Subependymal pseudocysts (SEPCs) result from germinolysis (i.e. germinal matrix cystic regression) (Larroche 1972). The term pseudocyst refers to the lack of ependymal lining. They should not be referred to as 'periventricular cysts', as this may faultily suggest periventricular leukomalacia. The most common location for SEPCs is the caudothalamic notch, while parafrontal and temporal germinolysis are less frequent. The cysts have a glial wall containing residual matrix pockets. Macrophages and some neuroblasts (NSE positive staining) were found in early postmortem descriptions. The nearby ependymal lining is intact. As germinal matrix begins to recede at approximately 28 weeks of gestation, but caudothalamic pockets remain until 34-35 weeks, frontal and temporal germinolysis are likely to form earlier than caudothalamic germinolysis. Often SEPCs are bilateral, though not necessarily symmetrical.
Germinolysis can thus be located in the rostral part of the temporal horns (Ramenghi et al. 1997), and a similar image of a thin strand of tissue crossing the distal end of the ventricle can be seen in the occipital horns (Averill et al. 2015). Temporal cysts and occipital horn septations are typical though not specific of congenital cytomegalovirus (CMV) infection. These septations may cause cystic dilatation in utero, which normally becomes less prominent after birth.
Different Locations
Caudothalamic SEPCs can be single or multiple, in the form of a multilocular rounded prominence protruding from the caudothalamic groove into the lumen of the lateral ventricle. Caudothalamic germinolysis is well illustrated by CUS, whereas MRI does not identify small cysts of a few millimeters in diameter.
A special antenatal variant, parafrontal germinolysis, has been described originating around the mid-second to early third trimester. This atypical type of germinolysis is not rare. In parafrontal germinolysis, SEPCs are adjacent to the lateral walls of the frontal horns of the lateral ventricles. They are located more medially and lower than the cysts of periventricular leukomalacia, and more laterally and anteriorly than the typical caudothalamic germinolytic SEPCs, well anterior to the foramina of Monro. On the coronal plane they can create the impression of an enlarged frontal horn, which has erroneously been interpreted as "coarctation of the lateral ventricle". On parasagittal section they appear elongated, sometimes with septa within ("string of beads germinolysis", with several compartments). It therefore lies in front of these foramina and is separated from the lateral ventricle by a single membrane, readily seen with high frequency probes.
There have been records of parafrontal germinolysis in infants with CMV fetopathy. Some cysts are almost 2 cm long. On coronal section they mimic a widened frontal horn, although a distinction can be made using ≥ 7.5 MHz US. At around 4 months after term nearly all cysts of this type have been integrated into the ventricle. As an isolated finding these germinolytic changes are most often not associated with developmental problems, but exceptions may exist. MRI in early childhood did not reveal gliosis around such benign parafrontal cysts and ventriculomegaly is not associated.
Friede 1989: parafrontal pseudocysts; multiloculated pseudocysts with budding germinal matrix remnants
Matrix Pockets
Germinal matrix is abundant within ganglionic eminences (present between 8 and 36 w PMA) in the floor of the lateral ventricle during the second trimester, but in the third it regresses, persisting mostly in the region around the foramina of Monro — the caudothalamic groove — and along the temporal horn lateral wall. These areas provide glutamatergic projection neurons, GABAergic interneurons and oligodendroglial precursors in the latter part of pregnancy. One can expect that subtle matrix lesions have an impact on telencephalic gliogenesis and on late stages of formation of the cortical plate.
GM volume reaches its maximum at 23-26 weeks PMA; reduction of this volume occurs site specific and is continues until the subventricular zone regresses at 36 weeks.
Part of the subventricular zone persists as a source of interneurons for the olfactory bulb as well as oligodendrocytes through adulthood.
Altman and Bayer 2015: matrix pockets at GA 24w
Main Conditions with Antenatal Subependymal Pseudocysts
Idiopathic
Fetal infection (de Vries et al. 2019): cytomegalovirus, rubella, zika virus, other
Antenatal asphyxia
Maternal substance abuse (cocaine) (Lucca and Baldisserotto 2013)
Twin-to-twin transfusion syndrome (Denbow et al. 1998, Jelin et al. 2008)
Congenital heart disease (McQuillen et al. 2007, Limperopoulos et al. 2010, Clouchoux et al. 2013, Brossard-Racine et al. 2014, Kelly et al. 2019)
Metabolic disorders
Organic acidurias (glutaric aciduria) (Mellerio et al. 2008)
Mitochondrial disorders (complex I, IV, pyruvate dehydrogenase deficiency) (Wada et al. 2004, van Straaten et al. 2005, Leijser et al. 2007)
Peroxisomal disorders (Zellweger syndrome) (Russel et al. 1995, Leijser et al. 2007)
Pyridoxine-dependent epilepsy (Jain-Ghai et al. 2014)
Holocarboxylase synthetase deficiency (Bandaralage et al. 2016)
Chromosomal abnormalities and genetic disorders (Esteban et al. 2015)
Examples of Antenatal Cystic Germinolysis
Small and single caudothalamic SEPCs are usually not pathological. Parafrontal pseudocysts can also be an incidental finding. In fact, SEPCs are found in 0.5-5 % of healthy neonates on CUS in the first days of life (Shen and Huang 1985, Heibel et al. 1993, Makhoul et al. 2001).
On the other hand, large or multiloculated caudothalamic SEPCs, as well as temporal cysts and occipital horn septations, require investigation of an underlying disease. In particular, CMV testing and metabolic testing are indicated. Prognosis is good in the absence of associated conditions. Most SEPCs disappear in the first few months after birth.
Examples encountered include: rubella; parafrontal, monoZ twin; post GMH; cystic and not; twins; inborn errors; unilateral; cystic and not, MRI; parafrontal and temporal; glutaric aciduria; CMV.
Postnatal Onset Germinolysis
Postnatal cyst formation at the rear end of the head of the caudate nucleus is mainly found after a perinatal subependymal haemorrhage. In the absence of typical GMH, regularly one finds one or several rounded cysts in the caudothalmic grooves, sometimes with trabeculation from the walls. During the following few months those cysts are gradually integrated into surrounding tissue. Although such cysts are often rounded, they may sometimes appear flattened. They do not usually bulge into the ventricle lumen. This so called hyperechoic and later cystic germinolysis initially consists of bilateral, symmetrical, teardrop-shaped hyperechogenicity within the caudothalamic grooves (Schlesinger et al. 1998, Horsch et al. 2010).
We and others have noted a possible association between extreme prematurity, bronchopulmonary dysplasia treated by dexamethasone and slow postnatal matrix regression with multilocular character (Smets et al. 1997). After a period of slow triangular densification (hyperechogenicity) of the matrix, this tissue disappears, with or without an intermediate (micro)cystic stage. Such changes in matrix density have been observed in infants with proven postnatal CMV fetopathy. But much more frequent is the incidental finding on CUS of hyperechoic change in caudothalamic groove matrix tissue, present at birth or appearing later, with CMV excluded (Larcos et al. 1994). During the following few months those cysts are gradually integrated into surrounding tissue. Although such cysts are often rounded, they may appear flattened.
One explanation could be that this change is associated with enhanced apoptosis in this area of the brain that is under way for normal developmental regression, and where some cell reaction (macrophages) is present and causes the hyperechoic aspect. The significance of this type of matrix regression for development is uncertain. There is the recent suggestion that it may be associated with inflammation, as during necrotising enterocolitis, disrupting the glial progenitors in third trimester matrix and leading to motor impairment (Epstein et al. 2024).
GA 34w, day 3, CMV excludedGA 34w, day 14, CMV excludedSpontaneous labour, PPROM; spontaneous vaginal delivery of twin 1; GA 30w5d, 1400 g, AS 8/9/10, male, surfactant, NIV_NAVA 4 days; maternal and neonatal covid-19 infection, no clinical signs; CMV negative, normal ABR
Pathology and Differential Diagnosis
There have been several descriptions of apparently enlarged (with cavitations or without) appearance of the matrix areas around the caudothalamic groove in fetal and neonatal MRI descriptions (Righini et al. 2013, 2016). Such findings have been associated with severe disorders of migration like microlissencephaly and ARX-related lissencephaly, but also in association with less pronounced changes like ventriculomegaly, small corpus callosum and small cerebellar vermis. In mitochondrial disorders (pyruvate carboxylase and pyruvate dehydrogenase deficiency) the combination of germinolytic cysts and ventriculomegaly is characteristic.
Haemorrhage and/or micro-infarction of this matrix, both in and ex utero, often lead to cyst formation in the affected area in the first weeks after the event. As we are dealing with cysts with glial walls encircled by germinal cells but not by ependyma, the term pseudocyst is appropriate (Larroche et al. 1972).
True ependyma-lined cysts are seen with unilateral hydrocephalus and other brain cavities.
The distinction with caudate to septum adhesions following bleeding or ventriculitis lies with the recognition of the typical location and with the elliptoid or rounded appearance of the pseudocysts.
Not surprisingly there have been many records of associated brain malformation, migration disorder or visceral anomaly (Mito et al. 1989), this may also be consequent to publication bias.