Prenatal Cerebellar Disruptions: Neuroimaging Spectrum of Findings in Correlation with Likely Mechanisms and Etiologies of Injury.

There is increasing evidence that the cerebellum is susceptible to prenatal infections and hemorrhages and that congenital morphologic anomalies of the cerebellum may be caused by disruptive (acquired) causes. Starting from the neuroimaging pattern, this report describes a spectrum of prenatal cerebellar disruptions including cerebellar agenesis, unilateral cerebellar hypoplasia, cerebellar cleft, global cerebellar hypoplasia, and vanishing cerebellum in Chiari type II malformation. The neuroimaging findings, possible causative disruptive events, and clinical features of each disruption are discussed. Recognition of cerebellar disruptions and their differentiation from cerebellar malformations is important in terms of diagnosis, prognosis, and genetic counselling.

MR imaging of the fetal cerebellar vermis: Biometric predictors of adverse neurologic outcome.

PURPOSE: To provide normal biometry of the cerebellar vermis using fetal MR and determine threshold values associated with abnormal neurologic outcome. MATERIALS AND METHODS: Cerebellar vermis biometry was applied in prospective, cross-sectional evaluation of fetal brains. Vermis length and inferior vermian distance were obtained in mid-sagittal planes using T2-weighted, single-shot sequences with 1.5 Tesla MR. Measurements were compared with reference nomograms from a retrospective review of fetal brains with normal intracranial anatomy. Observed and predicted measurements of the cerebellar vermis were recorded. Neurologic outcome was classified as normal or abnormal. Unpaired t-tests and discriminate analysis were applied to the two measurements and differences between the observed and predicted values. RESULTS: The reference group included 64 fetuses of 13 to 38 weeks gestation. Both vermis length and inferior vermian distance increased linearly with time (r = 0.92, P < 0.001; r = 0.32, P = 0.01). The prospective group included 64 additional fetuses with documented normal (39/64, 61%) and abnormal (25/64, 39%) outcomes. Significant differences were seen in vermis length, inferior vermian distance, and correlation with predicted values based on neurologic outcome (P < 0.001). Vermis length discrepancy ≥ 4 mm or inferior vermian distance ≥ 4 mm were associated with abnormal neurologic outcome. CONCLUSION: MR measurements of a short, raised vermis characterized by a vermis length discrepancy ≥ 4 mm or an inferior vermian distance ≥ 4 mm is associated with abnormal neurologic, syndromic, and developmental outcomes. J. Magn. Reson. Imaging 2016;44:1284-1292.

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.

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.

The Meckel syndrome protein meckelin (TMEM67) is a key regulator of cilia function but is not required for tissue planar polarity.

Meckel syndrome (MKS) is a lethal disorder associated with renal cystic disease, encephalocele, ductal plate malformation and polydactyly. MKS is genetically heterogeneous and part of a growing list of syndromes called ciliopathies, disorders resulting from defective cilia. TMEM67 mutation (MKS3) is a major cause of MKS and the related ciliopathy Joubert syndrome, although the complete etiology of the disease is not well understood. To further investigate MKS3, we analyzed phenotypes in the Tmem67 null mouse (bpck) and in zebrafish tmem67 morphants. Phenotypes similar to those in human MKS and other ciliopathy models were observed, with additional eye, skeletal and inner ear abnormalities characterized in the bpck mouse. The observed disorganized stereociliary bundles in the bpck inner ear and the convergent extension defects in zebrafish morphants are similar to those found in planar cell polarity (PCP) mutants, a pathway suggested to be defective in ciliopathies. However, analysis of classical vertebrate PCP readouts in the bpck mouse and ciliary organization analysis in tmem67 morphants did not support a global loss of planar polarity. Canonical Wnt signaling was upregulated in cyst linings and isolated fibroblasts from the bpck mouse, but was unchanged in the retina and cochlea tissue, suggesting that increased Wnt signaling may only be linked to MKS3 phenotypes associated with elevated proliferation. Together, these data suggest that defective cilia loading, but not a global loss of ciliogenesis, basal body docking or PCP signaling leads to dysfunctional cilia in MKS3 tissues.

Investigating embryonic expression patterns and evolution of AHI1 and CEP290 genes, implicated in Joubert syndrome.

Joubert syndrome and related diseases (JSRD) are developmental cerebello-oculo-renal syndromes with phenotypes including cerebellar hypoplasia, retinal dystrophy and nephronophthisis (a cystic kidney disease). We have utilised the MRC-Wellcome Trust Human Developmental Biology Resource (HDBR), to perform in-situ hybridisation studies on embryonic tissues, revealing an early onset neuronal, retinal and renal expression pattern for AHI1. An almost identical pattern of expression is seen with CEP290 in human embryonic and fetal tissue. A novel finding is that both AHI1 and CEP290 demonstrate strong expression within the developing choroid plexus, a ciliated structure important for central nervous system development. To test if AHI1 and CEP290 may have co-evolved, we carried out a genomic survey of a large group of organisms across eukaryotic evolution. We found that, in animals, ahi1 and cep290 are almost always found together; however in other organisms either one may be found independent of the other. Finally, we tested in murine epithelial cells if Ahi1 was required for recruitment of Cep290 to the centrosome. We found no obvious differences in Cep290 localisation in the presence or absence of Ahi1, suggesting that, while Ahi1 and Cep290 may function together in the whole organism, they are not interdependent for localisation within a single cell. Taken together these data support a role for AHI1 and CEP290 in multiple organs throughout development and we suggest that this accounts for the wide phenotypic spectrum of AHI1 and CEP290 mutations in man.

Cerebellar white matter injury following systemic endotoxemia in preterm fetal sheep.

Injury to the cerebellum and brainstem is becoming increasingly recognized in prematurely born infants. The role of infection/inflammation in mediating damage to those structures in the preterm brain is largely unknown. Preterm fetal sheep (70% gestation) received either saline-vehicle (control group; n=11) or Escherichia coli lipopolysaccharide (100 ng intravenous [i.v.]; lipopolysaccharide [LPS] group; n=9), and were allowed to recover for 3 days before sacrifice. A diffuse pattern of cerebellar white matter damage was observed in all animals exposed to LPS, while focal cerebellar white matter lesions were observed in three out of nine animals, and an intragyral white matter hemorrhage in one animal. Cerebellar white matter injury was associated with a statistically significant loss of oligodendrocyte transcription factor-2-positive oligodendrocytes and increased terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling-positive cell counts. Ionized calcium binding adapter molecule 1 (Iba1)-positive cells which had the morphology of activated microglia were commonly observed in areas of injury. There was no obvious injury to the cerebellar cortex or to cerebellar Purkinje cells, and no obvious injury in any region of the brainstem. These data provide support for a role of infection/inflammation in selective white matter injury in the immature cerebellum, and demonstrate a differential vulnerability of the brainstem and cerebellar white matter to injury at this time.

The fetal cerebellum. Pitfalls in diagnosis and management.

Prenatal diagnosis of congenital and acquired cerebellar disorders is possible by the use of ultrasound (US) and magnetic resonance imaging (MRI). Although numerous studies have been conducted in this field, diagnostic uncertainties are still common in daily clinical practice. This review outlines five possible pitfalls in the diagnosis of fetal cerebellar disorders: confusion between different entities describing vermian pathologies (Dandy-Walker variant, vermian hypoplasia and vermian agenesis); premature diagnosis of abnormal vermian formation; difficulties in the ultrasonographic differentiation between the cerebellar hemispheres and the vermis; late development of cerebellar hypoplasia/atrophy and differential diagnosis of unilateral cerebellar findings.

Uteroplacental inflammation results in blood brain barrier breakdown, increased activated caspase 3 and lipid peroxidation in the late gestation ovine fetal cerebellum.

Maternal infection is associated with perinatal brain damage, but effects on the cerebellum are not known in detail. In this study, we examined the effects of placental inflammation induced by administering lipopolysaccharide into the uterine artery of pregnant sheep at 134-136 days gestation. The fetal brain was collected 72 h later and compared to brains collected from age-matched untreated fetuses. Placental lipopolysaccharide treatment had substantial effects on the fetal cerebellum, including increasing the number of cells undergoing apoptosis, widespread lipid peroxidation, and extravasation of plasma albumin, suggesting compromise of the cerebellar blood-brain barrier. These effects may account for some of the learning and motor deficits that emerge in neonates from pregnancies compromised by infection.

Disorders of cerebellar growth and development.

PURPOSE OF REVIEW: This review summarizes for the pediatrician the current understanding of normal cerebellar and brainstem development, and then discusses selected malformations to highlight advances in the area. The impact of prematurity on cerebellar growth and development is then examined. The important insights provided by recent neuroimaging and genetic advances are reviewed. RECENT FINDINGS: Previous areas of dispute are being addressed by advances in two major areas. Advanced neuroimaging studies during fetal and postnatal life are now providing important insights into the nature of normal and abnormal development of the brainstem and cerebellum. These powerful new techniques for defining morphology in vivo, together with major advances in genetics, are accelerating our understanding of genotype-phenotype relationships. Conversely, the ability to link early brain injury to subsequent cerebellar development has challenged previous understanding of the distinction between acquired and primary dysgenesis, presumed to be genetic in origin. SUMMARY: The synthesis of a rational and clinically useful classification of posterior fossa malformations has been elusive. Recent developments promise to resolve ongoing disputes that have delayed progress. However, these insights into disturbed structural development demand rigorous examination of their long-term functional significance and caution before their prognostic significance is applied clinically.

[Cerebellar cortical dysplasia: MRI aspects and significance]. / Dysplasie du cortex cérébelleux: aspects en IRM et signification.

Because it is now possible to obtain high-resolution multiplanar MR imaging of the cerebellum and because of the developing interest on the role of the cerebellum on higher brain functions, we have decided to study the process of cerebellar fissuration. All brain MRI examinations performed in children for varied neurological and neurosurgical indications, especially children with non-specific mental retardation and patients with cerebral malformation detected at initial imaging work-up, were reviewed. Fissuration and lobulation anomalies (abnormal orientation of fissures, pseudopolymicrogyria, cortical thickening, subcortical cysts and heterotopia) were identified that we called cerebellar cortical dysplasia (CCD). In order to better understand the origin of this malformation, current data on cerebellar embryogenesis and histogenesis will be reviewed, and the pathological and radiological features will be illustrated. Milder forms of CCD represent a distinct group of anomalies that should be distinguished from other types of cerebellar dysplasia (agenesis, hypoplasia or complex dysplasia with involvement of the cerebellar vermis (rhombencephalosynapsis)) or combined cerebellar and cerebral dysplasia (muscular dystrophies and lissencephaly). Recognition of cerebellar cortical dysplasia could be a first step towards a broader understanding of its pathogenesis and significance.

Prenatal diagnosis of capillary telangiectasia of the cerebellum--ultrasound and MRI features.

OBJECTIVE: To report three cases of capillary telangiectasia (CT) of the cerebellum revealed as focal cerebellar lesions. METHODS: Ultrasound and magnetic resonance imaging (MRI) were performed in all cases in the prenatal period. Prenatal imaging findings were compared with either post-mortem examination (case 1) or post-natal MRI (cases 2 & 3). RESULTS: A discrepancy between a hyperechoic lesion without any mass effect on sonogram and normal T1 and T2 spin-echo fetal magnetic resonance images was found in all cases. The diagnosis of CT was made on post-mortem examination in case 1. Prenatal ultrasound and magnetic resonance imaging findings were suggestive of the diagnosis in cases 2 and 3. In both cases, the pregnancy was managed conservatively and the diagnosis of CT was documented on post-natal MRI after gadolinium injection. CONCLUSION: The diagnosis of CT of the cerebellum was strongly suggested in these three cases in the prenatal period by the combination of ultrasound and fetal MRI findings. In the vast majority of cases, CT has a benign clinical course and complication with haemorrhage appears to be exceedingly rare. This fact should be taken into account in the prenatal counselling.

[Imaging of the pediatric cerebellum]. / Imagerie du cervelet de l'enfant.

After a brief overview of embryology, histogenesis, anatomy, as well as terminology, the authors will review the main acquired (neoplastic and non-neoplastic) and congenital (malformative and non-malformative) cerebellar pathologies through a pictorial essay. Even though there is some overlap, malformations are classified into agenesis, hypoplasia, and dysplasia, either cystic or non-cystic. Their embryological origin will be discussed. The main known syndromes associated with vermian agenesis will be reviewed. Non-neoplastic acquired cerebellar lesions, including atrophy and isolated signal anomalies, will be briefly reviewed. A classification of the main cerebellar malformations will be proposed.

Prenatal sonographic diagnosis of vermal agenesis.

Agenesis of the vermis as detected during gestation by ultrasonography may indicate the existence of various malformation arrays or syndromes. We report on our observations of five cases of complete vermal agenesis that were detected at 22-31 weeks of gestation. All had a vertex presentation and transvaginal sonography established the diagnosis of vermal agenesis. Two of the vermal agenesis cases had no associated anomalies outside the central nervous system (CNS). In one, the cerebellar cleft was the only abnormality present and the other also had lobar holoprosencephaly. The three remaining fetuses had trisomy 13 and featured various additional extra-CNS anomalies. The association of complete vermal agenesis and trisomy 13 has not been previously reported. Our experience with this series suggests that supplementation with vaginal fetal sonography is a valuable tool for obtaining a more accurate view of the posterior fossa whenever a cyst or a cyst-like abnormality is detected by transabdominal sonography. A finding of isolated vermal agenesis appears to mandate a careful search for additional anomalies and the performance of karyotype analysis.

Chronological and immunohistochemical observations of cerebellar dysplasia and vermis defect in the hereditary cerebellar vermis defect (CVD) rat.

Hereditary cerebellar vermis defect (CVD) rats, a new neurological mutant, developed both cerebellar vermis defect and cerebellar dysplasia. Developmental alterations in the cerebellum of the CVD rats were studied chronologically and immunohistochemically. The earliest architectural abnormality was a maldevelopment of the inferior cerebellar peduncle from embryonic day 17 (E17), leading to an indistinct separation between the cerebellum and the pons. From E19, the CVD rats lacked vermis development and, therefore, the cerebellar hemispheres were fused. After birth, Purkinje cells and external granule cells (EGCs) penetrated into the pontine tissue, but retained their normal position until postnatal day 10. Cerebellar lamination began to be disturbed due to abnormal perivascular aggregations of the EGCs, resulting in convoluted and occasionally perivascular lamination. There were no Bergmann glia in the heterotopic cerebellum of the pons, and abnormally arranged Bergmann glia were observed in the mildly disorganized cerebellar hemispheres. Immunohistochemistry for calbindin revealed that abnormal orientation of the Purkinje cells might be related to the perivascular EGCs. Parvalbumin-immunopositive microneurons were seen only in the disarranged molecular layers, and synaptophysin-immunopositive cerebellar glomeruli were present in the afflicted internal granular layers. These findings suggest that perivascular EGCs may play an important role in cerebellar dysplasia and the developmental plasticity in the altered cerebellogenesis.

[Inhalation of organic solvents during the last third of pregnancy in Sprague-Dawley rats. Somatometric and cerebellar consequences in newborn animals]. / Inhalación de solventes orgánicos durante el último tercio del embarazo de ratas Sprague-Dawley. Consecuencias somatométricas y cerebelosas en neonatos.

Cerebellar morphogenesis as well as somatometric parameters of progenies from mothers exposed to ethyl-ether, chloroform, turpentine or thinner were registered a 24, 48 and 7 hours of age. 1. Mortality rate of 20 and 59% was observed in progenies of thinner or turpentine exposed mothers, correspondingly. 2. Delay of intrauterine growth manifested by body weight, size and cephalic diameter was evident in chloroform exposed groups (P < 0.01). 3. Cerebellar maturation delay was found in thinner or turpentine prenatally exposed litters. 4. The number of Purkinje cells was significantly reduced in ethyl-ether and chloroform exposed groups (P < 0.01). These cells were found less affected by thinner or turpentine exposure (P < 0.01).

The antioxidant butylated hydroxytoluene can retard cerebellar degeneration induced transplacentally by a single low dosage of N-methyl-N-nitrosourea.

Late-onset cerebellar degeneration can be induced transplacentally in mice by a single low-dose (1 mg/kg) injection of the direct-acting DNA alkylating agent N-methyl-N-nitrosourea (MNU) on day 16 of pregnancy. The offspring develop a mild ataxia that manifests by 12-16 weeks of age postnatally when the animals are challenged with a motor coordination task. Morphological evidence of degeneration includes pyknosis of Purkinje cells and abnormal foliation patterns. Additionally, these animals demonstrate a progressive retinopathy characterized by thinning of the nuclear and plexiform layers of the retina. Efforts to retard the cerebellar degeneration were undertaken in the present study. MNU-exposed and control animals were fed a standard mouse chow diet supplemented with 0.75% butylated hydroxytoluene (BHT), an antioxidant. This supplementation commenced 24 h following exposure to the teratogen and continued throughout the life of the offspring. A second group of MNU-exposed and control mice were fed a non-BHT-supplemented, standard Purina mouse chow diet. Quantitative histological evaluation of cerebellar coronal sections indicated that by 4 weeks of age BHT-fed, MNU-exposed mice had significantly fewer pyknotic Purkinje cells than non-BHT-fed, MNU-exposed animals. This was true for the vermal, paravermal, and lateral areas of the cerebellum. The findings suggest the usefulness of teratogenic models of degenerative diseases for the testing of potential intervention strategies.