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Pathology of Pediatric Hydrocephalus

Gurjit Nagra and Marc R. Del Bigio

ContentsIntroduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2Pathological Factors Causing Hydrocephalus: Anatomic Considerations . . . . . . . . . . . . . . . . . . . . . . 3

Interventricular Foramen Obstruction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3Cerebral Aqueduct Obstruction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5Fourth Ventricular and Aperture Obstruction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9Subarachnoid Space and Absorptive Site Obstruction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12

Effects of Hydrocephalus on the Brain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13Subependymal Zone, Ependyma, and Choroid Plexus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14White Matter and Myelin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14Cerebral Gray Matter . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15

Pathology Associated with Cerebrospinal Fluid Shunting . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17Cross-References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18

G. NagraDepartment of Pathology, University of Manitoba, Winnipeg, Manitoba, Canadae-mail: [email protected]

M. R. Del Bigio (*)Shared Services Manitoba, Winnipeg, Canada

Children’s Hospital Research Institute of Manitoba, Winnipeg, Canada

Department of Pathology, College of Medicine, Faculty of Health Sciences, University ofManitoba, Winnipeg, Manitoba, Canadae-mail: [email protected]

# Springer International Publishing AG, part of Springer Nature 2018G. Cinalli et al. (eds.), Pediatric Hydrocephalus,https://doi.org/10.1007/978-3-319-31889-9_43-1

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https://doi.org/10.1007/978-3-319-31889-9_43-1

AbstractThis chapter focuses on the pathology of hydrocephalus in children. With respectto causes of hydrocephalus, an anatomical approach is used highlighting abnor-malities that can impede cerebrospinal fluid movements at the interventricularforamina, the cerebral aqueduct, the fourth ventricular apertures, and the sub-arachnoid space. Inflammatory processes, some very subtle, secondary to infec-tions or hemorrhage can damage the ependymal layer and allow fusion ofadjacent brain surfaces or cause collagenous scarring in the subarachnoid space.Neoplasms and other lesions that can compress the cerebrospinal fluid pathwaysare briefly summarized. Several complex malformations of the posterior fossa(including Chiari type 2, Meckel-Gruber, Dandy-Walker) are also associated withhydrocephalus. Ventricular enlargement, when sufficiently severe or rapid, cancause secondary damage in the brain. Early-onset hydrocephalus (e.g., in fetusesor premature infants) might alter subsequent brain development. Periventricularaxon damage, which is caused by a combination of mechanical distortion andblood flow alterations, is preventable by shunting but is not reversible. Mostchanges in the neuron cell body are secondary to the axonal damage. Thehistopathology of shunt obstruction is briefly reviewed. In conjunction within vivo imaging and animal experimentation, there remains much to be learnedfrom autopsies, explanted cerebrospinal fluid shunts, and possibly brain biopsiesfrom hydrocephalic children.

KeywordsAutopsy · Axon · Ependyma · Human · Hydrocephalus · Myelin

Introduction

Hydrocephalus is a deceivingly complex disorder. Internal hydrocephalus refers toenlargement of the cerebral ventricles, and external hydrocephalus refers to enlarge-ment of the subarachnoid space. Both may be caused by disturbances in the dynamicmovements of cerebrospinal fluid (CSF) , sometimes crudely considered as animbalance between production and absorption. Rekate defined hydrocephalus asan active distension of the ventricular system of the brain resulting from inadequatepassage of CSF from its point of production within the cerebral ventricles to its pointof absorption into the systemic circulation (Rekate 2009). The focus of this chapter isto describe the pathology of hydrocephalus in fetuses and children. We use anatom-ical divisions to describe the causes of hydrocephalus and regional or cellulardivisions to describe its effects on the brain. Experimental work, which is coveredin another chapter, will be referenced only when necessary to explain pathophysio-logical processes. We will use anatomical terminology used in TerminologiaAnatomica (Federative Committee on Anatomical Terminology and InternationalFederation of Associations of Anatomists 1998).

2 G. Nagra and M. R. Del Bigio

Pathological Factors Causing Hydrocephalus: AnatomicConsiderations

Walter Dandy pioneered our understanding of hydrocephalus and offered a concep-tual framework. Based upon the movement of phenolsulfonphthalein injected intothe lateral ventricles, autopsy studies, and animal experiments, he suggested thatdiminished absorption of CSF could result in communicating hydrocephalus(wherein the CSF moves freely from the ventricles into the subarachnoid space,which is blocked by adhesions) or obstructive hydrocephalus (wherein the ventric-ular pathway is blocked by congenital atresias, adhesions, or tumors) (Dandy andBlackfan 1914, 1917; Dandy 1918). More recently, Rekate tried to simplify some ofthe terminology by classifying hydrocephalus according to the anatomic site of CSFobstruction, which allows rational choices of treatment (Rekate 2009, 2011). Thisclassification also makes sense from the perspective of pathological causes. Dandyproposed that some cases of hydrocephalus could be caused by increased productionof CSF associated with the inflammatory products of meningitis or trauma. Thisgeneral concept was discarded long ago, but there remain a small number ofhydrocephalus cases that seem to be caused by excess CSF production from hyper-plasia or papilloma of the choroid plexus (Fujimoto et al. 2004; Karimy et al. 2016).In those cases, one must still exclude an obstructive factor.

In simplest terms, the ventricles and subarachnoid space represent a series ofmorphologically varied channels with several narrow sites that are vulnerable toobstruction; these include the interventricular foramen (of Monro), the cerebralaqueduct (of Sylvius), and the subarachnoid space (SAS). Obstructions can occurthrough several possible means. First, the obstruction can be caused by an abnor-mality within the channel that forms a plug. Second, extrinsic abnormalities cancompress the channel, which might remain intact or become secondarily obliterated.Third, an inflammatory process can cause destructive and reactive changes in theaffected tissues, leading to scarring or obliteration of the channel. The timing of theinsult can affect the categorization of hydrocephalus, e.g., a cryptic in utero infectioncan cause “congenital” hydrocephalus while a similar infection in infancy might bedesignated “post-meningitis” hydrocephalus. Furthermore, the histologic features ofan obstruction may be modified by the passage of time. Finally, pathologic processesthat cause ventriculomegaly in an infant might cause raised intracranial pressure withsmall ventricles in an older child or young adult (Cardoso et al. 1989).

Interventricular Foramen Obstruction

Oi and Matsumoto categorized obstructions by cause, including space-occupyinglesions (i.e., tumors), maldevelopment (congenital atresia), and functional obstruc-tion (Oi and Matsumoto 1985). Obstruction at the interventricular foramen can causeunilateral or bilateral ventriculomegaly (Nigri et al. 2016). Hypothetically any typeof brain tumor with a propensity for growth in the region of the anterior thirdventricle (e.g., craniopharyngioma, pilocytic astrocytoma, hypothalamic glioma,

Pathology of Pediatric Hydrocephalus 3

germinoma) or ventricular wall (e.g., central neurocytoma, subependymal giant cellastrocytoma, ependymoma) can obstruct the foramen (Nishio et al. 2002). Colloidcyst is a benign lesion of the third ventricle that is critical to recognize because it isassociated with risk of sudden death due to acute hydrocephalus (Beaumont et al.2016). These cysts are typically lined by a simple ciliated epithelium and are filledwith proteinaceous fluid. Based upon ultrastructural and immunohistochemicalfeatures, these cysts likely arise from primitive endodermal rests rather than choroidplexus or ependyma (Kondziolka and Bilbao 1989; Lach and Scheithauer 1992;Uematsu et al. 1993).

Unilateral hydrocephalus associated with simple congenital atresia of the foramenis rare (Fig. 1). When unilateral ventriculomegaly is identified in a fetus, it oftenresolves spontaneously or is associated with a destructive lesion (Durfee et al. 2001).Occlusions that cause persistent ventriculomegaly requiring treatment (e.g., endo-scopic perforation or shunting) are typically described as translucent membranes or“smooth, glistening tissue” (Wilberger et al. 1983; Abderrahmen et al. 2008).Unfortunately there are few pathologic descriptions of the membranes. In a case ofunilateral hydrocephalus found incidentally in an adult autopsy, the “right foramenof Monro was found to be occluded by a bridge of glial tissue covered withependyma, indistinguishable from normal ventricular walls” (Pfeiffer and Friede1984). Obliteration of the interventricular foramen was postulated long ago to occuras a result of an inflammatory and reactive process (Dott 1927). This remains areasonable explanation. Relatively minor in utero infections are thought to becapable of damaging the ependymal lining of the ventricles, which in turn canpredispose to fusion of adjacent tissue walls (Del Bigio 2010a). Interventricularforamen occlusion might represent a miniature version of ventricular loculation(multiloculated hydrocephalus) that can occur after ventriculitis (Schultz andLeeds 1973; Schellinger et al. 1986; Lazareff and Sadowinski 1992).

Fig. 1 (a) Photograph showing severe right-sided ventriculomegaly in the brain of an 18-month-old girl who had left hemiplegia and developmental delay; she died from pneumonia. (b) Unilateralporencephaly had been diagnosed from the prenatal ultrasound examination performed at approx-imately 30 weeks’ gestational age (arrow). However, there was no focal ischemic damage.(c) Microscopic examination showed focal loss of ependyma and fusion of the fornix and adjacentthalamus with choroid plexus intervening (arrow; solochrome cyanin and eosin stain). There was noobvious scar tissue or active process


Functional obstruction of the interventricular foramen is associated with isolated(“trapped”) lateral ventricle. Midline shift of brain structures can bring the thalamusand fornix into apposition, thereby reducing the effective lumen of the foramen. Thiscan occur after shunting or due to a distant space-occupying lesion such as a subduralhematoma (Salmon 1970; Ang et al. 2006).

Cerebral Aqueduct Obstruction

The cerebral aqueduct is located in the midbrain and connects the third and fourthventricles. It is approximately 12 mm length at term birth and reaches a maturelength of 18 mm by about 1 year age. The aqueduct is not a simple cylindricalchannel. Its profile varies along the length, being slit-like at the rostral end, ovoid ordiamond shaped in the middle, and triangular at the caudal end. The smallest cross-sectional area (0.5 mm2) is about one quarter of the way from the third ventricle(Emery and Staschak 1972). The lumen of the aqueduct is lined by single layer ofcolumnar or cuboidal ciliated ependymal cells (Del Bigio 2010a). A recent reviewshowed that the cerebral aqueduct is the most common location of intraventricularobstruction to CSF flow (Cinalli et al. 2011). Obstruction of the cerebral aqueductcan occur in a broad range of pathological processes including congenital narrowing,blood clots, and neoplastic tumors (Jellinger and Schwingshackl 1973).

Within the category of congenital obstruction, many terms are used to describethe morphologic variations. Russell suggested the distinction between stenosis(histologically normal but abnormally small), forking (multiple small ependyma-lined channels), gliosis (“proliferation of the subependymal glia and disruption ofthe ependyma”), and septum formation; note that she advised against the term“atresia” (Russell 1949). This categorization has been perpetuated for decades(Jellinger 1986; Cinalli et al. 2011). However, it is not clear that it is useful from apathophysiologic vantage. In some cases, Russell’s own illustrations reveal negligi-ble differences between forking, gliosis, and “maximum stenosis.” Parker andKernohan wrote in 1933: “Chronic ependymitis, periaqueductal gliosis and congen-ital narrowing of the aqueduct represent minutiae, much argued over but littlecomprehended . . . One type may grade imperceptibly into the other, and dogmatismas to the type is out of place” (Parker and Kernohan 1933). Others have also beenreluctant to rigidly distinguish the categories (Drachman and Richardson 1961). Weagree that these abnormalities likely reflect a spectrum of change rather than discretepathologies (Fig. 2).

The pathogenesis of aqueductal narrowing has been discussed, without resolution,for decades. Most authors have artificially considered a distinction between devel-opmental, congenital, and inflammatory origins (Russell 1949; Beckett et al. 1950;Turnbull and Drake 1966). The ependymal lining of the ventricular system seems tobe important for maintaining the patency of the lumen. In experimental mice, geneticmutations that result in disruption of ependymal cell junctional complexes allowshedding of ependymal cells and secondary development of aqueduct stenosis(Wagner et al. 2003; Ma et al. 2007; Paez et al. 2007; Yamamoto et al. 2013).


Homologous mutants have not yet been discovered in humans. X-linked hydroceph-alus associated with mutations in L1CAM (L1 cell adhesion molecule) is associatedwith complex abnormalities of neuron migration and brain malformation; most caseshave aqueduct stenosis, but they do not have a generalized abnormality of ependymalintegrity (Adle-Biassette et al. 2013). The central canal of the spinal cord is histolog-ically very similar to the cerebral aqueduct; asymptomatic loss of patency occurs in

Fig. 2 Photomicrographs showing cerebral aqueducts in a range of obstructed forms (all hema-toxylin and eosin stain, 40� original magnification). (a) Normal tent-shaped aqueduct in the brainof a newborn infant. (b) Narrow but patent aqueduct in the brain of 20-month-old infant who hadbeen shunted at 1 month old. (c) Obstructed aqueduct with residual ependymal cells outlining theoriginal shape (arrows) in the brain of a 6-year-old child with myelomeningocele and shuntedhydrocephalus; he died of acute shunt failure. (d) Central region of the midbrain from a 36-weekgestation fetus with severe hydrocephalus; only a few residual ependymal cell clusters (arrow) existat the site of an obliterated aqueduct


almost all people during childhood and teenage years. Minor infection with commonviruses is the leading hypothesis for this process (Milhorat et al. 1994). Focal fusionof adjacent ependymal surfaces is a common observation in the patent aqueduct(Friede 1961; Alvarez et al. 1987). Therefore, it is possible that relatively minor viralinfections during the fetal period could damage the ependyma and lead to abnormal-ities in the cerebral aqueduct (Del Bigio 2010a). Indeed, it has been shown innewborn mice and hamsters that infection with mumps, parainfluenza 2, and influ-enza A causes shedding of ependymal cells and aqueduct stenosis without significantinflammation (Johnson and Johnson 1969). The general hypothesis that in utero orchildhood infection causes mild inflammation with focal ependymal shedding thatcauses disruption or fusion of the cerebral aqueduct is a reasonable one. Numerouscase reports document the temporal association between mumps infection and devel-opment of hydrocephalus in children (Ogata et al. 1992), and in large epidemiologicstudies, maternal infection and lack of prenatal care are potential risk factors forcongenital hydrocephalus (Kalyvas et al. 2016).

Cilia-driven flow of CSF is likely important in the immediate vicinity of theventricular wall with bulk flow driven by other mechanical factors (Siyahhan et al.2014). Hydrocephalus has been reported in ~20 children with proven structuralabnormalities of the cilia, representing a small fraction of cases with primary ciliarydyskinesia (Lee 2013). Based upon imaging characteristics, some appear to haveaqueductal obstruction (Vieira et al. 2012), while in others all of the ventricles aredilated (Greenstone et al. 1984). Few autopsies have been performed on affectedindividuals. In one fetal case with hydrocephalus, the aqueduct was dilated withnormal-appearing ependymal cells and the site of CSF obstruction could not beidentified (Kosaki et al. 2004; Del Bigio 2010a). At least 20 mutant mouse strainswith functional or structural ciliary abnormalities develop hydrocephalus, some butnot all of these have aqueduct stenosis (Lee 2013). The hy-3 mouse, which has amutation in HYDIN, develops severe aqueduct stenosis (Raimondi et al. 1976).However, no human with a HYDIN mutation has developed hydrocephalus (Olbrichet al. 2012). To summarize, the causal relationship between motility defects in ciliaand hydrocephalus remains unclear.

Other types of aqueduct obstruction are more easily explained. Intraventricularhemorrhage (IVH) associated with premature birth is a well-known cause ofaqueductal occlusion (Fig. 3), although multiple sites of CSF obstruction are possi-ble in this context (Rorke 1982). Rarely, in utero IVH leads to development ofhydrocephalus (Gunn et al. 1988). In some cases, the only evidence of a hemorrhagicevent is hemosiderin in the fused aqueduct with no obvious proximal source(Lategan et al. 2010). Small vascular malformations in the midbrain can compressthe aqueduct leading to hydrocephalus in children or adults; most are demonstratedangiographically (Cavallo et al. 2015). We have seen two examples of this entity inautopsy material (Fig. 4).

Theoretically any type of brain tumor might arise in the brain stem; however thelesion that most selectively is associated with aqueduct occlusion is the diffusemidline glioma (previously referred to as diffuse intrinsic pontine glioma/DIPG),which accounts for approximately 10% of pediatric brain tumors (Johnson et al. 2014;


Louis et al. 2016). These predominantly childhood tumors have a poor prognosis,especially when they are associated with the histone H3-K27M mutation(Solomon et al. 2016). Pineal gland tumors or cysts are the other rare, region-specificlesions associated with extrinsic aqueduct obstruction (Mottolese et al. 2015;Starke et al. 2016).

Fig. 3 Photomicrographs showing the brain samples from an infant born at 25 weeks’ gestationwho died 31 h after severe (grade 4) intraventricular hemorrhage. (a) The cerebral aqueduct isoccluded by blood clot at the level of the pontomesencephalic junction (arrow). (b) The fourthventricular apertures are also occluded by blood surrounding the choroid plexus (arrows), and thereis extensive subarachnoid blood at the level of the medulla oblongata (all hematoxylin and eosinstain, 12.5� original magnification)

Fig. 4 Apparently healthy, non-dysmorphic boy suffered from unexplained episodic bradycardiaand died of sudden respiratory arrest at 5.5 years. (a) The brain exhibited moderately severe chronicventriculomegaly. (b) This was caused by a venous malformation in the midbrain (arrow) withcompression of the cerebral aqueduct. (c) Although the aqueduct was narrow and irregular, theependymal lining was intact (arrow; 40� original magnification; hematoxylin and eosin)


Fourth Ventricular and Aperture Obstruction

The fourth ventricle is an irregular pyramid-shaped space located between thecerebellum and the brain stem (Matsushima et al. 1982). CSF enters proximallyfrom the cerebral aqueduct and leaves through the lateral (foramen of Luschka) andmedian (foramen of Magendie) apertures into the subarachnoid space (SAS). Manyof the same processes that obstruct the cerebral aqueduct can also cause obstructionof the fourth ventricle or its outlets. Blood from supratentorial IVH can track into thefourth ventricle (Rorke 1982); approximately 9% of preterm infants with IVH willdevelop post-hemorrhagic hydrocephalus (Christian et al. 2015). In the early stages,some of these cases are simply due to physical obstruction to CSF flow by a bloodclot (Fig. 3). Late or chronic cases involve inflammatory and reactive processes thatwill be discussed in the subarachnoid space section.

Medulloblastoma, pilocytic astrocytoma, and ependymoma, the most commonbrain tumors of childhood, usually grow in the cerebellum (Dolecek et al. 2012).They are often associated with hydrocephalus through compression of, or growthinto, the fourth ventricle. Although uncommon in children, subependymomas, whichappear as exophytic growths from the fourth ventricular wall, can also causehydrocephalus.

The Chiari malformation type 2 (also called Arnold-Chiari malformation) con-sists of herniation of the inferior cerebellar vermis and tonsils through the foramenmagnum and caudal descent of the brain stem in association with myelomeningocele(Caviness 1976; Cesmebasi et al. 2015) (Fig. 5). Among aborted fetuses14–24 weeks’ gestational age, approximately half have enlarged ventricles (Bellet al. 1980). In the era when spinal lesions were not necessarily closed, most infantswould die from infection or progressive hydrocephalus (Laurence 1964). If thespinal lesion is closed, approximately 80% develop hydrocephalus (Elgamal2012). The cause of hydrocephalus in this circumstance has been the subject ofmany publications. Early authors emphasized the relatively small posterior fossa andpossible traction effect, because the myelomeningocele anchors the spinal cord to thelengthening spine. The result is impaction of the cerebellum against the brain stemwith compression of the fourth ventricle and cerebral aqueduct along with functionalocclusion of the fourth ventricular apertures (Russell and Donald 1935; Lichtenstein1942; Emery and MacKenzie 1973). Some authors postulated a generalized over-growth phenomenon rather than a traction effect (Barry et al. 1957). Autopsy serieshave resulted in divergent opinions about the site of the CSF flow obstruction in theChiari 2 malformation. Among 100 children (newborn to 5 years old) withmyelomeningocele and hydrocephalus studied at autopsy by Emery, the cerebralaqueduct was reported to be short and narrow, but patent in all cases (Emery 1974).In a smaller study of 25 autopsies (newborn to 2 years old) performed by Rorke,approximately half had atresia or forking of the cerebral aqueduct (Gilbert et al.1986). A study by MacFarlane (newborn to 7 weeks’ old) showed “complexforking” in 4/20 cases, stenosis in 6/20 cases, and normal or enlarged aqueduct in10/20 cases (MacFarlane and Maloney 1957), and a study by Masters showedobliteration of the aqueduct in 4/24 cases (Masters 1978). In our experience, the


most brains from fetuses with myelomeningocele have a normal cerebral aqueduct.Intrauterine repair of the myelomeningocele reduces the hindbrain herniation andlater development of shunt-dependent hydrocephalus. This suggests that hydroceph-alus is secondary to the spinal anomaly in most cases (Tulipan et al. 2003, 2015).A detailed study of the aqueduct in five cases of myelomeningocele-associatedhydrocephalus showed that shedding of the ependymal cells is preceded by changesin junctional proteins such as N-cadherin (Sival et al. 2011). Although we disagreewith the authors’ suggestion that “abnormalities in the formation of gap and adherentjunctions result in defective ependymal coupling, desynchronized ciliary beating andependymal denudation, leading to hydrocephalus,” the study does reveal somepotentially important aspects of secondary ependymal changes in Chiari 2. Insummary, Chiari 2 malformation is associated with the potential for CSF flowinterruption at many sites in the posterior fossa, no single one of which should beconsidered the primary instigator. It remains to be determined if changes in theaqueduct lumen are a primary malformation or if they occur secondary to the forcedapposition of the ependymal surfaces.

Hydrocephalus is associated with a range of other rare posterior fossa malfor-mations and syndromes. Occipital encephaloceles, characterized by cerebellar andless often occipital lobe herniation, are often associated with hydrocephalus (Karchand Urich 1972; Caviness and Evrard 1975; Docherty et al. 1991). Usually thecerebral aqueduct is normal, although we have seen cases with distorted midbrainand secondarily obliterated aqueduct. When there is also caudal displacement of the

Fig. 5 Chiari 2 malformations. (a) Lateral view of a 19-week gestation fetal brain showing caudaldescent and posterior folding of cerebellar tonsils (arrow). (b) Posterior view of the cerebellum froma 9-month-old girl with lumbosacral myelomeningocele. The cerebellum is misshapen with aglobular shape and no obvious vermis (arrow shows midline)


hindbrain, some authors call the complex Chiari 3 malformation (Ivashchuk et al.2015). However, it is not clear to what extent the distinction is merely semantic, withthe term used more often in the clinical literature than in pathologic literature.

The fourth ventricle and the cisterna magna are normally in free communication(Barr 1948). Rarely, simple obstructions at the fourth ventricular outlets have beenreported as a cause of hydrocephalus (Karachi et al. 2003), although the pathology isnot clear. The Dandy-Walker malformation is defined as upward rotation andhypoplasia of the cerebellar vermis with cystic dilation of the fourth ventricle dueto atresia of the fourth ventricular apertures (Fig. 6) (Taggart and Walker 1942; Hartet al. 1972). The majority has hydrocephalus (Spennato et al. 2011).

Meckel syndrome type 1 (also known as Meckel-Gruber syndrome) is aciliopathy characterized by cystic renal disease, hepatic abnormalities, and posteriorfossa brain malformation (typically occipital encephalocele or, less often, posteriorfossa cyst, i.e., Dandy-Walker anomaly) (Cincinnati et al. 2000; Logan et al. 2011).Hydrocephalus, which is variably present, is usually secondary to aqueduct anom-alies (Ahdab-Barmada and Claassen 1990).

Rhombencephalosynapsis is a rare malformation characterized by agenesis of thecerebellar vermis and fusion of the hemispheres. The majority has severe hydro-cephalus with small fourth ventricles along with abnormalities of the cerebralaqueduct and mesencephalon (Pasquier et al. 2009; Ishak et al. 2012). There issome overlap with VACTERL, which is a constellation of congenital malformations

Fig. 6 Photograph showingthe ventral surface of the brainof a 4-month-old girl withlarge Dandy-Walker cyst; acyst-to-peritoneal shunt hadbeen placed shortly after birth.Note the absence of well-defined cerebellar tissue onthe posterior surface (arrow)


including vertebral anomalies, anal atresia, cardiac anomalies, tracheoesophagealfistula, renal anomalies, limb defects, and sometimes hydrocephalus (Evans et al.1989; Lomas et al. 1998). X-linked hereditary cases of VACTERL are causedby mutations in the FANCB gene, which can also cause Fanconi anemia (Holdenet al. 2006).

Subarachnoid Space and Absorptive Site Obstruction

From the fourth ventricle, CSF moves into the cranial and spinal subarachnoid space(SAS) and eventually to the sites of absorption. The SAS is mainly a sheetlike spacelocated between the arachnoid mater and the pia mater, with several large cisterns onthe ventral surface of the brain. Microscopic webs of collagenous tissue, the arach-noid trabeculae, traverse the narrower spaces. Major blood vessels, along withcranial and spinal nerves, pass through the SAS (Nauta et al. 1983; Alcolado et al.1988; Adeeb et al. 2013). The current dogma is that CSF is resorbed from the SASinto the venous sinuses and radicular veins through microscopic structures known asarachnoid villi, some of which enlarge to macroscopic structures known as arach-noid granulations (Gomez et al. 1982; Kida et al. 1988; Tubbs et al. 2007; Adeebet al. 2013). Solid experimental animal data show that up to half of CSF is alsoabsorbed into cranial (especially nasal) lymphatics along nerve rootlets; there issome support for this in humans (Johnston et al. 2004). There is also evidence insheep that the nasal lymphatics are relatively more important in the newborn stagethan in adults (Papaiconomou et al. 2002); some have written that this is likely so inhumans (Symss and Oi 2013), despite absence of direct evidence. The human duramater itself probably contains pathways that connect with the cranial lymphatics orvenous sinuses (Fox et al. 1996; Squier et al. 2009; Bucchieri et al. 2015). The extentto which CSF in the SAS exchanges with fluid in the paravascular pathways,including the Virchow-Robin spaces, and then into dural lymphatics remains unclear(Bakker et al. 2016). One must also consider that water, the main constituent of CSF,exchanges freely across cell membranes including the blood-brain barrier (He et al.2012; St. Lawrence et al. 2012).

Awide range of pathological processes can result in scarring of the SAS, with thesubsequent development of hydrocephalus. Hemorrhage and infection are the mostcommon offenders (Rorke 1982; Chatterjee and Chatterjee 2011). Acute hypoxic-ischemic brain damage can result from bacterial (including tuberculous) meningitisor subarachnoid hemorrhage (usually secondary to intraventricular hemorrhage ortrauma in children). In the subacute and chronic phase, the inflammatory activityreleases mediators that eventually cause fibrosis in the SAS (Weller 2005). Trans-forming growth factor beta 1 is currently the subject of considerable investigation asa cause, and potential therapeutic target, in this process (Del Bigio and Di Curzio2016). Also, many of the pediatric brain tumors discussed above can spread to theSAS, thereby further compromising CSF movement.

It is not clear if specific, direct developmental anomalies can affect the SAS orabsorption sites sufficiently to cause hydrocephalus. Four case reports apparently


documenting congenital absence of arachnoid villi in hydrocephalic children arefrequently cited (Gilles and Davidson 1971; Gutierrez et al. 1975). There are nomore similar reports since the 1970s. It is not clear if this condition is simplydiagnosed but not reported publically, or if it cannot be replicated, or if thediminishing frequency of autopsy is preventing recognition of more cases.

Notwithstanding the debate about sites of CSF absorption, it has been shown thatvenous hypertension can decrease CSF absorption, presumably by altering thepressure gradient across arachnoid villi (Portnoy et al. 1994). In infants and youngchildren, this may be associated with hydrocephalus. Bypass of venous sinusobstructions can reduce the severity of hydrocephalus in some children (Sainte-Rose et al. 1984). Achondroplasia and other forms of complex craniosynostosis maybe associated with elevated venous and intracranial pressure (Steinbok et al. 1989;Taylor et al. 2001). Causes of cerebral venous hypertension more distant from thebrain include superior vena cava occlusion (McLaughlin et al. 1997) and congenitalheart malformation (Rosman and Shands 1978). We have seen such cases at autopsy;the only abnormalities are diffuse venous congestion and mild ventriculomegaly.

Effects of Hydrocephalus on the Brain

Many disease processes can interfere with CSF dynamics and cause hydrocephalus.In addition to the brain damage associated with initial disease process (e.g., menin-gitis) or malformation, enlargement of the cerebral ventricles can cause secondarydamage to the surrounding brain tissue. The senior author has published numerousreview articles summarizing the pathology and pathogenesis of brain changes causedby hydrocephalus (Del Bigio 1993, 1995b, 2001a, b, 2004, 2010b, 2014). Verybriefly, the current literature suggests that hydrocephalic brain dysfunction anddamage are multifactorial. Mechanical stretching can physically disrupt axons andperiventricular blood vessels when hydrocephalus develops acutely. More gradualdamage seems to be the result of impaired blood flow, particularly in the whitematter, which leads to a cascade of oxidative and proteolytic processes that destroyaxons (Del Bigio et al. 2012). Retrograde and anterograde phenomena can causechanges in the neuron cell bodies and dendrites. In addition, alterations in themovement of extracellular fluid and clearance of CSF might adversely alter theextracellular environment. Below we will focus on brain changes that are seen inhuman pediatric hydrocephalus.

The type of brain damage depends on the state of maturation of the nervoussystem. We can identify three broad phases, which overlap to some extent. First isthe period of rapid cell proliferation, particularly in the subependymal zone, whichcontinues until approximately 34 weeks’ gestation (Del Bigio 2011). It must beconsidered in congenital hydrocephalus or in hydrocephalus affecting the prema-turely born infant. Second is the phase of rapid brain growth associated with cerebralmyelination and neuronal synaptogenesis during the 1st year of life (after full-termbirth) when the brain weight doubles (Yakovlev and Lecours 1967; Webb et al.2001). Third is the period of more gradual growth extending to the teenage years and


beyond, during which many pathways continue to myelinate and synaptic connec-tions are refined (de Graaf-Peters and Hadders-Algra 2006; Paus 2010).

Subependymal Zone, Ependyma, and Choroid Plexus

In the developing central nervous system, most cell proliferation occurs in theventricular and subventricular zones (SVZ), which are located along the lumen ofthe ventricular system. In the cerebral hemispheres, most glutamatergic excitatoryneurons appear by approximately 18 weeks’ gestation, although some are generatedas late as 28 weeks (Malik et al. 2013). The SVZ generates inhibitory interneuronsuntil ~35 weeks’ gestation (Rakic and Sidman 1969; Arshad et al. 2016). Prolifer-ative activity in the largest part of the SVZ (located over the caudate nucleus, i.e., theganglionic eminence) peaks at 20–26 weeks’ gestation and then diminishes rapidly(Del Bigio 2011). It has been postulated that CSF is important for normal function ofthe germinal matrix (Miyan et al. 2003). However, the animal data are somewhatcontradictory; in H-Tx rats the germinal epithelium is thicker than in controls(Vetsika et al. 1999), while in ferrets with kaolin-induced hydrocephalus, prolifera-tion in the SVZ is suppressed by hydrocephalus (Di Curzio et al. 2013). Human dataare very limited. In cases of fetal hydrocephalus associated with spina bifida,periventricular heterotopias were observed at the roof of the lateral ventricle.Disruption of the ventricular zone was postulated to be a primary event leading tohydrocephalus (Guerra et al. 2015), although we contend that this could also besecondary.

The mature ciliated ependymal epithelium has features that suggest it acts as abarrier between CSF and brain, preventing uncontrolled mixing of CSF and inter-stitial fluid (Del Bigio 1995a). Coordinated movements of the cilia create CSF flowgradients that might be important for movement of signaling molecules at theventricular surfaces (Faubel et al. 2016). Ependymal cells might also be importantfor preventing fusion of ventricular surfaces where they are in close apposition (DelBigio 2010a). Many studies have documented variable loss of ependyma over whitematter structures in hydrocephalic brains. This is generally assumed to be a destruc-tive process caused by stretching of the ventricular wall and the inability ofependymal cells to regenerate (Bruni et al. 1985; Del Bigio 1993, 2010a). Choroidplexus changes caused by hydrocephalus in children are not well documented (DelBigio 1993). There is weak evidence that choroidal cells might be shed into the CSFof hydrocephalic infants (Wilkins and Odom 1974).

White Matter and Myelin

Periventricular white matter is the main site of brain damage that occurs as aconsequence of ventricular enlargement (Del Bigio 1993, 2001b, 2010b). Autopsiesdone mainly in the 1960s have yielded important information. In comparison toage-matched non-hydrocephalic children, children who died of progressive


hydrocephalus had thinning of the corpus callosum and atrophy of the peri-ventricular white matter (Gadsdon et al. 1978). In spite of this gross atrophy dueto axon loss, the density of glial cells in residual white matter is within normal limits(Friede 1962). Pediatric hydrocephalic brains have a reduced density of capillaries inthe corpus callosum (Gadsdon et al. 1978). Atrophy of the corpus callosum and thefimbria-fornix (Fig. 7) is associated with motor and cognitive deficits (Del Bigioet al. 2003). Cerebral biopsies taken at the time of shunt insertion demonstrateextracellular edema with dispersion of the axons, rare damaged axons, and macro-phages (Weller and Shulman 1972; Del Bigio et al. 1985). An electron microscopicstudy of biopsies from hydrocephalic infant brains was reported to show degenera-tive changes in oligodendrocytes (Castejon et al. 2001; Castejon 2015), although weare not convinced that the interpretation of the findings is correct. Nevertheless,myelination is a vulnerable process in childhood brain development (Davison andDobbing 1966). An early magnetic resonance imaging study of hydrocephalicchildren showed changes suggestive of delayed myelination and that shuntingcould reverse the delay (Hanlo et al. 1997). More recent studies using fractionalanisotropy suggest that the changes are more nuanced (Williams et al. 2015).

Cerebral Gray Matter

Ventricular expansion in severe hydrocephalus can eventually cause gross thinningof the cerebral cortex, especially when the head is enlarged (Russell 1949). Hydro-cephalus that begins in the fetal or infantile period tends to be associated with

Fig. 7 Photograph showingthe horizontally sliced brain ofa severely hydrocephalic girlwho died shortly at the time ofdelivery at 42 weeks’gestation; she had multiplecongenital anomalies. Theaqueduct was obliterated.Important pathologicalfeatures to note aregeneralized thinning of thecerebral mantle, hemorrhagein the severely atrophicoccipital lobes (at bottom) dueto rupture of veins, destructionof the corpus callosum(arrow), and reduction of thefornix to narrow threads(arrowhead)


occipital horn enlargement, while hydrocephalus that begins later tends to causepredominantly frontal horn enlargement (O’Hayon et al. 1998). Hydrocephalicbrains may appear to have an excess of gyri, termed polygyria, which is causedby unfolding of the intrasulcal cortex onto the brain surface (Emery 1968; Friede1989). Cerebral mantle thickness is not predictive of the clinical outcome (Yashonet al. 1965).

Microscopic changes in the deep gray matter structures (caudate nucleus, thala-mus, hippocampus) of hydrocephalic children are subtle, even when the ventriclesare very large. In the most extreme cases, periventricular white matter destructioncan be near complete with focal loss of the deep cortical layers and rarely focalrupture of the thinned cerebrum (Fig. 7) (Pennybacker and Russell 1943; Torkildsen1948; Russell 1949; Humphreys et al. 2007). Electron microscopic examination wasconducted on superficial cortical biopsies taken at the time of shunting hydroce-phalic children. The authors reported subtle changes in pyknotic neurons (Glees andVoth 1988; Hasan and Glees 1990b), pinocytotic vesicles in endothelial cells(possibly related to altered fluid transport) (Glees et al. 1989; Hasan and Glees1990a), and microglial hypertrophy (likely a sign of activation). Some microscopicfeatures they claimed are indicative of “proliferation of oligodendrocytes” (Gleesand Hasan 1990); we do not agree with the latter interpretation. Dendritic changes ofuncertain significance have also been reported (Castejon and Arismendi 2003;Castejon 2004). The immunohistochemical detection of neuron-specific enolase(enolase 2) was used to study maturation of neurons in the cerebra of prematureinfants with hydrocephalus (Oi et al. 1989); major limitations of the study are theheterogeneity of cases and the absence of controls.

Pathology Associated with Cerebrospinal Fluid Shunting

Shunted brains from hydrocephalic children may have weights comparable tocontrols (Emery 1964), although they retain a range of abnormalities related to theprimary pathology despite reduction in the ventricular size. There is autopsy evi-dence that early shunting prevents atrophy of the periventricular white matter andcorpus callosum (Gadsdon et al. 1979). Secondary upward movement of the cere-bellum and development of subdural fluid collections are common (Emery 1965).The thickness of the subependymal layer of astrocytes remains slightly greaterthan in controls in spite of shunting (Del Bigio et al. 2003), although this is notnecessarily a correlate to subsequent development of slit ventricular syndrome (DelBigio 2002).

The subject of shunt obstruction by tissue ingrowth from brain has been reviewedin detail (Del Bigio 1998; Harris and McAllister 2012). To summarize briefly, shuntscan be occluded shortly after implantation (i.e., days) by blood clot, brain tissuedebris, or inflammatory cells (in the context of infection). In the following weeksto years, normal brain tissue (e.g., choroid plexus or vascularized astroglial tissue)with variable inflammation (e.g., eosinophils, lymphocytes, multinucleated foreign


body-type reactive cells) contributes to obstruction (Fig. 8). Histologic examinationof explanted shunts can in some cases contribute usefully to the management ofhydrocephalic children with recurring shunt obstruction (Ellis et al. 2008).

Summary

Much of what is known about hydrocephalus in the pediatric population has beenlearned from autopsies. In particular, quantitative evaluations of large numbers oftreated and untreated cases conducted by John Emery and coworkers in the 1960sand 1970s are invaluable. Biopsies of human brain conducted at the time of shuntinghave provided additional refinements. However, many of those studies have beenhampered by small sample sizes or inadequate controls leading to misleadingconclusions. Direct correlations between human brains and experimental animalbrains have helped to understand the pathogenesis of secondary brain damagecaused by hydrocephalus. More work is needed to understand how early-onsethydrocephalus, in fetuses and premature infants, interferes with subsequent braindamage. If protective therapies that might be used as supplements to shunting are tobe developed (Del Bigio and Di Curzio 2016), more work is also necessary tounderstand the pathophysiologic similarities and differences between humans and

Fig. 8 (a) Photograph of thetip of a flanged ventricularcatheter that became occludedby choroid plexus years afterimplantation (24-year-oldwoman with hydrocephalus ofuncertain etiology). (b)Photomicrograph ofvascularized astroglial tissuethat had grown into a simpleventricular catheter, yearsafter implantation (9-year-oldboy who had hydrocephalusassociated with in uteroischemic brain damage).Tissue pedicles pass throughthe holes of the catheter(arrows) and merge, filling thelumen (note that there is somedistortion when the catheter issectioned with the tissue insitu; original magnification40�; hematoxylin and eosinstain)


animals. A thorough understanding of the human state is necessary for the develop-ment of animal models that are useful for preclinical therapeutic studies. Conse-quently, the value of autopsies and biopsies in hydrocephalic humans has notdiminished despite the fact that imaging can now provide enormous detail.

Cross-References

▶Anatomy and Histology of Cerebral and Spinal Meninges▶Classification and Definition of Hydrocephalus▶Experimental Hydrocephalus: Models and Study Methods

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