Introduction

Hydrocephalus is a common medical condition characterized by abnormalities in the secretion, circulation and absorption of cerebrospinal fluid (CSF), resulting in ventricle dilatation. It is not only caused by congenital malformation, but also resulted from different kinds of neurological diseases. Recently, a seminar of hydrocephalus in Lancet and the basic researches of hydrocephalus have attracted extensive attention of neurosurgeons [1]. We present a new concept of the pathogenesis and therapeutic orientation of hydrocephalus base on the existing research result.

It is almost a century since Dandy made the first experimental studies on hydrocephalus, but its underlying mechanism remains unknown up till now [2]. As to our previous knowledge, the etiologies of hydrocephalus include hyper-secretion (papilloma choroideum), circulation disturbance (block of aqueduct, foramen of Monro, Aqueduct of Sylvius or subarachnoid space by congenital malformations, tumor or hemorrhage) and mal-absorption (communicating hydrocephalus) [3]. The former two reasons of hydrocephalus is easy to understand and can be cured by removing the etiological factor surgically. As for the communicating hydrocephalus, without etiological treatment, its pathogenesis has been considered as a research emphasis.

Homeostasis of CSF

The choroid plexus produces 400–500 ml CSF per 24 h and the total CSF volume is 120–150 ml. Thus, CSF recycles over three times per day. The traditional theory indicates that CSF secretes in choroid plexus, circulate in the CSF system and be absorbed in the subarachnoid space. But a recently proposed new working hypothesis suggests that CSF is permanently produced and absorbed in the whole CSF system as a consequence of filtration and reabsorption of water volume through the capillary walls into the surrounding brain tissue [4, 5]. The brain capillaries also produce a significant amount of fluid. The filtration and absorption of fluid in the brain capillaries is governed by the Starling principle [6, 7]. The interstitial fluid originating from the brain capillary adequately substitutes the CSF in the subarachnoid space.

CSF exchange remains a homeostasis status that the secretion and absorption can fluctuate within a certain range. It is also an important factor to remain the stability of intracranial pressure as it is dependent on the balance between the production and absorption of CSF. If the secretion increase or decrease on a small scale, the self-compensatory intracranial pressure will not impact the CSF circulation and thus the ventricle will not be enlarged. Homeostasis of CSF is maintained by the exchange of the interstitial fluid across the thin arachnoid membrane covering the outer surface of the brain. The homeostasis also exists in other organs which are surrounded by fluids, i.e. fluids in the eyes, pleura, peritoneum, pericardium and articulate joints [8, 9]. The excessive water can be absorbed quickly by ubiquitous fluid exchange in human body.

In terms of the pathogenesis, subdural hematoma and hydrocephalus are similar because they are all intracranial fluid metabolic disorders [10]. The balance has been broken down so that additional liquid cannot be absorbed either in ventricle or subdural. As ventricle enlargement and hydrocephalus mostly occur through a net increase in the overall brain water content, alterations to water regulation may be a contributory factor. Water movement across cell membranes can be facilitated by water channels called aquaporins (AQPs) [11–14]. According to Miyajima’s research, with the change of AQP4 expression in H-Tx rats, animals develop alternative pathways of CSF circulation [15].

Homeostasis disorder and irreversible hydrocephalus

Many neurological diseases, including brain trauma, infection, ICH, SAH, and even tumor surgery can damage the CSF system and become increase the risk of hydrocephalus. The damage influenced the whole absorb system in the CSF circulation pathway rather than a certain part. But according to our clinical experience, a big proportion of patients do not develop hydrocephalus. That is because the absorbing ability of CSF can compensate within a certain range. If the damage exceeds that range, hydrocephalus will occur. Once it occurs, it means the damage of CSF system is beyond the compensation range and it will be deteriorate because of the subsequent ventricle dilatation, white matter damage and the destruction of brain physiological structure. These symptoms are not likely to be reversed, so a shunt surgery is always needed (Fig. 1).

Fig. 1
figure 1

The secretion of CSF is 400–500 ml per day and there is also some compensatory of our CSF absorption system which is different for different people (a). Different brain damage or the damage for different people will due to different influence to CSF absorption. If the damage exceeds the compensation range that will cause hydrocephalus (b); while if the damage is within the compensation range, there will be no hydrocephalus for the patient (c)

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Therefore, we believe that neurosurgeons should focus on prevention in some high risk situation rather than trying to cure it when it already occurred. It is similar with chronic renal disease that the renal function cannot be reversed when the patient is already in renal failure stage. However, if the process of kidney failure can be intervened in the early stage, the kidney function could be recovered. According to the hypothesis, we divide the process of hydrocephalus into three stages. Stage 1: compensatory stage of CSF absorption. In this stage, the absorptive capacity of CSF is declining because of many different reasons but still in the compensation range and almost every brain damage will impact patients’ CSF absorptive capacity. Many patients stay at this stage and others will continue to progress into next stage. Stage 2: CSF absorption decompensatory stage. In this stage, the CSF secretion overtakes its absorption so that ventricle start to enlarge and clinical symptoms may occur. Without effective intervention, the process will progress. Stage 3: hydrocephalus stage. In this stage, with the enlarged ventricle, CSF circulation run into complete disorder and brain functions can be damaged continuously. This process cannot be reversed and a shunt will be the only solution. Therefore, we believe that our therapeutic orientation could transform from the treatment of patient who already showed hydrocephalus symptoms to prevent the occurrence in the patient with high risk of hydrocephalus (stage 1 and stage 2) (Table 1).

Table 1 Three stages of hydrocephalus
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Now, many research still focus on the treatment of existed hydrocephalus, try to alleviate the system and improve nerve function by drugs. So far, the result is inspiring that many research illustrate that hydrocephalus can be alleviated by different kinds of drugs in animal models which indicate that severe hydrocephalus animal have the potential to be cured or released [16–25]. It seems contradict to our hypothesis. However, in our opinion, drugs can only reduce the occurrence of hydrocephalus (prevent the development in stage 1). Researchers usually think that therapeutic effect exists, when the statistical analysis shows that the treatment group with milder average ventricle dilatation compared with control group. Then, most researchers killed all the animal models for histological detection at the same time (usually 2 weeks) and neglect the long-term effect of the animal which present smaller ventricle in MR scan [16–25].

We observed the early stage of hydrocephalus treatment and paid much attention to the average ventricle sizes. For the animals which have already developed ventricle dilatation, what if the drugs just delayed the process of hydrocephalus through certain mechanism, but the prognosis have not been changed. Advanced animal researches are needed to investigate the long-term result of the “cured” animals.

Potential treatment orientation

Base on the hypothesis above, we believe that to control the primary and secondary damage of the absorbing system to reduce of hydrocephalus occurrence is the key point of its treatment. The primary and secondary damage include alterations to the blood-CSF barriers reactive gliosis, neuro-inflammation, fibrosis, iron metabolism and so on. If there are any drugs that can release the inflammation response, prevent fibrosis and reduce the hydrocephalic brain damage into the compensatory range, the occurrence could be significant reduced [26]. Therefore, if the damage does not pull the trigger, hydrocephalus can be prevented (prevent its development in stage 1).

According to previous research, third ventriculostomy shows its potential in the treatment of communicating hydrocephalus. Third ventriculostomy offers an alternate treatment to shunting. It may also be used to replace the shunt when a child is older. This strategy has been successful in shunted premature children with post-hemorrhagic hydrocephalus [27]. In this way, many children may become shunt-independent. We believe that although it cannot change the absorption ability, it facilitates the CSF circulation, so that the excessive CSF can be absorbed more effectively. There are also some researches showed that external ventricular drainage and continuous lumbar drainage for intraventricular hemorrhage hydrocephalus can reduce the complication including chronic hydrocephalus [28–31]. It may because that these treatments accelerated the reduction of subarachnoid clots and alleviated the stimulation and damage to ventricle system. So these results demonstrate the hydrocephalus can be stopped at stage 2.

According to our previous knowledge, the absorptive capacity displays a long and slow declining process and hydrocephalus can occur in a long time range after brain damage, so the prevention strategies should sustain for a long time. Scientists already found some drugs with potential, but none of them, including glucocorticoid, antibiotics, deferoxamine, decorin and some fibrosis inhibitors, have been tried on the patients, which is out of the consideration of the known or unknown risk of long-term administration of those drugs [16–25]. Even if animal experiments have been finished, the approval process would still take a long time.

According to a lot of publications in the last several years and our previous research, statins shows its possibility in the prevention of hydrocephalus. Statins have strong anti-inflammatory effect by inhibiting the expression of many inflammatory factors and lower serum inflammatory markers [10, 32–34]. The effects of statins on the inflammation regulation and elimination of subdural hematoma has been reported recently [10, 35]. Besides, the long-term use of statins can significantly reduce chronic inflammation of the arteries and reveal no side effects even in long-term administration. In conclusion, the future research direction should be the prevention of hydrocephalus, which should take a long period from the immediate occurrence of brain injury to several months or even years after the injury.