Flooded brains: Swamped by ion pumps? or by venous insufficiencies?

It is a pity this treatise came to my notice only now:

Hladky SB, Barrand Margery A. Mechanisms of fluid movement into, through and out of the brain: evaluation of the evidence. Fluid Barriers CNS 2014; 11: 26

Insight into what controls production, distribution, and absorption of cerebral interstitial and cerebrospinal fluid, ISF and CSF, is it not elementary to understanding neuropathology?

Good reasons for pondering the text in depth.

The paper’s basic premise reads: Water follows salt

A metabolically driven transport mechanism brings blood ions through the blood-brain barrier out into the tissue. Enables them to cross the tight junctions between the endothelial cells which seal the microvessels.
The ensuing osmotic gradient draws water in its wake, forming cerebral ISF.

“The rate of secretion of fluid across the blood-brain barrier is determined by the net rate of solute transport.”

A similar energy consuming transport mechanism overcomes the tight junctions between the ependymal cells of the choroid plexuses. ISF drawn out of the tough matrix of the choroid plexuses into the ventricles becomes the main source of CSF.

All in all: “The Na+ -pump is the key link between energy released from metabolism and the secretion processes in the choroid plexuses and at the blood-brain barrier.”

Assertions which ask for their questioning on a number of grounds.

(1) The fluid movement into the brain

With an intact blood-brain barrier, the paper specifies, “The rate of secretion of Na+, Cl- and HCO3- is the primary determinant of the rate of fluid secretion into the parenchyma.”

What adds to this microvascular ISF production is CSF infiltrating the tissue along periarterial spaces and entering the choroid plexuses by pinocytosis, at about 1/10th the rate of secretion.

But whereto are these parenchymal ISF volumes going?

All along the blood vessels of the brain, the intravascular pressure has to balance the CSF pressure down to the last length of bridging vein or dural venous sinus which ambient or adjacent CSF volumes can compress. Otherwise the cerebral venous drainage, and with it the cerebral blood circulation, would be compromised.

Upstream of these venous passages at which CSF and blood pressure are leveled out, intravascular pressure constantly increases. And with this the propensity for intravascular fluid to leave veins, microvessels, and arteries.

Already under normal conditions, all the more with a no longer tight blood-brain barrier, it seems rather necessary that ISF can be brought back into than pumped out of the local blood vessels.

(2) Fluid movement through the brain

“For distances up to a millimeter or more, diffusion”, so the paper states, “appears to be the most important process.” The tight brain matrix, however, requires that “additionally there is convection along fibre tracts in white matter and other privileged pathways”.

In this intraparenchymal fluid transport, the perivenous spaces were not found to attain any significance. The microvessels, on their part, lack in a perivascular space. The only priviledged pathways to remain are, accordingly, the periarterial spaces.

But these periarterial spaces are said to have presented merely as virtual spaces on electron micrographs.

(3) Fluid movement out of the brain

An effective reabsorption of ISF into the cerebral blood vessels appears impossible.

There is “no mechanism for net transport of NaCl across the barrier in the direction from brain to blood”. Only “If salt could be transported [from parenchyma to blood], then water would follow [in this direction as well].”

In fact, “colloid osmotic or hydrostatic [pressures] cannot drive net removal of fluid across the intact blood-brain barrier at a rate capable of dealing with excess fluid brought into the parenchyma”. Already “removal of fluid across the intact blood brain barrier cannot match the rate at which fluid is produced.”

Nothing except “water derived from metabolism will either be absorbed across the blood-brain barrier or reduce the amount of water needed to accompany the secretion of solutes by the blood brain barrier.”

ISF has thus to leave the brain via its inner and outer surfaces, sealed nowhere except in the choroid plexuses. And this irrespective of the depth of the white matter expanses and the density of the grey matter formations waiting to be passed.

No easy task. It may be wondered what happens if the blood-brain barrier is no longer intact.

(4) CSF formation

The authors demur that “There is no single compelling definition of what CSF production means” and that “there can be no gold standard method for measuring CSF production”.

The doctrine that CSF is formed prominently by active fluid secretion on the part of the tiny and tough choroid plexuses is nonetheless maintained.

The ISF volumes bound to emerge from the other cerebral blood vessels — and this not only with an intact but especially an untight blood-brain barrier — are not demonstrably taken into account.

(5) CSF absorption

Of all the tissue expanses which confine cranial and spinal CSF spaces outwardly, the arachnoid villi and cribriform plate are singled out as those places via which CSF is primarily absorbed.

Tight though it may appear, the dura mater nonetheless opens in numerous tissue clefts. Such attend every nerve root, artery and vein which penetrates its layers.

In the tissues which encompass the craniovertebral space, the drainage of neither lymph nor, in contrast to the brain, venous blood is to be impeded by CSF pressures.

Instead, CSF escapes everywhere the faster, the higher its pressure.

It is rather the arachnoid villi whose drainage capacity seems less easy to tax.

Rising CSF pressures may close gaps which separate the outer surface of villi placed in a venous lacuna from the lacuna’s inner lining and so hinder the local CSF drainage.

Villi which contact bones, on the other hand, perforate at times into their spongiosa and so attain a higher CSF drainage capacity. A kind of emergency exit hard to access.

(6) Retrograde aqueductal CSF net flow

Ever more, increasingly precise observations tell of a retrograde CSF net flow, via the cerebral aqueduct, into the ‘closed tube’ of the forebrain.

It are patients with hydrocephalus and normal children under two years, whose brain chambers appear burdened by pulses, each of which adds to the CSF volume of third and lateral ventricles.

The authors’ quest for a CSF escape route from the forebrain ventricles led them to suggesting

a leak in thinned parts of the ventricle walls, conducting CSF out around the brain;
a reversal of the function of the choroid plexuses; and finally
a diffuse filtering out of CSF through the ventricular ependyma, forming a periventricular edema. This edema fluid leaves the outside of the brain via periarterial spaces [in addition to the normally produced ISF].

The CSF volumes making back their way, via the foramina of Luschka and Magendie, into the fourth ventricle would be running in circles.

(7) Complementary findings made in communicating hydrocephalus

In communicating hydrocephalus, the paper relates, the pulsatile CSF shifts up and down the cerebral aqueduct appear extremely intensified, reaching the 6-fold of the normal value. Adding up to, at times, the aforementioned net flow from forth to third ventricle.

The ventricular enlargements’ tend to associate, besides, with a periventricular edema and a ‘subarachnoid space contraction’.

No attempt has been made at explaining any of these findings.

Cerebral microvessels: Waterproof up to which arterial, which venous pressure loads?

The debate on chronic cerebral (and spinal) venous insufficiency has soon raged its decade.

With disputants speaking, in principle, but of venous stenoses located, besides, exclusively outside the skull. Dealing with them as autonomous, self-contained medical entities in their own right.

These findings are hardly ever put in their systemic context. Nobody seems to ask, what are the narrowed veins short of? And how does this their insufficiency impact on the brain?

Nobody seems to be willing to go into the more specific questions: How high rise, how far out fluctuate the pressures upstream of the diverse venous narrowings? Have they some bearing on the brain? and if — what are the effects?

Or, the other way round: Up to which pressure loads remain the involved vascular walls, the microvascular blood-brain barrier, the surrounding brain tissues intact?

Cerebral venous insufficiency: A Gordian knot knit of four threads

The confrontation on what is referred to as cerebral venous insufficiency inextricably entangles four different things.

Two are pathomechanisms, capable of injuring by themselves. The second one building up on the first.

Two are circumstances upon which the efficacy of the first ones depends.

These venous insufficiencies combine in various ways, some appearing deleterious.

D-R-I-C: The four forms of a cerebral venous insufficency

(D) Direct effects of a venous obstruction. They show as stasis — a slowing down, at worst standstill, of the blood circulation. First step is an engorgement of the obstructed venous channel’s vascular periphery on the part of reactively dilating arteries, varying in degree.

As long as they remain limited to veins outside the skull, even complete occlusions of the dominant cerebral venous pathways are, with ill-characterized exceptions, remarkably well tolerated.

The clinical outcomes of ligatures, thromboses, resections of even both internal jugular veins, Lemierre syndromes, radical neck dissections, occlusions of brachiocephalic and superior cava veins testify to this fact.

The experiences made with venous obstructions located inside the cranial cavity are worse.

Their poor local tolerance seems due to a lack of collateral outflow channels. In case they attain a wide to global efficacy, intracranial venous obstructions raise the CSF pressures in increasing the ISF formation out of their cerebral tributary vessels.

(R) Retrogradely propagating venous events. Insofar as they are not due to arterio-venous shunts, they complicate the direct efficacy of venous obstructions only if they are located at a certain distance from the skull. Either in the form of rejected blood volumes or, with a prestressed venous periphery, by retrogradely progressing pressure waves.

The two latter ways in which a venous obstruction is prone to have deleterious consequences appear insufficiently appreciated.

Observations of flow inversions in the left internal jugular vein tend to show that retrogradely propagating venous events need not threaten the brain. Exhausted, dissipated or channelled away via infra-, trans- and intracranial venous anastomoses, they do not reach, as a rule, the brain.

Once some retrogradely propagating venous event enters a larger domain of the cerebral vasculature, however, it is not the momentum, quantity and speed of the rejected blood volume, respectively the speed of ascent and amplitude of the retrograde pressure wave alone which determine what happens. Local tissue resistance and global CSF compliance come into play.

It is as it is with the arterial pulse wave: Also from the venous side, blood volumes only enter the brain to the extent as they are capable of displacing the same volume, of usually venous blood, from some separate compartment(s) of the craniovertebral space.

Which makes rejected blood volumes locally the more dangerous the smaller the burdened area and the higher the speed at which they invade the brain.

How severe the indicated pathomechanisms become depends on two further factors. Two contributory forms, so to speak, of a venous insufficiency.

(I) Interconnection insufficiency. This is a weakness, up to absence, of vascular interconnections best known from two vein crossings. The cavernous sinus at the base, and the confluence of sinuses at the back of the skull. With the point of union of the three cortical anastomotic veins of Sylvius, Trolard, Labbe working in a similar way.

Pressure loads which burden only one of the arms of a weakly interconnected vein crossing are insufficiently dissipated.

In this regard, the interconnection insufficiencies of the confluence of sinuses are of major interest.

Separations of the superior sagittal sinus (it drains most of the cortical veins in direction of preferentially the right internal jugular vein) from the straight sinus (draining the inner cerebral veins rather to the left) are long-known.

With the related lack of an interconnection between the two transverse sinuses, the leveling out of pressure gradients between the two internal jugular veins translocates from the confluence of sinuses to the brain. Dependent on the gradients’ speed of ascent and height, with more or less palpable consequences proceeding in direction of a shifting borderline of the respective vascular territories.

Quite remarkably, the flooding of a definite cerebral vascular territory via an internal jugular vein, reported in a paper of 1974, did not even burden the transverse sinus. Burdened instead was the unusually circumscribed territory of an inferior anastomotic vein. Which lacked, paradoxically, in any perceptible connection to other cortical veins.

Indications of an overburdening of the territory of the internal cerebral vein of one cerebral hemisphere, either the right or the left alone, are rarer. Here the excess pressures arising in one of the jugular veins can have made their way into the homolateral cerebral hemisphere by way of the homolateral channel of a lengthwise divided straight sinus vein or via a homolateral tentorial sinus.

(C) Collateralization insufficiency. It is given if there are no veins which compensate for the obstructed vein’s loss in flow conductivity. In its presence alone a venous obstruction will have any direct or retrograde effect.

What is here easily overlooked is this: Even though it seems harmless of and by itself, a venous obstructions can nonetheless predispose to deleterious retrogradely propagating venous events.

Even an impressively stenosed internal jugular vein commonly fails to dam up blood as far upstream as to have an effect on the brain. And yet, the vehement compression of an engorged, prestressed suprastenotic vein length may deleteriously impact on its strictly confined vascular periphery inside the cranial cavity.

The pressures required to drive the compressed blood instantaneously back to the heart increase with the vehemence of the vein compression. These pressures, however, work equally in direction of the brain. And may be raised further if the obstructed vein is impacted on headwards in direction.

Reassuring or alarming? The intracranial ‘vascular waterfall’

Down to their entrance into the dura mater, the cerebral bridging veins and vein of Galen require a filling pressure which prevents their collapse, their being made insufficient by ambient CSF pressures.

The dural venous sinuses needn’t, as a rule, to fulfill this demand. Their cover of dura mater doesn’t yield to CSF pressures so readily.

The dural venous sinuses accordingly tend to be filled at a somewhat lower blood pressure than the cerebral bridging veins. A circumstance referred to as vascular waterfall.

This waterfall prevents, in dependence on its height, retrograde propagations of cervical venous blood and excess pressures into the brain.

Its being leveled out down to some hindrance in the cerebral venous drainage in chest and neck is, on the other hand, fraught with the highest risk of a retrogradely propagating venous event.

Any impact flattening some intervening vein length tends to be immediately transmitted to the related cerebral vascular domain. Which won’t remain without consequences.

A widespread clogging of channels supposed to drain CSF, on the other hand, seems liable to raise the CSF pressures and, with it, the waterfall’s height. In particular after subarachnoidal infections and bleedings rising the osmotic CSF pressure besides.
Relationships which have hardly ever been focused on specifically.

With cerebral arterio-venous malformations, the exuberant shunting of pulsating arterial blood into dilated parenchymal veins amounts to a kind of relative venous insufficiency. Here ISF is filtered out even of cerebral veins.

CSF pressures and the height of the vascular waterfall raise. And this in a direct proportion to the malformation volume.

Which clearly shows: It isn’t ion pumps, but the arteries’ and veins’ interplay, on which the CSF formation, on which the CSF pressure directly depends.

Two further circumstances, eventually, each tending to boost the other again, are able to push up the height of the waterfall most.

There is the tightness of the blood-brain barrier. Anything affecting it causes excess ISF to be filtered out of first the cerebral microvessels. A process dramatically boosted by extravasations and bleedings to the extent they raise the vascular surroundings’ osmolarity.

The more widespread and severe such changes are, the more the increased ISF formation will come to be felt. First, by a delayed increase in the CSF formation. Next, by the ensuing cerebral edema’s space-consuming effect. Both being liable to raise the CSF pressure.

There are, on the other hand, the increases in the local intravascular pressures. Reaching their potential extremes with the surging up of retrograde venous pressure waves along prestressed pathways of the cerebral venous drainage.

The mutual aggravation of the two kinds of events leading up to the worst case scenario of a cerebral venous insufficiency type D.

Communicating hydrocephalus

The findings highlighted as being peculiar to communicating hydrocephalus find a plausible physical explanation in particular constellations of venous insufficiencies.

Ventricular enlargement

This finding itself tells of no more than a diffuse tissue atrophy spread about the cerebral ventricles.
As it may be produced by any kind of arterial and venous circulatory disturbances.

Vascular obstructions affecting the drainage of the right, left, or both internal cerebral veins swamp the involved parts of the forebrain ventricles’ immediate neighbourhood in an unsharply delimited pool of edema.

Retrogradely progressive venous events work in more varied and changeable ways.

Areas hit, struck, punched out, by splashes of blood columns rejected into the internal cerebral veins will tend to be irregularly scattered out. The lesions extending often eccentrically from their vein, its bends, its branching points. Extent and severity of the tissue affection changing with the momentum, the volume and speed, of the sporadic or recurring impacts.

Retrograde venous pressure waves, especially such with a slower ascent, will spread out from the ventricular borders more evenly. With succeeding waves invading the periventricular tissues to varying depths, however, the affected tissue domain(s) will be less clearly defined.

The effect is bound to change also with the waves’ amplitude: Small ripples may merely affect the vessel wall or distend the perivascular space; the higher the wave’s amplitude, however, the more extensive the perivascular parenchymal involvement will be.

Tissue straining by a massive interstitial edema, by slight mechanical impacts, affects the delicate white matter structures first. The delicate myelin sheaths, their flimsy connections to the oligodendrocytes, tolerating less tensile or shearing stress than the tough fibre matrix of the grey matter domains.

Intense CSF pulsation in the cerebral aqueduct

Once the tissues’ metabolism is compromised, venous obstructions provoke an arterial vascular dilation attempting to maintain the sufficient blood supply to, and circulation through, the affected venous periphery.

Ensuring an adequate tissue perfusion about the outer angles of the lateral ventricles requires a massively intensified pulsation of the brain’s longest arterial channels.

Both venous stasis and adaptative peripheral arterial hypertension threaten the tightness of the intact blood-brain barrier comparable to arterio-venous malformations. Tending again to increase the ISF filtration pressure.

The succeeding increase in the CSF production stabilizes the CSF pressure at a higher level. Demanding that the local arterial wall tension be further reduced. If not that the systemic arterial pressure beincreased.

Brain swelling and increased CSF pressure diminish the preeminently venous CSF compliance to arterial pulsations. In a situation which would require the opposite. This affects, with an elevated cranial outflow resistance, first the spinal canal, and, with momentarily engorged internal cerebral veins, last and the least the domain of the periventricular veins.

The pulsatile displacements of initially cisternal and subarachnoid CSF which normally take place in direction of the spinal canal switch direction. They pulsate instead, with the more vehemence, in part via the cerebral aqueduct, back in direction of the cerebral ventricles.

Periventricular edema

The abnormal infiltration of the tissue surrounding the cerebral ventricles has not (yet) been severe enough as to lead to their atrophy, manifest as ventricular dilation.

Brain edema leaves little room for the teaching on ISF producing ion pumps. Hladky and Barrand had no motif to go into capricious periventricular edema patterns, into their obscure vessel relationships. Relationships which the heading ventricular enlargement already necessitated to speak about.

One point may nonetheless be added here: Circumscribed areas of varied fluid accumulations scattered off the ventricular borders, and this in a close relationship to ramifications of the internal cerebral veins, had better not be categorized by the ways in which the become (or not) clinically manifest. And even less specified by some multiplicity in space and time.

CSF net flow into the forebrain

The fact that the cerebral vascular, down to venous, filling pressures exceed, on average, the CSF pressures makes observations of a CSF net flow into the third and lateral ventricles look paradoxical.

The key for solving the paradox are periods during which the given relationship is overturned. Moments with a higher ventricular CSF than periventricular tissue pressure.

During these periods even an otherwise stagnant outflow of blood from the periventricular collecting veins is speeded up. Together with an outflow of ISF via fenestrated microvessels of the choroid plexuses. And the outflow of periventricular edema fluid through untight microvessels.

These specifically human circumstances are hard to reproduce in experimental animals.

Infants and toddlers may help to understand what is going on.

The very young children show an extraordinary overdevelopment of their head over their spine. The insufficient compliance of their underdeveloped spinal canal, its scanty epidural venous plexuses, finds little compensation in open cranial sutures.

As in communicating hydrocephalus, so also in the first two years of life, the periventricular tissues, their microvessels and veins are sort of milked out by arterial pulses upon their entering the cranium and, next, the cerebral hemispheres. The wave of displaced cisternal and subarachnoid CSF pushing, instead of down into the spinal canal, up against the forebrain ventricles. To there encounter a wave of arterial blood approaching the same via cerebral cortex and basal ganglia.

In the end, the ventricular CSF tsunami has scarcely time enough to turn back into basal cisterns and subarachnoid space. Till the next arterial pulse wave comes in.

The subependymal edema stripes which contour the outer edges of the lateral ventricles appear as tokens of a corresponding tissue straining. Hinting at the same time at the site of the retrograde CSF net flows destination respectively transformation into epiventricular CSF.

Subarachnoid space contraction

The picture of a ‘contraction’, or attenuation, of the subarachnoid space can hardly be explained otherwise than by a pervasive, to a large extent intracellular brain swelling.

A finding which does not allow to identify the swelling’s nature and origin on its own.
But which does not exclude either it’s being due to some kind of venous insufficiency .

Conclusion

Hladky and Barrand’s treatise makes plain: The interactions between cerebral venous and ISF respectively CSF dynamics have not been considered as carefully and studied as thoroughly as the subject deserves.

Taking a closer look at what happens, in unexplainable cerebral affections, along both the extra- and intracranial cerebral venous passages may hold staggering surprises. Not only in patients with communicating hydrocephalus.

Franz Schelling, M.D.