Paediatric hydrocephalus

Abstract

Hydrocephalus is classically considered as a failure of cerebrospinal fluid (CSF) homeostasis that results in the active expansion of the cerebral ventricles. Infants with hydrocephalus can present with progressive increases in head circumference whereas older children often present with signs and symptoms of elevated intracranial pressure. Congenital hydrocephalus is present at or near birth and some cases have been linked to gene mutations that disrupt brain morphogenesis and alter the biomechanics of the CSF-brain interface. Acquired hydrocephalus can develop at any time after birth, is often caused by central nervous system infection or haemorrhage and has been associated with blockage of CSF pathways and inflammation-dependent dysregulation of CSF secretion and clearance. Treatments for hydrocephalus mainly include surgical CSF shunting or endoscopic third ventriculostomy with or without choroid plexus cauterization. In utero treatment of fetal hydrocephalus is possible via surgical closure of associated neural tube defects. Long-term outcomes for children with hydrocephalus vary widely and depend on intrinsic (genetic) and extrinsic factors. Advances in genomics, brain imaging and other technologies are beginning to refine the definition of hydrocephalus, increase precision of prognostication and identify nonsurgical treatment strategies.

FIGURE 1:. The cerebral ventricular system and cerebrospinal fluid homeostasis.

Cerebrospinal fluid (CSF) dynamics include CSF production, circulation, and reabsorption, which are only partially developed by term gestation. CSF is primarily produced by the choroid plexus (ChP) and distributes trophic factors to the ventricular neurogenic niche essential for brain growth and maintenance.^, The choroid plexus is functional by 22–23 weeks gestation, is highly vascularized, and creates pulsatile movement of the CSF during the cardiac cycle (which is present at birth). CSF hypersecretion owing to inflammation has been implicated in the development of acute hydrocephalus associated with infection or hemorrhage. Disordered intracranial pulsatility has also been implicated in the development of hydrocephalus. CSF flows through the brain via the ventricles. The cerebral aqueduct, connecting the third and fourth ventricles, is the primary site of CSF obstruction in multiple forms of hydrocephalus. However, obstruction of flow anywhere within the ventricular system can cause hydrocephalus. CSF circulation results from the hydrostatic pressure caused by continuing CSF secretion and by arterial pulsations and the respiratory cycle.^, The ventricular walls are comprised of ependymal cells with both motile and primary cilia. Ependymal cells begin to mature by mid-gestation and over the perinatal period through infancy.^– Ependymal motile cilia may aid CSF movement along the ventricular walls although its role in the development of hydrocephalus is still not clear.^,, The ependyma in humans is not fully developed until 6 months after term birth. Moreover, motile cilia require at least 3 weeks to develop or to regenerate after injury.^, The exchange of solutes between interstitial fluid and CSF occurs at the ventricular wall and in the subarachnoid space.^, Lymphatic drainage of CSF occurs along cranial nerve sheaths at the basil foramina as well as at the cribriform plate, the optic nerve, the lumbar and sacral nerves. The arachnoid granulations may also be a drainage site but mature during infancy.^,, Abbreviations: ChP (choroid plexus); CSF (cerebrospinal fluid).

FIGURE 2:. Etiologies of hydrocephalus in low- and middle-income countries and high-income countries.

Distribution (%) of the four primary (Congenital, neural tube defect (NTD)-associated, posthemorrhagic hydrocephalus (PHH), and post-infectious hydrocephalus (PIH)) hydrocephalus etiologies in low- and middle- income countries (LMIC) and high-income countries (HIC) countries. No firm estimates are available for PHH in LMIC. Data from Ref^,.

FIGURE 3:. Clustering of postinfectious hydrocephalus cases in Uganda.

A) Clustering of post-infectious hydrocephalus (PIH) patients in Uganda (red circles, PIH), compared with patients with congenital hydrocephalus (gray circles, non-post-infectious hydrocephalus (NPIH)) who are more uniformly distributed around the country. This clustering is in a region in Uganda with characteristic swamps along the northern banks of Lake Victoria and the northern and southern banks of Lake Kyoga. B) A clustering calculation, using the Ripley K statistic, demonstrates the significant nature of aggregation at scales above 35 km of patients with PIH compared with congenital hydrocephalus, in contrast with random confidence intervals in grey. Paenibacillus species were the primary cause of neonatal sepsis and meningitis and subsequently PIH in this cohort. A) and B) adapted from Morton et al, 2023.

FIGURE 4:. Primary signs and symptoms of paediatric hydrocephalus by age group and etiology.

Congenital etiologies of hydrocephalus are more likely to be diagnosed prenatally or during infancy whereas acquired etiologies of hydrocephalus are more commonly diagnosed after birth and during childhood. AVM (arteriovenous malformation); ICP (intracranial pressure); IVH (intraventricular hemorrhage); MMC (myelomeningocele); NTD (neural tube defect); PIH (posthemorrhagic hydrocephalus); TORCH (toxoplasmosis, other, rubella, cytomegalovirus, herpes simplex); US (ultrasonography). ^a Diagnosis of MMC/NTD, history of head trauma, or symptoms/diagnosis of a genetic syndrome can also trigger imaging. ^bTORCH screen alone is not sufficient to identify all cases of PIH.

FIGURE 5.. Convergence of cellular and molecular pathogenesis in post-hemorrhagic and -infectious hydrocephalus model.

The choroid plexus (ChP) is the blood-cerebrospinal fluid (CSF) barrier. Investigation of post-infectious hydrocephalus (PIH) and post-haemorrhagic hydrocephalus (PHH) models have revealed that lipopolysaccharides (LPS) and blood breakdown products trigger highly similar acute toll-like receptor-4 (TLR4)-dependent immune responses at the ChP-CSF interface. The resulting CSF “cytokine storm”, which is elicited from peripherally-derived and border-associated ChP macrophages causes increased CSF production from ChP epithelial cells via phospho-activation of the tumor necrosis factor (TNF)-receptor-associated kinase SPS1-related proline/alanine-rich kinase (SPAK), which serves as a regulatory scaffold of a multi-ion transporter protein complex. Activation of the mTOR – NF-κB pathway is part of this inflammatory cascade. Pharmacological immunomodulation (e.g. with Rapamycin (Rapa), an mTOR inhibitor) prevents PIH and PHH in animal models by antagonizing SPAK-dependent CSF hypersecretion. The expression of Aquaporin 1 (AQP1), a water transport protein, may also be involved in the development of hydrocephalus but its exact role has not been established. These results reveal the ChP as a dynamic, cellularly heterogeneous tissue with highly-regulated immune-secretory capacity.

FIGURE 6:

Fetal ultrasonography images. A| normal sized ventricles; B| moderate-severe ventriculomegaly (yellow markers: indicate width of lateral ventricle). Images courtesy of Dr. Yada Kunpalin, University of Toronto.