Fourth ventricle stent placement for treatment of type I Chiari malformation in children.

INTRODUCTION: Type I Chiari malformation (CM-I) is a common congenital malformation, often accompanied by syringomyelia. Obstruction of CSF circulation in the foramen magnum is the reason for the formation of the syringomyelia. Fourth ventricle stenting (FVS) could ensure the CSF flow from the fourth ventricle, which might represent an effective approach to achieve syringomyelia relief. METHODS: We have reviewed four cases of CM-I children who received FVS implantation from November 2021 to July 2022. Each of the patients underwent FMD. The ventricular catheter of an Ommaya reservoir (Medtronic, Inc.) was used as a stent. Duraplasty was performed with autologous fascia. Cervical MRI rechecks were routinely done 3 months later, and the clinical symptoms were followed up. RESULTS: Four children received FVS, including one boy and three girls, aged from 12 months to 10 years, with a mean age of 6.8 years. No major complication occurred. The syringomyelia or hydrocephalus in each patient were all attenuated, as observed on the reexamination MRI images. During the follow-up time with a mean of 10.8 months, no patient had new symptoms. CONCLUSION: FVS is an effective and safe method for operation of CM-1 in children. The indications of FVS include redo-FMD, difficulties to ensure post-FMD CSF circulation patency at the foramen magnum and with obstructive hydrocephalus. A long-term follow-up duration is necessary.

[Treatment of syringomyelia in patients with arachnopathy within craniovertebral junction]. / Lechenie siringomielii u patsientov s arakhnopatiei na urovne kraniovertebral'nogo perekhoda.

One of the causes of syringomyelia is arachnopathy following an infectious or non-infectious inflammation of the arachnoid membrane. It is extremely rare that adhesive arachnoiditis develops within the occipital cistern and impairs cerebrospinal fluid flow from the foramen of Magendie, along posterior cerebellar surface and into spinal subarachnoid space. These process result syringomyelia. OBJECTIVE: To evaluate postoperative outcomes in patients with syringomyelia following arachnopathy at the craniovertebral level. MATERIAL AND METHODS: A retrospective analysis included 27 patients with syringomyelia and arachnopathy within the occipital cistern for the period from 2013 to 2018. Eight patients (29.6%) underwent primary surgery. In this group, 2 patients had arachnopathy following post-traumatic subarachnoid hemorrhage, 1 - after non-traumatic subarachnoid hemorrhage in posterior cranial fossa, 2 - after bacterial meningitis, 3 - the cause was unclear. Nineteenth patients underwent redo surgery after previous procedures on posterior cranial fossa (tumor resection - 3 patients, suboccipital decompression for Chiari malformation - 16 cases). High-resolution MRI with special protocols for analysis of CSF circulation and mobility of brain structures was used to diagnose arachnopathy (phase contrast ECG-synchronized MRI, TrueFISP). RESULTS: Surgeries were aimed at mobilization of cerebellar tonsils and spinal cord and restoration of CSF circulation at the craniovertebral level. One year later, 13 (48.1%) patients noted improvement in their condition, 8 (29.6%) patients - clinical stabilization. In most cases, stabilization or improvement of sensory and coordination disorders. Syringomyelia symptoms progressed in 6 (22.2%) patients. Mean preoperative mJOA score was 11.86±1.24, in a year after surgery - 14.17±1.19. According to MRI data after 1 year, syringomyelia disappeared in 2 patients (7.4%), reduced in 13 (48.1%) cases, remained the same in 9 (33.3%) cases and deteriorated in 3 (11.1%) patients. Vaquero index reduced from 45.5% to 21.6 within a year after surgery. Early postoperative complications occurred in 3 (11.1%) patients: 1 (3.7%) had hydrocephalus and 2 (7.4%) had aseptic meningitis. CONCLUSION: Modern diagnostic and surgical methods for syringomyelia ensure favorable outcomes in 77.7% of cases.

Patient advice regarding participation in sport in children with disorders of cerebrospinal fluid (CSF) circulation: a national survey of British paediatric neurosurgeons.

BACKGROUND: Management of children with disorders of cerebrospinal fluid (CSF) circulation is a common aspect of paediatric neurosurgical practice. Sport and physical activity play an integral role in the lives of patients in this age group. However, there is little evidence to support the dissemination of appropriate advice to children regarding such activities. The aim of this study was to evaluate the perspectives of clinicians across the UK regarding the participation of children with disorders of CSF circulation in sports. METHODS: Questionnaires were distributed to Consultant Paediatric Neurosurgeons practising across the UK via the Society of British Neurological Surgeons (SBNS). Five different patient scenarios were supplied, and participants were asked to choose whether they would advise participation in the following sports: Taekwondo, rugby, skiing, and football. RESULTS: An overall response rate of 66.7% (36 out of 54 paediatric neurosurgeons) was achieved. The following percentages of clinicians advocated football, rugby, Taekwondo, and skiing across all scenarios: 96%, 75%, 77%, and 97%, respectively. The majority of responders (91.2%) relied on personal experience when providing advice, whilst 50% used available literature and 19.4% used available guidelines. CONCLUSIONS: There is a paucity of evidence in the literature to support the dissemination of appropriate advice to children with disorders of CSF circulation regarding participation in sports. Our findings demonstrate that the majority of clinicians rely on personal experience to make such decisions, emphasizing the necessity of larger scale studies to inform evidence-based guidelines.

Pineal cyst surveillance in adults - a review of 10 years' experience.

Objective: Pineal cysts are common benign incidental findings in adults. There are no commonly accepted criteria for follow up or indications for intervention. We looked at our outcomes for this condition to explore their natural history and review our surveillance criteria.Method: Retrospective review of multidisciplinary team meetings at a tertiary neurosurgical centre over 10 years. Data relating to demographics, presenting symptoms, maximum diameter, duration of surveillance, final diagnosis and overall outcome were extracted from electronic patient records and available MRI. Data were analysed using IBM SPSS version 24.Result: Seventy-seven pineal cysts were identified. Female to male ratio was 1.43, female mean age was 38.6 and male mean age was 50.4. An increase in referral frequency was observed over the study period (mean increase of 1.4 cases per year). Presenting symptoms of headache in 45% and visual and hearing symptoms in 38.5% were recorded and baseline mean maximum diameter was 13.4mm. 20 patients were discharged on presentation, 54 were booked for at least one follow-up scan with a median follow up period of 14 months. The mean change in maximum diameter was 0.04mm over 18 months. Three patients (3.9%) underwent endoscopic biopsy and CSF diversion for cysts all more than 20mm with radiological evidence of hydrocephalus. In 100% of cases, the initial MDT diagnosis and final diagnosis were concordant.Conclusions: No patient under surveillance required surgical treatment and those managed surgically were symptomatic with large cysts and hydrocephalus on presentation. A majority of pineal cysts remained unchanged during the MRI follow-up, therefore our review suggests that routine follow-up of pineal cysts is not necessary in the absence of unusual radiological characteristics or related clinical symptoms.

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.

Decompressive craniectomy arrests pulsatile aqueductal CSF flux: An in vivo demonstration using phase-contrast MRI. Case report.

We give a case study demonstration, using aqueductal cerebrospinal fluid (CSF) stroke volume quantification with phase-contrast magnetic resonance imaging, of a large opening in the rigid cranium by a decompressive craniectomy and its subsequent closure by bone flap repositioning resulted in the arrest and subsequent restoration of aqueductal CSF flow.

Blood-cerebrospinal fluid barrier opening by modified single pulse transcranial focused shockwave.

Transcranial focused shockwave (FSW) is a novel noninvasive brain stimulation that can open blood-brain barriers (BBB) and blood-cerebrospinal fluid barriers (BCSFB) with a single low-energy (energy flux density 0.03 mJ/mm2) pulse and low-dose microbubbles (2 × 106/kg). Similar to focused ultrasound, FSW deliver highly precise stimulation of discrete brain regions with adjustable focal lengths that essentially covers the whole brain. By opening the BCSFB, it allows for rapid widespread drug delivery to the whole brain by cerebrospinal fluid (CSF) circulation. Although no definite adverse effect or permeant injury was noted in our previous study, microscopic hemorrhage was infrequently observed. Safety concerns remain the major obstacle to further application of FSW in brain. To enhance its applicability, a modified single pulse FSW technique was established that present 100% opening rate but much less risk of adverse effect than previous methods. By moving the targeting area 2.5 mm more superficially on the left lateral ventricle as compared with the previous methods, the microscopic hemorrhage rate was reduced to zero. We systemically examine the safety profiles of the modified FSW-BCSFB opening regarding abnormal behavior and brain injury or hemorrhage 72 hr after 0, 1, and 10 pulses of FSW-treatment. Animal behavior, physiological monitor, and brain MRI were examined and recorded. Brain section histology was examined for hemorrhage, apoptosis, inflammation, oxidative stress related immunohistochemistry and biomarkers. The single pulse FSW group demonstrated no mortality or gross/microscopic hemorrhage (N = 30), and no observable changes in all examined outcomes, while 10 pulses of FSW was found to be associated with microscopic and temporary RBC extravasation (N = 6/30), and abnormal immunohistochemistry biomarkers which showed a trend of recovery at 72 hrs. The results suggest that single pulse low-energy FSW-BCSFB opening is effective, safe and poses minimal risk of injury to brain tissue (Sprague Dawley, SD rats).

Boron Delivery to Brain Cells via Cerebrospinal Fluid (CSF) Circulation in BNCT of Brain-Tumor-Model Rats-Ex Vivo Imaging of BPA Using MALDI Mass Spectrometry Imaging.

The blood-brain barrier (BBB) is likely to be intact during the early stages of brain metastatic melanoma development, and thereby inhibits sufficient drug delivery into the metastatic lesions. Our laboratory has been developing a system for boron drug delivery to brain cells via cerebrospinal fluid (CSF) as a viable pathway to circumvent the BBB in boron neutron capture therapy (BNCT). BNCT is a cell-selective cancer treatment based on the use of boron-containing drugs and neutron irradiation. Selective tumor targeting by boron with minimal normal tissue toxicity is required for effective BNCT. Boronophenylalanine (BPA) is widely used as a boron drug for BNCT. In our previous study, we demonstrated that application of the CSF administration method results in high BPA accumulation in the brain tumor even with a low dose of BPA. In this study, we evaluate BPA biodistribution in the brain following application of the CSF method in brain-tumor-model rats (melanoma) utilizing matrix-assisted laser desorption/ionization (MALDI) mass spectrometry imaging (MSI). We observed increased BPA penetration to the tumor tissue, where the color contrast on mass images indicates the border of BPA accumulation between tumor and normal cells. Our approach could be useful as drug delivery to different types of brain tumor, including brain metastases of melanoma.

Mathematical Modelling in Hydrocephalus.

BACKGROUND: Various studies highlight the significance of alterations in cerebrospinal fluid (CSF) and cerebral blood flow (CBF) dynamics in the pathogenesis of hydrocephalus and suggest the role of mathematical modeling in studying these complex interactions. OBJECTIVE: This narrative review discusses mathematical models of CSF and CBF dynamics, including Marmarou's compartmental model of CSF spaces and a model of cardiac changes in cerebral arterial blood volume. The diagnostic utility of CSF compensatory parameters is described along with current information on secondary model-based indices of cerebral hemodynamics in hydrocephalus. CONCLUSIONS: Compensatory parameters derived from the model of CSF circulation have long been used in the diagnosis and management of hydrocephalus patients. However, recent studies using mathematical models of cerebral circulation also show alterations in CBF dynamics, and model-based indices of cerebral hemodynamics, which can be calculated non-invasively using transracranial Doppler ultrasonography, can be used as a complementary source of information about the state of the cerebrospinal space.

In Xenopus ependymal cilia drive embryonic CSF circulation and brain development independently of cardiac pulsatile forces.

BACKGROUND: Hydrocephalus, the pathological expansion of the cerebrospinal fluid (CSF)-filled cerebral ventricles, is a common, deadly disease. In the adult, cardiac and respiratory forces are the main drivers of CSF flow within the brain ventricular system to remove waste and deliver nutrients. In contrast, the mechanics and functions of CSF circulation in the embryonic brain are poorly understood. This is primarily due to the lack of model systems and imaging technology to study these early time points. Here, we studied embryos of the vertebrate Xenopus with optical coherence tomography (OCT) imaging to investigate in vivo ventricular and neural development during the onset of CSF circulation. METHODS: Optical coherence tomography (OCT), a cross-sectional imaging modality, was used to study developing Xenopus tadpole brains and to dynamically detect in vivo ventricular morphology and CSF circulation in real-time, at micrometer resolution. The effects of immobilizing cilia and cardiac ablation were investigated. RESULTS: In Xenopus, using OCT imaging, we demonstrated that ventriculogenesis can be tracked throughout development until the beginning of metamorphosis. We found that during Xenopus embryogenesis, initially, CSF fills the primitive ventricular space and remains static, followed by the initiation of the cilia driven CSF circulation where ependymal cilia create a polarized CSF flow. No pulsatile flow was detected throughout these tailbud and early tadpole stages. As development progressed, despite the emergence of the choroid plexus in Xenopus, cardiac forces did not contribute to the CSF circulation, and ciliary flow remained the driver of the intercompartmental bidirectional flow as well as the near-wall flow. We finally showed that cilia driven flow is crucial for proper rostral development and regulated the spatial neural cell organization. CONCLUSIONS: Our data support a paradigm in which Xenopus embryonic ventriculogenesis and rostral brain development are critically dependent on ependymal cilia-driven CSF flow currents that are generated independently of cardiac pulsatile forces. Our work suggests that the Xenopus ventricular system forms a complex cilia-driven CSF flow network which regulates neural cell organization. This work will redirect efforts to understand the molecular regulators of embryonic CSF flow by focusing attention on motile cilia rather than other forces relevant only to the adult.

Intracranial pressure elevation alters CSF clearance pathways.

BACKGROUND: Infusion testing is a common procedure to determine whether shunting will be beneficial in patients with normal pressure hydrocephalus. The method has a well-developed theoretical foundation and corresponding mathematical models that describe the CSF circulation from the choroid plexus to the arachnoid granulations. Here, we investigate to what extent the proposed glymphatic or paravascular pathway (or similar pathways) modifies the results of the traditional mathematical models. METHODS: We used a compartment model to estimate pressure in the subarachnoid space and the paravascular spaces. For the arachnoid granulations, the cribriform plate and the glymphatic circulation, resistances were calculated and used to estimate pressure and flow before and during an infusion test. Finally, different variations to the model were tested to evaluate the sensitivity of selected parameters. RESULTS: At baseline intracranial pressure (ICP), we found a very small paravascular flow directed into the subarachnoid space, while 60% of the fluid left through the arachnoid granulations and 40% left through the cribriform plate. However, during the infusion, 80% of the fluid left through the arachnoid granulations, 20% through the cribriform plate and flow in the PVS was stagnant. Resistance through the glymphatic system was computed to be 2.73 mmHg/(mL/min), considerably lower than other fluid pathways, giving non-realistic ICP during infusion if combined with a lymphatic drainage route. CONCLUSIONS: The relative distribution of CSF flow to different clearance pathways depends on ICP, with the arachnoid granulations as the main contributor to outflow. As such, ICP increase is an important factor that should be addressed when determining the pathways of injected substances in the subarachnoid space. Our results suggest that the glymphatic resistance is too high to allow for pressure driven flow by arterial pulsations and at the same time too small to allow for a direct drainage route from PVS to cervical lymphatics.

Kaolin-induced chronic hydrocephalus accelerates amyloid deposition and vascular disease in transgenic rats expressing high levels of human APP.

BACKGROUND: Normal pressure hydrocephalus (NPH) is most common in the elderly and has a high co-morbidity with Alzheimer's disease (AD) and cerebrovascular disease (CVD). To understand the relationship between NPH, AD and CVD, we investigated how chronic hydrocephalus impacts brain amyloid-beta peptide (Aß) accumulation and vascular pathology in an AD transgenic rodent model. Previously we showed that the altered CSF physiology produced by kaolin-hydrocephalus in older wild-type Sprague-Dawley rats increased Aß and hyperphosphorylated Tau (Silverberg et. al. Brain Res. 2010, 1317:286-296). We postulated that hydrocephalus would similarly affect an AD rat model. METHODS: Thirty-five transgenic rats (tgAPP21) that express high levels of human APP and naturally overproduce Aß40 were used. Six- (n = 7) and twelve-month-old (n = 9) rats had hydrocephalus induced by cisternal kaolin injection. We analyzed Aß burden (Aß40, Aß42 and oligomeric Aß) and vascular integrity (Masson trichrome and Verhoeff-Van Gieson) by immunohistochemistry and chemical staining at 10 weeks (n = 8) and 6 months (n = 5) post hydrocephalus induction. We also analyzed whether the vascular pathology seen in tgAPP21 rats, which develop amyloid angiopathy, was accelerated by hydrocephalus. Age-matched naïve and sham-operated tgAPP21 rats served as controls (n = 19). RESULTS: In hydrocephalic tgAPP21 rats, compared to naïve and sham-operated controls, there was increased Aß 40 and oligomeric Aß in hippocampal and cortical neurons at 10 weeks and 6 months post-hydrocephalus induction. No dense-core amyloid plaques were seen, but diffuse Aß immunoreactivity was evident in neurons. Vascular pathology was accelerated by the induction of hydrocephalus compared to controls. In the six-month-old rats, subtle degenerative changes were noted in vessel walls at 10 weeks post-kaolin, whereas at six months post-kaolin and in the 12-month-old hydrocephalic rats more pronounced amyloid angiopathic changes were seen, with frequent large areas of infarction noted. CONCLUSIONS: Kaolin-hydrocephalus can accelerate intraneuronal Aß40 accumulation and vascular pathology in tgAPP21 rats. In addition, disrupted CSF production and reduced CSF turnover results in impaired Aß clearance and accelerated vascular pathology in chronic hydrocephalus. The high co-morbidity seen in NPH, AD and CVD is likely not to be an age-related coincidence, but rather a convergence of pathologies related to diminished CSF clearance.

A balanced view of choroid plexus structure and function: Focus on adult humans.

Recently tremendous progress has been made in studying choroid plexus (CP) physiology and pathophysiology; and correcting several misconceptions about the CP. Specifically, the details of how CP, a locus of the blood-CSF barrier (BCSFB), secretes and purifies CSF, generates intracranial pressure (ICP), maintains CSF ion homeostasis, and provides micronutrients, proteins and hormones for neuronal and glial development, maintenance and function, are being understood on a molecular level. Unequivocal evidence that the CP secretory epithelium is the predominant supplier of CSF for the ventricles comes from multiple lines: uptake kinetics of tracer (22)Na and (36)Cl penetration from blood to CSF, autoradiographic mapping of rapid (22)Na and (36)Cl permeation (high permeability coefficients) into the cerebroventricles, CSF sampling from several different in vivo and in vitro CP preparations, CP hyperplasia that increases CSF formation and ICP; and in vitro analysis of CP ability to transport molecules (with expected directionality) and actively secrete fluid against an hydrostatic fluid column. Furthermore, clinical support for this CP-CSF model comes from neurosurgical procedures to remove lateral ventricle CPs in hydrocephalic children to reduce CSF formation, thereby relieving elevated ICP. In terms of micronutrient transport, ascorbic acid, folate and other essential factors are transported by specific (cloned) carriers across CP into ventricular CSF, from which they penetrate across the ependyma and pia mater deeply into the brain to support its viability and function. Without these choroidal functions, severe neurological disease and even death can occur. In terms of efflux or clearance transport, the active carriers (many of which have been cloned and expressed) in the CP basolateral and apical membranes perform regulatory removal of some metabolites (e.g. choline) and certain drugs (e.g. antibiotics like penicillin) from CSF, thus reducing agents such as penicillin to sub-therapeutic levels. Altogether, these multiple transport and secretory functions in CP support CSF homeostasis and fluid dynamics essential for brain function.

A balanced view of the cerebrospinal fluid composition and functions: Focus on adult humans.

In this review, a companion piece to our recent examination of choroid plexus (CP), the organ that secretes the cerebrospinal fluid (CSF), we focus on recent information in the context of reliable older data concerning the composition and functions of adult human CSF. To accomplish this, we define CSF, examine the methodology employed in studying the CSF focusing on ideal or near ideal experiments and discuss the pros and cons of several widely used analogical descriptions of the CSF including: the CSF as the "third circulation," the CSF as a "nourishing liquor," the similarities of the CSF/choroid plexus to the glomerular filtrate/kidney and finally the CSF circulation as part of the "glymphatic system." We also consider the close interrelationship between the CSF and extracellular space of brain through gap junctions and the paucity of data suggesting that the cerebral capillaries secrete a CSF-like fluid. Recently human CSF has been shown to be in dynamic flux with heart-beat, posture and especially respiration. Functionally, the CSF provides buoyancy, nourishment (e.g., vitamins) and endogenous waste product removal for the brain by bulk flow into the venous (arachnoid villi and nerve roots) and lymphatic (nasal) systems, and by carrier-mediated reabsorptive transport systems in CP. The CSF also presents many exogenous compounds to CP for metabolism or removal, indirectly cleansing the extracellular space of brain (e.g., of xenobiotics like penicillin). The CSF also carries hormones (e.g., leptin) from blood via CP or synthesized in CP (e.g., IGF-2) to the brain. In summary the CP/CSF, the third circulation, performs many functions comparable to the kidney including nourishing the brain and contributing to a stable internal milieu for the brain. These tasks are essential to normal adult brain functioning.