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. 2023 Nov 21;34(1):bhad432. doi: 10.1093/cercor/bhad432

The “microcephalic hydrocephalus” paradox as a paradigm of altered neural stem cell biology

Phan Q Duy 1,2,#, Neel H Mehta 3,#, Kristopher T Kahle 4,5,6,✉
PMCID: PMC10793578  PMID: 37991277

Abstract

Characterized by enlarged brain ventricles, hydrocephalus is a common neurological disorder classically attributed to a primary defect in cerebrospinal fluid (CSF) homeostasis. Microcephaly (“small head”) and hydrocephalus are typically viewed as two mutually exclusive phenomenon, since hydrocephalus is thought of as a fluid “plumbing” disorder leading to CSF accumulation, ventricular dilatation, and resultant macrocephaly. However, some cases of hydrocephalus can be associated with microcephaly. Recent work in the genomics of congenital hydrocephalus (CH) and an improved understanding of the tropism of certain viruses such as Zika and cytomegalovirus are beginning to shed light into the paradox “microcephalic hydrocephalus” by defining prenatal neural stem cells (NSC) as the spatiotemporal “scene of the crime.” In some forms of CH and viral brain infections, impaired fetal NSC proliferation leads to decreased neurogenesis, cortical hypoplasia and impaired biomechanical interactions at the CSF–brain interface that collectively engender ventriculomegaly despite an overall and often striking decrease in head circumference. The coexistence of microcephaly and hydrocephalus suggests that these two phenotypes may overlap more than previously appreciated. Continued study of both conditions may be unexpectedly fertile ground for providing new insights into human NSC biology and our understanding of neurodevelopmental disorders.

Keywords: hydrocephalus, microcephaly, Zika virus, cytomegalovirus, TORCH, neurogenesis, neural stem cell

Introduction

In utero infections by certain viruses such as the Zika virus have a devastating impact on fetal development and are a major cause of birth defects in multiple organ systems in humans (Pierson and Diamond 2018; Megli and Coyne 2022). The brain is one organ system that is particularly vulnerable to in utero viral infections. One striking neurological sequela of viral infections, particularly in the case of the Zika virus, is microcephaly marked by profound underdevelopment of the cerebral cortex and severely reduced head circumference (Cauchemez et al. 2016; Heymann et al. 2016; Devakumar et al. 2018; Megli and Coyne 2022). Another common neurological sequela of viral infections is the development of hydrocephalus (Simeone et al. 2013; van der Linden et al. 2019), which is characterized by the enlargement of the cerebrospinal fluid (CSF)-filled brain ventricles leading to symptoms of raised intracranial pressure and progressive macrocephaly (enlarged head circumference) in infants (Whitehead and Weiner 2022). Microcephaly and hydrocephalus are thought of as two mutually exclusive brain malformations with different underlying pathogenic mechanisms. In the case of microcephaly, it is believed that impaired neural stem cell (NSC) growth and proliferation lead to decreased production of neurons (Thornton and Geoffrey Woods 2009; Phan and Holland 2021), resulting in cerebrocortical hypoplasia and the appearance of a small head. A related condition is hydrocephalus ex vacuo, in which neuronal loss secondary to neurodegeneration or vascular insult (stroke) results in compensatory filling of CSF in the ventricles and ventricular dilation. Hydrocephalus ex vacuo is not associated with progressive ventricular dilation and symptoms of intracranial hypertension, and therefore is not thought to reflect bona fide hydrocephalus (Kim et. al. 2021). Microcephaly is also sometimes associated with radiographic enlargement of ventricles, but no clinical symptoms or signs of intracranial hypertension expected with hydrocephalus. On the other hand, infantile hydrocephalus is often characterized the appearance of a large head and has been attributed to pathologic overaccumulation of CSF in the ventricles due to an imbalance in CSF production versus reabsorption, altered cilia-driven flow currents, or anatomical obstruction to CSF flow (Kahle et al. 2016; Whitehead and Weiner 2022; Duy, Greenberg, et al. 2022). Thus, microcephaly is thought of as a classic disorder of reduced NSC growth, whereas hydrocephalus is thought of as a classic example of impaired CSF dynamics.

Here, we review and discuss an underappreciated clinical-radiographic phenomenon that we term “microcephalic hydrocephalus,” which occurs in some in utero infections (most importantly the Zika virus) and certain genetic syndromes. In contrast to the prevailing view that microcephaly and hydrocephalus are two mutually exclusive conditions, the ostensibly paradoxical coexistence of both microcephaly and clinical hydrocephalus suggests more overlapping mechanisms between these entities than previously appreciated. At the cellular level, Zika virus targets NSCs of the developing brain, highlighting neural progenitors as the key cell-type involved in the pathogenesis of brain and ventricular malformations in microcephalic hydrocephalus. These observations add to the emerging hypothesis that some cases of hydrocephalus may in fact be a congenital brain malformation akin to microcephaly with secondary impact on brain–CSF interactions rather than a primary disorder of failed CSF homeostasis (Jin et al. 2020; Hale et al. 2021; Duy, Rakic, et al. 2022; Duy, Rakic, Alper, Robert, et al. 2022; Duy, Weise, et al. 2022). The recognition of microcephalic hydrocephalus and a better understanding of its underlying embryological mechanisms may reveal fundamental insights into human brain development and inform diagnostic and treatment strategies for hydrocephalus and other related neurodevelopmental disorders.

Viral microcephalic hydrocephalus: the “paradoxical” coexistence of microcephaly and hydrocephalus

Microcephaly and hydrocephalus have long been recognized as common and striking neurological consequences of some TORCH infections (McAuley et al. 1994; Cauchemez et al. 2016; Heymann et al. 2016; Mlakar et al. 2016; Devakumar et al. 2018; Megli and Coyne 2022). Infection-related microcephaly and hydrocephalus are usually thought of as two separate entities, since one leads to the appearance of a small head with preserved ventricular size (microcephaly), whereas the other leads to the appearance of a large head with enlarged cerebral ventricles (hydrocephalus). However, detailed examination of neuroimaging studies with longer term follow-up has revealed the paradoxical clinical-radiographic phenomenon of “microcephalic hydrocephalus” in which both microcephaly and clinical hydrocephalus can coexist, particularly in cases due to Zika virus infections (see Fig. 1 for an illustrative example of Zika-related microcephalic hydrocephalus and Tables 1–4 for representative examples of microcephaly co-occuring with ventricular dilation and/or hydrocephalus in the literature) (Faccini et al. 2022; Schuler-Faccini et al. 2022; Withoeft et al. 2022; Zhou et al. 2022; van der Linden et al. 2019; Werner et al. 2016; Hazin et al. 2016; de Oliveira-Szejnfeld et al. 2016; Martines et al. 2016; Mlakar et al. 2016; Li, Dan, et al. 2016; Driggers et al. 2016; Teissier et al. 2014; Malinger et al. 2003; Noyola et al. 2001; Barkovich and Lindan 1994; Twickler et al. 1993; Drose et al. 1991; Tassin et al. 1991). In fact, one of the first reported Zika virus-infected microcephalic fetuses was noted to also exhibit hydrocephalus in postmortem neuropathological examinations, indicating an early recognition that microcephaly and hydrocephalus can occur simultaneously in the same patient (Mlakar et al. 2016). In a neuroimaging study consisting of 45 patients with presumed or confirmed Zika infections, de Oliveira-Szejnfeld et al. (2016) found that the majority of patients exhibited radiographic ventriculomegaly (enlarged cerebral ventricles). Some of these patients then progressed to have severe ventriculomegaly and increased head circumference consistent with elevated intracranial pressure and clinical hydrocephalus, necessitating the placement of a ventriculoperitoneal shunt to reduce CSF volume.

Fig. 1.

Fig. 1

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Example of microcephalic hydrocephalus in a patient infected with Zika virus depicted by CT imaging. This patient required surgical shunting for the development of hypertensive clinical hydrocephalus despite initially exhibiting a predominantly microcephalic phenotype. Figure is from (Schuler-Faccini et al. 2022) permitted by the creative commons attribution license (https://creativecommons.org/licenses/by/4.0/).

Table 1.

Human examples of microcephaly occurring together with hydrocephalus and/or ventricular dilation in the context of in utero infection with Zika virus.

Author, Date PMID Pathogen Age/gestation Diagnostics (cUS, MRI, CT) Possible obstructions Total cases Co-occurring cases Summary
Driggers et al. 2016 27028667 Zika Virus 11 gestational weeks Neonatal sonogram None 1 1 Case of intrauterine Zika virus infection presenting with mild ventriculomegaly and decreasing head circumference (16–20 weeks of gestation). Postmortem analysis revealed diffuse cerebral cortical thinning.
Mlakar et al. 2016 26862926 Zika Virus 13 gestational weeks Neonatal sonogram Periventricular and cortical calficiations 1 1 Case report of patient presenting with microcephaly, complete agyria, hydrocephalus, and multifocal calcifications.
Martines et al. 2016 27372395 Zika Virus 11 gestational weeks–6 post-natal months Neonatal sonogram Microcalcifications 5 2 Two cases of Zika-infected patients presenting with microcephaly and hydrocephalus
Soares de Oliveira-Szejnfeld et al. 2016 27552432 Zika Virus 6–34 gestational weeks Neonatal sonogram, MRI, CT Periventricular calcifications 45 NS Imaging study of 45 cases of confirmed/suspected Zikv infection that documented ventriculomegaly, intracranial calcifications, microcephaly, and cranial dysmorphia
Hazin et al. 2016 27050112 Zika Virus 3 postnatal days–5 postnatal months Head CT Intracranial calcifications 23 23 Case series of 23 infants with congentinal Zika infection that all presented with microcephaly, intracranial calcifications, and ventriculomegaly
Werner et al. 2016 27316349 Zika Virus 10 gestational weeks Neonatal Sonogram Periventricular calcifications 1 1 Case report of patient with fetal microcephaly, posterior ventriculomegaly, and diffuse brain calcifications.
Van der Linder et al. 2019 30452526 Zika Virus 3–18 postnatal months Head CT Intracranial calcifications 24 24 Case series of 24 patients presenting with hydrocephalus and microcephaly. All patients underwent CSF diversion by neurosurgical shunting due to symptoms, signs, or radiographic findings suggestive of clinical hydrocephalus.
Mattar et al. 2017 28610628 Zika Virus 19 gestational weeks Head CT Intracranial calcifications 1 1 One case of a Zika-infected patient presenting with microcephaly and ventriculomegaly
Faccini et al. 2022 36164338 Zika Virus ~36 gestational weeks Neonatal Sonogram Intracranial calcifications 21 5 Report of 5 microcephalic patients who also presented with hydrocephalus
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Table 4.

Human examples of microcephaly occurring together with hydrocephalus and/or ventricular dilation in the context of in utero infection with herpes simplex virus.

Author, Date PMID Pathogen Age/gestation Diagnostics (cUS, MRI, CT) Possible obstructions Total cases Co-occuring cases Summary
Hoppen et al. 2001 11305194 HSV 19 gestational weeks Neonatal sonogram N/A 1 1 Case study of congenital HSV infection presenting with hydrocephalus, secondary microcephaly, and severe postnatal CNS malfunction.
Duin et al. 2007 17154224 HSV 20 gestational weeks Neonatal sonogram, MRI N/A 1 1 Case study of congenital HSV with microcephaly, stable cerebral ventriculomegaly, and cortical thinning
Marquez et al. 2011 20811312 HSV ~10 postnatal days Neonatal sonogram Intracranial calcifications 64 1 Case series of 64 infants with congenital herpes simplex virus that included reports of microcephaly, hydrocephalus, and one concurrent case.
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A later case series of 24 patients reported by van der Linden et al. (2019) further established severe hydrocephalus as part of the clinical spectrum of congenital Zika syndrome. These patients initially presented with a predominantly microcephalic phenotype consisting of reduced head circumference and small brain volume. Through longitudinal neuroimaging and clinical follow-up, van der Linden et al. found that these patients later developed clinical and/or radiographic findings suggestive of clinical hydrocephalus with elevated intracranial pressure, including progressively enlarging ventricular volume, further reduction of brain parenchymal volume on repeat imaging, vomiting, irritability, and sudden increases in head circumference. To prevent further neurologic decline, all patients underwent neurosurgical shunting. Importantly, even though their head circumferences were still considered to be microcephalic or normocephalic in a minority of cases, these patients also exhibited the prototypical clinical signs of hypertensive hydrocephalus that necessitated CSF diversion by placement of a shunt. These observations suggest that microcephaly and hydrocephalus are not mutually exclusive conditions but rather can coexist in the same patient, and in fact, an initial phenotype of microcephaly with ventriculomegaly may later evolve into severe hydrocephalus with probable high intracranial pressure in some cases.

The existence of microcephalic hydrocephalus has also been documented in animal models. For instance, the development of both microcephaly and hydrocephalus has been reported in a sheep fetus infected with the Neospora caninum parasite (Withoeft et al. 2022). Zhou et al. (2022) observed grossly enlarged ventricles and cortical atrophy in a mouse model of congenital cytomegalovirus infection, another known cause of both microcephaly and hydrocephalus in human patients. Mouse models of Zika virus infection have been shown to exhibit hydrocephalus and/or microcephaly (Li, Dan, et al. 2016; Xavier-Neto et al. 2017).

NSCs are a cellular target of congenitally acquired infections

All neurons and macroglia of the human brain originate from a sheet of NSCs termed neuroepithelial cells, which develop into radial glia NSCs that line the walls of the brain ventricles (the ventricular zone) for the bulk of in utero development (Rakic 1988; Silbereis et al. 2016). Radial glia NSCs generate neuronal progenies, either directly or indirectly via intermediate progenitor cells, that migrate away from proliferative zones near the ventricles to settle in the cortical plate (Bystron et al. 2008). After birth, radial glia NSCs differentiate into ependymal cells that form the ventricular lining of the postnatal brain. The precise timing and coordination of NSC fates and settling patterns are therefore essential for human brain development, and altered NSC development has a detrimental impact on brain morphogenesis and maturation.

At the mechanistic level, in vivo and in vitro studies using animal or cell culture models and primary human tissue have revealed perturbations in prenatal NSCs as a key cellular mechanism that is likely to drive the neurological consequences of viral infections (Devakumar et al. 2018). Multiple studies (see Table 1) have found that NSCs, including neuroepithelial cells and radial glia cells, are the main cellular targets of Zika virus and cytomegalovirus in the brain (Tang et al. 2016; Onorati et al. 2016; Li, Dan, et al. 2016; Cugola et al. 2016; Li, Saucedo-Cuevas, Shresta, et al. 2016; Li, Saucedo-Cuevas, Regla-Nava, et al. 2016; Yockey et al. 2016; Teissier et al. 2014). Experimental analyses of in vitro stem cell models, organotypic fetal brain slices from humans, and Zika-infected human brain tissues have shown that Zika virus preferentially infects NSCs, but not differentiated neurons (Garcez et al. 2016; Onorati et al. 2016; Tang et al. 2016). Zika infection disrupts NSC proliferation while increasing cell death, resulting in a smaller overall pool of progenitor cells available for cortical neurogenesis (Tang et al. 2016; Onorati et al. 2016; Miner et al. 2016; Li et al. 2019). Mechanistically, ZIKV inoculation of human cortical neuroprogenitors results in induction of a caspase-3 mediated cell-cycle dysregulation and apoptosis (Tang et al. 2016). Consistent with in vitro studies of human stem cell models, direct injection of Zika virus into the brain ventricles of mouse embryos results in global dysregulation of gene expression, NSC cell-cycle arrest, and defects in neural differentiation, manifesting as microcephaly with enlarged ventricles at the neuroanatomical level (Li, Dan, et al. 2016).

Additionally, microcephalic hydrocephalus and NSC-mediated pathophysiology have been well-documented in the cases of intrauterine cytomegalovirus, the leading cause of congenital viral infections (Ssentongo et al. 2021). Here, intrauterine diagnostics have identified periventricular and parenchymal calcifications, microcephalic hydrocephalus, intracranial abnormalities, and other systemic manifestations in cases of infection with CMV (see Table 2). Mechanistically, CMV infection likely alters NSC growth and induces precocious neural differentiation (Odeberg et al. 2006; Tsutsui et al. 2008; Luo et al. 2010; Zhou et al. 2022). Importantly, similar clinical presentation of viral-induced microcephalic hydrocephalus has been documented in cases of Toxoplasmosis (see Table 3) and Herpes Simplex Virus (see Table 4), with NSCs serving as key sites of viral effect (Wang et al. 2014; Zheng et al. 2020). Beyond cell-autonomous effects on NSCs, Zika virus and cytomegalovirus also induce a neuroinflammatory response that may further exacerbate brain injury and abnormal neurodevelopment (Zhou et al. 2022; Li, dan, et al. 2016; Mlakar et al. 2016; Driggers et al. 2016; Cloarec et al. 2016; Guibaud et al. 2004). Neuroinflammation might also have a secondary impact on CSF homeostasis by noncell autonomous effects on the choroid plexus and other cell types (Kim et al. 2020; Cloarec et al. 2016). Finally, temporal and developmental variations in the localization and proportion of NSCs in the subventricular zone may change over time, with peaks visible ~16 weeks of gestation followed by subsequent loss to differentiation (Yin et al. 2013). As such, the timing of viral infection may influence the severity of disease phenotype. These relationships, however, are unclear with murine modeling suggesting that early and late gestational infection (embryonic days 4 and 8 infection of Swiss-Webster dams) can produce similarly diminished brain sizes and growth outcomes (Valentine et al. 2018). Further work is needed to address the question of how gestational age at time of intrauterine transmission may differentially affect phenotypic variations in microcephalic hydrocephalus. Although the precise molecular mechanisms by which certain viruses disrupt NSC growth are still being investigated, these observations provide strong evidence that NSC defects are linked to brain and ventricular malformations observed in human patients.

Table 2.

Human examples of microcephaly occurring together with hydrocephalus and/or ventricular dilation in the context of in utero infection with cytomegalovirus.

Author, Date PMID Pathogen Age/gestation Diagnostics (cUS, MRI, CT) Possible obstructions Total cases Co-occuring cases Summary
Tassin et al. 1991 1846993 Cytomegalovirus 25 gestational weeks Neonatal sonogram, axial CT scan Periventricular calcifications 3 1 One case of patient presenting with microcephaly and progressive ventricular dilation
Drose et al. 1991 1846239 Cytomegalovirus (n = 10), Varicella-Zoster (n = 1) 37 gestational weeks Neonatal sonogram Periventricular calcifications 19 1 Case series (n = 19) of congenital infections detailing hydrocephalus, microcephaly, concurrent microcephalic hydrocephalus, and periventricular calcifications.
Twickler et al. 1993 8240605 Cytomegalovirus 20 gestational weeks, 27 gestational weeks Neonatal sonogram, Dandy-walker variant (n = 1) 2 2 Two cytomegalovirus-infected fetuses presented with microcephaly and ventriculomegaly
Barkovich and Lindan 1994 8010273 Cytomegalovirus 1 day-9 months (postnatal) MRI, CT Periventricular calcifications 11 7 Imaging series of 11 cases of congenital CMV infection displayed lissencephaly, enlargement of lateral ventricles, and periventricular calcifications.
Teissier et al. 2014 24423639 Cytomegalovirus 23–28.5 gestational weeks Neonatal sonogram Cerebral calcifications 16 3 Neuropathologic examination of 16 fetuses infected with cytomegalovirus revealed microcephaly cooccurring with ventricular dilation and hydrocephalus.
Isikay et al. 2013 23761501 Cytomegalovirus 4 postnatal months MRI, CT Periventricular calcifications 1 1 Case study of cCMV presenting with microcephaly, ventriculomegaly, and rare finger anomalieis.
Manara et al. 2011 21597906 Cytomegalovirus 5–54 postnatal months MRI Periventricular cysts 14 8 Case series of 14 children with symptomatic cCMV infection with cases of concurrent microcephaly and ventriculomegaly, and commonly occurring cortical malformations/abnormalities.
Yamada et al. 2023 37451620 Cytomegalovirus 25 gestational weeks MRI N/A 1 1 Case study of intrauterine cCMV presenting with mild ventriculomegaly, microcephay hearing loss, and white matter lesions followed through birth.
Bhattacharya et al. 2020 32437297 Cytomegalovirus ~ 3 postnatal months Neonatal sonogram, MRI Periventricular cysts 9 5 Case series of 9 children with cCMV infection universally presenting with microcephaly, and commoly cooccuring ventriculomegaly and white matter hyperintensity.
Mack et al. 2017 28649563 Cytomegalovirus 26 gestational weeks Neonatal sonogram, MRI Intraventricular cysts 1 1 Case study of cCMV infection presenting with microcephaly, mild ventriculomegaly, white matter hyperintensities, and sensorineural abnormalities
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Table 3.

Human examples of microcephaly occurring together with hydrocephalus and/or ventricular dilation in the context of in utero infection with toxoplasmosis.

Author, Date PMID Pathogen Age/gestation Diagnostics (cUS, MRI, CT) Possible obstructions Total cases Co-occuring cases Summary
Werner et al. 2017 28780216 Toxoplasmosis (1) cytomegalovirus (1), Zika virus (1) 32–37 gestational weeks Neonatal sonogram, MRI Periventricular calcifications 3 2 A comparative case study of three fetuses (cCMV, cT, and cZIKV) in which two presented with microcephaly and ventriculomegaly
Shahwan et al. 1996 8836988 Toxoplasmosis 27 postnatal days Neonatal sonogram Intracranial calcifications 1 1 Case study of a female neonate with cT infection presenting with borderline microcephaly, marked hydrocephalus, cortical abnormalities, and myelitis.
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Genetic mutations disrupting NSC regulation can cause microcephalic ventriculomegaly and congenital hydrocephalus

Human genetic studies of hydrocephalus, microcephaly, and related neurodevelopmental disorders lend further support to the hypothesis that NSC perturbations can cause microcephalic ventriculomegaly and hydrocephalus. There are numerous reports of genetic syndromes that present with microcephaly and reduced cortical volume together with ventriculomegaly (Fry et al. 2018; Donato et al. 2022; Scala et al. 2022), such as patients with mutations in KATNB1, which encodes a regulatory subunit of the microtubule-severing enzyme Katanin that is important for NSC cell division (Hu et al. 2014; Mishra-Gorur et al. 2014). Whole-exome sequencing investigations have identified new genetic causes of congenital hydrocephalus (CH; Shaheen et al. 2017; Furey et al. 2018; Jin et al. 2020; Kundishora et al. 2021; Jacquemin et al. 2023), including those due to TRIM71 mutation, which results in impaired NSC proliferation leading to reduced neurogenesis, decreased cortical cell mass, and ventricular enlargement from altered parenchymal compliance rather than a primary defect in CSF circulation (Duy et al. 2019; Duy, Weise, et al. 2022). Other exome-wide significant CH-associated genes include SMARCC1, PTEN, and PIK3CA, all of which are highly expressed in NSCs and are involved in the regulation of NSC growth (Groszer et al. 2001; Harmacek et al. 2014; Roy et al. 2019; DeSpenza et al. 2021). Collectively, the expression of de novo mutated genes in CH is enriched in human prenatal neuroepithelial and radial glia NSCs (Duy, Weise, et al. 2022). These human genetic studies coupled with functional investigations in model systems suggest a “NSC paradigm” of CH wherein heterogenous genetic mutations converge on altered NSC development, resulting in abnormal brain morphogenesis with secondary impact on brain–CSF interactions (Rodríguez and Guerra 2017; Duy, Rakic, Alper, Robert, et al. 2022).

Despite being thought of as mutually exclusive conditions, microcephaly and CH exhibit some genetic overlap. For example, mutations in WDR81 can cause both “classic” CH (ventriculomegaly and macrocephaly) (Shaheen et al. 2017; Su et al. 2021) and “classic” microcephaly (small cortex and low head circumference) (Cappuccio et al. 2017; Cavallin et al. 2017; Kalmár et al. 2021). In both situations (classic hydrocephalus vs classic microcephaly), a thin/small cerebral cortex is a shared feature in structural brain anomalies caused by WDR81 mutations. Microcephaly and hydrocephalus related to WDR81 mutations likely arise from an NSC defect, since loss of WDR81 functions leads to perturbed NSC mitosis and growth (Cavallin et al. 2017; Carpentieri et al. 2022). Altered function of other NSC regulatory genes can cause either microcephaly or hydrocephalus in mouse and human patients. DIAPH1 mutations cause microcephaly in humans while knocking out Diaph1 in the mouse results in hydrocephalus (Ercan-Sencicek et al. 2015). Similarly, knockout of CTNNB1, a known human microcephaly gene encoding a component of the Wnt signaling pathway crucial for NSC fate (Li et al. 2017), results in hydrocephalus in the mouse associated with premature NSC differentiation (Ma et al. 2022). These observations provide genetic evidence for a biological overlap between microcephaly and hydrocephalus, and that a convergent cellular pathology affecting NSC fate may give rise to both malformations. Indeed, functional integrative genomic analyses combining human genetic data with large-scale transcriptomic atlases of human brain development showed that hydrocephalus and microcephaly risk genes converged in multiple gene coexpression networks of the developing human brain, suggesting shared developmental mechanisms between the two disorders (Duy, Weise, et al. 2022).

Physiological mechanisms of microcephalic hydrocephalus: impact on brain–CSF biomechanics

How do NSC defects lead to the manifestation of microcephalic hydrocephalus in TORCH-infected human patients and patients with some types of genetic CH? Although the link between NSC defects and reduced brain volume in microcephaly is conceptually straightforward to understand, the physiological mechanisms that explain the co-occurrence of hydrocephalus are less obvious and likely multifactorial. Physical obstructions to CSF flow between ventricular compartments or deficits in CSF reabsorption have been the prevailing explanations for hydrocephalus due to TORCH infections (Diebler et al. 1985; Stahl and Kaneda 1997; Hutson et al. 2015; van der Linden et al. 2019). These physical obstructions may arise from inflammatory debris and/or calcifications that deposit along narrow passageways of CSF flow, such as ventricular foramina or cerebral aqueduct, and sites of CSF reabsorption into the systemic circulation, such as at the arachnoid granulations.

However, the emphasis on hydrocephalus as primarily a fluid “plumbing” problem is likely an oversimplification for several reasons. First, anatomical obstructions to CSF flow do not always lead to clinical hydrocephalus in human patients and experimental animal models (Klarica et al. 2009; Radoš et al. 2014; Campos-Ordonez and Gonzalez-Perez 2021; Radoš, Orešković, et al. 2021). Considering the hydrodynamics of CSF accumulation, the “ciliary hypothesis” of dysfunction of motile cilia in ependymal cells of the choroid plexus is often referenced at the mechanistic level. Given embryological and pathological data, it is unclear how ciliary abnormalities may mediate a “plumbing” dysregulation. Specifically, in humans, the general absence of systemic effects of ciliopathies outside of the CNS, coupled with evidence against cilia as the primary motile force of CSF at the ventricles, suggests that other mechanisms may warrant investigation (Duy, Greenberg, et al. 2022). Interestingly, the multimodal function of ciliary genes in regulating NSC fate, and the important role of cilia-mediated signaling early in neurogenesis, further questions the influence of the primary hydrodynamic hypothesis for hydrocephalus (Duy, Rakic, Alper, Robert, et al. 2022). Additionally, arachnoid granulations do not mature until after birth in humans (Radoš, Živko, et al. 2021), even though hydrocephalus can already be detected at birth or even in utero (Mlakar et al. 2016; van der Linden et al. 2019; de Oliveira-Szejnfeld et al. 2016), suggesting that impaired CSF drainage from arachnoid granulations cannot be the initiating cause of hydrocephalus. Despite this, alternative clearance mechanisms of CSF from the brain, including potential egress sites at cranial nerves and lymphatic vessels, may be considered as important and underappreciated sites of impaired CSF dynamics (Mehta, Sherbansky, et al. 2022; Vinje et al. 2020; Proulx 2021). Interestingly, there is continued debate on the magnitude of extracranial, lymphatic, and venous drainage of CSF in humans, and increased imaging sensitivity may be needed to clarify their role in normal CNS fluid balance (Mehta, Suss, et al. 2022). As such, future studies examining these extracranial clearance pathways as potential nodes in a “hydrodynamic” framework for hydrocephalus may be warranted. To date, however, these dynamic contributions to hydrocephalus are likely limited, as the ventricles often remain large despite permanent placement of a ventriculoperitoneal shunt that attempts to drain CSF from the ventricles (de Oliveira-Szejnfeld et al. 2016). These findings suggesting that ventricular enlargement may not arise from just a CSF hydrodynamics problem but may be a secondary consequence of an underlying developmental abnormality.

An alternative view of hydrocephalus is to consider it not only as a fluid plumbing problem per se but rather a more general problem of abnormal biomechanical interactions between the brain parenchyma and CSF spaces (Zee and Shapiro 1989; Pang and Altschuler 1994; Peña et al. 2002; Duy, Rakic, et al. 2022; Duy, Rakic, Alper, Robert, et al. 2022; Duy, Weise, et al. 2022; Duy and Kahle 2023). The pressure inside the cerebral ventricles is always positive, since otherwise the entire brain would collapse. The pressure generated by CSF in the ventricles exerts outward forces that must be counteracted by the surrounding brain tissue. These two forces at the brain–CSF interface, one stemming from intraventricular CSF and the other stemming from the brain parenchyma, must be balanced appropriately in order to maintain ventricular size. While increased intraventricular CSF pressure can expand the ventricles, ventricles may also enlarge if the biomechanical stability of the surrounding brain parenchyma were disturbed, rendering a “floppy” and hypercompliant vessel is unable to resist the intraventricular CSF pressure and thus engenders secondary enlargement of the ventricles when CSF circulation is normal (Peña et al. 2002). Decreased brain stiffness and altered viscoelasticity of the brain have been proposed as the physiological explanations underlying the phenomenon of hydrocephalus with paradoxically normal or low intracranial pressure (Pang and Altschuler 1994). Accordingly, measurements of brain biomechanics have revealed decreased brain stiffness and loss of brain elasticity in human hydrocephalic patients as well as animal models of hydrocephalus (Zee and Shapiro 1989; Wagshul et al. 2021; Duy, Weise, et al. 2022).

Similar to the mechanisms potentially involved in some genetic subtypes of CH, we hypothesize that an impact on brain biomechanics and brain–CSF interactions is the physiological link between NSC perturbations and microcephalic hydrocephalus in the context of TORCH infections (Fig. 2). Ventricular dilation likely begins as soon as a TORCH pathogen infects NSCs, especially given that ventriculomegaly can be detected in utero by prenatal imaging (de Oliveira-Szejnfeld et al. 2016). Since NSCs are the main cellular constituents of the ventricular wall, NSC quiescence and cell death may compromise the wall’s structural integrity, rendering the wall unable to resist the CSF pressure and thus ventricular dilation begins even in the absence of a CSF circulation problem. Consistent with this hypothesis, histological analysis of a Zika-infected fetus revealed the disorganization of the NSC scaffold and abnormal architecture of the ventricular zone (Onorati et al. 2016). As the NSC pool is depleted, cortical neurogenesis is reduced, resulting in a hypoplastic cortex that is structurally unstable and thus less able to resist the deformations generated by intraventricular CSF pressure. Continued production of CSF would further expand the already large, vacuous ventricular compartment and push the thin, low-resistance cortical ribbon to the dural–bone interface, leading to clinical hydrocephalus with progressive enlargement of ventricles. Altogether, NSC defects may be sufficient to account for the manifestation of both microcephaly as well as hydrocephalus in the context of TORCH infections. Our proposed hypothesis motivates future investigations of how brain biomechanical properties may be altered by in utero TORCH infections and emphasize the need to consider how the neural parenchyma may interface with CSF spaces to maintain normal intracranial physiology.

Fig. 2.

Fig. 2

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Proposed model of infection-related microcephalic hydrocephalus resulting from NSC defects and altered brain–CSF biomechanical interactions. Figure modified with permission from Duy et al. (2023), published in Cerebral Cortex.

Conclusion

Microcephalic hydrocephalus is an ostensibly paradoxical phenomenon wherein a microcephaly phenotype and a clinical hydrocephalus phenotype coexist in the same patient, despite the prevailing dogma that they are two mutually exclusive malformations with different pathogenic mechanisms. The phenomenon of infectious microcephalic hydrocephalus suggests that NSC defects and reduced neurogenesis may be an important pathophysiologic link between microcephaly and hydrocephalus, and further research into this understudied clinical presentation may shift the thinking of hydrocephalus away from just a fluid problem to that of a neurodevelopmental pathology in certain cases. Indeed, human genetic studies have revealed de novo mutations in genes that regulate NSC fate as important genetic causes of CH (Furey et al. 2018; Jin et al. 2020; Duy, Weise, et al. 2022). Thus, the NSC tropism of certain viral infections and the link to microcephalic hydrocephalus add support to the “NSC” hypothesis wherein diverse genetic and environmental factors converge on NSC perturbations as the common pathophysiologic mechanism that explains multiple forms of primary and acquired hydrocephalus in children (Duy, Rakic, et al. 2022). Despite numerous early reports of viral-induced “microcephalic hydrocephalus” across a wide range of intra-uterine infections, this paradoxical and rare clinical syndrome has been underappreciated, likely due to its relatively low incidence across pathogens. As such, additional population-based studies are needed to define its prevalence, and further investigations into the phenomenon of microcephalic hydrocephalus and its underlying cellular, molecular, and physiological mechanisms will add knowledge into the fundamental biology of brain development. This may pave the way for potentially harnessing NSCs as therapeutic targets for the treatment of microcephaly, hydrocephalus, and other related human neurodevelopmental disorders.

Contributor Information

Phan Q Duy, Department of Neurosurgery, University of Virginia School of Medicine, Charlottesville, VA 22908, United States; Department of Neuroscience, University of Virginia School of Medicine, Charlottesville, VA 22908, United States.

Neel H Mehta, Department of Neurosurgery, Massachusetts General Hospital, Boston, MA 02114, United States.

Kristopher T Kahle, Department of Neurosurgery, Massachusetts General Hospital, Boston, MA 02114, United States; Broad Institute of MIT and Harvard, Cambridge, MA 02142, United States; Harvard Center for Hydrocephalus and Neurodevelopmental Disorders, Massachusetts General Hospital, Boston, MA 02114, United States.

Author contributions

Phan Duy (Conceptualization, Writing—original draft, Writing—review & editing), Neel H. Mehta (Writing—original draft, Writing—review & editing), and Kristopher T. Kahle (Conceptualization, Supervision, Writing—original draft, Writing—review & editing)

Funding

This work was funded by the National Institute of Neurological Disorders and Stroke RO1NS111029 (to KTK).

Conflict of interest statement: The authors declare no competing interests.

Data availability

All data referenced in this study is publicly available and accessible through the PubMed database.

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Associated Data

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Data Availability Statement

All data referenced in this study is publicly available and accessible through the PubMed database.

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