Dysregulation of FLVCR1a-dependent mitochondrial calcium handling in neural progenitors causes congenital hydrocephalus.

Congenital hydrocephalus (CH), occurring in approximately 1/1,000 live births, represents an important clinical challenge due to the limited knowledge of underlying molecular mechanisms. The discovery of novel CH genes is thus essential to shed light on the intricate processes responsible for ventricular dilatation in CH. Here, we identify FLVCR1 (feline leukemia virus subgroup C receptor 1) as a gene responsible for a severe form of CH in humans and mice. Mechanistically, our data reveal that the full-length isoform encoded by the FLVCR1 gene, FLVCR1a, interacts with the IP3R3-VDAC complex located on mitochondria-associated membranes (MAMs) that controls mitochondrial calcium handling. Loss of Flvcr1a in mouse neural progenitor cells (NPCs) affects mitochondrial calcium levels and energy metabolism, leading to defective cortical neurogenesis and brain ventricle enlargement. These data point to defective NPCs calcium handling and metabolic activity as one of the pathogenetic mechanisms driving CH.

Prompt closure versus gradual weaning of external ventricular drain for hydrocephalus following aneurysmal subarachnoid haemorrhage: a statistical analysis plan for the DRAIN randomised clinical trial.

BACKGROUND: Insertion of an external ventricular drain (EVD) is a first-line treatment of acute hydrocephalus caused by aneurysmal subarachnoid haemorrhage (aSAH). Once the patient is clinically stable, the EVD is either removed or replaced by a permanent internal shunt. The optimal strategy for cessation of the EVD is unknown. Prompt closure carries a risk of acute hydrocephalus or redundant shunt implantations, whereas gradual weaning may increase the risk of EVD-related infections. METHODS: DRAIN (Danish RAndomised Trial of External Ventricular Drainage Cessation IN Aneurysmal Subarachnoid Haemorrhage) is an international multicentre randomised clinical trial comparing prompt closure versus gradual weaning of the EVD after aSAH. The primary outcome is a composite of VP-shunt implantation, all-cause mortality, or EVD-related infection. Secondary outcomes are serious adverse events excluding mortality and health-related quality of life (EQ-5D-5L). Exploratory outcomes are modified Rankin Scale, Fatigue Severity Scale, Glasgow Outcome Scale Extended, and length of stay in the neurointensive care unit and hospital. Outcome assessment will be performed 6 months after ictus. Based on the sample size calculation (event proportion 80% in the gradual weaning group, relative risk reduction 20%, alpha 5%, power 80%), 122 participants are required in each intervention group. Outcome assessment for the primary outcome, statistical analyses, and conclusion drawing will be blinded. Two independent statistical analyses and reports will be tracked using a version control system, and both will be published. Based on the final statistical report, the blinded steering group will formulate two abstracts. CONCLUSION: We present a pre-defined statistical analysis plan for the randomised DRAIN trial, which limits bias, p-hacking, and data-driven interpretations. This statistical analysis plan is accompanied by tables with simulated data, which increases transparency and reproducibility. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03948256. Registered on May 13, 2019.

Modified ventriculoperitoneal shunt applied to temporary external ventricular drainage.

External ventricular drainage (EVD) is a common procedure in neurosurgical practice. Presently, the three methods used most often include direct EVD (dEVD), long-tunneled external ventricular drains (LTEVDs), and EVD via the Ommaya reservoir (EVDvOR). But they possess drawbacks such as limited duration of retention, vulnerability to iatrogenic secondary infections, and challenges in regulating drainage flow. This study aimed to explore the use of a modified ventriculoperitoneal shunt (mVPS)-the abdominal end of the VPS device was placed externally-as a means of temporary EVD to address the aforementioned limitations. This retrospective cohort study, included 120 cases requiring EVD. dEVD was performed for 31 cases, EVDvOR for 54 cases (including 8 cases with previously performed dEVD), and mVPS for 35 cases (including 6 cases with previously performed EVDvOR). The one-time success rate (no need for further other EVD intervention) for dEVD, EVDvOR, and mVPS were 70.97%, 88.89%, and 91.42%, dEVD vs EVDvOR (P < 0.05), dEVD vs mVPS (P < 0.05), EVDvOR vs mVPS (P > 0.05). Puncture needle displacement or detachment was observed in nearly all cases of EVDvOR, while no such complications have been observed with mVPS. Apart from this complication, the incidence of postoperative complications was 35.48%, 14.81%, and 8.5%, dEVD vs EVDvOR (P < 0.05), dEVD vs mVPS (P < 0.05), EVDvOR vs mVPS (P > 0.05). Mean postoperative retention for EVD was 14.68 ± 9.50 days, 25.96 ± 15.14 days, and 82.43 ± 64.45 days, respectively (P < 0.001). In conclusion, mVPS significantly extends the duration of EVD, which is particularly beneficial for patients requiring long-term EVD.

Association between neuroimaging and clinical outcomes in individuals with central nervous system cryptococcosis.

BACKGROUND: The radiological manifestations of central nervous system (CNS) cryptococcosis are diverse and often subtle. There is heterogeneity on how different neuroimaging patterns impact prognosis. This study aims to assess the association between the neuroimaging and clinical outcomes of CNS cryptococcosis. METHODS: All patients with CNS cryptococcosis between July 2017 and April 2023 who underwent brain magnetic resonance imaging (MRI) were included. The primary outcome was mortality during hospitalisation. Secondary outcomes were readmission, ventricular shunting, duration of hospitalisation and time to the first negative cerebrospinal fluid culture. We compared the outcomes for each of the five main radiological findings on the brain MRI scan. RESULTS: We included 46 proven CNS cryptococcosis cases. The two main comorbidity groups were HIV infection (20, 43%) and solid organ transplantation (10, 22%), respectively. Thirty-nine patients exhibited at least one radiological abnormality (85%), with the most common being meningeal enhancement (34, 74%). The mortality rates occurred at 11% (5/46) during hospitalisation. We found no significant disparities in mortality related to distinct radiological patterns. The presence of pseudocysts was significantly associated with the need for readmission (p = .027). The ventricular shunting was significantly associated with the presence of pseudocysts (p = .005) and hydrocephalus (p = .044). CONCLUSION: In this study, there is no association between brain MRI findings and mortality. Larger studies are needed to evaluate this important issue.

Endoscopic Third Ventriculostomy and Pineal Biopsy from a Single Entry Point.

Pineal neoplasms have a significant impact on children although they are relatively uncommon. They account for approximately 3-11% of all childhood brain tumors, which is considerably higher than the <1% seen in adult brain tumors. These tumors can be divided into three main categories: germ cell tumors, parenchymal pineal tumors, and tumors arising from related anatomical structures. Obtaining an accurate and minimally invasive tissue diagnosis is crucial for selecting the most appropriate treatment regimen for patients with pineal gland tumors. This is due to the diverse treatment options available and the potential risks associated with complete resection. In cases where patients present with acute obstructive hydrocephalus caused by a pineal gland tumor, immediate treatment of the hydrocephalus is necessary. The urgency stems from the potential complications of hydrocephalus, including increased intracranial pressure and neurological deficits. To address these challenges, a minimally invasive endoscopic approach provides a valuable opportunity. This technique allows clinicians to promptly relieve hydrocephalus and obtain a histological diagnosis simultaneously. This dual benefit enables a more comprehensive understanding of the tumor and assists in determining the most effective treatment strategy for the patient.

Management of external ventricular drain: to wean or not to wean?

PURPOSE: External ventricular drain (EVD) is one of the most frequent procedures in neurosurgery and around 15 to 30% of these patients require a permanent cerebrospinal fluid (CSF) diversion. The optimal EVD weaning strategy is still unclear. Whether gradual weaning compared to rapid closure, reduces the rate of permanent CSF diversion remains controversial. The aim of this trial is to compare the rates of permanent CSF diversion between gradual weaning and rapid closure of an EVD. METHODS: This was a single-center, retrospective cohort study including patients between 2010 to 2020. Patients were divided into a weaning (WG) and non-weaning (NWG) group. The primary outcome was permanent CSF diversion rates, secondary outcomes included hospitalization time, EVD-related morbidity, and clinical outcome. RESULTS: Out of 412 patients, 123 (29.9%) patients were excluded due to early death or palliative treatment. We registered 178 (61.6%) patients in the WG and 111 (38.4%) in the NWG. Baseline characteristics were comparable between groups. The VPS rate was comparable in both groups (NWG 37.8%; WG 39.9%, p = 0.728). EVD related infection (13.5% vs 1.8%, p < 0.001), as well as non-EVD related infection rates (2.8% vs 0%, p < 0.001), were significantly higher in the WG. Hospitalization time was significantly shorter in the NWG (WG 24.93 ± 9.50 days; NWG 23.66 ± 14.51 days, p = 0.039). CONCLUSION: Gradual EVD weaning does not seem to reduce the need for permanent CSF diversion, while infection rates and hospitalization time were significantly higher/longer. Therefore, direct closure should be considered in the clinical setting.

Impact of aquaporin-4 and CD11c + microglia in the development of ependymal cells in the aqueduct: inferences to hydrocephalus.

AQP4 is expressed in the endfeet membranes of subpial and perivascular astrocytes and in the ependymal cells that line the ventricular system. The sporadic appearance of obstructive congenital hydrocephalus (OCHC) has been observed in the offspring of AQP4-/- mice (KO) due to stenosis of Silvio's aqueduct. Here, we explore whether the lack of AQP4 expression leads to abnormal development of ependymal cells in the aqueduct of mice. We compared periaqueductal samples from wild-type and KO mice. The microarray-based transcriptome analysis reflected a large number of genes with differential expression (809). Gene sets (GS) associated with ependymal development, ciliary function and the immune system were specially modified qPCR confirmed reduced expression in the KO mice genes: (i) coding for transcription factors for ependymal differentiation (Rfx4 and FoxJ1), (ii) involved in the constitution of the central apparatus of the axoneme (Spag16 and Hydin), (iii) associated with ciliary assembly (Cfap43, Cfap69 and Ccdc170), and (iv) involved in intercellular junction complexes of the ependyma (Cdhr4). By contrast, genes such as Spp1, Gpnmb, Itgax, and Cd68, associated with a Cd11c-positive microglial population, were overexpressed in the KO mice. Electron microscopy and Immunofluorescence of vimentin and γ-tubulin revealed a disorganized ependyma in the KO mice, with changes in the intercellular complex union, unevenly orientated cilia, and variations in the planar cell polarity of the apical membrane. These structural alterations translate into reduced cilia beat frequency, which might alter cerebrospinal fluid movement. The presence of CD11c + microglia cells in the periaqueductal zone of mice during the first postnatal week is a novel finding. In AQP4-/- mice, these cells remain present around the aqueduct for an extended period, showing peak expression at P11. We propose that these cells play an important role in the normal development of the ependyma and that their overexpression in KO mice is crucial to reduce ependyma abnormalities that could otherwise contribute to the development of obstructive hydrocephalus.

Risk factors of prognosis for spontaneous cerebellar hemorrhage: a systematic review and meta-analysis.

BACKGROUND: The most deadly type of spontaneous intracerebral hemorrhage is spontaneous cerebellar hemorrhage (SCH). The purpose of this meta-analysis was to investigate risk factors for prognosis in SCH patients to provide a basis for taking preventive and therapeutic measures. METHODS: Seven electronic databases were searched from inception to May 2023 for randomized controlled trial, cohort study, case control study and cross-sectional study on prognosis of spontaneous cerebellar hemorrhage. The quality of the selected studies were assessed by the American Agency for Healthcare Research and Quality (AHRQ). To assess the impact of the included risk factors on the prognosis of spontaneous cerebellar hemorrhage, combined odds ratios (ORs) with matching 95% confidence intervals (CIs) were combined. RESULTS: Eight studies were included, including 539 participants. And a total of 31 potentially associated risk factors were identified. Ultimately, 6 risk factors were included in the meta-analysis after assessing. The factors supported by moderate evidence include the hydrocephalus (OR = 4.3, 95% CI: 2.33 to 7.91) and drug-induced coagulopathy (OR = 2.74, 95% CI: 1.23 to 6.09). The factors supported by limited evidence include the intraventricular bleeding(OR = 1.86, 95% CI: 1.13 to 3.07) and hematoma size>3 cm(OR = 3.18, 95% CI: 1.87 to 5.39). Meta-analysis revealed no association between hypertension, diabetes mellitus and SCH prognosis. CONCLUSION: The current meta-analysis revealed obvious risk factors for prognosis in spontaneous cerebellar hemorrhage patients, including hydrocephalus, drug-induced coagulopathy, intraventricular bleeding and hematoma size>3 cm.

Regulation of brain fluid volumes and pressures: basic principles, intracranial hypertension, ventriculomegaly and hydrocephalus.

The principles of cerebrospinal fluid (CSF) production, circulation and outflow and regulation of fluid volumes and pressures in the normal brain are summarised. Abnormalities in these aspects in intracranial hypertension, ventriculomegaly and hydrocephalus are discussed. The brain parenchyma has a cellular framework with interstitial fluid (ISF) in the intervening spaces. Framework stress and interstitial fluid pressure (ISFP) combined provide the total stress which, after allowing for gravity, normally equals intracerebral pressure (ICP) with gradients of total stress too small to measure. Fluid pressure may differ from ICP in the parenchyma and collapsed subarachnoid spaces when the parenchyma presses against the meninges. Fluid pressure gradients determine fluid movements. In adults, restricting CSF outflow from subarachnoid spaces produces intracranial hypertension which, when CSF volumes change very little, is called idiopathic intracranial hypertension (iIH). Raised ICP in iIH is accompanied by increased venous sinus pressure, though which is cause and which effect is unclear. In infants with growing skulls, restriction in outflow leads to increased head and CSF volumes. In adults, ventriculomegaly can arise due to cerebral atrophy or, in hydrocephalus, to obstructions to intracranial CSF flow. In non-communicating hydrocephalus, flow through or out of the ventricles is somehow obstructed, whereas in communicating hydrocephalus, the obstruction is somewhere between the cisterna magna and cranial sites of outflow. When normal outflow routes are obstructed, continued CSF production in the ventricles may be partially balanced by outflow through the parenchyma via an oedematous periventricular layer and perivascular spaces. In adults, secondary hydrocephalus with raised ICP results from obvious obstructions to flow. By contrast, with the more subtly obstructed flow seen in normal pressure hydrocephalus (NPH), fluid pressure must be reduced elsewhere, e.g. in some subarachnoid spaces. In idiopathic NPH, where ventriculomegaly is accompanied by gait disturbance, dementia and/or urinary incontinence, the functional deficits can sometimes be reversed by shunting or third ventriculostomy. Parenchymal shrinkage is irreversible in late stage hydrocephalus with cellular framework loss but may not occur in early stages, whether by exclusion of fluid or otherwise. Further studies that are needed to explain the development of hydrocephalus are outlined.

Cranioplasty Outcomes from a Tertiary Hospital in a Developing Country.

BACKGROUND: Decompressive craniectomy (DC) is a surgical procedure to treat refractory increase in intracranial pressure. DC is frequently succeeded by cranioplasty (CP), a reconstructive procedure to protect the underlying brain and maintain cerebrospinal fluid flow dynamics. However, complications such as seizures, fluid collections, infections, and hydrocephalus can arise from CP. Our aim is to investigate these complications and their possible risk factors and to discuss whether early or late CP has any effect on the outcome. MATERIALS AND METHODS: A single-center retrospective cohort study was performed, including patients who underwent CP after DC between January 2014 and January 2022. Relevant information was collected such as demographics, type of brain injury, materials used in CP, timing between DC and CP, and postoperative complications. Ultimately, 63 patients were included in our study. We also compared the complication rate between patients who underwent late CP after DC (>90 days) against patients who underwent early CP (<90 days). RESULTS: Most patients were male (78%). The sample median age was 29 years, with pediatric patients, accounting for 36% of the samples. Overall complication rate was 57% and they were seizure/epilepsy in 50% of the patients, fluid collection (28%), infections (25%), posttraumatic hydrocephalus (17%), and bone defect/resorption (3%). Twenty-two percent of patients with complications required reoperation and underwent a second CP. The median (interquartile range) duration between the craniotomy and the CP was 56 (27-102) days, with an early (≤3 months) percentage of 68%. We found no significant difference between early (≤3 months) and late (>3 months) CP regarding complication rates. CONCLUSION: Despite CP being a simple procedure, it has a considerable rate of complications. Therefore, it is important that surgeons possess adequate knowledge about such complications to navigate these challenges more effectively.

Résumé Contexte:La craniectomie décompressive (DC) est une intervention chirurgicale destinée à traiter l'augmentation réfractaire de la pression intracrânienne. La DC est fréquemment remplacée par une cranioplastie (CP), une procédure reconstructive visant à protéger le cerveau sous-jacent et à maintenir la dynamique du flux du liquide céphalo-rachidien. Cependant, des complications telles que des convulsions, des collections de liquides, des infections et une hydrocéphalie peuvent survenir en raison de la CP. Notre objectif est d'étudier ces complications et leurs facteurs de risque possibles et de discuter si une CP précoce ou tardive a un effet sur le résultat.Matériels et méthodes:Une étude de cohorte rétrospective monocentrique a été réalisée, incluant des patients ayant subi une PC après une DC entre janvier 2014 et janvier 2022. Des informations pertinentes ont été collectées telles que les données démographiques, le type de lésion cérébrale, les matériaux utilisés dans la PC, le timing entre la DC et CP et complications postopératoires. Au final, 63 patients ont été inclus dans notre étude. Nous avons également comparé le taux de complications entre les patients ayant subi une CP tardive après une DC (> 90 jours) et ceux ayant subi une CP précoce (<90 jours).Résultats:La plupart des patients étaient des hommes (78 %). L'âge médian de l'échantillon était de 29 ans, les patients pédiatriques représentant 36 % des échantillons. Le taux global de complications était de 57 % et il s'agissait de convulsions/épilepsie chez 50 % des patients, d'accumulation de liquide (28 %), d'infections (25 %), d'hydrocéphalie post-traumatique (17 %) et de défauts/résorptions osseuses (3 %). Vingt­deux pour cent des patients présentant des complications ont dû être réopérés et ont subi une deuxième CP. La durée médiane (intervalle interquartile) entre la craniotomie et la CP était de 56 (27 à 102) jours, avec un pourcentage précoce (≤ 3 mois) de 68 %. Nous n'avons trouvé aucune différence significative entre la PC précoce (≤ 3 mois) et tardive (> 3 mois) en ce qui concerne les taux de complications.Conclusion:Bien que la CP soit une procédure simple, elle entraîne un taux de complications considérable. Il est donc important que les chirurgiens possèdent des connaissances adéquates sur ces complications pour relever ces défis plus efficacement.

Impact of dual procedures: How combining VP shunt placement for hydrocephalus and myelomeningocele repair in newborns affects complication rates?

To discern the efficacy of simultaneous versus delayed VPS surgery in managing hydrocephalus linked with MMC repair: The debate over the concurrent or deferred placement of ventriculoperitoneal shunts (VPS) during myelomeningocele (MMC) repair in hydrocephalic neonates necessitates a nuanced evaluation of associated risks and benefits. While VPS placement can mitigate cerebrospinal fluid (CSF) leaks and minimize wound dehiscence post-MMC repair, it concurrently introduces potential hazards such as infections and shunt-related malfunctions. This prospective cohort study focused on144 newborns with spinal myelomeningocele and hydrocephalus. Divided into two groups based on the timing of dysraphism repair and VPS placement, 101 children underwent concurrent procedures, while 43 received deferred VPS insertion post-MMC closure. Female patients constituted 60% of the cohort, with lumbar lesions being predominant. The median age for MMC closure was three days. Analysis revealed that the deferred insertion group exhibited higher rates of shunt malfunctions, CSF leaks, and wound dehiscence compared to the concurrent insertion group. Although indications hinted at a potential increase in shunt infections in the immediate insertion group, statistical significance was lacking. The study established a statistically significant association between the timing of shunt insertion during MMC repair and specific outcomes, such as CSF leaks and wound dehiscence. The findings suggest that concurrent shunt insertion during MMC repair may reduce the incidence of these complications compared to deferred insertion. However, no substantial differences emerged in terms of shunt infection and malfunction, emphasizing the persistent challenges associated with these major complications.

Tension Subdural Hygroma Following Resection of Posterior Fossa Tumour in a Child: A new clinico-radio-pathological entity.

Persistent hydrocephalus is common in children after resection of posterior fossa tumours. However, occurrence of subdural hygroma is very rare. We report the case of a 14-month-old child who presented at a paediatric neurology clinic in Muscat, Oman in 2021 who developed a tense subdural hygroma with stable hydrocephalus, in the early postoperative period, following posterior fossa tumour resection. We describe the distinctive clinical, radiological and pathological features associated with the development of a tense subdural hygroma. We also discuss the management by cerebrospinal fluid diversion, which includes either a ventriculoperitoneal or subduroperitoneal shunt. This unique condition is distinguished from external hydrocephalus by features that are critical to the management strategy.

Prenatal diagnosis of a severe form of frontonasal dysplasia with severe limb anomalies, hydrocephaly, a hypoplastic corpus callosum, and a ventricular septal defect using 3D ultrasound: a case report and literature review.

BACKGROUND: Frontonasal dysplasia (FND) is a rare congenital anomaly resulting from the underdevelopment of the frontonasal process, and it can be syndromic or nonsyndromic. The typical features of FND include a deformed nose and ocular hypertelorism, which are sometimes associated with cleft lip and/or palate. Only approximately 10 cases of prenatally diagnosed nonsyndromic FND have been reported in the past 30 years. CASE PRESENTATION: A 33-year-old woman (G2P1) was referred to our center at 20 gestational weeks for bilateral hydrocephaly. We detected typical features of FND, including severe hypertelorism, median nasal bifidity, a minor cleft lip, and multiple limb anomalies using three-dimensional (3D) ultrasound. A hypoplastic corpus callosum, unilateral microtia, and a ventricular septal defect were also detected. Genetic testing, including karyotype analysis, copy number variation (CNV) analysis, trio-whole exome sequencing (trio-WES), and trio-whole-gene sequencing (trio-WGS), was performed; however, we did not find any de novo gene variants in the fetus as compared to the parents. Postmortem examination confirmed the prenatal diagnosis of FND. CONCLUSION: The present case expands the wide phenotypic spectrum of prenatal FND patients. 3D ultrasound is a useful tool for detecting facial and limb deformities.

Post-infectious hydrocephalus complicating Listeria meningitis in a healthy newborn.

Listeria monocytogenes is a relatively uncommon cause of foodborne infection in the general population. Most cases of Listeriosis occur among newborns, pregnant women, the elderly and those with impairment of cellular immunity. Neonatal Listeria meningitis is rare. We present a case of Listeria meningitis at the age of 15 days in a previously healthy neonate who presented with acute onset of fever, poor feeding and lethargy. Sepsis workup revealed L. monocytogenes identified in cerebrospinal fluid PCR and culture. The infant's course was complicated by transient syndrome of inappropriate antidiuretic hormone and subsequent hydrocephalus that required a ventriculoperitoneal shunt placement. Though rare, neonatal infections due to Listeria can present with meningitis leading to serious and devastating complications. Our case emphasises the importance of considering Listeria in cases of neonatal meningitis and the value of close follow-up of such cases through early detection and management of acute and long-term complications.

Clinical Characteristics and Outcomes of Aneurysmal Subarachnoid Hemorrhage Patients Who Live Alone.

It has been shown that living alone is one of the risk factors for unfavorable outcomes in ischemic stroke patients, mostly due to delay in receiving appropriate treatment. A single-center retrospective observational study was conducted to evaluate whether living alone was associated with unfavorable outcomes in aneurysmal subarachnoid hemorrhage (SAH) patients. Among 451 SAH patients admitted to our institution between January 2013 and December 2022, 43 patients who lived alone had sustained SAH at home (group A) and 329 patients who lived with family had sustained SAH at home (group F). The mortality rate (46.5% vs. 29.8%, p = 0.04) and a tendency for having unfavorable outcomes were higher in group A than in group F. The incidence of concomitant hydrocephalus was significantly higher in the former (37.2% vs. 21.3%, p = 0.03). Group A was further classified to the Able to Call (n = 15, group AC) and Unable to Call (n = 28, group UC) subgroups based on their ability to call for help by themselves. Group AC tended to have favorable outcomes (27% vs. 4%, p = 0.04). Treatment to obliterate a ruptured aneurysm had particularly been challenging in group UC, in which the accurate time of onset often remained unidentifiable: Their overall mortality was as high as 57% and their capability to undergo surgical/interventional treatment was only 67%. Perioperative complications resulting from delayed presentation had been common. Considering the present finding that most of those who lived alone could not call for help, further effort is warranted to facilitate early detection of those patients.

Pathogenic variants in autism gene KATNAL2 cause hydrocephalus and disrupt neuronal connectivity by impairing ciliary microtubule dynamics.

Enlargement of the cerebrospinal fluid (CSF)-filled brain ventricles (cerebral ventriculomegaly), the cardinal feature of congenital hydrocephalus (CH), is increasingly recognized among patients with autism spectrum disorders (ASD). KATNAL2, a member of Katanin family microtubule-severing ATPases, is a known ASD risk gene, but its roles in human brain development remain unclear. Here, we show that nonsense truncation of Katnal2 (Katnal2Δ17) in mice results in classic ciliopathy phenotypes, including impaired spermatogenesis and cerebral ventriculomegaly. In both humans and mice, KATNAL2 is highly expressed in ciliated radial glia of the fetal ventricular-subventricular zone as well as in their postnatal ependymal and neuronal progeny. The ventriculomegaly observed in Katnal2Δ17 mice is associated with disrupted primary cilia and ependymal planar cell polarity that results in impaired cilia-generated CSF flow. Further, prefrontal pyramidal neurons in ventriculomegalic Katnal2Δ17 mice exhibit decreased excitatory drive and reduced high-frequency firing. Consistent with these findings in mice, we identified rare, damaging heterozygous germline variants in KATNAL2 in five unrelated patients with neurosurgically treated CH and comorbid ASD or other neurodevelopmental disorders. Mice engineered with the orthologous ASD-associated KATNAL2 F244L missense variant recapitulated the ventriculomegaly found in human patients. Together, these data suggest KATNAL2 pathogenic variants alter intraventricular CSF homeostasis and parenchymal neuronal connectivity by disrupting microtubule dynamics in fetal radial glia and their postnatal ependymal and neuronal descendants. The results identify a molecular mechanism underlying the development of ventriculomegaly in a genetic subset of patients with ASD and may explain persistence of neurodevelopmental phenotypes in some patients with CH despite neurosurgical CSF shunting.

Unlocking the Battle-Clipping vs. Endovascular Therapy for Shunt-Dependent Hydrocephalus After Aneurysm Rupture: An In-Depth Institutional Analysis.

AIM: To compare microsurgical clipping and endovascular therapy (EVT) for the management of shunt-dependent hydrocephalus (SDH) in patients with subarachnoid hemorrhage (SAH) and hydrocephalus. MATERIAL AND METHODS: This retrospective study was conducted from July 2018 to December 2022 and included 67 patients with SAH accompanied by acute hydrocephalus. Patients' demographic, clinical, and radiological data, such as age, sex, Glasgow Coma Scale scores, Hunt and Hess scale, Fischer grade, external ventricular drain (EVD) duration, complications, Ommaya reservoir placement, cerebrospinal fluid drainage, and outcomes, were obtained. Statistical analyses, including univariate analysis and stepwise logistic regression, revealed significant risk factors for shunt dependence. RESULTS: Of the 67 patients, 33 underwent microsurgical clipping and 34 received EVT. Spasmolysis reduced shunt dependency, whereas early EVD placement correlated with reduced shunt dependence (p=0.002). The Ommaya reservoir helped in the management of meningitis but was found to be associated with shunt dependency (p=0.04). Multiple logistic regression analysis revealed that perioperative infarct was a significant risk factor for shunt dependence (p=0.05). No significant difference in patient outcomes was observed between the two treatment groups. However, patients who received EVT had shorter intensive care unit and hospital stays. CONCLUSION: This study shows that managing clinical vasospasm with spasmolysis may reduce shunt dependency. Overall, both microsurgical clipping and EVT offer similar long-term outcomes and efficacy in preventing shunt dependence, but the latter has the advantage of shorter hospital stay. These findings provide crucial insights for clinical decision-making and patient care in SDH after SAH.

Ventriculoperitoneal shunt infection and malfunction in adult patients: incidence, risk factors, and long-term follow-up of single institution experience.

Ventriculoperitoneal shunt surgery was developed to manage excessive cerebrospinal fluid (CSF) in the brain's ventricles and is considered a mainstream treatment. Despite the development of the shunt device system, various complications still occur. In this study, we reported 307 cases and a long-term follow-up of at least five years of adult patients who underwent VP shunt surgery and analyzed various factors that may affect revision surgery. A retrospective study was conducted at Asan Medical Center, Korea, a tertiary medical center. We reviewed 307 cases from January 2012 to December 2018. The patients' neurological status, predisposing medical conditions, laboratory findings, and other operation-related factors were reviewed using electrical medical records. The normal function group comprised 272 cases (88.6%), and the overall incidence of revision group comprised 35 cases (11.4%). Of the 35 revision surgery cases, 30 (85.71%) were due to shunt malfunctions, such as obstruction, overdrainage, and valve-related errors while 5 (14.29%) were due to shunt infection. Patient demographics, mental status, and operation time did not influence revision as risk factors. Serum laboratory findings showed no statistical difference between the two groups. The white blood cell (WBC) count in the CSF profile differed significantly between the two groups. The Hakim Programmable valve (Codman, USA) is mainly used in our center. In addition, various shunt systems were used, including Strata Regulatory valve (Medtronic, USA), proGAV (Aesculap, USA), and Accu-Flo (Codman, USA). This study analyzed the factors affecting long-term outcomes. Based on these findings, efforts are needed to achieve more favorable outcomes in the future.