Reorganization of the Brain Extracellular Matrix in Hippocampal Sclerosis.

The extracellular matrix (ECM) is an important regulator of excitability and synaptic plasticity, especially in its highly condensed form, the perineuronal nets (PNN). In patients with drug-resistant mesial temporal lobe epilepsy (MTLE), hippocampal sclerosis type 1 (HS1) is the most common histopathological finding. This study aimed to evaluate the ECM profile of HS1 in surgically treated drug-resistant patients with MTLE in correlation to clinical findings. Hippocampal sections were immunohistochemically stained for aggrecan, neurocan, versican, chondroitin-sulfate (CS56), fibronectin, Wisteria floribunda agglutinin (WFA), a nuclear neuronal marker (NeuN), parvalbumin (PV), and glial-fibrillary-acidic-protein (GFAP). In HS1, besides the reduced number of neurons and astrogliosis, we found a significantly changed expression pattern of versican, neurocan, aggrecan, WFA-specific glycosylation, and a reduced number of PNNs. Patients with a lower number of epileptic episodes had a less intense diffuse WFA staining in Cornu Ammonis (CA) fields. Our findings suggest that PNN reduction, changed ECM protein, and glycosylation expression pattern in HS1 might be involved in the pathogenesis and persistence of drug-resistant MTLE by contributing to the increase of CA pyramidal neurons' excitability. This research corroborates the validity of ECM molecules and their modulators as a potential target for the development of new therapeutic approaches to drug-resistant epilepsy.

TRANSVENOUS APPROACH FOR INDIRECT CAROTID-CAVERNOUS FISTULA USING DETACHABLE COILS: A CASE REPORT AND REVIEW OF TREATMENT OPTIONS.

Carotid-cavernous fistula (CCF) is a relatively rare pathology with a low incidence compared with other vascular pathologies. They can be classified based on hemodynamics as low- or high-flow fistulas, and anatomically as direct or indirect fistulas. Anatomy of the shunt somewhat dictates the selection of endovascular treatment, meaning the venous or arterial approach and selection of embolizing materials. Although there is general agreement as to when to access CCF transvenously or transarterialy, which depends on the shunt being direct or indirect, there is no uniform agreement on which occlusion method should be used. Herein, we report a case of an 80-year-old woman treated for indirect CCF using detachable coils. We also provide a brief review of the literature, including recent advances in treatment of said entities. In conclusion, selection of both the approach and material used depends on the operator's experience and preference.

METEOROLOGICAL VARIABLES ASSOCIATED WITH SUBARACHNOID HEMORRHAGE: A SINGLE CENTER STUDY.

Spontaneous subarachnoid hemorrhage (SAH) can occur unexpectedly and independently of the classic risk factors. Several different factors could affect intracranial aneurysm (IA) rupture, such as morphological and hemodynamic factors. The aim of this study was to establish the potential association of meteorological data such as temperature, atmospheric pressure, and humidity, and the onset of clinical symptoms preceding hospital admission of patients with acute SAH due to IA rupture. This retrospective study included 130 consecutive patients admitted for non-traumatic SAH with a determinable onset of SAH symptoms. The effects of meteorological parameters of atmospheric pressure, ambient temperature, and relative air humidity on the day of acute SAH onset and 24 hours prior to the onset of symptoms were recorded and analyzed in each patient. Spearman rank correlation analysis was used to assess the risks of incident SAH on the basis of daily meteorological data. Seasonal incidence of acute SAH showed the peak incidence in winter and a trough in summer, with monthly incidence peak in January and December. The circadian rhythm analysis showed the peak incidence of SAH in the forenoon, followed by the evening. Acute SAH incidence showed moderate positive association with daily atmospheric pressure (p<0.05), while no association was found with ambient temperature and relative air humidity. Our results suggested no significant association of changes in ambient temperature and relative humidity with the risk of SAH. Increases in atmospheric pressure were weakly associated with a higher SAH risk. Additional studies are needed to establish in detail both meteorological and morphological factors important to predict IA rupture and SAH.

The role of mesencephalic aqueduct obstruction in hydrocephalus development: a case report.

We report on three patients with mesencephalic aqueduct obstruction, which completely blocked the cerebrospinal fluid communication between the third and fourth cerebral ventricle, demonstrated by standard and high-resolution magnetic resonance sequences. Only one patient developed radiological and clinical presentation of hydrocephalus, without radiological signs of increased intraventricular pressure. The remaining two patients did not show clinical signs of hydrocephalus and had a normal radiological presentation of the ventricular system. These findings contradict the classical concept of cerebrospinal fluid physiology. This concept assumes a unidirectional circulation of cerebrospinal fluid through the mesencephalic aqueduct from the secretion site, predominantly in the choroid plexuses, to the resorption site, predominantly in the dural venous sinuses. Therefore, the obstruction of the mesencephalic aqueduct would inevitably lead to triventricular hypertensive hydrocephalus in all patients. The current observations, however, accord with the new concept of cerebrospinal fluid physiology, which postulates that cerebrospinal fluid does not circulate unidirectionally because it is both formed and resorbed along the entire capillary network within the central nervous system.

The vicious interplay between disrupted sleep and malignant brain tumors: a narrative review.

Malignant brain tumors are among the most aggressive human neoplasms. One of the most common and severe symptoms that patients with these malignancies experience is sleep disruption. Disrupted sleep is known to have significant systemic pro-tumor effects, both in patients with other types of cancer and those with malignant brain lesions. We therefore provide a review of the current knowledge on disrupted sleep in malignant diseases, with an emphasis on malignant brain tumors. More specifically, we review the known ways in which disrupted sleep enables further malignant progression. In the second part of the article, we also provide a theoretical framework of the reverse process. Namely, we argue that due to the several possible pathophysiological mechanisms, patients with malignant brain tumors are especially susceptible to their sleep being disrupted and compromised. Thus, we further argue that addressing the issue of disrupted sleep in patients with malignant brain tumors can, not just improve their quality of life, but also have at least some potential of actively suppressing the devastating disease, especially when other treatment modalities have been exhausted. Future research is therefore desperately needed.

Decoding the Role of DVL1 in Intracranial Meningioma.

In the search for molecular candidates for targeted meningioma therapies, increasing attention has been paid to the role of signaling pathways in the development and progression of intracranial meningiomas. Although it is well known that the Wnt signaling pathway is involved in meningioma progression, the role of its central mediator, DVL1, is still unclear. In order to investigate the influence of DVL1 gene alterations on the progression of human intracranial meningioma, we focused on its central PDZ domain, which is responsible for DVL interaction with the Fzd receptor and the phosphorylation of DVL mediated through the casein kinases CK1 and CK2. A genetic analysis of genomic instability revealed the existence of microsatellite instability in 9.09% and the loss of heterozygosity in 6.06% of the samples. The sequencing of the PDZ gene region showed repetitive deletions of two bases located in intron 7 and exon 8, and a duplication in intron 8 in most samples, with different outcomes on the biological function of the DVL1 protein. Immunohistochemistry revealed that the nuclear expression of DVL1 was significantly correlated with a higher expression of active ß-catenin (p = 0.029) and a higher meningioma grade (p = 0.030), which leads to the conclusion that it could be used as biomarker for meningioma progression and the activation of the Wnt signaling pathway.

HbA1c in patients with intracranial meningiomas WHO grades I and II: A preliminary study.

Meningiomas are among the most common primary brain tumors. There is a growing need for novel ways of differentiating between benign (World Health Organization [WHO] grade I) and atypical (WHO grade II) meningiomas as well as for novel markers of the tumor's future behavior. A difference between glucose metabolism in atypical and benign meningiomas is well known. However, a significant correlation between the systemic metabolic status of the patient and the meningioma WHO grade has not yet been established. Our aim was to compare the WHO grades of intracranial meningiomas with the patient's HbA1c levels as a more reliable marker of the chronic systemic metabolic status than the fasting blood glucose value, which is usually looked at. We retrospectively analyzed 15 patients and compared their meningioma WHO grade with their preoperative HbA1c values. Our results show that patients with benign intracranial meningiomas have significantly lower HbA1c value. Conversely, patients with atypical intracranial meningiomas have higher HbA1c values. Furthermore, we showed that the proliferation factor Ki67 was statistically strongly correlated with the HbA1c value (p < .001. These results imply a possible positive correlation between meningioma cell proliferation and the chronic systemic glycemia. Further research in this area could not only lead to better understanding of meningiomas but could have significant clinical application.

Histological and MRI Study of the Development of the Human Indusium Griseum.

To uncover the ontogenesis of the human indusium griseum (IG), 28 post-mortem fetal human brains, 12-40 postconceptional weeks (PCW) of age, and 4 adult brains were analyzed immunohistochemically and compared with post-mortem magnetic resonance imaging (MRI) of 28 fetal brains (14-41 PCW). The morphogenesis of the IG occurred between 12 and 15 PCW, transforming the bilateral IG primordia into a ribbon-like cortical lamina. The histogenetic transition of sub-laminated zones into the three-layered cortical organization occurred between 15 and 35 PCW, concomitantly with rapid cell differentiation that occurred from 18 to 28 PCW and the elaboration of neuronal connectivity during the entire second half of gestation. The increasing number of total cells and neurons in the IG at 25 and 35 PCW confirmed its continued differentiation throughout this period. High-field 3.0 T post-mortem MRI enabled visualization of the IG at the mid-fetal stage using T2-weighted sequences. In conclusion, the IG had a distinct histogenetic differentiation pattern than that of the neighboring intralimbic areas of the same ontogenetic origin, and did not show any signs of regression during the fetal period or postnatally, implying a functional role of the IG in the adult brain, which is yet to be disclosed.

Importance of ovarian tissue cryopreservation in fertility preservation and anti-aging treatment.

Various oncological and non-oncological diseases, as well as their treatments, can cause premature ovarian insufficiency and reduce a woman's reproductive potential. Fertility preservation is, therefore, becoming an emerging field of reproductive medicine allowing these patients to have their own biological children. The aim of this review is to analyze the importance of ovarian tissue cryopreservation as a fertility preservation method as well as its new role as a hormone replacement treatment. Although ovarian tissue cryopreservation is currently regarded as an experimental procedure, it is rapidly advancing and may become an established fertility preservation method in the near future. This method does not require ovarian stimulation or a subsequent delay in the initiation of cancer treatment. Furthermore, orthotopic ovarian tissue transplantation offers the unique opportunity of spontaneous conception. Due to the restoration of endocrine function following the procedure, ovarian tissue cryopreservation may also be used as tissue hormone replacement therapy in cases of premature ovarian insufficiency, to postpone menopause and prevent its troublesome symptoms and diseases. Even though the role of ovarian tissue cryopreservation as a new anti-aging treatment modality is quite promising, the safety and efficacy of this approach should be investigated in clinical settings.

New Concepts of Cerebrospinal Fluid Physiology and Development of Hydrocephalus.

The goal of this review is the presentation of the new (Bulat-Klarica-Oreskovic) hypothesis of cerebrospinal fluid (CSF) physiology and the ensuing new concept of hydrocephalus development in light of this hypothesis. The widely accepted classic hypothesis of CSF physiology and the traditional concept of hydrocephalus are contradicted by numerous experimental and clinical data, which consequently results in unsatisfying clinical treatment and patient recovery. Therefore, the newly presented concept of hydrocephalus development and possible future treatments are discussed. A new definition suggests that hydrocephalus is a pathological state in which CSF is excessively accumulated inside the cranial part of the CSF system, predominantly in one or more brain ventricles as a consequence of impaired hydrodynamics of intracranial fluids between CSF, brain, and blood compartments.

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.

The Effect of Body Position on Intraocular and Intracranial Pressure in Rabbits.

BACKGROUND: The correlation between cerebrospinal fluid (CSF) and intraocular pressure (IOP) is still unclear. We compared CSF and IOP measured by the same invasive technique using a new experimental model in rabbits during changes of body position. METHODS: Pressure changes were recorded in the lateral ventricle (LV), the cortical subarachnoid space (CSS), and the anterior ocular chamber of anesthetized rabbits (n = 12). Animals and measuring instruments were both fixed on a board at an adequate hydrostatic level. RESULTS: In a horizontal position, control IOP (15.1 ± 1.6 cmH2O) and CSF pressure in the LV (12.4 ± 0.6 cmH2O) and CSS (12.2 ± 0.9 cmH2O) were similar during the 60-min period. When changing the body position from horizontal to vertical (upright), CSF pressures decreased drastically (LV = -5.5 ± 2.6 cmH2O and CSS = -7.7 ± 2.3 cmH2O), while the IOP decreased moderately (IOP = 13.3 ± 0.5 cmH2O). CONCLUSION: Change in body position from horizontal to vertical causes drastic changes in CSF pressure and moderate changes in IOP. Thus, IOP is not reflected by the CSF pressure. In an upright position, the values of CSF pressure were equal to the hydrostatic distance between measuring points and the foramen magnum, which suggests that CSF pressure inside the cranium depends on its anatomical and biophysical features, and not on CSF secretion and absorption.

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.

Measurement of cerebrospinal fluid formation and absorption by ventriculo-cisternal perfusion: what is really measured?

The generally accepted hypothesis on cerebrospinal fluid (CSF) hydrodynamics suggests that CSF is actively formed mainly by the choroid plexuses, circulates unidirectionally along the brain ventricles and subarachnoid space, and is passively absorbed mainly into the dural venous sinuses. CSF formation rate (Vf) has been extensively studied using the ventriculo-cisternal perfusion technique and the results have been used as the key evidence confirming the mentioned hypothesis. This technique and the equation for Vf calculation are based on the assumption that the dilution of the indicator substance is a consequence of the newly formed CSF, ie, that a higher CSF formation rate will result in a higher degree of dilution. However, it has been experimentally shown that the indicator substance dilution inside the CSF system does not occur because of a "newly formed" CSF, but as consequence of a number of other factors (departure of substances into the surrounding tissue, flowing around the collecting cannula into the cortical and spinal subarachnoid space, departure into the contralateral ventricle, etc). This technique allows "calculation" of the CSF formation even in dead animals, in an in vitro model, and in any other part of the CSF system outside the ventricles that is being perfused. Therefore, this method is indirect and any dilution of the indicator substance in the perfusate caused by other reasons would result in questionable and often contradictory conclusions regarding CSF formation rates.

Long lasting near-obstruction stenosis of mesencephalic aqueduct without development of hydrocephalus--case report.

The aim of this study is to present the five-year longitudinal magnetic resonance imaging (MRI) follow up of a patient with incidental finding of near-obstruction stenosis of the aqueduct of Sylvius due to a large pineal cyst. The patient was scanned 3 times on a 3T MR device using a set of standard structural sequences supplemented with high-resolution constructive interference of steady state (CISS) T2 sequence for precise delineation of the aqueduct of Sylvius and cardiac-gated phase-contrast sequences for the analysis of cerebrospinal fluid (CSF) movement. On all MR scans, the size of the pineal cyst and severity of near-obstruction aqueductal stenosis did not show any morphological changes. There was no significant ventricular enlargement although structural CISS sequence showed a near-obstruction stenosis and cardiac-gated phase-contrast sequences did not detect CSF movement through the aqueduct of Sylvius. Our findings are contradictory to the classic hypothesis of CSF physiology based on secretion, circulation, and absorption of CSF, which states that the impairment of CSF circulation through the aqueduct of Sylvius inevitably leads to a hypertensive hydrocephalus development involving the third and the lateral ventricle. Our research group previously proposed a new hypothesis of CSF physiology, which offers more suitable explanation for such clinical cases.

Volumetric analysis of cerebrospinal fluid and brain parenchyma in a patient with hydranencephaly and macrocephaly--case report.

The aim of this study was to perform for the first time the intracranial volumetric analysis of cerebrospinal fluid (CSF) and brain parenchyma in the supratentorial and infratentorial space in a 30-year-old female patient with hydranencephaly and macrocephaly. A head scan performed using a 3T magnetic resonance was followed by manual segmentation of the brain parenchyma and CSF on T2 coronal brain sections. The volume of CSF and brain parenchyma was measured separately for the supratentorial and infratentorial space. The total volume of the intracranial space was 3645.5 cm3. In the supratentorial space, the volume of CSF was 3375.2 cm3 and the volume of brain parenchyma was 80.3 cm3. In the infratentorial space, the volume of CSF was 101.3 cm3 and the volume of the brain parenchyma was 88.7 cm3. In the supratentorial space, there was severe malacia of almost all brain parenchyma with no visible remnants of the choroid plexuses. Infratentorial structures of the brainstem and cerebellum were hypoplastic but completely developed. Since our patient had no choroid plexuses in the supratentorial space and no obstruction between dural sinuses and CSF, development of hydrocephalus and macrocephaly cannot be explained by the classic hypothesis of CSF physiology with secretion, unidirectional circulation, and absorption as its basic postulates. However, the origin and turnover of the enormous amount of intracranial CSF volume, at least 10-fold larger than normal, and the mechanisms of macroencephaly development could be elucidated by the new hypothesis of CSF physiology recently published by our research team.