Congenital hydrocephalus pathogenesis
The pathogenesis of congenital hydrocephalus is complex and involves several mechanisms:
1. Genetic Factors
Mutations: Specific genetic mutations can cause congenital hydrocephalus. For example, mutations in the L1CAM gene are associated with X-linked hydrocephalus, a form of congenital hydrocephalus. This gene is important for neuronal adhesion and migration, and its mutation can disrupt normal brain development.
Ciliopathies: Abnormalities in cilia (microscopic hair-like structures) can impair the flow of CSF. Cilia play a role in the movement of CSF through the ventricles, and mutations affecting ciliary function can lead to hydrocephalus. Conditions like primary ciliary dyskinesia or Joubert syndrome involve such mutations.
2. Obstruction of CSF Flow
Aqueductal Stenosis: One of the most common causes of congenital hydrocephalus is the narrowing (stenosis) of the cerebral aqueduct (aqueduct of Sylvius), which is the passage that connects the third and fourth ventricles of the brain. When this passage is blocked or narrowed, CSF cannot flow freely, leading to its accumulation. Chiari Malformation: This condition occurs when the cerebellum is displaced downward into the spinal canal, which can block the flow of CSF and lead to hydrocephalus. Dandy-Walker Malformation: This involves an abnormal development of the cerebellum and the fourth ventricle, often leading to obstruction of CSF flow and hydrocephalus.
3. Impaired CSF Absorption
Arachnoid Granulations: CSF is normally absorbed into the bloodstream through structures called arachnoid granulations. If these structures are malformed or non-functional, CSF absorption can be impaired, leading to hydrocephalus. Venous Drainage Issues: Conditions that affect the veins draining the brain can also impair CSF absorption. For instance, congenital malformations of the venous system can lead to increased venous pressure, reducing the absorption of CSF and causing hydrocephalus.
4. CSF Overproduction
Choroid Plexus Papilloma: Though rare, tumors like choroid plexus papillomas can lead to the overproduction of CSF, contributing to hydrocephalus. The choroid plexus is the structure within the ventricles responsible for producing CSF, and any abnormal increase in its activity can result in excessive CSF accumulation.
5. Intrauterine Infections
Congenital Infections: Infections like cytomegalovirus (CMV), rubella, or toxoplasmosis during pregnancy can lead to inflammation and scarring in the brain, which may obstruct CSF pathways or damage brain tissue, resulting in hydrocephalus.
6. Developmental Abnormalities
Neural Tube Defects: Conditions such as spina bifida (especially myelomeningocele) are often associated with hydrocephalus. The malformation of the spinal cord can affect the normal flow of CSF, leading to its accumulation in the brain. Craniosynostosis: Premature closure of the skull sutures can restrict the space available for the brain and CSF, potentially causing hydrocephalus.
Genetic Influences and Recent Advances
Genetic influences are a major contributor to congenital hydrocephalus (CH) pathogenesis, with epidemiological evidence suggesting their involvement in up to 40% of all cases observed globally. Knowledge about an individual's genetic susceptibility can significantly improve prognostic precision while aiding clinical decision-making processes. However, the precise genetic etiology has only been pinpointed in fewer than 5% of human cases. More occurrences of CH are required for comprehensive gene sequencing aimed at uncovering additional potential genetic loci. A deeper comprehension of its underlying genetics may offer invaluable insights into the molecular and cellular basis of this brain disorder.
A review provides a summary of pertinent genes identified through gene sequencing technologies in humans, in addition to the four genes currently associated with CH (two X-linked genes L1CAM and AP1S2, two autosomal recessive genes MPDZ and CCDC88C). Others predominantly participate in aqueduct abnormalities, ciliary movement, and nervous system development. The prospective CH-related genes revealed through animal model gene-editing techniques are further outlined, focusing mainly on four pathways: cilia synthesis and movement, ion channels and transportation, Reissner's fiber (RF) synthesis, cell apoptosis, and neurogenesis. Notably, the proper functioning of motile cilia provides significant impulsion for CSF circulation within the brain ventricles, while mutations in cilia-related genes constitute a primary cause underlying this condition.
So far, only a limited number of CH-associated genes have been identified in humans. The integration of genotype and phenotype for disease diagnosis represents a new trend in the medical field. Animal models provide insights into the pathogenesis of CH and contribute to our understanding of its association with related complications, such as renal cysts, scoliosis, and cardiomyopathy, as these genes may also play a role in the development of these diseases. Genes discovered in animals present potential targets for new treatments but require further validation through future human studies 1)
Risk Factors
Several key risk factors have been identified as strongly associated with the development of congenital hydrocephalus in infants. The prevalence of familial patterns of inheritance for congenital hydrocephalus suggests a broader role for genetic factors in the pathogenesis of congenital hydrocephalus.
Although several studies have previously assessed child-related risk factors associated with CH development, there is a gap of knowledge on maternal environmental risk factors related to CH. Authors have systematically assessed extrinsic factors in the maternal environment that potentially confer an increased risk of CH development.
Methods: The Cochrane Library, MEDLINE, and EMBASE were systematically searched for works published between 1966 and December 2015 to identify all relevant articles published in English. Only studies that investigated environmental risk factors concerning the mother—either during gestation or pregestational—were included.
Results: A total of 13 studies (5 cohorts, 3 case series, 3 case-control studies, 1 meta-analysis, and 1 case report) met the inclusion criteria. Maternal medication or alcohol use during gestation, lifestyle modifiable maternal pathologies such as obesity, diabetes, or hypertension, lack of prenatal care, and a low socioeconomic status were identified as significant maternal environmental risk factors for CH development. Maternal infections and trauma to the mother during pregnancy have also been highlighted as potential mother-related risk factors for CH.
Summary The pathogenesis of congenital hydrocephalus involves a combination of genetic, developmental, and environmental factors. The condition results from disruptions in the balance between CSF production, flow, and absorption, leading to an accumulation of fluid in the brain's ventricles. Understanding the specific cause in each case is critical for targeted treatment, which may include surgical interventions like ventriculoperitoneal shunting to relieve pressure on the brain.
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