Review of Cerebrospinal Fluid Physiology and Dynamics: A Call for Medical Education Reform.

BACKGROUND: The flow of cerebrospinal fluid (CSF) has been described as a unidirectional system with the choroid plexus serving as the primary secretor of CSF and the arachnoid granulations as primary reabsorption site. This theory of neurosurgical forefathers has been universally adopted and taught as dogma. Many neuroscientists have found difficulty reconciling this theory with common pathologies, and recent studies have found that this "classic" hypothesis may not represent the full picture. OBJECTIVE: To review modern CSF dynamic theories and to call for medical education reform. METHODS: We reviewed the literature from January 1990 to December 2020. We searched the PubMed database using key terms "cerebrospinal fluid circulation," "cerebrospinal fluid dynamics," "cerebrospinal fluid physiology," "glymphatic system," and "glymphatic pathway." We selected articles with a primary aim to discuss either CSF dynamics and/or the glymphatic system. RESULTS: The Bulat-Klarica-Oreskovic hypothesis purports that CSF is secreted and reabsorbed throughout the craniospinal axis. CSF demonstrates similar physiology to that of water elsewhere in the body. CSF "circulates" throughout the subarachnoid space in a pulsatile to-and-fro fashion. Osmolarity plays a critical role in CSF dynamics. Aquaporin-4 and the glymphatic system contribute to CSF volume and flow by establishing osmolarity gradients and facilitating CSF movement. Multiple studies demonstrate that the choroid plexus does not play any significant role in CSF circulation. CONCLUSION: We have highlighted major studies to illustrate modern principles of CSF dynamics. Despite these, the medical education system has been slow to reform curricula and update learning resources.

Do neurosurgeons follow the guidelines? A world-based survey on severe traumatic brain injury.

BACKGROUND: Traumatic brain injury (TBI) is going to be the third-leading cause of death worldwide, according to the WHO. Two European surveys suggested that adherence to brain trauma guidelines is poor. No study has compared compliance between low- (LMICs) and high-income (UHICs) countries. Hence, this study aimed to investigate differences in the management of severe TBI patients, comparing low- and high-income, and adherence to the BTF guidelines. METHODS: A web-based survey was spread through the Global Neuro Foundation, different neurosurgical societies, and social media. RESULTS: A total of 803 neurosurgeons participated: 70.4 from UHICs and 29.6% from LMICs. Hypertonic was administered as an early measure by the 73% and 65% of the responders in LMICs and UHICs, respectively (P=0.016). An invasive intracranial pressure monitoring was recommended by the 66% and 58% of the neurosurgeons in LMICs and UHICs, respectively (P<0.001). Antiseizure drugs (P<0.001) were given most frequently in LMICs as, against recommendations, steroids (87% vs. 61% and 86% vs. 81%, respectively). In the LMICs both the evacuation of the contusion and decompressive craniectomy were performed earlier than in UHICs (30% vs. 17% with P<0.001 and 44% vs. 28% with P=0.006, respectively). In the LMICs, the head CT control was performed mostly between 12 and 24 hours from the first imaging (38% vs. 23%, P<0.001). CONCLUSIONS: The current Guidelines on TBI do not always fit to both the resources and circumstances in different countries. Future research and clinical practice guidelines should reflect the greater relevance of TBI in low resource settings.

Spinal dural arteriovenous fistulas: a report on outcomes in a single-center retrospective cohort treated surgically and/or endovascularly.

AIM: To report on the outcomes of spinal dural arteriovenous fistulas (sDAVFs) treatment in a single-center retrospective cohort. METHODS: Data were retrieved on sDAVF cases treated surgically and endovascularly between January 2009 and January 2020. Sociodemographic, clinical, imaging data, and outcomes were analyzed. RESULTS: Thirty-four patients were identified: 11 female, mean age 64.1 ± 11.5 years; mean time of symptom duration 12 (range 1-149) months. The sDAVF locations were the following: 18 (62.1%) thoracic, 4 (13.8%) lumbar, 4 (13.8%) sacral, and 3 (10%) with multiple location feeders. All patients had a motor deficit and affected walking, and the majority had a sensory deficit, bowel, and bladder dysfunction. Fifteen (44.1%) patients underwent surgical treatment, 7 (20.6%) underwent endovascular treatment, and 12 (35.3%) underwent both (crossover). Radiological myelopathy showed regression in 19 (55.9%) patients. Overall, clinical improvement (decrease in modified Rankin score) following treatment was observed in 14 patients (41.2%), worsening in 1 (2.9%), while other had unchanged status. The proportion of patients with initial treatment failure markedly differed between the before-2014 and after-2014 period. Patients who failed to improve had more extensive myelopathy. CONCLUSION: Patients who underwent surgery or endovascular treatment had on average significant clinical recovery, while those who underwent treatment crossover had negligible improvement. The extent of myelopathy seems to be associated with clinical improvement.

Predictors of Functional Outcome after Spinal Ependymoma Resection.

AIM: Spinal ependymomas are among the most common intramedullary neoplasms in both adults and children. While surgical resection is the golden treatment standard, the role chemotherapy and radiotherapy have in patients with spinal ependymomas remains unclear. The aim of this study is to determine the predictors of functional outcome following spinal ependymoma resection to single out patients that may require adjuvant therapy. METHODS: We conducted a retrospective study on patients that underwent spinal ependymoma resection in our institution in a 10-year period. Magnetic resonance imaging of the spine was used to set the diagnosis of an intradural/intramedullary neoplasm. All patients underwent either gross tumor resection or tumor mass reduction. Histological diagnosis and histopathological grading of spinal ependymoma were done for all collected samples. Patients' general and neurological examination were performed early after the surgery (within the 1st week) and in a 6-month follow-up. RESULTS: A total of 51 intradural and intramedullary ependymoma resection surgeries on 43 patients were performed. There were slightly more male patients (57%) and the average patient age was 41 years. About 76.5% of patients presented with a tumor affecting one vertebrae level, while 23.5% presented with tumors expanding over two or more spinal regions. Gross tumor resection was achieved in 80% of cases, while 25% of procedures were performed on a recurring ependymomas. Most of the tumors (57%) were classified as G2 histological grade, while 8% were anaplastic ependymomas. In 80% of cases, early postoperative patient status was either better or equivalent to the preoperative one, while in a 6-month follow-up, up to 60% of cases showed a significant improvement over the preoperative status. Different demographic and clinical parameters were not proven to be predictors of postsurgical patient outcome including age, gender, and initial neurological presentation. Interestingly, most tumor characteristics were also not associated with postoperative functional outcome (histological grade, number of vertebrae levels affected, whether it is a primary or recurrent tumor). Even the scope of surgical procedure did not affect the functional outcome. The spinal region affected by the tumor was proven to be a predictor of early postoperative outcome (ρ= 0.346, P = 0.033), with lumbar spine being associated with the best outcomes. As expected, the scope of the surgery and whether gross tumor resection or tumor mass reduction was performed were the only significant predictors of tumor recurrence (ρ= 0.391, P = 0.005). CONCLUSIONS: Spinal ependymoma resection is an efficient procedure that improves the patient outcomes. Spinal region affected by the tumor is likely to be the most important predictor of functional outcome, while the procedure scope seems to be the most important predictor of tumor recurrence.

Intracranial Epidural Haematoma following Surgical Removal of a Giant Lumbosacral Schwannoma: A Case Report and Literature Review.

Postoperative intracranial epidural haematoma (EDH) is an extremely rare complication following spinal surgery, with only a handful of cases described in the literature. We report the case of a 16-year-old girl who underwent a successful subtotal resection of a giant lumbosacral schwannoma (L2-S2 level). Recovery from general anaesthesia was uneventful; however, her neurological status deteriorated rapidly within 24 h after surgery. A head computed tomography scan revealed a large right frontoparietal EDH with midline shift. An immediate frontotemporoparietal osteoplastic craniotomy and evacuation of the EDH were performed. At 1 year postoperatively, the patient regained full neurological recovery with no radiological signs of growth of the residual tumour.

Cervical Disk Replacement With Discover Versus Fusion in a Single-Level Cervical Disk Disease: A Prospective Single-Center Randomized Trial With a Minimum 2-Year Follow-up.

STUDY DESIGN: Prospective randomized study. OBJECTIVE: To compare the clinical outcome after Discover arthroplasty versus anterior cervical discectomy and fusion (ACDF) in patients treated for symptomatic single-level cervical disk disease. SUMMARY OF BACKGROUND DATA: ACDF is still the gold standard for surgical treatment of cervical spine degenerative disk disease. However, results of many studies suggest that it may cause degenerative changes at levels immediately above and below the fusion, known as adjacent segment degenerative disease. Cervical arthroplasty has recently been introduced as an alternative to standard procedure of ACDF. It showed decreased surgical morbidity, decreased complications from postoperative immobilization, and an earlier return to previous level of function. MATERIALS AND METHODS: A total of 105 consecutive patients with single-level cervical disk disease, producing radiculopathy and/or myelopathy were randomly divided into groups to undergo ACDF or Discover arthroplasty. All patients were evaluated with preoperative and postoperative serial radiographic studies and clinically, using Neck Disability Index, Visual Analog Scale and neurological status at 3, 6, 12, and 24 months. RESULTS: The results of our study indicate that cervical arthroplasty using Discover Artificial Cervical Disc provides favorable clinical and radiologic outcomes in a follow-up period of 24 months. There has been significant improvement in clinical parameters, Visual Analog Scale and Neck Disability Index, at 3, 6, 12, and 24 months in arthroplasty group comparing to control group. CONCLUSION: The Discover artificial cervical disc replacement offers favorable outcome compared with ACDF for a single-level cervical disk disease at short-term and long-term follow-up.

The effects of lumboperitoneal and ventriculoperitoneal shunts on the cranial and spinal cerebrospinal fluid volume in a patient with idiopathic intracranial hypertension.

Lumboperitoneal (LP) and ventriculoperitoneal (VP) shunts are a frequent treatment modality for idiopathic intracranial hypertension (IIH). Although these shunts have been used for a long time, it is still not clear how they change the total craniospinal CSF volume and what portions of cranial and spinal CSF are affected. This report for the first time presents the results of a volumetric analysis of the total cranial and spinal CSF space in a patient with IIH. We performed an automated segmentation of the cranial and a manual segmentation of the spinal CSF space first with an LP shunt installed and again after the LP shunt was replaced by a VP shunt. When the LP shunt was in place, the total CSF volume was smaller than when the VP shunt was in place (222.4 cm(3) vs 279.2 cm(3)). The difference was almost completely the result of the spinal CSF volume reduction (49.3 cm(3) and 104.9 cm(3) for LP and VP, respectively), while the cranial CSF volume was not considerably altered (173.2 cm(3) and 174.2 cm(3) for LP and VP, respectively). This report indicates that LP and VP shunts in IIH do not considerably change the cranial CSF volume, while the reduction of CSF volume after LP shunt placement affects almost exclusively the spinal part of the CSF system. Our results suggest that an analysis of both the cranial and the spinal part of the CSF space is necessary for therapeutic procedures planning and for an early recognition of numerous side effects that often arise after shunts placement in IIH patients.

Monoamine Neurotransmitter Metabolite Concentration as a Marker of Cerebrospinal Fluid Volume Changes.

OBJECTIVE: In our previous papers we demonstrated that changes in blood and cerebrospinal fluid (CSF) osmolarity have a strong influence on CSF pressure and volume, which is in accordance with a new proposed hypothesis of CSF physiology. Thus, acute changes in CSF volume should be reflected in the CSF concentration of different central nervous system (CNS) metabolites. METHODS: In anesthetized cats (n = 4) we measured the outflow volume of CSF by cisternal free drainage at a negative CSF pressure (-10 cmH2O) before and after the intraperitoneal (i.p.) application of a hypo-osmolar substance (distilled water). In samples of CSF collected at different time intervals (30 min) we measured the concentration of homovanillic acid (HVA). RESULTS: In spite of fact that constant CSF outflow volume was obtained after a 30-min period in our model, the concentration of HVA gradually increased over time and became stable after 90 min. After the i.p. application of distilled water the outflow CSF volume increased significantly, whereas the concentration of HVA significantly decreased over 30 min. CONCLUSIONS: The results observed suggest that alterations in serum osmolarity change the CSF volume and concentrations of neurotransmitter metabolites because of the osmotic arrival of water from CNS blood capillaries in all CSF compartments.

General recommendations for the management of aneurysmal subarachnoid hemorrhage.

Subarachnoid hemorrhage is a neurologic emergency and a detrimental cerebrovascular event with a high rate of death and complications. Recommendations have been developed and based on literature search, evaluation of the results of large international clinical trials, collective experience of the authors, and endorsed by the Croatian Society of Neurovascular Disorders, Croatian Society of Neurology including Section for Neurocritical Care, Croatian Neurosurgical Society, Croatian Society for Difficult Airway Management and Croatian Medical Association. The aim of these guidelines is to provide current and comprehensive recommendations and to assist physicians in making appropriate decisions in the management of subarachnoid hemorrhage. Evidence based information on the epidemiology, risk factors and prognosis, as well as recommendations on diagnostic work up, monitoring and management are provided, with regard to treatment possibilities in Croatia.

Recommendations for the management of medical complications in patients following aneurysmal subarachnoid hemorrhage.

These are evidence based guidelines for the management of medical complications in patients following aneurysmal subarachnoid hemorrhage, developed and endorsed by the Croatian Society of Neurovascular Disorders, Croatian Society of Neurology including Section for Neurocritical Care, Croatian Neurosurgical Society, Croatian Society for Difficult Airway Management and Croatian Medical Association. They consist of recommendations for best monitoring, medical treatment and interventions based on the literature, evaluation of the results of large international clinical trials, and collective experience of the authors.

The application of ultrasound in neuroendoscopic procedures: first results with the new tool "NECUP-2".

In this paper, our experience with originally constructed Neurosurgical Endoscopic Contact Ultrasound Probe "NECUP-2" in neuroendoscopy is reported. Between June 1997 and June 2007, 132 neuroendoscopic procedures have been performed: 102 endoscopic thrid ventriculostomies (ETV), 15 arachnoid cysts and 5 intraventricular tumours operations. The "NECUP-2" was applied effectively in all cases in which blunt perforation was not possible: 38/102 ETY, 10/10 septostomies, 15/15 arachnoid cysts. In five cases of intraventricular tumours, neuroendoscopic procedure was combined with open microsurgery for tumour removal with preservation of vascular structures. There were no "NECUP-2" related complications. Of postoperative complications, we had liquorrhea (9 patients), and symptoms of meningitis (6 patients). In the follow-up period (6 months to 6 years), we had a patency rate of 80% (50/63 patients). All patients improved in clinical status. According to the first results, it seems that ultrasonic contact probe NECUP-2 presents a new device in neurosurgical armamentarium that can be used in various fields of neurosurgery. With minimal and controlled lesion that is produced at the tip of the probe, it can be used in highly demanding operations such as third ventriculostomy and tumour resection.

Hydroxyapatite ceramics in multilevel cervical interbody fusion - is there a role?

The aim of this study is to evaluate the efficacy of hydroxyapatite grafts in multilevel cervical interbody fusion during the one year follow-up. A total of 86 patients with degenerative cervical disc disease underwent all together 224 cervical interbody fusion procedures in which either Smith-Robinson or Cloward type hydroxyapatite grafts were used. The surgeries included radiculopathy in 38 cases, myelopathy in 20 cases and myeloradicuopathy in 28 patients. In 65 out of 86 patients, fusion was followed by an anterior instrumentation (plating). Postoperatively, patients were followed for a mean of 15.64 (range 11-23.3) months. All patients underwent radiography to evaluate fusion and the axis curvature. Excellent clinical results (86%), described as a complete or partial relief of symptoms with full return to preop activity, were obtained in patients with radiculopathy. There were 5 grafts mobilizations and one graft fracture. Two grafts extruded in non-instrumented patients and required repeated surgery. There were other three reoperations due to the hardware problems. One year fusion rate was obtained at 86% for two-level surgery, 80.1% for three-level surgery and 74% for four-level surgery. The mean (SD) hospital stay was 3.8 (0.7) days. A hydroxyapatite cheramic can be a very effective synthetic material for multilevel cervical interbody fusion. It is characterized by a high fusion rate and a small percentage of graft-related complications, especially when fusion procedure is followed by plating.

Effect of osmolarity on CSF volume during ventriculo-aqueductal and ventriculo-cisternal perfusions in cats.

The effect of cerebrospinal fluid (CSF) osmolarity on the CSF volume has been studied on different CSF/brain tissue contact areas. It has been shown, on anesthetized cats under normal CSF pressure, that the perfusion of CSF system (12.96 µl/min) by hyperosmolar CSF (400 mOsml/l) leads to significantly higher outflow volume (µl/min) during ventriculo-cisternal perfusion (29.36 ± 1.17 and 33.50 ± 2.78) than the ventriculo-aqueductal perfusion (19.58 ± 1.57 and 22.10 ± 2.31) in experimental period of 30 or 60 min. Both of these hyperosmolar perfusions resulted in significantly higher outflow volume than the perfusions by isoosmolar artificial CSF (12.86 ± 0.96 and 13.58 ± 1.64). These results suggest that the volume of the CSF depends on both the CSF osmolarity and the size of the contact area between CSF system and surrounding tissue exposed to hyperosmolar CSF. However, all of these facts imply that the control of the CSF volume is not in accordance with the classical hypothesis of cerebrospinal fluid hydrodynamic. According to this hypothesis, the CSF volume should be regulated by active formation of CSF (secretion) inside the brain ventricles and passive CSF absorption outside of the brain. Obtained results correspond to the new hypothesis which claims that the volume of CSF depends on the gradients of hydrostatic and osmotic forces between the blood on one side and extracellular fluid and CSF on the other. The CSF exchange between the entire CSF system and the surrounding tissue should, therefore, be determined by (patho)physiological conditions that predominate within those compartments.

Fluid perfusion as a method of cerebrospinal fluid formation rate--critical appraisal.

The aim of the study was to evaluate whether or not cerebrospinal fluid formation rate (Vf) calculated according to the equation of Heisey et al., truly show the produced cerebrospinal fluid. For this reason Vf was simulated (40.6 microL/min) by an infusion pump in a plastic cylinder and the evaluation was done by comparing the results obtained between the calculated Vf and the simulated one. In both cases the result should be the same (40.6 micro/min). Other types of experiments were carried out by ventriculocisternal perfusion (92.4 microL/min) on anaesthetized and sacrificed cats. If the equation is correct, the calculated Vf for sacrificed animals should be zero, because there is no Vf in dead animals. The fact that the calculated Vf (46.5 microL/min) in the plastic cylinder was different (p < 0.0001) from the simulated one (40.6 microL/min) and that Vf was calculated even for dead animals (3-5 microL/min) clearly shows the that perfusion method may not be an accurate method for determination of Vf.

Evaluation of ventriculo-cisternal perfusion model as a method to study cerebrospinal fluid formation.

AIM: To evaluate ventriculo-cisternal perfusion as a method for measuring cerebrospinal fluid formation rate, calculated by means of the Heisey et al equation. Method. All experiments were carried out on anesthetized domestic cats fixed in the sphinx position in a stereotaxic frame. Ventriculo-cisternal perfusion was used at an intracranial pressure of -10 cm H2O at different perfusion rates (32.0, 65.5, 125.0, and 252.0 microL/min). Dextran blue was applied as an indicator substance and the concentration of the indicator was measured with a spectrophotometer at a wavelength of 635 nm. Cerebrospinal fluid formation rate was calculated with the equation of Heisey et al. Results. The indicator substance was less diluted at a higher perfusion rate, and the calculated cerebrospinal fluid formation rate was lower. The increase in perfusion rate from 65.5 to 125.0 to 252.0 microL/min increased the concentration of indicator substance from 0.75 to 0.89 to 0.97 mg/mL and decreased calculated cerebrospinal fluid formation rate from 21.8 to 15.4 to 7.8 microL/min. This reduction was linear and an increase in the perfusion rate by 1.0 microL/min decreased the cerebrospinal formation rate by 0.05 microL/min. Conclusion. The calculated cerebrospinal fluid formation rate depends on different perfusion rates. The increase in the perfusion rate diminishes the calculated formation rate. Ventriculo-cisternal perfusion may not be a suitable method to calculate the cerebrospinal fluid formation rate according to the equation of Heisey et al.

The formation and circulation of cerebrospinal fluid inside the cat brain ventricles: a fact or an illusion?

Formation and circulation of cerebrospinal fluid (CSF) have been studied in the isolated brain ventricles of anesthetized cats by a new approach and under direct observation. A plastic cannula was introduced into the aqueduct of Sylvius through the vermis cerebelli and the outflow of CSF from the cannula was used as the CSF formation and circulation index. During the 60 min of observation at a physiological CSF pressure not a single drop of CSF escaped out of the end of the cannula. This indicates that CSF net formation and circulation inside the brain ventricles, proposed by classical hypothesis regarding CSF dynamics, should be at least re-evaluated.