Continuous intraventricular vancomycin for treatment of ventriculitis using IRRAflow®: A case report

Background: Ventriculitis usually occurs as the result of infection and results in the inflammation of the ependymal lining of the ventricular system. Mortality rates remain high despite treatment. Case Description: We present the case of a 66-year-old man who presented with altered mental status and progressively became comatose. He was found to have fulminant ventriculitis due to a ruptured intracranial abscess. He was treated with bilateral IRRAflow® catheter (IRRAS, Stockholm, Sweden) placement through which continuous irrigation with vancomycin was initiated. Conclusion: This treatment was safe and led to improvement in the patient’s neurologic examination, imaging findings, and cerebrospinal fluid profiles.

The regulatory roles of motile cilia in CSF circulation and hydrocephalus

Background Cerebrospinal fluid (CSF) is an ultra-filtrated colorless brain fluid that circulates within brain spaces like the ventricular cavities, subarachnoid space, and the spine. Its continuous flow serves many primary functions, including nourishment, brain protection, and waste removal. Main body The abnormal accumulation of CSF in brain cavities triggers severe hydrocephalus. Accumulating evidence had indicated that synchronized beats of motile cilia (cilia from multiciliated cells or the ependymal lining in brain ventricles) provide forceful pressure to generate and restrain CSF flow and maintain overall CSF circulation within brain spaces. In humans, the disorders caused by defective primary and/or motile cilia are generally referred to as ciliopathies. The key role of CSF circulation in brain development and its functioning has not been fully elucidated. Conclusions In this review, we briefly discuss the underlying role of motile cilia in CSF circulation and hydrocephalus. We have reviewed cilia and ciliated cells in the brain and the existing evidence for the regulatory role of functional cilia in CSF circulation in the brain. We further discuss the findings obtained for defective cilia and their potential involvement in hydrocephalus. Furthermore, this review will reinforce the idea of motile cilia as master regulators of CSF movements, brain development, and neuronal diseases.

Case Report: Sellar Ependymomas: A Clinic-Pathological Study and Literature Review

Ependymomas are primary glial tumors arising from cells related to the ependymal lining of the ventricular system. They are classified into at least nine different molecular subtypes according to molecular phenotype, histological morphology, and tumor location. Primary sellar ependymoma is an extremely rare malignancy of the central nervous system, with only 12 known cases reported in humans. We herein report a case of ependymoma located at the pituitary region in a 44-year-old female patient and discuss the molecular subtype, natural history, clinical presentation, radiological findings, histological features, immunohistochemical characteristics, ultrastructural examinations, treatment, and prognosis of sellar ependymoma. This case report may serve as a helpful reference for clinicians and radiologists in clinical practice.

EPCT-22 SAFETY AND EFFICACY OF INTRAVENTRICULAR IMMUNOVIROTHERAPY WITH ONCOLYTIC HSV-1 G207 FOR TREATMENT OF LEPTOMENINGEAL DISEASE

Leptomeningeal metastatic disease (LMD) occurs in 30–50% of newly diagnosed and recurrent pediatric malignant cerebellar tumors and 20–45% of malignant supratentorial tumors. Radiation and chemotherapy often cause substantial long-term neurotoxicity and outcomes remain poor for patients with LMD. At recurrence, LMD is generally minimally responsive to conventional therapies. Immunovirotherapy with engineered oncolytic HSV-1 G207 has emerged as a promising treatment for children with high-grade brain tumors. G207 infects and kills tumor cells while sparing normal cells and stimulates a robust anti-tumor immune response. Intratumoral G207 inoculation demonstrated safety and preliminary efficacy in a pediatric Phase 1 trial in recurrent/progressive high-grade glioma (NCT02457845), and a Phase 2 trial (NCT04482933) is forthcoming. Additionally, a Phase 1 trial of intratumoral G207 in recurrent/progressive malignant pediatric cerebellar tumors is ongoing (NCT03911388). While intratumoral inoculation delivers G207 directly to a primary tumor, it requires neurosurgical procedures thereby limiting repeat doses. Thus, we sought to establish the safety and efficacy of intraventricular G207. Utilizing an immunocompetent, HSV-sensitive murine strain, we determined that a standard 1x107 plaque-forming units (PFU) dose of G207 resulted in damage to the ependymal lining. However, interferon induction with an intraventricular low-dose (1x104 PFU) of G207 or polyinosinic-polycytidylic acid (poly I:C), a toll-like receptor 3 agonist, three days prior to standard treatment dose protected the ependymal lining. This approach enabled safe delivery of multiple subsequent doses. Importantly, with these protective measures, G207 significantly prolonged survival in pediatric patient-derived xenograft models and an immunocompetent murine LMD model of group 3 medulloblastoma, the most aggressive and fatal subtype. Collectively, these data indicate that toxicity from intraventricular G207 can be safely mitigated prior to a therapeutic dose, and that intraventricular G207 effectively targets group 3 medulloblastoma including LMD. These findings provide support for clinical translation of intraventricular G207.

Kidins220 deficiency causes ventriculomegaly via SNX27-retromer-dependent AQP4 degradation

Several psychiatric, neurologic and neurodegenerative disorders present increased brain ventricles volume, being hydrocephalus the disease with the major manifestation of ventriculomegaly caused by the accumulation of high amounts of cerebrospinal fluid (CSF). The molecules and pathomechanisms underlying cerebral ventricular enlargement are widely unknown. Kinase D interacting substrate of 220 kDa (KIDINS220) gene has been recently associated with schizophrenia and with a novel syndrome characterized by spastic paraplegia, intellectual disability, nystagmus and obesity (SINO syndrome), diseases frequently occurring with ventriculomegaly. Here we show that Kidins220, a transmembrane protein effector of various key neuronal signalling pathways, is a critical regulator of CSF homeostasis. We observe that both KIDINS220 and the water channel aquaporin-4 (AQP4) are markedly downregulated at the ventricular ependymal lining of idiopathic normal pressure hydrocephalus (iNPH) patients. We also find that Kidins220 deficient mice develop ventriculomegaly accompanied by water dyshomeostasis and loss of AQP4 in the brain ventricular ependymal layer and astrocytes. Kidins220 is a known cargo of the SNX27-retromer, a complex that redirects endocytosed plasma membrane proteins (cargos) back to the cell surface, thus avoiding their targeting to lysosomes for degradation. Mechanistically, we show that AQP4 is a novel cargo of the SNX27-retromer and that Kidins220 deficiency promotes a striking and unexpected downregulation of the SNX27-retromer that results in AQP4 lysosomal degradation. Accordingly, SNX27 silencing decreases AQP4 levels in wild-type astrocytes whereas SNX27 overexpression restores AQP4 content in Kidins220 deficient astrocytes. Together our data suggest that the KIDINS220-SNX27-retromer-AQP4 pathway is involved in human ventriculomegaly and open novel therapeutic perspectives.

Retinal Ependymoma: A Rare Extra-Axial Presentation

Introduction/Objective Ependymomas are well-demarcated and slow-growing neuroepithelial neoplasms that comprise 3–9% of primary CNS tumors. The vast majority of ependymomas arise either intracranially, mostly in children, or in the spinal cord and are associated with ependymal lining. Histologic hallmarks are perivascular pseudorosettes, ependymal rosettes and alternating zones of nuclear crowding and nuclear free zones composed of coarse cell processes. In high grade ependymomas increased mitoses, necrosis and nuclear pleomorphism may be seen. Methods We present the case of a 63-year-old woman in with a past medical history of retinopathy of prematurity, glaucoma and right eye enucleation. She presented with a painful blind left eye refractory to medical treatment and subsequently underwent left eye enucleation. Results On histologic examination, an incidental retinal ependymoma was identified. The neoplastic cells were fusiform and had long coarsely fibrillar cell processes. Characteristic periodicity of nuclear crowding and scarcity was observed. In places, neoplastic cell processes extended radially to delicate and sometimes hyalinized blood vessels, forming so-called perivascular pseudorosettes. Definite ependymal rosettes were not recognized in the examined sections. Stigmata of chronicity were found, such as ischemic type necrosis, blood vessels with dystrophic calcifications and foci of ossification replete with fibroadipose tissue in the marrow spaces. The neoplastic cells labeled with antibodies against glial fibrillary acidic protein (GFAP), thus confirming glial lineage in the neoplastic cell. Additionally, there was scattered intracytoplasmic expression of epithelial membrane antigen (EMA) in a dot-like or circular pattern. The latter is well described in ependymomas and often used to support the diagnosis. Conclusion Ependymomas rarely occur at extracranial sites, such as the chest, abdomen and pelvis. We are presenting the fourth case of retinal ependymoma reported in literature. The tumor had classical immunomorphologic findings.

Supratentorial Pure Cortical Ependymoma: An Unusual Lesion Causing Focal Motor Aware Seizure

ABSTRACTEpendymomas usually arise from the ependymal lining cells of the ventricular system and central canal of the spinal cord. Supratentorial ependymoma is a rare entity with the variable clinical course. In a small number of cases, ependymoma arises from supratentorial parenchyma. Only a few cases are reported in the literature. We report a case of 3-year-old girl with left frontal mass. Total removal of the mass lesion was performed without any neurological deficit. Pathological examination of the excised tumor was consistent with anaplastic ependymoma. We have discussed management strategy of this rare entity.

Cervicothoracic nonterminal myelocystocele with mature teratoma

Nonterminal myelocystocele is a rare type of spinal dysraphism characterized by a closed defect with an underlying CSF-filled cyst, either contiguous with the central spinal canal or attached to the spinal cord by a fibrovascular stalk. The authors report the unusual case of a neonate with a prenatal diagnosis of cervicothoracic nonterminal myelocystocele who underwent postnatal surgical untethering of the lesion. Pathological analysis of the excised lesion revealed neuroglial tissue with an ependymal lining associated with a mature teratoma. Three months after surgery, the patient has normal lower-extremity sensorimotor function and no evidence of bowel or bladder dysfunction. To the best of the authors' knowledge, this is the first report of a patient with a nonterminal myelocystocele found to have an associated mature teratoma.

Pyogenic Ventriculitis ComplicatingAggregatibacter aphrophilusInfective Endocarditis: A Case Report and Literature Review

Pyogenic ventriculitis (PV) is an uncommon, but frequently fatal infection that results from inflammation of the ventricular ependymal lining associated with a purulent ventricular system. PV has been rarely reported as a secondary complication of infective endocarditis. Prompt diagnosis and treatment with appropriate culture-directed antibiotics with adequate central nervous system penetration is crucial when managing patients who are suspected of having PV. The present study reports on a fatal case of a previously well 42-year-old alcoholic woman with infective endocarditis caused byAggregatibacter aphrophilus,with secondary brain abscess and spontaneous rupture into the ventricles causing PV.