What happens if cerebrospinal fluid is not drained properly

Try out PMC Labs and tell us what you think. Learn More. The central nervous system's CNS complicated design is a double-edged sword. On the one hand, the complexity is what gives rise to higher order thinking; but on the other hand, damage to the CNS evokes its unforgiving nature.

The cerebrospinal fluid CSF circulation system is an intricate system embedded in and around the CNS that has been the topic of debate since it was first described in the 18 th century. It is underscored by the choroid plexus's distinct vascular network which has conventionally been seen as the most prominent structure in CSF production through a variety of active transporters and channels. Despite the ubiquity of this circulation system in vertebrates, some aspects remain understudied.

Recent advances in scientific methodology and experimentation have proven to be effective tools for elucidating the mechanisms of the CSF circulation system and the pathological conditions associated with its malfunction. In this review, we capitulate the classical understanding of CSF physiology as well as a new, emerging theory on CSF production.

Cerebrospinal fluid CSF is a clear, proteinaceous fluid that exists in the surrounding spaces of mammalian central nervous systems CNS. It is a multifaceted marvel, able to continuously support the nervous system through the lifespan of the organism. In the average adult human, there is roughly mL of CSF circulating at any given moment.

CSF forms at a rate of about 0. In this review, we will outline the physiology of CSF in the typical adult, as well as the pathologies associated with CSF circulation, malabsorption, and production. The existence of CSF has been known for centuries.

Hippocrates was among the first to describe the fluid as water that surrounded the brain. Since then, this theory has been taken as fact, and many studies conducted on the choroid plexus and CSF secretion have revolved around this concept.

The secretion of CSF from any of the four choroid plexuses occurs as a two-stage process. The ultrafiltrate then undergoes active transport across the choroidal epithelium into the ventricular spaces.

They call into question nearly years of research which elucidated the role of the plexuses in the CSF system, citing faulty methodologies that are highly subject to error and misinterpretation as well as experimental settings ex vivo and in vitro that do not represent the true physiology of the system.

The authors assert that no experiment has undoubtedly confirmed the capacity of the choroid plexus to completely generate the predicted volume of CSF. The main criticism asserted is that Dandy's previously mentioned experiment was not reproducible and conducted on only a single canine subject, yet served as a foundation for the classical theory.

The new working theory they posit sees CSF formation as an active process that is not affected by intracranial pressure. In balanced physiological conditions, the rate of CSF formation must be equal to the rate of absorption.

They postulate that this could extend to flow rate, given that formation and absorption occur in different compartments of the system. To them, it is, therefore, logical to say that secretion of CSF is the driving force of flow and circulation if there is going to be a steady volume of CSF.

According to the classical theory, a choroid plexectomy should significantly reduce the overall secretion of CSF, therefore providing some pressure relief in patients who have hydrocephalus. However, this is not always the outcome of the procedure; in fact, research shows that two-thirds of patients who receive the treatment should be shunted due to the recurrence of hydrocephalus.

The new theory takes a more systematic approach, it shifts attention to the Virchow—Robin spaces also known as perivascular spaces , which exist between where the cerebral vasculature descends from the subarachnoid space into the CNS, perforating the pia mater. This would indicate that CSF is continually produced throughout the circulatory route and not in localized secretory organs, and any changes in the volume of CSF are influenced by the CSF osmolarity.

While there is evidence to support these claims of CSF mixing and production, there is also a wealth of literature describing the ebbs and flows of CSF, and net flow. The composition of CSF varies from that of serum due to the differential expression of membrane-associated channels and transport proteins, ultimately resulting in the unidirectional nature of the choroidal epithelium.

Compared to plasma, CSF generally contains a higher concentration of sodium, chloride, and magnesium and lower concentrations of potassium and calcium. Movement of water across the apical membrane has been shown to be due to the presence of aquaporin-1 AQ-1 ; in fact, a study conducted by Mobasheri and Marples revealed that choroid plexus was among the tissues with the highest expression of AQ-1 in the body.

The function of CSF has been one focus of mechanistic study, and the study of disease states which influence production, absorption, or CSF composition. Similarly, the microenvironment composition surrounding periventricular cells, and their activity, are manipulated by changes in solute transporters and CSF pathologies. Hydrocephalus present at birth congenital or shortly after birth can occur because of any of the following:. In most cases, hydrocephalus progresses, which means complications, including intellectual, developmental and physical disabilities, can occur if it's not treated.

It can also be life-threatening. Less severe cases, when treated appropriately, might have few, if any, serious complications. Hydrocephalus care at Mayo Clinic. Mayo Clinic does not endorse companies or products. Advertising revenue supports our not-for-profit mission. This content does not have an English version. This content does not have an Arabic version. Overview Hydrocephalus is the buildup of fluid in the cavities ventricles deep within the brain.

Request an Appointment at Mayo Clinic. Brain ventricles Open pop-up dialog box Close. Brain ventricles Your brain floats in a bath of cerebrospinal fluid. You should seek medical attention immediately if you have any reason to suspect that your shunt is not functioning properly. The shunt will not be removed even if you do not experience any more symptoms and follow-up scans show no further signs of increased pressure in the brain. A small number of adults with hydrocephalus are treated with a procedure called a third ventriculostomy where a tiny hole is made below the third ventricle in the brain to allow the CSF to bypass a blockage.

Your neurosurgeon will assess your possible suitability for this treatment and discuss this with you. The prognosis for hydrocephalus depends on the individual and is affected by factors such as age, general health, the specific cause of the hydrocephalus, how far the condition has progressed and the extent of the damage to the brain caused by the increased pressure. Left untreated, hydrocephalus can be fatal as increased pressure in the brain can eventually compress the brainstem which is responsible for regulating our heartbeat and breathing.

Shunts are usually a successful treatment. It is possible for adults with hydrocephalus to make a full recovery when treated with a shunt. Support and information on spina bifida and hydrocephalus for people in England, Wales and Northern Ireland. Please tell us what you think of our information so we can keep improving it, and click the link below to fill in our feedback form. Fill in our feedback form. Should you wish to view the references for this publication, please contact luke.

Call to talk to the team. Our online communities are a great way for people affected by neurological problems to interact, share their experiences and provide mutual support. Your donation will ensure we are there for people affected by neurological conditions, providing support at the right time, in the right way. Home Our publications Fact sheets Hydrocephalus and shunts. You can download this fact sheet to view offline or print by clicking the link below.

The normal range of ICP in healthy adults is around 5—15 mmHg with increases to 30 mmHg considered pathological, and 40 mmHg life threatening [ ]. Current mechanisms of mitigating elevations in ICP often involve invasive surgical intervention. Therefore, investigations of approaches to pharmacologically attenuate these elevations are in high demand [ 2 ].

Values are based on a baseline mean arterial pressure MAP of 80 mmHg. In the compensated model, an increase in cerebral blood volume produces a decrease in cerebrospinal fluid CSF volume; this allows ICP and CPP to remain at baseline level. Increased intracranial pressure is reported as a symptom or complication in several CNS pathologies like hydrocephalus [ 2 , ], IIH [ , , ], TBI [ ], intracerebral haemorrhage ICH [ ], subarachnoid haemorrhage SAH [ 26 , , ], and ischaemic stroke [ , ].

A comprehensive review of altered CSF dynamics in each of these CNS disorders would be beneficial; however, the depth required is outside the scope of this review. Instead, this section will briefly outline CSF dynamics in CNS disorders with an extended focus on literature regarding altered CSF dynamics in the context of ischaemic stroke and SAH to reflect the research interests of the authors.

Hydrocephalus occurs as a result of several congenital and idiopathic conditions characterised by increased fluid accumulation in the brain and swollen ventricles. Hydrocephalus may also be non-obstructive, in which CSF flow within the ventricular system is not impaired but there is decreased absorption. Additionally, tumours of the choroid plexus may also produce increased CSF secretion in rare cases and if this increased secretion is not compensated for by increased outflow, then hydrocephalus can occur [ 2 ].

The incidence of IIH varies worldwide with an estimated incidence of 0. The primary treatment of IIH is acetazolamide, which, as discussed above, is a carbonic anhydrase inhibitor capable of reducing CSF secretion. However, this seems to be a case of targeting the symptom rather than the cause, and often patients are referred for a ventricular or lumbar CSF shunt [ ].

Further, the use of acetazolamide to mitigate the symptoms of IIH may be detrimental in other aspects of CNS health, since CSF has roles in protein and metabolite clearance [ ]. Studies have implicated the role of aquaporins in the oedema development in cases of TBI, and upregulation of AQP4 and AQP9 is observed across the whole brain in experimental animal models [ ].

This demonstrates that in TBI, aquaporin upregulation can be attributed to hypoxia, and is relevant in other conditions of CNS injury, like ischemic stroke, in which hypoxia and oedema also occur. The result of increased vascular permeability associated with BBB disruption, or vasogenic oedema is the paracellular leakage of protein and ion rich fluid into the brain. This can lead to a number of complications after TBI. Conversely, proteins normally sequestered in the brain will then have access to peripheral circulation and tissues [ , ].

There are some recent preclinical studies indicating that modulation of the BBB using small inhibitory RNA directed against claudin-5 may markedly improve the outcome of patients with cerebral oedema [ ].

Signs of cytotoxic oedema, like cellular swelling, can be induced in as soon as 30 min following ischaemia, hypoxia and structural injuries. Changes in osmotic balance between the intracellular compartment and the ECS occur as a result of this cytotoxic oedema.

This process leads to a net movement of water from the ECS to the intracellular compartment, and swelling of the brain may occur as a consequence of the ion gradient setup between the ECS and cerebral microvasculature. Williamson et al. Additionally, ICP was more stable in drug-treated rats—a marker of improved intracranial compliance. In this example, although CSF was not the primary cause of the elevated pressure, it was still beneficial as a target in attenuating the effects of ICH [ ].

Neurological injury following SAH can be described as biphasic. Global ischaemia and toxicity of subarachnoid blood cause initial brain injury on the incidence of vessel rupture [ , ]. The predicted long-term outcomes of SAH are worse than that of ischaemic stroke, and many survivors continue to experience cognitive deficits, decreased quality of life, altered mood and fatigue even years after the incident [ ].

Secondary physiological responses to SAH can have drastic consequences on the survival of tissue within the brain parenchyma. There is significant evidence of hydrocephalus, vasospasm and increased ICP in response to vessel rupture [ , ]. However, as the study was conducted in patients, a causative relationship has not been tested. Others have also reported increases in ICP following vessel rupture, along with hydrocephalus and vasospasm [ , , , ].

A clinical study of 27 SAH patients found that all patients within their cohort experienced some degree of ICP elevation following vessel rupture [ 26 ]. The mechanisms driving this ICP could be attributed to blood entry from the ruptured vessel or oedema development in response to injury. Overall, the rise in ICP observed in patients was associated with poor clinical outcome; therefore, investigations of therapies to target this elevation in ICP are required.

However, some clinical observations have reported disruptions to CSF flow associated with SAH [ , , , ], and studies of animal SAH models support these observations [ , ]. The authors proposed that this attenuation in CSF flow was tissue-factor TF dependent; however, a causative relationship could not be determined as increased haemorrhaging in the presence of TF antibodies dampened the fluorescent signal of the tracers.

Reports of impaired CSF flow following SAH provide insight into the mechanisms underlying this ICP rise and create new pathways for exploring therapeutic tactics to reduce this ICP in the hope of preventing secondary degeneration. A better understanding of CSF circulation and outflow pathways would further advance efforts to minimise deterioration after SAH.

ICP elevation has been demonstrated following ischaemic stroke in both animals and humans [ , , ]. These observations have long been associated with oedema development; however, oedema may not be the sole determinant of increased ICP. Oedema is a known complication of ischaemic stroke, particularly in cases of large cerebral infarction.

A higher degree of neurological deficit is reported in stroke patients presenting with oedema when compared to those without [ ]. In some cases, this oedema requires medical intervention mannitol, diuretics, corticosteroids, barbiturates and surgical decompression to alleviate the consequently high ICP [ ].

The attenuation of oedema volume in a rodent model of ischaemic stroke improves functional outcome, which offers a potential target for improving symptoms in humans [ ]. Human studies of ICP elevations following ischaemic stroke primarily investigate patients with large oedema, and because of the invasive procedures involved, the studies do not include patients suffering smaller strokes [ ].

This leaves us with questions surrounding elevations in ICP in patients suffering smaller strokes: is oedema, in fact, the underlying cause; and if not, what is? A recent study using a preclinical rodent model of ischaemic stroke demonstrated a transient ICP elevation approximately 24 h after ischaemic stroke [ 17 ]. This investigation provides evidence of ICP elevation after relatively minor stroke. Oedema was observed in the ipsilateral hemisphere of the experimental group, which could be prevented by therapeutic short-term moderate hypothermia However, volume of oedema could not be correlated with elevations in ICP, suggesting that oedema was not the only cause of ICP elevation in these animals [ ].

This study casts doubt on the causative relationship of oedema and ICP that was previously assumed. It is highly likely that a change in CSF volume could be a contributing factor to these observations when there is no change in cerebral blood volume.

So how might CSF secretion be altered following ischaemic stroke? Ischaemic stroke is a major stressor in the CNS and can drastically alter the physiology of individual cells, tissue and fluid transport.

As discussed above, the choroid plexus is regarded as a major site of CSF secretion; therefore, alterations to its function as an outcome of ischaemic stroke may have an impact on CSF secretion and consequently, ICP.

At 6-h of reperfusion, they found that 10 min of occlusion doubled the BCSFB permeability, while 30 min of occlusion trebled permeability [ ].

The influence of ischaemia on BCSFB integrity may be significant in understanding how fluid exchange at the choroid plexus alters following ischaemic stroke. However, permeability of the BCSFB was not investigated following MCAo, therefore, it is unclear if this model produces a significant loss of barrier integrity or whether drastic major occlusion is necessary for a noticeable difference.

We do know that MCAo causes loss of integrity of the BBB, which can increase fluid, ion and lymphocyte entry into the brain [ ]. Ennis and Keep [ ] also noted oedema of the choroid plexus after 24 h of permanent occlusion.

Additional morphological studies have identified swelling of the choroid plexus epithelium and markers of proliferation through bromodeoxyuridine staining post-stroke [ ]. Before that study, no morphological changes were identified by Nagahiro et al. Further study of morphological changes to the choroid plexus during and after ischaemic stroke are warranted and may give us more of an understanding of how CSF secretion is affected by ischaemia and an indication of how long disruptions to CSF physiology persist.

Recently, a nonselective cation channel has piqued interest within research of the choroid plexus. Preston et al. The authors of this study postulate that the channel plays a role in the regulation of CSF secretion. This suggestion that TRPV4 is involved in the regulation of CSF is interesting considering other groups have detected an upregulation of TRPV4 in the ipsilateral hemisphere following ischaemia which contributes to greater neuronal injury [ ].

Although highly expressed in choroid plexus epithelial cells, as far as we are aware, the expression and activity of TRPV4 in the choroid plexus has not been investigated following ischaemic stroke. Given the results presented by other groups, it would be an interesting path of exploration—particularly considering its potential role in CSF secretion regulation.

Interestingly, a recent study detected AQP4 expression in the choroid plexus of aged mice, which was undetectable in young mice [ ]. They also observed an increase in ventricular size and intraventricular pressure in aged animals when exposed to hypoxia that was less prominent in young animals. This increase in ventricular size was absent in a homogenous AQP4 knockout model. These data implicate AQP4 in hypoxia-induced hydrocephalus and subsequent cognitive decline, likely because of increased CSF secretion.

Experiments using AQP knockout mice indicate that osmotically driven water transport following ischaemia or acute water intoxication leading to cytotoxic oedema is mediated by AQP4 in the presence of an intact BBB [ ]. Following MCAo in mice, AQP4 expression has been shown to be temporarily reduced or lost around 24 h post stroke during the reperfusion phase, and a partial recovery by 72 h post stroke [ ]. The authors concluded that the biphasic change in perivascular AQP4 expression might define water influx subsequent to oedema at 24 h, followed by supporting absorption of excess fluid by 72 h.

In addition, hydrocephalus induced by hypoxia during ischaemic stroke would contribute to an overall elevation in ICP, and if increased CSF secretion does in fact occur in response to hypoxia, then this is an important consideration in current animal models of stroke, particularly MCAo, in which occlusion of the anterior choroidal artery can induce a degree of hypoxia within the choroid plexus.

Several attempts have been made to develop pharmacological inhibitors of AQP4 to reduce brain oedema following ischaemia with little success [ ].

Recently, Far et al. This review summarises our current understanding of CSF dynamics with a focus on effects on ICP during neurological diseases, and highlights some of the discrepancies within the field. The implications of such findings are of high clinical relevance for understanding and treating neurological diseases where brain fluid homeostasis is impaired. Our efforts to elucidate the regulators and mechanisms involved in CSF secretion are still ongoing.

Some evidence suggests the involvement of AQP1 at the choroid plexus [ 83 ], and more recent discoveries implicate the molecular transfer of water via NKCC1 in CSF secretion [ 70 ]; these insights may provide targets for therapeutic control of CSF in conditions of excessive secretion and elevated ICP.

Regarding CSF drainage, the conventional view of transport into the superior sagittal sinus by arachnoid projections is challenged with evidence of the involvement of extracranial lymphatics [ 14 , 15 , 16 , 17 , 18 ]. Other hypotheses of CSF drainage have been proposed but are currently criticised within the field. Inhibitors of CSF production, like acetazolamide, are widely used in clinic for lowering ICP, and animal studies have demonstrated their ability to decrease ICP in rats [ , ].

However, their efficacy in humans is controversial with some reporting attenuated symptoms of elevated ICP in IIH patients prescribed acetazolamide [ ], and others reporting that weight loss was more efficacious than acetazolamide [ ].

Further, a recent Cochrane review concluded that there is currently insufficient evidence to support or reject the clinical use of acetazolamide in treating symptoms of elevated ICP in IIH [ ]. Determining the exact role of these proteins in modulating CSF dynamics and the resulting influence on ICP offers potential to identify therapies that are of translational value.

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