Altered Cerebrospinal Fluid Flow Research Articles

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.

Cerebrospinal Fluid Flow Analysis in Tuberculous Meningitis Using Phase Contrast Technique on 3 Tesla MRI: A New Paradigm and Our Initial Experience.

Phase-contrast magnetic resonance imaging (PC-MRI) has been used for studying cerebrospinal fluid (CSF) dynamics in various CSF related disorders at aqueduct of Sylvius. To analyze the CSF flow dynamics qualitatively and quantitatively using PC-MRI across the aqueduct of Sylvius in diagnosed patients of tuberculous meningitis. Thirty patients, clinically diagnosed with tuberculous meningitis and mean age of 24 years (range: 12-60 years) were taken up to study the changes in CSF flow dynamics using PC-MRI with retrospective cardiac gating. Thirty age and sex matched healthy volunteers were also included for comparison and reference values. Flow quantification was done by through-plane scans acquired in the axial plane perpendicular to the aqueduct. For qualitative examination, in-plane phase contrast scans were acquired in the mid-sagittal plane. Encoding velocity was kept in craniocaudal direction. Calculated parameters were peak velocity (cm/s), average velocity (cm/s), average flow (mL/s), net forward volume (mL), and stroke volume (μL). Qualitatively, loss of normal sinusoidal waveform of CSF flow was noted in two cases of hydrocephalus with exaggerated flows. Quantitatively, CSF flow parameters showed marked numerical difference in tuberculous meningitis patients with hydrocephalus on comparison with healthy volunteers and with cases without hydrocephalus. PC-MRI is a sensitive technique to analyze altered CSF flow dynamics in tuberculous meningitis patients. This is a useful adjunct in imaging these patients to extract both the qualitative and quantitative information about CSF flow for comprehensive evaluation.

Anatomical basis and physiological role of cerebrospinal fluid transport through the murine cribriform plate.

Cerebrospinal fluid (CSF) flows through the brain, transporting chemical signals and removing waste. CSF production in the brain is balanced by a constant outflow of CSF, the anatomical basis of which is poorly understood. Here, we characterized the anatomy and physiological function of the CSF outflow pathway along the olfactory sensory nerves through the cribriform plate, and into the nasal epithelia. Chemical ablation of olfactory sensory nerves greatly reduced outflow of CSF through the cribriform plate. The reduction in CSF outflow did not cause an increase in intracranial pressure (ICP), consistent with an alteration in the pattern of CSF drainage or production. Our results suggest that damage to olfactory sensory neurons (such as from air pollution) could contribute to altered CSF turnover and flow, providing a potential mechanism for neurological diseases.

Visualizing flow in an intact CSF network using optical coherence tomography: implications for human congenital hydrocephalus

Cerebrospinal fluid (CSF) flow in the brain ventricles is critical for brain development. Altered CSF flow dynamics have been implicated in congenital hydrocephalus (CH) characterized by the potentially lethal expansion of cerebral ventricles if not treated. CH is the most common neurosurgical indication in children effecting 1 per 1000 infants. Current treatment modalities are limited to antiquated brain surgery techniques, mostly because of our poor understanding of the CH pathophysiology. We lack model systems where the interplay between ependymal cilia, embryonic CSF flow dynamics and brain development can be analyzed in depth. This is in part due to the poor accessibility of the vertebrate ventricular system to in vivo investigation. Here, we show that the genetically tractable frog Xenopus tropicalis, paired with optical coherence tomography imaging, provides new insights into CSF flow dynamics and role of ciliary dysfunction in hydrocephalus pathogenesis. We can visualize CSF flow within the multi-chambered ventricular system and detect multiple distinct polarized CSF flow fields. Using CRISPR/Cas9 gene editing, we modeled human L1CAM and CRB2 mediated aqueductal stenosis. We propose that our high-throughput platform can prove invaluable for testing candidate human CH genes to understand CH pathophysiology.

Spinal arachnoid web-a review article.

The spinal arachnoid web is an abnormal formation of an arachnoid membrane in the subarachnoid space. It is a rare entity with some degree of uncertainty surrounding its etiology. It can result in a displacement of the spinal cord causing pain and neurological symptoms as well as blockage of cerebrospinal fluid (CSF) flow and subsequent syringomyelia. The syrinx resulting from the altered CSF flow dynamics has been described to assume variable positions relative to the web itself. The "scalpel sign" is regarded as a pathognomonic feature of a spinal arachnoid web. The arachnoid web, however, is relatively thin and may be elusive of routine radiological investigations. As such, a myriad of preoperative and intraoperative investigations have been postulated to improve the sensitivity of detecting this abnormality. Management of spinal arachnoid webs ranges from conservative management to surgical excision where in the latter, the extent of excision remains the subject of debate. The authors herein present a review of the available information on this rare topic.

Elevated Surfactant Protein Levels and Increased Flow of Cerebrospinal Fluid in Cranial Magnetic Resonance Imaging.

Surfactant proteins (SPs) are a multifunctional group of proteins, responsible for the regulation of rheological properties of body fluids, host defense, and cellular waste clearance. Their concentrations are changed in cerebrospinal fluid (CSF) of patients suffering from communicating hydrocephalus. Hydrocephalic conditions are accompanied by altered CSF flow dynamics; however, the association of CSF-SP concentrations and CSF flow has not yet been investigated. Hence, the aim of this study was to evaluate the association between SP concentrations in the CSF and marked CSF flow phenomena at different anatomical landmarks of CSF spaces. Sixty-one individuals (15 healthy subjects and 46 hydrocephalus patients) were included in this study. CSF specimens were analyzed for SP-A, SP-B, SP-C, and SP-D concentrations by the use of enzyme-linked immunosorbent assays (ELISA). CSF flow was evaluated in axial T2_turbo inversion recovery magnitude (TIRM)-weighted and sagittal T2-weighted magnetic resonance imaging sections using a 4-grade scale (1-no flow, 2-subtle flow, 3-moderate flow, and 4-strong flow). CSF-SP concentrations (mean ± standard deviation) of the overall collective were as follows: SP-A = 0.73 ± 0.58ng/ml, SP-B = 0.17 ± 0.93ng/ml, SP-C = 0.95 ± 0.75ng/ml, and SP-D = 7.43 ± 5.17ng/ml. The difference between healthy controls and hydrocephalic patients regarding CSF concentrations of SP-A (0.34 ± 0.22 vs. 0.81 ± 0.59ng/ml) and SP-C (0.48 ± 0.29 vs. 1.10 ± 0.79ng/ml) revealed to be statistically significant as calculated by means of ANOVA (p values of 0.022 and 0.007, respectively). CSF flow voids were detectable at all investigated landmarks of the CSF spaces (foramina of Monro, third ventricle, mesencephalic aqueduct, prepontine cistern, fourth ventricle, cisterna magna, and craniocervical junction). CSF flow voids, reported as mean ± standard deviation, revealed to be significantly increased in hydrocephalic patients compared to controls as calculated by means of ANOVA (respective p values are given in brackets following values of descriptive statistics) at the following sites: foramina of Monro (1.60 ± 0.91 vs. 2.37 ± 0.99, p = 0.01), fourth ventricle (1.67 ± 0.98 vs. 2.52 ± 1.05, p = 0.007), and the cisterna magna (1.93 ± 1.10 vs. 2.72 ± 1.13, p = 0.022). Spearman's rank order calculation identified significant correlations for CSF flow voids at the foramina of Monro and the third ventricle with SP-A (r = 0.429, p = 0.001 and r = 0.464, p < 0.001) and CSF flow void at the mesencephalic duct with SP-D (r = - 0.371, p = 0.039). Furthermore, SP-C showed a moderate inverse correlation with age (r = - 0.302, p = 0.022). The present study confirmed statistically significant differences in SP-CSF concentrations between healthy controls and hydrocephalic patients. Additionally, significant correlations between SP concentrations in CSF with increased CSF flow were identified. These findings underline the role of SPs as regulators of CSF rheology.

Inferiorly-Directed Posterior Cranial Vault Distraction for Treatment of Chiari Malformations

PURPOSE: Chiari I malformations involve a small posterior fossa and subsequent herniation of the hindbrain, causing altered cerebrospinal fluid flow and intracranial hypertension (Figure 1). Traditional decompressive management uses a posterior fossa craniectomy, which carries limitations and complication risks, including over-correction or the need for re-operation. A large single-stage craniectomy can lead to cerebellar ptosis and new or recurrent symptoms. Distraction of the posterior vault has been effective for relieving intracranial pressure in small case series.1,2 The authors present the largest series of patients with Chiari I malformations treated with posterior cranial vault distraction osteogenesis. Also introduced is a previously unpublished technique utilizing a vertical distraction vector for vault expansion while mitigating the risks of scaphocephaly and cerebellar ptosis.Figure 1: Pre-operative MRI.METHODS: This multi-center study included patients with syndromic and non-syndromic Chiari I malformations treated with vertical-vector distraction osteogenesis of the posterior cranial vault from 2008 to 2014. All patients had follow-up of at least 1 year except one who recently completed the full protocol. Demographics, pre- and post-operative clinical symptoms, and perioperative details were assessed. Postoperative aesthetics, complications, and symptomatic improvement were evaluated with neurosurgery. RESULTS: Nine patients were identified. Five had known syndromes, two likely had unidentified syndromes, and two were non-syndromic. Seven had prior Chiari-related surgeries. Most presented with hydrocephalus, motor symptoms, and developmental delay. Operatively, internal distraction fixators were applied with the distraction vector following a cephalad-caudad axis. Devices were activated on POD5 and distracted 1 mm/day. Three post-operative complications included a dislodged distraction arm, device extrusion, and local cellulitis. No complications affected the clinical outcome. All patients completed the distraction protocol. Radiographic follow-up showed good bone formation, posterior fossa decompression, improved CSF flow, and no cerebellar ptosis (Figure 2). Neurological surveillance showed improvement in intracranial pressure, hydrocephalus, motor symptoms, and behavioral problems. Importantly, with average follow-up of 3.5 years, no patient required reoperation for persistent or recurrent symptoms.Figure 2: Post-Operative MRI.CONCLUSION: The authors have presented the largest experience to date of Chiari I malformations treated with distraction osteogenesis, along with a novel technique to safely and effectively expand the posterior fossa while minimizing risk of cerebellar ptosis, scaphocephaly, and reoperations. With excellent functional, aesthetic, and clinical outcomes from this technique, it appears valuable as an initial or secondary operation for symptomatic Chiari I malformations.

IgG dynamics of dietary antigens point to cerebrospinal fluid barrier or flow dysfunction in first-episode schizophrenia.

Schizophrenia is a complex brain disorder that may be accompanied by idiopathic inflammation. Classic central nervous system (CNS) inflammatory disorders such as viral encephalitis or multiple sclerosis can be characterized by incongruent serum and cerebrospinal fluid (CSF) IgG due in part to localized intrathecal synthesis of antibodies. The dietary antigens, wheat gluten and bovine milk casein, can induce a humoral immune response in susceptible individuals with schizophrenia, but the correlation between the food-derived serological and intrathecal IgG response is not known. Here, we measured IgG to wheat gluten and bovine milk casein in matched serum and CSF samples from 105 individuals with first-episode schizophrenia (n=75 antipsychotic-naïve), and 61 controls. We found striking correlations in the levels of IgG response to dietary proteins between serum and CSF of schizophrenia patients, but not controls (schizophrenia, R(2)=0.34-0.55, p⩽0.0001; controls R(2)=0.05-0.06, p>0.33). A gauge of blood-CSF barrier permeability and CSF flow rate, the CSF-to-serum albumin ratio, was significantly elevated in cases compared to controls (p⩽0.001-0.003). Indicators of intrathecal IgG production, the CSF IgG index and the specific Antibody Index, were not significantly altered in schizophrenia compared to controls. Thus, the selective diffusion of bovine milk casein and wheat gluten antibodies between serum and CSF in schizophrenia may be the function of a low-level anatomical barrier dysfunction or altered CSF flow rate, which may be transient in nature.

Cine cerebrospinal fluid imaging in multiple sclerosis

To investigate cerebrospinal fluid (CSF) dynamics in the aqueduct of Sylvius in multiple sclerosis (MS) patients and healthy controls (HC) using cine phase contrast imaging. In all, 67 MS patients (48 relapsing-remitting [RR] and 19 secondary-progressive [SP]), nine patients with clinically isolated syndrome (CIS), and 35 age- and sex-matched HC were examined. CSF flow and velocity measures were quantified using a semiautomated method and compared with clinical and magnetic resonance imaging (MRI) disease outcomes. Significantly decreased CSF net flow was detected in MS patients compared to HC (-3.7 vs. -7.1 μL/beat, P = 0.005). There was a trend for increased net positive flow between SP, RR, and CIS patients. Altered CSF flow and velocity measures were associated with more severe T1 and T2 lesion volumes, lateral and fourth ventricular volumes, and third ventricular width in MS and CIS patients (P < 0.01 for all). In CIS patients, conversion to clinically definite MS in the following year was related to decreased CSF net flow (P = 0.007). There was a trend between increased annual relapse rate and altered CSF flow/velocity measures in RRMS patients (P < 0.05). CSF flow dynamics are altered in MS patients. More severe clinical and MRI outcomes in RRMS and CIS patients relate to altered CSF flow and velocity measures.

Imaging of cerebrospinal fluid space and movement of hydrocephalus mice using near infrared fluorescence

We have studied optical imaging of mice cerebrospinal fluid (CSF) space and flow using near infrared (NIR) fluorescence. We applied our method to image CSF space and flow in a mice hydrocephalus model. Hydrocephalus was induced in mice with intracranial injections of transforming growth factor. Hydrocephalic and control mice were imaged using our NIR fluorescence imaging system. Hydrocephalic mice showed diminished intracranial CSF flow. Our system is sufficient to show altered CSF flow in a mouse hydrocephalus model. Optical imaging using near infrared is an effective modality to image CSF space and movement.

Improved cerebrospinal fluid flow measurements using phase contrast balanced steady-state free precession

We present a demonstration of phase contrast balanced steady-state free precession (PC-bSSFP) for measuring cerebrospinal fluid (CSF) flow in the brain and spine, and a comparison of measurements obtained with this technique to conventional phase contrast using incoherent gradient echoes (PC-GRE). With PC-GRE sequences, CSF images suffer from low signal-to-noise ratio (SNR), due to short repetition times required for adequate temporal resolution, and the long relaxation time of CSF. Furthermore, CSF flow is often nonlaminar, causing phase dispersion and signal loss in PC-GRE images. It is hypothesized that PC-bSSFP can improve CSF flow measurements with its high SNR and insensitivity to turbulent flow effects. CSF images acquired from the two techniques were compared in 13 healthy volunteers. Three measures were used to objectively evaluate the PC-bSSFP sequence: the CSF flow percentage, defined as the percentage of the total CSF region exhibiting pulsatile flow, net stroke volume and SNR. Images acquired with PC-bSSFP demonstrated pulsatile CSF flow in 35.8% (P<.005), 11.2% (P<.05) and 27.8% (P<.0005) more pixels than PC-GRE in the prepontine cistern, anterior and posterior cervical subarachnoid space (SAS), respectively. Likewise, measurements of stroke volume in these regions increased by 61.6% (P<.05), 16.8% (P<.001) and 48.3% (P<.0001), respectively. Similar comparisons in the aqueduct showed no statistical difference in stroke volumes between the two techniques (P=.5). The average gain in SNR was 3.3+/-1.7 (P<.001) in the prepontine cistern, 5.0+/-0.2 (P<.01) at the cervical level and 2.0+/-0.4 (P<.001) in the aqueduct in PC-bSSFP magnitude images over PC-GRE images. In addition to the obvious advantage of increased SNR, these results indicate that PC-bSSFP provides more complete measurements of CSF flow data than PC-GRE. PC-bSSFP can be used as a reliable technique for CSF flow quantification for the characterization of normal and altered intracranial CSF flow patterns.

Ophthalmoparesis in Idiopathic Intracranial Hypertension

To report unusual ocular motility disturbances in the setting of idiopathic intracranial hypertension (IIH). Interventional case series. Two cases with IIH and unusual ophthalmopareses are reported. Two patients with confirmed IIH presented with headache, diplopia, and papilledema. The first patient had bilateral sixth nerve palsies and a partial right third nerve palsy, which resolved rapidly after a cerebro spinal fluid (CSF) shunting procedure; the second patient had alternating skew deviation and upbeat nystagmus. Both cases had normal brain magnetic resonance imaging (MRI) and magnetic resonance venography (MRV) and normal CSF contents, ruling out a secondary cause of intracranial hypertension. These exceptional vertical and horizontal ophthalmopareses in the setting of IIH may be related directly to very elevated CSF pressures and may be secondary to altered CSF flow in the posterior fossa.

The “presyrinx” state: is there a reversible myelopathic condition that may precede syringomyelia?

Alteration of cerebrospinal fluid (CSF) flow has been proposed as an important mechanism leading to the development of syringomyelia. We hypothesize that a "presyrinx" condition due to potentially reversible alteration in normal CSF flow exists and that its appearance may be due to variations in the competence of the central canal of the spinal cord. Five patients with clinical evidence of myelopathy, no history of spinal cord trauma, enlargement of the cervical spinal cord with T1 and T2 prolongation but no cavitation, evidence for altered or obstructed CSF flow, and no evidence of intramedullary tumor or a spinal vascular event underwent MR imaging before and after intervention that alleviated obstruction to CSF flow. Preoperatively, all patients demonstrated enlarged spinal cords and parenchymal T1 and T2 prolongation without cavitation. Results of magnetic resonance (MR) imaging examinations following intervention in all patients showed resolution of cord enlargement and normalization or improvement of cord signal abnormalities. In one patient with severe arachnoid adhesions who initially improved following decompression, late evolution into syringomyelia occurred in association with continued CSF obstruction. Nontraumatic obstruction of the CSF pathways in the spine may result in spinal cord parenchymal T2 prolongation that is reversible following restoration of patency of CSF pathways. We refer to this MR appearance as the "presyrinx" state and stress the importance of timely intervention to limit progression to syringomyelia.

Study of cerebrospinal fluid flow dynamics in TGF-β1 induced chronic hydrocephalic mice

In a previous study, we found that the CSF level of transforming growth factor/11 (TGF-fll) is elevated following subarachnoid hemorrhage (SAH) in patients who later develop communicating hydrocephalus, while in mice, an intrathecal injection of TGF-fll can induce communicating hydrocephalus. Recently, histopathological changes in the leptomeninges were studied using the above TGF-fll induced mice model of hydrocephalus. In the present study, in order to further clarify the ventricular dilatation mechanism, we examined cerebrospinal fluid (CSF) flow dynamics in TGF-fll induced hydrocephalic mice. To assess CSF flow, Indian ink was injected into the passage pathway and the time taken for the ink to pass from the parietal intrameningeal CSF space to cervical lymph nodes was determined. The ink study revealed a significant lengthening of the ink passage time due to altered CSF flow dynamics, while a histological examination showed ink stasis in the altered leptomeningeaI CSF space compared to PBS injected control mice. TGF-fl 1 induced increased cellularity in the leptomeninx and fibrosis, and a subsequent narrowing of the intrameningeal CSF space. This narrowing causes a disturbance in CSF flow, thus generating a mild pressure gradient, which ultimately leads to the development of slowly progressive ventricular dilatation. After SAH, elevated TGF-fll in the CSF may play a similar role, in concert with other factors, in the development of communicating hydrocephalus in human. [Neurol Res 2000; 22: 215-222]