Anatomy, Physiology and History of Cerebrospinal Fluid

#### **Chapter 1**

## History, Anatomy, Histology, and Embryology of the Ventricles and Physiology of the Cerebrospinal Fluid

*Pinar Kuru Bektaşoğlu and Bora Gürer*

### **Abstract**

Cerebrospinal fluid is an essential, clear, and colorless liquid for the homeostasis of the brain and neuronal functioning. It circulates in the brain ventricles, the cranial and spinal subarachnoid spaces. The mean cerebrospinal fluid volume is 150 ml, with 125 ml in subarachnoid spaces and 25 ml in the ventricles. Cerebrospinal fluid is mainly secreted by the choroid plexuses. Cerebrospinal fluid secretion in adults ranges between 400 and 600 ml per day and it is renewed about four or five times a day. Cerebrospinal fluid is mainly reabsorbed from arachnoid granulations. Any disruption in this well-regulated system from overproduction to decreased absorption or obstruction could lead to hydrocephalus.

**Keywords:** arachnoid villi, cerebrospinal fluid pressure, choroid plexus, hydrocephalus, ventricular system

#### **1. Introduction**

Cerebrospinal fluid (CSF) is located in the brain ventricles, the cranial and spinal subarachnoid spaces [1, 2]. It acts as a cushion and plays a significant role in brain development, in the regulation of the interstitial fluid of the brain parenchyma and healthy neuronal functioning [1]. CSF is mainly produced from the choroid plexuses and mainly absorbed through arachnoid villi. The mean CSF volume is 150 ml, with 125 ml in subarachnoid spaces and 25 ml in the ventricles. In this chapter, historical understanding, anatomy, histology, embryology of ventricles, and physiology of CSF will be discussed.

#### **2. Historical understanding of the ventricular system and cerebrospinal fluid**

In ancient times, ventricles were thought to be the site of emotions, mind, judgment, and memory. Hippocrates (460–375 BC), described congenital hydrocephalus as 'water' around the brain [3]. Most likely, Aristotle (384–322 BC) was the first one who noticed the presence of brain cavities, especially the lateral ventricles [4]. A Greek physician, Herophilos of Chalcedon (335–280 BC) was the true discoverer

of the first human cadavers dissections [5]. He also described the choroid plexuses [6]. Erasistratus of Ceos (304–250 BC), a scholar of Herophilus, suggested the ventricular theory [7]. Rufus of Ephesus (110–180), master of Galen of Pergamum, elaborated the lateral, third, and fourth ventricles and the mesencephalic aqueduct [7]. Galen (130–200) also described the ventricular system detailly and mentioned pneuma, a breath that arises from the cosmos which circulates through the brain cavities, and serves as a mediator between body and soul [7, 8]. He also specified that obstruction of the ventricular system causes seizures. In Anathomia (1316), Mondino de Luzzi (1270–1326) preserved the tricameral theory for cerebral ventricles, which is mostly influenced by Galenic tradition [9]. Leonardo da Vinci (1452–1519) made the first ventriculography on the ox brain and extracted a threedimensional template that showed the shape of the ventricular labyrinth [2, 10]. In 1859, a German anatomist and surgeon Benedict Stilling (1810–1879) describe the terminal ventricle as a cystic cavity lined by ependymal cells located in the conus medullaris for the first time [7]. Then, in 1875, Krause called it the fifth ventricle, named after him as Krause's ventricle [7].

Cerebrospinal fluid is discovered by E. Swedenborg (1688–1772) [11]. In 1747, a Swiss physician A. von Haller (1708–1777), presented that in the brain the 'water' is secreted into the ventricles and absorbed in the veins. Hydrocephalus has resulted from excess secretion, which descends to the skull base and into the "spinal marrow" [12]. Domenico Felice Antonio Cotugno [13] was the one who first defined the connection between cerebral ventricles and subarachnoid space. A French physiologist, F.J. Magendie (1783–1855) also confirmed this finding [13]. An opening in the roof of the fourth ventricle, foramen Magendie, was discovered by Magendie, however, erroneously mentioned that CSF was secreted by the pia mater [14]. T. Willis (1621–1675), an English physician, described "a liquid" in the aqueduct of Sylvius that connects the ventricles, and continued that the consistency of the "liquid" is altered in "epidemic fever," i.e., meningitis [15]. In 1891, W.E. Wynter (1860–1945) by tapping the spinal subarachnoidal space treated tuberculous meningitis [16]. H. Quincke (1842–1922), a German internist and surgeon popularized lumbar puncture and advocated its use for diagnostic and therapeutic reasons [17]. In 1912, a neurologist W. Mestrezat (1883–1928) described the chemical composition of the CSF accurately [18], and in 1914, a pioneer neurosurgeon H.W. Cushing (1869–1939), made it clear that the CSF is secreted by the choroid plexus [19].

#### **3. Anatomy of the ventricular system**

In the brain, there are 4 ventricles: 2 lateral ventricles, the third ventricle in the diencephalon, and the fourth ventricle in the hindbrain (**Figure 1**) [2]. It is continuous with the central canal of the spinal cord caudally.

#### **3.1 The lateral ventricles**

The lateral ventricle is a C-shaped cavity with a capacity of 7–10 ml [2]. It encompasses the thalamus and diencephalon and is divided into five segments. The lateral ventricle has body (central portion), atrium (trigone), and 3 horns (cornua); anterior (frontal), posterior (occipital), and inferior (temporal) horns [21, 22]. The corpus callosum forms the roof of the lateral ventricle, and the posterior portion of the septum pellucidum lies medially. Septum pellucidum is a thin vertical sheet of nervous tissue covered with ependyma on both sides of the ventricles. The caudate nucleus, the lateral dorsal surface of the thalamus, the anterior part of the body of the fornix, the choroid plexus, and stria terminalis form the floor of the lateral ventricle.

*History, Anatomy, Histology, and Embryology of the Ventricles and Physiology… DOI: http://dx.doi.org/10.5772/intechopen.101463*

**Figure 1.** *Illustration of ventricular system anatomy [20].*

#### *3.1.1 The body of lateral ventricle (central part)*

The body of the lateral ventricle lies within the parietal lobe [2]. The anterior limit is the interventricular foramen and the posterior limit is the splenium of the corpus callosum. The inferior surface of the body of the corpus callosum forms the roof. Mostly septum pellucidum forms the medial wall and in the lower part of the medial wall, there is the body of the fornix. From medial to lateral; choroid fissure, choroid plexus that invaginate into the lateral ventricle through a slit space between the fornix and upper surface of the thalamus, the lateral part of the superior surface of the thalamus, thalamostriate vein, stria terminalis, and the body of the caudate nucleus forms the concave floor.

#### *3.1.2 The horns of the lateral ventricle*

#### *3.1.2.1 The anterior (frontal) horn*

The frontal horn is located anterior to the interventricular foramen and moves anteriorly and slightly lateral and downward to lie in the frontal lobe [2]. It has an anterior and medial wall, a roof, and a floor. The posterior surface of the genu of the corpus callosum and the rostrum forms the anterior wall. The medial wall is formed by the septum pellucidum. The roof is formed by the inferior surface or anterior part of the body of the corpus callosum. By a majority, the floor is formed by the head of the caudate nucleus, while the upper surface of the rostrum of the corpus callosum forms a small portion on the medial side.

#### *3.1.2.2 The posterior (occipital) horn*

Posterior horn turn inversely and medially to lie in the occipital lobe [2, 21, 22]. It is mostly asymmetrical. The tapetum (sheet of fibers of corpus callosum) forms the roof and lateral wall. The posteriorly sweeping optic radiation is separated with tapetum from the cavity of the posterior horn. The upper part of the medial wall is formed by the forceps major (fibers of the occipital lobe sweeping backward). The

calcar avis, the lower part of the medial wall corresponds to the in-folding of the anterior part of the calcarine sulcus. There is no choroid plexus at the anterior and posterior horn.

#### *3.1.2.3 The inferior (temporal) horn*

The inferior horn is located inside of the temporal lobe, and it is the longest and largest of the 3 horns [2]. It creates a trajectory around the posterior end of the thalamus, goes posterolaterally and anteriorly into the temporal lobe. The roof is covered laterally by the inferior surface of the tapetum of the corpus callosum and medially by the tail of the caudate nucleus and stria terminalis. The floor is formed medially by collateral eminence produced by the hippocampus and laterally by a collateral sulcus. The hippocampal fibers form the alveus which covers the ventricular surface and form the fimbria converges medially. On the most medial side on the floor, the choroid plexus passes through the choroid fissure rest. The choroid plexus passes from the lateral ventricle into the inferior horn. The amygdaloid complex is situated at the anterior end of the inferior horn [21, 22]. The atrium (collateral trigone) connects the body of the lateral ventricle with the occipital and temporal horns.

#### **3.2 Foramen of monro**

Interventricular foramen of Monro is the communication between lateral and third ventricles, and it is bordered by the fornix, caudate nucleus, septum pellucidum, corpus callosum, and thalamus. The size of the ventricles determined the size and shape of the foramen. If the ventricular size is big, each foramen is rounded-shaped. As the ventricular size decreases, the foramen takes a crescent shape. The medial posterior choroidal arteries, the septal veins, and the superior choroidal vein pass through this structure [23].

#### **3.3 Third ventricle**

The third ventricle is located in-between the 2 thalami and some portion of the hypothalamus. This narrow vertical cavity of the diencephalon communicates with the lateral ventricles in the anterosuperior aspect, while on its posteroinferior aspect through the cerebral aqueduct of Sylvius, it communicates with the fourth ventricle [2]. The third ventricular cavity is lined by ependyma and is traversed by massa intermedia (interthalamic adhesion) that connects the 2 thalami which are located posterior to the foramen of Monro. It has a roof, a floor, 2 lateral walls, anterior and posterior walls.

A sheet of ependyma forms the **roof** which connects the upper border of the lateral wall of the ventricle. A triangular fold of pia mater, tela choroidea, covers the roof and it gives rise to the choroid plexus of the third ventricle. The **floor** descends ventrally and is formed by the optic chiasma, mammillary body, tuber cinereum, infundibulum, posterior perforated substance, and tegmentum of the midbrain [2].

From the interventricular foramen to the cerebral aqueduct, a curved hypothalamic sulcus extends and forms the **lateral wall**. The lateral wall is divided into 2 parts by the sulcus. The medial surface of the anterior two-thirds of the thalamus forms the larger upper part. The hypothalamus forms the smaller lower part and it is continuous with the floor. The anterior columns of the fornix that divided laterally into the lateral walls, the anterior commissure, and the lamina terminalis form the **anterior wall**. The lamina terminalis is a thin sheet of gray matter that extends superiorly from the rostrum of the corpus callosum, inferiorly to the optic *History, Anatomy, Histology, and Embryology of the Ventricles and Physiology… DOI: http://dx.doi.org/10.5772/intechopen.101463*

chiasma. The cerebral aqueduct, the pineal gland, and the posterior commissure form the **posterior wall**.

The anterior recess (vulva of the ventricle), infundibular recess, optic recess, pineal recess, and supraspinal recess are the protrusions of the third ventricle into surrounding structures [24].

#### **3.4 The aqueduct of sylvius**

The Sylvian aqueduct measures 18 mm approximately and it is the narrowest part of the brain ventricular system. From the second fetal month, the luminal size of the aqueduct reduces due to the development of neighboring neural tissue [25]. The interventricular blockade mostly occurs here.

#### **3.5 Fourth ventricle**

The fourth ventricle is a wide, diamond-shaped cavity of the hindbrain [2]. It is located posterior to the pons and rostral part of the medulla, and anteroinferior to the cerebellum. On the sagittal section, it is seen as triangular, and on the horizontal section, it is seen as a rhomboidal shape. The floor of the fourth ventricle is also named the rhomboid fossa. It is continuous superiorly with the cerebral aqueduct and inferiorly with the central canal of the spinal cord. The fourth ventricle has 2 *lateral recesses*, a *medial dorsal recess*, and 2 *lateral dorsal recess*.

The fourth ventricle is bounded superolateral by the superior cerebellar peduncle and inferolateral by cuneate and gracile tubercles and inferior cerebellar peduncles.

Two superior cerebellar peduncles form the cephalic portion of the roof. Their medial margins overlap the ventricle on reaching the inferior colliculi. Superior medullary velum bridges the space between the superior cerebellar peduncle. Dorsally, it is covered by the lingula of the superior vermis of the cerebellum. The caudal portion of the roof is covered by the inferior medullary velum, which is formed by the tela choroidea of the fourth ventricle and the ventricular ependyma.

The lateral foramen of Luschka (located near the flocculus of the cerebellum) and the median foramen of Magendie (a large midline aperture, located in the roof of the ventricle at the lower part of inferior medullary velum) are the openings where the fourth ventricle communicates with the subarachnoid space. Mostly, the CSF passes through the medial foramen into the cerebellomedullary cistern, i.e., cisterna magna. The cerebral aqueduct does not contain choroid plexus.

#### **4. The histology and embryology and the ventricular system**

Ependymocytes (ependyma), which are a special type of cells that are columnar or cuboidal epithelium derived from the neuroepithelium cover the ventricular system of the brain [2]. The choroid plexus lies just below the ependymal layer and is responsible for CSF production.

A layer of subependymal glial cells tighten with the astrocyte processes and form the blood-brain barrier. Circumventricular organs are lack this barrier and have fenestrated capillaries with increased permeability. They have secretory and sensory functions. These are the area postrema, median eminence, pineal gland, organum vasculum of lamina terminalis, neurohypophysis, subcommissural organs, and subfornical organ [26]. The ciliary movement is oriented in the anteroposterior neuroaxis which is essential for the movement of CSF.

#### *Cerebrospinal Fluid*

The ventricular system of the brain develops from the cavity of the neural tube [2]. Around the fourth week of gestation the neural tube is formed. Soon after, the spinal neurocele closes, and the neural cavity is separated from the amniotic cavity.

The choroid plexuses firstly appear in the 4th ventricle on the 41st day [27]. Different embryonic tissues give rise to cerebral and spinal meninges. At the third month of intrauterine life, the three meningeal layers differentiate [1]. The choroid plexus epithelium which is derived from the neural tube is continuous with the ependyma. The leptomeningeal axis is derived from the paraxial mesoderm. From the 26th week, cerebral veins dilate in the superior sagittal sinus at their anastomosis site. In the 35th week, the arachnoid villi are formed. The arachnoid stroma lined by endothelium protrudes into the lumen of the superior sagittal sinus via a defect in the dura mater. At the 39th week, real arachnoid granulations appear [28] and continue to develop around 18 months [29].

#### **5. The blood supply and lymphatics of the ventricular system**

The choroid plexus of the lateral ventricle is supplied from the anterior and posterior choroidal arteries, which are the internal carotid artery and the posterior cerebral artery branches respectively [2]. The posterior choroidal arteries supply the choroid plexus of the third ventricle. The anterior and posterior inferior cerebellar arteries supply the choroid plexus of the fourth ventricle.

#### **6. The physiology of the cerebrospinal fluid**

#### **6.1 The cerebrospinal fluid secretion**

Normal CSF formation rate is about 0.35 ml/min for adults, and this ranges from 400 to 600 ml per day [1, 30, 31]. CSF is renewed about four times a day. CSF production is elevated nocturnally and this may be due to cerebral metabolism alterations during sleep [32]. CSF formation also alters in disease states [33]. The choroid plexuses of the lateral ventricles and the tela choroidea of the third and fourth ventricles are responsible for most of the CSF secretion (60–70%) [1, 30]. Other sources of CSF are interstitial fluid, ependyma, and capillaries.

An asymmetrically positioned ion transporters at the blood- and CSF-facing membranes mediates fluid secretion into the ventricles. The choroid plexus epithelium is like the kidney proximal tubule, and transfer copious volumes of fluid [34]. The net transfer of sodium (Na+ ) and chloride (Cl− ) from blood to ventricles determine CSF production [35–37]. From plasma across the basolateral membrane, Na+ entry into choroid plexus epithelium is on a downhill gradient. Potassium (K<sup>+</sup> ), Cl− , and bicarbonate (HCO3 − ) move downhill across the apical membrane into CSF at the other side of the choroid cell. These downhill ionic movements are set up by uphill active transport through the primary Na<sup>+</sup> pump both basolaterally and apically. This process requires chemical energy as adenosine triphosphate [ATP]. Choroid cell Na<sup>+</sup> concentration is kept relatively low by active Na<sup>+</sup> pumping into CSF [38] so a basolateral inward driving force for Na+ transport from plasma into the epithelium was established [39].

For fluid formation the epithelial transport polarity is essential. From blood to CSF net fluid movement is enabled by the polar distribution of certain active transporters and passive channels. Streaming of ions and water were mediated by basolateral (interstitial) and apical (CSF) transporters and channels.

#### *History, Anatomy, Histology, and Embryology of the Ventricles and Physiology… DOI: http://dx.doi.org/10.5772/intechopen.101463*

The direction of fluxes in CSF formation is mostly from interstitium to parenchyma to ventricles. K+ and Cl− passive diffusion (apical efflux) were allowed by channels into nascent CSF [40]. CSF formation is mainly produced by net secretion of Na+ , Cl− , and HCO3 − . Other ions, i.e., K<sup>+</sup> , Mg2+, and Ca2+ also have a role. Through the apical membrane water osmotically follows ion transport.

#### *6.1.1 Sodium secretion*

In CSF formation, the pivotal initiating step is the primary active transport of Na+ from choroidal epithelium to ventricle [41]. Na<sup>+</sup> , K+ -ATPase creates the electrochemical gradient, generates ATP, and empowers Na+ pumping [42]. While CSF is being produced, the apical Na+ efflux is balanced by permanent basolateral Na+ influx through the epithelial Na+ channel (ENaC) and Na+ -inward transport coupled with HCO3 − , by the Na<sup>+</sup> , HCO3 − cotransporter, NBCn2/NCBE in order to equilibrate choroid pH and epithelial volume [39, 43–45].

#### *6.1.2 Chloride secretion*

Chloride, one of the primary anion in CSF secretion, is actively transported through the transcellular route in exchange for cellular HCO3 − across the basolateral membrane [46]. Then for gathering above electrochemical equilibrium, plasma Cl− goes into the epithelium [47]. In certain circumstances, intraepithelial Cl<sup>−</sup> diffuses into CSF through the efflux arm of the Na<sup>+</sup> -K+ -Cl− cotransporter [48]. The downhill diffusion of Cl− into CSF across apical Cl<sup>−</sup> channels is the main pathway by which Cl− accesses the ventricles to sustain fluid formation [40].

#### *6.1.3 Bicarbonate secretion*

In the choroid plexus, HCO3 − has two sources. First, in choroid plexus epithelial cells to form H<sup>+</sup> and HCO3 − ions carbonic anhydrase catalyzes the hydration of carbon dioxide (CO2) [49]. Acetazolamide inhibits CSF secretion at least 50% which indicates that carbonic anhydrase is involved in CSF secretion [50]. Additionally, via Na<sup>+</sup> -coupled HCO3 − transport, HCO3 − is pulled from plasma into the epithelium [43]. When the HCO3 − accumulates, by two mechanisms it is ready for release through the CSF facing membrane. Firstly, in the epithelium downhill through an anion channel HCO3 − diffuses into CSF [51]. Secondly, at the apical membrane HCO3 − is transferred through an electrogenic Na<sup>+</sup> -coupled HCO3 − cotransporter [45, 52]. CSF rich in HCO3 − show increased movement of HCO3 − into ventricles as CSF is produced [53].

#### *6.1.4 K+ transport*

K+ enters into the cells in two ways: from the blood by the Na<sup>+</sup> -K+ -2Cl− cotransporter-1 (NKCC1) and from the interstitial fluid by the Na<sup>+</sup> -pump [54]. On both sides the influx exceeds the net flux across the cells, and thus at each membrane, there are thought to be pathways for efflux of most of the K<sup>+</sup> that enters through K+ channels.

#### *6.1.5 Water secretion*

CSF has excretory, distributive, and buffering functions [31]. Water constitutes 99% of the CSF. After osmotically active Na+ , Cl− , and HCO3 − ions are transport into CSF, water follows them into the ventricles via a transcellular route by diffusing down its chemical potential gradient in the apical membrane through aquaporin 1 (AQP1) channels [55, 56]. AQP1 facilitates water transport from the interstitium to the CSF in the luminal and basolateral membrane [42]. Across the choroid plexus, transcellular water diffusion is a potential drug target to modulate CSF dynamics [55]. In regulating water molecule traffic through AQP1 channels agents structurally related to acetazolamide, furosemide, and bumetanide, and steroid hormones show promise [55, 57]. The composition of CSF and comparison with serum content were summarized in **Table 1**.

#### **6.2 Regulation of cerebrospinal fluid regulation secretion and composition**

The choroid plexuses receive adrenergic, peptidergic, cholinergic, and serotoninergic autonomic innervation [1]. The cholinergic system increases CSF secretion while the sympathetic nervous system reduces CSF secretion. Circadian variations of CSF secretion may be regulated by the autonomic nervous system.

The targets of humoral regulation are enzymes and membrane transporters. The activity of carbonic anhydrase is regulated by the acid-base disorders, membrane carrier proteins (i.e., the NaK2Cl cotransporter), and aquaporins. Neuropeptide factors and monoamines also have a role. Atrial Natriuretic Peptide (ANP), Arginine Vasopressin (AVP) dopamine, serotonin, and melatonin receptors are present on the surface of the choroidal epithelium. ANP and AVP decrease CSF secretion [60], as ANP acts on AQP1.

Carbonic anhydrase inhibitors and loop diuretics decrease CSF secretion and turnover via enzymatic mechanisms, which could change the neuronal milieu, making prone the elderly to age-related neurodegenerative disorders.

#### **6.3 Cerebrospinal fluid circulation**

There is a one-way rostrocaudal CSF flow in ventricular cavities and a multiway CSF flow in subarachnoid spaces from the sites of secretion to the sites of absorption (**Figure 2**) [1]. CSF flow is mainly affected by the systolic pulse wave in choroidal arteries and rapid respiratory waves. In the lateral ventricles, through interventricular foramina, CSF enters the third ventricle, and through the cerebral aqueduct, it enters the fourth ventricle. Thereafter, through the foramen of Magendie CSF goes to the subarachnoid spaces. Rostrally CSF circulates to the


#### **Table 1.**

*The composition of cerebrospinal fluid and comparison with serum [58, 59].*

*History, Anatomy, Histology, and Embryology of the Ventricles and Physiology… DOI: http://dx.doi.org/10.5772/intechopen.101463*

#### **Figure 2.** *Important structures for cerebrospinal fluid circulation [61].*

villous sites of absorption and caudally it circulates to the spinal subarachnoid space in the cranial subarachnoid space. The spinal arachnoid villi partly absorb the CSF, and CSF circulates rostrally to the cranial subarachnoid space.

The subcommissural organ also has a role in CSF circulation. It is a differentiation of the ependyma at the rostral extremity of the cerebral aqueduct and synthesizes SCO-spondin [62]. This protein accumulates and forms Reissner fibers, which direct the CSF circulation via the cerebral aqueduct. Early during development in man, the subcommissural organ disappears. Certain forms of congenital hydrocephalus could be explained by an intrauterine abnormality of the subcommissural organ [63].

#### **6.4 Cerebrospinal fluid absorption**

CSF circulation was determined mainly by the arterial pulse from secretion site to absorption site [1]. The main site for CSF absorption into the venous outflow system are the cranial and spinal arachnoid villi. The cribriform plate, the cranial and spinal nerve sheaths, and the adventitia of cerebral arteries may also serve as alternative pathways for CSF drainage into the lymphatic system.

Arachnoid villi or granulations are endothelium-lined finger-like protrusions of the arachnoid outer layer via the dura mater in the venous sinus lumen (**Figure 3**) [65]. Villous absorption of CSF both in the brain or spine is a dynamic process that adapts the filtration rate to CSF pressure. The pressure gradient among the venous sinus and subarachnoid spaces is essential to assure CSF drainage is between 3 and 5 mmHg [66]. Especially during physical exertion, spinal arachnoid villi and the epidural venous plexus offer an alternative pathway for CSF absorption.

The cranial and spinal nerve sheaths and ependyma can also absorb CSF with respect to pressure gradients [1]. Via Virchow-Robin perivascular spaces, absorption through the interstitial compartment happens. On meningeal sheaths, CSF absorption surfaces have also been shown, especially the meningeal recesses of cranial and spinal nerve roots (i.e., the trigeminal and cochlear nerve). In its meningeal sheath, the optic nerve exerts a long extracranial course. With constructive interference in steady-state magnetic resonance imaging, a high-intensity ring around the optic nerve was observed in hydrocephalus. This finding indicates that when needed there is also a salvage pathway for reabsorption.

#### **Figure 3.**

*Diagrammatic representation of a section across the top of the skull, showing the membranes of the brain, and arachnoid granulation [64].*

When the cranial arachnoid villi capacities are exceeded, lymphatic absorption of CSF establishes an accessory pathway [1]. Particularly, this pathway is active in neonates. Arachnoid villi are completely functional after the age of 18 months. It becomes dysfunctional in the elderly due to fibrous changes of arachnoid granulations.

The cochlear aqueduct, which is located in the petrous part of the temporal bone, has a connection between the perilymphatic space of the cochlea and the subarachnoid space of the posterior cranial fossa. It is patent in 93% of cases [67]. This could clarify the effect of intracranial pressure changes on cochlear function (i.e., tinnitus after ventriculoperitoneal shunting and at high altitude).

#### **6.5 Cerebrospinal fluid pressure**

Ventricular cavity is a dynamic pressure system. CSF pressure is defined as the intracranial pressure (ICP) in the prone position. It is the outcome of a dynamic equilibrium between CSF secretion, resistance to flow, and absorption [1]. CSF pressure can be monitored invasively with a pressure transducer placed in the brain parenchyma or via an external ventricular/lumbar drain connected to CSF spaces. On Doppler ultrasound, to evaluate CSF pressure vascular flow can be traced as a non-invasive method. CSF pressure determines ICP with physiological values. In infancy, it ranges between 3 and 4 mmHg, and in adults, it ranges between 10 and 15 mmHg. Higher values indicate intracranial hypertension. Respiratory waves, jugular venous pressure, state of arousal, abdominal pressure, the subject's posture, and physical effort also modulate CSF flow dynamics and pressure.

The cranial content includes parenchymal, venous, and CSF compartments. CSF pressure is established by parenchymal and venous pressures. When fontanelles are open if ICP increases macrocephaly could be observed due to an increase in intracranial volume. When the fontanelles are closed, blood volume (particularly venous) reduction is seen as compensation.

Brain compliance is described as the volume needed to change ICP. It is the indication of the intracranial contents capacity to adapt to volume changes. Brain compliance is lower in men and changes with age. The volume needed to induce a *History, Anatomy, Histology, and Embryology of the Ventricles and Physiology… DOI: http://dx.doi.org/10.5772/intechopen.101463*

10-times increase in ICP is 8 ml in neonates, 20 ml in 2-year-old children, and 26 ml in adults. The brain volume must be considered when brain compliance is calculated (average of 335 ml in neonates and 1250 ml in young adults).

The regulation of CSF pressure occurs at the secretion, circulation, absorption phase of CSF. When intraventricular pressure is increased, the cerebral perfusion pressure (CPP) and the pressure gradient across the blood-CSF barrier decreases, and choroidal secretion is negatively affected. The concentrations of neuropeptides (ANP and AVP) in CSF and their receptor expression in the choroidal epithelium increase with CSF pressure increase and in the state of acute hydrocephalus [68, 69]. These neuropeptides cause a decreased choroidal secretion of CSF. They also induce dilatation of pial arteries to compensate for the reduction of CPP in acute hydrocephalus [70].

#### **6.6 Cerebrospinal fluid homeostasis**

CSF protects the neuraxis hydromechanically. CSF plays an important role in the regulation of cerebral interstitial fluid and the neuronal environment via arranging the circulation of active molecules, electrolyte balance, and elimination of catabolites. Via CSF, the products of choroid plexus secretion are transported to their action sites. The activity of certain brain regions is modulated by impregnation by this way. However, more rapid changes of activities happen via synaptic transmission [71].

#### **7. Hydrocephalus**

In hydrocephalus, an increased amount of fluid accumulates in the brain ventricular system [2]. Impairment in the CSF circulation at any point could lead to this disease. Mostly, abnormal enlargement of the cerebral ventricle and increased ICP are observed. The common symptoms include headache, irritability, blurred vision, vomiting, gait disturbance, and drowsiness. A rapid increase in head circumference is the main sign in infants.

Hydrocephalus can be classified as communicating or non-communicating type. Impaired absorption of CSF by the arachnoid granulations causes communicating hydrocephalus and this can be the result of any leptomeningeal processes (i.e., inflammation due to infectious or carcinomatous meningitis or hemorrhage as in acute subarachnoid hemorrhage).

Hydrocephalus can also be classified as congenital or acquired. Aqueductal stenosis is the most common cause of congenital hydrocephalus. This can be seen in the case of aqueductal atresia (genetical) or in the case of tumors of neighboring structures compressing the aqueduct or epididymitis (acquired). This results in the enlargement of both lateral and third ventricles with a normal fourth ventricle. The foramen of Magendie and Luschka could be obstructed in Chiari malformation. In this condition, the downward displacement of the cerebellum via the foramen magnum could result in internal hydrocephalus. In the case of inflammatory fibrosis of the meninges, the foramen could be obstructed and result in congenital hydrocephalus [25]. Trauma, infection, tumor, and hemorrhage could result in acquired hydrocephalus.

#### **8. Surgical approaches**

Here we will briefly mention the most preferred methods for hydrocephalus management.

#### *Cerebrospinal Fluid*

In ventriculostomy, a hole in the ventricles is created for CSF drainage and/or ICP monitoring. External ventricular drain is placed in the ventricle. Kocher's point is the commonest entry point on the skull which is 3–4 cm lateral to the midline and 11 cm posterior to the glabella. The frontal horn of the lateral ventricle is the target [72].

In ventricular shunting, CSF is diverted from ventricles to body compartments such as the peritoneal cavity (ventriculoperitoneal shunt), right atrium (ventriculoatrial shunt), pleural space (ventriculopleural shunt).

In order to drain the CSF directly into the basal cisterns, an incision could also be made on the floor of the third ventricle.

#### **9. Conclusion**

CSF is an essential liquid for brain homeostasis. It has a well-balanced ionic content and has a certain secretion and absorption rate. Choroid plexuses are the main secretion site, while arachnoid villi are the main absorption site. When there is disequilibrium in secretion, absorption or any obstruction in the ventricular system hydrocephalus could be seen. There are alternative treatment methods for this condition which depend on the etiology. In this chapter, we review the historical understanding of ventricular anatomy and CSF, main anatomical structures of the ventricular system, histology of embryology of the ventricular system, CSF physiology. We also briefly mentioned hydrocephalus and the main treatment alternatives.

#### **Conflict of interest**

The authors declare no conflict of interest.

#### **Appendices and nomenclature**


*History, Anatomy, Histology, and Embryology of the Ventricles and Physiology… DOI: http://dx.doi.org/10.5772/intechopen.101463*

### **Author details**

Pinar Kuru Bektaşoğlu1 \* and Bora Gürer2

1 Department of Neurosurgery, University of Health Sciences, Istanbul Fatih Sultan Mehmet Education and Research Hospital, Istanbul, Turkey

2 Department of Neurosurgery, Istinye University Faculty of Medicine, Istanbul, Turkey

\*Address all correspondence to: drpinarkuru@gmail.com

© 2021 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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#### **Chapter 2**

## Circulation of Cerebrospinal Fluid (CSF)

*Hayriye Soytürk, Murat Yılmaz, Cansu Önal, Eylem Suveren and Ümit Kılıç*

#### **Abstract**

Circulation of cerebrospinal fluid (CSF) is a clear, colorless liquid that circulates between the ventricular system and the subarachnoid space. In addition to its function as a natural cushion for the brain, CSF provides the circulation of metabolic products, hormones, and neurotransmitters. Moreover, it has tasks such as maintaining the homeostatic balance of the central nervous system, protecting the brain against mechanical injuries, preventing direct contact of the brain with the extracellular region. It also has a role in maintaining cerebral interstitial fluid (ISF) homeostasis and neuronal regulation. Normal CSF production, its circulation, and absorption have a critical role for the development and functioning of the brain. In an average adult person, roughly 150 ml of CSF circulates at any given moment. The ventricular part accounts for about 17% of the total volume of fluid, with the rest located in the subarachnoid cisterns and space. CSF is produced at a rate of about 0.3–0.4 mL/min, translating to 18–25 mL/H and 430–530 mL/day.

**Keywords:** circulation of cerebrospinal fluid (CSF), production of CSF, absorption of CSF, cerebral interstitial fluid (ISF), physiology of circulation of CSF

#### **1. Introduction**

A large amount of cerebrospinal fluid (CSF) is produced in the choroid plexus in the lateral ventricle. This produced CSF reaches the 3rd ventricle via the foramen Monroe, from here to the 4th ventricle via the Aquaduct Sylvius, and passes to the subarachnoid space via the foramen Magendie and the foramen Luschkas. From here, the CSF moves upwards, reaching the interpedincular cistern through the prepontin cistern, and from here to the convexity through the chiasmatic cistern. The CSF circulating from the dorsal, however, reaches convexity via the quadrigeminal cistern, ambient cistern, and vena cerebri magna cistern through the cerebellar hemispheres. CSF also passes into the central canal through the spinal cord and into the spinal subarachnoid space [1]. Absorption occurs from the arachnoid villi to the venous sinuses [2, 3].

The choroid plexus consists of villi. Each villi is covered with monolayer cubic epithelium with cilia. These cells are located on a basal membrane consisting of collagen, fibroblast, and nerve fibers. In the middle of each villi is a capillary vessel with no tight connections between endothelial cells with a loose wall structure. The blood–brain barrier in the choroid plexus is not formed by the tight connections between endothelial cells in the capillaries, unlike the parenchyma, but by the tight connections between cells on the villi [4].

Tight junction on the apical surface of the epithelium above the basal membrane form the blood–brain barrier [2, 4]. The choroid plexus, the epandymal layer, and the parenchyma are the production sites of CSF. As a result of studying isolated choroid plexus preparations, it has been shown that the choroid plexus is responsible for the production of approximately 80% of the CSF. However, the extrachoroidal source of CSF is not well known [5]. The first step of choroidal secretion involves passive filtration of plasma from the choroidal capillaries along a pressure gradient to the choroidal interstitial compartment.

CSF production from the choroid plexus occurs as a two-step process [6]. The first stage in CSF production is the accumulation of ultrafiltrate in the villi, which leaks out of the vein as a result of hydrostatic pressure due to tight connections between endothelial cells from the capillaries in the middle of the villi. This accumulation is secreted by the choroid plexus cell by converting it into CSF. Ultrafiltrate, which accumulates on the side of the basal membrane, is transferred by the sodium-potassium pump which actively pumps sodium into the cell, while water passively enters the cell along with sodium. The same pump also helps chloride. In addition, chloride enters the cell independently of this pump. Fluid with CSF properties inside the cell is again actively released into the ventricular cavity by the cell wall facing the ventricle with the help of a sodium-potassium pump [4, 5]. In normal physiological conditions, CSF production is not affected by intracranial pressure, but when intracranial pressure increases, there may be a decrease in CSF production, as it will affect ultrafiltrate production, which is the first stage of CSF production [5]. Changes in body temperature and serum osmolarity are not effective in CSF production [6].

CSF absorption occurs in arachnoid granulations located along the superior sagittal sinus. Coming from the subarachnoid region to the venous lakes in the arachnoid granulations, the CSF is absorbed into the cerebral veins. It is believed that these pathways work more, especially during an increase in intracranial pressure. CSF absorption is sensitive to pressure. CSF absorption increases when intracranial pressure increases, and absorption decreases if it is below the basal value [4, 7]. This is followed by the bulk ion transport from blood to CSF which occurs via the transcellular pathway facilitated by membrane ion carrier proteins and cytoplasmic carbonic anhydrase. Carbonic anhydrases catalyze the conversion of H2O and CO2 to H+ and HCO3. Transcellular transport of sodium (Na+ ) and chloride (Cl− ) (together with HCO3) are the most important ions carried by the choroid plexus epithelium, forming the osmotic gradient that activates H2O secretion [8].

ATP-dependent ion pumps of the apical membrane allow the passage of Na+ , Cl− , HCO3, and Potassium (K<sup>+</sup> ) ions towards the ventricular lumen, forming the electrochemical gradient for CSF secretion. Transepithelial water movement also occurs through the transcellular pathway. It follows the osmotic gradient created by ATP dependent mechanisms and is facilitated by the aquaporins (AQP1) of the apical basolateral and luminal membranes [8, 9].

Aquaporins, which have different variations in the body, are found in many tissues. It has tissue specific variants. They are expressed in various secretory epithelium. For example, AQP1 and AQP5 are expressed in the pancreas, AQP3 and AQP5 are expressed in the salivary glands. AQP1 is abundantly expressed in the choroid plexus epithelium and contributes to the high water permeability of the membrane [8].

There are some substances that affect CSF production, and one of these substances is furosemide. Feurosemide's mechanism has little effect on carbonic anhydrase, but its main effect is that it can reduce CSF production by stopping chloride entering the cell. Another substance is acetazolamide, which causes a decrease in CSF production in humans and experimental models by blocking the carbonic anhydrase enzyme in the cell [5].

#### *Circulation of Cerebrospinal Fluid (CSF) DOI: http://dx.doi.org/10.5772/intechopen.99621*

In physiological conditions, the rate of CSF production should be equal to the rate of absorption. Given that production and absorption occur in different parts of the system, it is assumed that its flow rate will be affected [9].

Oreskovic and Klarica studied the effects of the choroid in CSF physiology via plexectomies [9]. According to classical theory, a large decrease in the overall secretion of CSF is expected when choroid plexectomy is performed, and therefore some pressure relief can be achieved in patients with hydrocephalus with this method. Studies have shown that two-thirds of patients treated for a recurrence of hydrocephalus should be shunted [10].

The choroid plexectomy study conducted by Oreskovic and Klarica on rhesus monkeys showed that the chemical component of CSF remained normal, suggesting that the choroid plexus played a less role in molecular transport [11]. While there is evidence to support these claims regarding CSF production, there is also a large amount of literature describing the tides and the net flow of CSF [12].

According to Spector, active secretion and absorption of CSF are carried out by movable cilia located in the ependymal wall. CSF involves the transport of growth factors to certain areas of the brain in the circulatory system [12]. The composition of cerebrospinal fluid, CSF, consists mainly of 99% of water, while the remaining 1% consists of proteins, ions, neurotransmitters, and glucose [8, 13, 14]. The concentration, total viscosity, and surface tension of each of these proteins found in CSF vary in different conditions [15, 16], CSF absorption increases, and if below the basal value, absorption decreases [4, 17].

This is followed by the bulk ion transport from blood to CSF which occurs via the transcellular pathway facilitated by membrane ion carrier proteins and cytoplasmic carbonic anhydrase. Carbonic anhydrases catalyze the conversion of H2O and CO2 to H+ and HCO3. Transcellular transport of Na<sup>+</sup> and Cl− (together with HCO3) are the most important ions carried by the choroid plexus epithelium, forming the osmotic gradient that activates H2O secretion [8].

The composition of CSF differs from serum due to different expressions of membrane-associated channels and transport proteins, which in this case causes the choroidal epithelium to be unidirectional [18]. On the apical side, epithelial cells are interconnected by tight junction that limit the movement of these molecules, and intercellular space connections form the blood–brain barrier. The apical side of the epithelium is covered with microvilli, while the basolateral side has folds that increase the surface area of the cells and make it more suitable for absorption.

Compared to plasma, CSF usually contain high concentrations of sodium (Na+ ), chloride (Cl− ), and magnesium (Mg+2), while lower concentrations contain potassium (K<sup>−</sup> ) and calcium (Ca+2) [14]. On the apical side, active transport pumps release ions into the ventricular cavities. The movement of water in the apical membrane has been shown to be caused by the presence of aquaporin 1 (AQP1). Indeed, a study by Mobasheri and Marples revealed that the choroid plexus is among the tissues with the highest expression of AQP1 in the body [19].

Many studies have different conclusions regarding the AQP 4 as the main candidate for water transport in the basolateral membrane. The common focus of the studies has been the study of disease conditions that affect the production, absorption, or composition of CSF. Apart from its mechanical role, CSF has an important role in biochemical homeostasis throughout the CNS [12].

By using new techniques to analyze the diversity of CSF components, proteins, lipids, hormones and microRNAs, it will be possible to track the development of the disease over time in disease conditions [20]. The production and absorption of some CSF biomolecules, such as growth factors, neurotransmitters, cytokines, extracellular matrix proteins, permeability-related proteins, binding proteins, and adhesion molecules can affect CSF homeostasis. Similarly, the microenvironment surrounding periventricular cells and their activities may vary in disease states [20].

CSF production is regulated by the autonomic nervous system and neuropeptides such as dopamine and atrial natriuretic peptide. The sympathetic nervous system reduces CSF production, while the cholinergic system increases its production. There is a circadian rhythm in CSF production [21]. Most of the hormones that regulate systemic water and electrolyte homeostasis, such as aldosterone, angiotensin II, and arginine vasopressin, are also present in the choroid plexus and ventricular system. These hormones are believed to have two tasks: the first is the production of CSF locally, and the second is the regulation of extracellular fluid in the brain, but they also have tasks in the central regulation of blood pressure [8]. CSF production can be reduced by the administration of diuretics and carbonic anhydrase inhibitors. In addition, any increase in intraventricular pressure can reduce plasma filtration and, as a result, CSF production by lowering the pressure gradient in the blood–brain barrier. In CSF and interstitial brain fluid, water and solutes change constantly, and this balance provides an optimal environment for neurons. This is directly proportional to the rate of formation of CSF and inversely proportional to the volume of CSF. In aging, there is less efficient active transport, with a slower CSF cycle causing the accumulation of potentially harmful metabolites in the interstitium of the brain. Clearance of brain metabolites per minute depends on the CSF regeneration at a rate of 0.3–0.4%. Brain catabolites form when fluid turnover rates drop by more than 50%, and the reduction in amyloid b decrease in CSF clearance is now believed to be associated with the development of Alzheimer's disease [22].

After production, CSF movement is usually carried out through the ventricular system, while it is also supported by the cilia ependyma [23]. The net flow of the CSF passes through the ventricular system, starting from the lateral ventricles [24]. The CSF flows from the lateral ventricles, through the left and right foramen of the Monro to the third ventricle. Then, it passes to the 4th ventricles. From the fourth ventricle, the CSF may flow laterally from the foramen of Lushka, or medially from the foramen of Magendie to the subarachnoid space. Passing through the foramen of Magendie results in the filling of the spinal subarachnoid space. CSF outflow from the foramen of Luschka goes into the subarachnoid space of cisterns and into the subarachnoid space that covers the cerebral cortex. CSF from the subarachnoid space is eventually reabsorbed into the superior sagittal sinus (SSS), known as the arachnoid. Arachnoid granulations provide reabsorption of CSF into the bloodstream by a pressure-dependent gradient [6]. In arachnoid granulations, outlets towards the CNS are seen due to the fact that the pressure in the subarachnoid space is greater than the venous sinus pressure. Similar to new theories about CSF production, there are also absorption theories. Studies in animal models have revealed that CSF can also be significantly absorbed through cervical lymphatics [6].

CSF, which is not reabsorbed by arachnoid granulations, can reach cervical lymphatics in two alternative ways. The first is along the subarachnoid space of the emerging cranial nerves [6]. This provides a direct route through which CSF can be transferred from cisterns to extracranial lymphatics. The second way in which CSF can reach lymphatics is through the Virchow-Robin space of the arteries and veins that penetrate the parenchyma of the brain [25].

The Virchow-Robin Space (VRS) is the area surrounding the arteries and veins of the brain parenchyma, which can vary in size depending on disease status. When the CSF is not absorbed by the classical way, it can enter the VRS or be directed to the brain interstitial fluid (ISF). The brain interstitial fluid ISF is believed to be a compartment with a subarachnoid space (SAS) that is mediated by AQP s and bidirectional flow to VRS, but it is not yet clear. If the CSF enters the ISF, it will

#### *Circulation of Cerebrospinal Fluid (CSF) DOI: http://dx.doi.org/10.5772/intechopen.99621*

either be reabsorbed into the bloodstream, or it will enter the VRS, or it will enter the subarachnoid space again. From the VRS, CSF can reenter into the SAS or be reabsorbed by cervical lymphatics, depending on the forces exerted by cardiac pulsations and pulmonary respiration. In addition to the circulation of CSF to cervical lymphatics, studies have also been conducted explaining the reabsorption of CSF to the dural venous plexus. Arachnoid granulations at birth are not fully developed, and CSF absorption is based on the venous plexus of the inner surface of dura, which is more robust in infants [26]. Although not common in adults, the dural venous plexus is believed to play a role in absorption. Adult and fetal cadaver dissections and animal models with intradural injection have all been shown to fill the parasagittal dural venous plexus [27].

#### **2. Physiology of circulation of cerebrospinal fluid**

The CSF physiology, in the classical sense, is based mainly on animal experiments [28]. In recent research, the structure of CSF circulation has been questioned, challenging significant aspects of the classical model. Recently, CSF production and absorption have been reevaluated [9, 29–31].

According to the classical view described by Cushing in 1926 as the "third circulation" [32, 33], CSF flows from the ventricular system through the Lushka and Magendie foramen into the subaracanoid area in a one-way, rostrocaudal manner. The CSF then continues to flow either downwards around the spinal cord or upwards over the cerebral convexities, and is eventually absorbed by arachnoid granulations and arachnoidal villi on either side of the upper sagittal sinus.

Recent studies have highlighted a secondary pathway of CSF, circulation through perivascular VRS, similar to the lymphatic system in other parts of the body [34, 35]. This CSF circulatory system, which has a similar function to the lymphatic system with the participation of astroglia, has been called the "glymphatic system" [36, 37]. The glial membrane of the brain consists of the astrocytic end-feet and forms theVRS, it has high amounts of aquaporin channels and facilitates CSF transfer from VRS to the interstitial space of the brain cavity is cleaned and then empty the drainage paths paravenous makes it easy to carry along [36]. The in vivo imaging taken using fluorescent substances in mice also showed how this microcirculation removes amyloid beta and other waste products from the central nervous system [34].

CSF flow is pulsatile and depends on pulsational arterial perfusion. A central ventricular pulse wave is formed, followed by brain expansion, followed by a subarachnoid CSF frontooccipital pulse wave [38]. During systole, blood flows into the brain, expanding into the brain, compressing the ventricles and the cortical vessels outwards and SAS. Inward expansion of the brain leads to the pulsatile transfer of CSF from the the cerebral aqueduct and the rest of the ventricular system. During diastole, the volume of the brain decreases, and CSF flows in the opposite direction along the the cerebral aqueduct and the foramen magnum. The movement of CSF to the brain through VRS is also supported by arterial vibrations [35]. This suggests a link between decreased arterial pulses, which are often seen in some elderly patients, and amyloid B accumulation in Alzheimer's disease [36, 37]. Although in-vivo studies in humans are needed to confirm these findings, there is growing evidence that plaque may be another key site for extracranial output [24, 39].

Since Cushing, the collective flow character of CSF circulation has been accepted by most researchers. Even in recent studies, it is assumed that the CSF circulation is directed towards the arachnoid villus along the ventricles and subarachnoid space [24, 40]. VRS are a histologically defined anatomical area surrounding blood vessels

as they enter the brain tissue from the subarachnoid space Initially, VRSs were believed to be connected to the subarachnoid space, allowing for free fluid transfer. This concept was later elucidated by microscopic investigations that showed perivascular cavities as dead ends, open to the subarachnoid space but closed to the parenchyma, and therefore not a channel for flow [41].

Considering the microscopic anatomy of VRS, its thin structure is actually located on layers of endothelial, pial, and glial cells, each defined by different basal membranes [42]. The glia covering the brain parenchyma forms the outer wall of the VRSs [43]. In the capillary bed, the basal membrane of the glia merges with the outer vascular membrane, forming the VRS [44].

The arterial and venous vessels, which are located in the cortical subarachnoid space (SAS), are covered by a layer of pial cells that surround the vessels. The pial sheath forms a cavity next to the vessel wall, called the perivascular space (PVS) [45]. At the entrance of the cortical vessels to the VRS, the pial sheaths merge with the layer of pial cells lining the brain surface, forming a funnel-like structure that accompanies the VRS to the vessels only for a short distance [46]. However, the pial sheath of the arterial vessels extends to the VRS. Near the capillary bed, the pial sheath becomes more and more windowed and leaky [45].

Some authors use the terms "Virchow-Robin space" and "perivascular space" as synonyms [47], while others use the terms to name different areas as discussed above [48]. Studies with electron microscopy show that pial membranes separate VRS from the cortical subarachnoid space [46]. Since electron microscopy of human brain samples shows that VRS and PVS have collapsed, it has been a matter of debate whether these histologically characterized compartments are really openings or spaces [45]. However, studies in rodents have shown that VRS is filled with fluid, electron microscopic dense material [46], macrophages and other inflammatory cells [42].

Although pial cell layers separate the VRS from the cortical subarachnoid space, physiologically there is strong evidence that fluid circulates throughout the VRS. There are species-related differences in the pial layer. In mice, for example, the pial layer is very thin, while in humans it is thicker [49].

In humans, the pial sheath is described as a sensitive but seemingly continuous layer of cells, connected by desmosomes and cavity connections but without obvious tight connections [50]. As a result of numerous experimental studies, it has been recognized that the pia mater does not have permeable properties against liquids [51]. Given that the flow within the VRS depends on the pulsatility of the arteries [52], hydrostatic forces can move liquids and solutes along the pial membranes. However, while VRS basically allows for a two-way exchange between CSF and ISF, there is not much data to explain the scope and kinetics of such fluid movements.

Although it has been shown that the pial membranes between PVS and SAS can prevent the exchange of larger molecules, the intraparenchymal injection has not been shown to spread to cisternal CSF, although it has accumulated in PVS [53]. This observation is supported by clinical findings that red blood cells are confined in the subarachnoid space and do not enter the VRS following aneurysm rupture in humans [49]. It has been shown both experimentally and clinically that PVS, and possibly, more importantly, pathways between the essential membranes of arterioles and the wall of arteries, provide drainage for ISF and the brain's waste molecules.

There is experimental evidence that paraarterial drainage pathways are connected to the lymphatics of the posterior skull base [54]. In reality, the solutes and fluids can be discharged through the VRS from the brain interstitium through the arteries, into the cervical lymphatics [55]. This view was supported experimentally by immunohistochemical and confocal microscopic observations showing that

#### *Circulation of Cerebrospinal Fluid (CSF) DOI: http://dx.doi.org/10.5772/intechopen.99621*

fluorescent dyes such as 3 kD dextran or 40 kD ovalbumin move along the basic membranes of capillaries and arteries after being injected into the corpus striatum in mice.

These findings are clinically significant as beta-amyloid accumulates in the vascular wall of arterioles and arteries, based on observations in patients with cerebral amyloid angiopathy. The accumulation of insoluble amyloid can block this drainage pathway and therefore inhibit the elimination of beta-amyloid and interstitial fluid from the brain in Alzheimer's disease [54]. The size of amyloid deposition is so pronounced that it has been proposed as a natural determinant for peri-arterial drainage pathways [55]. Peri-arterial drainage of liquids and solutes has important effects not only in neurodegenerative diseases but also in immunological CNS diseases [55]. Similar to arteries, veins in the subarachnoid space have pial sheath forming a PVS [42].

#### **Author details**

Hayriye Soytürk1 \*, Murat Yılmaz2 , Cansu Önal3 , Eylem Suveren4 and Ümit Kılıç5

1 Department of Interdisciplinary Neuroscience, Bolu Abant Izzet Baysal University, Bolu, Turkey

2 Department of Neurology, Bolu Abant Izzet Baysal University, Bolu, Turkey

3 Department of Biology, Bolu Abant Izzet Baysal University, Bolu, Turkey


\*Address all correspondence to: hayriyesoyturk1@gmail.com

© 2021 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Section 2

## Normal Pressure Hydrocephalus

#### **Chapter 3**

## Normal Pressure Hydrocephalus: Revisiting the Hydrodynamics of the Brain

*Fernando Hakim, Daniel Jaramillo-Velásquez, Martina González, Diego F. Gómez, Juan F. Ramón and Mateo Serrano-Pinzón*

#### **Abstract**

Normal pressure hydrocephalus syndrome is the most common form of hydrocephalus in the elderly and produces a dementia which can be reversible surgically. It is characterized by ventriculomegaly and the classic triad of symmetric gait disturbance, cognitive decline and urinary incontinence, also known as Hakim's triad. To date, the exact etiology of the disease has not been elucidated and the only effective treatment is a cerebrospinal fluid shunting procedure which can be a ventriculoatrial, ventriculoperitoneal or lumboperitoneal shunt. The most important problem is the high rate of underdiagnosis or misdiagnosis due to similarities in symptoms with other neurodegenerative disorders, and in some cases, coexistence. Hence, increasing awareness amongst the community and medical professionals in order to increase clinical suspicion, timely diagnosis and treatment are paramount. The best way to achieve this is by having a structured protocol with patientcentered tests that evaluates the entire myriad of alterations a clinician might encounter whenever treating patients with this disorder. Recent advances in imaging technology as well as cerebrospinal fluid biomarkers have given interesting insight into the pathophysiology of the disease and will certainly contribute greatly in diagnostic advancements. We finally present an institutional protocol which has been accredited by international peers with promising results in diagnostic and outcome rates.

**Keywords:** Normal pressure hydrocephalus syndrome (NPH), cerebrospinal fluid (CSF), ventriculoatrial shunt (VAS), ventriculoperitoneal shunt (VPS), lumboperitoneal shunt, intracranial pressure (ICP), lumbar puncture (LP), center of excellence (COE)

#### **1. Introduction**

Normal Pressure Hydrocephalus (NPH) is a type of chronic communicating hydrocephalus recognized as the most common form of hydrocephalus in the elderly with an estimated prevalence of 5.9% in those aged over 80 years [1]. NPH was first described by Hakim in 1965, hence, it is sometimes found as Hakim's syndrome. NPH is characterized by enlarged brain lateral ventricles

(ventriculomegaly) with normal cerebrospinal fluid (CSF) pressure and the classic clinical triad of symmetric gait disturbance, gradually progressive cognitive decline, and urinary incontinence, also known as Hakim's triad [2].

In this chapter, we present a concise review of all available evidence regarding epidemiology, pathophysiology, diagnostic and treatment methods including some diagnostic novelties that could be determinant sometime in the near future.

#### **2. Epidemiology**

NPH is the main cause of surgically reversible dementia in the population aged 50–80 years with a global estimated prevalence of 0.2% in the group aged 70– 79 years and 5.9% in those over 80 according to epidemiologic studies in Sweden [1]. However, the estimated prevalence reported by populated-based studies in Japan is 1.6% [3–6]. If surveys in Sweden had used diagnostic criteria in Japanese guidelines, their weighted average would have been 1.5% [7]**.** These data may underestimate the actual prevalence and incidence because some studies have flawed methodology and use different criteria. The prevalence and incidence of any hydrocephalus, especially NPH, will increase as mean life expectancy increases. Mortality associated with untreated hydrocephalus ranges from 20 to 87% depending on the etiology [8]. Therefore, diagnosing and treating chronic hydrocephalus is a public health problem that requires attention and active participation of the entire scientific community and health personnel.

NPH is a condition with a high rate of underdiagnosis because it can be confused with other types of dementia, especially Alzheimer's dementia (AD) and Parkinson's disease, and because in many cases there is simply no clinical suspicion by medical staff. Approximately 5–10% of patients with some type of dementia may suffer from chronic hydrocephalus and another concomitant disorder such as AD, frontotemporal dementia (FTD), subcortical arteriosclerotic dementia (SAD) also known as Binswanger's disease, Lewy bodies dementia, amongst others. In fact in epidemiologic studies, 24% of patients with clinical suspicion of NPH had typical histopathologic findings of AD in brain tissue samples. Furthermore, the components of the clinical triad, although useful, are not always sufficient since they are not pathognomonic to NPH. Thirty-five percent (35%) of people over 70 have dementia from any cause, 40% of women and 20% of men over 60 have urinary incontinence from another cause, and 20% of people over 70 have some type of gait impediment [9].

To date, the only effective treatment for NPH is a CSF shunting procedure, typically ventriculo-peritoneal shunt (VPS) or ventriculo-atrial shunt (VAS) and sometimes, lumbo-peritoneal shunt (LPS), with a success rate that ranges between 60 and 80%. Hence the importance of appropriate diagnosis and adequate selection of patients for surgery.

#### **3. Pathophysiology**

The Monro-Kellie doctrine describes the relationship between the contents of the cranium and intracranial pressure (ICP). The doctrine dictates that the adult cranial vault is a rigid, non-expansible container inside of which there is constant balance of blood, CSF, and brain tissue. If one of the components increases, one of the others or both must decrease, or vice versa, to keep the ICP within the normal range (5–15 mm Hg). This system of homeostasis in the CNS is known as autoregulation. Although the brain is viscoelastic and can change shape and volume after mechanical stimuli, it is the blood and CSF that determine this balance. If one

#### *Normal Pressure Hydrocephalus: Revisiting the Hydrodynamics of the Brain DOI: http://dx.doi.org/10.5772/intechopen.98813*

of the components increases in a progressive fashion, and overcomes the autoregulatory mechanisms, a point of no return or decompensation is reached with an increase in central venous pressure (CVP) and an exponential increase in ICP. When this happens, cerebral perfusion pressure (CPP), which is the difference between mean arterial pressure (MAP) and ICP (CPP = MAP-ICP) decreases, causing brain edema. If this is not corrected, intracranial hypertension (ICH) invariably ensues. It is considered pathologic when ICP levels are more than 30 mm Hg, and life-threatening if more than 40 mm Hg. [10]. CVP is therefore essential in the pathophysiology of ICH.

CSF is the electrochemical medium that provides the appropriate conditions for neuronal metabolism, in addition, since the CNS is immersed, its net weight is �20– 30 g, considerably reducing the risk of mechanical damage [9]. Eighty to ninety percent (80–90%) of CSF is produced in the choroid plexuses of the four cerebral ventricles, richly vascularized epithelial structures whose epithelium constitutes the blood-cerebrospinal fluid brain barrier (BCSFBB) [11]. The remaining 10–20% is produced in the extra-choroidal blood–brain barrier (BBB). Starling's laws (hydrostatic and oncotic pressure gradients), as well as the ionic concentration within the medium are probably the main mechanisms responsible for production, although the exact mechanism is still unknown [11]. CSF flows from the lateral ventricles through the foramen of Monro to the third ventricle, from there through the cerebral aqueduct or Sylvian aqueduct in a pulsatile manner, closely related to heartbeat and respiratory rate, to the fourth ventricle. From the fourth ventricle it passes through the medial opening of Magendie and lateral foramina of Luschka to the subarachnoid space (SAS) and flows upward bathing the tentorium towards the venous sinuses. A smaller amount of volume flows down the spinal SAS. Production is constant and so is reabsorption. Classically it has been said that CSF reabsorption occurs in arachnoid granulations and villi, fenestrated endothelial structures that protrude macroscopically and microscopically, respectively, towards the lumen of the venous sinuses, especially the superior sagittal sinus. It is collectively accepted that retrograde flow from arachnoid granulations is impossible. Some authors point out that almost a third of the CSF leaves the neural sheaths of the cranial nerves to enter the glymphatic system [11]. Therefore, the exact mechanism of reabsorption also remains to be elucidated.

ICP gradients cancel as long as there is constant CSF flow and thus there is no risk of brain herniation. Important concept because when there are abrupt changes in pressure gradients as happens in traumatic brain injury (TBI) or space-occupying lesions, the critical threshold is 20–25 mm Hg, whereas pressure-volume studies in patients with communicating hydrocephalus indicate that these patients tolerate values of ICP in the range of 40–50 mm Hg without symptoms of ICH [12](7). Now, the fact that NPH patients have ventriculomegaly and symptomatic hydrocephalus, but normal ICP is what constitutes the same clinical problem and paradoxical situation that interested S. Hakim and still eludes us today. However, it is important to highlight that some patients with NPH may have episodes of elevated ICP, especially in the early stages of the disease. This phenomenon was explained by S. Hakim based on Laplace's law that explains the behavior of a spherical elastic container containing fluid. The pressure of the fluid inside the container (P) is directly proportional to the elastic tension of its wall (T) and is inversely proportional to the radius (r) of the container [12]:

$$\mathbf{P} = \mathbf{\mathcal{T}} \mathbf{\dot{\mathbf{\mathcal{T}}}} \mathbf{\dot{\mathbf{\mathcal{T}}}} \tag{1}$$

S. Hakim used the analogy of rubber balloons. As one inflates a balloon, initial pressure is higher than final pressure, as air volume inside the balloon increases, less pressure is required to be able to introduce more air. Therefore, due to the viscoelastic properties of the brain, as the size of the ventricles (the rubber balloon) increases, pressure required to stretch them decreases. In other words, the pressure inside the container increases until, after a certain stretch point, pressure drops with a subsequent increase in size independent of the wall tension. CSF pressure exerts greater force on the wall of dilated ventricles than in normal sized ventricles. Clarifying this concept, CSF pressure is the necessary pressure to prevent fluid from escaping through a needle that enters the SAS or the ventricle and represents the force per unit of ventricular surface area and/or subarachnoid surface. This is Pascals' law: the total force exerted (F) on the brain would be the result of the multiplication of the pressure (P) and the surface area of ventricular walls (A) subjected to the fluid pressure inside [2]:

$$\mathbf{F} = \mathbf{P} \ge \mathbf{A} \tag{2}$$

Hence,

$$\mathbf{P} = \mathbf{F}/\mathbf{A} \tag{3}$$

To illustrate this, imagine that ICP (CSF pressure) is 150 mm H2O. This means that each squared millimeter of ventricular surface is subjected to the weight of a 150-mm column of water. Now imagine two ventricles of different sizes subjected to the same pressure:

Ventricle A (Av) with a surface area of 20 cm2 and ventricle B (Bv) with a surface area of 40 cm2 . The force exerted on Av (FAv) is different from Bv (FBv).

$$\text{FAv} = \mathbf{150} \ge \mathbf{20} \tag{4}$$

Whereas, in Bv:

$$\mathbf{F} \mathbf{B} \mathbf{v} = \mathbf{1} \mathbf{50} \ge \mathbf{40} \tag{5}$$

Thus, we now understand why pressure in both ventricles is the same, but the force exerted on the ventricular wall has increased in relation to the proportional increase in its surface area. Hakim called this phenomenon the *hydraulic press effect*. Of course, this analogy could be criticized, because the visco-elastic properties of the brain also depend on other variables, but due to its mathematical simplicity, it is pertinent [2].

Imbalance between CSF production and reabsorption is the cause of progressive ventriculomegaly. The reason why there is functional obstruction to CSF reabsorption is currently unknown. It must be an alteration in hydrodynamics. CSF reabsorption (Re), which is linear and unidirectional, depends on the gradient between the subarachnoid ICP (ICPSA) and sagittal venous sinus pressure (PSS), a constant parameter that depends on CVP, and is inversely proportional to CSF outflow resistance into the venous space (RCSF), sometimes referred to as *Rout* calculated experimentally at 6–10 mm Hg mL-1 min�<sup>1</sup> [12]:

$$\text{Re} = \text{ICP}\_{\text{SA}} - \text{P}\_{\text{SS}} / \text{R}\_{\text{CSF}} \tag{6}$$

Venous compliance is the ability of veins to distend when intravascular volume and transmural pressure increases against tendency to return to the original dimensions on application of the distending force. In mechanics, it is the inverse of stiffness and the reciprocal of elastance or *coefficient of elasticity*. The increase in CSF within the ventricles causes ventricular dilation and mechanical stretching of the

*Normal Pressure Hydrocephalus: Revisiting the Hydrodynamics of the Brain DOI: http://dx.doi.org/10.5772/intechopen.98813*

periventricular white matter, altering viscoelastic properties of the brain, compromising the Windkessel effect, widely studied in systemic circulation but its role in the CNS is also recognized. Mechanical stretching generates intraparenchymal capillary compression which eventually leads to ischemia of *watershed* areas in the territory of the anterior cerebral artery, which reasonably explains the symptoms of the clinical triad. Therefore, one of the most accepted theories about NPH etiology is decreased cortical venous compliance that increases RCSF accompanied by chronic ischemia. This is the reason why if CSF pressure is reduced to subnormal levels after lumbar puncture (LP), venous pressure returns to normal and pushes the dilated ventricles back to their normal position, reversing hydrocephalus. Some authors have reported that RCSF > 12 mm/Hg/mL/min is a suitable threshold for predicting responsiveness after surgery [13]. Parallelly, a rise of 3–4 mm Hg in PSS can halt CSF absorption via the arachnoid granulations [14]. Experimental studies in hydrocephalus-induced animal models and prospective clinical studies are needed to elucidate the reasons why cortical venous compliance decreases and why RCSF increases in NPH patients.

Chronic hypoperfusion have shown to cause progressive loss of compliance as well as astrogliosis and neuroinflammation. In fact, glial fibrillar acidic protein (GFAP), a marker of astrocyte axon reactivity and damage is increased in brain biopsy specimens of NPH patients. Additionally, astrogliosis further worsens parenchymal stiffness and contributes to decreased CSF hydrodynamics [15, 16]. Furthermore, NPH patients have significantly more blood–brain barrier (BBB) disruptions than controls which have shown to play a key role in neurologic dysfunction by allowing leakage and entry of blood-borne products into the CNS [17, 18]**.** BBB disruption and leakage are associated with greater astrogliosis [19].

The recently discovered glymphatic system, which presumably participates to a certain extent in CSF reabsorption, is mediated by aquaporin-4 (AQP4) channels on astrocytic perivascular pedicles [20]. Normal glymphatic system functioning depends on appropriate arterial pulsation, intact AQP4 and healthy sleep pattern [20]. NPH patients have a delayed removal of intrathecal tracers in phase-contrast imaging studies which suggests impaired functioning of the glymphatic system [21, 22]. Decreased AQP4 channel density in perivascular endfeet of NPH patients have also been reported. And it is not unusual that elderly patients suffer from concomitant sleep disorders that might contribute to the pathogenesis [23–27].

#### **4. Etiology and classification**

Hydrocephalus is a syndrome caused by a heterogeneous group of pathologies that share an increase in intracranial CSF volume manifested by ventriculomegaly and compatible symptoms. They can be classified as congenital or secondary (acquired), non-communicating or communicating, adult or childhood onset and with ICH or normal pressure. NPH is an acquired type of chronic communicating hydrocephalus with normal ICP whose etiology is still unknown.

NPH could be part of aging process and senescence of the venous endothelium and loss of brain viscoelastic properties, but it has not been possible to determine whether it is related to cerebrovascular and/or cardiovascular risk factors, since not all patients with NPH have a cardiocerebrovascular comorbidity. It could be a degenerative process secondary to the deposit of specific material such as betaamyloid, something similar to what happens in AD, but its causal relationship has not been determined since not all patients with NPH have neurodegenerative comorbidity. The etiology of NPH still remains unknown for neurologists, neurosurgeons, and neurophysiologists. Thus, is known as idiopathic hydrocephalus.

#### **5. Clinical manifestations**

Unlike other types of hydrocephalus, neurologic exam of patients with NPH, except for the clinical triad and minor neurologic signs, is essentially normal. Important, because any sign that suggests focal deficit must make the clinician suspicious of other disorders. Paresis, hyperreflexia, and other first motor neuron signs are atypical. NPH should be suspected in adults with any of the three components of Hakim's triad, but it is not necessary for all three to be present to diagnose NPH. Of the triad components, typically the first one to appear, most frequently encountered and most severe is symmetric apraxia or magnetic gait not explained by another cause and for this reason some authors have called it the cardinal symptom [1]. It is also the first to resolve after surgery in patients with more than one component. Most reports agree that the triad is complete in approximately 60% of cases [28–30]**.** Nevertheless, a large-scale questionnaire conducted in Japan in 2012 revealed that only 12.1% of a cohort of 1524 patients had the full triad [31]**.**

When all three components are present, the odds of NPH are higher. When there is cognitive impairment, it is important that the patient is accompanied by a family member, preferably his partner or one who lives with the patient to build a medical history and reach the correct clinical diagnosis. After detailed questioning, it has been confirmed that most patients have insidious onset of symptoms within a period of 3–6 months [1]. It is essential to inquire about past medical history, especially cranial surgery or intracranial bleeding, trauma, infection, or CNS tumors, since many of these patients are at risk of secondary hydrocephalus. In patients with ventriculomegaly who only have cognitive impairment or only have urinary incontinence, different diseases should be suspected.

Polyneuropathy is common in the elderly and is a frequent cause of urinary and motor comorbidity. Patients with gait impairment and incontinence without cognitive impairment should be studied for spinal lesions such as cervical or lumbosacral myelopathy secondary to cervical/lumbosacral canal stenosis or discovertebral disease at any level [1].

#### **5.1 Gait**

It is the most prominent and frequent (94–100% of patients) [32]. Magnetic gait or gait apraxia is symmetrical, otherwise it suggests other pathologies. Patients drag their feet, as if they are attached to the ground (hence, the term magnetic), the movement is clumsy and hasty, it is accompanied by small steps, frequent stumbling, falls and fear. Walking becomes unstable and slow. Difficulty standing and starting movement is characteristic, as well as erratic turns with many unstable steps, like a compass. Severity is variable and it is sometimes difficult to distinguish between parkinsonism and other dementias such as Lewy's. Unlike in Parkinson's disease, external triggers such as command lines and landmarks have little effect on improving gait [33].

#### **5.2 Cognitive impairment**

Cognitive decline in NPH is remarkably similar to that seen in other types of dementia. It includes infantile behaviors, mood fluctuations, amnesia, difficulty managing finances, taking medications, driving, and honoring commitments. Patient denial is common. Psychomotor speed is markedly declined, there is also evident attention and working memory impairment as well as diminished verbal fluency and dysexecutive syndrome [34, 35]**.**

*Normal Pressure Hydrocephalus: Revisiting the Hydrodynamics of the Brain DOI: http://dx.doi.org/10.5772/intechopen.98813*

#### **5.3 Incontinence**

Urgency and frequency are the most common symptoms, initially without incontinence which appears progressively [36]. Amongst patients with NPH, 90.9% experience dribbling and 75% have incontinence [37]. They mostly are aware of this problem which causes great frustration. A patient with incontinence who is indifferent or unaware is unusual and should raise suspicion of another disorder. All this information is obtained from the patient's companion, usually his/her partner.

#### **5.4 Other symptoms**

There are other less frequent manifestations, which traditionally are not listed under NPH manifestations, therefore not commonly searched for, and not treated. An important example is hearing loss. Hypoacusis is present in a non-negligible number of patients with any type of chronic hydrocephalus. Thirty-four percent (34%) of patients who develop post-infectious hydrocephalus and a percentage that can range from 5 to 15% of patients with NPH have some degree of hypoacusis. Its mechanism is not well understood, but it could be secondary to hydrops of the endolymphatic and perilymphatic space, which is continuous with the SAS in the cochlear aqueduct in the posterior aspect of the petrous portion of the temporal bone [38]. In patients with NPH and hypoacusis, significant improvement has been observed after surgery [38]. Possibly if the problem is actively sought and specialized rehabilitation is offered, the outcome could improve significantly.

Approximately, 55% of NPH patients have bradykinesia, 84% have a snout reflex, 77% have an eyebrow reflex and 65% have some degree of paratonia [39]. In a study that compared patients with NPH, Parkinson's and healthy controls, the NPH group had decreased speed when lifting things and used more strength to grip compared to healthy controls. This correlates with involuntary motor dysfunction which resembles frequent neurologic deficit seen in Parkinson's.

#### **5.5 Symptom assessment**

The most important thing is to detect the components of the triad and to explore their characteristics in depth. As mentioned previously, other diseases should be ruled out [1].

When clinical suspicion is high, some important domains such as motor and cognitive performance should be evaluated profoundly. Different formal tests have been developed that allow objective and quantitative measures of compromise in all domains. We summarize tests that have been validated and recommended by clinical practice guidelines. Those tests are used in our NPH center of excellence (COE) at Fundación Santa Fe de Bogotá (FSFB), the only COE of its kind in Colombia currently accredited by Joint Commission International (JCI).

#### *5.5.1 Gait*


• Tinetti: Test that integrates gait and balance with a maximum possible score of 30. The higher the score, the better motor performance. It has proven useful in evaluating response in patients undergoing CSF shunting surgery [42].

#### *5.5.2 Cognitive decline*


#### *5.5.3 Incontinence*

• ICIQ-SF (international consultation on incontinence questionnaire-short form): Validated questionnaire addressed to the patient and his/her companion evaluating frequency, severity, and impact of incontinence on the patient's quality of life. Score is 0–21, the higher the result, the more symptoms and the greater the negative impact on quality of life. There is a significant decrease in ICIQ-SF mean score after CSF shunting surgery [42].

### *5.5.4 Others*


#### **6. Diagnostic tests**

Despite the immense amount of research on NPH, to date, there is no gold standard test for its diagnosis. Therefore, diagnosing NPH is a challenging task that results from gathering information on clinical manifestations, radiographic findings, clinical response after tap test, and recently, certain CSF biomarkers.

#### **6.1 Imaging**

After the aforementioned tests, a CNS image is necessary. Of choice, brain magnetic resonance imaging (MRI) or computed tomography (CT) if MRI is contraindicated or not feasible; MRI is preferred due to its higher resolution and definition of parenchymal structures whether healthy or pathological.

#### *Normal Pressure Hydrocephalus: Revisiting the Hydrodynamics of the Brain DOI: http://dx.doi.org/10.5772/intechopen.98813*

According to the Japanese Guidelines for management of Idiopathic Normal Pressure Hydrocephalus, the imaging findings that suggest NPH are: ventriculomegaly not attributable to other pathology, disproportionately enlarged subarachnoid space hydrocephalus (DESH), acute callosal angle and posterior narrowing of the cingulate sulcus seen on sagittal plane MRI [32].

The main finding is ventriculomegaly assessed with the Evans' Index (EI), which is calculated by measuring the maximum width of both frontal horns of the lateral ventricles and dividing it by the maximum intracranial width in the same slice of axial plane; a normal value is <0.3 (**Figure 1a**). A newly proposed z-Evans' Index has shown an increased diagnostic value, it is measured in the coronal plane and is a ratio of the maximum frontal horn height and the vertical diameter of the skull at the midline, the normal value is <0.42 (**Figure 1b**) [45, 46]. The distribution of subarachnoid spaces changes with NPH as well as neurodegenerative diseases such as AD and Parkinson's disease. A characteristic pattern that aids in differentiating NPH from other pathologies is DESH, its imaging features are narrowed subarachnoid spaces of the midline and high convexity with dilation of the Sylvian fissures, associated with ventriculomegaly (**Figure 1c**). In contrast,


#### **Figure 1.**

*NPH imaging findings. a. T2WI axial MRI. Evans' index b. T2WI coronal MRI. Z-Evans' index c. T2WI coronal MRI. DESH d. T2WI coronal MRI. Callosal angle e. T2WI axial MRI. Temporal horns f. T2W1 coronal MRI. Ventricle ballooning g. axial CT. Transependymal CSF flow h. T2WI axial MRI. Transependymal CSF flow i. T2WI Flair. Transependymal CSF flow. Images obtained from FSFB NPH COE database.*

generalized widened sulci with ventriculomegaly is seen on neurodegenerative cerebral atrophy [47]. Due to morphological changes attributed to DESH, vertical distortion of the lateral ventricles is more commonly associated with NPH and is evidenced in the CA, which is the angle formed by the right and left parts of the corpus callosum and is measured in a plane perpendicular to the anterior commissure-posterior commissure plane (AC-PC) through the posterior commissure; patients with NPH have an acute angle (<90°) whereas healthy patients or patients suffering from other diseases have an angle >90° (**Figure 1d**). Proper alignment of the true perpendicular plane must be achieved to avoid over or underestimation of the CA [48]. A systematic review conducted by Park et al. analyzed the diagnostic performance of the EI and CA and demonstrated that the CA yields a higher diagnostic value than EI (CA: 91% sensitivity and 93% specificity versus EI: 96% sensitivity and 83% specificity) [49].

A less common method is to measure the thickness of both temporal horns of the lateral ventricles in an axial section and if this value is >2 mm it is highly suggestive of ventriculomegaly (**Figure 1e**). Lateral ventricle ballooning and/or slit-shaped third ventricle also suggest ventriculomegaly (**Figure 1f**). In cases of third and fourth ventricular dilation, it is important to rule out triventricular or tetraventricular hydrocephalus due to mechanical obstruction of another cause [50]. Other signs are low periventricular density on CT or hyperintensity on T2WI or FLAIR MRI sequences immediately adjacent to the ventricular wall, which is highly suggestive of transependymal flow of CSF (indirect sign of hydrocephalus) (**Figure 1g–i**). More peripheral white matter lesions, such as those in corona radiata, suggest ischemic changes [50]. It is important to differentiate ventriculomegaly in NPH from compensatory *ex vacuo* ventriculomegaly secondary to atrophy, typical of other diseases. Focal atrophy indicates other types of dementia, especially if it is asymmetric, as in FTD or hippocampal atrophy in AD.

There are MRI techniques that analyze the movement of CSF and water that offer further insight about the pathophysiology of NPH. One is phase contrast MRI (PC-MRI) which is an invasive technique that measures flow of ejected CSF in specific anatomic regions, especially the cerebral aqueduct. It is based on the pulsatile relationship of CSF flow with heartbeat and respiratory rate and known relaxation times of CSF in T1WI and T2WI sequences with respect to static tissue. Limitations include that it is invasive, gathers information from many cardiac cycles, and evaluates only certain regions [51]. Another reported issue in NPH is increased CSF pulsatility. Aqueduct flow is reduced or even absent in phase contrast MRI (PC-MR) [52–54]. Aqueduct stroke volume (ASV), defined as the average of flow volume through the aqueduct during diastole and systole, may be an indirect parameter of CSF pulsatility. Various studies have shown increased ASV in NPH patients compared to healthy controls. Luetmer et al. demonstrated that ASV elevation assists in diagnosis and in differentiating NPH from other dementias. ASV greater or equal to 42 L has been applied to identify patients who might benefit from shunting procedure [55]. Scollato et al. reported that patients with higher ASV may benefit from shunting [56]**.** Aqueduct pulsatility reflects capillary expansion, mainly influenced by the pulsatile dampening of arteries in the Windkessel *effect* [57, 58]*.*

Time-spatial labeling inversion pulse or *SPLIT*, a non-invasive technique that synchronizes CSF flow with the arterial pulse. SPLIT evaluates both linear and turbulent movement of CSF between two compartments in any anatomic region of the CNS for periods of up to 5 seconds (22). The observed flow patterns are not the same as those classically described, even in brains without hydrocephalus. In fact, retrograde aqueduct flow generates sustained pressure gradients that favor compressive stress and shearing force on the ependyma. The causal relationship

#### *Normal Pressure Hydrocephalus: Revisiting the Hydrodynamics of the Brain DOI: http://dx.doi.org/10.5772/intechopen.98813*

between ASV and ventricular volume has been confirmed [59]. Further improvements in this technology will probably offer valuable information on the pathophysiology of NPH in the short-coming future.

Arterial spin-labeling or ASL-MR perfusion is a non-invasive technique without the need of intravenous contrast administration. Instead, ASL-MR perfusion technique is based on the principle of magnetically labeled water molecules in blood, hence, water in blood entering the CNS is used as an endogenous tracer. Unlabeled images are subtracted from labeled images obtaining a regional blood flow map. Some authors have used ASL-MR to study changes in cerebral flow in patients with NPH and have found a positive correlation with clinical changes before and after surgery [8]. Diffusion tensor imaging (DTI) has gained popularity for the diagnosis of NPH, following dilation of the lateral ventricles comes abnormalities and compression of the surrounding periventricular white matter. The research on the usefulness of DTI in NPH has been focused on its diagnostic value and ability to differentiate NPH from other neurodegenerative diseases, the areas of interest are the corpus callosum, internal capsule, hippocampus and the corticospinal tracts to which gait disturbance could be attributed. Fractional anisotropy (FA) which is a measure of the direction of diffusion, is reported in absolute values ranging from 0 to 1 where 0 means free flow of molecules and 1 means restricted linear flow. Increased FA signal is reported as a prominent characteristic in NPH compared to other neurodegenerative diseases like AD or Parkinson's disease where FA is decreased. However, recent research reports decreased FA of the corticospinal tracts in NPH [60].

Single photon emission computed tomography (SPECT) can be used for analysis of cerebral blood flow (CBF) when studying NPH, the characteristic CBF pattern observed in NPH is known as convexity apparent hyperperfusion (CAPPAH) which consists in increased CBF in midline and convexity with decreased perisylvian perfusion congruent with DESH morphology [32, 46]. Glucose metabolism assessed with Positron Emission Tomography is useful for distinguishing NPH from other pathologies when decreased basal ganglia metabolism is present. MRI flowmetry and spectroscopy have not been shown superior to the aforementioned imaging methods, therefore cannot be recommended [32]. Other nuclear medicine techniques such as dopamine transporter scintigraphy, fluorodeoxyglucose-PET (FDG-PET) and amyloid-PET have also been studied in NPH offering possible diagnostic aids.

Given the interobserver variation in the findings on brain imaging suggesting NPH, an objective standardized guideline or scale would be warranted. A radiologic scale (iNPH Radscale) was proposed in 2017 by Kockum et al., evaluating the correlation of NPH symptoms and seven radiological findings in CT: EI, CA, DESH (Sylvian fissure dilation and narrowing of parafalcine or high convexity sulci), temporal horn enlargement, focal enlargement of sulci and periventricular hypodensities, with a score ranging from 0 to 12. The study results showed that a higher score was related with a higher symptom burden, however the cohorts studied were only from a Swedish town [61]. In 2020 the diagnostic performance of the iNPH Radscale was evaluated by its author, the follow-up results showed that a cutoff value of 4 had high diagnostic value with a sensitivity of 100% and specificity of 96%, which could be a useful diagnostic tool in the future when further studies are conducted with regards of its diagnostic values in other populations [62].

#### **6.2 Tap test**

One of S. Hakim's most important lesson is that lumbar puncture (LP) is a technically simple procedure, with roughly null complication rate and cost-effective that provides valuable information on neurophysiology. Tap test simulates a

drainage device improving NPH symptoms. However, it has a low sensitivity and there is no consensus on the parameters that should be used nor the volume to be extracted. In our NPH COE at FSFB, all suspicious cases of NPH undergo a modified tap test that consists in a conventional LP: the patient is in a lateral decubitus position and an 18-gauge (18.0 Ga) spinal needle is used. The amount of CSF obtained is determined by reaching a closing pressure of 0 cm H2O regardless of the volume, thus there is no fixed volume to extract. We recently carried out a descriptive cross-sectional study in which 92 patients with a mean age of 79.4 years were included. The diagnosis was confirmed in 73.9% of cases (validity comparable to that reported in the literature). The mean opening pressure was 14.4 cm H2O and the mean volume extracted was 43.4 mL [63]. These results warrant further trials to determine if this modified tap test could eventually become the gold standard. If opening pressure is normal and there is objective improvement in symptoms and formal tests 24 hours after LP, the patient is considered candidate for CSF shunting surgery.

#### **6.3 Lab tests**

Although most patients have one or more symptoms of the clinical triad, as well as typical findings in imaging, and procedures that can lean towards the diagnosis of NPH, no gold standard has been established. For this reason, since 1990 some authors have studied the role of biomarkers in serum and CSF that had not been frequently used before despite their proved diagnostic value in other neurodegenerative disorders, especially AD. Results using serum biomarkers were not promising, and the authors concluded that as long as the BBB is intact, as it would be expected in NPH, serum levels of those markers would not have diagnostic utility [64–66].

To date, there is no consensus on the biochemical profile of NPH and the differences with the profile of some neurodegenerative disorders, but interesting data has been obtained on some biomarkers:

Amongst neurotransmitters, activity of AChE in CSF has been positively correlated with MMSE scores in patients with NPH and AD, which is reduced in these diseases [67–69]. Other neurotransmitters have not been proven to be useful due to their ubiquity in the CNS and poor correlation.

Somatostatin (SOM) levels have been described as lower in NPH patients compared to controls and these levels have increased after CSF shunting surgery. Increase in SOM levels correlates positively with cognitive performance (memory and visuo-motor) after surgery, but this does not persist over time [70, 71]. Neuropeptide Y (NPY) levels are also reduced in NPH compared to controls and increase after surgery, although they are also low in patients with AD, so this finding is not specific of NPH [71, 72]. Vasoactive intestinal peptide (VIP) is markedly elevated in patients with SAD or Binswanger's disease and in general in vascular dementias. VIP levels are higher in patients with NPH and cerebrovascular comorbidity compared to a NPH group without any comorbidities [73].

Tumor necrosis factor alpha (TNF-alpha) levels may be increased up to 45-fold above reference range in NPH patients and interestingly, TNF-alpha levels normalize after surgery, suggesting a pro-inflammatory component not yet studied in NPH. Its half-life is short and therefore researchers highlight it is not related to stagnant CSF or siphoning effect after implantation of the shunting device. It could be a specific marker with a high PPV [74]. Vascular endothelial growth factor (VEGF) is a proangiogenic cytokine that serves as a marker for chronic hypoxia. Its levels are elevated in patients with NPH compared to controls; the higher VEGF levels, less response to surgery and worse clinical outcome [75, 76].

#### *Normal Pressure Hydrocephalus: Revisiting the Hydrodynamics of the Brain DOI: http://dx.doi.org/10.5772/intechopen.98813*

Myelin basic protein (MBP) is a reliable marker of demyelination, and hydrocephalus is known to cause periventricular demyelination by mechanical stretch, hence, the degree of ventriculomegaly has been positively correlated with MBP levels. Brain atrophy, though, does not raise MBP levels [77, 78]. These levels decrease after surgery, which supports the theory that ventriculomegaly in NPH does not produce atrophy but cerebral pseudoatrophy, studied by some authors including Fernando Hakim et al. and correlates with clinical improvement after surgery [79–83].

In a study of experimentally-induced hydrocephalus in rats, postoperative MBP levels were lower in models operated 1 week after induced hydrocephalus compared to models operated 4 weeks later [84]. This supports the idea that the earlier hydrocephalus is diagnosed and treated, the better the outcome for NPH patients.

Beta-amyloid is a peptide synthesized from amyloid precursor protein (APP) whose biologic functions include enzymatic co-factor, cholesterol transport, and pro-inflammatory activity. The diagnostic role of beta-amyloid deposits in AD has been largely studied. Especially the ratio of its isoforms (AB42 / AB40) which has a higher diagnostic value than AB42 alone. The levels of AB42 and AB40 isoforms are low in NPH compared to AD [84, 85]. They could be helpful in distinguishing between NPH and AD. Nearly half of NPH patients show certain degree of amyloid deposition in brain biopsy specimens while only 10% show concomitant amyloid and tau pathology [86]. Tau is a protein of neural tissue microtubules and serves as a marker of neuronal degeneration in other types of dementia like AD, Lewy's, corticobasal degeneration, and prion disease (Creutzfeldt-Jakob). The levels of total tau (t-tau) and phosphorylated tau (p-tau) have been positively correlated with the severity of dementia in AD, as well as with cognitive decline and urinary incontinence in NPH, although they are lower in NPH compared to AD [84, 87]. Neurogranin (NRGN) has also been studied in AD patients and has been associated with amyloid plaques [88, 89].

Neural growth factor (NGF) mRNA levels are elevated in the basal nuclei of experimentally-induced hydrocephalus models, this is why they could act as markers of early neuronal injury that stimulates glial recruitment [90]. Neurofilament light chain (NFL) is increased in NPH, AD, and other dementias, but there is no correlation with clinical manifestations, severity, or response to surgery. A Swedish study reported 100% PPV for positive outcome after surgery, with 17% sensitivity and 100% specificity [91, 92]. It could be a marker of ongoing axonal damage.

Sulfatide is a glycosphingolipid component of myelin. Its levels are higher in NPH and cerebrovascular comorbidity, but no correlation with postoperative outcome has been reported. According to one study, sulfatide differentiates NPH from SAD with 74% sensitivity and 94% specificity [93]. Glial fibrillary acid protein (GFAP) and S-100 are markers used in tumor immunohistochemistry that have not shown conclusive data in NPH.

Recently, the first longitudinal comparison of CSF biomarkers in NPH patients and AD was conducted by a group in Finland. Furthermore, they compared the gradients of biomarker concentrations lumbar and ventricular CSF which are discordant. All markers increased notably by 140–810% in lumbar CSF, except beta amyloid that had an erratic behavior. All studied biomarkers (tau, NFL, NRGN and beta amyloid) correlated highly between lumbar and ventricular samples but were systematically lower in ventricular samples [94]. Longitudinal follow-up shoed that after initial postoperative increase, tau and NRGN levels are stable in NPH regardless of brain biopsy amyloid pathology. NFL normalized after surgery to preshunting levels. Amyloid is the less affected by shunting and may be the best predictor of concomitant AD risk in NPH patients [94]. Tau levels (both p-tau and

t-tau) have shown a steady increase of 2% per year in AD [95]. In cases of TBI, t-tau levels increase but normalize to baseline levels by day 20–43 post trauma [96, 97]. This is different, however, for patients who suffer chronic TBI like boxers, for example [97]. Interestingly, NFL levels after surgery correlated with tau and NRGN, raising the question if their increase is related to disease process or the shunting procedure itself. Future larger randomized trials are warranted to elucidate the role of CSF biomarkers in NPH progression, surgical prognosis, and risk of concomitant neurodegenerative disorders.

#### **7. Brief history of CSF shunting devices**

The main principle is shunting CSF to another sterile cavity with constant flow and/or where fluid can be reabsorbed to the systemic circulation. The quest for an effective system is not recent. Le Cat performed the first documented ventricular puncture in 1744 [98, 99]. Throughout the XIX and XX centuries, different devices were designed as well as different shunting techniques that included ventriculosubarachnoid-subgaleal, lumbo-peritoneal, ventriculo-peritoneal, venous, pleural, and uretheral. All failed in the short-term because implant materials that included glass, rubber and guttapercha were not adequate and aseptic techniques were extremely poor with high rates of infection [99]. There were also cases of sudden death before the advent of appropriate imaging techniques which fortunately decreased after Dandy introduced the pneumo-ventriculography in 1918. Pneumoventriculography remained the gold standard until 1980 when Humphrey introduced the computed tomography [99]. During the first half of the XX century different techniques were proposed such as choroid plexus cauterization and draining systems to intra and extracranial veins. Infection and material rejection were the main causes of failure. Developing a biocompatible unidirectional system was paramount.

Torkildsen described the ventriculo-cysternostomy in 1938 in a case of spontaneous cure of hydrocephalus after an accidental rupture of the fourth ventricle during surgery. This became a popular method to treat obstructive hydrocephalus until the early 1970's [100]. Vannevar Bush engineering professor at Massachussets Institute of Technology (MIT) and Donald Matson, surgeon at Harvard Children's Hospital were possibly the first to develop a magnetically-operated valve by 1950. Although there is no certainty on the exact date of implantation, around 18 devices were implanted by 1957 but this project was soon abandoned because results were not promising [99]. Ommaya invented the subcutaneous reservoir in 1963, his device is still today the method of choice for obstructive hydrocephalus in children with minor modifications to the original design [101].

#### **7.1 First effective devices**

The long-sought biocompatible material is silicone, an inorganic polymer derived from polysiloxane (series of oxygen and silicon atoms) whose properties include inert, malleable, resistant to high temperatures and stretching. Silicone has its origins in World War II, like many other inventions, because materials that resisted high temperatures, provided electrical insulation, and resisted mechanical stress for aircraft construction were urgently needed. In 1946, a silicone tube was implanted to repair a bile duct. In 1956, it was used as a CSF drainage device by Holter and Pudenz and thus became the ideal material for different valve designs [99]. However, these devices failed because, due the mechanism of the opening slit when CSF pressure increased, they were imprecise.

#### *Normal Pressure Hydrocephalus: Revisiting the Hydrodynamics of the Brain DOI: http://dx.doi.org/10.5772/intechopen.98813*

In 1964, S. Hakim introduced his first valve that consisted of two twin valved systems made of stainless steel and synthetic sapphire manufactured by himself in his home lab. It was one of the first precise models that controlled pressure [102]. By 1965, S. Hakim had published his observations in the NEJM and NPH or Hakim's syndrome was recognized as a separate entity by the scientific community. A second generation of devices intended to solve the problem of overdrainage in the upright position. Kuffer and Strub designed a piston-based system in 1969, but it never became popular and the same happened with some successive designs. S. Hakim introduced a valve that could be operated magnetically and percutaneously in 1973 [99]. In that same year, he introduced a self-regulating device, nonetheless, the first patented self-regulating valve was that of Sainte-Rose in 1984 (Cordis Orbis-Sigma). Portnoy later designed his *anti-siphon* device patented by Schulte in 1973 (Heyer-Schulte ASD). This is a flapping membrane mechanism that closes progressively when subjected to the weight of a hydrostatic column in the distal catheter. These mechanisms failed because they were highly susceptible to external tissue pressure. In 1975, S. Hakim patented the first *anti-gravitational* device [99].

At the time, S. Hakim's oldest son, Carlos, was already a mechanical engineer starting his post-doctoral fellowship at MIT in biomedical engineering. Carlos studied hydrocephalus in animal models. In his thesis he questioned some aspects of his father's original theory including the concept of brain elasticity. Carlos demonstrated that if the brain were elastic, dilated ventricles would return to normal dimensions after a shunting device was implanted. This does not happen in all cases and it depends on how much time ventricles have been subjected to the *hydraulic press effect.* He introduced the concept of brain *plasticity.* Carlos Hakim also demonstrated that the thin walls of the venous system in an adult human are easily compressible when subjected to high external pressure in the upright position. Thence, demonstrated that the anti-siphon effect was not true. Instead, he associated with Swiss watchmakers who were pioneers in micromechanics and developed the first *programmable* valve with 18 pressure positions ranging from 30 to 200 mm H2O (Medos-Hakim). This device was first implanted in Colombia by S. Hakim and was approved for commercialization in 1989. It soon demonstrated superiority compared with all other available designs and entered Europe in 1990 [99]. Today, this design is distributed by Johnson & Johnson as the Codman Hakim™ programmable valve which has proved superiority systematically.

By 1999, at least 127 models of different mechanisms were available. Most of them rudimentary unidirectional systems based on pressure gradient with ball and cone (13 models), diaphragm (>35) and slit (>50) [99]. To date, >60 models were never evaluated in lab and 40 were only in tested in one or two specimens, hence, their value is only anecdotal. Compared with other high-tech devices in the biomedical field, like pacemakers, most valves are imprecise, unsafe, obsolete, and cheap. By 2000, the mean cost per device was \$600 USD. Assuming a mean device lifespan of 10 years, this equates to 17-dollar cents/day. The total cost of sold devices in the USA by 1995 was 20.8 million dollars which was the equivalent of 8-dollar cents/per capita [99, 103].

#### **8. Surgical treatment**

#### **8.1 Surgery**

To date, the only effective treatment of NPH is a CSF shunting procedure that involves implantation of a draining system that diverts excess intracranial CSF into a sterile cavity where CSF returns to or is reabsorbed into the systemic circulation.

The system should ideally be a programmable valved device. Shunting techniques include VAS, VPS, LPS, and rarely ventriculo-pleural shunt (VPlS). VAS and VPS are the most commonly used in clinical practice. S. Hakim originally described VAS arguing that it was physiological and of choice at our NPH COE. LPS is very common amongst Japanese surgeons, however, it is technically complex and can have a higher rate of perioperative complications. DVPl is seldom used due to a high complication rate and lower reproducibility. It is consensus that endoscopic third ventriculostomy (ETV) is not effective for treating NPH.

#### *8.1.1 VAS*

It is considered the technique of choice. Between 1970 and 1980 it was hardly criticized because it was an expensive technique that required vascular dissection, hence, with multiple complications such as vascular rupture, embolism, and infection. However, with the advent of Seldinger-type techniques guided by ultrasound (US) and constant electrocardiographic monitoring, which do not require vascular dissection, incidence of complications in VAS does not exceed that of VPS [104, 105].

At our NPH COE, VAS is performed in all patients unless contraindicated. The technique consists of puncturing the internal jugular vein (IJV) using a US-guided Seldinger technique and continuous EKG monitoring. A 7-Fr peel-away disposable sheath catheter is used. This allows easy, safe, fast, and reproducible insertion and positioning of the distal catheter in the cavo-atrial junction which is the correct position (guided by fluoroscopy) [105]. Trained surgeons can perform the whole procedure within 30 minutes, with a lower perioperative complication rate than other techniques. Hung et al. reported that patients with NPH undergoing VAS are less likely to develop obstruction and/or require device revision compared to the group undergoing VPS [105]. Serious thromboembolic complications associated with VAS such as in situ thrombus formation, intracardiac thrombi, pulmonary artery thromboembolism and pulmonary hypertension, which have a high morbidity and mortality rate, are uncommon, with an estimated prevalence <1%. Adjuvant therapy with direct anticoagulant agents like rivaroxaban has been proposed, but currently, there is no robust evidence to support such recommendation as a preventive strategy [105–107].

#### *8.1.2 VPS*

Became the most popular technique since 1970 because of the vascular complications encountered in VAS. However, there is a non-negligible percentage of patients in whom it is advisable not to use a distal peritoneal catheter due to inflammatory or infectious diseases in the abdominal cavity, as well as a slightly higher incidence of distal obstruction. Patients undergoing VPS, have an estimated incidence of device-related complications in the peritoneal cavity ranging from 5 to 47%, depending on the series. Complications include device infection, pseudo-cyst, adhesion, and malposition (scrotum, bladder, small intestine, and hernia) [108].

#### *8.1.3 LPS*

Murtagh was the first to introduce a lumbo-peritoneal catheter through a Touhy needle [83]. Rarely used amongst Western surgeons, but extremely popular amongst Japanese neurosurgeons. Described as a less invasive and effective alternative in high-risk patients in whom the right atrium and peritoneal cavity cannot be used. Significant improvement has been reported in the components of Hakim's

triad, however, the complication rate is 20% [28, 109, 110]. This technique is not routinely recommended unless the surgical staff is highly experienced.

#### *8.1.4 VPlS*

An alternative when VAS or VPS are contraindicated, however, the complication rate is high including hydrothorax, pneumonia, and pleural effusion. It is not considered an efficient long-term option [111].

#### *8.1.5 ETV*

Described in 1990 as an alternative approach for cases of obstructive hydrocephalus and some selected cases of communicating hydrocephalus, has recently gained attention as an alternative approach that saves device implantation. However, conducted trials have small numbers of patients and lack randomization, therefore its effectiveness and generalizability in NPH is still limited [112, 113]**.**

The thorough description of each surgical technique is beyond the scope of this chapter.

#### **8.2 Prognosis after shunting procedure**

Despite variability in evaluation methods, gait disturbance has systematically showed the highest rate of improvement (60–77%). Cognitive decline improves in 60–70% of cases and urinary incontinence improves in 52% of cases [114–118]. Surely, these rates vary according to different diagnostic criteria, evaluation methods and improvement thresholds.

Short-term outcomes are mainly affected by perioperative complications and by severity and duration of disease before treatment. Long-term outcomes strictly depend on other neurologic comorbidities, hence the importance of diagnosis these disorders using biomarkers before and after surgery to help patients and their families conveying their expectations. Frailty and/or comorbidity indices can be helpful for perioperative outcome evaluation.

#### **8.3 Shunt procedure cost-effectiveness**

Based on SINPHONI and SINPHONI-2 results, incremental cost-effectiveness ratio 1 year after shunt surgery was 29934–40742 USD/quality-adjusted life year (QALY) for VPS and 58346–80392 USD/QALY for LPS. Additionally, the sum of surgical cost and nursing cost for NPH is reduced to 18 months after VPS and 21 months after LPS, compared with untreated NPH patients [119].

Some authors studied the economic effect of NPH treatments using the Markov model based on epidemiologic data from Sweden. These authors reported that an additional lifetime of 2.2 years and 1.7 QALY was gained with treatment, with an additional cost of 13,000 GBP [120].

#### **8.4 Non-surgical treatment**

To date, there are no FDA-approved pharmacological therapies for NPH. Clinical trials suggest that carbonic anhydrase inhibitors (CAIs) such as acetazolamide can reduce periventricular white matter hyperintensities and thence improve NPH symptoms [121]. However, these studies have flawed designs which confound their results and render their conclusions temporarily invalid. Prospective, double-blinded, and placebo-controlled trials are warranted.

Future improvements in technology within the pharmaceutical industry may offer novel supplementary agents that tackle NPH pathogenesis. These drugs could normalize CSF hydrodynamics by tackling CSF production, pulsatility and Rout. They could also restore cerebral blood perfusion and parenchymal compliance as well as promote brain waste products providing neuroprotection and reducing neuroinflammation.

#### **9. Complications after CSF shunting surgery**

Main complications include infection, catheter malposition (proximal and distal), and hydraulic device-associated complications. Infections are responsible for 10–15% of device revisions, but their impact on morbidity and mortality is high. The cost of managing a patient with an infected device is approximately \$30,000 USD [103]. Most infections are secondary to intraoperative contamination of the implant [99]. Trained surgical staffs that meet strict aseptic techniques and are able to reduce operating time have infection rates <1%. In 3 independent metaanalyses, the use of prophylactic systemic antibiotic decreased infection rate to 5–6% compared to 10–12% in controls without prophylaxis [122–124]. At our NPH COE, intravenous Vancomycin is infused during a 60-minute period before incision.

Catheter malposition, both proximal and distal, is the most common cause of shunt system failure, but it is an unpopular topic in the literature [125]. Probably due to ambiguity in the definition of perioperative complication and the methods used to analyze them. At some point in the post-operative follow-up period, approximately 17% of patients develop complications associated with overdrainage such as hygromas and subdural hematomas, postural headache, slit ventricular syndrome and, occasionally, bone table deformities. Other less frequent ones include proximal occlusion, sequestered ventricle, upright ventricular hyperemia, intraparenchymal or intraventricular hemorrhage and/or partial sometimes irreversible loss of cerebral compliance [126]. Postural headache along with hygromas and laminar subdural hematomas, can be managed with pressure adjustment of the device. According to a recent metanalysis, the need for additional surgery was 9– 16% of patients operated with an adjustable device and 26–38% in patients with a fixed-pressure device [127]**.** These are the main reasons to use programmable devices because percutaneous pressure adjustment saves additional surgical interventions for complications that can be resolved non-invasively. When the hygroma or subdural hematoma is large, it produces intractable headache and/or progressive neurologic deficit, surgery to drain the space-occupying lesion, device revision and proximal catheter relocation is indicated.

Novel shunt catheters manufactured with advanced biomaterials that avoid cell and bacterial adhesion as well as *smart* devices with auto-regulating monitors are underway which promise better treatment outcomes [128].

#### **10. NPH COE protocol**

At FSFB, we designed a NPH protocol based on the best available evidence and standards. Our protocol has been certified and accredited by Joint Commission International (JCI). The protocol consists of 5 phases with specific goals to diagnose and treat NPH in an optimal way. The main purpose of this protocol is helping the patient reintegrate to his/her daily activities and community (**Figure 2**).

*Normal Pressure Hydrocephalus: Revisiting the Hydrodynamics of the Brain DOI: http://dx.doi.org/10.5772/intechopen.98813*

Gait impairment (praxia/symmetric magnetism) or cognitive decline or urinary urgency/incontinence Radiographic signs suggestive of NPH Absence of other neurologic disorder that could explain current symptoms

#### **Table 1.**

*Inclusion criteria. Patients should have at least one of the following (*≥ *1).*

#### **10.1 Phases**

#### *10.1.1 Phase 1 (clinical suspicion)*

Patients either consult or are referred because have signs and symptoms suggestive of NPH. The objective of this phase is to identify suspicious cases. Patients undergo a complete neurologic examination and interview by one neurosurgeon of our team. The physician orders a brain MRI or CT scan whenever MRI is contraindicated. Suspicious cases are those who meet the inclusion criteria listed in **Table 1**.

#### *10.1.2 Phase 2 (diagnostic tests)*

Patients who met the inclusion criteria and consent are admitted for a 2-day inpatient analysis. The patient undergoes thorough evaluation by neuropsychology, speech and language therapy, rehabilitation medicine and geriatrics specialist using all diagnostic tests that have been mentioned before. In all patients >64 years, an elder adult frailty test is performed. Depending on each individual case, social work and nutrition specialist may also be involved. Then we perform the modified tap test we described above by taking the system to a closing pressure of 0 cm H2O. All tests are repeated 24 hours after tap test. Tests performed before and after tap test are listed in **Table 2**. Thereafter, the patient is discharged and followed during 7 days via phone call to inquire on symptom improvement.

After this week of follow-up, a multidisciplinary team consisting of all neurosurgeons, psychology, speech and language therapy, rehabilitation medicine and geriatrics meets to analyze objective changes in all tests before and after tap test. Diagnosis is confirmed when patients objectively improve in at least 1 of the triad components. Diagnostic criteria are listed in **Table 3**. Once the diagnosis of NPH is confirmed, the team decides if the patient benefits or not of a CSF shunting surgery. When NPH is discarded, patients are referred to the required specialty.

Patient companions undergo the Zarit caregiver's burden test before and after tap test to evaluate the degree of burden/fatigue.

#### *10.1.3 Phase 3 (preoperative assessment)*

If patient and family agree with the team's decision, the patient undergoes regular preoperative tests, anesthetic evaluation, and an institutional risk mitigation


#### **Table 2.**

*Tests performed before and after tap test.*


#### **Table 3.**

tightness

*Diagnostic criteria at FSFB NPH COE.*

form. Patients are then scheduled for CSF shunting. Patients and family receive rigorous education on the procedure and postoperative care.

#### *10.1.4 Phase 4 (surgery)*

Patients are admitted for VAS or VPS when VAS is contraindicated. All cases include:


#### *Normal Pressure Hydrocephalus: Revisiting the Hydrodynamics of the Brain DOI: http://dx.doi.org/10.5772/intechopen.98813*

After surgery, patients stay for 48 hours as inpatient for close postoperative follow-up. During these 48 hours, physical rehabilitation specialist designs an individual rehabilitation plan. Again, education on device care, hygiene and urgent signs that may require visit to the emergency room are provided.

Patients are discharged on the third postoperative day. A control CT scan is ordered, and patients are instructed to visit their surgeon on the tenth postoperative day at the outpatient clinic.

#### *10.1.5 Phase 5 (follow-up)*

Patients are followed on months 1, 3, 6 and 12 after surgery. The main objective is to evaluate shunting device functionality and symptom improvement. Psychology tests are performed on months 6 and 12. Rehabilitation plans are adjusted according to every individual's needs.

#### **11. Conclusions**

Despite the huge amount of research since its original description, NPH remains an underdiagnosed disorder due to lack of clinical suspicion amongst the medical community. Therefore, the main concern is raising interest and suspicion amongst all medical professionals.

Recent advances in diagnostic imaging and lab biomarkers have given interesting insight into the pathophysiology of NPH that will probably be fundamental in the future. The best proven method for diagnosing and treating patients with NPH is following a standardized multidisciplinary protocol.

#### **Conflict of interest**

None of the authors have any conflict of interest to disclose.

#### **Abbreviations**



*Normal Pressure Hydrocephalus: Revisiting the Hydrodynamics of the Brain DOI: http://dx.doi.org/10.5772/intechopen.98813*


#### **Author details**

Fernando Hakim<sup>1</sup> \*, Daniel Jaramillo-Velásquez<sup>1</sup> \*†, Martina González<sup>1</sup> , Diego F. Gómez<sup>1</sup> , Juan F. Ramón<sup>1</sup> and Mateo Serrano-Pinzón<sup>2</sup>

1 Neurosurgery Department, Fundación Santa Fe de Bogotá, Bogotá D.C., Colombia

2 Medical School, Pontificia Universidad Javeriana, Bogotá D.C., Colombia

\*Address all correspondence to: fhakimd@gmail.com; djaramillomd@gmail.com

†This was the author who did the main review of the available literature and wrote the whole manuscript.

© 2021 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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#### **Chapter 4**

## Clinical Diagnosis and Treatment Management of Normal Pressure Hydrocephalus

*Hüseyin Yakar*

#### **Abstract**

Inadequate absorption of cerebrospinal fluid (CSF) at the arachnoid granulation level during circulation results in an increase in CSF in the ventricle and certain neuropsychiatric clinical findings. This syndrome, which often presents with ventricular dilatation, progressive cognitive decline, walking difficulties, and urinary incontinence symptoms in elderly individuals, is called Normal Pressure Hydrocephalus (NPH). It is projected that as people's quality of life improves and their life expectancy rises, more old people would develop this condition. Although a clear clinical triad has been defined, the identification of patients with NPH and the application of effective treatment modalities still pose a number of challenges for neurosurgeons today. However, despite all these difficulties, if diagnosed and treated early, the unusual appearance of these symptoms affecting elderly individuals can be prevented and significant improvements in quality of life can be achieved.

**Keywords:** normal pressure hydrocephalus, elderly individuals, neurodegenerative diseases, cognitive deficits, early surgical treatment

#### **1. Introduction**

The brain and spinal cord are soft and vulnerable structures by their very nature. Cerebrospinal fluid (CSF) is the air cushion of the central nervous system (CNS), which protects the nerve tissue by reducing the speed of the blows to the CNS. 90% of this fluid is produced continuously by specialized cells called choroid plexus in the ventricle and 10% by ependymal cells lining the ventricle surface. CSF, which flows through F. Luschka and F. Magendie into the subarachnoid space to surround the brain and spinal cord, drains into the venous system via arachnoid granulation. Colombian neurosurgeon Hakim et al. [1–3] described a clinic in 1964 characterized by progressive cognitive decline with ventricular dilatation (normal CSF pressure during lumbar puncture), difficulty walking, and urinary incontinence syndrome. Hakim named this syndrome Normal Pressure Hydrocephalus (NPH). Although a clear clinical triad has been defined, there are important differences in the clinical presentation and progression of this syndrome. This situation leads to an increase in the problems related to the diagnosis and treatment of NPH. In fact, although there have been remarkable developments in the field of medicine since NPH was first defined in 1964, the guidelines determining the diagnosis, management, and operation criteria of NPH were first prepared in 2004 to be implemented only in

Japan. Only in 2008 did Ishikawa et al. [4] produce worldwide applicable guidelines for its diagnosis and treatment. The information presented above is the most convincing evidence of the type of dynamic disease we are dealing with. On the other hand, due to reasons such as advancements in health, improved treatment options, increased education level, and conscientious diet, the share of the older population is constantly increasing. It is projected that as people's quality of life improves and their life expectancy rises, more old people would develop this condition. In the light of current information, it is predicted that 20% of the world population will be individuals over 65 years old by 2050. While the world's population has grown 4 times in the last 100 years (1950–2050), the fact that the elderly population will grow 10 times is a significant point that should be highlighted. In this case, it becomes even more important to age healthy and to keep the elderly population active. The most important task of neurologists, neurosurgeons, and psychiatrists in society is to provide early diagnosis and appropriate treatment of patients with NPH in society, especially given the socioeconomic consequences of this disease, particularly the burden of dementia on the individual, their families, and society. This is because it is emphasized that the earlier these patients are diagnosed and treated correctly, the more (most if not all) of the clinical symptoms are reversible.

#### **2. Classification**

NPH is divided into two groups as secondary NPH (sNPH) that develops due to decreased resorption of CSF due to inflammation and fibrosis at the arachnoid granulation level caused by subarachnoid hemorrhage, intraventricular hemorrhage, meningitis, or traumatic brain injury, and the second is the idiopathic NPH (iNPH) which does not have a causal disorder. A common feature of both diseases is that they do not contain any obstructions to the flow of CSF within the ventricular system of the brain. iNPH and sNPH do not differ in terms of prognosis. The sole significant clinical difference between them is that sNPH affects people of all ages, whereas iNPH often occurs more in the 60-70s [5, 6].

#### **3. Incidence-prevalence**

Epidemiological data on NPH are limited. Furthermore, due to the lack of uniform diagnostic criteria, reports on the incidence and prevalence of this disease, which has a wide clinical range, are partially inconsistent. The annual incidence of NPH is estimated to be between 0. 2 and 5.5 cases per 100,000 individuals. Its prevalence is reported to be 0.003% for persons under 65 years of age and 0. 2% to 2.9% for persons 65 years and older [7, 8]. In an epidemiological study conducted by Jaraj et al. [9], the probable prevalence of iNPH was found to be 0. 2% in people aged 70–79, and 5.9% in people aged 80 and older. Another recent epidemiological study also confirmed the inadequacy of incidence-prevalence reports of NPH [10]. Like other neurodegenerative diseases, the prevalence and incidence of NPH increases in direct proportion to age. In various studies, it was determined that there was no difference between males and females in terms of incidence [11–13].

#### **4. Pathophysiology**

It is important to clarify its pathophysiology for reliable diagnosis and treatment of NPH patients. Its pathophysiology is yet unknown, and it differs from other adult

#### *Clinical Diagnosis and Treatment Management of Normal Pressure Hydrocephalus DOI: http://dx.doi.org/10.5772/intechopen.99222*

hydrocephalus causes. In addition to the fact that pathological alterations change CSF pressure, it is also related to changes in CSF dynamics. The CSF circulation spaces in the brain parenchyma within a rigid cranium work as a dynamic system that continually seeks to adapt to new situations in order to keep the ICP constant. These structures give instantaneous responses to changes in CSF production-absorption, changes in arterial–venous flow to the brain, changes in the compliance of intracranial structures, and changes in intracranial pressure. This process is very important in terms of ensuring the correct functioning of the brain. Cerebral blood flow differs with heart rhythm. The arterial supply is pulsative, whereas the venous flow is non-pulsative, causing temporary rises in CSF pressure. In two ways, the system tries to compensate for this. First, vascular structures can reduce arterial blood flow by changing compliance. The second is that the outflow of CSF increases along the cerebral aqueduct. ICP is attempted to be kept constant thanks to these compensatory mechanisms. The decrease in arterial modulation is first compensated by increased pulsatile CSF flow. However, the progressive increase of the pulsatility amplitude causes large ICP pulsations that determine the "water-hammer" effect. These enhanced vibrations create venous damage in the periventricular region, and the process of pushing the brain against the skull continues to expand the ventricles, resulting in hydrocephalus. As a result, the compensatory mechanisms, that are activated in order to maintain the ICP stable, create pathological changes in neural tissue [14]. In fact, hydrocephalus can be defined as the expansion of the ventricles in response to the reduction of the subarachnoid space in the cerebral tissue. This situation is secondary to the increase in the pressure gradient between the ventricles and the subarachnoid space, known as the transmantle pressure [15]. It is still unclear what triggers the initial reduction in arterial compliance in this process. Ischemia emerging in the white matter surrounding arterioles could explain the insufficiency in autoregulation. The ventricular enlargement causes the arterioles and venules around the ventricle to compress and stretch over time, resulting in poor/insufficient cerebral perfusion [16–19]. Moreover, a strong relationship has been described between impaired cerebral blood flow and NPH. Therefore, clinically, the association of NPH with cerebrovascular disease is frequently encountered. Ischemic changes in cerebral tissue caused by decreased/ insufficient perfusion were shown in Cranial MRI. These structural changes detected by neuro-radiological imaging have also been supported by neuropathological studies [20–23]. Vascular changes that occur as a natural consequence of aging in humans may be the triggering mechanism in the reduction of vascular compliance. This may explain the relationship between iNPH and vascular disease [24].

NPH also reduces compliance in large vascular structures such as the superior sagittal sinus [25, 26]. Increased transvenular resistance in the sagittal sinuses has been hypothesized as a factor in the onset of NPH. According to this viewpoint, CSF resorption will be affected by increased transvenular resistance [27, 28]. As a result, none of the proposed theories can adequately explain how NPH develops, what factors trigger it, or how structural alterations occur. Although these presented hypotheses appear to complement one other, the debates about pathogenesis continue.

#### **5. Clinic**

Symptoms in NPH have been defined as a "triad". However, having all of the symptoms at the same time is not necessary for diagnosis. The presence of two or more of the key symptoms (even a cardinal clinical symptom) such as apraxia of gait, dementia, and urinary incontinence, as well as bilateral dilatation of the ventricles, is necessary to diagnose the disease. The clinical signs and symptoms of this syndrome are highly diverse. Symptoms of this disease, which has an insidious onset, appear gradually over a period of at least 6 months. The rate and extent of worsening of symptoms vary from one patient to another. Some patients and families are unaware of symptoms until a triggering event, such as surgery, occurs. Careful questioning can clarify the nature of symptom onset.

Decreased cerebral perfusion as a result of ventriculomegaly may be a reason for the classic symptoms of NPH. Neurological signs and symptoms, such as apraxia of walking, are thought to be caused by a combination of mechanical stretching of the periventricular fiber tracts, disruption of brain parenchyma tissue as a result of reduced cerebral blood flow, and periventricular edema [29–34]. Neuro-psychiatric symptoms have been suggested to be associated with brain regions such as the anterior cingulate cortex (ACC) and thalamus [35–37] because it has been determined that there is low perfusion in the anterior cingulate cortex and thalamus in NPH patients. Dysfunction in these regions is effective in the emergence of psychiatric symptoms. Therefore, increased/improved cerebral perfusion and oxygen metabolism from the frontal cortex and thalamus may cause neuropsychiatric and other symptoms in NPH patients after shunt surgery [38, 39]. There are publications reporting that psychiatric symptoms and syndromes occurring in the NPH clinic are related to changes in central neurotransmitter activity [40].

Although any of the main symptoms can present as the initial symptom in the NPH clinic, gait and balance disorders usually occur early and have a substantial impact on the individual's life. Dementia and urinary incontinence are symptoms that progress with the disease, albeit they usually appear at later stages of the disease [41].

#### **6. Gait disorder**

As described in many published series and guidelines, gait disturbance is the first clinical symptom that affects almost all patients. Dizziness is a common initial complaint among patients. The instability in NPH is better with the patient's eyes open, but patients still stand on a wide base even with their eyes open. When a patient's walking ability is compromised, it has a detrimental influence on their quality of life. At first, gait and balance disorders may appear to be mild. Patients initially complain of climbing and descending stairs, as well as getting up and sitting in a chair. Parallel to the progression of the disease, the patient's gait pattern deteriorates. Instead of the heel-to-toe gait cycle, which should normally be accomplished by raising the feet, these patients tend to slide their feet on the ground. This way of walking is described as "robotic", "sticky-footed" or "magnetic phenomenon" [42]. The disconnection between the basal ganglia and the frontal cortex during walking, as well as the co-contraction of opposing muscles, is suggested to be the source of this gait pattern, which is usually found in parkinsonism (bradykinetic, magnetic) [43, 44]. In the absence of primary sensorimotor deficits, these patients have a higher level of gait disturbance and impaired postural and locomotor reflexes [45]. Gait apraxia develops with the advent of cognitive disorders in the later stages of the disease, and individuals become unable to walk. If these patients are not diagnosed and treated early, they are eventually confined to a wheelchair.

Extrapyramidal symptoms may occur rarely in patients with NPH, but spasticity, hyperreflexia, and other upper motor neuron signs and lateralizing findings are not common. Since the symptoms are bilateral in NPH, lateralizing findings should alert the clinician to the presence of other neuropsychiatric disorders in the differential diagnosis. To assess diagnosis and prognosis, a standard gait assessment (e.g., Tinetti score, Boon Scale) should be performed both before and after the lumbar puncture (LP). The clinical finding with the highest probability of recovery (more than 85 percent) after shunt surgery is apraxia of walking, which is frequently the first main symptom of the disease [46–48].

*Clinical Diagnosis and Treatment Management of Normal Pressure Hydrocephalus DOI: http://dx.doi.org/10.5772/intechopen.99222*

#### **7. Cognitive disorder**

Cognitive deficit in NPH is basically of the "subcortical" type, which includes memory impairment, psychomotor retardation, and impaired ability to apply/use the acquired knowledge [49, 50]. These cognitive and behavioral disorders accompanying NPH are generally defined as "frontal-subcortical dementia or frontal-subcortical dysfunction" [51, 52]. This term is used to describe a pattern of mental decline marked by a lack of interest (apathy) in one's surroundings and oneself, as well as a lack of inner strength (amotivation) that drives one's activities and behaviors [53, 54]. For this reason, patients have difficulty in performing their daily living activities even at the onset of the disease. In this period, it is possible that an abnormality will not be identified in the psychometric tests that will be done on the patients.

Dementia is the most serious symptom in the clinical triad, as it has a negative impact on patients' work capacity as well as their social functioning. NPH is thought to be the etiological cause of 5% of dementia [55]. Even everyday activities like driving, shopping, and keeping track of appointments are challenging for these patients. There is no single type of dementia since dementia symptoms in NPH span a broad clinical spectrum. Instead, depending on the degree of permanent brain damage that has occurred, there are variable degrees of cognitive alteration. For this reason, it is not a very correct approach to define cognitive disorders that occur in NPH as dementia in the early period. Some patients have no clinical evidence of dementia, only mild or moderate cognitive deficits, and most of these patients respond well to shunt surgery [56, 57]. At least two of the following must be present for cognitive abnormalities in NPH patients to be defined as dementia.


Since the Mini-Mental State Test and the DEMTEC Test were designed to evaluate cortical dementias, they are not appropriate for evaluating subcortical frontal lobe deficiencies (cognitive deficits) in NPH [59]. The Stroop test, digit span test, and Rey auditory-verbal learning test can be used instead. However, personality changes, anxiety, depression, psychotic syndromes such as delusions, hallucinations, and aggression may also be seen in NPH patients, as well as obsessive–compulsive disorder, Othello syndrome, and various other cognitive disorders such as theft, and mania [60–63]. Depression can be seen in the NPH clinic, although it is rare. In fact, only a tiny portion of these patients who show clinical signs of depression is really diagnosed with depression. Symptoms such as apathy and bradyphrenia that occur in NPH patients may mimic depression. Differential diagnosis between depression and NPH can be challenging as neuropsychological assessment profiles are similar [64, 65]. Therefore, before being diagnosed with depression, NPH patients should have a thorough psychiatric examination, and therapy should be started if actual depression is present. Again, delirium is not encountered in the NPH clinic, and its presence implies the existence of another disease or pharmacological side effect accompanying the disease [41]. Boon AJ et al. [66] reported that iNPH patients showed severe attention deficits. Although the

NPH clinic contains quite different and complex neuropsychiatric symptoms, the decision to have an early shunt surgery can continue to improve cognitive deficits in approximately 80% of patients with NPH, however, the presence of vascular dementia, Alzheimer's dementia, or comorbid diseases at the same time affects the success of surgical treatment negatively and reduces the recovery rate.

#### **8. Urinary incontinence**

Urinary symptoms in NPH may occur as urinary frequency, urgency, or incontinence. The bladder dysfunction of NPH is usually in the form of urinary urgency and this condition is almost always present [67, 68]. These patients have difficulty in preventing bladder emptying [69]. Patients have difficulties keeping urinary continence and may suffer urgency with a few drops of urine leakage before reaching the toilet, even though they are aware of the need to urinate at first. Therefore, nocturia is common in NPH patients. Incontinence or having wet clothes are not characteristic of NPH. True urinary incontinence develops later in the course of the disease. While patients initially suffer from increased urinary frequency, they then develop sudden incontinence and eventually persistent urinary incontinence. Bladder dysfunction is due to stretching of the periventricular nerve fibers and loss of subsequent inhibition (partial) of bladder contractions. Bladder function disorders in NPH are caused by detrusor overactivity due to a lack of central inhibitory control, which can be partial or complete [70]. It is extremely rare for fecal incontinence to occur as a symptom of NPH. Therefore, the presence of fecal incontinence in a patient with NPH should first raise suspicion of another type of neurodegenerative disease in the clinician. If a patient with NPH has fecal incontinence as one of the clinical indicators, it suggests he has severe frontal subcortical dysfunction.

When applied early, a CSF shunt can help about 80% of NPH patients with bladder dysfunction; however, if surgery is done at an advanced stage in the disease, as in other symptoms, the percentage would be no more than 50-60%.

#### **9. Diagnosis**

For diagnosis, the physical and neurological examinations, clinical symptoms, neuropsychological and neuroimaging findings should all be evaluated as a whole. For this purpose, the clinician should clearly demonstrate the presence of hydrocephalus and the absence of severe cortical atrophy. All patients with NPH should have enlarged ventricles. Although ventriculomegaly is detected in many neurodegenerative diseases and senile cerebral atrophy, these patients may not have any clinical signs of hydrocephalus. Hence, the terms hydrocephalus and ventriculomegaly are not synonymous. To summarize, not all elderly patients with large ventricles have NPH. Ventriculomegaly makes sense when accompanied by clinical symptoms.

Today, in most cases where neurological symptoms are new, Computerized Brain Tomography (CBT) is often used because it is quick and easy to obtain, or Magnetic Resonance Imaging (MRI) because it provides more detailed information about cerebral anatomy/pathology. Furthermore, high-speed and high-resolution MRI techniques can better define aqueductal stenosis, and MRI phase-contrast techniques show the hyperdynamic aqueductal CSF flow that has been associated with shunt-responsive NPH.

Radiological findings detected by MRI/CBT (**Figure 1**).

• Disproportionate ventricular enlargement to sulcal atrophy with typical rounding of frontal horns.

*Clinical Diagnosis and Treatment Management of Normal Pressure Hydrocephalus DOI: http://dx.doi.org/10.5772/intechopen.99222*


#### **Figure 1.**

*MRI images of NPH a: Periventricular hyperintensity, B: Enlargement of Sylvian cistern (sagittal), C: Enlargement of Sylvian cistern (coronal), D: Dilatation in the third ventricle, E: Callosal angle, F: Evans index, G: Hyperintensity in white matter, H: Bulging on the roof of the ventricle, I: Effacement of sulci at midline vertex.*

The presence of a narrow CSF area in high convexity/midline areas on radiological imaging, and disproportionately enlarged subarachnoid spaces particularly in the Sylvian fissure and basal cisterns, are termed 'Disproportionally Enlarged Subarachnoid Spaces Hydrocephalus' (DESH). This is an indirect sign that CSF flow between the basal cisterns and the arachnoid granulations is being blocked. The existence of this symptom is thought to be the most sensitive indicator for shunt surgery, while its absence indicates brain atrophy [74]. So far, no characteristic neuropathological lesion of NPH has been detected [75–77].

Neuroimaging tests are necessary but not sufficient to diagnose NPH. Invasive tests such as lumbar puncture (LP). and External Lumbar Drainage (ELD) are needed in addition to non-invasive procedures like radiological imaging to improve diagnostic and prognostic accuracy in these patients. Both International and Japanese guidelines recommend diagnostic LP and/or ELD to all patients with suspected NPH. While there is a response to CSF intake in the presence of NPH, there is no response to CSF intake in the absence or minimal level of NPH. CSF drainage also has predictive value for shunt surgery. Patients whose symptoms are relieved by CSF drainage are expected to respond positively to shunt surgery as well. With LP taking 30–50 mL of CSF, changes in gait and cognitive functions are expected after 30 minutes to 4 hours (rarely a few days). If there is a positive response to the tap test, shunt surgery may be recommended, but failure to respond does not exclude the shunt response, because even in patients with normal CSF pressure in the LP, recovery was observed in approximately 50% of them following shunt surgery [78–82]. ELD may be considered in patients who do not respond to the Tap test but are still clinically suspected of having NPH. With ELD, controlled CSF drainage of approximately 10 mL/h for 2–3 days or 150 to 200 mL per day for 2 to 7 days is performed. The patient's gait and neuropsychological tests are recorded daily before the procedure, during CSF drainage, and after catheter removal.

It is difficult to explain the detection of CSF pressure at normal levels in NPH dynamics. Although normal CSF pressure can be detected with a single LP, in fact, 24-hour monitoring might occasionally reveal abnormally high pressures or consistently high/normal pressures. Although CSF pressure has been found to be normal in a single LP, there is a consensus that episodes of increased CSF pressure occur in NPH. For the development of iNPH or sNPH, it is predicted that the baseline ICP is high, at least during the disease stages, and that this high pressure decreases with dilatation of the ventricles. Long-term intracranial pressure (ICP) measurements, such as those taken by some centers for 24 to 72 hours, are not advised for routine usage, both because their predictive values have not yet been adequately documented and because they necessitate specialized equipment and expertise.

#### **10. Differential diagnosis**

Regression in motor and cognitive functions, as well as urine incontinence, are common with aging. The addition of other neurodegenerative diseases, such as those that increase with age, and some surgery (cervical/lumbar spinal stenosis) and internal diseases (hypothyroidism, vitamin B12 deficiency) make the differential diagnosis difficult. It may not be easy to distinguish Alzheimer's disease (AD) and Parkinson's disease, which exhibit similar clinical symptoms such as gait disturbance and dementia, from NPH. Also, having vascular or Alzheimer's dementia simultaneously in three-quarters (75%) of their patients with NPH makes the situation even more complicated. On the other hand, because each of the cardinal symptoms of NPH has a variety of etiologies, it might mimic a variety

#### *Clinical Diagnosis and Treatment Management of Normal Pressure Hydrocephalus DOI: http://dx.doi.org/10.5772/intechopen.99222*

of neurodegenerative diseases. Patients with isolated NPH are extremely uncommon in clinical practice due to the numerous comorbidities that often accompany the symptoms of NPH. The clinical triad peculiar to this disease is actually nonclassical, as similar symptoms can be found in a variety of disorders. Therefore, a comprehensive differential diagnosis table ranging from psychiatric disorders to neurological diseases should be considered when distinguishing NPH from other diseases in elderly patients. The differential diagnosis of gait disorders includes peripheral neuropathy, inner ear disorders, spinal cord diseases, alcohol use, and deficiencies of vitamins such as B6 and B12. Clinical and neuroimaging data are very important in the differential diagnosis. Early and accurate determination of the differential diagnosis will save both the clinician and the patient from a series of invasive and noninvasive tests.

Findings that make a diagnosis of NPH less likely include the following:


Some of the diseases frequently encountered in the differential diagnosis are Alzheimer's disease (AD) and Parkinson's disease. Similar to Parkinson's disease, episodes of hesitation and freezing may occur in the gait of NPH patients. However, resting tremors and the typically unilateral symptoms of Parkinson's disease are uncommon in NPH. NPH patients' failure to respond to anti-parkinsonian medicines may also help with diagnosis.

The subject AD, another common disease in differential diagnosis, is quite complex and difficult. AD is thought to account for 50–60% of all dementias in the elderly [83–85]. It is not always possible to distinguish between patients with NPH and those with AD based solely on their medical history and physical examination. Thanks to data gained from MRI and neuropsychological tests, distinguishing AD from NPH is now easier than in past years. The mental disorder in NPH is a subcortical type. While the severity of cognitive impairment is mild or moderate in patients with NPH, mental disorders in AD patients are both the first symptom and advanced. Again, dementia signs occur with more severe symptoms in AD than in NPH. This condition was confirmed by the presence of hippocampal atrophy on CT or MRI [86–89]. Again, motor symptoms such as gait disturbance are rare in AD. In AD, long-term, short-term, and sensory memories are all impaired, while in NPH memory is partially preserved. In NPH, brain dysfunction mainly arises in the frontal cortex, whereas in AD, the major dysfunction originates from the medial temporal lobe, thus, medial temporal lobe atrophy on MRI suggests AD [90]. On the other hand, when considering the response to shunt surgery, it is critical to distinguish these two diseases, which overlap in terms of clinical symptoms. From this standpoint, many studies have investigated biomarkers in CSF to both improve diagnosis and predict shunt efficacy. The specific combination of low Aβ-42 and increased P-tau detected in the CSF has actually been accepted as the biological

signature of AD [91]. In contrast, Graff-Radford [92] reported that CSF markers are not useful in distinguishing between the NPH patients from the patients with comorbid AD. Complete blood count, biochemical profile, neuropsychological tests, MRI of the cervical, thoracic or lumbar spine in addition to cranial MRI, electromyography/nerve conduction velocity study and urology consultation can be performed to comprehensively evaluate the differential diagnosis.

#### **11. Treatment**

Although NPH is a clinically well-known disease, the indications for shunt surgery and the estimation of surgical outcomes are not clear. Although many devoted articles have been published to identify the most suitable candidates for surgical treatment, there is still no consensus on who is the best candidate for surgery and how to select these patients. Reliable indications of good surgical response are still lacking, particularly with regard to the shunt procedure. In the presence of short history, a known cause of hydrocephalus, predominance of gait disturbances, and CT or MRI findings for hydrodynamic hydrocephalus, it is not difficult to decide on surgery and recommend a shunt to the patient. Today, identifying patients with NPH and applying effective treatment methods still pose challenges for neurosurgeons. However, despite all these difficulties, if diagnosed and treated early, the unusual appearance of these symptoms affecting elderly individuals can be prevented and significant improvements in their life quality can be achieved.

Advanced diagnostic and therapeutic methods and clinical successes have shown that surgical treatment for NPH is superior to conservative treatment. Even if one or two main symptoms are present, NPH should be diagnosed and treated, as waiting for the clinical triad to occur for diagnosis can drastically diminish the response to shunt surgery. This is because the longer NPH patients go without treatment, the worse their prognosis becomes and the shorter their life expectancy becomes.

Using a catheter to alter the flow path of CSF is now the recognized therapeutic procedure all around the world. Shunt surgery is indicated for patients who respond to CSF drainage or who have CSF hydrodynamic variables consistent with NPH [75, 93–95].

However, it is crucial to identify other diseases that mimic NPH before deciding on surgical treatment as it will directly affect the quality of life of patients. There is no evidence that the time spent identifying and treating these disorders in the differential diagnosis lowers the chances of response to shunt surgery. The most essential component that promotes surgical success is a more thorough evaluation performed without haste. Moreover, it should be noted that not all patients with NPH are candidates for shunt surgery. For each patient, the benefit–risk ratio should be assessed separately. Before the surgical operation, possible complications of shunt surgery (infection, embolization, shunt failure, subdural hematoma, and effusion) should be considered and patients should be informed about the surgical risks as well as the potential benefit. Patients should be informed about the problems they will encounter in their daily lives (such as gait disturbance, dementia, incontinence) and potential complications of shunt surgery if they are not operated on. Providing information on the following issues prior to surgical consent will improve the patient's and their relatives' compliance with post-surgery treatment.


#### *Clinical Diagnosis and Treatment Management of Normal Pressure Hydrocephalus DOI: http://dx.doi.org/10.5772/intechopen.99222*

c.The complication rate of surgical treatment varies between 20% and 40%, but serious complications do not exceed 5-8%.

The passage of CSF from one compartment to another by bypassing the natural flow pathways with the aid of a catheter remains the main treatment method for NPH. This shunt procedure is based on the notion that it will minimize the elevated transmantle pressure caused by ventriculomegaly, therefore relieving the symptoms associated with NPH [14]. Today, ventriculoperitoneal (VP) shunts are the most commonly used ones for this purpose. Shunt valves and configuration are dependent on surgeon experience and patient preference. There is no objective evidence that one type of shunt is superior to another. Low-pressure shunts were frequently employed in the past, and the clinical response was better. However, because complications including excessive drainage and subdural hematoma are more common with these shunts, they have been phased out except in rare circumstances. Today, medium pressure shunts or adjustable shunts are more preferred. Adjustable shunts have the advantage of allowing the pressure setting to be gradually lowered or raised until the patient's symptoms improve. In this way, complications that may arise as a result of under or excess drainage can be avoided by changing the pressure without surgery. Another advantage is that it can be administered safely in patients who are on anticoagulation therapy for cardiac or neurological disorders [96].

In Japan, patients with iNPH are mainly treated with lumbar peritoneal shunts. In recent years, this surgical procedure has been widely used all over the world. In terms of effectiveness, one type of shunt has no superiority over the other. However, although the complication rate associated with the device itself is higher in lumbar peritoneal shunts than in ventriculoperitoneal shunts, the fact that lumbar peritoneal shunts are minimally invasive, do not have the fatal complications seen in ventriculoperitoneal shunts, and are more economical has allowed them to be a step forward in treatment [97]. Endoscopic third ventriculostomy has not been proven to be effective in the treatment of iNPH. In patients who are debilitated and shunt surgery is contraindicated, serial lumbar punctures are not recommended as an alternate treatment, except for a limited period of time.

Although it is difficult to draw definitive conclusions, three decades of publications on NPH and surgical experience have summarized the factors that can help predict post-shunt outcomes as follows [98].

a.Factors predicting a good surgical outcome.


b.Factors predicting poor surgical outcomes.


Although some studies have indicated a high success (recovery) rate of roughly 80-90% in the improvement of clinical symptoms following surgery [99, 100], the overall rate has been reported to be 65-70% for sNPH cases and 30-50% for iNPH cases [50, 82, 101]. This discrepancy in surgical outcomes could be attributed to the presence of other NPH-related neurodegenerative and/or cerebrovascular disorders. Therefore, meticulousness in differential diagnosis and early treatment of comorbidities can eliminate this inconsistency.

However, the reasons why patients treated with shunts do not respond to shunt surgery are not fully understood. Before concluding that the surgical treatment was unsuccessful, it should be suspected that the failure was due to candidate selection or that the shunt was ineffective in cases where the desired clinical improvement was not achieved after surgery, particularly in patients whose ventricular size did not decrease after shunt or in those who only experienced temporary improvement after surgery [102].

#### **Acknowledgements**

I would especially like to thank my colleague İsmail KAYA for his help in English editing of the chapter.

#### **Author details**

Hüseyin Yakar Department of Neurosurgery, Faculty of Medicine, Niğde Ömer Halisdemir University, Niğde, Turkey

\*Address all correspondence to: hsyakar@gmail.com

© 2021 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

*Clinical Diagnosis and Treatment Management of Normal Pressure Hydrocephalus DOI: http://dx.doi.org/10.5772/intechopen.99222*

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Section 3
