyant force to support the brain", which - being a squishy soft organ made of fat and filled with fluid blood - would, under the effects of gravity, naturally tend to deform into some kind of flattened pie. The net weight of the brain, while suspended in fluid, is only 50g (whereas it's mass is 1400g), these official sources state. As Abdalla (2021) rightly pointed out, it is impossible to weigh the living brain as it floats in CSF, and so these numbers must be pure speculation. However, mathematically, the relationship between brain density and CSF density can be incorporated into models which do conform to this supposed weight reduction, and which are capable of estimating the buoyancy of the brain well enough to accurately predict a change in its position intraoperatively (when some CSF is drained out). The most important buoyancy-related role is played by the ventricles, which act in the same way as the swim bladder of fishes. By sitting centrally inside the brain they can act as a low-density bubble of variable volume, buffering quick changes in brain density which occur with the pulse or respiration.
Cerebrospinal fluid plays a major role in the compensation for raised intracranial pressure. It can be displaced from the cranium into the spinal canal in order to compensate for abrupt changes in ICP, and it can be gradually reabsorbed via the arachnoid granulations to compensate for a sustained change. Interestingly, CICM examiners are divided on this matter. In Question 16 from the first paper of 2015 ("describe the physiology of cerebrospinal fluid") they remarked that "Better answers also discussed raised ICP and CSF’s role in the compensation for raised ICP". In contrast, in the college comments for Question 2 from the first paper of 2013 (also "describe the physiology of cerebrospinal fluid"), they complained that "Some candidates described the displacement of CSF when intracranial pressure rises as a function of CSF", and reported that "no marks were given for this".
So does the CSF in fact have some sort of ICP-defending function? Could the college examiners be wrong? Reader, they could. Di Terlizzi & Platt (2006) list this as literally the first function of the CSF (though, to be fair, their veterinary article was mainly aimed at readers interested in the biology of companion animals). Under normal circumstances, the intracranial CSF volume and intracranial blood volume are traded against each other, and this is demonstrated in the pressure fluctuations observed during lumbar puncture. When the manometer or pressure transducer is attached, there is a 1-2 mmHg fluctuation in lumbar CSF pressure with arterial pulse (Herndon & Brumback, 1989, p. 36) which occurs because about 1.5ml of CSF moves in and out of the spinal CSF spaces with every arterial systole (Haughton & Mardal, 2014). Similarly, the same "spatial displacement" occurs when intracranial volume changes because of some other incompressible presence (I'm looking at you, subdural haematoma). If there is time, quite a substantial amount of CSF can be displaced in this way- for example, in the context of a slowly growing tumour (Tameem & Krovvidi, 2013)
Under the heading "Circulation", most textbooks tend to include a crossectional image of the central nervous system with little arrows tracking the path of CSF flow, like rows of marching ants. Here's a particularly formic diagram from The Anatomy Colouring Book:
In case this schematic is uninformative for the non-visual learner, it can be easily expressed in words:
Or at least that is what the examiners want you to write in the exam papers, and what is often seen in physiology textbooks. This origin myth of the CSF, where 75% of it is created by the choroid plexus and then pushed around unidirectionally, is based on experiments which go back to Cushing (circa 1914), and which have all been debunked in the modern era. Realistically, the situation is much more complex. For example, it is possible to secrete plenty of CSF even without a choroid plexus, and flow at every point is often demonstrably reversible under normal physiological conditions. An excellent overview of the different theories and their controversies awaits the patient reader in Mantovani et al (2018). To summarise, rather than a unidirectional flow and a single dominant site of CSF secretion, there is "a dynamic equilibrium among parenchyma, interstitial space, [subarachnoid space], vascular compartment, and ventricles", where the direction and magnitude of regional flow seems to be determined mainly by regional hydrostatic and osmotic pressure gradients. This concept will take some years to percolate into official college textbooks, and the exam-going candidate should cultivate some doublethink about it.
The rate of CSF production being around 25ml/hr, and there being about 150mls in the normal adult CNS, leads to the conclusion that there must be a constant turnover of this fluid, of around four exchanges per day. This cycling is possible because of the continuous reabsorption of the CSF by arachnoid granulations and cervical lymphatics.
So what are these "arachnoid granulations" and "arachnoid villi"? In short, these are weird little herniations of arachnoid space material that protrude into the cavity of dural venous structures. They are normally very small; villi can be microscopic, and to get called a "granulation" you'd have to be 2mm in diameter. They increase in size with age and anything larger than 10mm gets called "giant" because it can become clinically significant by obstructing venous flow through the sinus. Instead of gross cadaver images or uninspiringly grey electron microscopy, some truly excellent pencil artwork from Shabo & Maxwell (1968) will be used here to illustrate these structures:
The absorption of CSF from the loose mesh space inside the granulation occurs mainly by ultrafiltration. The pressure of the CSF is usually higher than the venous pressure, particularly in the upright human, and even when supine there will be periods during the respiratory cycle when the venous pressure drops. When the CSF pressure drops below 7 cm H2O, the hydrostatic gradient driving this bulk flow of fluid becomes negligible, and CSF reabsorption stops (Orešković & Klarica, 2014).
Apart from arachnoid villi and granulations, multiple other sites of CSF absorption are recognised, including through the walls of the ventricles, and through the cervical lymphatics. The exact dynamics of how this works or what regulates it remains to be firmly established, and there's some excellent literature to discuss this evolving area (eg. Miyajima & Arai, 2015). As CICM examiners are naturally drawn to well-described phenomena found in textbooks, it would probably be better not to mention this, sticking to simple explanations with arachnoid granulations and hydrostatic gradients.