Definition

A widely recognized definition for hydrocephalus is lacking. Historically, hydrocephalus is believed to result from an imbalance between cerebrospinal fluid (CSF) production and absorption, with net accumulation of fluid in the cranial cavity, characterized by an increase in the size of the cerebral ventricles and elevation of intracranial pressure, which produces the clinical manifestations of hydrocephalus.

More recently, hydrocephalus has been more broadly defined as a disturbance of formation, flow, or absorption of CSF that leads to an increase in volume occupied by this fluid in the central nervous system (CNS) [Rekate, 2009]. This definition excludes other abnormalities of CSF dynamics, such as benign intracranial hypertension, in which the ventricles are not enlarged. It does not specify the source of production or absorption of CSF nor does it presuppose the mechanisms inherent in ventricular distension.

Conditions such as cerebral atrophy and focal destructive lesions also lead to an abnormal increase of CSF in the CNS. In these situations, ventricular dilatation is not an active process; loss of cerebral tissue leaves a vacant space that is filled passively with CSF. Such conditions are not the result of a hydrodynamic disorder and therefore are not classified as hydrocephalus. An older term used to describe these conditions is hydrocephalus ex vacuo.

Classification

A number of classification systems for hydrocephalus have been suggested [Mori, 1995; Boaz and Edwards-Brown, 1999; Beni-Adani et al., 2006; Oi and Di Rocco, 2006; Rekate, 2009]. These include the following types of hydrocephalus:

communicating vs. noncommunicating

obstructive vs. absorptive

acquired vs. congenital

genetic or CNS malformation-associated vs. isolated

intraventricular-obstructive vs. extraventricular

simple vs. complicated.

The terms compensated and uncompensated hydrocephalus generally refer to whether an increase in ventricular size is associated with evidence of raised intracranial pressure. In compensated, or arrested, hydrocephalus, a gradual increase in ventricular size stabilizes by reaching a new equilibrium and the patient has no symptoms or signs of raised intracranial pressure. In contrast, uncompensated hydrocephalus is associated with clinical symptoms and signs of raised intracranial pressure and usually with progressive dilatation of the ventricles. This is the clinical situation where treatment is indicated. No classification is completely adequate for hydrocephalus at all ages. The classification of hydrocephalus into communicating or noncommunicating dates back to the early 1900s and is based on Walter Dandy’s experimental studies into the pathophysiology of hydrocephalus [Richards, 1990].

In communicating hydrocephalus, the flow is not obstructed but CSF is inadequately reabsorbed in the subarachnoid space, whereas in noncommunicating or obstructive hydrocephalus, the flow of CSF from the ventricles to the subarachnoid space is obstructed.

Obstructive is usually synonymous with noncommunicating hydrocephalus and absorptive with communicating hydrocephalus.

Hydrocephalus is also categorized as congenital, which is present at birth and often associated with developmental defects; and acquired, which occurs after development of the brain and ventricles [Mori, 1995; Chahlavi et al., 2001]. Hydrocephalus has also been classified based on the stage of development at the time that the ventricles became dilated [Oi and Di Rocco, 2006]. The various subtypes of fetal hydrocephalus are classified according to the mechanism of obstruction to the flow of CSF to include:

This classification is cross-referenced to the stage of fetal development (e.g., neuronal maturation, cell migration); it may prove useful in deciding when treatment may be futile if beyond the legal period for terminating a pregnancy, and in identifying potential candidates for early delivery or fetal surgery [Rekate, 2009].

Extraventricular obstructive hydrocephalus is now recognized to represent, almost universally, benign pericerebral collections of infancy that are usually familial, resolve with time, and almost never require treatment [Drake, 2008].

Benign extra-axial collections of infancy involve abnormal enlargement of the head and excessively large subarachnoid space. In infants whose neurological development is normal and in whom the enlargement of the subarachnoid space resolves by 24 months of age, no further work-up or treatment is required. In infants whose neurological development is abnormal or in whom the enlargement of the subarachnoid space does not resolve by 24 months of age, further investigations may be warranted. Several genetic conditions, such as certain mucopolysaccharidoses, achondroplasia, Sotos’ syndrome, and glutaric aciduria type I, can feature enlargement of the subarachnoid spaces as either an early or an associated finding on neuroimaging. In the case of the mucopolysaccharidoses, enlargement of the subarachnoid spaces may be a direct consequence of impairment of CSF absorption by the storage material. Thus, enlargement of the subarachnoid spaces may be an important clue to an early genetic diagnosis, which is important, as therapeutic options exist for many forms of mucopolysaccharidosis and for glutaric aciduria type I [Paciorkowski and Greenstein, 2007].

Epidemiology

The overall incidence of hydrocephalus is not known. This is because hydrocephalus not only occurs in isolation, but also can be associated with a large number of conditions, including tumors, infections, trauma, and prematurity. Consequently, epidemiological studies of its incidence, prevalence, and complication rates are difficult to ascertain.

In newborns, the overall incidence of hydrocephalus ranges from 0.3 to 4 per 1000 live births. Occurring as a single congenital disorder, the incidence of hydrocephalus has been reported as 0.9–1.5 per 1000 births [Milhorat, 1972; Serlo et al., 1986; El Awad, 1992; Blackburn and Fineman, 1994; Fernell and Hagberg, 1998]. It is estimated that approximately 125,000 persons are living with ventricular shunts and that 33,000 shunts are placed annually in the United States [Bondurant and Jimenez, 1995].

The incidence of pediatric hydrocephalus has declined in many developed countries [Drake, 2008]. Antenatal screening, genetic testing, and pregnancy termination have reduced the incidence of congenital malformations of the brain that cause hydrocephalus. The incidence of open neural tube defects has also decreased precipitously as a result of maternal folate supplementation, antenatal screening, and termination of pregnancy based on superior antenatal imaging with ultrasound and magnetic resonance imaging (MRI). The incidence of CSF shunting in open neural tube defects, formerly reported to be as high as 90 percent, has also declined, possibly as a result of a general, more conservative approach, and also the selection of lower-grade lesions for delivery with a lower need for shunting [Tulipan et al., 2003; Chakraborty et al., 2008]. The incidence of intraventricular hemorrhage (IVH) has also decreased as a result of better perinatal management of prematurity, and, as such, one of the major complications of post-hemorrhagic hydrocephalus (see Chapter 19) [Fernell and Hagberg, 1998].

CSF Production, Circulation, and Absorption

CSF is produced by two mechanisms: Most of the CSF (50–80 percent) is thought to be secreted by the choroid plexus within the cerebral ventricles. Extrachoroidal CSF production in subarachnoid sites and by way of a transependymal route has also been documented. About 20 percent or more of CSF is derived from brain extracellular fluid created as a byproduct of cerebral metabolism [Bering, 1962; Fishman, 1980; Rekate, 1997]. Normally, rates of production (0.35 mL per minute or approximately 400–500 mL/day) and absorption of CSF are equal. Total CSF volume is 65–140 mL in children, and 90–150 mL in adults. In one study of premature infants born at gestational age 32 ± 1.6 wk, CSF volume was estimated to be 23.33 ± 9.6 mL at birth and 40.66 ± 21.23 mL at term equivalent. Full-term infants have a CSF volume of 32.4 ± 11.1 mL at birth [Zacharia et al., 2006].

The process of CSF formation by the choroid plexus includes plasma ultrafiltration and secretion. Secretion, an energy-dependent process, is initiated by hydrostatic pressure in the choroidal capillaries and by active transport of sodium. The enzymes sodium-potassium adenosine triphosphatase (ATPase) and carbonic anhydrase partly regulate CSF secretion [Fishman, 1980]. CSF production has been reported to remain constant across the normal intracranial pressure range [Pollay, 1977], with CSF production decreasing when intracranial pressure approaches mean arterial pressure. There have been reports, however, of downregulation of CSF production in patients with chronic hydrocephalus [Silverberg et al., 2002].

By contrast, the process of CSF reabsorption is not an energy-dependent process [Rekate, 1997]. After formation, CSF exits from the lateral ventricles through the foramina of Monro into the third ventricle (Figure 27-1). CSF then traverses the aqueduct of Sylvius into the fourth ventricle, leaving though the foramina of Lushka and foramen of Magendie into the cisterna magna, from where it flows through the subarachnoid space around the cerebral hemispheres. Information gained from MRI analysis of CSF movement demonstrates pulsatile to-and-fro motion of CSF within the lateral ventricles, produced from a brain-pumping motion that ejects the CSF and causes a net downward flow [Feinberg and Mark, 1987].

Fig. 27-1 Cerebrospinal fluid pathway.

The diagram depicts the structures and spaces through which CSF flows, from its manufacture in and secretion from the choroid plexus in the ventricles, to its ultimate resorption from the subarachnoid space. CSF exits from the lateral ventricles through the foramina of Monro into the third ventricle. It then traverses the aqueduct of Sylvius into the fourth ventricle, leaves though the foramina of Lushka and foramen of Magendie and passes into the cisterna magna, and flows through the subarachnoid space around the cerebral hemispheres.

Historically, it has been held that CSF is absorbed into the vascular system mainly through the arachnoid villi within the arachnoid granulations covering the brain and spinal cord leptomeninges [Alksne and Lovings, 1972; Welch, 1975]. This process is thought to be passive and not energy-dependent. A layer of endothelium within the arachnoid villi separates the subarachnoid CSF space from the vascular system. Water and electrolytes pass freely across these arachnoid membranes. There is normally 5–7 mmHg difference in pressure between the dural venous sinuses and the subarachnoid space. This is presumed to be the hydrostatic force behind the absorption of CSF. Larger proteins and macromolecules cannot pass through intercellular junctions but are selectively transported across the cytoplasm of endothelial cells by an active process involving micropinocytosis [Welch, 1975]. Increased absorption through the arachnoid villi protects the brain from transient increases in intracranial pressure [Mann et al., 1978]. Newborn infants do not have visible arachnoid granulations, suggesting that the maximum capacity for reabsorption is less than in the adult, or that CSF is absorbed by different mechanisms in the neonate.

For some time, arachnoid granulations were thought to be the only CSF absorption pathway; however, other mechanisms have been identified, with evidence emerging that arachnoid granulations have only a secondary role. Olfactory nerves, the cribriform plate, and nasal lymphatics have been identified as important sites for CSF absorption [Johnston and Papaiconomou, 2002; Johnston, 2003; Johnston et al., 2004].

Absorption of CSF across brain tissue into capillaries has also been proposed [Greitz, 2004]. According to this theory, the distending force in the production of chronic hydrocephalus is an increased systolic pulse pressure in the brain tissue, due to decreased intracranial compliance.

Etiology and Pathophysiology

Hydrocephalus can be a symptom of a large number of disorders, and a list of conditions in which it has been reported is summarized in Box 27-1. It is associated with tumors and infections, and may be a complication of prematurity and trauma [Renier et al., 1988; Schrander-Stumpel and Fryns, 1998; Chi et al., 2005]. It is also seen in apparent isolation. High-resolution MRI of postnatal life has provided clues to the etiology of hydrocephalus, which in the past would have been labeled as idiopathic; some of these include IVH (Figure 27-2), aqueductal stenosis (Figure 27-3), and migrational abnormalities [Drake, 2008].

Box 27-1 Differential Diagnosis of Hydrocephalus

Congenital Malformations

Agenesis of the corpus callosum

Arnold–Chiari malformation

Autosomal-recessive aqueductal stenosis

Aqueductal stenosis

Arachnoid cyst

Basilar impression

Cerebellar agenesis

Dandy–Walker malformation

Encephalocele

Peters’ anomaly

Porencephaly

Infectious Causes

Congenital syphilis

Cytomegalic inclusion disease

Elevated cerebrospinal fluid protein content with endocardial fibroelastosis, cataracts

Mumps

Postmeningitis

Postencephalitis

Toxoplasmosis

Miscellaneous

Neoplasms

Brainstem glioma

Cerebellar astrocytoma

Choroid plexus papilloma

Colloid cyst of third ventricle

Ependymoma

Histiocytosis X

Leukemia

Lymphoma

Medulloblastoma

Neuroblastoma

Pinealoma

Syndromes

Achondroplasia

Agyria and retinal dysplasia

Apert’s syndrome

Cockayne’s syndrome

Coffin–Lowry syndrome

Crouzon’s syndrome

Biemond’s syndrome

Fryns’ syndrome

Hirschsprung’s disease

Gaucher-like disease

Glutaric aciduria type I

Hurler’s syndrome

Incontinentia pigmenti

Larsen’s syndrome

Klippel–Trenaunay–Weber syndrome

Knobloch’s syndrome

Krabbe’s disease

Meckel–Gruber syndrome

Mucopolysaccharidosis VI

Muscle-eye-brain disease

Myotonic dystrophy

Myotubular myopathy

Neurofibromatosis

Osteopetrosis

Ruvalcaba’s syndrome

Thoracic dysplasia

Shprintzen–Goldberg syndrome

VACTERL association

Walker–Warburg syndrome

X-linked aqueductal stenosis (CRASH syndrome)

Traumatic Causes

Hemorrhage

Hypoxic-ischemic encephalopathy

Posterior fossa surgery

Vascular Causes

Arteriovenous malformation

Jugular vein catheterization

Vein of Galen malformation

Venous sinus thrombosis

CRASH, corpus callosum agenesis, retardation, adducted thumbs, spastic paraparesis, hydrocephalus; VACTERL, vertebral anomalies, anal atresia, cardiac defect, tracheoesophageal fistula with esophageal atresia, renal abnormalities, limb abnormalities.

Fig. 27-2 Post-hemorrhagic hydrocephalus.

Hemorrhage into the ventricles and/or subarachnoid space can ultimately result in impairment of CSF flow through the foramina and/or resorption of CSF through the arachnoid villi. Note the intraventricular (A and B) and periventricular (A) hemorrhages with enlargement of the ventricles and subarachnoid space.

Fig. 27-3 Aqueductal stenosis.

Occlusion of the aqueduct of Sylvius results in enlargement of the lateral and third ventricles (proximal to the aqueduct), with relative normalcy of the fourth ventricle (distal to the aqueduct).

The etiologies of hydrocephalus in one series of pediatric patients are shown in Table 27-1 [Drake et al., 1998]. Hydrocephalus is due to either abnormal CSF reabsorption, or flow, or, rarely, overproduction. The main situation in which CSF production is increased enough to cause hydrocephalus is the presence of a choroid plexus papilloma. These tumors contain functional choroid epithelium and can produce very large amounts of CSF. However, even in the latter case, reabsorption is probably defective, as normal individuals can usually tolerate the elevated CSF production rate of these tumors. CSF accumulation, in turn, leads to raised intracranial pressure.

Table 27-1 Causes of Hydrocephalus

(Modified from Drake JM, et al: Randomized trial of cerebrospinal fluid shunt valve design in pediatric hydrocephalus. Neurosurgery 43[2]:294–303, 1998; discussion 303–295.)

The etiology of hydrocephalus depends upon the age of the child. During the neonatal to late infancy period (0–2 years), hydrocephalus is usually caused by a perinatal hemorrhage, meningitis, and developmental abnormalities, the most common being aqueductal stenosis. The hydrocephalus seen in babies with spina bifida usually results from an associated Chiari malformation. In early to late childhood (2–10 years), the most common causes of hydrocephalus are posterior fossa tumors and aqueductal stenosis.

Clinical Characteristics

The clinical features of hydrocephalus depend on the age of the child at presentation and the time of onset in relation to closure of the cranial sutures. With the current advances in antenatal monitoring, the majority of congenital cases of hydrocephalus are diagnosed early (Figure 27-4), allowing for planned cesarian delivery in the moderate to severe cases where cephalopelvic disproportion is expected.

Fig. 27-4 Antenatal MRI showing fetal hydrocephalus.

Symmetrical enlargement of the ventricular system is readily seen in the brain of this fetus.

Genetics

Although commonly considered a single disorder, hydrocephalus is a collection of heterogeneous complex and multifactorial disorders. A growing body of evidence suggests that genetic factors play a major role in its pathogenesis [Zhang et al., 2006].

Congenital hydrocephalus may occur alone (nonsyndromic) or as part of a syndrome with other anomalies (syndromic). It is estimated that about 40 percent of individuals with hydrocephalus have a genetic etiology [Haverkamp et al., 1999]. The isolated (nonsyndromic) form of congenital hydrocephalus is a primary and major phenotype caused by a specific faulty gene. In syndromic forms, it is difficult to define the defective gene because of the association with other anomalies. A discussion of the genetics of all syndromic forms of hydrocephalus is beyond the scope of this chapter and is reviewed elsewhere in this section on developmental malformations. This chapter will focus mainly on the genetic disorders associated with isolated forms of hydrocephalus.

Autosomal-recessive, autosomal-dominant, X-linked recessive [Castro-Gago et al., 1996] and X-linked dominant [Ferlini et al., 1995] forms of hydrocephalus are recognized (Table 27-2).

At least 43 gene mutations linked to hereditary hydrocephalus have been identified in animal models and humans. To date, nine genes associated with hydrocephalus have been identified in animal models, whereas only one such gene has been identified in humans: the hydrocephalus (X-linked) gene [Haverkamp et al., 1999]. X-linked hydrocephalus (HSAS1, OMIM) occurs in approximately 5–15 percent of congenital cases in which a genetic etiology is determined [Halliday et al., 1986; Haverkamp et al., 1999]. The gene responsible for X-linked human congenital hydrocephalus is at Xq28, encoding for L1CAM (L1 cell adhesion molecule) [Jouet et al., 1993]. Mutations are distributed over the functional protein domains. The exact mechanisms by which these mutations cause a loss of L1 protein function are still under investigation. L1CAM belongs to the immunoglobulin superfamily of neural cell adhesion molecules that is expressed in neurons and Schwann cells and appears to be essential for brain development and function. It plays a role in cell adhesion, axon growth and path-finding, and neuronal migration and myelination [Wong et al., 1995]. One of the possible mechanisms leading to the pathogenesis of hydrocephalus is the disruption of neural cell membrane proteins that play an important function during brain development.

The L1 disorders were initially described as different entities:

During the 1990s, it became clear that these disorders resulted from a mutation in a single gene, L1CAM [Fransen et al., 1995]. Some investigators have suggested that these separately named conditions be combined under the acronym CRASH (corpus callosum agenesis, retardation, adducted thumbs, shuffling gait, and hydrocephalus). The clinical phenotype is variable, even within a single family, but some genotype–phenotype correlations have been made [Fransen et al., 1998]. Hirschsprung’s disease (HSCR) is characterized by the absence of ganglion cells and the presence of hypertrophic nerve trunks in the distal bowel. There have been several reports of patients with X-linked hydrocephalus and HSCR with a mutation in the L1CAM gene. Decreased L1CAM may therefore be a modifying factor in the development of HSCR [Okamoto et al., 2004]. Congenital aqueductal stenosis can also be inherited as an autosomal-recessive disorder (OMIM 236635) [Lapunzina et al., 2002].

In general, the recurrence risk for congenital hydrocephalus excluding X-linked hydrocephalus is low. Empiric risk rates range from <1 to 4 percent [Burton, 1979], indicating the rarity of autosomal-recessive congenital hydrocephalus [Halliday et al., 1986; Chow et al., 1990; Haverkamp et al., 1999]. However, multiple human kindreds have been reported [Halliday et al., 1986; Teebi and Naguib, 1988; Haverkamp et al., 1999; Zhang et al., 2006]. The loci or genes for human autosomal-recessive congenital hydrocephalus have not yet been identified, but there is at least one locus for this trait. Furthermore, since there is heterogeneity among clinical phenotypes, there may be more genetic loci in human autosomal-recessive congenital hydrocephalus.

Two kindreds in which congenital hydrocephalus was transmitted in an autosomal-dominant fashion have been reported. One was associated with aqueductal stenosis but was not associated with mental retardation or pyramidal tract dysfunction, which is in contrast to X-linked or recessive congenital hydrocephalus with HSAS, in which these abnormalities are common [Verhagen et al., 1998]. The other kindred in which hydrocephalus developed had an 8q12.2–q21.2 microdeletion. This trait was also transmitted in an autosomal-dominant pattern [Vincent et al., 1994].

Hydrocephalus has been observed in many mammals [Zhang et al., 2006]. Animal hydrocephalus models have many histopathological similarities to humans and can be used to understand the genetics and pathogenesis of these disorders. It has been well documented that the majority of cases of congenital hydrocephalus in animal models occur on a genetic basis with specific mapping and identification of different loci. The development and progression of congenital hydrocephalus constitute a dynamic process that is not yet well understood. It is probably the consequence of abnormal brain development and perturbed cellular function, which emphasizes the important roles that congenital hydrocephalus genes play during brain development. It is thought that it may develop at an important and specific embryonic time period of neural stem-cell proliferation and differentiation [Zhang et al., 2006].

Although advances have been made in determining the genetic basis of congenital hydrocephalus in animal models, there are much fewer genetic data regarding this condition in humans. The histopathological similarities of animal models can be used to help understand the pathogenesis and genetic underpinnings of human hydrocephalus. Such knowledge will hopefully lead to better diagnostic tools and more effective therapeutic modalities.

The current molecular genetic evidence from animal models indicates that, in the early stages of development, impaired and abnormal brain development, caused by abnormal cell signaling and functioning, eventually lead to the congenital hydrocephalus. However, it is not certain whether these data can be extrapolated to infants and children. The known hydrocephalus genes mostly code for important cytokines, growth factors, or related molecules in cell signaling pathways during early brain development. It is likely that perturbation of almost any molecule that plays a crucial role in early brain development and regulation of CSF dynamics potentially could cause congenital hydrocephalus.

Hydrocephalus may also be caused by alterations in ependymal cell function [Takano et al., 1993; Wagner et al., 2003]. The protein of the axonemal heavy chain 5 gene (Mdnah5), dynein, is specifically expressed in ependymal cells, and is essential for ultrastructural and functional integrity of ependymal cilia. In Mdnah5-mutant mice, lack of ependymal flow causes closure of the aqueduct and subsequent formation of triventricular hydrocephalus during early postnatal brain development. The higher incidence of aqueductal stenosis and hydrocephalus formation in patients with disorders associated with ciliary defects supports the relevance of this novel mechanism in humans [Ibanez-Tallon et al., 2004].

Hydrocephalus may be caused by changes in the development and function of mesenchymal cells. In murine embryonic brain, the Msx1 gene is expressed along the dorsal midline. This regulatory gene is involved in epithelio-mesenchymal interactions in limb formation and organogenesis. In homozygous Msx1 mutants, there is absence or malformation of the posterior commissure and of the subcommissural organ, collapse of the cerebral aqueduct, and hydrocephalus. About one-third of the heterozygous mutants also develop hydrocephalus, suggesting that the phenotype may be determined by the Msx1 gene dosage during a critical developmental period [Ramos et al., 2004]. An example of this is the autosomal-recessive congenital hydrocephalus mouse model in which a truncated protein lacking the DNA-binding domain of the forkhead/winged helix gene, Mf1, was generated. Mesenchymal cells from Mf1lacZ embryos differentiate poorly into cartilage in micromass culture, and the differentiation of arachnoid cells in meninges of the mutant mice also was abnormal. Human patients with deletions in the region containing human Mf1 homolog FREAC3 were also found to develop multiple developmental disorders, including hydrocephalus [Kume et al., 1998].

Another mechanism for development of hydrocephalus may be associated with changes in growth factor signaling [Fukumitsu et al., 2000]. In mouse models, severe hydrocephalus has been observed in transgenic mice overexpressing TGF-β1, an important cytokine and growth-signaling molecule, in astrocytes [Galbreath et al., 1995]. In mouse models, fibroblast growth factor-2 (FGF-2) seems to play a predominant role in the proliferation of neuronal precursors and in neuronal differentiation in the developing cerebral cortex, even at relatively late stages of brain neurogenesis [Ohmiya et al., 2001].

Hydrocephalus may also be caused by disruption of the extracellular matrix (ECM). In the TGF-β1 overexpression mouse model, the changing expressions of a remodeling protein, matrix metalloproteinase-9 (MMP-9), and its specific inhibitor, tissue inhibitor of metalloproteinases-1 (TIMP-1), were found to be important factors in the spontaneous development of hydrocephalus by altering the ECM environment [Crews et al., 2004]. Furthermore, increased expression of cytokines such as TGF-β1 might reciprocally play an important role by disrupting vascular ECM remodeling, promoting hemorrhage and altering reabsorption of CSF. In another mouse model, ablation of the non-muscle myosin heavy chain II-B (NMHC-B) results in severe hydrocephalus with enlargement of the lateral and third ventricles. These defects may be caused by abnormalities in the cell adhesive properties of neuroepithelial cells, and suggest that NMHC-B is essential for early and late developmental processes in the mammalian brain [Tullio et al., 2001].

Other genetic mutations identified in animal models of hydrocephalus include those coding α-SNAP protein, which is essential for apical protein localization and cell fate determination in neuroepithelial cells [Chae et al., 2004]. α-SNAP plays a key role in a wide variety of membrane fusion events in eukaryotic cells, a function which is required for transport of molecules to inter- and intracellular compartments and for intercellular communication.

Neuroimaging

Diagnosis

Modern ultrasonography and, since the late 1980s, fetal MRI have significantly improved the ability to detect ventricular enlargement as a result of hydrocephalus in utero. Antenatal ultrasound and MRI provide reasonably detailed fetal brain anatomy and can detect malformations (at 17–21 weeks) and fetal ventriculomegaly (at 8–21 weeks) [Benacerraf and Birnholz, 1987; Oi et al., 1998]. Normative data for ventricular size allow serial investigation during gestation [Rich et al., 2007].

Anatomical ventriculomegaly is not sufficient to diagnose hydrocephalus. When diagnosing hydrocephalus in neonates or infants, it is essential to establish that there is a truly abnormal rate of skull growth. Records of head circumference (HC) measurements and its comparison with body weight and length centile charts are an integral part of postnatal follow-up of any child. Head circumference must be recorded and plotted on an accepted growth curve chart, with the patient’s exact age (see Chapter 4 for standardized charts). In the presence of hydrocephalus, any of the following may be observed: HC more than 2 SD above normal or disproportionate to body length or weight, accelerated growth crossing centile curves, or continued head growth of more than 1.25 cm per week.

Evaluation of the patient with an enlarged head entails consideration of the many causes of macrocephaly, including hydrocephalus. Evaluation should include a history of trauma or CNS infection. The family history may demonstrate X-linked hydrocephalus caused by stenosis of the aqueduct of Sylvius or may reveal familial macrocephaly.

After a full review of the pregnancy, delivery, and neonatal history, as well as the clinical examination, and ultrasound examination, it is usually possible to classify hydrocephalus into an etiological group. If no obvious explanation can be determined, then the possibility of an intrauterine infection should be investigated. Coagulation factor deficiencies, as well as thrombocytopenia, should be excluded, as isoimmune thrombocytopenia and coagulation factor V deficiency can present as congenital hydrocephalus resulting from congenital IVH.

Differential Diagnosis

Besides hydrocephalus, causes of increasing head size include chronic subdural effusions or hematomas, pseudotumor cerebri, neurofibromatosis, metabolic abnormalities of bone or brain, cerebral gigantism (Sotos’ syndrome), and benign familial forms.

Benign extracranial hydrocephalus is a condition in infants and children with enlarged subarachnoid spaces accompanied by increasing head circumference with normal or mildly dilated ventricles. This condition is also known as “benign subdural collections of infancy” or “pericerebral CSF collections.” This disorder has been postulated by some to be a variant of communicating hydrocephalus, but tends to run a benign course and stabilize by 12–18 months of age [Ment et al., 1981; Barlow, 1984; Alvarez et al., 1986]. Close serial monitoring of head circumference and serial imaging with CT or MRI are recommended to monitor for ventriculomegaly. Shunting is rarely, if ever, required.

A rare but striking condition that can mimic hydrocephalus is hydranencephaly or anencephaly, a postneurulation defect that results in total or near-total absence of the cerebral tissue, with the intracranial cavity being filled with CSF. This is usually due to fetal bilateral internal carotid artery infarction or infection. Other brain malformations, such as agenesis of the corpus callosum and alobar holoprosencephaly, may also be associated with hydrocephalus, but more often represent expansion of the third ventricle and separation of the lateral ventricles. These are described in other chapters of this section.

Other conditions may present as hydrocephalus. Hydrocephalus ex vacuo is due to atrophy rather than altered CSF dynamics. Certain metabolic and degenerative disorders, such as glycogen storage and Alexander’s disease, can cause macrocephaly. Brain tumors of infancy may reach an enormous size, producing a large head, whether there is associated hydrocephalus or not. Finally, there may be a family history of large heads. In these instances, there is often no increase in intracranial pressure or developmental abnormality, and both the brain and the cerebral ventricles are larger than normal.

Pathology

The precise pathologic features of hydrocephalus vary, depending on the age of onset, the rate of ventricular enlargement, and the degree of ventriculomegaly. Typically, elevated CSF pressure initially enlarges the frontal horns of the lateral ventricles, followed by enlargement of the entire ventricular system above the site of obstruction. Hydrocephalus is associated with flattening and destruction of the ventricular ependymal lining, as well as edema and necrosis of the periventricular white matter [Weller and Shulman, 1972]. Periventricular glial cells proliferate, resulting in a layer of reactive gliosis. The pathologic findings may be a result of reduced blood flow to the white matter, causing hypoxic injury or toxicity to the white matter due to build-up of waste products not removed appropriately because of changes in the extracellular matrix [Del Bigio, 2004]. In PHH, high concentrations of proinflammatory cytokines [Savman et al., 2002], free iron, and hypoxanthine [Bejar et al., 1983; Savman et al., 2001], which can generate highly reactive radicals, have been measured in the CSF.

Separation of the ependymal lining of the ventricles enhances permeability, which increases edema formation in adjacent white matter (transependymal fluid absorption). The expanding ventricles flatten the cerebral gyri and obliterate the sulci over the cortical surface. Unless the acute obstruction is relieved, increasing pressure may hinder cerebral blood flow, cause cerebral herniation and compromising brainstem function.

Increasing pressure and ventricular enlargement are associated with necrosis of brain parenchyma. Cerebral white matter is more vulnerable to destruction than gray matter in the presence of progressive hydrocephalus [Rubin et al., 1972]. The corpus callosum may also be preferentially affected, with evidence of transcallosal swelling, thickening, or demyelination [Spreer et al., 1996; Suh et al., 1997]. These effects do not appear to be associated with cognitive changes nor neuropsychologic evidence of callosal disconnection.

Management

Management of hydrocephalus is the most common problem in pediatric neurosurgery. In infants and children with symptomatic or progressive ventriculomegaly, the decision to treat with a CSF diversion procedure poses no therapeutic dilemma. However, not all patients with enlarged ventricles require treatment.

In patients with obstructive hydrocephalus secondary to a mass that is surgically accessible, resection of the mass may lead to resolution of the hydrocephalus and a shunt might not be necessary. This situation occurs infrequently in comparison with communicating hydrocephalus. If no documented obstruction or operable lesion is present and the hydrocephalus is mild and slowly progressive, a trial period of observation or medical management may be indicated, especially in preterm infants.

Another situation where observation is reasonable is arrested hydrocephalus, which is an uncommon state of chronic hydrocephalus in which the CSF pressure has returned to normal and there is no pressure gradient between the cerebral ventricles and the brain parenchyma. Patients should be followed carefully, with neurological examinations, neuropsychological assessments, and careful assessment of their development. A shunt will be necessary if there is any deterioration of those parameters.

Rapid-onset hydrocephalus with increased intracranial pressure is an emergency. Depending on the specific patient, any of the following procedures can be performed:

Complications

The overall failure rate of shunts is 40 percent in the first year after placement [Drake et al., 1998; Pollack et al., 1999; Kestle et al., 2000]. Common reasons for failure are obstruction, infection, mechanical failure, overdrainage, loculated ventricles, and abdominal complications. Shunt malfunction caused by disconnection, kinking, or obstruction of the tubing results in typical signs and symptoms of increased intracranial pressure, or may present with more subtle symptoms. Fever may occur if infection is present, but shunt infection occasionally can be asymptomatic. In neonates, shunt malfunction manifests as alteration of feeding, irritability, vomiting, fever, lethargy, somnolence, and a bulging fontanel. Older children and adults present with headache, fever, vomiting, and meningismus. With VP shunts, abdominal pain may occur. Staphylococcus epidermidis and Staphylococcus aureus are the most common causes of shunt-related infection, which usually occurs within 2 months of shunt placement.

The infection rate varies but can be up to 10 percent [Drake, 2008]. Organisms that ordinarily are nonpathogenic may cause infection in the presence of shunt tubing in the ventricles, body cavities, or circulation. Whenever suppurative infection is suspected, appropriate blood and CSF specimens for culture must be obtained, the organism isolated, and sensitivities determined to facilitate effective antimicrobial therapy. Most shunts can be tapped to obtain CSF specimens and to assess CSF dynamics. If infection leads to impairment of the shunt mechanism, removal and replacement usually are required; temporary insertion of an external ventriculostomy may be necessary until the infection is controlled. In one series of patients whose shunts were tapped, normal CSF values correlated with an overall incidence of complications of 39.2 percent, whereas abnormal CSF values were correlated with a complication rate of 90.9 percent [Caldarelli et al., 1996]. Rates of infective complications were 2.7 percent in the patients with normal CSF and 77.3 percent in patients with abnormal CSF.

Other complications of VP shunts include peritonitis, CSF ascites, inguinal hernia, intra-abdominal cysts, intracranial granulomas, gastrointestinal obstruction, migration of the shunt within the peritoneal cavity, headache, and perforation of abdominal viscera [Sgouros et al., 1995; Caldarelli et al., 1996]. Abdominal pseudocysts manifest with nausea, vomiting, and abdominal distention and pain; abdominal ultrasonography may demonstrate the cysts [Hann et al., 1985]. Thromboembolic phenomena, cardiac dysrhythmias, cardiovascular perforation, endocarditis, catheter embolization, pulmonary hypertension and thromboembolism, and immune complex shunt nephritis are special complications of ventriculoatrial shunts [Lam and Villemure, 1997]. Correction of long-standing hydrocephalus may cause subdural hematomas.

The “slit ventricle syndrome” (SVS; Figure 27-5) is defined as severe, life-modifying headaches in patients with shunts for the treatment of hydrocephalus and normal or smaller than normal ventricles [Rekate, 2008]. There are five potential pathophysiologies that may be involved in this condition. These pathologies are defined by intracranial pressure measurement as severe intracranial hypotension analogous to spinal headaches, intermittent obstruction of the ventricular catheter, intracranial hypertension with small ventricles and a failed shunt (normal-volume hydrocephalus), intracranial hypertension with a working shunt (cephalocranial hypertension), and shunt-related migraine [Rekate, 2008]. Management of SVS requires an understanding of the specific pathogenesis of the problem in individual patients, whether based on monitoring of intracranial pressure or observation at the time of shunt failure or symptoms. Overdrainage syndromes are managed with valve upgrades and the addition of devices that retard siphoning. Other management options used for this condition are subtemporal decompression, calvarial expansion or shunting devices that access the cortical subarachnoid space, such as lumboperitoneal shunts, or shunts involving the cisterna magna.

Fig. 27-5 Slit ventricle syndrome.

Patients who have undergone ventricular shunting for hydrocephalus and develop severe headache may have normal or small (as seen in this figure) ventricles on imaging studies. The etiology of this syndrome is best determined in the individual patient by intracranial pressure measurement and can include severe intracranial hypotension analogous to spinal headaches, intermittent obstruction of the ventricular catheter, intracranial hypertension with small ventricles and a failed shunt (normal-volume hydrocephalus), intracranial hypertension with a working shunt (cephalocranial hypertension), or shunt-related migraine.

Prognosis

Before the 1950s, the outlook of untreated hydrocephalus was extremely poor. Some 49 percent of patients had died by the end of the 20-year observation period and only 38 percent of survivors had an IQ greater than 85 [Laurence and Coates, 1962]. The development of satisfactory shunting substantially improved the outlook of children with hydrocephalus but brought its own set of problems and complications. Most children with hydrocephalus will require multiple shunt revisions. Shunt dependence carries a 1 percent per year mortality [Sainte-Rose et al., 1991; Iskandar et al., 1998]. Another series of 907 patients reported a mortality rate of 12 percent at 10 years from the time of initial shunt insertion [Tuli et al., 2004], with the main risk factor for death being a history of shunt infection. Shunt-related complications, including death, have been reported to be greater in patients with myelomeningocele than in those who required shunt placement for the treatment of other conditions [Iskandar et al., 1998; Tuli et al., 2003].

The neurologic and intellectual disabilities among patients with hydrocephalus depend on many factors, including etiology and degree of hydrocephalus, thickness of the cortical mantle and corpus callosum [Fletcher et al., 1992], requirement for a shunt, and presence of other brain anomalies [Dennis et al., 1981]. Associated conditions, such as IVH, CNS infection [Tuli et al., 2004], and hypoxia, may dictate the ultimate prognosis more than the hydrocephalus.

A series of 233 patients with congenital hydrocephalus evaluated for longer than 20 years reported a mortality rate of 13.7 percent [Lumenta and Skotarczak, 1995]. The average number of shunt revisions was 2.7. In this series, 115 patients underwent psychological evaluation; approximately 63 percent showed normal performance, whereas 30 percent had mild retardation, and 7 percent had severe retardation. Another study found that children with congenital hydrocephalus were less likely to require special education placement (29 percent) than those in whom hydrocephalus was due to meningitis (52 percent) or IVH (60 percent) [Casey et al., 1997].

Epilepsy also is more prevalent in patients with hydrocephalus, and complications of shunt surgery appear to play a relatively minor role in its development [Piatt and Carlson, 1996].

Intellectual sequelae include significant scatter among Wechsler Intelligence Scale for Children-Revised (WISC-R) subtest scores, often with greater impairment of performance and motor tasks, as well as of nonverbal compared with verbal skills [Brookshire et al., 1995]. Normal intellectual function is present in 40–65 percent of patients who received appropriate treatment [Dennis et al., 1981]. The probability of normal intelligence is enhanced if shunts are placed early and proper function is maintained. A study of 99 children ranging in age from 6 to 13 years with shunted or arrested hydrocephalus demonstrated a close correlation between the area of the corpus callosum and nonverbal cognitive skills and motor abilities [Fletcher et al., 1996]. Behavioral problems also are more common in children with hydrocephalus, irrespective of etiology [Fletcher et al., 1995].

Definition

Intracranial arachnoid cysts are benign, nongenetic developmental cysts that contain spinal fluid and occur within the arachnoid membrane [Gosalakkal, 2002]. The mechanism of formation during embryogenesis is uncertain [Hirano and Hirano, 2004; Naidich et al., 1985–1986]. Several mechanisms could account for the enlargement of these cysts, including secretion by the cells forming the cyst walls, a unidirectional valve, or liquid movements secondary to pulsations of the veins [Gosalakkal, 2002]. The cysts occur in proximity to arachnoid cisterns, most often in the sylvian fissure (Table 27-3). Common neurologic features are headache, seizures, hydrocephalus, focal enlargement of the skull, and signs and symptoms of elevated intracranial pressure and developmental delay, as well as specific signs or symptoms resulting from neural compression. Some arachnoid cysts remain asymptomatic [Mason et al., 1997]. Progressive enlargement and intracystic or subdural hemorrhage are potential complications. Suprasellar arachnoid cysts may produce neuroendocrine dysfunction, hydrocephalus, and optic nerve compression. Posterior fossa cysts are now more frequently recognized with the use of MRI and CT, and frequently require surgical treatment [Domingo and Peter, 1996].

Table 27-3 Distribution of Arachnoid Cysts

(Modified from Rengachary SS, Watanabe I. Ultrastructure and pathogenesis of intracranial cysts. J Neuropathol Exp Neurol 40:61, 1981.)

In a series of 61 children with arachnoid cysts, about 53 percent of cases were diagnosed before age 1 year; 42 percent were supratentorial and 46 percent infratentorial [Pascual-Castroviejo et al., 1991]. Macrocephaly was the presenting symptom in 72 percent, and associated features included cranial asymmetry in 39 percent, aqueductal stenosis in 16 percent, and agenesis of the corpus callosum in 13 percent. Developmental delay was a common finding. Skull radiographs may suggest the diagnosis; CT or MRI is the definitive diagnostic procedure [Weiner et al., 1987] (Figure 27-6). Injection of contrast medium into the cyst to document communication with the ventricular system is seldom necessary.

Fig. 27-6 Arachnoid cyst.

A, A cystic mass with signal intensity suggestive of cerebrospinal fluid is seen to deform the right temporal lobe (arrows) on this parasagittal image from a T1-weighted magnetic resonance imaging (MRI) study. B, Note the eroded appearance of the greater sphenoid wing (arrows) from the arachnoid cyst on this axial image from a spin density-weighted MRI study.

(Courtesy of Joseph R Thompson, Department of Radiation Sciences, Loma Linda University School of Medicine, Loma Linda, California.)

Clinical Characteristics

Symptoms vary, depending on the size of the cyst and its location. Several common locations have been well described in the literature.

Complications

Several clinical complications are believed to be associated with arachnoid cysts, although the relation between cyst presence and development of symptoms remains controversial; thus, the decision to operate is difficult and must be made on a patient-by-patient basis. Surgery is indicated when the cyst is causing obstructive hydrocephalus or if neuroimaging demonstrates mass effect, with compression of normal brain or brainstem structures. The relation between symptoms such as attention-deficit disorder, aphasia, or migraine-like headaches is uncertain, and correlation between cyst location and specific symptoms or congruent electroencephalogram (EEG) abnormalities is necessary before symptoms can be attributed to the cyst.

Management

When symptoms warrant, surgical intervention to decompress the cyst, including endoscopic management or shunting procedures, is required [Abbott, 2004; Germano et al., 2003; Godano et al., 2004; Raffel and McComb, 1988]. Arachnoid cysts may occur with or without hydrocephalus. The success rate of fenestration is higher in those patients without hydrocephalus (i.e., 73 percent required no additional treatment) than in hydrocephalus patients (32 percent) [Fewel et al., 1996]. About 12 percent of patients with hydrocephalus treated with fenestration alone may require a cystoperitoneal shunt. In general, cyst fenestration should be the primary procedure in patients without hydrocephalus. If hydrocephalus is present, cyst fenestration is still recommended, but a VP shunt should be placed if hydrocephalus is marked or after fenestration if the hydrocephalus is progressive [Fewel et al., 1996]. Congenital intraspinal cysts also can occur and require surgical evaluation [Chang, 2004].