Cerebellar Patterning Defects in Mutant Mice

The cerebellar cortex is highly compartmentalized and serves as a remarkable model for pattern formation throughout the brain. In brief, the adult cerebellar cortex is subdivided into five anteroposterior units—transverse zones—and subsequently, each zone is divided into ∼20 parasagittal stripes. Zone-and-stripe pattern formation involves the interplay of two parallel developmental pathways—one for inhibitory neurons, the second for excitatory. In the inhibitory pathway, progenitor cells of the 4th ventricle generate the Purkinje cells and inhibitory interneurons. In the excitatory pathway, progenitor cells in the upper rhombic lip give rise to the external granular layer, and subsequently to the granular layer of the adult. Both the excitatory and inhibitory developmental pathways are spatially patterned and the interactions of the two generate the complex topography of the adult. This review briefly describes the cellular and molecular mechanisms that underly zone-and-stripe development with a particular focus on mutations known to interfere with normal cerebellar development and the light they cast on the mechanisms of pattern formation.

Effects of Compression of the 4th Ventricle (CV4) Treatment on Medical Student Anxiety

Introduction: This study explores the effects of one Compression of the 4th Ventricle (CV4) treatment performed by experienced osteopathic physicians on reactive anxiety in healthy medical students. Anxiety was assessed with heart rate, blood pressure, and the Hamilton Anxiety Scale (HAM-A). Methods: Western University of Health Sciences IRB #15/IRB/113 was obtained for this single blind study. Volunteer first and second year medical students naïve to Osteopathic Cranial Manipulative Medicine, both in curriculum and as a patient, were recruited for this two-day study. Students were de-identified and demographic information was collected. On the first day, all 64 students received a sham treatment. Eight practitioners agreed on CV4 and sham techniques (mastoid cranial hold). In the CV4 technique, the operator’s thenar eminences contact the lateral angles of the occiput, and the operator encouraged the extension phase and discouraged the flexion phase of the CRI. Compression continued until a still point was reached in each student as identified by the practitioner. Students were evaluated before and after treatment using heart rate, blood pressure, and the Hamilton Anxiety Rating Scale (HAM-A). Results: No significant difference was found in demographics of the two groups. A significant difference between sham and CV4 treatments was found for heart rate (p=0.036), but not for systolic or diastolic blood pressure (p=0.446 and p=0.799, respectively). Average heart rate reduction of CV4 group was 3.11 and of sham group was 1.12, with p=0.036 (Mann Whitney U = 1271). Heart rate increased in a few students after both CV4 and sham treatments. Average HAM-A score for students before and after CV4 treatment were 21.9 and 18.3, with an average net reduction of 3.58 compared to the sham’s 2.77, but results were not found to be statistically significant (p=0.09, U=1172). Conclusion: A statistically significant average reduction in heart rate, but not in blood pressure or HAM-A scores, was found after CV4 treatment compared to sham treatment. More studies with larger samples are needed to further investigate the effects of CV4.

3D Reconstruction of the Clarified Rat Hindbrain Choroid Plexus

The choroid plexus (CP) acts as a regulated gate between blood and cerebrospinal fluid (CSF). Despite its simple histology (a monostratified cuboidal epithelium overlying a vascularized stroma), this organ has remarkably complex functions several of which involve local interaction with cells located around ventricle walls. Our knowledge of CP structural organization is mainly derived from resin casts, which capture the overall features but only allow reconstruction of the vascular pattern surface, unrelated to the overlying epithelium and only loosely related to ventricular location. Recently, CP single cell atlases are starting to emerge, providing insight on local heterogeneities and interactions. So far, however, few studies have described CP spatial organization at the mesoscale level, because of its fragile nature and deep location within the brain. Here, using an iDISCO-based clearing approach and light-sheet microscopy, we have reconstructed the normal rat hindbrain CP (hCP) macro- and microstructure, using markers for epithelium, arteries, microvasculature, and macrophages, and noted its association with 4th ventricle-related neurovascular structures. The hCP is organized in domains associated to a main vessel (fronds) which carry a variable number of villi; the latter are enclosed by epithelium and may be flat (leaf-like) or rolled up to variable extent. Arteries feeding the hCP emerge from the cerebellar surface, and branch into straight arterioles terminating as small capillary anastomotic networks, which run within a single villus and terminate attaching multiple times to a large tortuous capillary (LTC) which ends into a vein. Venous outflow mostly follows arterial pathways, except for the lateral horizontal segment (LHS) and the caudal sagittal segment. The structure of fronds and villi is related to the microvascular pattern at the hCP surface: when LTCs predominate, leaflike villi are more evident and bulge from the surface; different, corkscrew-like villi are observed in association to arterioles reaching close to the CP surface with spiraling capillaries surrounding them. Both leaf-like and corkscrew-like villi may reach the 4th ventricle floor, making contact points at their tip, where no gap is seen between CP epithelium and ependyma. Contacts usually involve several adjacent villi and may harbor epiplexus macrophages. At the junction between medial (MHS) and lateral (LHS) horizontal segment, arterial supply is connected to the temporal bone subarcuate fossa, and venous outflow drains to a ventral vein which exits through the cochlear nuclei at the Luschka foramen. These vascular connections stabilize the hCP overall structure within the 4th ventricle but make MHS-LHS joint particularly fragile and very easily damaged when removing the brain from the skull. Even in damaged samples, however, CP fronds (or isolated villi) often remain strongly attached to the dorsal cochlear nucleus (DCN) surface; in these fronds, contacts are still present and connecting “bridges” may be seen, suggesting the presence of real molecular contacts rather than mere appositions.

Stereotactic surgery for neurocysticercosis of the 4th ventricle: illustrative cases

BACKGROUND Neurocysticercosis, caused by the larval stage of Taenia solium, affects the cerebral ventricles in 20–30% of cases and may lead to hydrocephalus and other neurological morbidity. Conventional treatment for cysts in the 4th ventricle includes open surgery (suboccipital approach) and neuroendoscopy, with the latter being the option of choice. Stereotactic surgery, minimally invasive, offers a good alternative for this type of deep lesion. OBSERVATIONS The authors report the cases of two women, 30 and 45 years old, who presented with headache, dizziness, and ataxia and were diagnosed with 4th ventricle cysticercosis. Magnetic resonance imaging (MRI) revealed dilated 4th ventricles (approximately 2.5 cm in both cases, with cystic images inside the ventricular cavity). Both patients were treated with stereotactic surgery via a suboccipital transcerebellar approach. Cyst material was extracted, and the diagnosis was confirmed by pathological examination. The surgeries had no complications and resulted in clinical improvement. Control MRI scans showed reduction of the volume of the ventricle without residual cysts. LESSONS Minimally invasive stereotactic surgery provided a safe alternative for 4th ventricle neurocysticercosis cysts, with more benefits than risks in comparison with conventional techniques.

Unmet Needs in Clinical Practice: A Proposal and Application of A Diagnostic and Severity Scale to Grade Cerebellar Mutism Syndrome

BACKGROUND: The post-operative Pediatric Cerebellar Mutism Syndrome (CMS) affects about one-third of children and adolescents following surgical removal of a posterior fossa tumor (PFT). According to the Posterior Fossa Society consensus working definition, CMS is characterized by delayed onset mutism/reduced speech and emotional lability after cerebellar or 4th ventricle tumor surgery in children, with additional common features that include hypotonia and oropharyngeal dysfunction/dysphagia. The main objective of this work was to propose a diagnostic scale to grade CMS duration and severity.METHOD: Thirty consecutive subjects, aged 1-17 years (median 8 years, IQR 7) were evaluated with the proposed Post-Operative Pediatric CMS Survey after surgical resection of a PFT and, in cases of CMS, for the next 30 days after the onset (T0) or until symptom remission. At day 30th (T1), CMS was classified into mild, moderate, or severe according to the proposed Scale.RESULTS: CMS occurred in 13 patients (43.3%, 95% C.I.: 25.5-62.6%), with mild severity in 4 cases (31%), moderate in 4 (31%), and severe in 5 (38%). At T1, longer symptom persistence was associated with greater severity (p=0.01). Greater severity at T0 predicted greater severity at T1 (p=0.0001). Children with a midline tumor location and those aged under 5 years at diagnosis were at higher risk of CMS (p=0.025 and p=0.008, respectively).CONCLUSIONS: The proposed scale is a simple and applicable tool for estimating the severity of CMS at its onset, monitoring its course over time, and providing an early prognostic stratification to guide treatment decisions.

MEIS-WNT5A axis regulates development of 4th ventricle choroid plexus

The choroid plexus (ChP) produces cerebrospinal fluid and forms a critical brain barrier. ChP tissues form in each brain ventricle, each one adopting a distinct shape, but remarkably little is known about the mechanisms underlying ChP development. Here, we show that epithelial WNT5A is critical for determining fourth ventricle (4V) ChP morphogenesis and size. Systemic Wnt5a knockout, or forced Wnt5a overexpression beginning at E10.5, profoundly reduced ChP size and development. However, Wnt5a expression was enriched in Foxj1-positive epithelial cells of 4V ChP plexus, and its conditional deletion in these cells affected the branched, villous morphology of the 4V ChP. We found that WNT5A was enriched in epithelial cells localized to the distal tips of 4V ChP villi, where WNT5A acted locally to activate non-canonical Wnt signaling via Ror1/Ror2 receptors. During 4V ChP development, MEIS1 bound to the proximal Wnt5a promoter, and gain- and loss-of-function approaches demonstrated that MEIS1 regulated Wnt5a expression. Collectively, our findings demonstrate a dual function of WNT5A in ChP development and identify MEIS transcription factors as upstream regulators of Wnt5a in the 4V ChP epithelium.

Morphometric Evaluation of Fourth Ventricle by Using Magnetic Resonance Imaging

Background: The fourth ventricle is one of the components of the ventricular system in the brain, along with the lateral and third ventricles. The ventricular size is considered as a potential indicator in determination of many brain diseases. There are dimensional differences between males and females which appeared larger in males. Aim: The aim of this study was to determine the radiological dimensions of fourth ventricle and to assess their relationship with gender and age. Subjects and methods: Brain Magnetic Resonance Images (MRI) of 100 patients (44 males and 56 females) were examined. The dimensions of the fourth ventricle were estimated. Additionally, the variation with sex and age were also described. After collection and checking of data, Statistical Package for Social Sciences (SPSS) was used for data entry and analysis. Results: The AP length of 4th ventricle of all patients ranged from 6.5-13.9 mm with mean (± SD) 10.67 ± 1.66 mm. In females, it ranged from 6.5-13.9 mm with mean (± SD) 10.48 ± 1.76 mm while in males; it ranged from 7-13.9 mm with mean (± SD) 10.92 ± 1.51 mm. The mean of 4th ventricle AP length of males were comparatively higher than females. Similarly, the 4th ventricle width of all patients ranged from 8.7-16.1 mm with mean (± SD) 12.06 ± 1.41 mm. In females, it ranged from 8.7-14.6 mm with mean (± SD) 11.85 ± 1.32 mm while in males; it ranged from 9.1-16.1 mm with mean (± SD) 12.32 ± 1.48 mm. The study showed that width of fourth ventricle was more than the AP length and both were greater in males than in females. AP length and width showed negative correlation with age. Conclusion: The normal reference values of ventricles obtained from MRI are necessary to form the baseline data for interpreting pathological changes, planning surgery, and determining presence and progress of some neurological diseases. Furthermore, the dimension of fourth ventricle should be taken into consideration during radiological reports and during clinical examination.

Spitzer: A case of tumor at the bottom of the diamond pit. Contribution to the knowledge of the posterior longitudinal bundle. (From the nervous department of Prof. Krafft-Ebing and from the laboratory of Prof. Obersteiner in Vienna). — Yearbooks f. Psychiatry and neurology. Vol. 18. 1899

The tuberculosis, located at the bottom of the 4th ventricle, destroyed: the triangular nucleus of the VIII pair, the left nucleus of the VI pair, part of the raphe, both posterior longitudinal bundles, the cerebral part of the left nucleus of the X pair, part of the left nucleus of Deitersa, the cerebral tracts from the left n. ambiguus n. vagi, roots VII and VI pairs.

LINC-16. MEDULLOBLASTOMA IN A BOY WITH RUBINSTEIN-TAYBI SYNDROME: A CASE REPORT

BACKGROUND Rubinstein–Taybi syndrome (RTS) is characterized by multiple congenital anomalies and associated with mutations in CREBBP (70%) and EP300 (5–10%). Previous reports have suggested an increased incidence of benign and possibly also malignant tumors, but the correlation remains unclear. Here we present a case of a patient with RTS and medulloblastoma. CLINICAL CASE: A 5-year-old male presented with increased intracranial pressure. An MRI revealed a 4.2 x 4.7 cm mass in the midline of cerebellum arising from the floor of 4th ventricle. The patient underwent a complete resection and pathology revealed medulloblastoma, classic histology. Staging established no disseminated disease. At diagnosis, a peculiar phenotype consisting in mild mental retardation, microcephaly, down-slanting palpebral fissures, broad nasal bridge, highly arched palate, mild micrognathia, screwdriver incisors and wide thumbs and toes was noted. Clinical genetics evaluation was consistent with RTS. Karyotype was performed and normal. Further genetics testing was not done. Treatment consisted in 8 cycles of chemotherapy and craniospinal radiation (2300 cGy to spine, 5500 cGy Total). At the end of treatment, there was no evidence of disease. He was under surveillance for 33 months free of disease, but relapsed with a supratentorial meningeal disease that ultimately resulted in death. CONCLUSION This report highlights the fact that pediatric medulloblastoma can be associated to RTS, in this case associated to classical histology and recurrent disease.