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Neurodevelopment outcome of newborns with cerebral subependymal pseudocysts at 18 and 46 months: a prospective study
  1. Manon Cevey-Macherel,
  2. Margarita Forcada Guex,
  3. Myriam Bickle Graz,
  4. Anita C Truttmann
  1. Department of Pediatrics and Pediatric Surgery, Follow up Unit, Clinic of Neonatology, University Hospital Center and University of Lausanne, Lausanne, Vaud, Switzerland
  1. Correspondence to Dr Anita C Truttmann, Clinic of Neonatology, Maternity Building, University Hospital Center of Lausanne, Avenue Pierre Decker 10, Lausanne 1011, Switzerland; anita.truttmann{at}


Objectives Subependymal pseudocysts (SEPC) are cerebral periventricular cysts located on the floor of the lateral ventricle and result from regression of the germinal matrix. They are increasingly diagnosed on neonatal cranial ultrasound. While associated pathologies are reported, information about long-term prognosis is missing, and we aimed to investigate long-term follow-up of these patients.

Study design Newborns diagnosed with SEPC were enrolled for follow-up. Neurodevelopment outcome was assessed at 6, 18 and 46 months of age.

Results 74 newborns were recruited: we found a high rate of antenatal events (63%), premature infants (66% <37 weeks, 31% <32 weeks) and twins (30%). MRI was performed in 31 patients, and cystic periventricular leukomalacia (c-PVL) was primarily falsely diagnosed in 9 of them. Underlying disease was diagnosed in 17 patients, 8 with congenital cytomegalovirus (CMV) infection, 5 with genetic and 4 with metabolic disease. Neurological examination (NE) at birth was normal for patients with SEPCs and no underlying disease, except one. Mean Developmental Quotient and IQ of these patients was 98.2 (±9.6SD; range 77–121), 94.6 (±14.2SD; 71–120) and 99.6 (±12.3SD; 76–120) at 6, 18 and 46 months of age, respectively, with no differences between the subtypes of SEPC. A subset analysis showed no outcome differences between preterm infants with or without SEPC, or between preterm of <32 GA and ≥32 GA.

Conclusions Neurodevelopment of newborns with SEPC was normal when no underlying disease was present. This study suggests that if NE is normal at birth and congenital CMV infection can be excluded, then no further investigations are needed. Moreover, it is crucial to differentiate SEPC from c-PVL which carries a poor prognosis.

  • Neurodevelopment
  • Imaging
  • Neonatology
  • Subependymal pseudocyst
  • Germinolytic cyst

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What is already known on this topic

  • Subependymal pseudocysts are increasingly detected on routine neonatal cranial ultrasound.

  • Association with underlying disease is reported (cytomegalovirus, metabolic disease).

  • If no underlying pathology is associated, short-term follow-up seems to be normal on small cohorts.

What this study adds

  • The neurodevelopment of a large cohort of infants with isolated subependymal pseudocysts (SEPC) and no underlying disease is normal at 46 months.

  • Neurological examination at birth in case of SEPC diagnosed by ultrasound is a good outcome predictor and a good guide for complementary investigations for the clinicians.

  • If the SEPCs are isolated and urinary cytomegalovirus is negative, then parents should be reassured about the prognosis of their child.


The germinal matrix (GM) is a richly vascularised, transient structure that corresponds to the subependymal ventricular zone and has a proliferative function in fetal life. It regresses between 28 and 38 weeks of age, when only residual GM in the caudothalamic groove can be found. The best known pathology related to GM is subependymal haemorrhage, which is a major source of intraventricular bleeding affecting premature infants.

Other less known entities are the germinolytic cysts, also called periventricular pseudocysts (PP), subependymal pseudocysts (SEPC) or connatal cysts. They are thought to be sequelae of GM infarctions due to either thrombosis or infectious vasculitis.1 Findings from autopsy studies show either one large cavity cyst, most often in the frontal horn location, or multiloculated (honeycomb) cysts lacking a well defined wall and, therefore, named pseudocysts.1 Their localisation is mostly in the caudothalamic groove (germinolytic cyst), frontally on the floor of the lateral ventricles (frontal horn cyst), or more rarely in the temporal horn.1 ,2 Since their first description, more than 40 pathologies have been associated with SEPC, such as metabolic disorders,3 ,4 congenital infections5 ,6 or chromosomal anomalies.6 ,7 Isolated SEPCs with no underlying disease have also been described with an incidence of 0.5% in a large study.8 The localisation, below the superolateral margin of the lateral ventricle, differentiates SEPC from cystic periventricular leukomalacia (c-PVL) which occurs above this level.9

Several studies about SEPCs in newborns looked at their neurodevelopment, but numbers are small, follow-up limited and prognosis uncertain.9–15 The detection of SEPCs has increased with the use of routine cerebral ultrasound (CUS); however, to our knowledge, there is no algorithm in the literature guiding clinicians, who face this pathology. As suggested in a recent meta-analysis,16 we prospectively enrolled newborns with SEPCs for follow-up, described the population characteristics and assessed the neurodevelopment at 6, 18 and 46 months.



All patients born between 1 January 2004 and 30 November 2009 with a diagnosis of SEPC were enrolled. The population studied included newborns admitted to our unit and some from the maternity ward requiring a CUS (twins, microcephaly-macrocephaly, and HIV+mother). Informed parental consent was obtained. The use of data for epidemiological research was approved by the local ethical committee (University of Lausanne).

Clinical dataset

Prenatal and neonatal history, investigations, such as brain MRI at term equivalent age (TEA), urinary PCR for cytomegalovirus (CMV), metabolic or genetic analyses, were recorded. Socioeconomic status (SES) according to Largo was rated on a six-point scale based on mother's education and father's occupation, ‘1’ representing an academic position and ‘6’ unskilled work.17 All patients had a neurological examination (NE) according to Dubowitz.18

Cranial ultrasound examination

CUS were performed according to our internal guidelines, adapted from19: newborns <32 weeks of gestational age (GA) were examined on postnatal days 1, 3, 7, and then once a week until discharge or 36 weeks. Newborns ≥32 weeks were examined on postnatal day 3 and before discharge, or at 36 weeks. All patients admitted to the unit had at least one ultrasound. CUS were performed using an Acuson Sequoia real-time scanner (multifrequency high-resolution transducer 5–10 MHz) during 2004–2008, and since 2009, a General Electrics (GE) Vivid S6 (multifrequency high-resolution probe 5–8 MHz). All CUS were performed by neonatology fellows and reviewed individually by two experienced staff neonatologists. In case of disagreement, images were reviewed by two senior neonatologists.

Neurodevelopment outcome measures

Assessment of neurodevelopment was performed at 6 and 18 months (corrected age (CA) for the preterm children) by paediatricians of the follow-up unit, and at preschool age by paediatricians and psychologists. The Developmental Quotient (DQ) of The Griffiths Mental Development Scales test revised edition (GMDS) was used at 6 months. At 18 months, the GMDS was performed from 2004 onwards (n=22 tests)20 and from 2010 onwards, the Mental Developmental Index of the Bayley Scales of Infant Development (BSID-II)21 (n=26 tests). At 42 months, IQ was evaluated with the Wechsler Preschool and Primary Scale of Intelligence (WPPSI-R) (n=13 tests), producing a total IQ.22 At 60 months, the Mental Processing Composite score of Kaufmann's K-ABC23 (n=13 tests) was used as an equivalent of IQ. All the tests used are standardised for an expected value of 100 with a SD of 15. For the patients lost to follow-up, the child's paediatrician reported the child's development as normal or abnormal.

To analyse the impact of prematurity, we compared the DQ/IQ of the subgroups of patients <32 GA and ≥32 GA. We also matched each of the 23 patients of our population of <32 weeks GA with an infant without SEPC who was born just after the case infant, controlling for birth weight (BW), GA and gender, tolerating a difference of 5 days (GA) and 50 g (BW).

Statistical analyses

Data were analysed using the Statistical Package for Social Science software (SPSS, V.20.0). Univariate analysis of variance, and the χ2 test with Yates correction, or the Fischer's test (for small numbers) were performed for comparisons between groups. Multivariable analysis using ANOVA was performed with GA as covariable to control for prematurity. Paired t tests for the matched patients were performed for the DQ and IQ. The level of statistical significance was defined as p<0.05.


Population characteristics

Of 75 patients eligible, 65 patients (88%) were recruited from the neonatology unit, nine from the maternity ward (one refusal). The incidence of SEPCs per admissions/year varied from 1.4% to 1.6% (2004–2007), to 4.4% and 3.5% for 2008 and 2009 (maternity newborns not considered). The mean admission rate/year was 526.3 newborns (range 435–668 over 6 years). The main population characteristics are summarised in table 1.

Table 1

Main neonatal characteristics of the population (n=74)

The antenatal characteristics of the population are detailed in table 2.

Table 2

Details of the antenatal characteristics of the 70 pregnancies (74 infants for 70 pregnancies because of 4 twin sets)

Postnatal characteristics

SEPCs were diagnosed as follows: in 61 infants (82%) before the 7th postnatal day and were considered of antenatal origin (one made by fetal ultrasound at 26 weeks); in eight infants between the 7th and 21st postnatal day; in five after the 21st postnatal day. These last five were considered of postnatal origin because they were not seen on the first four CUS. Among these five, three had a difficult neonatal course (<28 weeks, necrotising enterocolitis, severe anaemia, bronchopulmonary dysplasia).

Two types of cysts were distinguished based on their location: germinolytic cysts, in 50 infants (68%), and frontal horn cysts in 22 patients (30%) (figure 1). Two patients showed both types simultaneously. Unilateral cysts were seen in 36 infants (49%) with similar distribution of subtypes, predominantly on the left side (26).

Figure 1

Cerebral ultrasound images of newborns at term equivalent age showing A–B frontal horn cysts (FHC; white arrows) and C–D germinolytic cysts in the caudothalamical groove (GC; white arrows) A and C represent a sagittal, and B and D a coronal view.

A PCR urinary analysis for CMV was performed in 43 patients (58%), and was positive in eight (four symptomatic at birth, two twin sets; four asymptomatic). There was one proven maternal seroconversion, one mother with positive immunity (whose twins developed symptomatic CMV), three mothers with negative and one with unknown status. No CMV testing was performed in 31 patients, because of the presence of an underlying disease (n=9), a positive maternal immune status (n=8), a negative last trimester serology (n=14).

Metabolic and chromosomal testing for 11 patients is described in figure 2.

Figure 2

This scheme represents the population of newborns presenting with subependymal pseudocysts, and their evolution in regard to their neurological exam at birth. *Abnormal neurological exam at birth was considered when severe hypotonia, floppiness and or severe feeding difficulties were present. †1 Zellweger Syndrome, 2 mitochondriopathies. ‡2 chromosomal anomalies (Triple X Syndrome with microdeletion 15q13; microdeletion 5q14.3), 1 Sotos Syndrome diagnosed at 9 months, 1 VACTERL (Vertebral defects, Anal atresia, TracheoEsophageal fistula, Radial dysplasia) association with microcephaly and 1 suspicion of a metabolic disease. •Patient who presented with severe intrauterine growth retardation at birth (birth weight 900 g at 34 weeks of gestation), and growth failure and severe persistent anaemia after birth, but normal neurodevelopment. This patient died at 10 months from a severe ARDS (acute respiratory distress syndrome), in the context of complementary investigations and general anaesthesia. A metabolic disorder of unknown origin was suspected.

MR imaging

A total of 30 MRIs were performed at TEA; one fetal MRI at 26 weeks GA (figure 3). Indications were prematurity (<32 weeks, n=9), floppy baby syndrome (seven), congenital CMV infection (five), asphyxia (five), mild ventriculomegaly (three), suspected c-PVL on ultrasound (two), suspicion of haemorrhage in the head of the nucleus caudatus (one). In 26/31 cases, the SEPC was confirmed.

Figure 3

Fetal MR-images at 26 3/7 weeks of gestation, (A) coronal and (B) transverse plane, 1.5 T Magnet, Symphony Siemens, T2 HASTE. Indications for MR was slight ventriculomegaly and macrocephaly at the fetal ultrasound (bi-parietal measure >90P). The white arrows show the large frontal horn cysts (4×15 mm on the right and 5×17 mm on the left). The short arrow shows a small temporal cyst on the left side, on other images, temporal cysts were seen both sides (not shown here). Beside slight ventriculomegaly, no other anomaly was seen and this baby went well. The frontal horn cysts became smaller at birth (CUS) and resolved completely at 2 months of age, the temporal cysts were not seen at birth. HASTE, half-fourier acquisition single-shot turbo spin-echo.

A misdiagnosis of c-PVL was made in nine MRIs (two cases mislead by a false diagnosis on CUS). The diagnosis was corrected for all nine cases after multidisciplinary reviewing. In one case, the SEPC was first misinterpreted as haemorrhage in the head of the nucleus caudatus, later also corrected by MRI. The misinterpretation of c-PVL happened more often during 2004–2006 than 2008–2009.

Other cerebral pathologies were high apparent diffusion coefficient values of the white matter (n=11; nine premature and two floppy babies), occipital cysts (three CMV), mild ventriculomegaly (n=3), cerebellar haemorrhages (n=1; premature+asphyxia), polymicrogyria (n=1; Zellweger Syndrome), IVH grade II (n=1; premature). Except for IVH grade II, mild ventriculomegaly and occipital cysts, the other pathologies were only detected by MRI.

Short-term outcome

The results of the neonatal NE are shown in figure 2. All infants with severe persistent hypotonia (n=9), turned out to have an underlying disease and an abnormal outcome (except one with moderate hypotonia at birth and normal DQ at 18 months). The three patients who died perinatally had voluminous bilateral cysts (one frontal horn, two germinolytic cysts). The five others with variable syndromes had cysts of heterogeneous types and localisation. Heterogeneity of types and localisation of the cysts was also seen in patients with congenital CMV.

Neurodevelopment outcome

The follow-up rate at 6 months (CA) of the 71 survivors was 86% (n=61). Ten patients lost to follow-up had a normal neurodevelopment according to their paediatrician. The DQ at different ages is shown in figure 4. The mean DQ of the population (n=61) followed in our unit was 95.1 (±14.1SD; range 49–121) at 6 months, CA. The mean DQ of patients with normal NE at birth was 98.2 (±9.6SD; range 77–121; n=49). CMV positive and severely hypotonic infants were analysed separately.

Figure 4

Neurodevelopmental outcome at 6, 18 and 46 months of children presenting at birth with SPECs and normal NE. The congenital cytomegalovirus (CMV) children were analysed separately (orange boxplots). While no difference in DQ was noted at 6 months between the two groups, DQ decreased significantly in the CMV group at 18 months, with 50% of the CMV positive infants showing a severe delay in development. DQ, developmental quotient; NE, neurological exam at birth.

At 18 months, the follow-up rate of the 70 survivors was 71% (n=50), the mean DQ of patients with normal NE at birth was 94.6 (±14.2SD; range 71–120). The five additional patients lost to follow-up had a normal neurodevelopment according to their paediatrician. One patient died at 8 months. Surviving children with severe hypotonia at birth (n=5) had a mean DQ±SD of 65.8 (±14.3; range 49–104) and 60.8 (±12.3; range 49–90) at 6 and 18 months, respectively. We found no statistical differences between the DQ of germinolytic cyst and frontal horn cyst subgroups (p=0.1 for the DQ at six and p=0.26 at 18 months) or between unilateral and bilateral cysts (p=0.1 at six; p=0.6 at 18 months). The mean parents’ SES was seven (±2SD; range 2–10).

At the time of submission, 34 children reached preschool age (healthy at birth). The mean age of follow-up was 46±9.5SD months with a mean IQ of 99.6±12.3SD; range 76–120, n=26)); six children were reported as normal by their paediatrician; information was missing for two.

Given the non-homogenous distribution of our population's GA, 23 premature infants were matched with a preterm group without SEPC: mean GA was 28.5 (weeks/days) (±14.2) and 28.6 (±12.8); mean BW was 1139g (±380.6) and 1147g (±360.8), respectively. There were 20 matched pairs at 18 months and 13 at preschool age. There was no statistical significant difference between the mean DQ and IQ+SD between the two groups: 97.2±9.8 versus 98.4±7.1 (paired t test: −0.642, p=0.528), 95.2±16.6 versus 95.7±16.1 (−0.112, p=0.912) and 97.4±14.1 versus 98.2±19.1 (−0.181, p=0.860) at 6, 18 and 46 months, respectively.

The DQ of the 23 infants <32 weeks GA (subgroup 1) was not statistically different from the patient's ≥32 weeks GA (subgroup 2). The mean DQ (±SD) at 6 months was 97.2±9.8 for subgroup 1 and 93.9±16.1 for subgroup 2 (F=0.8; p=0.4); at 18 months 95.0±16.2 for subgroup 1 and 90.6±15.7 for the subgroup 2 (F=0.8; p=0.4); at preschool age 97.7±13.6 and 96.1±17.1 (F=0.1; p=0.8).

These results remained similar when GA was added as a covariate.


Between 2004 and 2009, 74 newborns with a diagnosis of SEPCs were prospectively followed-up for 46 months, to establish whether SEPCs are associated with adverse neurodevelopment. To our knowledge, this is the largest study of its kind.

The incidence of SEPCs varied from 1.4% to 4.4%, in accordance with several previous reports,8 ,24 but less than the recently published (15%).25 The rate increased over time because of a more accurate diagnosis of SEPCs and sensibilisation of the medical staff.

Since most of the SEPCs were diagnosed at birth, SEPCs were assumed to occur around 22–26 weeks of gestation, which corresponds to the peak of GM proliferation.2 As reported before, we found several antenatal events (bleeding or maternal medication use) suggesting an unspecified link with the germinolytic events.26–29 Therefore, our observations support the hypothesis that unspecific changes in placental blood flow leads to a dysregulation of the well-vascularised GM and results in an infarct of the GM.24 The possible ischaemic nature is supported by the fact that ischaemia leads to multiple cysts, while haemorrhage leads to one larger cyst.2 Further, while Larroche1 found iron-negative cysts in her autopsy studies, hemosiderin in the SEPCs was never found on MR images.

The fact that frontal horn cysts were less frequently seen than germinolytic cysts may be because regression of the GM starts in the frontal and occipital parts of the ventricles. The last remnants are located in the caudothalamical groove and are still visible at birth. Indeed, SEPCs tend to disappear after 2–3 months.8

Unilateral cysts were found more on the left side. This was previously described,30 and suggests involvement of vascular anatomical factors, as is the case for middle cerebral artery stroke.31

C-PVL was primarily misdiagnosed in a high proportion of MRIs. Misdiagnoses diminished over time, probably due to increased awareness of the medical staff. The confusion between c-PVL and SEPC has been reported in cases of metabolic disorders, turning out later to be SEPCs.32 This is important, as it leads to false a announcement to parents.

NE around birth turned out to be a good predictor of neurodevelopment (positive predictive value: 89%; negative predictive value: 86%). One patient had a moderate hypotonia at birth but normal long-term outcome. The other severely hypotonic infants all had an adverse outcome, in the context of genetic or metabolic disorders. On the other hand, all the infants with a normal NE at birth, except for one, showed a normal neurodevelopment at 6, 18 and 46 months regardless of the type and localisation of cysts, and in accordance with the literature.9–11 ,33 ,34

Congenital CMV infection was found in one out of five patients, as previously reported5 ,13 ,35; neurodevelopment was normal in 50% of the CMV-positive and asymptomatic infants, while 50% (symptomatic) had severe cognitive and sensorial impairment. Therefore, SEPCs in congenital CMV, seems to be more an indirect marker than direct viral brain injury.36 While the follow-up was done prospectively, the analysis of the different investigations was retrospective, and only 2/3 of the patients had CMV testing at birth. Therefore, our proportion of CMV-positive infants could, in reality, be higher.

In our cohort, one patient had a fetal MRI showing prominent frontal horn cysts in the lateral and temporal ventricle horns. As previously described,37 SEPCs can be seen in the fetus. Investigations in this case were negative and parents opted for continuation of pregnancy. This infant finally developed very well, and the only abnormality found at birth was macrocephaly, probably constitutional. At 42 months, he was diagnosed with severe myopia. Microcephaly and macrocephaly were, with twin pregnancy, the most frequent findings associated with SEPCs, suggesting a potential link between brain growth and SEPCs.

In summary, our results lead us to propose an algorithm when facing SEPCs (figure 5).

Figure 5

Proposed algorithm when facing subependymal pseudocysts on c-US of newborns.

If the NE at birth is normal and the urinary CMV negative, prognosis is good and no other investigations are needed. In case of prenatal counselling, we recommend checking for maternal CMV serology, polyhydramnios, decreased fetal movements, and cerebral structural anomalies. Without such risk factors, prognosis should be considered good.

One limitation of our study is the lack of homogeneity of the newborn population. However, this issue was addressed by conducting a subgroup analysis comparing the outcome of premature infants with and without SEPC-matched premature infants, and no differences were found. Despite the fact that the neurodevelopment quotients were in the normal range limits (±1SD) they were closer to the lower limit, reflecting the known neurodevelopment impairment of very premature infants. Another limitation was the heterogeneity of the tests used to assess the development, although they are all standardised with the same SD. Furthermore, because of the timeframe of the study, not all patients have been seen at preschool age.


In this study, newborns with SEPCs with a normal NE at birth and a negative CMV showed normal short-term and long-term neurodevelopment. Furthermore, it is crucial to differentiate SEPCs from c-PVL and to inform parents about its benign nature and good prognosis. Further studies assessing neurodevelopment of these children at school age will be needed.


We would like to thank the parents for their participation, Dr Pierre-Yves Jeannet for careful reading of the manuscript and Dr Juliane Schneider for the help in graphics. We confirm that we have no competing interests to disclose. No tertiary funding was necessary.



  • Contributors We confirm that all authors involved in this paper have contributed substantially to this study. MC-M was implicated in recruiting patients, evaluating the follow-up of the infants, collecting, analysing the data and in redaction of parts of the manuscript. MFG was involved in analysing the data, especially follow-up data, and assisted with statistics. MBG was involved in evaluating the follow-up of the infants; analysis and revision of the manuscript, and ACT drew the conception and design of the study, participated in the analysis of the data, drawing of the tables and figures and drafting of the manuscript, as well as its revision. We are all guarantors for this study.

  • Funding None.

  • Competing interests None.

  • Ethics approval Local ethical committee, Lausanne, Canton de Vaud.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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