**2. Cerebrospinal fluid circulation and biomechanical properties of the craniospinal system (CSS)**

#### **2.1 Cerebrospinal fluid**

CSF is normally a pure colorless liquid with a relative density of 1.007 and a pH of ≈7.33–7.35. Basically, it is produced by the vascular plexuses of the lateral, III and IV ventricles, passing through the holes of Monroe, the water supply of the brain, the holes of Mazhandi and Lyushka, and enters the subarachnoid space of the brain and spinal cord, from where it is absorbed into the venous system through a system of channels and pachyonic granulations [9, 10]. Two-thirds of the CSF volume is considered to be of choroidal origin. The other part of CSF is produced by the ependyma of the brain, its membranes, and brain tissue [11].

The rate of CSF production is 0.3–0.5 ml/min and it depends mainly on blood pressure, from the pressure in the choroidal artery, and from the activity of the membrane mechanisms involved in the formation of CSF—to be precise.

CSF absorption occurs through the membranes of the parasagittal zone (arachnoid granulations) of the brain. This is how the resorption of the main volume (2/3) of CSF is carried out. The other part of the CSF is absorbed through the membranes of the meningeal sheaths of spinal and cranial nerves, membranes, and parenchyma of the

*CSF Bypass Surgery in Children with Hydrocephalus: Modern Possibilities, Prospects… DOI: http://dx.doi.org/10.5772/intechopen.110871*

brain. Under normal conditions, the rate of CSF resorption is balanced with its production [5, 10, 11].

#### **2.2 Structural units of the cerebrospinal fluid circulation system**

The ways of CSF circulation are fairly well described. The CSF circulates in a certain direction. Under normal conditions, CSF from the lateral ventricles through the holes of Monroe enters the III ventricle, then into the water supply of the brain and the IV ventricle. Further, through the holes of Luschka and Magendie, CSF enters the cisterns of the base of the brain (cerebellar-cerebral, covering the cistern of the bridge, chiasmal, and the cistern of the Sylvian furrow) and then onto the convexital surface into the subarachnoid space. Channels and cells of arachnoid shells are structural units of the liquor outflow pathway system. However, in pathological conditions, the arachnoid shell, being highly reactive, is able to rapidly proliferate arachnoid cells with the walls thickening, to accumulate water by collagen fibers, which finally disrupts normal circulation of the CSF.

Part of the CSF from the spanning cistern of the bridge enters the cisterns of the cerebellar worm. A smaller volume part of the CSF enters the cerebrospinal subarachnoid space (**Figure 1**).

The volume of the cranial part of the CSF is about 68% of the total volume of the craniospinal cavity, and the spinal part is 32%, respectively. Approximately 1/3 of the CSF volume is located in the ventricles of the brain, 1/3—in the subarachnoid cerebral and 1/3 of the volume—in the spinal subarachnoid spaces [4, 5, 10–12].

#### **2.3 Physiological support of CSF circulation**

CSF outflow is provided by the presence of a pressure gradient (15–30 mm of water) between the ventricles of the brain and the subarachnoid space [9].

CSF absorption is achieved due to the difference in pressure in the brain sinuses and CSF pressure. The rate of CSF resorption is directly proportional to the amount of CSF pressure and inversely proportional to the venous pressure in the upper

longitudinal sinus [5, 9]. The intracranial pressure remains relatively stable, and with an increase in intracranial pressure up to 300 mm of water column CSF resorption becomes inhibited. The pressure in the upper sagittal sinus is about 12 mm Hg. With the CSF and intrasinus pressures being equalized (below 5 mm Hg), CSF resorption is disrupted. With an increase in intracranial pressure greater than 7 mm of water column, a linear increase in the rate of CSF resorption is observed [13, 14].

Resorption resistance is a characteristic reflecting the state of the CSF pathways and CSF outflow pathways into the venous system. Due to the fact that the resorption rate is linearly dependent on the pressure gradient, a change in the resorption resistance of the CSF is of practical importance [9, 11].

Pulse fluctuations have a significant effect on the CSF circulation, the volume of blood in the cranial cavity, and the waves propagate in the caudal direction.

Respiratory wave fluctuations in liquor pressure caused by the formation of respiratory pressure waves in the pleural and abdominal cavities are transmitted to the veins in the cavities of the skull and spine. Respiratory waves of venous pressure cause the flow of CSF from the cranial to the spinal cavity. Respiratory waves of arterial pressure and pressure in the inferior vena cava normally do not affect the fluctuation of intracranial pressure.

The liquor pressure equal to 112–130 mm of water column (about 9–10 mm Hg) is theoretically a "normal" pressure [5, 10, 11]. Normally, at constant pressure in the craniospinal cavity, the amount of liquor produced is equal to the volume of the absorbed.

#### **The reasons for the excessive accumulation of CSF can be**:


Excessive accumulation of CSF leads to a violation of the dynamic equilibrium of "production-resorption" and to the expansion of the cerebrospinal cavities and the decrease in the volume of the medulla [11, 15, 16].

#### **2.4 Volumetric components of CSS**

The "Monro-Kellie" theory describes the volumetric relationships within the CSF, or craniospinal cavity. The up-to-date version of the theory asserts that three volumetric components capable of changing their quantitative values are determined in the relatively rigid cavities of the skull and spine [5]:


The craniospinal cavity is represented by a closed space, limited by the meninges, in which the brain and spinal cord are enclosed. Some elasticity of the formations of the cranial cavities was also noticed due to the malleability of the tissues of the atlanto*CSF Bypass Surgery in Children with Hydrocephalus: Modern Possibilities, Prospects… DOI: http://dx.doi.org/10.5772/intechopen.110871*

occipital membrane, the multitude of holes at the base of the skull, as well as the possibility of divergence of sutures in children with intracranial hypertension (ICH). Spinal tissues have significantly greater elasticity due to the extensibility of the intervertebral ligaments and the possibility of protrusion of the dura mater at the exit points of the spinal nerves. With the development of the pathological process at the compensation stage, an increase in one of these volumes is accompanied by a change in the other.

CSS has the properties of elastic materials of malleability (elasticity), viscosity (fluidity) and can be expressed mathematically [5, 10, 11, 17].

The malleability of brain tissue is characterized by the ability to deform under mechanical action. Malleability is closely related to the extensibility of interstitial spaces. The viscoelastic characteristics of the CSS vary depending on the inner pressure.

The biomechanical properties of CSF consist of the malleability of the bones of the cranial vault, the connective tissue membranes of the spine, the state of CSF circulation, changes in blood volume, and the degree of accumulation of water by the brain tissue. The malleability of the entire CSF is an algebraic sum of these indicators for the cranial and spinal cavities [5, 9, 11].

Blood volume and blood pressure level play an important role in changing the elasticity of the CSF. An increase in blood pressure leads to an increase in the volume of the brain due to an increase in the volume of blood in its vessels, an increase in the volume of water filtration, and an increase in the volume of the brain tissue itself, which occurs with a sharp increase in systolic blood pressure, when compensatory constriction of the arteries does not have enough time to develop in response to the increase in blood flow. Unlike arterial pressure, an increase in the venous pressure of the brain immediately leads to the directly proportional increase in intracranial pressure [11].

#### **2.5 Quantitative indicators of liquor circulation and viscoelastic properties of CSF**

Liquor circulation has a significant effect on the mechanical properties of CSF. The change of individual links of the liquor circulation is aimed at maintaining the constancy of the value of the resulting characteristic—the liquor pressure. Disruption of the compensatory capabilities of the CSS is manifested in the development of cerebrospinal hypertension.

Quantitative indicators of CSF circulation and viscoelastic properties of CSF are studied by the method of artificial change of CSF volume and registration of pressure changes in the craniospinal cavity [10, 15, 18].

Two reciprocal curves are used for quantitative characterization: "pressure–volume" P/V, characterized by an "exponential" dependence, or "volume–pressure" V/P (inverse P/V dependence). Both curves display the viscoelastic properties of the CSS and have three characteristic sections (**Figure 2**, **A**, **B**).

The fragment of the curve (a-b) has a flat section, as well as a section of a sharp increase in pressure (c-d) and an intermediate period (b-c). These sections of the curve correspond to the state of the system's backup capabilities. In other words, the elasticity of the system increases exponentially with the development of ICH.

There are three phases in ICH the system goes through: compensation, sub-, and decompensation. In the phase of compensated ICH (site a–b), there is a moderate increase in intracranial pressure, a slight increase in the elasticity gradient, a decrease in malleability, a normal value of resorption resistance, and the rate of CSF production.

**Figure 2.**

*Viscoelastic properties of SCC. A—P/V-dependence graph; B—V/P-dependence graph; C—logarithmic indicator of P/V dependence (pressure-volume index, PVI); D—CSS compliance. P—liquor pressure, V—liquor volume, C—compliance CSS.*

In the subcompensation phase (b–c), there is an increase in intracranial pressure and an increase in resorption resistance. The decompensation phase (c–d) is characterized by the exhaustion of reserve mechanisms, increasing intracranial pressure, decreased CSF production, increased resorption resistance, and elasticity [5, 10, 11].

Marmarou A. and co-authors (1975) proposed a characteristic of the elastic properties of the system—the "pressure-volume" index (Eq. (1)).

$$PVI = \frac{dV}{\lg\left(\frac{P\_p}{P\_0}\right)} (\text{ml})\tag{1}$$

where:

*PVI*—index "pressure-volume",

*dV*—volume change of the CSS,

*Pp*—increased liquor pressure after bolus administration,

*Ro*—initial liquor pressure before the bolus.

They processed the obtained data of the pressure-volume relationship using the logarithmic method and obtained a linear relationship [5] (**Figure 2**, **C**).

A linear equation for determining the compliance of the CSS was also proposed (**Figure 2**, **D**).

$$C = 0,4343 \cdot \frac{PVI}{P} \text{ (ml/mm of water)}\tag{2}$$

where:

*C*—compliance (compliance),

*P*—the liquor pressure at a given time.

The angle of inclination of the curve is an individual constant characteristic of each individual CSS and reflects its compliance, individual ability to maintain constant

*CSF Bypass Surgery in Children with Hydrocephalus: Modern Possibilities, Prospects… DOI: http://dx.doi.org/10.5772/intechopen.110871*

parameters during the development of any volumetric process (Eq. (2)). The pressure-volume index is a constant characteristic of the system in the compensation stage. Compliance is a dynamic characteristic of the system; it inversely depends on intracranial pressure [5, 11].

Pliability, elasticity of the CSS are individual characteristics. As the compensation mechanisms of the system are depleted in conditions of growing ICH, the elasticity of the CSF increases. According to various authors, normal PVI values are considered to be more than 25 ml. PVI indicators in children range from 8.2 to 30.1 ml [9, 10].

Thus, the viscoelastic properties of the craniospinal cavity are due to:


#### **3. Pathomorphology of hydrocephalus**

Occlusive hydrocephalus is the most common among all types of hydrocephalus. It develops in early childhood and is associated with malformations of the CNS, the consequences of birth trauma, or intrauterine infection, accompanied by occlusion of the Lyushka holes and Majandi spikes.

In the first months of life the child's head circumference increases rapidly (sometimes up to 2 cm per week), reaching 50–100 cm by the age of 12 months. At the same time, the bones of the skull become thinner, the cranial sutures diverge, the bone structures of the Turkish saddle atrophy, and the pituitary gland is usually somewhat reduced in size and compressed (flattened). The ventricles of the brain are expanded to one degree or another, the brain cloak gradually atrophies, and its thickness can decrease to 5 mm. The brain in this case is a bubble filled with CSF. A child suffering from severe hydrocephalus is practically deprived of both coordinating systems nervous and endocrine ones. Such patients can suddenly die from pain or emotional stress, mild acute respiratory viral diseases, etc. Without treatment they die, as a rule, at the age of two years.

#### **4. Genetics and genomics of anomalies in hydrocephalus**

Abnormalities of CNS are multifactorial. Both genetic and external factors may be critical, and they may be presented in the combination with synergy effect.

As of today, several groups of genes, associated with CNS abnormalities, are described. Methods of system genomics proved very useful for understanding

neuropathology development [19]. Our analysis was based on OMIM database actual at 17.01.23.

The most catastrophic scenario is neural tube defect up to hydroanencephaly. Combination of genetic and environmental factors is well described in Ref. [20]. Group of genes, associated with susceptibility to neural tube defects (182940), is presented in **Table 1**.

VANGL1 and VANGL2 are very similar with 73.1% primary amino acid sequences identity. Clinical cases are described both in family and sporadic forms [21]. All the forms in this group are autosomal dominant.

Errors in the folic acid cycle may cause neural tube defects. Group of folatesensitive neural tube defects (NTDFS) (601634) is presented in **Table 2**.

Variants in MTHFR, MTR, MTRR, and MTHFD1 may lead to change in folic acid and cysteine concentration. Moreover, they may change individual need in folic acid and cobalamin. Clinical aspects are well described in [22].

Three autosomal recessive forms of congenital hydrocephalus are described (**Table 3**).

Additionally, 3 clinical variants (307000) with X-linked recessive inheritance are associated with L1CAM gene. Typical mechanism observed in this case is congenital stenosis of the aqueduct of Sylvius [23].

Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome (MPPH) is caused by heterozygous mutation in 3 genes. This fact illustrates genetic heterogeneity of clinically similar states [24] (**Table 4**).


#### **Table 1.**

*Susceptibility to neural tube defects.*


#### **Table 2.**

*Folate-sensitive neural tube defects.*

*CSF Bypass Surgery in Children with Hydrocephalus: Modern Possibilities, Prospects… DOI: http://dx.doi.org/10.5772/intechopen.110871*


#### **Table 3.**

*Congenital hydrocephalus.*


#### **Table 4.**

*Megalencephaly-polymicrogyria-polydactyly-hydrocephalus syndrome.*

Several forms of genetic hydrocephalus in combination with other clinical features are described, usually as clinical cases. Generally, mutations in different genes may cause similar phenotypes, and mutations in one gene may lead to different clinical variants. Many pathways may be discussed, but the two are evident: errors in folic acid exchange and genetic-related stenosis of the aqueduct of Sylvius.
