Aqueductal Stenosis

The aqueduct of Sylvius allows passage of cerebral spinal fluid between the third and fourth ventricles. Aqueductal stenosis (AS) results from a narrowing or occlusion of the aqueduct of Sylvius. This results in in dilation of the third and lateral ventricles (ventriculomegaly) but a normal fourth ventricle and posterior fossa. Associated supratentorial intracranial hypertension can compress the cerebral cortex decreasing perfusion to the brain which can lead to tissue ischemia and noncommunicating (obstructive) hydrocephalus and increased head size (macrocephaly) (1).

Incidence is 1:5000 (2)

Male: Female ratio 2:1

Aqueductal stenosis comprises approximately 20% of all congenital hydrocephalus cases (3).

Most cases of aqueductal stenosis have no identifiable etiology or risk factors.

The etiology of aqueductal stenosis is often not known and is likely multifactorial. It is estimated that 25% of cases in males result from an X-linked disorder (4). These X-linked disorders are often part of malformation syndromes. It is rare to have hereditary etiologies of aqueductal stenosis outside of the sex-linked genetic changes (5). Infectious etiologies such as parvovirus, cytomegalovirus, mumps, and toxoplasmosis can cause gliosis and associated aqueductal stenosis (6, 7). One study in a French population found that toxoplasmosis was identified as the etiology of AS in 15% of cases (8). Other viral infections, such as influenza, are hypothesized to be able to cause similar gliosis and resulting aqueductal stenosis (7). Other inflammatory etiologies have been identified including hemorrhage and tumors causing obstruction and resulting stenosis (7).

Screening and diagnosis of fetal aqueductal stenosis often occurs during a routine fetal anatomic survey. Aqueductal stenosis should be suspected when there is ventriculomegaly of the lateral and third ventricles or hydrocephalus (ventriculomegaly and a large fetal head size) with a normal posterior fossa. A nomogram of third ventricle size has been published (9).  Lateral ventricle measurements more than 10mm are considered abnormal and more than 15mm is considered severe ventricular dilation (9, 10).

The posterior fossa (cerebellum, vermis, fourth ventricle and cisterna magna) should be normal, although in cases of severe hydrocephalus, the cerebellum and posterior fossa contents may be inferiorly displaced and the cisterna magna obliterated, giving a Chiari 1 appearance (11).

The constellation of findings including bilateral lateral ventriculomegaly and a dilated third ventricle in the presence of a normal 4^th ventricle and posterior fossa is sufficient to diagnose all cases of fetal aqueductal stenosis (1, 9).

The median age of diagnosis of AS by ultrasonography is 23 weeks and 3 days (1). Unfortunately, there are late-onset cases of AS which appear in late pregnancy after a normal second trimester scan.

When there is severe ventriculomegaly, the choroid plexus can be seen “dangling” or floating” in the ventricle (more than 3 mm of distance between the wall of the medial ventricle and the border of the choroid) (12). Occasionally, the choroid can dangle into the opposite (dependent) ventricle through the foramen of Monroe, which is called a “double dangle”. The corpus callosum is often thinned and may not be visible and the cavum septi pellucidi (CSP) may be absent as the walls of the CSP may be fenestrated due to severe ventriculomegaly.

Transvaginal neurosonogram should be considered to fully investigate the corpus callosum and other midline brain structures and to exclude additional brain abnormalities which may be suspected only with transvaginal scanning (1).

Additional findings associated with X-linked hydrocephalus should be sought. This diagnosis requires the fetus to be male. Adducted thumbs are seen in 50% of cases of X-linked hydrocephalus so careful attention to the fetal hands is warranted.

Once suspected, the fetus should be carefully evaluated for other structural abnormalities, signs of infection with parvovirus, syphilis, rubella, cytomegalovirus, and toxoplasmosis (See relevant VISUOG Chapters) hemorrhage and tumors in the brain.

Over time, the fetal head size may become large (macrocephaly) which is indirect evidence of increased intracranial pressure. The combination of large fetal head size and ventriculomegaly is called hydrocephalus. The lateral and third ventricles may also increase in size during pregnancy (1).

Colour Doppler may be used to evaluate middle cerebral artery (MCA) flow which can be altered when there is increased intracranial pressure (6, 13).

MRI may be used to diagnose aqueductal stenosis and may be helpful in cases where the cortical mantle is quite thin. MRI findings of a narrow/funnel shaped aqueduct or hemorrhage within the aqueduct are rarely seen but have 100% positive predictive value (14). This funnel-shaped region of the aqueduct has been identified prenatally with ultrasound as well (15). Enlargement of the third ventricular recess and presence of a lateral ventricular diverticulum are both associated with high specificity for aqueductal stenosis (14).

There are multiple genetic syndromes, all of which are X-linked, which can be found in fetuses with aqueductal stenosis. All of them are associated with adducted thumbs, however adducted thumbs are identified in only 50% of cases where there is X-linked inheritance (16, 17). Associated syndromes are the result of the L1CAM gene mutation, with varying phenotypic expressions (18).

These syndromes include:

• CRASH syndrome: hypoplasia of the corpus callosum, mental retardation, adducted thumbs, spastic paraplegia and hydrocephalus (18).
• MASA syndrome: mental retardation, aphasia, shuffling gate, adducted thumbs, and aqueductal stenosis (19).
• HSAS syndrome: hereditary stenosis of the aqueduct of Sylvius (19)

HSAS syndrome is the most severe phenotypic expression (19). Spastic paraplegia type 1 is also associated with L1CAM gene mutation, but may not be associated with intracranial anomalies (19).

Not all of the features of these diseases can be identified prenatally.

(See VISUOG chapters for diagnostic criteria)

1. Hydranencephaly: absence of cerebral hemispheres
2. Holoprosencephaly: failure of cerebral hemisphere division, resulting in single lobed brain structure
3. Congenital hydrocephalus, which may be difficult to distinguish or even develop as part of aqueductal stenosis.

Amniocentesis should be considered to exclude chromosome abnormalities and fetal infection (19). When a male fetus with or without adducted thumbs, is identified, targeted L1CAM sequencing or exome and genome sequencing can be used to investigate genetic etiologies.

Since there can be severe neurological deficits in children with AS, some parents may not be committed to the pregnancy. Investigating outcomes of ventriculomegaly and aqueductal stenosis, can be challenging as many patients proceed with termination (1). Neonates with severe prenatal ventriculomegaly demonstrate worse outcomes (20).

When AS is suspected, growth studies should be performed to assess the fetal head size and brain structures throughout pregnancy. Late preterm or early term delivery is suggested with macrocephaly (1). Cesarean delivery is not mandatory but may need to be performed if the head size is unusually large or for usual obstetric indications including malpresentation (1, 21).

Fetuses affected by AS should have amniocentesis to evaluate the fetus for chromosome or microarray abnormalities and infection studies including toxoplasmosis, cytomegalovirus, syphilis, rubella, and parvovirus. If indicated, additional testing for L1CAM can be done with targeted sequencing, exome or genome testing as available.

Genetic counseling is suggested as there are several X-linked genetic syndromes which may be diagnosed only after birth. Prenatal consultation with Neurosurgery may be considered.

Intrauterine shunting should not be performed outside of a clinical trial.

In the neonatal period, the fetal head structures should be evaluated using head ultrasound or MRI as per local protocols. CSF diversion procedures are typically performed shortly following birth on a non-urgent basis. These procedures include ventricular shunting and endoscopic third ventriculostomy (8). There are no data which demonstrate that the timing of intervention after birth is statistically related to different rates of developmental delay or need for individualized educational planning (21). Therefore, children with aqueductal stenosis should be managed as would any other child with ventriculomegaly.

Overall prognosis is guarded. Studies in a mixed population of fetuses with AS and severe ventriculomegaly have demonstrated up to 40% mortality rate with 27% dying in the first three months of life (13).

In neonates found to have isolated aqueductal stenosis, one study evaluated 41 patients at 5.9 year average follow up. 68% had evidence of developmental delay, and 32% had normal neurological outcome (21). Associated problems included ophthalmologic disfunction in 61% and epilepsy in 49% (21). Nearly 80% of children required individualized learning plans (21).

If genetic (X-linked) etiology is suspected, the recurrence can be as high as 50% for future male neonates (22). If not genetic, the recurrence is as high as 4.5% for sporadic cases of aqueductal stenosis (23). Prenatal diagnosis and preimplantation genetic diagnosis for L1CAM mutations is available.

Future pregnancies should have ultrasound evaluation of the fetal head in the third trimester as AS can be identified only late in the third trimester or in neonatal life.

1. Emery, Stephen P., et al. “Fetal Aqueductal Stenosis: Prenatal Diagnosis and Intervention.” Prenatal Diagnosis, vol. 40, no. 1, 2019, pp. 58–65., https://doi.org/10.1002/pd.5527.
2. Zarei, Fariba, et al. “A Case of Aqueductal Obstruction by Web with No Sign except a Headache.” Radiology Case Reports, vol. 17, no. 10, 2022, pp. 3767–3769., https://doi.org/10.1016/j.radcr.2022.07.036.
3. McKechnie, Liz, et al. “Neonatal Outcome of Congenital Ventriculomegaly.” Seminars in Fetal and Neonatal Medicine, vol. 17, no. 5, 2012, pp. 301–307., https://doi.org/10.1016/j.siny.2012.06.001.
4. Verhagen, Wim I.M, et al. “Familial Congenital Hydrocephalus and Aqueduct Stenosis with Probably Autosomal Dominant Inheritance and Variable Expression.” Journal of the Neurological Sciences, vol. 158, no. 1, 1998, pp. 101–105., https://doi.org/10.1016/s0022-510x(98)00097-5.
5. Jellinger G. Anatomopathology of non-tumoral aqueductal stenosis. Journal of Neurosurgical Sciences. 1986 Jan-Jun;30(1-2):1-16. PMID: 3772492.
6. Zajicek, Michal, et al. “Prenatal Diagnosis of Obstructive Hydrocephalus Associated with Parvovirus B19 Infection.” Obstetrics & Gynecology, vol. 116, no. 2, 2010, pp. 521–522., https://doi.org/10.1097/aog.0b013e3181e7597e.
7. Cinalli, Giuseppe, et al. “Hydrocephalus in Aqueductal Stenosis.” Child's Nervous System, vol. 27, no. 10, 2011, pp. 1621–1642., https://doi.org/10.1007/s00381-011-1546-2.
8. Hirsch, J. F. et al. “Stenosis of the aqueduct of Sylvius. Etiology and treatment.” Journal of neurosurgical sciences 30 1-2 (1986): 29-39 .
9. Emery, Stephen P., et al. “Accuracy of Prenatal Diagnosis of Isolated Aqueductal Stenosis.” Prenatal Diagnosis, vol. 35, no. 4, 2015, pp. 319–324., https://doi.org/10.1002/pd.4520.
10. Almog, Benny, et al. “Fetal Lateral Ventricular Width: What Should Be Its Upper Limit?” Journal of Ultrasound in Medicine, vol. 22, no. 1, 2003, pp. 39–43., https://doi.org/10.7863/jum.2003.22.1.39.
11. Humphreys, Peter, et al. “Focal Cerebral Mantle Disruption in Fetal Hydrocephalus.” Pediatric Neurology, vol. 36, no. 4, 2007, pp. 236–243., https://doi.org/10.1016/j.pediatrneurol.2006.12.013.
12. Zhou, Yong-Hai, and Ming-Hua Zheng. “Abnormality in a Fetus on Ultrasound.” BMJ, 2017, https://doi.org/10.1136/bmj.j688.
13. Emery, Stephen P., et al. “Fetal Therapy for Isolated Aqueductal Stenosis.” Fetal Diagnosis and Therapy, vol. 38, no. 2, 2015, pp. 81–85., https://doi.org/10.1159/000382015.
14. Heaphy-Henault, K.J., et al. “Congenital Aqueductal Stenosis: Findings at Fetal MRI That Accurately Predict a Postnatal Diagnosis.” American Journal of Neuroradiology, vol. 39, no. 5, 2018, pp. 942–948., https://doi.org/10.3174/ajnr.a5590.
15. Viñals, Fernando, et al. “Two-Dimensional Ultrasound Evaluation of the Fetal Cerebral Aqueduct: Improving the Antenatal Diagnosis and Counseling of Aqueductal Stenosis.” Fetal Diagnosis and Therapy, vol. 42, no. 4, 2017, pp. 278–284., https://doi.org/10.1159/000458439.
16. Graf, William D. “X-Linked Hydrocephalus (L1 Syndrome).” Developmental Malformations, Edited by Harvey B Sarnat, 5 Nov. 2021, https://www.medlink.com/articles/x-linked-hydrocephalus-l1-syndrome.
17. Haverkamp, F., et al. “Congenital Hydrocephalus Internus and Aqueduct Stenosis: Aetiology and Implications for Genetic Counselling.” European Journal of Pediatrics, vol. 158, no. 6, 1999, pp. 474–478., https://doi.org/10.1007/s004310051123.
18. Yamasaki, M., et al. “Crash Syndrome: Mutations in L1CAM Correlate with Severity of the Disease.” Neuropediatrics, vol. 28, no. 03, 1997, pp. 175–178., https://doi.org/10.1055/s-2007-973696.
19. Kniffin, Cassandra L. “MASA Syndrome.” OMIM, 3 Oct. 2002, https://omim.org/entry/303350. Accessed 8 Mar. 2023.
20. Gaglioti, P., et al. “Fetal Cerebral Ventriculomegaly: Outcome in 176 Cases.” Ultrasound in Obstetrics and Gynecology, vol. 25, no. 4, 2005, pp. 372–377., https://doi.org/10.1002/uog.1857.
21. Tonetti, Daniel A., et al. “Clinical Outcomes of Isolated Congenital Aqueductal Stenosis.” World Neurosurgery, vol. 114, 2018, https://doi.org/10.1016/j.wneu.2018.03.123.
22. Haverkamp, F., et al. “Congenital Hydrocephalus Internus and Aqueduct Stenosis: Aetiology and Implications for Genetic Counselling.” European Journal of Pediatrics, vol. 158, no. 6, 1999, pp. 474–478., https://doi.org/10.1007/s004310051123.
23. Howard, F M, et al. “A Family Study of Hydrocephalus Resulting from Aqueduct Stenosis.” Journal of Medical Genetics, vol. 18, no. 4, 1981, pp. 252–255., https://doi.org/10.1136/jmg.18.4.252.

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