Severe and progressive neuronal loss in myelomeningocele begins before 16 weeks of pregnancy.

BACKGROUND: Despite undisputable benefits, midtrimester prenatal surgery is not a cure for myelomeningocele (MMC): residual intracranial and motor deficits leading to lifelong handicap question the timing of prenatal surgery. Indeed, the timing and intensity of intrauterine spinal cord injury remains ill defined. OBJECTIVE: We aimed to describe the natural history of neuronal loss in MMC in utero based on postmortem pathology. STUDY DESIGN: Pathology findings were analyzed in 186 cases of myelomeningocele with lesion level between S1 and T1. Using a case-control, cross-sectional design, we investigated the timewise progression and topographic extension of neuronal loss between 13 and 39 weeks. Motor neurons were counted on histology at several spinal levels in 54 isolated MMC meeting quality criteria for cell counting. These were expressed as observed-to-expected ratios, after matching for gestational age and spinal level with 41 controls. RESULTS: Chiari II malformation increased from 30.7% to 91.6% after 16 weeks. The exposed spinal cord displayed early, severe, and progressive neuronal loss: the observed-to-expected count dropped from 17% to ≤2% after 16 weeks. Neuronal loss extended beyond the lesion to the upper levels: in cases <16 weeks, the observed-to-expected motor neuron count was 60% in the adjacent spinal cord, decreasing at a rate of 16% per week. Progressive loss was also found in the upper thoracic cord, but in much smaller proportions. The observed-over-expected ratio of motor neurons was not correlated with the level of myelomeningocele. CONCLUSIONS: Significant neuronal loss is present ≤16 weeks in the exposed cord and progressively extends cranially. Earlier prenatal repair (<16 weeks) could prevent Chiari II malformation in 69.3% of cases, rescue the 17% remaining motor neurons in the exposed cord, and prevent the extension to the upper spinal cord.

Embryology of the craniocervical junction and posterior cranial fossa, part I: Development of the upper vertebrae and skull.

Although the embryology of the posterior cranial fossa can have life altering effects on a patient, a comprehensive review on this topic is difficult to find in the peer-reviewed medical literature. Therefore, this review article, using standard search engines, seemed timely. The embryology of the posterior cranial fossa is complex and relies on a unique timing of various neurovascular and bony elements. Derailment of these developmental processes can lead to a wide range of malformations such as the Chiari malformations. Therefore, a good working knowledge of this embryology as outlined in this review of its bony architecture is important for those treating patients with involvement of this region of the cranium. Clin. Anat. 31:466-487, 2018. © 2018 Wiley Periodicals, Inc.

Embryology and pathophysiology of the Chiari I and II malformations: A comprehensive review.

Although the Chiari malformations are well-studied and described developmental anomalies, there remains some incongruity in regards to their underlying etiologies. A number of theories have been proposed with the purpose of accounting for the embryology and pathogenesis of the Chiari I and II malformations and their associated complications and clinical syndromes. The present review aims to review the pertinent literature for all of the main theories that have been proposed, and outline their validity and relevance to our contemporary understanding of these anomalies. Clin. Anat. 31:202-215, 2018. © 2017 Wiley Periodicals, Inc.

Evolution of posterior fossa and brain morphology after in utero repair of open neural tube defects assessed by MRI.

OBJECTIVES: To describe characteristics of foetuses undergoing in utero repair of open neural tube defects (ONTD) and assess postoperative evolution of posterior fossa and brain morphology. METHODS: Analysis of pre- and postoperative foetal as well as neonatal MRI of 27 foetuses who underwent in utero repair of ONTD. Type and level of ONTD, hindbrain configuration, posterior fossa and liquor space dimensions, and detection of associated findings were compared between MRI studies and to age-matched controls. RESULTS: Level of bony spinal defect was defined with exactness of ± one vertebral body. Of surgically confirmed 18 myelomeningoceles (MMC) and 9 myeloschisis (MS), 3 MMC were misdiagnosed as MS due to non-visualisation of a flat membrane on MRI. Hindbrain herniation was more severe in MS than MMC (p < 0.001). After repair, hindbrain herniation resolved in 25/27 cases at 4 weeks and liquor spaces increased. While posterior fossa remained small (p < 0.001), its configuration normalised. Lateral ventricle diameter indexed to cerebral width decreased in 48% and increased in 12% of cases, implying a low rate of progressive obstructive hydrocephalus. Neonatally evident subependymal heterotopias were detected in 33% at preoperative and 50% at postoperative foetal MRI. CONCLUSION: MRI demonstrates change of Chiari malformation type II (CM-II) features. KEY POINTS: • Hindbrain herniation is significantly more pronounced in myeloschisis than in myelomeningocele • Resolution of hindbrain herniation 4 weeks after in utero closure of ONTD • MRI is valuable for preoperative assessment and postoperative evaluation following in utero repair.

Fetal diffusion tensor quantification of brainstem pathology in Chiari II malformation.

OBJECTIVES: This prenatal MRI study evaluated the potential of diffusion tensor imaging (DTI) metrics to identify changes in the midbrain of fetuses with Chiari II malformations compared to fetuses with mild ventriculomegaly, hydrocephalus and normal CNS development. METHODS: Fractional anisotropy (FA) and apparent diffusion coefficient (ADC) were calculated from a region of interest (ROI) in the midbrain of 46 fetuses with normal CNS, 15 with Chiari II malformations, eight with hydrocephalus and 12 with mild ventriculomegaly. Fetuses with different diagnoses were compared group-wise after age-matching. Axial T2W-FSE sequences and single-shot echo planar DTI sequences (16 non-collinear diffusion gradient-encoding directions, b-values of 0 and 700 s/mm(2), 1.5 Tesla) were evaluated retrospectively. RESULTS: In Chiari II malformations, FA was significantly higher than in age-matched fetuses with a normal CNS (p = .003), while ADC was not significantly different. No differences in DTI metrics between normal controls and fetuses with hydrocephalus or vetriculomegaly were detected. CONCLUSIONS: DTI can detect and quantify parenchymal alterations of the fetal midbrain in Chiari II malformations. Therefore, in cases of enlarged fetal ventricles, FA of the fetal midbrain may contribute to the differentiation between Chiari II malformation and other entities. KEY POINTS: • FA in the fetal midbrain is elevated in Chiari II malformations. • FA is not elevated in hydrocephalus and mild ventriculomegaly without Chiari II. • Measuring FA may help distinguish different causes for enlarged ventricles prenatally. • Elevated FA may aid in the diagnosis of open neural tube defects. • Elevated FA might contribute to stratification for prenatal surgery in Chiari II.

Cryopreserved human umbilical cord patch for in-utero spina bifida repair.

OBJECTIVE: To identify a patch system to repair surgically created spina bifida in a sheep model for its efficacy in healing the skin defect, protecting the underlying spinal cord and reducing the Chiari II malformation. METHODS: Spina bifida was created surgically in 16 fetuses from eight timed-pregnant sheep at gestational age of 75 days. Two fetuses did not survive the procedure. Repeat hysterotomy was performed at 95 days' gestation to cover the defect with either biocellulose film with underwater adhesive (BCF-adhesive) (n = 7) or human umbilical cord with suture (HUC-suture) (n = 7). Three fetuses without formation of the defect served as reference controls. The skin healing was examined by direct visualization after a planned Cesarean section at term, followed by histological analysis using hematoxylin and eosin and Masson's trichrome stains. Mid-sagittal sections of the fetal cranium and upper cervical spine were analyzed by a pediatric neuroradiologist who was blinded to the type of patch received. RESULTS: Three fetuses that received the BCF-adhesive and six fetuses that received the HUC-suture survived to term for final analysis. As a result of dislodgment of the BCF-adhesive, all spina bifida defects repaired using BCF-adhesive were not healed and showed exposed spinal cord with leakage of cerebrospinal fluid. In contrast, all spinal defects repaired by HUC-suture were healed with complete regrowth of epidermal, dermal and subdermal tissue components, with no exposed spinal cord. The maximal skin wound width was 21 ± 3.6 mm in the BCF-adhesive group but 3 ± 0.8 mm in the HUC-suture group (P < 0.001). The spinal cord area (P = 0.001) and the number of anterior horn cells (P = 0.03) was preserved to a greater degree in the HUC-suture group than in the BCF-adhesive group, whilst psammoma bodies, signifying neuronal degeneration, were only observed in the BCF-adhesive group. Anatomic changes, indicative of Chiari II malformation, were seen in all three fetuses of the BCF-adhesive group but in none of the HUC-suture group (P < 0.01). CONCLUSION: Cryopreserved umbilical cord graft is a promising regenerative patch for intrauterine repair of spina bifida.

Assessment of fetal midbrain and hindbrain in mid-sagittal cranial plane by three-dimensional multiplanar sonography. Part 2: application of nomograms to fetuses with posterior fossa malformations.

OBJECTIVES: To apply fetal midbrain (MB) and hindbrain (HB) nomograms, developed using three-dimensional multiplanar sonographic reconstruction (3D-MPR) in the mid-sagittal cranial plane, to fetuses with known posterior fossa malformations. METHODS: In this retrospective study we examined sonographic volumes obtained by sagittal acquisition in 43 fetuses diagnosed with posterior fossa abnormalities and evaluated in the mid-sagittal cranial plane, using 3D-MPR, the following: MB parameters tectal length (TL) and anteroposterior midbrain diameter (APMD), and HB parameters anteroposterior pons diameter (APPD), superoinferior vermian diameter (SIVD) and anteroposterior vermian diameter (APVD). Fetuses were grouped, according to malformation, into eight categories: cobblestone malformation complex (CMC, n = 3), Chiari-II malformation (C-II, n = 7), pontocerebellar hypoplasia (PCH, n = 2), rhombencephalosynapsis (RES, n = 4), Dandy-Walker malformation (n = 8), vermian dysgenesis (VD, n = 7), persistent Blake's pouch cyst (n = 6) and megacisterna magna (n = 6). In each case and for each subgroup, the MB-HB biometric parameters and their z-scores were evaluated with reference to our new nomograms. RESULTS: The new MB-HB nomograms were able to identify the brainstem and vermian anomalies and differentiate fetuses with MB-HB malformations from those with isolated enlarged posterior fossa cerebrospinal fluid spaces. Use of the nomograms enabled detection of an elongated tectum in fetuses with CMC, C-II and RES, and a flattened pontine belly in cases of CMC, PCH and VD. In the fetuses with VD, the nomograms enabled division into three distinctive groups: (1) those with small SIVD and APVD, (2) those with normal SIVD but small APVD, and (3) those with small SIVD but normal APVD. CONCLUSIONS: Application of our new reference data, that for the first time include the MB, enables accurate diagnosis of brain malformations affecting the MB and HB and makes possible novel characterization of previously described features of posterior fossa anomalies.

Single-Access Fetal Endoscopy (SAFE) for myelomeningocele in sheep model I: amniotic carbon dioxide gas approach.

BACKGROUND: This study aimed to assess the feasibility of single-access fetal endoscopy (SAFE) for the management of myelomeningocele (MMC) using intrauterine carbon dioxide as a distension medium in a sheep model. METHODS: This prospective experimental case-control study investigated 12 lamb fetuses that had a myelomeningocele-like defect surgically created on the 75th day of gestation. Four fetuses remained untreated (control group), and eight fetuses had MMC repair using two fetoscopic approaches with carbon dioxide used to distend the amniotic cavity. A collagen patch was placed over the defect and secured with surgical sealant. Four animals had a two-port fetoscopic procedure, and four animals had SAFE. Clinical and pathologic studies were performed after delivery. RESULTS: This study confirmed the validity of the animal MMC model. None of the control animals was able to stand or walk, and all had a significant defect in the lumbar area with continuous leakage of cerebrospinal fluid, ventriculomegaly, and a Chiari-II malformation. All the treated animals, independently of the number of ports used in the repair, were able to walk and had a closed defect with resolution of the Chiari malformation. CONCLUSIONS: The SAFE patch and glue coverage of surgically created fetal MMC is feasible and effective in restoring gross neurologic function in the fetal lamb model.

Cerebral ventricular system in fetuses with open spina bifida at 11-13 weeks' gestation.

OBJECTIVE: To determine if in fetuses with open spina bifida at 11-13 weeks' gestation there are alterations in the cerebral ventricular system. METHODS: In this study we selected 10 cases of open spina bifida and 410 normal singleton pregnancies which subsequently resulted in the delivery of phenotypically normal neonates. In all cases transvaginal sonography was carried out at 11-13 weeks' gestation and three-dimensional (3D) brain volumes were acquired. The fetal head was systematically assessed in a series of transverse views and measurements were obtained of the area of the lateral ventricles, the diameter of the roof of the third ventricle, the diameter of the aqueduct of Sylvius and the diameter of the fourth ventricle. The measurements obtained on the normal and affected fetuses were compared. RESULTS: In normal fetuses the area of the lateral ventricles and the diameter of the roof of the third ventricle increased, the diameter of the aqueduct of Sylvius decreased and the diameter of the fourth ventricle did not change significantly with biparietal diameter (BPD). In fetuses with open spina bifida, compared with normal fetuses, the measurements of the lateral ventricle area, the diameter of the roof of the third ventricle, the diameter of the aqueduct of Sylvius and the diameter of the fourth ventricle were significantly decreased (P < 0.01). CONCLUSION: In fetuses with open spina bifida at 11-13 weeks' gestation the intracranial collection of cerebrospinal fluid is substantially reduced.

Spinal Dysraphia, Chiari 2 Malformation, Unified Theory, and Advances in Fetoscopic Repair.

Fetal spina bifida, the most common nonlethal birth defect of the central nervous system, results in substantial neurologic morbidity. The unified theory describes the complex relationship between local spinal lesions and development of Chiari 2 malformation, contributing to hydrocephalus. Prenatal ultrasonography reliably allows diagnosis, but fetal MR imaging is an important complement to identify additional brain abnormalities. Fetal surgery improves neurologic and motor outcomes, but various approaches, either open hysterotomy or minimally invasive to the uterus, carry substantial obstetric risks. Optimization of the fetoscopic approach aims to minimize maternal and obstetric risks, but data regarding longer-term outcomes are awaited.

Trans-amniotic stem cell therapy (TRASCET) minimizes Chiari-II malformation in experimental spina bifida.

PURPOSE: We sought to study the impact of trans-amniotic stem cell therapy (TRASCET) in the Chiari-II malformation in experimental spina bifida. METHODS: Sprague-Dawley fetuses (n=62) exposed to retinoic acid were divided into three groups at term (21-22 days gestation): untreated isolated spina bifida (n=21), isolated spina bifida treated with intra-amniotic injection of concentrated, syngeneic, labeled amniotic fluid mesenchymal stem cells (afMSCs) on gestational day 17 (n=28), and normal controls (n=13). Analyses included measurements of brainstem and cerebellar placement on high resolution MRI and histology. Statistical comparisons included ANOVA. RESULTS: In parallel to the expected induced coverage of the spina bifida in the afMSC-treated group (P<0.001), there were statistically significant differences in brainstem displacement across the groups (P<0.001), with the highest caudal displacement in the untreated group. Significant differences in cerebellar displacement were also noted, albeit less pronounced. Pairwise comparisons were statistically significant, with P=0.014 between treated and normal controls in caudal brainstem displacement and P<0.001 for all other comparisons. Labeled afMSCs were identified in 71% of treated fetuses. CONCLUSIONS: Induced coverage of spina bifida by TRASCET minimizes the Chiari-II malformation in the retinoic acid rodent model, further suggesting it as a practical alternative for the prenatal management of spina bifida.

Congenital basis of posterior fossa anomalies.

The classification of posterior fossa congenital anomalies has been a controversial topic. Advances in genetics and imaging have allowed a better understanding of the embryologic development of these abnormalities. A new classification schema correlates the embryologic, morphologic, and genetic bases of these anomalies in order to better distinguish and describe them. Although they provide a better understanding of the clinical aspects and genetics of these disorders, it is crucial for the radiologist to be able to diagnose the congenital posterior fossa anomalies based on their morphology, since neuroimaging is usually the initial step when these disorders are suspected. We divide the most common posterior fossa congenital anomalies into two groups: 1) hindbrain malformations, including diseases with cerebellar or vermian agenesis, aplasia or hypoplasia and cystic posterior fossa anomalies; and 2) cranial vault malformations. In addition, we will review the embryologic development of the posterior fossa and, from the perspective of embryonic development, will describe the imaging appearance of congenital posterior fossa anomalies. Knowledge of the developmental bases of these malformations facilitates detection of the morphological changes identified on imaging, allowing accurate differentiation and diagnosis of congenital posterior fossa anomalies.

Pathogenesis of the Arnold-Chiari malformation: the significance of hydrocephalus and aqueduct stenosis.

In 24 cases of spina bifida, correlations were made comparing the degree of hydrocephalus with the cross-sectional area of the supratentorial compartment, posterior fossa, hindbrain prolapse, size of myelocele, and degree of fibrovascular reaction at the base of the brain. The size and postion of the aqueduct and fourth ventricle were compared with the degree of hydrocephalus. The results demonstrate that the aqueduct stenosis is usually due to external compression of the mesencephalon. The results also suggest that the size of the posterior fossa and hindbrain prolapse are secondary to hydrocephalus. It is postulated that the hydrocephalic process may be initiated by fibrovascular occlusion of the basal subarachnoid space.

The Dandy-Walker and Arnold-Chiari malformations. Clinical, developmental, and teratological considerations.

Five patients with the Dandy-Walker syndrome had dysgenesis of the cerebellar vermis, cystic dilatation of the fourth ventricle, and a high position of the tentorium cerebelli. When only these features are present, the patient may lead a normal life. Additional defects usually account for the prominent clinical and pathological features of this syndrome. In this series, one patient had aqueductal stenosis, four had agenesis of the corpus callosum, two had hydrocephalus, one had cerebral abiotrophy, and one (a 72-year-old man) had no additional defects and no symptoms from his Dandy-Walker syndrome. An analysis of development and teratological considerations indicates that the Dandy-Walker and Arnold-Chiari malformations are complex disorders that have different causes and mechanisms and begin at different times in the emryonic period. The causes are still unknown.

Transitional forms of Arnold-Chiari and Dandy-Walker malformations.

The morphological findings in 12 cases of Arnold-Chiari and 3 cases of Dandy-Walker malformations are described and compared to those in 2 cases of congenital hydrocephalus of unknown origin, 1 case of isolated meningo-myelocele and 2 cases of normal newborn brains. Lesions common to both types of malformation indicate a same time-related embryogenetic defect of the roofplate of the rhombencephalon, that does not allow the inferior vermis and the choroid plexus to turn inward into the fourth ventricle.

Neuroanatomic examination of spina bifida aperta and the Arnold-Chiari malformation in a 130-day human fetus.

A 130-day human female fetus with the Arnold-Chiari malformation and thoracolumbar myeloschisis revealed evidence of neuroectodermal-mesodermal spatial dyssynchrony. The rhombencephalon and the cervico-medullary junction appear most affected. The phylogenetic and ontogenetic development of the transition zone between brain and spinal cord is reviewed. It is hypothesized that the etiologic event responsible for the Arnold-Chiari malformation is the caudal "displacement" of the site of initial fusion of the neural folds. This is believed to result in the posterior displacement of the cervico-medullary junction and myeloschisis (the Arnold-Chiari malformation, type II).

Morphogenesis of experimentally induced Arnold--Chiari malformation.

The administration of a single dose of vitamin A to pregnant hamsters, early during the morning of their 8th day of gestation, induces types I and II Arnold--Chiari malformation (ACM), as well as various types of axial skeletal-dysraphic disorders known to be associated with the human disease. This new model provides a means of carrying comparative studies between the axial skeletal defects and neurological anomalies of this complex developmental malformation with those which characterize the other induced disorders related to it. Study of this experimental model has demonstrated that the basichondrocranium of fetuses with ACM is shorter than normal and slightly elevated (lordotic) in relation to the axis of the vertebral column. The shortness of the basichondrocranium of these fetuses is caused by the underdevelopment of the occipital bone specially noticeable in its basal component (basioccipital). This basic defect has resulted in a short and small posterior cerebral fossa which is inadequate to contain the developing nervous structures of that region. The developing cerebellum is displaced downward to an anomalous position just above the foramen magnum; and, the developing medulla is compressed or crowded into the small posterior cerebral fossa of affected fetuses. The lordotic elevation of the basichondrocranium is also responsible for the reduction of the pontine flexure and the increased angle of the cervical flexure of the hindbrain found in these fetuses. All of these neurological anomalies, which are characteristic and diagnostic of clinical ACm as well, are considered here to be secondary to the axial skeletal defects rather than primary abnormalities, as is generally believed. The peculiar type of protrusion of the odontoid process into the cranial cavity found in fetuses with ACM, as well as in those with cranioschisis aperta and occulta, is also considered to be caused by the slight depression of the underdeveloped basioccipital and therefore, comparable to the so-called basilar impression often described in clinical ACM. This study has emphasized various developmental features which are closely related with the morphogenesis of ACM, including: the somitic origin of the occipital bone, and the late growth of the cerebellum which is predominantly postnatal in almost all experimental animals. It has been pointed out that some developmental defects involving the occipital bone and the caudal vertebral column, such as those which characterize ACM type II, may be more closely related than previously recognized. It has been also pointed out that the so-called cerebellar herniation into the cervical spinal canal described in the human disease represents a late addition to this disorder which is related to the relatively late growth of the cerebellum...

Myelomeningocele before birth.

The authors report a study of 92 human embryos and four fetuses with myeloschisis. The characteristics of embryonic myeloschisis compared with spina bifida cystica in infants are: 1) the lesion is often more diffuse, involving the whole spinal cord (12 embryos); 2) the cervical cord is frequently affected (23 of the remaining 80 embryos); 3) holoprosencephaly is frequently associated (18 embryos); 4) meningocele is not found; and 5) hydrocephalus and Arnold-Chiari malformation are not yet developed. Hydrocephalus and Arnold-Chiari malformation are found in myeloschistic fetuses. Almost all embryos with diffuse and cervical myeloschisis or with holoprosencephaly are extruded before birth by spontaneous abortion. Absence of meningocele in the embryonic period implies that its appearance is deferred to the fetal period. The development of hydrocephalus and Arnold-Chiari malformation also seems to be delayed until the fetal period. Our observation implies that myelomeningocele is induced by non-closure of the neural tube, not by rupture once it was closed. "Neural overgrowth" and disturbed "recanalization process" are discussed in relation to the pathogenesis of myelomeningocele.

In vitro high-field magnetic resonance imaging-documented anatomy of a fetal myelomeningocele at 20 weeks' gestation. A contribution to the rationale of intrauterine surgical repair of spina bifida.

OBJECT: It remains uncertain if closure of a myelomeningocele at midgestation changes the neurological condition at birth in an infant born with spina bifida. The authors conducted a study to provide a detailed analysis of the morphology of the spinal cord with the myelomeningocele at the time fetal surgery usually is performed. METHODS: The myelomeningocele of a 20-week-gestation-age fetus was examined, and data were compared with those obtained in a neurologically intact specimen of the same age. In vitro high-field 9.4-tesla magnetic resonance (MR) microscopy was used to examine the fetal material. High-field MR spectroscopy provided images in the three orthogonal planes with a resolution comparable with low-power optical microscopy. The authors observed that the fetal cord of the myelomeningocele specimen was tapered and tethered at S3-4 while the conus medullaris in the normal fetus reaches L-4. No neurulation defects were noted. The axial MR images clearly revealed the nonfusion of the mesodermal structures. The absence of neurulation defects suggests that at least in some cases of spina bifida the spinal cord initially is well developed but is damaged later on chemically and mechanically. This might be an argument in favor of intrauterine myelomeningocele repair. By 20 weeks' gestation, however, the deformation of the cord inside the myelomeningocele is severe. An optimization of the preoperative assessment by means of MR imaging therefore might be considered a valuable contribution to intrauterine surgery. The in vitro high-field MR microscopic findings of this study could be used as references for clinical intrauterine MR imaging. CONCLUSIONS: The detailed in vitro high-field MR analysis of a 20-week-gestation-age fetus with spina bifida demonstrated that an improvement of the preoperative intrauterine imaging should be pursued to detect those cases without neurulation defects and with minimal deformation of the spinal cord.

Pre-natal ventriculomegaly and hydrocephalus.

Ultrasonic imaging of the human fetal brain has allowed ventriculomegaly and hydrocephalus to be categorized. In this study 40 fetuses with ventriculomegaly and 21 with an Arnold-Chiari malformation and a myelomeningocele had ventriculomegaly that resolved, stabilised or progressed in utero. Within the progressive group were those with hydrocephalus, hydrocephalus being defined as expansion of the cerebral ventricular atria together with disproportionate increase in the head circumference. The prognosis for fetuses with resolving and stable ventriculomegaly was good, reflecting the fact that the ventricular dilatation in these cases was probably caused by delayed parenchymal and cerebrospinal fluid pathway development. Whereas the prognosis for progressive ventriculomegaly was generally poor, suggesting that the causes were likely to have been chromosomal, genetic, an infective agent or a catastrophic event which had an adverse effect on parenchymal development. The causes of hydrocephalus also adversely affected brain development but additional damage was caused by raised intracranial pressure.