Congenital Hydrocephalus

58 Congenital Hydrocephalus Stephen L. Kinsman, MD

Keywords: brain malformations, cerebrospinal fluid, hydrocephalus, increased

intracranial pressure, ventriculomegaly

I. Brief History and Nomenclature II. Etiology III. Pathogenesis IV. Pathophysiology V. Relevant Structural Details VI. Pharmacology, Biochemistry, and Molecular Mechanisms VII. Natural History References

I. Brief History and Nomenclature In the early 1700s, Vesalius was the first to accurately recognize hydrocephalus as an accumulation of fluid within the cerebral ventricles. During the remainder of the 18th century, Morgagni and others described the neuroanatomical and pathological causes of hydrocephalus. In the next century, the physiology of cerebrospinal fluid (CSF) circulation began to be elucidated. Magendie is credited with developing the concept of an active bulk flow of CSF. The first half of the 20th century was a time of rapid increases in our understanding of the clinical and radiographic aspects of hydrocephalus. Of particular importance is the contribution of Dandy with the introduction of pneumoencephalography in 1918. The work of Russell is

Neurobiology of Disease

important with regards to the addition of systematic pathological studies of the causes of hydrocephalus. The past 3 decades have provided us with better, less invasive techniques for the diagnosis of hydrocephalus with the developments of computed tomography, cranial sonography, and magnetic resonance imaging (MRI). MRI has been particularly important because of its ability to accurately image hindbrain structures as well as to identify areas of CSF flow. Finally, improvements in CSF pressure monitoring and analysis have added to our ability to determine the presence of decompensated CSF accumulation, although to date this is used more frequently for adult hydrocephalus than for pediatric forms [1]. 641

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Congenital Hydrocephalus

All of these developments have led to modern definitions of hydrocephalus. Rekate has developed an acceptable definition: “an accumulation of excessive volumes of CSF within the intracranial compartment with higher pressures than would occur in a steady state and which may be treated with a drainage procedure before it becomes intractable” [2]. The notion of early hydrocephalus versus late or intractable hydrocephalus is particularly important when determining the urgency of intervention and possibly prognosis. The modern era of hydrocephalus began with the development of the valve-regulated shunt system by Nulsen and Spitz in the 1950s. Since that time, valve-regulated shunts have become the standard of care. Recently, there has been resurgence in the use of endoscopic third ventriculostomy as a method of treatment. A few studies have reported effective medical treatments of certain forms of infantile hydrocephalus using isosorbide or furosemide and acetazolamide. However, study results have not been consistent, and these treatments have not received widespread acceptance. Also, some investigators have suggested medical approaches to provide at least temporary treatment of the cellular-damaging effects of the late decompensated (or intractable) phase of hydrocephalus [3]. A review of nomenclature is useful for this discussion. Increased accumulation of CSF suggests an alteration in CSF flow at some level. It is first important to identify the site of the blockade to CSF circulation, absorption, or both. Terms originating from the era of pneumoencephalography, such as “internal” versus “external” or “obstructive” versus “nonobstructive” hydrocephalus, are confusing and outdated. External hydrocephalus is sometimes mistaken with subdural hygromas, and all hydrocephalus is to some degree caused by obstruction to normal CSF circulation (thus it would all be termed “internal hydrocephalus”). The terminology that best describes CSF blockade is communicating versus noncommunicating hydrocephalus. Noncommunicating hydrocephalus denotes a blockade of CSF pathways at or proximal to the outlet foramina of the fourth ventricle (foramina of Luschka and Magendie). Communicating hydrocephalus denotes a blockade distal to this point, in the basal subarachnoid cisterns, in the subarachnoid spaces over the brain surface, or within the arachnoid granulations (specialized units at which CSF is absorbed back into the circulation) [2].

II. Etiology The causes of hydrocephalus relate to any pathophysiological process capable of altering CSF production, circulation, or absorption in such a way as to allow an increased accumulation of CSF in a brain that is unable to compensate for the resulting increase in CSF volume and, in some

circumstances, decreased CSF flow. Causes of hydrocephalus include congenital malformations of the central nervous system (CNS), infections, hemorrhage, trauma, teratogens, and tumors. Increasingly, we are seeing the power of investigational convergence, brought about by progress in the study of genetic animal models and human genetic disease, in advancing our understanding of the etiology of hydrocephalus. Analysis of human cases of X-linked hydrocephalus, particularly in multiplex families, has led to an understanding of the role of L1CAM, a molecule now felt to be more of a neural recognition molecule than a cell adhesion molecule, in producing a hydrocephalic state. Many cases of congenital hydrocephalus with adducted thumbs are accounted for by a mutation in the L1CAM gene [4]. With regard to understanding the clinical etiologies of hydrocephalus, distinguishing between nongenetic and genetic causes of hydrocephalus helps in organizing the differential diagnosis of this condition. Among genetic causes, further separation into syndromic and nonsyndromic etiologies is also helpful [5]. Certain metabolic disorders, such as Hurler’s syndrome and nonketotic hyperglycinemia (NKH), also can be associated with hydrocephalus. Conditions associated with skeletal anomalies such as VACTERL (vertebral anomalies, anal atresia, cardiac defect, tracheoesophageal fistula, renal abnormalities, and limb abnormalities) and skullbase anomalies are also often associated with hydrocephalus. Finally, abnormalities of the development of the posterior fossa are also seen in association with hydrocephalus; this is especially true of the Dandy-Walker malformation. The etiologies of several mouse models of congenital hydrocephalus have recently been unraveled via molecular analysis. Recently, the Hydin gene, which when mutated is responsible for causing hydrocephalus in the mouse, has been cloned [6]. The product of this novel gene with unknown function is expressed in the ciliated ependymal cell layer that lines the lateral, third, and fourth ventricles and may interact with the cytoskeleton. Its role in altering CSF dynamics remains unknown. The hydrocephalus mouse model hyh has been shown to be due to a mutation in the gene encoding -SNAP. -SNAP plays a key role in a wide variety of membrane fusion events in eukaryotic cells, including the regulated exocytosis of neurotransmitters [7]. The hyh mutant points to potential roles of -SNAP in embryogenesis and brain development [8]. The next step is to link the human homologues of these genes to conditions associated with clinical hydrocephalus. This approach has been very successful with many other genetic conditions.

III. Pathogenesis Pathogenesis of hydrocephalus should consider both biomechanical and fluid dynamic factors. Equally important

Congenital Hydrocephalus is the brain’s built-in compensatory mechanisms as it responds to alterations in the previously mentioned processes. Finally, once compensatory capacity has been exhausted, hydrocephalus begins to cause injury to the CNS, mostly in the form of periventricular axonal cellular damage [3]. The pathogenesis of hydrocephalus encompasses the anatomical (gross and microscopic), biochemical, and physiological abnormalities that can result in an increased accumulation of CSF. As stated previously, anatomical, biochemical, and physiological processes also attempt to accommodate (compensate for) the resulting CSF accumulation. These processes include changes in skull shape, lymphatic drainage within the dura, and changes in brain tissue composition.

A. Basic Physiology and Anatomy of CSF Circulation The normal circulation of CSF requires a balance between the formation of CSF and its absorption and the unimpeded flow of CSF through its normal travel routes. Most of the formation of CSF (at least 80%) takes place in the choroid plexus [2]. This complex tissue is found in the lateral, third, and fourth ventricles, with some of the tissue extending via the foramina of Luschka into the cerebellopontine angles. The bulk of this tissue resides within the lateral ventricles. The cellular composition of the tissue includes endothelial cells that form capillaries and specialized cuboidal epithelium. Specialized tight junctions that are present at the apical sides of the epithelial cells provide the blood-CSF barrier. This barrier provides for the chemical integrity of the CSF. CSF is formed by the ultrafiltration of plasma through choroidal capillary epithelium as well as through uptake of the ultrafiltrate and secretion of CSF (by an active metabolic process) into the ventricular system. It should be noted that several enzymes are believed to be important in the process of CSF formation, with sodium-potassium-adenosine triphosphate pumps and carbonic anhydrase being particularly prominent. It appears that the other 20% of CSF production, so-called nonchoroidal CSF, is formed from brain extracellular fluid. Brain extracellular space accounts for about 15% of brain volume under normal conditions [2]. With the exception of the choroids plexus papilloma, there is scant evidence that CSF overproduction/secretion is an important factor in the pathogenesis of hydrocephalus. Under normal circumstances, CSF is produced at a rate of 0.3–0.35 mL/minute, and production equals absorption. CSF is absorbed into the sagittal sinus through the arachnoid villi. The process is passive and therefore requires no energy.

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B. Pathophysiology of Abnormal CSF Circulation It is important to note that the causes of hydrocephalus are extremely varied. Etiology plays a critical role in determining such factors as the age of onset, presence and degree of blockade to CSF circulation, degree and course of ventricular dilatation, brain and cranial compliance, and type of associated intracranial pathology. It should be emphasized at this juncture that the term “congenital hydrocephalus” is deceiving because presentation of hydrocephalus caused by a congenital malformation or process has been reported to present clinically at any age. Therefore age of onset does not always lead immediately to easy determination of the etiology. However, most so-called “congenital hydrocephalus” becomes symptomatic in the fetal, newborn, infant, or childhood intervals. Classification of hydrocephalus starts with identification of the site of CSF circulation blockage, the probable or precise etiology, the state of progression, and the dynamic status of the disorder (i.e., progressive or arrested). Not all ventriculomegaly, even if progressive, is hydrocephalus because it is sometimes difficult to determine whether a case of progressive ventriculomegaly is due to hydrocephalus or atrophy. Certain patterns of ventriculomegaly suggest that hydrocephalus is likely present, in particular the size and shape of the temporal horns and the shape of the third ventricle on midsagittal MRI [9]. The main branch point of many classification systems for the etiology of hydrocephalus is a separation between congenital cases and those due to other causes, such as inflammatory or neoplastic. However, it would be better to abandon the term “congenital hydrocephalus” when discussing etiology. The issue is really whether the cause of the hydrocephalus is a malformation (such as DandyWalker malformation), a genetic process (e.g., X-linked or autosomal recessive types), inflammation of either the leptomeninges or ventricular lining, chemical irritation (e.g., subarachnoid or ventricular blood), or neoplasm. Also important in the development of hydrocephalus is the viscoelastic response of the brain to the biomechanical effects of hydrocephalus, so-called brain turgor [2]. Differences in the brain’s response to the accumulation of CSF and stretch of brain tissues and their effects on cerebral blood volume all influence how the abnormal accumulation of CSF leads to clinical symptoms and signs in an individual with hydrocephalus. One can also hypothesize that individual differences in this process may account at least in part for the likelihood and possibly severity of brain injury seen in hydrocephalus. Studies to date do not address the issue of effects of pathophysiological processes on altering compensatory mechanisms that could lead to the development and/or maintenance of hydrocephalus in various situations. Clinical experience supports the concept that “the ability to recruit alternative pathways of CSF absorption appears to

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differ among individuals” [2]. One important difference is an individual’s ability to alter central venous pressure (and possibly volume). Another important factor is brain turgor.

IV. Pathophysiology Hydrocephalus is a condition that involves multiple intracranial compartments, is dynamic in nature, is variable in its onset and severity for each etiology, includes both biomechanical and fluid dynamic aspects, and is in need of novel treatment strategies. This section focuses on the measurement of abnormal intracranial pressure (ICP) and CSF flow. Increased understanding and detection of the various abnormal processes in a dynamic and potentially more longitudinal manner will enhance our understanding and treatment of hydrocephalus. In cases of communicating hydrocephalus, traditional measurements of ICP have been made by lumbar puncture and consist of static pressure measurements. A level of >20 centimeters of H2 O has been considered abnormally elevated. Others consider a mean ICP of 15 mm Hg on continuous ICP monitoring to be abnormal [1]. The detection of hydrocephalus in newborns and infants is more related to the detection of the clinical symptoms and/or signs of increased CSF pressure. In this age group, increasing head circumference is particularly important. Widening of the cranial sutures and fullness of the fontanelles are also important signs. Neuroimaging then provides evidence of abnormal accumulation of CSF (see later discussion), sometimes with evidence of increased periventricular accumulation of fluid (Fig. 1).

The condition known as normal-pressure hydrocephalus denotes abnormal CSF accumulation with significant CNS dysfunction but no increase in intracranial pressure. This condition can occur in children. A decrease in brain turgor occurring at the same time as an increased resistance to CSF outflow into the spinal subarachnoid space is the best current explanation of this condition’s pathophysiology [2]. Others note that a better term for this clinical situation might be chronic hydrocephalus, which separates the term from an instrument-based definition [10]. Importantly, the notion that hydrocephalus can even exist as a low-pressure state has received some attention [11]. One unique pathophysiological state, unique to shunted hydrocephalus, has been called the slit ventricle syndrome. This is considered a state of long-term shunt overdrainage and brain stiffness. These individuals, who have small or slit-sized ventricles, lose their ability to compensate for small changes in CSF volume and respond to small increases in volume with large increases in ICP. Often this condition can be treated with shunt revision, but sometimes other treatment is required, such as furosemide, acetazolamide, corticosteroids, antimigrainous treatments, and subtemporal cranial vault decompression (Fig. 2). This condition is considered by some to represent two quite different clinical problems, the aforementioned one and one in which slit ventricles result from shunt overdrainage. It is important to recognize that some individuals with congenital hydrocephalus go undetected for many years or are in fact asymptomatic for many years. Symptoms then begin in adulthood. Some authors have called this condition long-standing ventriculomegaly (LOVA), described as a unique form of hydrocephalus that develops during childhood and manifests symptoms during adulthood. Some of these individuals become symptomatic with symptoms

A

Figure 1 Acute infantile hydrocephalus with periventricular fluid accumulation.

B

Figure 2 A, Computed tomography (CT) scan of a child with shunted hydrocephalus and slit ventricles. Child had multiple episodes of headache and altered consciousness. B, After a diagnosis of slit ventricle syndrome was made, the shunt was revised and the child became asymptomatic. This follow-up CT scan shows that the lateral ventricles have expanded to a more normal size.

Congenital Hydrocephalus and signs of increased ICP, whereas others present more a more normal pressure hydrocephalus (NPH)-like picture of dementia/mental retardation, gait disturbance, and urinary incontinence [12].

V. Relevant Structural Details The first step in the workup of infantile hydrocephalus is to determine the distribution of abnormal CSF accumulation. Cases of external hydrocephalus are either familial, postprematurity, traumatic (usually nonaccidental), or metabolic (in particular, glutaric aciduria). In internal hydrocephalus, the distribution of abnormal CSF accumulation helps differentiate the site of blockade to CSF flow. The site of the blockade is often helpful in narrowing the search for causes of the hydrocephalus. However, it is often the case that a given pathological process demonstrates elements of both communicating and noncommunicating hydrocephalus, although one type usually predominates. The final step in proper diagnosis is to determine the etiology of the blockade. It is important to reemphasize that not all ventriculomegaly is the result of a hydrocephalic process. Brain atrophy also leads to ventriculomegaly, so-called hydrocephalus ex vacuo. Important differences between true hydrocephalus and the ex vacuo form include the degree of temporal horn dilatation relative to sulcal prominence, the angle of frontal horn displacement, and alterations in the shape of the third ventricle [9]. Fetal ventriculomegaly poses some special circumstances in this regard. Most ventriculomegaly identified in the fetal period is static in nature. Brain architecture is not mature enough to distinguish between loss of brain tissue volume and tissue stretch from abnormal CSF accumulation. Serial sonographic measurement of the ventricles is required to distinguish these situations [13]. Optimal treatment of this situation remains unproven, and fetal surgery for this condition remains for the most part unsuccessful. A few comments are also in order with regard to the relationship between malformations of the posterior fossa and congenital hydrocephalus. Dandy-Walker syndrome (DWS), which is a triad of agenesis or hypoplasia of the cerebellar vermis, cystic dilatation of the fourth ventricle, and supratentorial hydrocephalus, accounts for 1–4% of childhood hydrocephalus. Most of these patients have normal ventricles at birth and that nearly 80% develop symptomatic hydrocephalus by 1 year of age [14].

VI. Pharmacology, Biochemistry, and Molecular Mechanisms The molecular mechanisms of congenital hydrocephalus are beginning to be unraveled. As noted previously, several

645 mouse models of hydrocephalus have been created via molecular cloning. These discoveries suggest that the molecular function of the ependymal lining plays a critical role in CSF dynamics. Experimental mutation of the axonemal dynein heavy chain gene Mdnah5 also effects ependymal cell function and leads to hydrocephalus [15]. The Mdnah5 is specifically expressed in ependymal cells and is essential for ultrastructural and functional integrity of ependymal cilia. In these Mdnah5-mutant mice, lack of ependymal flow causes closure of the aqueduct and subsequent formation of triventricular hydrocephalus during early postnatal brain development. These findings suggest that the higher incidence of aqueduct stenosis and hydrocephalus formation in patients with ciliary defects proves the relevance of this novel mechanism in humans. The mouse model of hydrocephalus hyh has been found to be due to a mutation in the gene Mf1, a winged helix/forkhead transcription factor [16]. The mechanisms by which this altered transcription factor causes hydrocephalus remain to be elucidated. Alteration of Msx1, a regulatory gene involved in epithelio-mesenchymal interactions during organogenesis, leads to mice that lack a subcommissural organ, with resultant collapse of the cerebral aqueduct and the development of hydrocephalus [17]. Finally, increased expression of transforming growth factor (TGF)-, as seen in subarachnoid hemorrhage, leads to hydrocephalus by a proposed mechanism of alteration in the composition of the brain’s extracellular matrix [18].

VII. Natural History The advent of the valve-regulated shunt system has radically changed the prognosis for individuals with most forms of hydrocephalus. In the U.S., virtually all children with hydrocephalus, with the possible exception of some with massive in utero–acquired hydrocephalus, receive intervention. Laurence and Coates’s series of 182 untreated individuals gives us some idea of the historical prognosis for untreated cases [19]. In this series, only 20% of infants reached adulthood. Many of the deaths occurred in the first 1.5 years of life. Of those with untreated hydrocephalus who lived, 60% had intellectual impairment, 25% were “completely ineducable,” and 25% had “cocktail party syndrome.” Some patients had intelligence quotient (IQ) scores in the normal range but often with significant disparities between verbal and performance scores. Also of concern was the finding that “some cases with compensated hydrocephalus” had sudden death or a downhill spiral of deterioration. There is little question that for most individuals, untreated hydrocephalus is bad for health, intellect, and function. How well do patients do with treatment? Studies show that in general, a postshunting mantle of about 3 cm or more is important for normal intellectual

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development [20]. Preshunt scans do not appear predictive of ultimate function in most cases. The most important prognostic factors are the cause of hydrocephalus, duration of the condition before shunting, and presence of associated brain malformations or injury. A study of the efficacy of various shunt types in contributing to shunt failure rates in the first year post-shunt placement is our best analysis of the symptoms and signs presenting in childhood hydrocephalus [21]. Table 1 summarizes these findings. This study also gives us some sense of the frequency of etiologies presenting with childhood hydrocephalus, as summarized in Table 2. This study was a multicenter trial of shunt placement, not an epidemiological study. However, epidemiological studies show similar incidences. Most interestingly, this study concludes that clearly more research is needed “into the complexities of CSF and brain fluid dynamics and biomechanics.” As noted previously, technologies now exist to better study CSF flow and composition, alterations in brain and ventricular architecture over the course of hydrocephalus and its successful (and unsuccessful) treatment, and imaging of brain water content as well as brain tissue compromise, such as the magnetic resonance property anisotropy. A key question remains: Is there a critical point during the development of hydrocephalus at which irreversible damage occurs? When children with infection and related

Table 1 Presenting Symptoms and Signs of Childhood Hydrocephalus Signs or Symptoms

Percentage of Cases

Presenting symptoms Irritability Delayed developmental milestones Nausea or vomiting Headache Lethargy New seizures or change in seizures Diplopia Worsening school performance Fever

26.6 19.8 19.0 17.5 17.5 6.6 5.8 4.2 2.6

Presenting signs Increased head circumference Bulging fontanelle Delayed developmental milestones Loss of upward gaze Decreased level of consciousness Other focal neurological deficits Papilledema Sixth nerve(s) palsy Hemiparesis Nuchal rigidity

81.3 70.6 20.9 15.8 12.6 12.4 12.0 4.6 3.8 1.3

From Drake, J. M., Kestle, J. R., Milner, R., et al. (1998). Randomized trial of cerebrospinal fluid shunt valve design in pediatric hydrocephalus. Neurosurgery 43, 294–305.

Table 2 Hydrocephalus Etiology∗ Cause

Percentage of Cases

Intraventricular hemorrhage Myelomeningocele Tumor Aqueduct stenosis Cerebrospinal fluid infection Head injury Other Unknown Two or more causes ∗

24.1 21.1 9.0 7.0 5.2 1.2 11.3 11.0 8.7

Excluding Dandy-Walker malformation. From Drake, J. M., Kestle, J. R., Milner, R., et al. (1998). Randomized trial of cerebrospinal fluid shunt valve design in pediatric hydrocephalus. Neurosurgery 43, 294–305.

complications are excluded from the sample, studies yielded normal IQ scores within groups of uncomplicated, shunted hydrocephalic children. Longitudinal study of the effects of hydrocephalus on cognitive development has been difficult. When studies examine a more select and appropriate group of these “uncomplicated, shunted hydrocephalic children,” some findings do seem to emerge. As Wills summarizes in a 1993 review: Overall, the consensus of these findings appears to be that it is the presence of brain anomalies, cytoarchitectonic defects, or a history of trauma or infection rather that the presence and extent of hydrocephalus per se that accounts for most cognitive deficits. The “pure” effect of hydrocephalus, if such exists, seems to impair visuospatial and visuomotor performance specifically and may depend on selective compression or posterior brain regions. [22]

A quantitative MRI-based study by Fletcher and colleagues adds quantitative confirmation of this assertion [23].

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647 16. Hong, H. K., Lass, J. H., and Chakravarti, A. (1999). Pleiotropic skeletal and ocular phenotypes of the mouse mutation congenital hydrocephalus (ch/Mf1) arise from a winged helix/forkhead transcription factor gene. Hum. Mol. Genet. 8, 625–637. 17. Fernandez-Llebrez, P., Grondona, J. M., Perez, J., LopezAranda. M. F., Estivill-Torrus, G., Llebrez-Zayas, P. F., Soriano, E., Ramos, C., Lallemand, Y., Bach, A., and Robert, B. (2004). Msx1-deficient mice fail to form prosomere 1 derivatives, subcommissural organ, and posterior commissure and develop hydrocephalus. J. Neuropathol. Exp. Neurol. 63, 574–586. 18. Crews, L., Wyss-Coray, T., and Masliah, E. (2004). Insights into the pathogenesis of hydrocephalus from transgenic and experimental animal models. Brain Pathol. 14, 312–316. 19. Laurence, K. M., and Coates, S. (1962). The natural history of hydrocephalus. Detailed analysis of 182 unoperated cases. Arch. Dis. Child 37, 345–362. 20. Nulsen, F. E., and Rekate, H. L. (1982). Results of treatment for hydrocephalus as a guide to future treatment. In: “Pediatric Neurosurgery: Surgery of the Developing Nervous System” (R. L. McLaurin, ed.), pp. 229–241. Grune & Stratton, New York. 21. Drake, J. M., Kestle, J. R., Milner, R., Cinalli, G., Boop, F., Piatt, J. Jr., Haines, S., Schiff, S. J., Cochrane, D. D., Steinbok, P., and MacNeil, N. (1998). Randomized trial of cerebrospinal fluid shunt valve design in pediatric hydrocephalus. Neurosurgery 43, 294–303; discussion 303–305. 22. Wills, K. E. (1993). Neuropsychological functioning in children with spina bifida and/or hydrocephalus. J. Clin. Child Psychol. 22, 247–265. 23. Fletcher, J. M., McCauley, S. R., Brandt, M. E., Bohan, T. P., Kramer, L. A., Francis, D. J., Thorstad, K., and Brookshire, B. L. (1996). Regional brain tissue composition in children with hydrocephalus. Relationships with cognitive development. Arch. Neurol. 53, 549–557.