congenital_hydrocephalus

Congenital hydrocephalus

Congenital hydrocephalus is a prevalent condition, that leads to fetal cerebral ventricle dilation and increased intracranial pressure. It is associated with significant neurological impairments, partly due to the disruption of neurogenesis and gliogenesis.

Types

Panventriculomegaly with a wide foramen of Magendie and a large cisterna magna may belong to a subtype of congenital hydrocephalus with familial accumulation, younger age at onset, and symptoms of normal pressure hydrocephalus. In addition, a family with PaVM has a gene mutation associated with dysfunction of motile cilia 1).

Etiology

Congenital hydrocephalus is present at birth and can be caused by a variety of factors, often linked to abnormal brain development during gestation. Some of the common causes include:

#### a. Aqueductal Stenosis

  1. Cause: This is the most common cause of congenital hydrocephalus. It occurs when the aqueduct of Sylvius, a narrow passage between the third and fourth ventricles in the brain, becomes blocked. This prevents the normal flow of CSF, leading to its accumulation in the ventricles.
  2. Associated conditions: Aqueductal stenosis may be associated with genetic syndromes, such as X-linked hydrocephalus, or it may occur sporadically without a known cause.

#### b. Chiari Malformation

  1. Cause: Chiari malformation is a condition in which part of the brain (the cerebellum) extends into the spinal canal. This malformation can obstruct the flow of CSF and lead to hydrocephalus.
  2. Types: Type I Chiari malformation is often asymptomatic, but types II and III are associated with more severe neurological complications, including hydrocephalus.

#### c. Genetic and Environmental Factors

  1. Cause: Some congenital hydrocephalus cases are related to genetic mutations or abnormalities in fetal development. These may be associated with conditions like Craniofacial syndromes (e.g., Dandy-Walker malformation or Agenesis of the Corpus Callosum) or Neural Tube Defects (e.g., Spina Bifida).
  2. Infections: Infections during pregnancy, such as rubella or toxoplasmosis, can disrupt brain development and lead to hydrocephalus in the infant.
  3. Intrauterine Bleeding: In rare cases, hemorrhage in the fetal brain can obstruct CSF pathways and result in hydrocephalus.

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Duy et al. found convergence of congenital hydrocephalus risk genes in embryonic neuroepithelial stem cells. Of all CH risk genes, TRIM71/lin-41 harbors the most de novo mutations and is most specifically expressed in neuroepithelial cells. Mice harboring neuroepithelial cell-specific Trim71 deletion or CH-specific Trim71 mutation exhibit prenatal hydrocephalus. CH mutations disrupt TRIM71 binding to its RNA targets, causing premature neuroepithelial cell differentiation and reduced neurogenesis. Cortical hypoplasia leads to a hypercompliant cortex and secondary ventricular enlargement without primary defects in CSF circulation. These data highlight the importance of precisely regulated neuroepithelial cell fate for normal brain-CSF biomechanics and support a clinically relevant neuroprogenitor-based paradigm of CH 2).

Secondary to intra-uterine germinal matrix hemorrhage or intraventricular hemorrhage.

Few systematic assessments of developmental forms of hydrocephalus exist. Tully et al reviewed magnetic resonance images (MRIs) and clinical records of patients with infancy-onset hydrocephalus. Among 411 infants, 236 had hydrocephalus with no recognizable extrinsic cause. These children were assigned to 1 of 5 subtypes and compared on the basis of clinical characteristics and developmental and surgical outcomes. At an average age of 5.3 years, 72% of children were walking independently and 87% could eat by mouth; in addition, 18% had epilepsy. Distinct patterns of associated malformations and syndromes were observed within each subtype. On average, children with aqueductal obstruction, cysts, and encephaloceles had worse clinical outcomes than those with other forms of developmental hydrocephalus. Overall, 53% of surgically treated patients experienced at least 1 shunt failure, but hydrocephalus associated with posterior fossa crowding required fewer shunt revisions. We conclude that each subtype of developmental hydrocephalus is associated with distinct clinical characteristics, syndromology, and outcomes, suggesting differences in underlying mechanisms 3).

Pathogenesis

Congenital hydrocephalus pathogenesis.

Case series

Integrating human brain transcriptomics with whole-exome sequencing of 483 patients with congenital hydrocephalus (CH), Duy et al. found convergence of CH risk genes in embryonic neuroepithelial stem cells. Of all CH risk genes, TRIM71/lin-41 harbors the most de novo mutations and is most specifically expressed in neuroepithelial cells. Mice harboring neuroepithelial cell-specific Trim71 deletion or CH-specific Trim71 mutation exhibit prenatal hydrocephalus. CH mutations disrupt TRIM71 binding to its RNA targets, causing premature neuroepithelial cell differentiation and reduced neurogenesis. Cortical hypoplasia leads to a hypercompliant cortex and secondary ventricular enlargement without primary defects in CSF circulation. These data highlight the importance of precisely regulated neuroepithelial cell fate for normal brain-CSF biomechanics and support a clinically relevant neuroprogenitor-based paradigm of CH 4).

Experimental animal studies

Karakaya et al. aims to investigate alterations in the proliferation and differentiation of neural progenitor cells (NPCs) in a fetal lamb model of obstructive HCP induced by intracisternal BioGlue injection, to identify the potential optimal intervention time for prenatal surgery.

This study involved 22 fetal lambs, divided into control (n = 10) and HCP (n = 12) groups with hydrocephalus induced at approximately 85-90 gestational days. Histological and molecular techniques, including hematoxylin and eosin staining, triple immunofluorescence, Western blot analysis, and RT-qPCR, were utilized to assess changes in NPCs, astrocytes, and oligodendrocytes across three different gestational stages (E105, E125, and E140). The analysis of data was done by using multiple (unpaired) two-sample t-test and was represented as mean and standard deviation.

HCP led to significant disruptions in the ventricular zone (VZ), with the translocation of NPCs into the intraventricular CSF and formation of periventricular heterotopias. This study revealed an initial surge in the expression of NPC markers (Pax6 and Sox2), which decreased as HCP progressed. Astroglia reaction intensified, as indicated by increased expression of GFAP, vimentin, and aquaporin 4, particularly at later stages of pregnancy (p < 0.001, p < 0.001 and p < 0.001, control and HCP E140, respectively). Myelin formation was also adversely affected, with reduced expression of oligodendrocyte markers (Olig2 and Sox10, p = 0.01 and p = 0.009, control and HCP E140, respectively) and myelin proteins (MOBP, MOG and MBP, p = 0.02, p = 0.049 and p = 0.02 control and HCP E140, respectively).

This study contributed to clarify the profound impact of congenital HCP on neurogenesis and gliogenesis in an experimental fetal lamb model. The VZ disruption and altered expression of key neurogenic and glial markers suggested a significant pathological process underlying neurodevelopmental abnormalities. The findings suggested a potential window for prenatal surgical intervention between E105 and E125 in the sheep model, offering new avenues for prenatal therapeutic approaches and improving surgical outcomes in affected fetuses and neonates 5)

1)
Kageyama H, Miyajima M, Ogino I, Nakajima M, Shimoji K, Fukai R, Miyake N, Nishiyama K, Matsumoto N, Arai H. Panventriculomegaly with a wide foramen of Magendie and large cisterna magna. J Neurosurg. 2015 Dec 4:1-9. [Epub ahead of print] PubMed PMID: 26636390.
2) , 4)
Duy PQ, Weise SC, Marini C, Li XJ, Liang D, Dahl PJ, Ma S, Spajic A, Dong W, Juusola J, Kiziltug E, Kundishora AJ, Koundal S, Pedram MZ, Torres-Fernández LA, Händler K, De Domenico E, Becker M, Ulas T, Juranek SA, Cuevas E, Hao LT, Jux B, Sousa AMM, Liu F, Kim SK, Li M, Yang Y, Takeo Y, Duque A, Nelson-Williams C, Ha Y, Selvaganesan K, Robert SM, Singh AK, Allington G, Furey CG, Timberlake AT, Reeves BC, Smith H, Dunbar A, DeSpenza T Jr, Goto J, Marlier A, Moreno-De-Luca A, Yu X, Butler WE, Carter BS, Lake EMR, Constable RT, Rakic P, Lin H, Deniz E, Benveniste H, Malvankar NS, Estrada-Veras JI, Walsh CA, Alper SL, Schultze JL, Paeschke K, Doetzlhofer A, Wulczyn FG, Jin SC, Lifton RP, Sestan N, Kolanus W, Kahle KT. Impaired neurogenesis alters brain biomechanics in a neuroprogenitor-based genetic subtype of congenital hydrocephalus. Nat Neurosci. 2022 Apr 4. doi: 10.1038/s41593-022-01043-3. Epub ahead of print. PMID: 35379995.
3)
Tully HM, Ishak GE, Rue TC, Dempsey JC, Browd SR, Millen KJ, Doherty D, Dobyns WB. Two Hundred Thirty-Six Children With Developmental Hydrocephalus: Causes and Clinical Consequences. J Child Neurol. 2016 Mar;31(3):309-20. doi: 10.1177/0883073815592222. Epub 2015 Jul 16. PubMed PMID: 26184484.
5)
Karakaya D, Lampe K, Encinas JL, Duru S, Peiro L, Oge HK, Sanchez-Margallo FM, Oria M, Peiro JL. Neurogenesis and glial impairments in congenital hydrocephalus: insights from a BioGlue-induced fetal lamb model. Fluids Barriers CNS. 2025 Feb 24;22(1):20. doi: 10.1186/s12987-025-00630-3. PMID: 39994758.
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