Hydrocephalus in children: Physiology, pathogenesis, and etiology

INTRODUCTION — Hydrocephalus is a disorder in which an excessive amount of cerebrospinal fluid (CSF) accumulates within the cerebral ventricles and/or subarachnoid spaces, resulting in ventricular dilation and increased intracranial pressure (ICP) [1,2].

The physiology, pathogenesis, and etiology of hydrocephalus will be reviewed here. The clinical features, diagnosis, management, and prognosis of hydrocephalus are discussed separately. (See "Hydrocephalus in children: Clinical features and diagnosis" and "Hydrocephalus in children: Management and prognosis".)

Normal pressure hydrocephalus, a condition seen predominantly in adults in which the cerebral ventricles are pathologically enlarged, but the ICP is not elevated, is also discussed separately. (See "Normal pressure hydrocephalus".)

TERMINOLOGY — The following terms are used this topic:

●Obstructive hydrocephalus – Obstructive hydrocephalus (also called noncommunicating hydrocephalus) refers to excess accumulation of cerebrospinal fluid (CSF) due to structural blockage of CSF flow within the ventricular system. This is the most common form of hydrocephalus in children and is almost always associated with increased intracranial pressure (ICP). (See 'Obstruction' below.)

●Communicating hydrocephalus – Communicating hydrocephalus refers to CSF accumulation due to impaired absorption that occurs in the subarachnoid spaces. Rarely, CSF accumulates because of excessive production. Communicating hydrocephalus is also typically associated with increased ICP. (See 'Impaired absorption' below and 'Excessive production' below.)

There is some overlap in these categories. Many causes of hydrocephalus have both obstructive and absorptive components (table 1), and the absorptive component of the hydrocephalus may change over time.

●Normal pressure hydrocephalus – In normal pressure hydrocephalus (NPH), the cerebral ventricles are pathologically enlarged, but the ICP is not elevated. NPH is most often seen in adults over the age of 60 years. NPH is discussed separately. (See "Normal pressure hydrocephalus".)

●Ventriculomegaly – Ventriculomegaly is a general term used to describe enlargement of the ventricles as seen on neuroimaging. Ventriculomegaly is a common finding in all forms of hydrocephalus. It is also seen in other conditions that are not associated with hydrocephalus (eg, brain atrophy).

The forms of hydrocephalus described above are distinct from two radiographic findings that include the same word:

●"Hydrocephalus ex-vacuo" – This term refers to enlargement of the CSF spaces caused by reduced volume of brain tissue due to atrophy or malformation. It is not accompanied by increased ICP.

●"Benign external hydrocephalus" – Benign external hydrocephalus (also called "benign enlargement of the subarachnoid space" or "benign extra-axial fluid of infancy") is a relatively common cause of macrocephaly in infancy and frequently occurs in other family members (image 1) [3,4]. As the name implies, the condition is self-limited and affected infants usually do not require any intervention. (See "Macrocephaly in infants and children: Etiology and evaluation", section on 'Benign enlargement of the subarachnoid space'.)

EPIDEMIOLOGY — The reported prevalence of congenital and infantile hydrocephalus in the United States and Europe ranges from 0.5 to 0.8 per 1000 live and still births [5-8]. Myelomeningocele is the most common cause of congenital hydrocephalus and accounts for approximately 15 to 25 percent of these cases [6,8,9]. The most common cause of acquired hydrocephalus in infants is hemorrhage, usually as a consequence of prematurity [10]. Other common causes of acquired hydrocephalus include tumors and infections. (See 'Etiology' below.)

Factors associated with an increased risk of infantile hydrocephalus include [6,9]:

●Birth weight <1500 g

●Prematurity (gestational age ≤30 weeks)

●Maternal diabetes

●Low socioeconomic status

●Male sex

●Race/ethnicity (the risk is decreased in Asians)

There is substantial familial aggregation for congenital hydrocephalus. In a population-based study of congenital hydrocephalus (not including cases associated with neural tube defects), the recurrence risk ratios for same-sex twins, first-degree relatives, and second-degree relatives were 34.8, 6.2, and 2.2, respectively [11].

PHYSIOLOGY — Cerebrospinal fluid (CSF) is produced primarily by the choroid plexus. It circulates through the ventricular system, then through the subarachnoid space to the arachnoid villi, and from there it is absorbed into the systemic blood circulation. The flow of CSF is primarily cephalad.

CSF production — CSF is produced primarily by the choroid plexus, which is responsible for 60 to 80 percent of CSF production. The choroid plexus tissue is located in each cerebral ventricle and consists of villous folds lined by epithelium with a central core of highly vascularized connective tissue. The choroidal epithelial cells produce CSF using active transport dependent upon carbonic anhydrase, which can be blocked by acetazolamide (Diamox), a carbonic anhydrase inhibitor. In addition to the active secretion, there is a diffusion component that is not blocked by acetazolamide.

The remainder of the CSF is produced by cerebral tissue, which secretes CSF directly into the extracellular space. This fluid flows through the ependymal layer into the cerebral ventricles or the spinal central canal.

CSF production rates are constant in physiologic conditions unless extremely high levels of intracranial pressure (ICP) are reached. Thus, absorption of CSF generally matches the rate of production to accommodate the volume of CSF being formed each day. In adults, the production rate of CSF is approximately 20 mL/hour, which results in complete turnover of the CSF three or four times per day. In newborns and young children, the CSF production rate is proportional to the size of the brain. Estimates of CSF production rates in infants and children are derived from measurements of the hourly output of the CSF from external ventricular drains. These studies suggest that CSF output increases logarithmically with age and body weight, ranging from 0.1 to 26.5 mL/hour [12]. Output increases rapidly in infancy; by the age of two years, output is approximately two-thirds of adult levels.

The total volume of CSF in the newborn is approximately 50 mL, compared with 125 to 150 mL in a healthy adult. In adults, approximately 25 percent of the CSF is within the ventricular system. (See "Cerebrospinal fluid: Physiology and utility of an examination in disease states", section on 'Physiology of CSF formation and flow'.)

CSF circulation — The CSF originating in the choroid plexus and in cerebral tissue circulates through the ventricular system into the subarachnoid space (figure 1). The ventricular system is comprised of a pair of lateral ventricles, each of which connects to the midline third ventricle through an interventricular foramen (of Monro) (figure 2). There are no direct connections between two lateral ventricles because they are separated by a membrane (the septum pellucidum). The third ventricle is connected to a midline fourth ventricle by the cerebral aqueduct (of Sylvius). The CSF exits from the fourth ventricle into the subarachnoid space via three foramen: the paired lateral foramina of Luschka and a midline foramen of Magendie. Focally enlarged areas of subarachnoid spaces known as cisterns are present at the base of the brain. The cisterns in the posterior fossa connect to the subarachnoid spaces over the cerebral convexities through pathways that cross the tentorium. The basal cisterns connect the spinal and intracranial subarachnoid spaces.

CSF absorption — CSF is absorbed into the systemic venous circulation primarily across the arachnoid villi into the venous channels of the major sinuses (figure 1). The arachnoid villi consist of a cluster of cells that project from the subarachnoid space to the sinus lumen; these are covered by a layer of endothelium with tight junctions that are continuous with the inner layer of the sinuses. This assembly acts as a one-way valve, allowing passive absorption of CSF down a pressure gradient; if the CSF pressure is less than the venous pressure, the arachnoid villi close and do not allow blood to pass into the ventricular system. The rate of absorption is relatively linear over the physiologic range. Some CSF absorption also occurs across the ependymal lining of the ventricles and the choroid plexus, as well as from the spinal subarachnoid space to the perineural spaces.

In addition to these well-described transport mechanisms, other pathways that may be involved in the movement of CSF include perivascular pathways and dura-associated lymphatic vessels. However, the role of these lymphatic pathways has not been elucidated. These issues are discussed in greater detail separately. (See "Cerebrospinal fluid: Physiology and utility of an examination in disease states", section on 'Physiology of CSF formation and flow'.)

PATHOGENESIS — Hydrocephalus results from an imbalance between the intracranial cerebrospinal fluid (CSF) inflow and outflow. It is caused by obstruction of CSF circulation, by inadequate absorption of CSF, or (rarely) by overproduction of the CSF. Regardless of the cause, the excessive volume of CSF causes increased ventricular pressure and leads to ventricular dilatation.

It is increasingly recognized that many cases of hydrocephalus have both obstructive and absorptive components [13]. This accounts for the variable response to third ventriculostomy for cases of hydrocephalus previously presumed to be purely obstructive, as discussed separately. Moreover, the absorptive component of the hydrocephalus and the response to treatment may change over time. (See "Hydrocephalus in children: Management and prognosis", section on 'Endoscopic third ventriculostomy'.)

Obstruction — The most common mechanism of hydrocephalus is anatomic or functional obstruction to CSF flow (known as obstructive or non-communicating hydrocephalus). The obstruction occurs at the foramen of Monro, at the aqueduct of Sylvius, or at the fourth ventricle and its outlets. Dilatation of the ventricular system occurs proximal to the obstruction. The ventricle just proximal to the obstruction usually dilates most prominently. Examples include:

●Obstruction of the aqueduct of Sylvius (aqueductal stenosis) causes dilation of the lateral and third ventricles, while the size of the fourth ventricle remains relatively normal (image 2 and image 3). This is a very common cause of hydrocephalus in infants and children.

●Obstruction at the body of the lateral ventricle causes dilation of the distal temporal horn and atrium (image 4).

●Obstruction of one foramen of Monro causes dilatation of the lateral ventricle on that side (image 5).

●Obstruction of outflow from the fourth ventricle causes dilation of all four ventricles (image 6).

Impaired absorption — Less commonly, hydrocephalus is caused by impaired absorption of CSF, known as communicating hydrocephalus. This is typically due to inflammation of the subarachnoid villi but also may be caused by impaired CSF absorption or increased pressure in the venous sinuses. The radiographic hallmark of communicating hydrocephalus is dilation of the entire ventricular system, including the fourth ventricle. Impaired CSF absorption also can occur when cranial venous sinus pressure is elevated.

Excessive production — Excessive production of CSF is a rare cause of hydrocephalus. This condition may occur with a functional choroid plexus papilloma (image 7). It leads to enlargement of the entire ventricular system and of the subarachnoid spaces, with a radiographic appearance that is similar to communicating hydrocephalus from other causes. (See 'Choroid plexus papilloma or carcinoma' below.)

PATHOPHYSIOLOGY — The pathophysiology of hydrocephalus depends upon the underlying cause, how quickly the condition develops, and the presence or absence of compensatory mechanisms:

●Hydrocephalus that begins in infancy before fusion of the cranial sutures, if untreated, typically results in marked enlargement of the head and in less compromise of brain tissue, compared with hydrocephalus that develops acutely. This is because the skull expands, partially relieving the intracranial pressure (ICP). In addition, the force of the ICP is distributed over the greater surface area of an enlarged ventricular system, so there is less pressure on the brain parenchyma compared with hydrocephalus that develops in a ventricular system that is not previously enlarged.

●If hydrocephalus occurs acutely or occurs after fusion of the cranial sutures, the head does not enlarge. This results in significantly increased ICP and in more rapid destruction of brain tissue.

The progression of ventricular dilatation is usually uneven. The frontal and occipital horns typically enlarge first and to the greatest extent. Their progressive enlargement disrupts the ependymal lining of the ventricles, allowing the cerebrospinal fluid (CSF) to move directly into the brain tissue. This reduces CSF pressure but also leads to edema of the subependymal areas and to progressive involvement of the white matter.

As the hydrocephalus progresses, edema and ischemia develop in the periventricular brain tissue, leading to atrophy of the white matter. The gyri become flattened, and the sulci become compressed against the cranium, obliterating the subarachnoid space over the hemispheres. The width of the cerebral mantle may be substantially reduced; gray matter is better preserved than white matter, even in advanced stages. The vascular system is compressed, and the venous pressure in the dural sinuses increases.

ETIOLOGY — Hydrocephalus can be congenital or acquired [14]. Both categories include a diverse group of conditions (table 1).

Congenital — Congenital hydrocephalus can result from central nervous system (CNS) malformations (which include nonsyndromic and syndromic disorders), infection, intraventricular hemorrhage, genetic defects, trauma, and teratogens [15]. A rare cause of hydrocephalus is obstruction caused by a congenital CNS tumor (image 8), especially if located near the midline.

The disorders can be grouped according to the primary pathogenic mechanism (obstructive versus absorptive) (table 1).

Neural tube defects — The majority of patients with myelomeningocele have hydrocephalus. In this setting, hydrocephalus is caused by the Chiari II malformation which obstructs outflow of cerebrospinal fluid (CSF) from the fourth ventricle and/or flow through the posterior fossa (image 9 and figure 3). In addition, there is often associated aqueductal stenosis. Hydrocephalus associated with myelomeningocele tends to have both an obstructive component and a communicating component [13]. (See "Myelomeningocele (spina bifida): Anatomy, clinical manifestations, and complications", section on 'Chiari II malformation'.)

Encephalocele is another relatively common neural tube defect, in which the brain and/or meninges herniate through a defect in the skull. Up to 50 percent of individuals with occipital encephalocele have associated hydrocephalus. (See "Primary (congenital) encephalocele".)

Isolated hydrocephalus — Isolated hydrocephalus is frequently caused by aqueductal stenosis (image 2). This can be due to congenital narrowing of the aqueduct or can result from inflammation due to intrauterine infection. (See 'Intrauterine infection' below.)

An association with maternal antidepressant use was suggested by a large registry study (rate ratio 2.52, 95% CI 1.47-4.29) [16]. However, other large registry studies and meta-analyses have not found an association. Risks of antidepressants during pregnancy are discussed in greater detail separately. (See "Antenatal use of antidepressants and the potential risk of teratogenicity and adverse pregnancy outcomes: Selective serotonin reuptake inhibitors" and "Antenatal use of antidepressants and risks of teratogenicity and adverse pregnancy outcomes: Drugs other than selective serotonin reuptake inhibitors".)

X-linked hydrocephalus — The most common genetic form of congenital hydrocephalus is X-linked hydrocephalus due to stenosis of the aqueduct of Sylvius (aqueductal stenosis), which accounts for approximately 5 percent of cases of congenital hydrocephalus [15]. Approximately 50 percent of affected boys have adducted thumbs, which is helpful in making the diagnosis. Some have other CNS abnormalities such as agenesis (or dysgenesis) of the corpus callosum, small brainstem, pachygyria, polymicrogyria, or absence of the pyramidal tract [17].

This disorder is due to mutations in the gene encoding L1, a neuronal cell adhesion molecule that belongs to the immunoglobulin superfamily and that is essential in neurodevelopment [18]. The gene for L1 has been mapped to Xq28. Mutations in L1 also result in other conditions, known as the L1 spectrum, that are characterized by neurologic abnormalities and by mental retardation. These include MASA spectrum (Mental retardation, Aphasia, Shuffling gait, Adducted thumbs), X-linked spastic paraplegia type 1, and X-linked agenesis of the corpus callosum.

CNS malformations — CNS malformations are frequently associated with hydrocephalus.

●In the Chiari malformations, which often accompany a neural tube defect, portions of the brainstem and cerebellum are displaced caudally into the cervical spinal canal. This obstructs the flow of CSF in the posterior fossa, leading to hydrocephalus (see "Chiari malformations"). The Chiari II malformation seen in spina bifida is acquired and is accompanied by other features on magnetic resonance imaging (MRI), such as agenesis of corpus callosum, low lying torcular herophili, tectal breaking, medullary kinking, and heterotopias (image 9 and image 10).

●The Dandy-Walker malformation consists of a large posterior fossa cyst that is continuous with the fourth ventricle and defective development of the cerebellum, including partial or complete absence of the vermis (image 11). Hydrocephalus develops in 70 to 90 percent of patients with Dandy-Walker malformation and is caused by atresia of the foramina of Luschka and Magendie. Dandy-Walker malformation is a heterogeneous disorder. Some patients have a syndromic form with associated congenital anomalies including dysgenesis of the corpus callosum, orofacial deformities, and congenital abnormalities of the heart, genitourinary, and gastrointestinal systems [19]. There is a wide range in neurodevelopmental outcomes, which depend upon the effectiveness of management of hydrocephalus as well as the associated CNS abnormalities. (See "Prenatal diagnosis of CNS anomalies other than neural tube defects and ventriculomegaly", section on 'Dandy-Walker malformation'.)

●A vein of Galen malformation is a rare cause of hydrocephalus. The hydrocephalus in these patients is primarily caused by arterial pressure in the venous system rather than by compression of the aqueduct (image 12). Presentation in the neonatal period typically includes intractable heart failure [20]. (See "Prenatal diagnosis of CNS anomalies other than neural tube defects and ventriculomegaly", section on 'Aneurysm of the vein of Galen'.)

Syndromic forms — Hydrocephalus can be part of syndromes associated with dysmorphic features and with other congenital abnormalities [15]. A complete list of syndromes associated with hydrocephalus is too numerous to include here. The most frequent cytogenetic disorders include trisomies 13, 18, 9, and 9p, as well as triploidy [15]. Rare autosomal recessive disorders include Walker-Warburg syndrome, which is also characterized by ocular anomalies, and hydrolethalus syndrome, which is associated with micrognathia, postaxial polydactyly of the hands, and preaxial polydactyly of the feet. (See "Oculopharyngeal, distal, and congenital muscular dystrophies", section on 'Walker-Warburg syndrome'.)

Intrauterine infection — Intrauterine infections such as rubella, cytomegalovirus, toxoplasmosis, lymphocytic choriomeningitis (LCM), syphilis, and Zika virus can result in congenital hydrocephalus. The mechanism is inflammation of the ependymal lining of the ventricular system and the meninges in the subarachnoid space [15]. This may lead to impaired absorption of CSF and/or to obstruction of CSF flow through the aqueduct or basal cisterns [13]. (See "Overview of TORCH infections".)

Choroid plexus papilloma or carcinoma — A papilloma or carcinoma of the chorioid plexus may cause communicating hydrocephalus because of increased CSF secretion. This disorder usually can be identified by MRI (image 7).

Acquired hydrocephalus

CNS infections — Hydrocephalus may occur as a consequence of CNS infections (eg, bacterial meningitis or viral infections such as mumps). The mechanism can involve obstruction of CSF flow and/or impaired CSF absorption [13]. Globally, infection is the most common cause of hydrocephalus in infants and children [14,21].

Posthemorrhagic hydrocephalus — Another important cause is hemorrhage into the subarachnoid space or, less commonly, into the ventricular system, by ruptured aneurysms, arteriovenous malformations, trauma, or systemic bleeding disorders. The hemorrhage induces an inflammatory response followed by fibrosis (image 13A-B). The main mechanism for hydrocephalus is impaired absorption of CSF (communicating hydrocephalus), although some obstruction to CSF flow also may occur. (See "Hemorrhagic stroke in children".)

Posthemorrhagic hydrocephalus occurs commonly in preterm infants with intraventricular hemorrhage (IVH), particularly following grade III IVH or periventricular hemorrhagic infarction. It can be obstructive, communicating, or both and can be transient or sustained, with slow or rapid progression. (See "Germinal matrix and intraventricular hemorrhage (GMH-IVH) in the newborn: Management and outcome".)

CNS tumors — CNS tumors (particularly posterior fossa medulloblastomas, astrocytomas, and ependymomas) are a common cause of acquired hydrocephalus in children [22]. The mechanism usually involves obstruction of CSF flow by the tumor; however, impaired CSF absorption may also occur [13]. Hydrocephalus may be seen at the initial presentation or may occur as a later complication. (See "Clinical manifestations and diagnosis of central nervous system tumors in children".)

Low pressure hydrocephalus — This is an uncommon entity in children and is extremely challenging to manage. It is diagnosed when neurologic improvement is attained by external ventricular drainage. Patients usually have symptomatic ventriculomegaly and very low intracranial pressure. This condition may result from tumors, chronic hydrocephalus, subarachnoid hemorrhage, and infections. Management is with low pressure shunts [23]. (See "Normal pressure hydrocephalus".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Pediatric hydrocephalus".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or email these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword[s] of interest.)

●Basics topics (see "Patient education: Hydrocephalus in babies and children (The Basics)")

SUMMARY

●Pathogenesis – Most cases of hydrocephalus in children are due to excess accumulation of cerebrospinal fluid (CSF) due to structural blockage of CSF flow within the ventricular system (referred to as obstructive or non-communicating hydrocephalus). Communicating hydrocephalus is less common and occurs when CSF accumulates because of impaired absorption or rarely because of excessive CSF production. (See 'Terminology' above and 'Pathogenesis' above.)

●Epidemiology – The reported prevalence of congenital and infantile hydrocephalus in the United States and Europe ranges from 0.5 to 0.8 per 1000 live and still births. Approximately 15 to 25 percent of these cases are associated with myelomeningocele (spina bifida). Additional factors associated with an increased risk of infantile hydrocephalus include low birth weight, prematurity, maternal diabetes, low socioeconomic status, male sex, race/ethnicity (the risk is decreased in Asians), and positive family history. (See 'Epidemiology' above.)

●Progression – Untreated hydrocephalus that begins in infancy before fusion of the cranial sutures typically results in marked enlargement of the head and in less compromise of brain tissue compared with hydrocephalus that develops acutely. This is because the skull expands, partially relieving the intracranial pressure. As hydrocephalus progresses, edema and ischemia develop in the periventricular brain tissue, leading to atrophy of the white matter. (See 'Pathophysiology' above.)

●Congenital and acquired causes – Common causes of congenital hydrocephalus include intraventricular hemorrhage and neural tube defects, including myelomeningocele. Other causes include infection, genetic defects (X-linked hydrocephalus), trauma, tumors, and teratogens. These disorders are categorized as congenital or acquired and can be further grouped according to the primary pathogenic mechanism (obstructive versus absorptive) (table 1). (See 'Etiology' above.)