Enhanced Meningeal Lymphatic Drainage Ameliorates Neuroinflammation and Hepatic Encephalopathy in Cirrhotic Rats.

BACKGROUND & AIMS: Hepatic encephalopathy (HE) is a serious neurologic complication in patients with liver cirrhosis. Very little is known about the role of the meningeal lymphatic system in HE. We tested our hypothesis that enhancement of meningeal lymphatic drainage could decrease neuroinflammation and ameliorate HE. METHODS: A 4-week bile duct ligation model was used to develop cirrhosis with HE in rats. Brain inflammation in patients with HE was evaluated by using archived GSE41919. The motor function of rats was assessed by the rotarod test. Adeno-associated virus 8-vascular endothelial growth factor C (AAV8-VEGF-C) was injected into the cisterna magna of HE rats 1 day after surgery to induce meningeal lymphangiogenesis. RESULTS: Cirrhotic rats with HE showed significantly increased microglia activation in the middle region of the cortex (P < .001) as well as increased neuroinflammation, as indicated by significant increases in interleukin 1ß, interferon γ, tumor necrosis factor α, and ionized calcium binding adaptor molecule 1 (Iba1) expression levels in at least 1 of the 3 regions of the cortex. Motor function was also impaired in rats with HE (P < .05). Human brains of patients with cirrhosis with HE also exhibited up-regulation of proinflammatory genes (NFKB1, IbA1, TNF-α, and IL1ß) (n = 6). AAV8-VEGF-C injection significantly increased meningeal lymphangiogenesis (P = .035) and tracer dye uptake in the anterior and middle regions of the cortex (P = .006 and .003, respectively), their corresponding meninges (P = .086 and .006, respectively), and the draining lymph nodes (P = .02). Furthermore, AAV8-VEGF-C decreased microglia activation (P < .001) and neuroinflammation and ameliorated motor dysfunction (P = .024). CONCLUSIONS: Promoting meningeal lymphatic drainage and enhancing waste clearance improves HE. Manipulation of meningeal lymphangiogenesis could be a new therapeutic strategy for the treatment of HE.

Correlation of hydromyelia with subarachnoid hemorrhage-related hydrocephalus: an experimental study.

Although the central canal is an integral component of the cerebral ventricular system, central canal dilation has not been examined adequately during the progression of subarachnoid hemorrhage-related hydrocephalus (SAH-H). Central canal dilation-associated ependymal cell desquamation or subependymal membrane rupture has been rarely reported. Herein, we try to describe possible mechanisms of central canal dilation "Hydromyelia," developing after SAH. A total of 25 New Zealand hybrid female rabbits were recruited. Five served as controls, and five received sham operations. In the remaining animals (n = 15), 0.5 mL/kg of autologous blood was injected into the cisterna magna twice on 0 and 2nd days. Five of these animals died within a few days. A total of 10 survivor animals decapitated 3 weeks later, and the brains and cervical spinal cords were histologically examined. Central canal volumes, ependymal cell numbers on the canal surfaces, and the Evans' indices of the ventricles were compared. On histological examination, central canal occlusion with desquamated ependymal cells and basement membrane rupture were evident. The mean Evans' index of the brain ventricles was 0.31, the mean central canal volume was 1.054 mm3, and the normal ependymal cell density was 4.210/mm2 in control animals; the respective values were 0.34, 1.287 mm3, and 3.602/mm2 for sham-operated animals, and 0.41, 1.776 mm3, and 2.923/mm2 in the study group. The differences were statistically significant (p < 0.05). Hydromyelia, an ignored complication of SAH-H, features ependymal cell desquamation, subependymal basement membrane destruction, blood cell accumulation on the subependymal cell basement membrane, and increased CSF pressure. Hydromyelia may be a significant complication following SAH.

Cisterna magna meningiomas without dural attachment: Report of two cases.

Meningiomas within the cisterna magna without dural attachment are extremely rare. To the best of our knowledge, only three cases of meningiomas within the cisterna magna have been reported in the literature. The authors present two cases of patient with the cisterna magna meningioma without dural attachment. (Case 1) A 36-year-old female presented with a 10-month history of numbness in the left hand. Magnetic resonance imaging (MRI) disclosed the presence of a contrast-enhanced tumor in the posterior fossa. A suboccipital craniectomy was performed, and the tumor located within the cisterna magna with no attachment to the dura. Diagnosis is made as clear cell meningioma. The postoperative course was uneventful, and a recurrence has not been observed for three years. (Case 2) A 58-year-old man presented with a well-circumscribed mass in the posterior fossa. At surgery, the tumor located within the cisterna magna with a connection to the right tenia. The tumor was totally removed without neurological deficits. At a 7-year follow-up, no evidence of a recurrence was observed. It is quite difficult to preoperatively diagnose as a cisterna magna meningioma without dural attachment. However, complete removal of the tumor should be achieved.

Widespread and efficient transduction of spinal cord and brain following neonatal AAV injection and potential disease modifying effect in ALS mice.

The architecture of the spinal cord makes efficient delivery of recombinant adeno-associated virus (rAAV) vectors throughout the neuraxis challenging. We describe a paradigm in which small amounts of virus delivered intraspinally to newborn mice result in robust rAAV-mediated transgene expression in the spinal cord. We compared the efficacy of rAAV2/1, 2/5, 2/8, and 2/9 encoding EGFP delivered to the hindlimb muscle (IM), cisterna magna (ICM), or lumbar spinal cord (IS) of neonatal pups. IS injection of all four capsids resulted in robust transduction of the spinal cord with rAAV2/5, 2/8, and 2/9 vectors appearing to be transported to brain. ICM injection resulted in widespread expression of EGFP in the brain, and upper spinal cord. IM injection resulted in robust muscle expression, with only rAAV2/8 and 2/9 transducing spinal motor and sensory neurons. As proof of concept, we use the IS paradigm to express murine Interleukin (IL)-10 in the spinal cord of the SOD1-G93A transgenic mouse model of amyotrophic lateral sclerosis. We show that expression of IL-10 in the spinal axis of SOD1-G93A mice altered the immune milieu and significantly prolonged survival. These data establish an efficient paradigm for somatic transgene delivery of therapeutic biologics to the spinal cord of mice.

Wide field fluorescent imaging of extracellular spatiotemporal potassium dynamics in vivo.

Potassium homeostasis is fundamental for the physiological functioning of the brain. Increased [K(+)] in the extracellular fluid has a major impact on neuronal physiology and can lead to ictal events. Compromised regulation of extracellular [K(+)] is involved in generation of seizures in animal models and potentially also in humans. For this reason, the investigation of K(+) spatio-temporal dynamics is of fundamental importance for neuroscientists in the field of epilepsy and other related pathologies. To date, the majority of studies investigating changes in extracellular K(+) have been conducted using a micropipette filled with a K(+) sensitive solution. However, this approach presents a major limitation: the area of the measurement is circumscribed to the tip of the pipette and it is not possible to know the spatiotemporal distribution or origin of the focally measured K(+) signal. Here we propose a novel approach, based on wide field fluorescence, to measure extracellular K(+) dynamics in neural tissue. Recording the local field potential from the somatosensory cortex of the mouse, we compared responses obtained from a K(+)-sensitive microelectrode to the spatiotemporal increases in fluorescence of the fluorophore, Asante Potassium Green-2, in physiological conditions and during 4-AP induced ictal activity. We conclude that wide field imaging is a valuable and versatile tool to measure K(+) dynamics over a large area of the cerebral cortex and is capable of capturing fast dynamics such as during ictal events. Moreover, the present technique is potentially adaptable to address questions regarding spatiotemporal dynamics of other ionic species.

CSF flow pathways through the ventricle-cistern interfaces in kaolin-induced hydrocephalus rats-laboratory investigation.

PURPOSE: The goal of this study was to identify direct cerebrospinal fluid (CSF) pathways in the interface between ventricles and cisterns. Such routes are hypothesized to be involved in alternative CSF flows in abnormal circumstances of CSF circulation. METHODS: Chronic obstructive hydrocephalus models were induced in ten Sprague-Dawley rats with kaolin injection into the cisterna magna. Three weeks after the kaolin injection, when thick arachnoid fibrosis obliterated the fourth ventricular outlets, cationized ferritin was stereotactically infused as a tracer into the lateral ventricle in order to observe the pathways from the ventricles to the subarachnoid space. Animals were killed in 48 h and brains were sectioned. CSF flow pathways were traced by the staining of ferritin with ferrocyanide. RESULTS: Eight out of ten rats developed hydrocephalus. The subarachnoid membranes of the convexity and basal cisterns were severely adhered such that most of the ferritin remained in the ventricles whereas basal and convexity cisterns were clear of ferritin. In six out of the eight hydrocephalus rats, ferritin leaked from the third ventricle into the quadrigeminal cistern, and from the lateral ventricle into the ambient cistern. CONCLUSIONS: The interfaces between the third ventricle and the quadrigeminal cistern, and between the lateral ventricle and the ambient cistern appear to be alternative CSF pathways in a pathologic condition such as obstructive hydrocephalus.

Psychiatric manifestations associated with mega cisterna magna.

The Dandy-Walker variant is a milder form of the Dandy-Walker complex and is characterized by normal-sized posterior fossa, mild vermian hypoplasia, and a cystic lesion that communicates with the fourth ventricle. This syndrome has been described in association with schizophrenia, obsessive-compulsive disorder, manic episode, psychosis (delusional type), and recurrent catatonia. The authors present two cases of mega cisterna magna associated with mania and catatonic schizophrenia.

Intracisternal interleukin-1 receptor antagonist prevents postoperative cognitive decline and neuroinflammatory response in aged rats.

To investigate the role of the pro-inflammatory cytokine interleukin-1ß (IL-1ß) in postoperative cognitive dysfunction (POCD) in aged rats, we used laparotomy to mimic human abdominal surgery in adult (3 months) and aged (24 months) F344/BN rats. We demonstrated that memory consolidation of the hippocampal-dependent contextual fear-conditioning task is significantly impaired in aged but not young rats 4 d after surgery. Hippocampal-independent auditory-cued fear memory was not disrupted by laparotomy in either age group. The hippocampal-dependent memory impairment was paralleled by elevations of IL-1ß in the hippocampus of aged animals 1 and 4 d after surgery. These findings support our substantial line of previous research showing that aged animals are more vulnerable to cognitive decline after a peripheral immune challenge. In addition, we demonstrated that a single intracisternal administration of interleukin-1 receptor antagonist (IL-1RA; 112 µg) at the time of surgery was sufficient to block both the behavioral deficit and the neuroinflammatory response. Injecting the same dose of IL-1RA peripherally failed to have a protective effect. These data provide strong support for the specific role of central, not peripheral, IL-1ß in POCD. Furthermore, the long-lasting presence of IL-1RA in the brain (4 d) compared with in the blood (<24 h) underscores the value of intracisternal administration of IL-1RA for therapeutic purposes.

Spontaneous resolution of syringomyelia in an adult patient with tight cisterna magna.

Spontaneous resolution of syringomyelia in adult patients with Chiari malformation is exceptionally rare, with only 10 cases having been reported. A 21-year-old man working as a carpenter presented with a 1-year history of paresthesias in his right arm. A magnetic resonance imaging scan disclosed a cervicothoracic syrinx associated with tight tonsillar impaction of the cisterna magna without herniation. The patient left the carpentry job and underwent close monitoring with serial clinical and neuroradiological controls. The patient's symptoms gradually disappeared and magnetic resonance imaging studies revealed progressive shrinkage of the syrinx despite persistence of crowding of posterior fossa structures at the level of the foramen magnum. This case suggests that spontaneous resolution of syringomyelia can occasionally be triggered by the cessation of daily physical strain in patients with tight cisterna magna. Health care professionals should be aware that strenuous physical activities could affect the natural history of syringomyelia.

Morphological and morphometric analysis of the hippocampus in Wistar rats with experimental hydrocephalus.

BACKGROUND: The present study aims at better establishing the alterations caused by the usual enlargement of brain ventricles in this structure. METHODS: Hydrocephalus was induced in 7-day-old Wistar rats by the injection of kaolin into the cisterna magna. Morphological studies were performed on the hippocampus 7, 14 and 21 days after injection. The total number of neurons in each hippocampus subarea as well as that of pyknotic neurons were counted. Then we calculated the pyknotic index (PI) by hippocampal subarea, taking into account the level of ventricular dilatation and time of induction of hydrocephalus. RESULTS: PI was statistically larger in the CA1 subarea of the experimental group after 1 week of hydrocephalus induction as compared to the corresponding control as well as in animals that had developed mild hydrocephalus in groups G1, G2 and G3. CONCLUSION: Hydrocephalus caused morphological alterations in the hippocampus, leading to important changes in its shape.

Initial experience with combined endoscopic third ventriculostomy and choroid plexus cauterization for post-hemorrhagic hydrocephalus of prematurity: the importance of prepontine cistern status and the predictive value of FIESTA MRI imaging.

PURPOSE: Post-hemorrhagic hydrocephalus of prematurity (PHHP) is among the most common causes of infant hydrocephalus in developed nations. This population has a high incidence of shunt failure, infection, and slit ventricle syndrome. Although effective for other etiologies of infant hydrocephalus, the efficacy of combined endoscopic third ventriculostomy and choroid plexus cauterization (ETV/CPC) in PHHP has not been investigated. This pilot study reports the initial experience. METHODS: Ten patients (four grade III and six grade IV intraventricular hemorrhage) requiring definitive treatment for PHHP underwent ETV/CPC within 6 months of birth. Seven had a prior ventriculo-subgaleal shunt. Mean age at birth was -12.8 weeks, or 25.2 weeks gestation (24-28 weeks), and at surgery was -1.6 weeks (-11 to +11 weeks). Mean weight at surgery was 3.3 (1.0-5.5 kg). Each patient had preoperative magnetic resonance imaging (MRI) with fast imaging employing steady-state acquisition (FIESTA). RESULTS: Four of ten (40%) required no further operations related to hydrocephalus (mean follow-up, 29.7 months). Six required another procedure (five ultimately shunted). Prepontine cistern status correlated with outcome (p = 0.033). Procedures in all infants with unobstructed cisterns were successful but failed in six of seven with cisternal obstruction, with the one success having an alternative lamina terminalis endoscopic third ventriculostomy. Preoperative MRI FIESTA images correlated well with intraoperative assessment of the cistern. CONCLUSIONS: Results from this small homogenous cohort suggest cistern status is an important determinant of outcome. FIESTA imaging correlated with endoscopic observation. Preliminary analysis suggests ETV/CPC as an effective treatment for PHHP, but only when the cistern is unscarred. This information should guide patient selection for future study protocols.

Phase-contrast MRI and 3D-CISS versus contrast-enhanced MR cisternography for the detection of spontaneous third ventriculostomy.

PURPOSE: To compare the diagnostic efficacies of phase-contrast MRI (PC-MRI) and three-dimensional constructive interference in steady-state (3D-CISS) sequence for the detection of spontaneous third ventriculostomy (STV) on the basis of contrast-enhanced MR cisternography (MRC). PATIENTS AND METHODS: Eleven obstructive hydrocephalus patients with clinically-radiologically suspected STV and ten controls were examined by PC-MRI, 3D-CISS and MRC. PC-MRI and 3D-CISS sequence were applied to view the third ventricle and basal cisterns. Following injection of 0.5-1ml intrathecal Gd-DTPA injection, postcontrast MRC images were obtained in three planes. Presence of STV was scored as follows: grade 0, no existence of STV; grade 1, STV present. Results of PC-MRI and 3D-CISS were compared with the MRC findings. RESULTS: In PC-MRI, five patients were assessed as grade 0 and six cases grade 1. As a result of 3D-CISS sequence, eight cases were evaluated as grade 0 and three cases grade 1. Based on MRC, nine cases were assessed as grade 0 and two cases grade 1. False positivity was found in four cases by PC-MRI and in one case by 3D-CISS. The sensitivity, specificity and accuracy of PC-MRI and 3D-CISS sequence regarding demonstration of STV, were 100, 100, 56, 89, 64, and 91% respectively. DISCUSSION: PC-MRI and 3D-CISS are helpful in confirming the STV. PC-MRI and 3D-CISS should be the first preference. If PC-MRI and 3D-CISS give negative results, then MRC is not required. MRC should be performed on patients who demonstrate suspected STV findings on PC-MRI and 3D-CISS sequences. MRC may prevent false positive results.

Impaired meningeal lymphatic vessels exacerbate early brain injury after experimental subarachnoid hemorrhage.

BACKGROUND AND PURPOSE: Blood that enters the subarachnoid space (SAS) and its breakdown products are neurotoxic and are the principal inducers of brain injury after subarachnoid hemorrhage (SAH). Recently, meningeal lymphatic vessels (MLVs) have been proven to play an important role in clearing erythrocytes that arise from SAH, as well as other macromolecular solutes. However, evidence demonstrating the relationship between MLVs and brain injury after SAH is still limited. Therefore, we performed this study to observe the effects of meningeal lymphatic impairment on early brain injury (EBI) after experimental SAH. METHODS: The MLVs of C57BL/6 male adult mice were ablated by injecting Visudyne into the cisterna magna and transcranially photoconverting it with laser light. The MLVs were then examined by immunofluorescence staining for lyve-1. Next, both the MLV-ablated group and the control group (normal mice) underwent filament perforation to model SAH or sham operation. We assessed the cortical perfusion of all the mice before SAH induction, 5 min after SAH and 24 h after SAH. In addition, we evaluated neurological function deficits by Garcia scores and measured brain water content at 24 h post SAH. Then, neuroinflammation and neural apoptosis in the mouse brain were also examined. RESULTS: Visudyne and transcranial photoconversion treatment notably ablated mouse MLVs. Five minutes after SAH induction, cortical perfusion was significantly impaired, and after 24 h, this impairment was ameliorated considerably in the control group but ameliorated only slightly or worsened in the MLV-ablated group. Additionally, the MLVablated group presented worse neurological function deficits and more severe brain edema than the control group. More notably, neuroinflammation and neural apoptosis were also observed. CONCLUSION: Ablation of MLVs by Visudyne treatment exacerbated EBI after experimental SAH in mice. The worsening of EBI may have arisen from limited drainage of blood and other breakdown products, which are thought to cause brain edema, neuroinflammation, neuronal apoptosis and other pathological processes.

Subtemporal-Transtentorial Approach for Microsurgical Resection of Hemorrhagic Ambient Cistern Arteriovenous Malformation.

Arteriovenous malformations (AVMs) of the ambient cistern are an extremely rare and complex subgroup of vascular malformation, representing a clinical challenge due to the deep-seated, highly eloquent anatomic location and the debilitating, life-threatening consequences related to hemorrhagic presentation and surgical morbidity. Ultimately, a tailored treatment, based on the presenting symptoms, AVM angioarchitecture, and annual risk of hemorrhage should be discussed among a multidisciplinary team to find the best individualized strategy balancing between the pros and cons of each approach. In Video 1, we present the case of a 60-year-old man with a hemorrhaged AVM of the right ambient cistern, present the pros and cons of each possible treatment strategy, and illustrate the successful resection of this lesion through a subtemporal-transtentorial microsurgical approach.

An Uncommon Case of Neuroenteric Cyst Located at the Lateral Cerebellomedullary Cistern.

We present the case of a 42-year-old woman with a 5-week history of headache, progressive dysphagia, dysphonia, and hoarseness. A brain magnetic resonance imaging revealed an extra-axial cyst of the left lateral cerebellomedullary cistern. The subsequent histopathologic examination diagnosed a neuroenteric cyst. This case sheds light on the pivotal role of histologic identification of neuroenteric cyst, which could be crucial for further diagnostic investigations, especially in pediatric patients.

Intracranial tumors: cisternal angle as a measure of midbrain compression for assessing risk of postembolization clinical deterioration.

PURPOSE: To identify objective imaging characteristics that are predictors of clinical deterioration after embolization of large intracranial tumors. MATERIALS AND METHODS: This HIPAA-compliant retrospective study was approved by the institutional review board, and informed consent was waived. The records of twelve patients with large intracranial tumors who underwent embolization were analyzed for imaging characteristics that would portend acute neurologic deterioration following embolization. The degree of midbrain compression was calculated by using the cisternal angle (the angle formed at the intersection of a line drawn along the midsagittal plane and a line drawn along the anterior aspect of the cerebral peduncle). Angiograms were evaluated for the degree of pre- and postembolization tumor blush. Neurologic status before and after embolization was evaluated. The Wilcoxon signed rank test was used to compare the cisternal angles ipsilateral and contralateral to the tumor. The cisternal angle was measured in 100 control subjects with no mass lesions to evaluate its normal distribution. RESULTS: Of the 12 patients, three experienced acute clinical deterioration after embolization. A feature common to these patients was substantial preprocedure midbrain compression, as indicated by a cisternal angle of less than 25 degrees , which was significantly less than the mean angle in the control group. Another consistent risk factor was a strong initial tumor blush pattern and a major blush reduction following embolization. CONCLUSION: Cisternal angle is an objective measure of midbrain compression. The presence of a cisternal angle less than 25 degrees (indicating severe midbrain compression), strong tumor blush, and major postprocedure blush reduction are predictors of clinical deterioration after embolization.

A new approach for observing cerebral cisterns and ventricles via a percutaneous lumbosacral route by using fine, flexible fiberscopes.

OBJECT: To establish a new method for the diagnosis of central nervous system diseases, the authors visualized the cerebral cisterns and ventricles via a percutaneous lumbosacral route by using newly developed fine, flexible fiberscopes. METHODS: Fine, flexible fiberscopes, 0.9 and 1.4 mm in diameter, were introduced up to the cerebral cisterns and ventricles through a percutaneous lumbosacral route in awake patients with chronic headache and/or neck pain or those undergoing spinal surgery and in whom MR imaging did not disclose any particular abnormalities in the brain. A lumbosacral subarachnoid puncture was made with a modified method of a continuous epidural block. RESULTS: In 25 of 31 patients tested, the cerebellomedullary and/or pontine/interpeduncular cisterns were easily and safely reached, and the brainstem structures were visualized. Advancement of the fiberscope beyond the spinal level was abandoned in 6 patients with adhesive spinal arachnoiditis, because the fiberscopes encountered resistance seemingly caused by arachnoid adhesions. Further advancement of the fiberscopes up to the fourth and third ventricles was successfully achieved in 2 patients. A number of arachnoid filaments were found in the cerebellomedullary cistern in 4 patients: 2 with chronic spinal arachnoiditis, 1 with a spinal arachnoid cyst, and 1 with posttraumatic pain syndrome. None of the patients reported pain or any major complication except a postspinal headache and light fever, which were encountered in 4 and 1 patient, respectively. CONCLUSIONS: The approach to the supraspinal structures via the lumbosacral route by using a fine, flexible fiberscope may provide a new, minimally invasive, and safe way to observe the cerebral cisterns and/or brainstem regions.

Non-dysraphic intramedullary lipoma of the craniocervical region in an adult: Case report.

Intradural spinal lipomas with intracranial extension are very rare and are typically diagnosed in childhood. Radical surgical excision usually causes a high rate of morbidity because of the firm adherence between the lipoma and neural tissues. In this report, we present a case of craniocervical intradural intramedullary lipoma in an adult patient. The patient underwent surgery with excision of the mass, leaving a sheet of lipoma on the tumor bed.

The Clinical and Molecular Characteristics of Molybdenum Cofactor Deficiency Due to MOCS2 Mutations.

BACKGROUND: We explored the clinical and molecular characteristics of molybdenum cofactor deficiency due to MOCS2 muations. METHODS: We summarize the genetic and clinical findings of previously reported patients with a MOCS2 mutation. We also present a new patient with novel neuroradiological findings associated with molybdenum cofactor deficiency due to a novel homozygous variant in the 5' untranslated region of the MOCS2 gene. RESULTS: The study population comprised 35 patients with a MOCS2 gene mutation. All reported children had delayed motor milestones. The major initial symptom was seizures in neonatal period. Facial dysmorphism was present in 61% of the patients. Only one patient had ectopia lentis. Agenesis of the corpus callosum and an associated interhemispheric cyst in our case are novel neuroradiological findings. CONCLUSIONS: The occurrence of neonatal seizures and feeding difficulties can be the first clinical signs of molybdenum cofactor deficiency. Although there is no effective therapy for this condition, early diagnosis and genetic analysis of these lethal disorders facilitate adequate genetic counseling.