Utilization trends in cerebrospinal fluid shunt infection prevention techniques in the United States from 2007 to 2015.

OBJECTIVE: The objective of this study was to describe trends in the utilization of infection prevention techniques (standard care, intrathecal [IT] antibiotics, antibiotic-impregnated catheters [AICs], and combination of IT antibiotics and AICs) among participating hospitals over time. METHODS: This retrospective cohort study at six large children's hospitals between 2007 and 2015 included children ≤ 18 years of age who underwent initial shunt placement between 2007 and 2012. Pediatric Health Information System + (PHIS+) data were augmented with chart review data for all shunt surgeries that occurred prior to the first shunt infection. The Pearson chi-square test was used to test for differences in outcomes. RESULTS: In total, 1723 eligible children had initial shunt placement between 2007 and 2012, with 3094 shunt surgeries through 2015. Differences were noted between hospitals in gestational age, etiology of hydrocephalus, and race and ethnicity, but not sex, weight at surgery, and previous surgeries. Utilization of infection prevention techniques varied across participating hospitals. Hydrocephalus Clinical Research Network hospitals used more IT antibiotics in 2007-2011; after 2012, increasing adoption of AICs was observed in most hospitals. CONCLUSIONS: A consistent trend of decreasing IT antibiotic use and increased AIC utilization was observed after 2012, except for hospital B, which consistently used AICs.

Polyvinylpyrrolidone-coated catheters decrease choroid plexus adhesion and improve flow/pressure performance in an in vitro model of hydrocephalus.

PURPOSE: Proximal catheter obstruction is the leading cause of ventricular shunt failure in pediatric patients. Our aim is to evaluate various types of shunt catheters to assess in vitro cellular adhesion and obstruction. METHODS: Four catheter types were tested: (1) antibiotic and impregnated, (2) barium-stripe polyvinylpyrrolidone coated (PVP), (3) barium-stripe, and (4) barium-impregnated. Catheters were seeded with choroid plexus epithelial cells to test cellular adhesion and inoculated with the same cells to test flow/pressure performance under choroid plexus growth conditions. Ventricular catheters were placed into a three-dimensional printed phantom ventricular replicating system through which artificial cerebrospinal fluid (CSF) was pumped. Differential pressure sensors were used to measure catheter performance. RESULTS: PVP catheters had the lowest median cell attachment (10 cells) compared to antibiotic-impregnated (230 cells), barium stripe (513 cells), and barium-impregnated (146 cells) catheters after culture (p < 0.01). In addition, PVP catheters (- 0.247 cm H2O) and antibiotic-impregnated (- 1.15 cm H2O) catheters had significantly lower pressure in the phantom ventricular system compared to the barium stripe (0.167 cm H2O) and barium-impregnated (0.618 cm H2O; p < 0.01) catheters. CONCLUSIONS: PVP catheters showed less cellular adhesion and, together with antibiotic-impregnated catheters, required less differential pressure to maintain a consistent flow. Our findings suggest clinical relevance for using PVP ventricular catheters in patients with recurrent catheter obstruction by choroid plexus.

Is Antihelminthics Necessary in Postoperative Treatment of Intraventricular Neurocysticercosis? A Systematic Review.

OBJECTIVE: Patients with intraventricular neurocysticercosis (IVNCC) may require cerebrospinal fluid diversion surgery for late-onset hydrocephalus in the postsurgical period. Controversy exists regarding cysticidal treatment. Our main objective was to compare surgically treated cases of IVNCC that received postoperative anthelmintics with those that did not regard the incidence and treatment of late-onset hydrocephalus. METHODS: We searched the Medline database and extracted the following data: age, gender, stage of development of cysticercosis, type of operation, frequency of delayed hydrocephalus, cerebrospinal fluid diversion surgery, outcome, and follow-up. RESULTS: We analyzed 130 articles on intraventricular cysticercosis and identified 117 cases of isolated IVNCC and 314 patients in the case-control series who met inclusion criteria. There was no significant difference in postoperative delayed hydrocephalus between isolated IVNCC and case-control study groups. Children under the age of 16 received anthelmintic drugs more frequently during the postoperative period. Statistical relevance was observed in all patient groups regarding the application of steroids in favor of cysticidal therapy Endoscopy was a better option than craniotomy for cases of isolated IVNCC and case-control studies. Other variables were not relevant. CONCLUSIONS: Patients who received antihelminths did not show a statistically significant reduction in delayed hydrocephalus compared to individuals who did not receive after surgical resection of the parasite. Corticosteroid therapy prevailed in people who have been treated with anthelmintics. Children under the age of 16 were administered anthelmintic drugs more frequently during the postoperative period. Endoscopy was the preferred method for all groups, but some patients with cysts in the fourth ventricle required a craniotomy.

Celecoxib attenuates neuroinflammation, reactive astrogliosis and promotes neuroprotection in young rats with experimental hydrocephalus.

Hydrocephalus is a neurological condition with altered cerebrospinal fluid flow (CSF). The treatment is surgical and the most commonly used procedure is ventricle-peritoneal shunt. However, not all patients can undergo immediate surgery or achieve complete lesion reversal. Neuroprotective measures are valuable in such cases. It was evaluated whether the use of celecoxib, a selective inhibitor of COX-2, associated or not with ventricular-subcutaneous derivation, could offer benefits to the brain structures affected by experimental hydrocephalus. Seven-day-old male Wistar Hannover rats induced by intracisternal injection of kaolin 15% were used, divided into five groups with ten animals each: intact control (C), untreated hydrocephalus (H), hydrocephalus treated with celecoxib 20 mg/kg intraperitoneal (HTC), hydrocephalus treated with shunt (HTS) and hydrocephalus treated with shunt and celecoxib 20 mg/kg intraperitoneal (HTCS). Celecoxib was administered for 21 consecutive days, starting the day after hydrocephalus induction and continuing until the end of the experimental period. The surgery was performed seven days after inducing hydrocephalus. Multiple assessment methods were used, such as behavioral tests (water maze and open field), histological analysis (hematoxylin and eosin), immunohistochemistry (caspase-3, COX-2, and GFAP), and ELISA analysis of GFAP. The results of the behavioral and memory tests indicated that celecoxib improves the neurobehavioral response. The improvement can be attributed to the reduced neuroinflammation (p < 0.05), and astrogliosis (p < 0.05) in different brain regions. In conclusion, the results suggest that celecoxib holds great potential as an adjuvant neuroprotective drug for the treatment of experimental hydrocephalus.

Minocycline attenuates hydrocephalus and inhibits iron accumulation, ependymal damage and epiplexus cell activation after intraventricular hemorrhage in aged rats.

Intracerebral hemorrhage is primarily a disease of the elderly and it is frequently accompanied by intraventricular hemorrhage (IVH) which can lead to posthemorrhagic hydrocephalus and poor prognosis. Red blood cell iron has been implicated in brain injury after cerebral hemorrhage. The current study examined using T2* magnetic resonance imaging (MRI) to detect periventricular iron deposition after IVH and investigated the effects of minocycline on hydrocephalus in an aged rat IVH model. It had three parts. In part 1, male aged rats received a 200 µl injection of saline or autologous blood into the lateral ventricle and were euthanized at day 14. In parts 2 and 3, aged IVH rats were treated with vehicle or minocycline and euthanized at day 7 or 14. Rats underwent MRI to quantify hydrocephalus and iron deposition followed by brain histology and immunohistochemistry. Periventricular iron overload was found after IVH using T2* MRI and confirmed by histology. IVH also caused ventricular wall damage and increased the number of CD68(+) choroid plexus epiplexus cells. Minocycline administration reduced iron deposition and ventricular volume at days 7 and 14 after IVH, as well as ventricle wall damage and epiplexus cell activation. In summary, IVH-induced hydrocephalus is associated with periventricular iron deposition, ependymal damage and choroid plexus epiplexus cell activation in aged rats. Minocycline attenuated those effects and might be a potential treatment for posthemorrhagic hydrocephalus in the elderly.

Inhibition of serum- and glucocorticoid-induced kinase 1 ameliorates hydrocephalus in preclinical models.

BACKGROUND: Hydrocephalus is a pathological accumulation of cerebrospinal fluid (CSF), leading to ventriculomegaly. Hydrocephalus may be primary or secondary to traumatic brain injury, infection, or intracranial hemorrhage. Regardless of cause, current treatment involves surgery to drain the excess CSF. Importantly, there are no long-term, effective pharmaceutical treatments and this represents a clinically unmet need. Many forms of hydrocephalus involve dysregulation in water and electrolyte homeostasis, making this an attractive, druggable target. METHODS: In vitro, a combination of electrophysiological and fluid flux assays was used to elucidate secretory transepithelial electrolyte and fluid flux in a human cell culture model of the choroid plexus epithelium and to determine the involvement of serum-, glucocorticoid-induced kinase 1 (SGK1). In vivo, MRI studies were performed in a genetic rat model of hydrocephalus to determine effects of inhibition of SGK1 with a novel inhibitor, SI113. RESULTS: In the cultured cell line, SI113 reduced secretory transepithelial electrolyte and fluid flux. In vivo, SI113 blocks the development of hydrocephalus with no effect on ventricular size of wild-type animals and no overt toxic effects. Mechanistically, the development of hydrocephalus in the rat model involves an increase in activated, phosphorylated SGK1 with no change in the total amount of SGK1. SI113 inhibits phosphorylation with no changes in total SGK1 levels in the choroid plexus epithelium. CONCLUSION: These data provide a strong preclinical basis for the use of SGK1 inhibitors in the treatment of hydrocephalus.

A Paternal Methylation Error in the Congenital Hydrocephalic Texas (H-Tx) Rat Is Partially Rescued with Natural Folate Supplements.

Folate deficiencies, folate imbalance and associated abnormal methylation are associated with birth defects, developmental delays, neurological conditions and diseases. In the hydrocephalic Texas (H-Tx) rat, 10-formyl tetrahydrofolate dehydrogenase (FDH) is reduced or absent from the CSF and the nuclei of cells in the brain and liver and this is correlated with decreased DNA methylation. In the present study, we tested whether impaired folate metabolism or methylation exists in sexually mature, unaffected H-Tx rats, which may explain the propagation of hydrocephalus in their offspring. We compared normal Sprague Dawley (SD, n = 6) rats with untreated H-Tx (uH-Tx, n = 6 and folate-treated H-Tx (TrH-Tx, n = 4). Structural abnormalities were observed in the testis of uH-Tx rats, with decreased methylation, increased demethylation, and cell death, particularly of sperm. FDH and FRα protein expression was increased in uH-Tx males but not in folate-treated males but tissue folate levels were unchanged. 5-Methylcytosine was significantly reduced in untreated and partially restored in treated individuals, while 5-hydroxymethylcytosine was not significantly changed. Similarly, a decrease in DNA-methyltransferase-1 expression in uH-Tx rats was partially reversed with treatment. The data expose a significant germline methylation error in unaffected adult male H-Tx rats from which hydrocephalic offspring are obtained. Reduced methylation in the testis and sperm was partially recovered by treatment with folate supplements leading us to conclude that this neurological disorder may not be completely eradicated by maternal supplementation alone.

Outcomes of Combined Endoscopic Surgery and Fibrinolytic Treatment Protocol for Intraventricular Hemorrhage: A Randomized Controlled Trial.

BACKGROUND: Intraventricular fibrinolysis (IVF) and endoscopic surgery (ES) are the new promising treatment strategies to enhance the rate of hematoma clearance, which might improve functional outcome. This study investigated and compared the outcomes among these interventions. METHODS: A randomized (1:1) double-blinded trial was carried out between August 2018 and December 2021. The intervention and control groups comprised patients receiving IVF and/or ES and external ventricular drainage (EVD), respectively. All participants had experienced primary or secondary intraventricular hemorrhage (IVH) from spontaneous intracerebral hemorrhage with obstructive hydrocephalus complications. The primary outcome was modified Rankin Scale score 180 days post treatment. Interim assessments were planned for every 50 participants enrolled to ensure safety and efficacy. RESULTS: After enrollment of 110 participants (55 participants in each group), there was a difference in 30-day mortality (2 [3.6%] vs. 13 [32.7%] in the EVD group, P = 0.002), reaching the predetermined boundaries for termination of the trial. We demonstrated a better favorable outcome (modified Rankin Scale score 0-3) at 180 days in the intervention group, compared with the control group (35 [63.6%] vs. 24 [43.6%], P = 0.04). Participants in the intervention group experienced a higher IVH removal rate (91% [9.0] vs. 69.5% [38.0], P < 0.01) and had lower shunt conversion (1 [1.8%] vs. 16 [29.3%], P < 0.01). Treatment complications were comparable between the two groups. CONCLUSIONS: This study demonstrated that combined ES and IVF is safe and effective for the treatment of IVH. In addition, it concluded that aggressive but safe procedures used to remove IVH could improve clinical outcome in patients with IVH.

Primary Intraventricular Phaeohyphomycosis: An Atypical Presentation of Neurotropic Fungus.

Cerebral fungal infections are usually reported secondary to contiguous spread from paranasal sinuses or orbit, hematogenous spread, traumatic brain injury, or immunocompromised conditions. Primary isolated intraventricular phaeohyphomycosis is rare. We report a 29-year-old man who presented with acute symptomatic unilateral hydrocephalus with an intraventricular lesion. Intraventricular endoscopy demonstrated 3 lesions along the choroid plexus with turbid cerebrospinal fluid. The lesions were yellowish in appearance. Excision of all lesions was done along with septostomy. The histopathology of the lesion as well as cerebrospinal fluid showed thin, septate, pigmented hyphae suggestive of phaeohyphomycosis. The patient initially responded to oral voriconazole but later developed acute symptoms and died 3 months after surgery despite continuous antifungal treatment. Primary intraventricular phaeohyphomycosis is uncommon and may have a dismal prognosis even with early diagnosis and prompt treatment.

Memantine associated with ventricular-subcutaneous shunt promotes behavioral improvement, reduces reactive astrogliosis and cell death in juvenile hydrocephalic rats.

Hydrocephalus is defined as the accumulation of cerebrospinal fluid in the brain ventricles. The usual treatment of hydrocephalus is surgical (shunt), but not all patients can undergo treatment immediately after diagnosis. Thus, neuroprotective measures were tested to minimize the tissue damage involved. Memantine is a non-competitive antagonist of the N-methyl-D-aspartate (NMDA) receptor, which has shown a neuroprotective action in neurodegenerative diseases. This study aimed to evaluate the neuroprotective response of memantine in animals treated with or without a ventricular-subcutaneous shunt. Seven-day-old male Wistar rats induced by intracisternal injection of kaolin were used, divided into five groups: intact control (n = 10), hydrocephalic (n = 10), hydrocephalic treated with memantine (20 mg/kg/day) (n = 10), hydrocephalic treated with shunt (n = 10), hydrocephalic treated with shunt and memantine (20 mg/kg/day) (n = 10). Memantine administration was started on the day after hydrocephalus induction and continued until the last day of the experimental period, totaling 21 consecutive days of drug application. The CSF shunt surgery was performed seven days after hydrocephalus induction. Behavioral tests (open field, and modified Morris water maze), histological, and immunohistochemical evaluations were performed. Treatment with memantine resulted in significant improvement (p < 0.05) in sensorimotor development, preservation of spatial memory, reduction of astrocytic reaction in the corpus callosum, cortex, and germinal matrix. When associated with the shunt, it has also been shown to reduce the cell death cascade. It is concluded that memantine is a promising adjuvant drug with beneficial potential for the treatment of lesions secondary to hydrocephalus.

Immune activation after intraventricular hemorrhage.

OBJECTIVES: Intraventricular hemorrhage (IVH) is a subtype of stroke which has high mortality and morbidity, while comprehensive mechanism investigations and effective therapies are still in great need. Plenty of studies have shown that inflammation after stroke plays a critical role in disease outcomes. However, the inflammation after IVH remains unclear. This study aims to observe the immune response after IVH, thus providing therapeutic targets for IVH treatments. MATERIALS AND METHODS: IVH was induced by autologous blood infusion model in SD rats. Totally 588 rats were assigned either in the sham or IVH group. T2* lesion and hemoglobin quantities, ventricular volume, brain edema, ventricular wall damage, blood-brain-barrier (BBB) continuity and immune response were observed by magnetic resonance image (MRI), hematoxylin-eosin staining (HE), Evans Blue, flow cytometry (FACS), and enzyme-linked immunosorbent assay (ELISA) at baseline, 6 h, 1 d, 3 d, 7 d, 14 d after surgery. RESULTS: We found that ventricular volume enlargement occurred hours after IVH and peaked at 3 d after IVH, then mildly reduced till 14 d. Similar changes happened in brain edema, ventricular wall damage and BBB leakage. Immune cells and cytokines in the central nervous system and peripheral blood also increased after IVH and experienced similar trends as ventricular enlargement. T2* lesion and hemoglobin degradation occurred 6 h after IVH and kept decreasing till 14 d after IVH. CONCLUSIONS: Our investigation illustrates that immune response exists after IVH, which may have a close relationship with disease outcomes. These results may provide promising immune related clues for mechanism and intervention studies in IVH.

Study of Compound Sanqi Nanoparticles for Local Infection of Hydrocephalus Patients after Neurosurgery Medium Craniocerebral Injury.

Panax notoginseng is the dried root and rhizome of Panax notoginseng, which has the effect of lowering blood lipid, lowering blood pressure and promoting blood circulation to remove blood stasis. At present, the research on Panax notoginseng is mainly focused on its pharmacological action and its compound preparation, but the research on the granule of Panax notoginseng is less. This paper mainly studied the clinical study of compound notoginseng nanoparticles in the treatment of local infection in patients with hydrocephalus after medium craniocerebral injury in neurosurgery. The purpose of this article is to investigate the effects of compound notoginseng nanoparticles on serum TNF-α, IL-2 and IL-6 in rats with craniocerebral injury and to verify the protective effect of compound notoginseng nanoparticles on the body after craniocerebral injury. In this paper, 90 patients admitted to a hospital in this city were divided into a control group, model group and compound notoginseng nanoparticle group. According to the Zealonga method, the neurological function deficit score of experimental rats in each group was evaluated. The levels of TNF-α, IL-2 and IL-6 in the serum of the three groups were observed 1, 3 and 5 days after treatment. RESULTS: Compared with serum TNF-α, IL-2 and IL-6 of the three groups, there were significant differences in the main effects of time and intervention (P < 0.05). CONCLUSIONS: Compound notoginseng nanoparticles can reduce the contents of TNF-α and IL-6 in serum and increase the expression of IL-2 in rats with craniocerebral injury.

Metformin Preserves VE-Cadherin in Choroid Plexus and Attenuates Hydrocephalus via VEGF/VEGFR2/p-Src in an Intraventricular Hemorrhage Rat Model.

Hydrocephalus induced by intraventricular hemorrhage (IVH) is associated with unfavorable prognosis. The increased permeability of choroid plexus and breakdown of the blood-brain barrier (BBB) was reported as a prominent mechanism of IVH-induced hydrocephalus, and vascular endothelial-cadherin (VE-cadherin) was demonstrated to be relevant. Metformin was reported to protect endothelial junction and preserve permeability widely; however, its role in hydrocephalus remains unclear. In this study, the decreased expression of VE-cadherin in the choroid plexus, accompanied with ventricle dilation, was investigated in an IVH rat model induced by intraventricular injection of autologous blood. Metformin treatment ameliorated hydrocephalus and upregulated VE-cadherin expression in choroid plexus meanwhile. We then observed that the internalization of VE-cadherin caused by the activation of vascular endothelial growth factor (VEGF) signaling after IVH was related to the occurrence of hydrocephalus, whereas it can be reversed by metformin treatment. Restraining VEGF signaling by antagonizing VEGFR2 or inhibiting Src phosphorylation increased the expression of VE-cadherin and decreased the severity of hydrocephalus after IVH. Our study demonstrated that the internalization of VE-cadherin via the activation of VEGF signaling may contribute to IVH-induced hydrocephalus, and metformin may be a potential protector via suppressing this pathway.

Neurocysticercosis Complicating Pregnancy.

OBJECTIVE: Infection with the pork tapeworm can result in neurocysticercosis caused by infestation of central nervous system tissues by the parasite cysts. Parenchymal brain infection can cause symptoms from mass effect that include headache, seizures, confusion, and even coma. Our objective was to describe the clinical course of neurocysticercosis infections in pregnant women. METHODS: This was a case series that described clinical findings and pregnancy outcomes of women diagnosed with neurocysticercosis from 1994 through 2016 at a single institution. Their medical records were reviewed, cranial computed tomography and magnetic resonance imaging scans were assessed, and the infections were classified according to the criteria of the 2018 Infectious Diseases Society of America and the American Society of Tropical Medicine and Hygiene. RESULTS: Overall, 37 pregnant women with neurocysticercosis were identified. Of the 37 women, 32 were symptomatic, and 16 each had severe headaches or new-onset seizures or other neurologic sequelae. Some of these women had multiple symptoms. Others were diagnosed when neuroimaging was done for a history of neurocysticercosis or evaluation of a preexisting seizure disorder. The most common treatment was with anthelmintics-albendazole, praziquantel, or both-usually given with anticonvulsants and corticosteroids to decrease inflammation. There were eight women in whom invasive neurosurgical procedures were performed, usually for hydrocephaly. Overall, 32 healthy neonates were born at term, and there was one preterm delivery at 34 weeks of gestation. The four pregnancy losses included two molar pregnancies, one anembryonic miscarriage, and a 23-week stillbirth of a pregnancy complicated by preeclampsia with severe features. CONCLUSION: Neurocysticercosis in pregnant women may be asymptomatic or result in headaches, seizures, confusion, nausea and vomiting, altered mental status, or obtundation. Anthelmintic treatment is usually successful, but in some women neurosurgical procedures are necessary to relieve obstructive hydrocephaly.

Ventriculoperitoneal shunt infection by Cryptococcus neoformans sensu stricto: Case report and literature review.

BACKGROUND: Cryptococcal ventriculoperitoneal shunt infection is known to occur due to an underlying infection in the patient rather than by nosocomial transmission of Cryptococcus during shunt placement. A case of chronic hydrocephalus due to cryptococcal meningitis that was misdiagnosed as tuberculous meningitis is described. CASE REPORT: Patient details were extracted from charts and laboratory records. The identification of the isolate was confirmed by PCR-restriction fragment length polymorphism of the orotodine monophosphate pyrophosphorylase (URA5) gene. Antifungal susceptibility was determined using the CLSI M27-A3 broth microdilution method. Besides, a Medline search was performed to review all cases of Cryptococcus ventriculoperitoneal shunt infection. Cryptococcus neoformans sensu stricto (formerly Cryptococcus neoformans var. grubii), mating-type MATα was isolated from the cerebrospinal fluid and external ventricular drain tip. The isolate showed low minimum inhibitory concentrations for voriconazole (0.06mg/l), fluconazole (8mg/l), isavuconazole (<0.015mg/l), posaconazole (<0.03mg/l), amphotericin B (<0.06mg/l) and 5-fluorocytosine (1mg/l). The patient was treated with intravenous amphotericin B deoxycholate, but died of cardiopulmonary arrest on the fifteenth postoperative day. CONCLUSIONS: This report underlines the need to rule out a Cryptococcus infection in those cases of chronic meningitis with hydrocephalus.

The Anti-Inflammatory Agent Bindarit Attenuates the Impairment of Neural Development through Suppression of Microglial Activation in a Neonatal Hydrocephalus Mouse Model.

Neonatal hydrocephalus presents with various degrees of neuroinflammation and long-term neurologic deficits in surgically treated patients, provoking a need for additional medical treatment. We previously reported elevated neuroinflammation and severe periventricular white matter damage in the progressive hydrocephalus (prh) mutant which contains a point mutation in the Ccdc39 gene, causing loss of cilia-mediated unidirectional CSF flow. In this study, we identified cortical neuropil maturation defects such as impaired excitatory synapse maturation and loss of homeostatic microglia, and swimming locomotor defects in early postnatal prh mutant mice. Strikingly, systemic application of the anti-inflammatory small molecule bindarit significantly supports healthy postnatal cerebral cortical development in the prh mutant. While bindarit only mildly reduced the ventricular volume, it significantly improved the edematous appearance and myelination of the corpus callosum. Moreover, the treatment attenuated thinning in cortical Layers II-IV, excitatory synapse formation, and interneuron morphogenesis, by supporting the ramified-shaped homeostatic microglia from excessive cell death. Also, the therapeutic effect led to the alleviation of a spastic locomotor phenotype of the mutant. We found that microglia, but not peripheral monocytes, contribute to amoeboid-shaped activated myeloid cells in prh mutants' corpus callosum and the proinflammatory cytokines expression. Bindarit blocks nuclear factor (NF)-kB activation and its downstream proinflammatory cytokines, including monocyte chemoattractant protein-1, in the prh mutant. Collectively, we revealed that amelioration of neuroinflammation is crucial for white matter and neuronal maturation in neonatal hydrocephalus. Future studies of bindarit treatment combined with CSF diversion surgery may provide long-term benefits supporting neuronal development in neonatal hydrocephalus.SIGNIFICANCE STATEMENT In neonatal hydrocephalus, little is known about the signaling cascades of neuroinflammation or the impact of such inflammatory insults on neural cell development within the perinatal cerebral cortex. Here, we report that proinflammatory activation of myeloid cells, the majority of which are derived from microglia, impairs periventricular myelination and cortical neuronal maturation using the mouse prh genetic model of neonatal hydrocephalus. Administration of bindarit, an anti-inflammatory small molecule that blocks nuclear factor (NF)-kB activation, restored the cortical thinning and synaptic maturation defects in the prh mutant brain through suppression of microglial activation. These data indicate the potential therapeutic use of anti-inflammatory reagents targeting neuroinflammation in the treatment of neonatal hydrocephalus.

C3/C3aR inhibition alleviates GMH-IVH-induced hydrocephalus by preventing microglia-astrocyte interactions in neonatal rats.

Activation of microglia and astrocytes following germinal matrix hemorrhage and intraventricular hemorrhage (GMH-IVH) plays a detrimental role in posthemorrhagic hydrocephalus (PHH). It is still unclear whether or how an interaction occurs between microglia and astrocytes in PHH. Here, we investigated the role of the C3/C3aR pathway in microglia and astrocyte interactions and whether C3/C3aR-targeted inhibition could alleviate PHH following GMH-IVH. A total of 152 Sprague-Dawley rats at postnatal day seven (P7) were enrolled in the study, and collagenase VII was used to induce GMH-IVH. Minocycline (45 mg/kg) was administered to inhibit microglial activation. Complement C3a peptide and C3aR antagonist (SB 290157, 10 mg/kg) were used to regulate the C3/C3aR pathway. As a result, the data demonstrated that periventricular C3aR+/Iba-1+ microglia and C3+/GFAP+ astrocytes were significantly increased in GMH-IVH pups at 28 days after surgery. Intranasal C3a peptide upregulated C3aR expression in microglia. Inhibition of microglia by minocycline decreased both C3+/GFAP+ astrocytes and the colocalization volume of Iba-1 and GFAP. In addition, intraperitoneally injected C3aRA alleviated the periventricular colocalization volume of microglia and astrocytes. Compared with vehicle-treated pups, the protein level of IL-1ß, IL-6 and TNF-α in cerebral spinal fluid and brain tissue at 28 days following GMH-IVH were reduced in C3aRA-treated pups. Moreover, hydrocephalus was alleviated, and long-term cognitive ability were improved in the C3aRA-treated group. Our data presented simultaneous periventricular astrogliosis and microgliosis of pups following GMH-IVH and proved their potential interaction through the C3/C3aR pathway, indicating C3aRA as a potential pharmacological treatment of PHH in neonates.

A clinical study of high-dose urokinase for the treatment of the patients with hypertension induced ventricular hemorrhage.

OBJECTIVE: This study discusses the therapeutic effect of high-dose urokinase treatment for hypertension ventricular hemorrhage. METHODS: A total of 60 patients with hypertension ventricular hemorrhage were randomly assigned to two groups: treatment group (n=30) and control group (n=30). Both groups received bilateral external ventricular drain. The treatment group was injected with 50,000IU urokinase to the lateral ventricle every day; the total injection volume per day was 100,000IU. The control group was injected with 20,000IU urokinase to the lateral ventricle every day with a total injection volume per day of 40,000IU. Lumbar puncture was performed in both groups after the later ventricular drain was removed to release cerebrospinal fluid (CSF). Head Computed tomography(CT) examination was performed regularly to observe changes in the ventricular hematoma as well as the occurrence of complications such as intracranial infection and hydrocephalus. Patient prognosis 6 weeks after surgery was compared between the two groups. RESULTS: In the treatment group, the intraventricular hemorrhage clearance time and the number of instances of urokinase treatment were significantly less than those of the control group (P<0.05). The total urokinase dosage of the treatment group was significantly higher than that of the control group (P<0.05). With respect to post-surgery complications, in the treatment group, there were three cases of hydrocephalus and one case of intracranial infection. In the control group, there were four cases of hydrocephalus and three cases of intracranial infection. Intraventricular re-hemorrhage was not observed in either group. Intracranial infection was relieved after strengthened anti-infective therapy and continuous drainage. There was a statistically significant difference in the occurrence of complications between the treatment group and the control group (P<0.05). The rate of good prognosis in the treatment group was higher than that of the control group (P<0.05), and the inefficiency rate was lower (P<0.05). CONCLUSIONS: High-dose urokinase treatment produces a significant therapeutic effect in hypertension ventricular hemorrhage. This treatment can quickly eliminate intraventricular hemorrhage, shorten the ventricular drain tube indwelling time, decrease the occurrence of intracranial infection, and increase the likelihood of a good prognosis.

The effect of mTOR inhibition on obstructive hydrocephalus in patients with tuberous sclerosis complex (TSC) related subependymal giant cell astrocytoma (SEGA).

PURPOSE: Mammalian target of rapamycin inhibitors (mTORi) are known to effectively reduce the size of subependymal giant cell astrocytomas (SEGAs), which are benign brain lesions associated with Tuberous Sclerosis Complex (TSC) that commonly cause obstructive hydrocephalus (OH). This retrospective case series reviews an institutional experience of the effect of mTORi on OH in patients with TSC-related SEGA. METHODS: Thirteen of 16 identified patients with TSC-related SEGA treated with mTORi from October 2007 to December 2018 were included. Serial magnetic resonance imaging (MRI) and clinical charts were reviewed to correlate symptoms and signs of increased intracranial pressure (iICP) with ventriculomegaly on MRI. A proposed ventriculomegaly scale was used: none (< 7 mm), mild (7-10 mm), moderate (11-30 mm), and severe (> 30 mm). OH was defined as moderate or severe ventriculomegaly, based on the largest measurement. RESULTS: Patients' median age at start of mTORi was 13 (6-17) years and five (38%) patients were female. Eight patients had OH at the time of mTORi initiation, five of whom were asymptomatic. Six patients had improvement of hydrocephalus on serial MRI imaging with mTORi therapy, while seven patients had no change based on the ventriculomegaly scale used. All three patients who presented with symptoms of iICP and had OH also had papilledema. None had worsening of hydrocephalus or required shunt placement. Out of five patients with symptoms of iICP, four avoided surgery. CONCLUSION: Most patients had asymptomatic OH at the time of diagnosis, and ventricular enlargement was not correlated with iICP symptoms. mTORi was successful for treatment of OH from TSC-related SEGA, even in the setting of acute symptoms of iICP.