On closure of the neuropores, the choroid plexus is not yet functional. However, CSF pressure in the neural tube and the volume of the cephalic cavities already increase, suggesting initial secretion of CSF outside choroid plexus. Some subarachnoid spaces appear on the 32nd day at the ventral rhombencephalon, then extend caudally and dorsally (Sakkaa et al. 2011). However, the fourth ventricle is not yet open and CSF circulation is only effective on the 41st day (postmenstrual week 16), weeks after onset of CSF production (Robinson and Goldstein 2007).
Even later opening of the foramina of Luschka in the lateral recesses of the fourth ventricle hence leads to prolonged dilatation of the fourth ventricle, referred to as Blake's pouch (Paladini et al. 2012). Formation of the subarachnoid spaces is therefore not exclusively due to CSF pressure, but capillaries elsewhere play an initial role in secretion of CSF. A microscopic flow of CSF has been described in brain interstitial spaces (Iliff et al. 2012), the significance of which is not yet known in the fetus or newborn. So fluid circulation in the cranium depends on maturation of arachnoid villi, development of glymphatics and of nasal lymphatic fluid drainage (Adeeb et al. 2013, Nakada and Twee 2018). Arachnoid villi mature near term, and change into arachnoid granulations is mainly a postnatal event (Gomez et al. 1982).
The human subcommissural organ is differentiated ependyma caudal to the pineal gland at the entrance to the aqueduct (Galarza 2002). It becomes an active "gland" at midgestation, to regress during the first year of postnatal life (Rodriguez et al. 2001). Changes in the subcommissural organ were described in all species developing congenital hydrocephalus and in human fetuses, but the precise role of their secreted glycoproteins is unknown in the human fetal context.
Plexus Histology
The choroid plexus sits between two barriers (blood and cerebrospinal fluid) with as primary goal the production and regulation of cerebrospinal fluid (Catala 1998). Plexus expansion may initially also just increase ventricular surface and thus spread the proliferation of neocortical precursors (Desmond and Jacobsen 1977, Altman and Bayer 2015). Differentiating neurons leave the neuroepithelium in larger numbers early during the 9th week after conception, associated in time with a rapid expansion of choroid plexus in equally expanding ventricles. The nuclei of precursors shuttle to the ventricular margin to undergo mitosis. The size of any neuronal population depends on the size of that wall space occupied by its precursors. An immense number of neurons in the neocortex can be achieved due to the volume of the ventricles, before they begin to shrink and in some regions disappear altogether. The expansion of that large space requires production of CSF with adequate pressure, and that appears to be initially dependent, before the vascular system develops (Padget, 1957), on the enlarged meninges and the hypertrophied choroid plexus.
The cranial meninges originate from the prechordal plate, the parachordal mesoderm and the neural crest (O'Rahilly and Müller 1986). They induce proliferation of neuroblasts and axonal growth. The loose mesenchyme around the brain at 5 weeks of development (stage 15) forms a primary meninx. At 6 weeks (stage 17), the dural limiting layer is found basally and the skeletogenous layer of the head becomes visible. At 7 weeks (stage 19), a cranial pachy- and leptomeninx are distinguishable.
In orange, separation of pial and dural vessels in the meninx primitiva (from Altman and Bayer 2015)
Source and Staging of Development of Choroid Plexus
Choroid plexus first appears in the roof of the fourth ventricle at stage 18 (day 41), in the lateral ventricles at stage 19, and in the third ventricle at stage 21 (Ariëns Kappers 1958; Bartelmez and Dekaban 1962). The primordia appear as simple or club-shaped folds protruding into the ventricles, emanating from pial mesenchymal vascular extensions covered by single ependymal epithelium. The stroma of the plexus originates from extensions of the arachnoid into the interior of the brain forming the vela interposita. The contemporary enlargement of meningeal constituents is most pronounced in the middle part of the neocortex, where this leads to the mid-cephalic constriction of the cerebrum (the frontal-temporal dimple and the invaginating insula). As vascularization of the expanding neocortex starts, that dimple becomes the widening frontal-temporal cleavage, where arterial branches of the MCA expand over the convexity. As white matter begins to expand in 4-months-old fetuses, there is concurrent shrinkage of the lateral ventricles.
The time at which choroid plexus starts to secrete CSF has not been clearly determined, but carbonic anhydrase (for bicarbonate excretion) is present two weeks after appearance of plexus. It may be that an early nutritional role for plexus is present, but this function is lost during development.
In the eight week, spreading from the choroidal fissure, the lobular character of the plexus gradually changes into an arrangement of wavy folds; capillaries form single loops under the cuboidal epithelium (Kraus and Jirasek 2002). The mechanisms involved in formation of a blood-CSF barrier at choroid plexus combine diffusion restraint (tight junctions between the plexus epithelial cells) with specification of exchange. One unique barrier mechanism transfers specific proteins from blood to CSF, via tubulocisternal endoplasmic reticulum in plexus epithelial cells.
This results in a high concentration of proteins in early CSF. Proteins may function as colloid osmotic agents for ventricle expansion but also as specific carriers and growth factors. Some proteins are not imported but are locally produced, like transthyretin and IGF II.
During stage 21, the choroid plexuses become vascularized. The early choroid plexus is lobulated with vessels running in the mesenchymal stroma to form capillary nets under the single-layered ependyma. The embryonic plexus is converted into the fetal type during the ninth week of development as this net is replaced by elongated loops of wavy capillaries that lie under regular longitudinal epithelial folds (Kraus and Jirásek 2002).
Bone morphogenetic proteins and tropomyosin are involved in specification of plexus development. Four histological stages of lateral ventricle plexus development have been defined (Dziegielewska et al. 2001): stage 1: 7-9 weeks after conception, no glycogen, ill defined blood islets, pseudostratified epithelium; stage 2: 9-17 weeks after conception, abundant glycogen, primari villi, low columnar epithelium, subepithelial capillaries, very large relative size in relation to ventricle; stage 3: fetal period, moderate glycogen, many primary villi, cuboidal epithelium, mature capillaries in villous core; stage 4: after 29 weeks: villi with multiple fronds, disappearing glycogen, cuboidal or squamous epithelium, relatively small plexus in relation to ventricle size.
Plexus is absent at GW 7, CR 15 mm fetus; the stalk of the choroid plexus is beginning to produce the rudiment of the choroid plexus in GW 8; the blooming of the choroid plexus in the expanded lateral ventricle is in GW 10 (from Altman and Bayer 2015)
Choroid Plexus Ultrasound Anatomy
In viable preterms, at 24 weeks PMA, choroid plexus still dominates the coronal sections through the atria of the lateral ventricle; at term this relative dominance has disappeared due to expansion of hemispheric white matter tracts
Thick Temporal Horn Plexus
Thick Tela
A rare condition exists, with an abnormal gain of parts of chromosome 9, where choroid plexus is hyperplastic (Boxill et al. 2018); even at term the plexus dominates the atrial section and due to overproduction of CSF the ventricles progressively dilate until treatment by coagulation; vascular anatomy and flow indices are normal.
Plexus Pseudocysts
Human fetal choroid plexus sometimes contains a large central mass of amorphous material with a few poorly distinguishable blood vessels, surrounded by a single layer of epithelial cells (Voetmann 1949, Netsky and Shuangshoti 1975). Its significance is uncertain, but the resemblance to Wharton's jelly suggests it may have a mechanical function.
In many fetuses plexus cysts appear (and often regress) in which fluid accumulates in a mesenchymal space without epithelial lining (unlike colloid cysts). The cysts have irregular angiomatous capillaries in there walls, unlike the normal capillary loops (Kraus and Jirasek 2002).
As an isolated finding this is within normal, often an incidental sonographic finding. Already at 9 weeks, with transvaginal ultrasound, the plexus can be seen at the level of both lateral ventricles. Between 9 and 11 weeks, plexus covers most of the surface of the standard transventricular fetal ultrasound axial section. As pregnancy progresses, the volume ratio between choroid plexus and the ventricles decreases. As the ventricles develop, the choroid plexus grows to occupy the atrium, covering posterior thalamus (Timor-Tritsch et al. 2012). The finding of isolated choroid plexus separation by more than 3 mm from the medial ventricle wall is usually temporary in the second trimester, resolving in most cases within 4 weeks of the initial diagnosis in the second trimester. Most infants with this finding have no abnormalities (Bronsteen et al. 2006). During stage 21, the choroid plexuses become vascularized. Choroid plexus vessels are first seen with doppler ultrasound at 10 to 11 weeks GA.
After Netsky and Shuangshoti 1975
Choroid Plexus Cysts
It has been estimated that in the course of the second trimester 0.3–0.6 % of all fetuses develop echographically detectable cysts in the plexus of one or both lateral ventricles. Microcysts are thus frequent. In fact plexus cyst formation is normal between the 17th and 28th gestational weeks. One should follow cysts when their diameter exceeds 3 mm (incidence rate < 0.5 per 1000 healthy live births). The pseudocysts consist of CSF and cell debris surrounded by a connective tissue membrane and an angiomatous capillary plexus (Kraus and Jirasek 2002). As a rule they do not follow an antecedent plexus haemorrhage and they are not bordered by ependyma unlike neuroepithelial (colloid) cysts. They naturally evolve towards regression before the end of the second trimester. Some cysts are big enough to bulge into the ventricle where they may rarely cause obstructive hydrocephalus. In the tela choroidea of the third ventricle similar cysts may be observed.
Plexus cysts have been described in association with cysts of the germinal matrix at the foramen of Monro. Differentiation between those two is in some cases echographically impossible. Cysts identified in the perinatal period, even if their diameter is less than 7 mm, may remain visible for more than a year.
If a plexus cyst persists after 22–24 gestational weeks, or if it is exceptionally big (> 1cm), and above all if in combination with high maternal age or another anomaly, an underlying condition such as a chromosomal disorder should be excluded. Plexus cysts are not more common than usual in trisomy 21, but they are in trisomy 18. Other associations are with Aicardi syndrome (cysts in half of cases, uni- or bilateral, small or large), nevoid basal cell carcinoma and chondrodysplasia punctata.
MECP2 duplication is associated with ventriculomegaly, hydrocephalus, agenesis of the corpus callosum, choroid plexus cysts, foetal growth restriction and hydronephrosis.
Midline interhemispheric cyst walls (see callosal agenesis) may contain choroid tissue.
The existence of smaller cysts, however, does not exclude an anomaly of the karyotype. Isolated plexus cysts predict karyotype disorders in less than 1 %, and their isolated recognition therefore does not warrant amniocentesis.
Clinical Cases
Preterm infant of 28w GA without other problems; chance finding of intermediate size plexus cystTemporal plexus cyst in an infant with genetic cobalamine deficiencyWith in vivo imaging it is not possible to differentiate a germinolytic cyst from an anterior choroid plexus cystTerm infant, small for gestational age: first day 7.5 MHz sections (left, coronal; right, parasagittal) of an anomaly detected antenatally in the third trimester. A large cyst can be seen in the glomus of the choroid plexus of the right lateral ventricle: this child had trisomy 18. Cerebellar hypoplasia was an additional finding.Single plexus cyst in a term infant with early onset infection without meningitis