Publications by authors named "Darko Orešković"

41 Publications

Structural changes in brains of patients with disorders of consciousness treated with deep brain stimulation.

Sci Rep 2021 Feb 23;11(1):4401. Epub 2021 Feb 23.

Department of Neurosurgery, Dubrava University Hospital, Avenija Gojka Suska 6, 10000, Zagreb, Croatia.

Disorders of consciousness (DOC) are one of the major consequences after anoxic or traumatic brain injury. So far, several studies have described the regaining of consciousness in DOC patients using deep brain stimulation (DBS). However, these studies often lack detailed data on the structural and functional cerebral changes after such treatment. The aim of this study was to conduct a volumetric analysis of specific cortical and subcortical structures to determine the impact of DBS after functional recovery of DOC patients. Five DOC patients underwent unilateral DBS electrode implantation into the centromedian parafascicular complex of the thalamic intralaminar nuclei. Consciousness recovery was confirmed using the Rappaport Disability Rating and the Coma/Near Coma scale. Brain MRI volumetric measurements were done prior to the procedure, then approximately a year after, and finally 7 years after the implementation of the electrode. The volumetric analysis included changes in regional cortical volumes and thickness, as well as in subcortical structures. Limbic cortices (parahippocampal and cingulate gyrus) and paralimbic cortices (insula) regions showed a significant volume increase and presented a trend of regional cortical thickness increase 1 and 7 years after DBS. The volumes of related subcortical structures, namely the caudate, the hippocampus as well as the amygdala, were significantly increased 1 and 7 years after DBS, while the putamen and nucleus accumbens presented with volume increase. Volume increase after DBS could be a result of direct DBS effects, or a result of functional recovery. Our findings are in accordance with the results of very few human studies connecting DBS and brain volume increase. Which mechanisms are behind the observed brain changes and whether structural changes are caused by consciousness recovery or DBS in patients with DOC is still a matter of debate.
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http://dx.doi.org/10.1038/s41598-021-83873-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7902623PMC
February 2021

The Accuracy of Direct Targeting Using Fusion of MR and CT Imaging for Deep Brain Stimulation of the Subthalamic Nucleus in Patients with Parkinson's Disease.

J Neurol Surg A Cent Eur Neurosurg 2021 Feb 22. Epub 2021 Feb 22.

Department of Neurosurgery, Clinical Hospital Dubrava, Zagreb, Croatia.

Introduction:  In 33 consecutive patients with Parkinson's disease (PD) undergoing awake deep brain stimulation (DBS) without microelectrode recording (MER), we assessed and validated the precision and accuracy of direct targeting of the subthalamic nucleus (STN) using preoperative magnetic resonance imaging (MRI) and stereotactic computed tomography (CT) image fusion combined with immediate postoperative stereotactic CT and postoperative MRI, and we report on the side effects and clinical results up to 6 months' follow-up.

Materials And Methods:  Preoperative nonstereotactic MRI and stereotactic CT images were merged and used for planning the trajectory and final lead position. Immediate postoperative stereotactic CT and postoperative nonstereotactic MRI provided the validation of the final electrode position. Changes in the Unified Parkinson's Disease Rating Scale III (UPDRS III) scores and the levodopa equivalent daily doses (LEDD) and appearance of adverse side effects were assessed.

Results:  The mean Euclidian distance (ED) error between the planned position and the final position of the lead in the left STN was 1.69 ± 0.82 mm and that in the right STN was 2.12 ± 1.00. The individual differences between planned and final position in each of the three coordinates were less than 2 mm. The UPDRS III scores improved by 75% and LEDD decreased by 45%. Few patients experienced complications, such as postoperative infection (= 1), or unwanted side effects, such as emotional instability ( = 1).

Conclusion:  Our results confirm that direct targeting of an STN on stereotactic CT merged with MRI could be a valid method for placement the DBS electrode. The magnitude of our targeting error is comparable with the reported errors when using MER and other direct targeting approaches.
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http://dx.doi.org/10.1055/s-0040-1715826DOI Listing
February 2021

Hemoglobin A1c in Patients with Glioblastoma-A Preliminary Study.

World Neurosurg 2020 09 31;141:e553-e558. Epub 2020 May 31.

Department of Neurosurgery, Clinical Hospital Dubrava, Zagreb, Croatia; Department of Surgery, Zagreb University School of Medicine, Zagreb, Croatia.

Background: Glioblastomas are among the most common primary brain tumors with an abysmal prognosis. The significance of glucose metabolism in glioblastoma cell metabolism and proliferation is well-known. However, a significant correlation between the systemic metabolic status of the patient and the cellular proliferation of the glioblastoma has not yet been established.

Methods: Our aim was to observe and analyze for a possible correlation between glioblastoma cellular proliferation and patients' glycated hemoglobin (HbA1c) levels as a marker of chronic systemic glycemia. We analyzed the data from 25 patients and compared their Ki-67 values with their preoperative HbA1c values.

Results: We observed a statistically significant correlation (P < 0.03) between chronic glycemia (measured using HbA1c) and the cellular proliferation of glioblastoma (measured by cellular Ki-67 expression).

Conclusions: These results imply a possible positive correlation between glioblastoma cell proliferation and chronic systemic glycemia, a correlation that, to the best of our knowledge, has not yet been reported. Further research in this area could not only lead to a better understanding of glioblastoma but also have significant clinical applications in treating this devastating disease.
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http://dx.doi.org/10.1016/j.wneu.2020.05.231DOI Listing
September 2020

A biphasic tumor in posterior cranial fossa and the pineal region in young adult.

Surg Neurol Int 2020 11;11:64. Epub 2020 Apr 11.

Departments of Neurosurgery, University Hospital Dubrava, Zagreb, Croatia.

Background: Biphasic tumors of the central nervous system are rarely described and mainly consisted out of the glial and mesenchymal component. The tumor originated out of both astrocytes and pinealocytes, best to our knowledge, has not been described. We present a case of a brain tumor consisted out of pilocytic astrocytoma (PA) and pineocytoma as components situated in the pineal region and posterior cranial fossa in young adult.

Case Description: We present a 21-year-old patient with a history of intermittent headache, followed by nausea and vomiting, double vision, and dextropulsion. Magnetic resonance imaging revealed an extensive cystic-solid expansive formation in the posterior cranial fossa with a solid part in the area of the pineal gland. The patient underwent surgical resection. The pathohistological analysis showed two types of tumor cells; the major part of tumor showed features of PA, while minor part corresponded to pineocytoma.

Conclusion: PA accounts for 5% of all gliomas and is most common in children and young adults. It usually occurs in the cerebellum, the optic pathway, third ventricular region, etc. Pineocytomas are rare, accounting up to 1% of all intracranial tumors. Since tumors origin is different, there must be complex molecular events or mutations that can lead to cell rearrangements and generation of two histologically different tissues in the same tumor mass. The course of treatment options is different for PA and pineocytoma; therefore, the case of brain mass consisted out of two different tissues can be helpful when deciding about the treatment of tumors in posterior cranial fossa and pineal region.
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http://dx.doi.org/10.25259/SNI_288_2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7193197PMC
April 2020

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

IUBMB Life 2020 Jul 5;72(7):1426-1432. Epub 2020 Mar 5.

Department of Neurosurgery, Clinical Hospital Dubrava, Zagreb, Croatia.

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.
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http://dx.doi.org/10.1002/iub.2268DOI Listing
July 2020

The Dubrava Model-A Novel Approach in Treating Acutely Neurotraumatized Patients in Rural Areas: A Proposal for Management.

J Neurosci Rural Pract 2019 Jul 7;10(3):446-451. Epub 2019 Oct 7.

Department of Neurosurgery, University Hospital Dubrava, Zagreb, Croatia.

Neurotrauma is one of the leading causes of death and disabilities nowadays and represents one of the largest socioeconomic problems in rich countries, as well as developing ones. A satisfying, medically viable, and cost-effective model of managing acutely neurotraumatized patients, especially ones who come from distant and/or rural areas, has yet to be found. Patient outcome after acute neurotrauma depends on many factors of which the possibility of urgent treatment by an experienced specialist team has a crucial role. Here, we present our own way of managing acutely neurotraumatized patients from distant places which is unique in Croatia, the Dubrava model. We present our 5-year experience cooperating with general hospitals in four neighboring cities (Ĉakovec, Bjelovar, Sisak, and Koprivnica) in managing, operating, and taking care of acutely neurotraumatized patients. More than 300 surgeries have been performed in these hospitals through the Dubrava model. Our experience so far provides encouraging results that this system could also be successfully implemented in other institutions. Furthermore, we recorded an increased number of surgeries each year, as well as a good mutual cooperation with the local general hospitals. This trauma managing model is one of a kind in Croatia. We argue that it is not only better for the patients, providing them with better chances of survival, and disability-free recovery, but is also far superior in many ways to the dominant and currently prevalent way of treating these patients in other parts of Croatia. The Dubrava model of treating patients in rural and distant areas is a reliable and proven model with many benefits and as such its implementation should be considered in other institutions as well.
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http://dx.doi.org/10.1055/s-0039-1697777DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6779563PMC
July 2019

The Movement of Cerebrospinal Fluid and Its Relationship with Substances Behavior in Cerebrospinal and Interstitial Fluid.

Neuroscience 2019 08 3;414:28-48. Epub 2019 Jul 3.

Ruđer Bošković Institute, Department of Molecular Biology, Zagreb, Croatia. Electronic address:

The cerebrospinal fluid (CSF) movement and its influence on substance distribution and elimination from the CSF system have been thoroughly analyzed and discussed in the light of the new hypothesis of CSF physiology. As a result, CSF movement is not presented as a circulation, but a permanent rhythmic systolic-diastolic pulsation in all directions. Such movement also represents the main force of substance distribution inside the CSF system. This distribution occurs in all directions, i.e., in the direction of the imagined circulation, as well as in the opposite direction, and depends on the application site and the resident time of tested substance, where longer resident time means longer distribution distance. Transport mechanisms situated on the microvessels inside the central nervous system (CNS) parenchyma play the key role in substance elimination from the CSF and interstitial fluid (ISF) compartments, which freely communicate. If a certain transport mechanism is not available at one site, the substance will be distributed by CSF movement along the CSF system and into the CNS region where that transport mechanism is available. Pharmacological manipulation suggests that the residence time and the substance travel distance along the CSF system depend on the capacity of transport mechanisms situated on CNS blood capillaries. Physiological absorption of the CSF into the venous sinuses and/or lymphatics, due to their small surface area, should be of minor importance in comparison with the huge absorptive surface area of the microvessel network.
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http://dx.doi.org/10.1016/j.neuroscience.2019.06.032DOI Listing
August 2019

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

Gynecol Endocrinol 2019 Nov 11;35(11):919-923. Epub 2019 Jun 11.

Department of Clinical Oncology, School of Medicine, University of Zagreb , Zagreb , Croatia.

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.
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http://dx.doi.org/10.1080/09513590.2019.1611763DOI Listing
November 2019

Corrigendum to: Histological and MRI Study of the Development of the Human Indusium Griseum.

Cereb Cortex 2021 Jan;31(2):1409

Croatian Institute for Brain Research, School of Medicine, University of Zagreb, Šalata12, Zagreb, Croatia.

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http://dx.doi.org/10.1093/cercor/bhz100DOI Listing
January 2021

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

Cereb Cortex 2019 12;29(11):4709-4724

Croatian Institute for Brain Research, School of Medicine, University of Zagreb, Šalata12, Zagreb, Croatia.

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.
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http://dx.doi.org/10.1093/cercor/bhz004DOI Listing
December 2019

New Insight into the Mechanism of Mannitol Effects on Cerebrospinal Fluid Pressure Decrease and Craniospinal Fluid Redistribution.

Neuroscience 2018 11 29;392:164-171. Epub 2018 Sep 29.

Department of Pharmacology and Croatian Institute for Brain Research, School of Medicine, University of Zagreb, Zagreb, Croatia. Electronic address:

Intracranial hypertension, which often follows a severe brain injury, is usually treated with intravenous (i.v.) application of hyperosmolar solutions. The mechanism of intracranial cerebrospinal fluid (CSF) pressure decrease after such a treatment is still unclear. The aim of this article was to try to explain the mechanism of CSF pressure reduction after i.v. hyperosmolar mannitol bolus in regard to the changes in CSF volume. Two types of experiments were done on anesthetized cats before and after hyperosmolar mannitol application: ventriculo-cisternal perfusion at different perfusion rates, simultaneously measuring the perfusate outflow volume, and CSF pressure recording in the lateral ventricle before and during artificial CSF infusion. Mannitol application in the first group of cats significantly reduced collected prefusate volume during ventriculo-cisternal perfusion, and in the second group it prevented CSF pressure increase caused by artificial CSF infusion. Our results strongly suggest that the mechanism of hyperosmolar mannitol action after its i.v. application is based on osmotic fluid retrieval from interstitial and cerebrospinal compartments into the microvessels. This shift, without significant volume change inside the cranium, causes a predominant decrease of CSF volume in the spinal part of the system, which in turn leads to lowering of the CSF pressure. Spinal CSF volume decrease is enabled by the extensibility of the spinal dura, this way providing the possibility for CSF volume redistribution inside the CSF system, together with CSF pressure decrease. This mechanism of mannitol action is in accordance with the new hypothesis of CSF physiology.
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http://dx.doi.org/10.1016/j.neuroscience.2018.09.029DOI Listing
November 2018

Traumatic Optic Neuropathy - Case Report with Discussion on Diagnostic Procedures and Therapy.

Acta Clin Croat 2018 Mar;57(1):166-172

Stubičke Toplice Special Hospital for Medical Rehabilitation, Stubičke Toplice, Croatia.

Traumatic optic neuropathy (TON) is a serious vision threatening condition that can be caused by ocular or head trauma. Indirect damage to the optic nerve is the most common form of TON occurring in 0.5% to 5% of all closed head trauma cases. Although the degree of visual loss after indirect TON may vary, approximately 50% of all patients are left with 'light perception' or 'no light perception' vision, making TON a significant cause of permanent vision loss. We present a 47-year-old male patient with a history of right eye keratoconus following a motorcycle crash. Visual acuity was of 'counting fingers at 2 meters' on the right eye due to keratoconus and 'counting fingers at 1 meter' on the left eye as a consequence of trauma. The Octopus visual field showed diffuse re-duction in retinal sensitivity and the Ishihara color test indicated dysfunction of color perception on the left eye. Relative afferent pupillary defect was also present. Computed tomography revealed multifragmentary fracture of the frontal sinus and the roof of the left orbit without bone displacement. Based on the findings, conservative corticosteroid therapy without surgery was conducted. The patient responded well to treatment with complete ophthalmologic recovery.
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http://dx.doi.org/10.20471/acc.2018.57.01.22DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6400363PMC
March 2018

Reply to Comment on "Role of Choroid Plexus in Cerebrospinal Fluid Hydrodynamics".

Neuroscience 2018 06 7;380:165. Epub 2018 Mar 7.

Ruđer Bošković Institute, Department of Molecular Biology, Zagreb, Croatia; Department of Pharmacology and Croatian Institute for Brain Research, School of Medicine, University of Zagreb, Zagreb, Croatia.

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http://dx.doi.org/10.1016/j.neuroscience.2018.02.040DOI Listing
June 2018

The recent state of a hundred years old classic hypothesis of the cerebrospinal fluid physiology.

Croat Med J 2017 Dec;58(6):381-383

Darko Orešković, Ruđer Bošković Institute, Department of Molecular Biology, Zagreb, Croatia,

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5778680PMC
http://dx.doi.org/10.3325/cmj.2017.58.381DOI Listing
December 2017

Role of choroid plexus in cerebrospinal fluid hydrodynamics.

Neuroscience 2017 06 27;354:69-87. Epub 2017 Apr 27.

Department of Pharmacology and Croatian Institute for Brain Research, School of Medicine University of Zagreb, Zagreb, Croatia. Electronic address:

The classic hypothesis presents the cerebrospinal fluid (CSF) as the "third circulation," which flows from the brain ventricles through the entire CSF system to the cortical subarachnoid space to eventually be passively absorbed into the superior sagittal sinus through arachnoid granulations. The choroid plexus (CP) represents a key organ in the classic CSF physiology and a powerful biological pump, which exclusively secretes CSF. Thereby, the CP is considered to be responsible for CSF pressure regulation and hydrocephalus development. This article thoroughly analyzes the role of the CP in the CSF dynamics, presenting arguments in favor of the thesis that the CPs are neither biological pumps nor the main site of CSF secretion; that they do not participate in regulation of ICP/CSF pressure; are not the reason for the existence of hydrostatic pressure gradient in the CSF system and that this gradient is not permanent (disappeared in the horizontal position); and that they do not generate imagined unidirectional CSF circulation, hydrocephalus development and increased ICP/CSF pressure. The classic hypothesis cannot provide an explanation for these controversies but the recently formulated Bulat-Klarica-Orešković hypothesis can. According to this hypothesis, CSF production and absorption (CSF exchange) are constant and present everywhere in the CSF system, and although the CSF is partially produced by the CP, it is mainly formed as a consequence of water filtration between the capillaries and interstitial fluid.
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http://dx.doi.org/10.1016/j.neuroscience.2017.04.025DOI Listing
June 2017

New Concepts of Cerebrospinal Fluid Physiology and Development of Hydrocephalus.

Pediatr Neurosurg 2017 21;52(6):417-425. Epub 2016 Dec 21.

Department of Molecular Biology, Ruđer Bošković Institute, Zagreb, Croatia.

The goal of this review is the presentation of the new (Bulat-Klarica-Orešković) 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.
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http://dx.doi.org/10.1159/000452169DOI Listing
August 2018

Cerebrospinal fluid secretion by the choroid plexus?

Physiol Rev 2016 10;96(4):1661-2

Ruđer Bošković Institute, Department of Molecular Biology, Zagreb, Croatia; and Department of Pharmacology and Croatian Institute for Brain Research, School of Medicine University of Zagreb, Zagreb, Croatia.

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http://dx.doi.org/10.1152/physrev.00021.2016DOI Listing
October 2016

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

Croat Med J 2016 Jun;57(3):293-7

Marijan Klarica, School of Medicine University of Zagreb, Department of Pharmacology and Croatian Institute for Brain Research, Šalata 11, 10 000 Zagreb, Croatia,

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.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4937228PMC
http://dx.doi.org/10.3325/cmj.2016.57.293DOI Listing
June 2016

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

Acta Neurochir Suppl 2016 ;122:283-6

Department of Molecular Biology, Ruđer Bošković Institute, Zagreb, Croatia.

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.
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http://dx.doi.org/10.1007/978-3-319-22533-3_56DOI Listing
July 2017

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

Acta Neurochir Suppl 2016 ;122:279-82

Department of Molecular Biology, Rudjer Boskovic Institute, Zagreb, Croatia.

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.
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http://dx.doi.org/10.1007/978-3-319-22533-3_55DOI Listing
July 2017

Experimental Spinal Stenosis in Cats: New Insight in Mechanisms of Hydrocephalus Development.

Brain Pathol 2016 11 14;26(6):701-712. Epub 2015 Dec 14.

Department of Molecular Biology, Ruđer Bošković Institute.

In our new experimental model of cervical stenosis without inflammation we have tested hypothesis that cranio-spinal communication impairment could lead to hydrocephalus development. Spinal and cranial cerebrospinal fluid (CSF) space separation was obtained with positioning of plastic semiring in epidural space at C2 level in cats. Brain ventricles planimetry, and CSF pressure recording in lateral ventricle (LV) and lumbar subarachnoid space (LSS) were performed in acute and subchronic experiments. In all experiments opening CSF pressures were normal. However, in acute experiments, an infusion of artificial CSF into the LV led to increase of CSF pressure and significant gradient pressure development between LV and LSS due to limited pressure transmission. After 3 or 6 weeks spinal cord atrophy was observed at the site of cervical stenosis, and pressure transmission from LV to LSS was improved as a consequence of spinal tissue atrophy. Planimetry of both the coronal brain slices and the ventricles' surface showed that control ventricular surface was 0.6 ± 0.1% (n = 5), and 1.6 ± 0.2% (n = 4) in animals with subchronic cervical stenosis (P < 0.002). These results support the mentioned hypothesis claiming that CSF volume cranio-spinal displacement impairment could start pathophysiological processes leading to development of hydrocephalus.
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http://dx.doi.org/10.1111/bpa.12337DOI Listing
November 2016

The controversy on choroid plexus function in cerebrospinal fluid production in humans: how long different views could be neglected?

Croat Med J 2015 Jun;56(3):306-10

Darko Orešković, Ruđer Bošković Institute, Department of Molecular Biology, Zagreb, Croatia,

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4500964PMC
http://dx.doi.org/10.3325/cmj.2015.56.306DOI Listing
June 2015

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

Croat Med J 2014 Aug;55(4):394-8

Darko Orešković, Rudjer Bošković Institute, Department of Molecular Biology, Bijenička 54, 10 000 Zagreb, Croatia,

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.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4157388PMC
http://dx.doi.org/10.3325/cmj.2014.55.394DOI Listing
August 2014

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

Croat Med J 2014 Aug;55(4):388-93

Marijan Klarica, University of Zagreb, School of Medicine, Department of Pharmacology and Croatian Institute for Brain Research, Šalata 11, 10 000 Zagreb, Croatia,

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.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4157378PMC
http://dx.doi.org/10.3325/cmj.2014.55.388DOI Listing
August 2014

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

Croat Med J 2014 Aug;55(4):317-27

Darko Orešković, Rudjer Bošković Institute, Department of Molecular Biology, Bijenička 54, 10 000 Zagreb, Croatia,

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.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4157383PMC
http://dx.doi.org/10.3325/cmj.2014.55.317DOI Listing
August 2014

Enigma of cerebrospinal fluid dynamics.

Croat Med J 2014 Aug;55(4):287-90

Marijan Klarica, Department of Pharmacology and Croatian Institute for Brain Research, University of Zagreb School of Medicine, Zagreb, Croatia,

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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4157379PMC
http://dx.doi.org/10.3325/cmj.2014.55.287DOI Listing
August 2014

A new look at cerebrospinal fluid movement.

Fluids Barriers CNS 2014 27;11:16. Epub 2014 Jul 27.

Department of Pharmacology and Croatian Institute for Brain Research, School of Medicine University of Zagreb, Zagreb, Croatia ; Ruđer Bošković Institute, Department of Molecular Biology, Bijenička 54, 10 000 Zagreb, Croatia.

Brinker et al. extensively reviewed recent findings about CSF circulation in a recent article: "A new look at cerebrospinal circulation", but did not analyze some important available data in sufficient detail. For example, our findings as well as some clinical data and experimental results obtained from different animal species, do not support unidirectional CSF circulation but strongly suggest that there are cardiac cycle-dependent systolic-diastolic to-and-fro cranio-spinal CSF movements. These are based on: a) physiological oscillations of arterial and venous blood during cranio-spinal blood circulation; b) respiratory activity, and c) body activity and posture. That kind of complex CSF movement could explain the observed distribution of many different substances in all directions along the CSF system and within central nervous system tissue. It seems that efflux transport systems at capillary endothelium may be more important for brain homeostasis than the removal of metabolites by CSF flow. Thus, when discussing the CSF dynamics we suggest that a more appropriate term would be CSF movement rather than CSF circulation.
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http://dx.doi.org/10.1186/2045-8118-11-16DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4118619PMC
August 2014

The influence of body position on cerebrospinal fluid pressure gradient and movement in cats with normal and impaired craniospinal communication.

PLoS One 2014 18;9(4):e95229. Epub 2014 Apr 18.

Department of Molecular Biology, Ruđer Bošković Institute, Zagreb, Croatia.

Intracranial hypertension is a severe therapeutic problem, as there is insufficient knowledge about the physiology of cerebrospinal fluid (CSF) pressure. In this paper a new CSF pressure regulation hypothesis is proposed. According to this hypothesis, the CSF pressure depends on the laws of fluid mechanics and on the anatomical characteristics inside the cranial and spinal space, and not, as is today generally believed, on CSF secretion, circulation and absorption. The volume and pressure changes in the newly developed CSF model, which by its anatomical dimensions and basic biophysical features imitates the craniospinal system in cats, are compared to those obtained on cats with and without the blockade of craniospinal communication in different body positions. During verticalization, a long-lasting occurrence of negative CSF pressure inside the cranium in animals with normal cranio-spinal communication was observed. CSF pressure gradients change depending on the body position, but those gradients do not enable unidirectional CSF circulation from the hypothetical site of secretion to the site of absorption in any of them. Thus, our results indicate the existence of new physiological/pathophysiological correlations between intracranial fluids, which opens up the possibility of new therapeutic approaches to intracranial hypertension.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0095229PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3991613PMC
January 2015

Body mass index and retinopathy in type 1 diabetic patients.

Int J Endocrinol 2014 18;2014:387919. Epub 2014 Feb 18.

University of Zagreb, School of Medicine, Šalata 3b, 10000 Zagreb, Croatia.

Aim. To investigate whether body mass index (BMI) independently or in correlation with other risk factors is associated with diabetic retinopathy (DR) progression. Methods. The study included 176 patients with type 1 diabetes divided into three groups according to DR status: group 1 (no retinopathy; n = 86), group 2 (mild/moderate nonproliferative DR; n = 33), and group 3 (severe/very severe NPDR or proliferative DR; n = 57). Results. A significant deterioration of HbA1c, an increase in total cholesterol, systolic, diastolic blood pressure, and diabetic nephropathy with the progression of retinopathy were found. DR progression was correlated with diabetes duration, HbA1c, hypertension, total cholesterol, and the presence of nephropathy. In patients without nephropathy, statistical analyses showed that progression of retinopathy increased significantly with higher BMI (gr. 1: 24.03 ± 3.52, gr. 2: 25.36 ± 3.44, gr. 3: 26.93 ± 3.24; P < 0.01). A positive correlation between BMI and a significant deterioration of HbA1c, an increase in cholesterol, triglycerides, and hypertension was observed. Conclusion. BMI in correlation with HbA1c, cholesterol, and hypertension appears to be associated with the progression of DR in type 1 diabetic patients without nephropathy. However, additional studies are required to investigate the pathogenic role of obesity and weight loss in retinal diabetic complications particularly relating to nephropathy.
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http://dx.doi.org/10.1155/2014/387919DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3948586PMC
April 2014

Assessing the clinical significance of tumor markers in common neoplasms.

Front Biosci (Elite Ed) 2012 Jun 1;4:2558-78. Epub 2012 Jun 1.

University of Zagreb School of Medicine, Zagreb, Croatia.

The term tumor markers include a spectrum of molecules and substances with widely divergent characteristics whose presence in the significant amount can be related to the malignant disease. An ideal tumor marker should have high specificity and sensitivity, which would allow its use in early diagnosis and prognosis of malignant disease, as well as in prediction of therapeutic response and follow-up of the patients. Numerous biochemical entities have emerged as potentially valuable tumor markers so far, but only few markers showed to be of considerable clinical reliability and have been accepted into standard clinical practice. Recent development of genomics and proteomics has enabled the examination of many new potential tumor markers. Scientific studies on discovery, development, and application of tumor markers have been proceeding quite rapidly providing great opportunities for improving the management of cancer patients. This review is focusing on the clinical usefulness of various tumor markers already in clinical practice as well as certain potential markers, giving a brief description of their prognostic and predictive significance in most common malignancies.
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http://dx.doi.org/10.2741/e566DOI Listing
June 2012