Ventricles of the Brain

The ventricles of the brain are a communicating network of cavities filled with cerebrospinal fluid (CSF) and located within the brain parenchyma. The ventricular system is composed of two lateral ventricles (one in each cerebral hemisphere), the third ventricle (located in the diencephalon), the cerebral aqueduct, and the fourth ventricle (located in the hindbrain; see the images below). The choroid plexuses are located within the lateral, third, and fourth ventricles and produce CSF through specialized ependymal cells.

Ventricles of brain. The image represents a casting of the normally fluid-filled ventricular system of the brain. (Courtesy of Todd Hoagland, PhD)

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The choroid plexuses of the four ventricles filter blood plasma to form CSF, which enters the four ventricles and flows out of the fourth ventricle via three apertures — the midline median aperature (foramen of Magendie) and the paired lateral aperatures (foramina of Luschka). Once CSF flows out of the median and lateral apertures, it flows into the subarachnoid space, between the arachnoid mater and pia mater, where the CSF buoys the brain and spinal cord. CSF drains from the subarachnoid space back into the dural venous sinuses via the arachnoid villi and granulations, and capillary absorption. The CSF fills the ventricles and subarachnoid space, following a cycle of constant production and reabsorption.

This ventricular system allows the CSF to circulate in a designated path. Any impediment in its circulation and clearance may lead to abnormal accumulation of CSF, called hydrocephalus. Thus, understanding the neuroanatomy of the ventricular system can help in comprehending the finer nuances in the etiopathology of hydrocephalus such as the role of genetic mutations in congenital structural malformations and their impact on the development and proliferation of neurons and neural stem cells as well as in providing insights into the syndromic causes of hydrocephalus. ^[1]

Evaluating ventricular parameters can also help diagnose central nervous system (CNS) degenerative diseases (e.g., Parkinson's, Alzheimer's, Huntington's, multiple sclerosis) and certain psychiatric disorders (e.g., schizophrenia). ^[2]

Brain, coronal view.

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Meninges and ventricles of the brain.

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Embryology

The ventricular system is embryologically derived from the central lumen of the embryonic neural tube and the cerebral vesicles to which it gives rise. ^[3]  The three brain vesicles (the prosencephalon or forebrain, mesencephalon or midbrain, and rhombencephalon or hindbrain) form around the end of the first gestational month. The neural canal dilates within the prosencephalon, leading to the formation of the lateral ventricles and third ventricle. The cavity of the mesencephalon forms the cerebral aqueduct. The dilation of the neural canal within the rhombencephalon forms the fourth ventricle (see Table 1).

Table 1. Components of the Ventricular System Derived from Cerebral Regions (From Caudal to Rostral) ^[3] (Open Table in a new window)

Choroid plexuses:  The choroid plexus forms early in development, shortly after closing of the neural tube. The ependymal cells coming in contact with the adjacent mesodermally derived tissue form pseudorosettes, which protrude within the neural tube at the sites of ventricular system formation. The differentiation of these cells with the resulting development of the choroid plexus is largely completed by 22 weeks' gestation. ^[4]

Tufts of capillaries invaginate the roofs of prosencephalon and rhombencephalon, forming the choroid plexuses of the ventricles. CSF is secreted by the specialized ependymal cells of the choroid plexuses, filling the ventricular system. CSF flows out of the fourth ventricle through the three apertures formed at the roof of the fourth ventricle by 12 weeks' gestation. ^[5] The early choroid plexuses secrete protein-rich CSF into the ventricular system, likely serving as a nutritive medium for developing epithelial neural tissues. As these tissues become more vascularized, the histochemical properties of the cuboidal cells and the CSF transition to the adult phenotype. ^[3]

Ventricular system of the human brain : Each cerebral hemisphere contains a large lateral ventricle that communicates with the third ventricle via the interventricular foramen (foramen of Monro). The third ventricle, a midline, slit-like cavity located between the thalamus and hypothalamus, extends to the cerebral aqueduct, which connects with the fourth ventricle. The fourth ventricle, positioned between the brainstem and cerebellum, communicates with the subarachnoid space of the cisterna magna through the midline foramen of Magendie and with the cerebellopontine angles through the bilateral foramina of Luschka. Caudally, it is continuous with the vestigial central canal of the spinal cord (see the image below). ^[3]

During early development, the septum pellucidum is formed by the thinned walls of the two cerebral hemispheres and contains a fluid-filled cavity — the cavum — which may persist.

Ventricles of brain in situ. This image highlights the ventricular system of the brain and some adjacent structures. (Courtesy of Todd Hoagland, PhD)

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Choroid plexus: The vascular pia mater in the roofs of the third and fourth ventricles and the medial wall of the lateral ventricle along the choroid fissure is intimately associated with the ependymal lining of the ventricles. This association forms the tela choroidea, which gives rise to the highly vascularized choroid plexuses. These plexuses are responsible for:

1. Secretion of CSF into the lateral, third, and fourth ventricles
2. Create a blood-CSF barrier along with the arachnoid mater ^[3]

The choroid plexus stroma is composed of numerous capillaries, which are separated from the ventricular spaces by the pia mater and the choroid ependymal cells. ^[3]

Lateral ventricles

The largest cavities of the ventricular system are the lateral ventricles. In lateral view, the lateral ventricle exhibits a C-shaped configuration resulting from the developmental expansion of the frontal, parietal, occipital and temporal lobes of the cerebral hemisphere. It consists of five segments: the frontal (anterior) horn, occipital (posterior) horn, temporal (inferior) horn, body, and atrium (see Table 2). ^[3]

Table 2. Parts of the Lateral Ventricle: Location and Boundaries (Open Table in a new window)

See the image below.

Ventricles and the borders of major adjacent anatomy.

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Choroid Plexus of the Lateral Ventricle

Capillaries of the choroid arteries from the pia mater project into the ventricular cavity, forming the choroid plexus of the lateral ventricle (see the image below). The choroid plexus extends from the lateral ventricle into the inferior horn. The anterior and posterior horn have no choroid plexus.

Location: The choroid plexus of the lateral ventricle is connected with the choroid plexus of the contralateral ventricle and the third ventricle through the interventricular foramen. Throughout the body of the ventricle, the choroid fissure lies between the fornix superiorly and the thalamus inferiorly. ^[3]  The choroid plexus is attached to the adjacent brain structures by a double layer of pia mater called the tela choroidea. The tela choroidea has a triangular shape when viewed from above. Its apex is located between the interventricular foramina and is often indented by the anterior columns of the fornices. The lateral edges are bordered by the fornix (taeniae fornicis), with the thalamus attached to the taeniae on both sides (taeniae thalami). ^[3]

Vascular supply: The anterior choroidal arteries (branch of the internal carotid artery) and lateral posterior choroidal arteries (branch of the posterior cerebral artery) feed the choroid plexus. Capillaries drain into a rich venous plexus served by a single choroidal vein. ^[3]

Meninges and ventricles of the brain.

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Third ventricle

The third ventricle is a midline, slit-like narrow vertical cavity of the diencephalon that lies between the two thalami and part of the hypothalamus. It communicates with the lateral ventricle via the interventricular foramen (foramen of Monro) and is continuous caudally with the fourth ventricle via the cerebral aqueduct. ^[3]  It has a roof, a floor, anterior and posterior walls, and two lateral walls.

Boundaries of the third ventricle: ^[3]

• Lateral wall - Upper part is formed by the medial surface of the anterior two thirds of the thalamus, while the lower part is formed by the hypothalamus. The lateral walls of the third ventricle are commonly joined by interthalamic adhesion (massa intermedia).
• Anterior wall - By the lamina terminalis (stretches from the optic chiasma inferiorly to the rostrum of the corpus callosum superiorly and represents the rostral boundary of the embryonic neural tube), diverging columns of the fornices, and the transversely orientated anterior commissure
• Posterior wall - By a suprapineal recess, the habenular commissure, a pineal (epiphysial) recess, and the posterior commissure
• Floor - Anteriorly by hypothalamic structures and optic chiasma and posteriorly by the tuber cinereum and the mammillary bodies
• Roof - It consists of four layers. The most superior layer is made up of the two fornices (bodies anteriorly and crura posteriorly). The tela choroidea forms two of the three layers located below the fornices. The final layer contains the internal cerebral veins and the medial posterior choroidal arteries.

Recesses of Third Ventricle

The third ventricle extends into the surrounding structure, forming distinct recesses that include: ^[3]

• Suprapineal recess
• Pineal (epiphysial) recess - It extends into the pineal stalk
• Infundibular recess - It lies immediately posterior to the optic chiasma and extends into the pituitary stalk.
• Optic recess - It occurs inconsistently at the base of the lamina terminalis just dorsal to and extending into the optic chiasma.

Choroid Plexus of the Third Ventricle:

Location: It extends from the floor of the lateral ventricle through the interventricular foramen into the roof of the third ventricle. It is connected to the tela choroidea, which forms the thin roof of the third ventricle during fetal development. ^[3]

Features: In coronal sections of the cerebral hemispheres, the choroid plexus of the third and lateral ventricles appear continuous. ^[3]

Vascular supply: It is supplied by branches of the internal carotid and several choroidal branches of posterior cerebral arteries. ^{[7, 3]}

Cerebral aqueduct

It is a narrow tube, approximately 1-2 mm in diameter, roughly circular in cross-section, and does not contain choroid plexus. It is divided into the pars anterior, antrum, and pars posterior. Primary aqueductal stenosis can cause congenital hydrocephalus in newborns. ^[7]

Boundaries: Rostrally, it originates just below the posterior commissure of the third ventricle and spans the dorsal midbrain, surrounded by periaqueductal gray matter. Caudally, it connects with the fourth ventricle at the midbrain-pons junction. ^[3]

Relations: The superior and inferior colliculi are located dorsally, while the midbrain tegmentum is located ventrally. ^[3]

Fourth ventricle

The fourth ventricle lies between the brainstem and the cerebellum. ^[3]  Rostrally, it is connected to the third ventricle by a narrow cerebral aqueduct and caudally, it is continuous with the central canal of the spinal cord. The fourth ventricle is a diamond-shaped cavity located posterior to the pons and upper medulla oblongata and anterior-inferior to the cerebellum. In the sagittal section, the fourth ventricle has a distinct triangular shape, with the apex of its tented roof extending into the lower part of the cerebellum. ^[3]

Inferiorly, it extends into the central canal of medulla. The fourth ventricle communicates with the subarachnoid space through the bilateral foramina of Luschka, located near the flocculus of the cerebellum at the cerebellopontine angle, behind the upper roots of the glossopharyngeal nerves, ^[3]  and through the median foramen of Magendie, located in the roof of the ventricle.

Boundaries:

• Roof -  It is formed by the superior cerebellar peduncles and the superior and inferior medullary veli.

  See the list below:

  • The thin superior medullary velum spans the ventricle between the converging superior cerebellar peduncles and continues into the cerebellar white matter.
  • The inferior medullary velum mainly consists of a thin sheet without neural tissue, formed by ventricular ependyma and the pia mater of the tela choroidea. ^[3]
  • The apex or fastigium is the extension of the ventricle up into the cerebellum.
  • The median aperture known as the foramen of Magendie opens the roof of the fourth ventricle into the cisterna magna. It forms when a membranous structure (Blake's pouch) perforates into the fourth ventricle during early development. ^[3]
• Floor  - It is a shallow diamond-shaped, or rhomboidal, depression (rhomboid fossa) on the dorsal surfaces of the pons and the rostral half of the medulla. It consists largely of grey matter and the nuclei of cranial nerves V-XII. It can be divided into two triangular parts known as superior and inferior parts, separated by the striae medullare. ^[3]

  See the list below:

  • Superior triangle - Its apex is directed superiorly toward the aqueduct and is bound laterally by the superior cerebellar peduncles.
  • Inferior triangle - Its apex is known as the obex. It is bounded caudally by the gracile and cuneate tubercles (containing the dorsal column nuclei) and rostrally, by the diverging inferior cerebellar peduncles.

A longitudinal median sulcus divides the floor into two halves. Each half is further divided by the sulcus limitans into a medial region known as the medial eminence and a lateral region known as vestibular area (containing vestibular nuclei). ^[5]

• In the superior part, the medial eminence is marked by the facial colliculus while in the inferior part, it is represented by the hypoglossal triangle (trigone), which lies over the hypoglossal nucleus.
• The sulcus limitans widens between the facial colliculus and the vestibular area to form the superior fovea, whereas laterally, it widens to form the inferior fovea.
• Above the superior fovea lies a small region of bluish-grey pigmentation known as locus coeruleus.
• Below the inferior fovea, between the hypoglossal triangle and the vestibular area, the vagal triangle (trigone) covers the dorsal motor nucleus of the vagus nerve. ^[5]

Choroid Plexus of the Fourth Ventricle:

Location: The roof of the lower part of the fourth ventricle is a thin sheet where the pia mater directly touches the ependymal lining, forming the tela choroidea. This sheet is located between the cerebellum and the bottom of the ventricle's roof.

Structure: The choroid plexus of the fourth ventricle is T-shaped, i.e., it has vertical and horizontal limbs whose forms vary, ranging from a single vertical limb to an extended 'T' shape passing through the foramina of Luschka into the cerebellopontine angle. The vertical (longitudinal) limb is double, flanks the midline, and adheres to the roof of the ventricle. They fuse at the superior margin of the median aperture (foramen of Magendie). The horizontal limbs of the plexus project into the lateral recesses of the ventricle. ^[3]

Vascular supply: The trunk of the posterior inferior cerebellar artery supplies the choroid plexus of the fourth ventricle. ^[3]  The tela choroidea of the fourth ventricle, which is supplied by branches of the posterior inferior cerebellar arteries, is located in the posterior medullary velum. ^{[5, 8]}

Circumventricular Organs:

These are specialized midline areas where the blood-brain barrier is absent. They include the vascular organ (organum vasculosum), area postrema of the fourth ventricle, median eminence, basal hypothalamus/neurohypophysis (posterior pituitary), pineal gland, subfornical and subcommissural organs, and lamina terminalis (see Table 3). ^[3]

Table 3. Location, Features, and Functions of Circumventricular Organs of the Brain (Open Table in a new window)

Cerebrospinal fluid

CSF is a clear, watery fluid that fills the ventricles of the brain and the subarachnoid space around the brain and spinal cord. CSF is not simply an ultrafiltrate of blood but is actively secreted by the choroid plexuses in the lateral, third, and fourth ventricles; ^[3] most of it is formed by the choroid plexus of the lateral ventricles. The ependymal lining of the ventricles and the extracellular fluid from the brain parenchyma are additional sources of CSF. ^{[3, 5]}  CSF flows from the lateral ventricles, through the interventricular foramina, and into the third ventricle, cerebral aqueduct, and the fourth ventricle. Only a very small amount enters the central canal of the spinal cord. CSF flow is the result of a combination of factors, which include the hydrostatic pressure generated during CSF production (known as bulk flow), arterial pulsations of the large arteries, and directional beating of the ependymal cilia. Hydrostatic pressure has a predominant role in the CSF flow within the larger ventricles, whereas cilia favor the movement of the CSF in the narrow regions of the ventricular system, such as the cerebral aqueduct. Immotile cilia syndrome is a rare cause of hydrocephalus in children. ^[4]

The ventricles constitute the internal part of a communicating system containing CSF. The external part of the system is formed by the subarachnoid space and cisterns. Communication between the two parts occurs at the level of the fourth ventricle through the median foramen of Magendie (into the cistern magna) and the two lateral foramina of Luschka (into the spaces around the brainstem cerebellopontine angles and prepontine cisterns). CSF is absorbed from the subarachnoid space into the venous blood (of the sinuses or veins) by the small arachnoid villi, which are clusters of cells projecting from the subarachnoid space into a venous sinus, and the larger arachnoid granulations. ^{[4, 9]}

The total CSF volume contained within the communicating system in adults is approximately 150 mL, with approximately 25% filling the ventricular system. CSF is produced at a rate of approximately 20 mL/h, and an estimated 400-500 mL of CSF is produced and absorbed daily. CSF absorption capacity is normally approximately 2-4 times the rate of production. The normal CSF pressure is between 5-15 mm Hg (65-195 mm H₂O) in adults. In children younger than 6 years, normal CSF pressure ranges between 10 and 100 mm H₂O. ^{[4, 9]}

CSF plays an important role in supporting brain growth during development, protecting against external trauma as a shock absorber, removal of metabolites or waste products produced by neuronal and glial cell activity, transport of biologically active substances (such as hormones and neuropeptides) throughout the brain, and regulating intracranial pressure (ICP). ^[4]

CSF is an ultrafiltrate of plasma. Sodium is secreted into the CSF by the sodium-potassium ATPase pump, followed by the passive transfer of water molecules. Intracellular carbonic anhydrase generates bicarbonate and hydrogen ions. Most proteins are excluded from the CSF by the blood-brain barrier. ^[4]

Apart from providing a supportive environment for the brain, the CSF also plays a role in mediating signaling pathways through its flow properties (such as direction and speed) and the variety of molecules it contains (such as proteins, neuropeptides, and membrane-bound vesicles). ^[10]

Ependyma:

The ventricles and central canal of the spinal cord are lined by a single layer of ciliated squamous or columnar ependymal cells. Their apical surfaces are covered with abundant microvilli and/or cilia that facilitate CSF circulation. These cells exhibit planar cell polarity within the epithelial sheets, which is essential for creating a directed CSF flow that helps in distributing various signaling molecules and trophic factors, including insulin-like growth factors, Sonic hedgehog, retinoic acid, bone morphogenetic proteins, and others, throughout the ventricles. ^[3]

The ependymal cells develop from tanycytes, types of transitional cells with radially extending processes, which contact the blood vessels, neurons, and glia. Based on their location and features, ependyma have been broadly classified into four major types (see Table 4). ^[3]

Table 4. Different Types of Ependymal Cells Located in the Brain ^[3] (Open Table in a new window)

Choroid plexus:

It consists of highly vascularized masses of pia mater enclosed by pockets of specialized ependymal cells, which have the following features: ^[3]

• They have numerous long microvilli with only a few cilia interspersed between them.
• They have numerous mitochondria, large Golgi complexes, and basal nuclei, consistent with their secretory activity, producing most components of the CSF.
• They do not have basal processes, but their lateral margins are highly folded.
• They are linked by tight junctions and desmosomes, which form a transepithelial barrier (a component of the blood-CSF barrier)
• Choroidal capillaries are lined by a fenestrated endothelium.

The choroid plexus has a villous structure containing stroma made of pial meningeal cells and fine bundles of collagen and blood vessels. During fetal life, the stroma is filled with bone marrow-like cells and contributes to erythropoiesis. In adults, the stroma contains phagocytic cells that, along with the choroid plexus epithelium, ingest particles and proteins from the ventricular lumen. Age-related changes in the choroid plexus can be observed through neuroimaging, by x-ray or computed tomography (CT) scan, with visible calcification typically limited to the glomus region. ^[3]

Circumventricular organs

They are lined with specialized ependymal cells and tanycytes with unique features. Their ependymal lining lacks tight junctions between endothelial cells, allowing the free exchange of molecules between the blood and surrounding brain tissue. ^[3] It has discontinuous gap junctions, few tight junctions, and fenestrated capillaries that are highly permeable. The specialized ependymal cells and tanycytes are responsible for secretion into the CSF; transport of neurochemicals from subjacent neurons, glia, or vessels to the CSF; transport of neurochemicals from the CSF to the same subjacent structures; and chemoreception. ^[3]

The following three main barriers separate blood from the CNS compartments:

• The vascular endothelial barrier
• The blood-CSF barrier
• The subarachnoid barrier

The blood-brain barrier is located at the capillary endothelium within the brain. It is formed by capillary endothelial cells, pluripotent pericytes, a dense basement membrane, and perivascular end-feet of astrocytes. The features of each component of the blood-brain barrier are:

• The vascular endothelial barrier is formed by tight junctions (occluding junctions, zonulae occludentes) and adherence junctions between endothelial cells. ^[3]
• The astrocytes form specialized structures that contact blood vessels; their end-feet entirely enwrap blood vessels and are instrumental in the establishment of the blood-brain barrier. ^[3]
• Cerebral capillary endothelial cells lack fenestrations, have fewer pinocytic vesicles, have an increased number of mitochondria, and have a thicker basement membrane (30-40 mm thick). A single cell usually spans the entire circumference of a cerebral capillary lumen.

In the blood, the CSF barrier and epithelial cells of the plexus are connected by tight junctions, forming a continuous layer that permits the passage of selected substances. The capillaries of the choroid plexuses have more fenestration than the brain capillaries. The choroid plexus capillaries are separated from the choroidal cells by a basement membrane and a layer of connective tissue. The ependymal cells form the lining of the ventricles and are continuous with the epithelium of the choroid plexus.

The arachnoid barrier is formed by the outer layer of the cells of the arachnoid, which are joined by tight junctions and have similar permeability to those of the brain blood vessels. ^{[8, 4]}

The main functions of the blood-brain barrier are to prevent the entry of potentially harmful substances into the CNS. Generally, lipophilic molecules and small molecules, such as oxygen and carbon dioxide, can cross the blood-brain barrier, while hydrophilic ones (except glucose), and particulate matter, such as bacteria cannot. ^[3] It also helps to maintain ion and volume regulation and maintain metabolic as well as immunologic function. A dysfunction or disruption in the blood-brain barrier may be encountered in many disease states, such as infection, inflammation, presence of tumors, and hypoxic-ischemic events, with potential severe neurologic sequelae. ^[4]

The blood-brain barrier is formed during embryogenesis but might not be fully mature at birth. ^[3] In the adult brain, the blood-brain barrier is absent in certain midline sites in the ventricular walls, known as circumventricular organs.

ICP is the pressure within the closed craniospinal compartment, which encompasses three main components: brain parenchyma, intracranial CSF, and cerebral blood volume.

Intracranial contents comprise 10% CSF, 10% blood, and 80% brain tissue. The Monro-Kellie hypothesis suggests that changes in the brain tissue volume, cerebral blood volume, or CSF volume cause reciprocal adjustments in the other components to maintain cerebral homeostasis. The volume of CSF plays a crucial role in maintaining a stable ICP. Any disruptions in CSF secretion or drainage rates can result in elevated ICP, leading to secondary injury to the brain parenchyma due to inadequate blood perfusion, oxygenation, and metabolism. ^[11]

An increase in ICP can occur due to an increase in the volume of brain tissue (e.g., tumors), blood volume (e.g., hemorrhage), or CSF volume (e.g., hydrocephalus). ^[11]

Hydrocephalus

The diagnosis of hydrocephalus involves clinical and neuroradiological parameters and is marked by an abnormal accumulation of CSF with or without concomitant changes in ICP. In cases of hydrocephalous with normal ICP, it is believed that compensatory mechanisms, either at the expense of cortical tissue or through skull expansion, and rarely both, maintain the ICP. ^[11]

Classification

The old classification divides hydrocephalus into two types: noncommunicating and communicating. In noncommunicating or obstructive hydrocephalus, the CSF accumulates within the ventricles as a result of an obstruction within the ventricular system. This commonly occurs at the level of the interventricular foramen or Monro or the cerebral aqueduct of Sylvius. In communicating hydrocephalus, the CSF flows freely through the outflow foramina of the fourth ventricle into the arachnoid space, but a failure to absorb CSF through normal drainage pathways or, rarely, an overproduction of CSF leads to its build-up. ^[11]  Impaired CSF absorption can be caused by various injuries, such as infection (e.g., meningitis), trauma, and intracranial hemorrhage (e.g., subarachnoid hemorrhage). ^[11]

Current imaging techniques, including computed tomography (CT) scanning and magnetic resonance imaging (MRI; see the image below), make inferences about the level of obstruction, depending on the presence or absence of ventriculomegaly, especially fourth ventricle dilatation. Fourth ventricle dilatation implies obstruction distally, usually at the level of the subarachnoid space. A small fourth ventricle suggests obstruction proximal to the fourth ventricle. ^{[8, 12]}

Coronal magnetic resonance image shows a colloid cyst (arrow) in the roof of the third ventricle. The patient has mild hydrocephalus.

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Current terminology classifies all types of hydrocephalus as obstructive at some level, except for the rare cause of CSF overproduction associated with choroid plexus papilloma. ^{[7, 13]}

Intraventricular obstructive hydrocephalus refers to hydrocephalus resulting from obstruction within the ventricular system (e.g., aqueductal stenosis). Continuous production of the CSF leads to dilatation of one or more ventricles, depending on the site of obstruction. In the acute obstruction phase, transependymal flow of CSF may occur. The gyri are flattened against the skull. If the skull sutures are not calcified, such as in children younger than 2 years, the head may get enlarged.

Extraventricular obstructive hydrocephalus indicates an obstruction outside the ventricles (e.g., at the level of arachnoid villi, as a result of previous bleeding, infection, or inflammation, which results in thickening of the arachnoid and decreased absorption of the CSF). ^{[12, 13]}

Symptoms/signs

Hydrocephalus causes symptoms mainly due to increased ICP. The symptoms and findings vary with age. Clinical features of hydrocephalus in infants include irritability, lethargy, poor feeding, vomiting, and failure to thrive. In older children and adults, morning headaches associated with vomiting, diplopia, gait dysfunction due to stretching of the paracentral corticospinal fibers, coordination problems, and impairment in higher functions are observed.

Macrocephalus, cracked pot sound with percussion, separation of sutures, frontal bossing, or occipital prominence are usually seen in children with hydrocephalus that has developed before the closing of the cranial vault. Papilledema, exudates or hemorrhages, and optic atrophy may be seen upon funduscopic examination in children or adults. Enlargement of the blind spot is also noted.

Diplopia is usually caused by bilateral sixth nerve palsy due to increased ICP. Paralysis of the upgaze or partial Parinaud syndrome (setting sun sign) is seen as a result of pressure on the superior colliculus or tectum. Other findings include hormonal changes as a result of third ventricle dilatation and pressure on the hypothalamic-pituitary structures, cognitive dysfunction, changes in personality, and occasionally seizures. Posterior fossa tumors may cause transforaminal herniation of the cerebellar tonsils with neck stiffness. ^[12]

Etiopathophysiology

The etiologies and pathogenesis of hydrocephalus include overproduction, blockage, or diminished absorption. The only known etiology of excess production is choroid plexus papilloma, which accounts for less than 2% of childhood tumors.

A recent study by Hochstetler et al has broadly classified hydrocephalus as either primary (syndromic and/or idiopathic) or secondary to another condition. ^[11]

• Causes of Primary hydrocephalus -

  • Genetic mutations - Underlying genetic etiologies that may impact neuronal adhesion, vesicle trafficking, growth factors, and PI3K-AKT-mTOR pathway and can cause conditions such as dystroglycanopathies, ciliopathies, and RASopathies (mutations in the RAS-MAPK pathway) ^[1]
  • Developmental disorders related to congenital CNS anomalies such as neural tube defects, arachnoid cysts, Dandy-Walker syndrome, and Chiari malformation. ^[11]
  • In the aging adult population, there is a growing recognition of idiopathic normal pressure hydrocephalus (NPH). ^[11]
• Secondary hydrocephalus - It can result from various causes, including infections, hemorrhage, and traumatic injuries. ^[11]

  See the list below:

  • In developed countries, post-hemorrhagic hydrocephalus is the most common cause of secondary hydrocephalus in pediatric patients. It often results from intraventricular hemorrhage of prematurity, caused by the rupture of delicate vessels in the developing germinal matrix of the brain, leading to blockages or scarring in the ventricles or drainage pathways along the meningeal vessels. ^[11]
  • In developing countries, CNS infections, such as meningitis, are the more common cause of pediatric hydrocephalus, resulting in post-infectious hydrocephalus due to inflammation of the ependymal lining and subventricular zone cells, and scarring of CSF drainage sites at the meninges, which obstruct CSF flow. ^[11]
  • Post-traumatic hydrocephalus can occur following head injuries that damage neurons, glial cells, and blood vessels, affecting CSF production, flow, and/or drainage. ^[11]
  • Secondary to blockage or diminished absorption include developmental abnormalities, tumors, inflammatory, and idiopathic. Solid tumors produce hydrocephalus by obstruction of the ventricles, whereas nonsolid tumors (e.g., leukemia, carcinomatous infiltration) impair CSF absorption within the subarachnoid space. ^{[12, 13]} The following are some causes of obstruction at specific locations in the ventricular system: 

                                 • Foramen of Monro obstruction may be caused by a suprasellar mass (e.g., glioma, arachnoid cyst, craniopharyngioma), septum pellucidum tumor, colloid cyst, or tuberous sclerosis

                                 • Third ventricle obstruction may result from a colloid cyst, large hypothalamic-optic or thalamic glioma, or suprasellar mass

                                 • Cerebral aqueduct obstruction may be the result of aqueductal stenosis, vascular malformations (e.g., arteriovenous malformations or vein of Galen aneurysm), ventriculitis, ependymitis, or tumors (e.g., pineal, brainstem, cerebellar, or mesencephalic)

                                 • Obstruction at the level of the fourth ventricle may be caused by posterior fossa tumors, hemorrhage, or ventriculitis

                                 • Obstruction of the fourth ventricle foramina of Luschka and Magendie may be due to a Dandy-Walker malformation, arachnoid cyst, infection (e.g., ventriculitis, meningitis), or cerebellar tumors

                                 • Obstruction at the level of the subarachnoid space is usually caused by hemorrhage (subarachnoid or subdural), meningitis, and rarely by Chiari malformation

Congenital hydrocephalus

Congenital hydrocephalus has an incidence of 0.4-0.8 per 1000 live births and stillbirths; noncommunicating hydrocephalus is the most common form of hydrocephalus in fetuses. Aqueductal stenosis is the most common cause of congenital hydrocephalus, whereas mass lesions are the most common cause of aqueductal obstruction during childhood. ^[12] Other causes of congenital noncommunicating hydrocephalus include the following:

• Dandy-Walker malformation, which consists of a markedly dilatated fourth ventricle associated with failure of the foramen of Magendie to open, aplasia of the posterior cerebellar vermis, heterotopias of the inferior olivary nuclei, pachygyria, agenesis of the corpus callosum, and other abnormalities ^[12]
• Klippel-Feil syndrome, defined by obstructive hydrocephalus at the level of fourth ventricle associated with malformation of the craniocervical skeleton. This condition may be associated with Chiari malformation and basilar impression.
• Chiari malformation
• Congenital brain tumors, with the most common being astrocytoma, medulloblastoma, teratoma, and choroid plexus papilloma. These tumors are more often supratentorial and midline, usually compressing the cerebral aqueduct.
• Vein of Galen malformation
• Walker-Warburg syndrome, a congenital syndrome characterized by hydrocephalus, agyria, and retinal dysplasia, with or without encephalocele, associated with congenital muscular dystrophies ^[12]
• X-linked hydrocephalus - It is associated with stenosis of the aqueduct of Sylvius (cerebral aqueduct) and is the most severe phenotype associated with L1 syndrome, an X-linked recessive disorder. It occurs due to mutations in L1CAM on chromosome region Xq28, affecting the locus of a gene coding for the neural cell adhesion molecule L1 that causes defective neuronal migration. ^[1]
• Tuberous sclerosis complex - It is an autosomal dominant genetic syndrome caused due to disruption of the mTOR pathway resulting in cortical and subcortical tubers, subependymal nodules along the lateral ventricles, and subependymal giant cell astrocytomas. ^[1]
• Neurofibromatosis 1 - Alterations in CSF circulation can occur due to optic pathway gliomas, aqueductal webs, midbrain tumors leading to obstruction or narrowing of the ventricular system, particularly at the level of the cerebral aqueduct. It is an autosomal dominant disorder caused by mutations on chromosome 17q11.2 that affect the production of neurofibromin. ^[1]

Emerging research with the help of next-generation sequencing techniques has identified genetic mutations that can be attributed to hydrocephalus in various syndromes: ^[1]

• Pettigrew syndrome - It is an X-linked disorder, caused by mutations in the AP1S2 gene that encodes a subunit of the AP1 adaptin protein. It is associated with intellectual disabilities, iron and calcium deposition, and hydrocephalus. ^[1]
• RASopathies - Mutations in the Ras-MAPK pathway cause faulty neurogenesis and differentiation, leading to structural defects that contribute to hydrocephalus in these cases rather than direct effects on CSF flow. ^[1]
• PI3K-Akt-mTOR pathway - Four distinct gene mutations within the PI3K-Akt-mTOR pathway, which is crucial for cell proliferation, growth, and function, have been demonstrated to cause symptoms associated with megalencephaly, ultimately leading to hydrocephalus. ^[1]

Hydranencephaly, porencephaly, and schizencephaly

Hydranencephaly (HE) is a rare congenital malformation that results from replacement of the brain parenchyma with the CSF.

Etiopathogenesis: The exact cause of HE remains unknown, but most researchers believe that brain damage in HE is linked to early internal carotid artery involvement. This is supported by angiographic and autoptic observations showing internal carotid artery anomalies (both aplastic and hypoplastic) and the anatomic distribution of the anomaly following the internal carotid artery supply. Consequently, HE is classified as a circulatory developmental encephalopathy. ^[14]

Potential causes that may act directly or indirectly on the internal carotid arteries or other cerebral regions, causing significant brain alterations include:

• Intrauterine infections (e.g., toxoplasmosis, enterovirus, adenovirus, parvovirus, cytomegalovirus, herpes simplex virus, Epstein-Barr virus, respiratory syncytial virus)
• Exposure to certain toxins or drugs(e.g., smoking, cocaine abuse, estrogens, sodium valproate)
• Factor XIII (fibrin stabilizing factor) deficiency and intracerebral hemorrhage

Porencephaly  refers to hemispheric cysts resulting from the destruction of immature brain parenchyma, which may or may not communicate with the lateral ventricle and subarachnoid space. Porencephalic cysts may be present in any lobe or lobes of the brain hemispheres. Congenital brain lesions encompass two types of porencephaly: ^[15]

• Genetic porencephaly, which arises from maldevelopment during early neuronal migration
• Encephaloclastic porencephaly, a late prenatal or perinatal vascular lesion caused by arterial ischemic stroke or venous thrombosis

Schizencephaly  is a rare congenital disorder of the brain characterized by the formation of clefts or fissures lined with heterotrophic gray matter, which connects the surface of the cerebral hemispheres to the lateral ventricle. ^[16]

Based on their communication with the ventricular system, two types of malformation, closed-lip and open-lip schizencephaly, have been classified. It is associated with various neurodevelopmental disorders, including intellectual disability, epilepsy, cerebral palsy, motor deficits, and potentially psychiatric disorders.

Potential causes that may cause schizencephaly include:

• Genetic factors - Mutations in several genes, including the EMX2 gene, involved in brain development regulation
• Environmental factors - Maternal infections, exposure to toxins, and other prenatal influences
• Developmental factors - Issues during neuronal migration and differentiation

Normal pressure and arrested hydrocephalus

Uniformly dilated ventricles with normal CSF pressure are classified as NPH. Arrested hydrocephalus may represent a form of NPH. NPH is one of the very few reversible causes of dementia; therefore, early diagnosis and treatment are imperative. It may be accompanied by gait disorder, incontinence, and dementia in older patients. The etiology is presumed to be idiopathic. The CSF disturbance theory suggests that disruptions in CSF flow and reabsorption lead to alterations in brain parenchyma and vascular abnormalities, resulting in clinical manifestations of NPH. ^[17] A remote history of trauma, infection, or subarachnoid hemorrhage may be elicited occasionally. CT scanning or MRI reveals uniform ventricular dilatation out of proportion to cortical atrophy, with periventricular lucency, ^[4] while lumbar puncture yields a normal opening pressure. ^[17]

Further confirmatory testing is often done with trials of CSF drainage, either through a large volume lumbar puncture or through placement of a lumbar drain – patients with NPH will show improvement in presenting symptoms with CSF drainage. ^[18]  Additional diagnostic studies used in selecting surgical candidates include isotope cisternography, perfusion tests, and CSF flow imaging. ^[19]

Idiopathic intracranial hypertension

Idiopathic intracranial hypertension (IIH, also known as pseudotumor cerebri) is a unique disorder of elevated ICP in the setting of small, or slit-like, ventricles. While not technically hydrocephalus, it is thought to arise from impaired compliance of the brain and ventricular system. it is predominantly seen in young (20-40 years old), obese women (female-to-male ratio, 3:1). IIH typically manifests with the following symptoms: ^[20]

• Migraine-like headaches which often occur daily and worsen with maneuvers that increase ICP further such as Valsalva maneuver or coughing
• Pulsatile tinnitus (whooshing ear noises in time with one's heartbeat), which worsens in supine position ^[20]
• Visual disturbances such as visual obscuration (transient momentary darkening of vision on standing or bending), horizontal diplopia (secondary to abducens nerve palsy), reduced peripheral vision, or blurred vision with loss of acuity and color sensitivity ^[20] ; in the most severe cases, visual loss may occur.

Eye examination findings are related to increased ICP and include papilledema, retinal hemorrhages, exudates, enlargement of the blind spot, and sixth cranial nerve palsies. On CT scans or MRI, the ventricular system appears normal. Empty sella may be seen in a small percentile of patients. Lumbar puncture reveals elevated CSF opening pressure greater than 250 mm H₂O, with normal CSF composition. ^{[21, 20]}

Recently, venous sinus stenosis has been identified as a potential cause of IIH. Stenosis within a major venous sinus, such as the transverse sinus, can impede venous outflow from the brain, leading to elevated ICPs. Pressure measurements on either side of the venous sinus stenosis may reveal a pressure gradient. In that setting, endovascular venous sinus stenting can be performed to restore normal flow through the venous sinus and eliminate the pressure gradient. ^[21]

Management

Several treatments for hydrocephalus exist, including conservative and surgical approaches, depending upon the underlying abnormality and the site of obstruction. ^{[12, 13]}

In general, temporary relief of elevated ICPs can be achieved with CSF drainage through a lumbar puncture or temporary drain inserted into a CSF space (e.g., lumbar subarachnoid drain or external ventricular drain). These methods are often used in acute ICP elevations, such as with subarachnoid hemorrhage or trauma.

Permanent ICP reduction is most commonly treated with CSF diversion using a surgically implanted shunt. A shunt is essentially a tube, one end of which is placed within a CSF space, and the other end into another space in the body that can absorb the CSF. Shunts are typically placed within a ventricle (ventricular shunt) or the lumbar CSF space (lumbar shunt). The most common location for the distal end is within the peritoneum (e.g., ventriculoperitoneal or lumboperitoneal shunt). Other possible locations for the distal end include the pleural space, central venous space, and even the gall bladder.

In the setting of communicating hydrocephalus, a shunt can be inserted into any CSF space. In noncommunicating hydrocephalus, however, a shunt must be inserted proximal to the level of obstruction. An alternative mode of CSF diversion in noncommunicating hydrocephalus where the obstruction is at the level of the cerebral aqueduct or lower is an endoscopic third ventriculostomy. In this procedure, the anterior floor of the third ventricle is fenestrated to create a direct connection between the third ventricle and the prepontine CSF cistern, providing an alternative pathway for CSF to flow from the lateral and third ventricles into the subarachnoid space.

Additional treatment options exist for IIH beyond CSF shunting. ^{[21, 22]}  The most effective treatment in obese patients is weight loss. This can be achieved with diet and exercise or bariatric surgery. ^[23]  Carbonic anhydrase inhibitors (e.g., acetazolamide) can reduce CSF production by the choroid plexus and are often used with exacerbations of IIH or to temporize vision changes prior to more definitive treatments. When vision loss is the primary symptom, optic nerve sheath fenestration can be performed to reduce the pressure transmitted to the optic nerve. In the setting of venous sinus stenosis, venous sinus stenting has proven effective. ^{[24, 25]}  Vision loss is the main symptoms that prompts surgical intervention as headaches can often be managed medically with standard headache regimens. CSF leak and intracranial hypotension may occur after lumbar puncture, intradural surgical procedures, or spontaneously. A headache that worsens in the upright position but is relieved when lying flat is a clinical hallmark of a CSF leak. Treatment depends on the etiology and includes bedrest, hydration, and an autologous blood patch. ^[26]