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Intrinsic cerebrospinal fluid (CSF) dynamics in the brain have been extensively studied, particularly the egress sites of tagged intrinsic CSF in the meninges. Although spinal CSF recirculates within the central nervous system (CNS), we hypothesized that CSF outflows from the lumbar spinal canal. We aimed to visualize and semi-quantify the outflow using non-contrast MRI techniques. We utilized a 3 Tesla clinical MRI with a 16-channel spine coil, employing time-spatial labeling inversion (Time-SLIP) with tag-on and tag-off acquisitions, T2-weighted coronal 2D fluid-attenuated inversion recovery (FLAIR) and T2-weighted coronal 3D centric ky-kz single-shot FSE (cSSFSE). Images were acquired using time-spatial labeling inversion pulse (Time-SLIP) with tag-on and tag-off acquisitions with varying TI periods. Ten healthy volunteers with no known spinal diseases participated. Variations in tagged CSF outflow were observed across different thoracolumbar nerve root segments in all participants. We quantified CSF outflow at all lumbar levels and the psoas region. There was no significant difference among the ROIs for signal intensity. The tagged CSF outflow from the spinal canal is small but demonstrates egress to surrounding tissues. This finding may pave the way for exploring intrathecal drug delivery, understanding of CSF-related pathologies and its potential as a biomarker for peripheral neuropathy and radiculopathy.

This study exercises a new mathematical model to search for unappreciated therapeutic targets in Alzheimer’s disease. The model describes detailed mechanisms underlying the glymphatic pump mechanism, which removes toxic proteins of Alzheimer’s disease from the interstitial fluid of the brain. It shows that the glymphatic pump is driven by the amplitude of intracranial pressure pulsations in the subarachnoid space, which are correlated with the arterial pulse and modulated by many other factors. Implementing ways to increase intracranial pressure pulses quickly comes to mind as a potential treatment strategy. Specific interventions include drugs that increase arterial pulse volume and small devices similar to balloon pumps to create increased subarachnoid pressure pulsations. Computer simulations of such balloon-like pumps, expanding and contracting in synchrony with the heartbeat, show effective enhancement of subarachnoid space pressure pulsations and resulting interstitial fluid flow in the brain. Design concepts for both totally implanted and externally wearable pumps are presented.

In a previous paper the author presented details of a new mechanism for the perivascular pump driving glymphatic flow—the brain’s waste removal system. The goal was to capture the essence of complex three-dimensional anatomy and physiology of the brain in a reduced order geometric model. The complexity required to make the model even approximately brain-like tended to obscure the most basic features of the perivascular pump. Here a bare-bones, “simplissimo” model of the perivascular pump is presented. It highlights only the most essential features of the pump mechanism. It also reveals components of brain anatomy and physiology that are not strictly necessary to make the pump work. Interestingly, these unnecessary features include pulsatile motion of the vascular walls, pressures inside the arteries and veins within the Virchow-Robin space, differences in arterial and venous compliance, the tapering of vascular branches, and the details of vascular branching. Instead, the softness of surrounding brain tissue and the relative diameters of venous vs. arterial perivascular cuffs are critical. Wave-like deformations of the soft brain tissue can create time averaged positive pressure in periarterial spaces, greater than that in perivenous spaces, owing to differences between antegrade and retrograde resistance to axial fluid flow along the annular channels of Virchow-Robin spaces. This new mechanism is scale independent from mouse to man, and can work despite the widely differing pulse rates of small versus large animals.

Objective. To explore the biophysics of interstitial tissue fluid flow in the brain, based upon the anatomy and mechanics of the perivascular spaces, in order to better understand how glymphatic flow happens. Methods. The dynamics of fluid flow at cardiac frequencies are investigated in rapidly computable, branched, geometric models of brain tissue at multiple scales. The models are supplied by intermingled trees of penetrating arteries and veins. They include pulsatile changes in intracranial pressure and intravascular pressure, elastic expansion of brain tissue, and nonlinear changes in resistance to flow of cerebrospinal fluid along the axis of the Virchow-Robin space. Resulting changes in periarterial and perivenous pressures and the resulting bulk flow of interstitial fluid from arteriolar to venular perivascular spaces are calculated on a laptop computer. Results. Under typical physiological conditions a time averaged positive pressure of ~ 0.5 mmHg develops between the smaller, distal periarteriolar and perivenous branches. Based on tissue geometry and hydraulic resistance, the resulting flow is sufficient to refresh the interstitial fluid once every 1 to 10 hours. The effect is degraded by increasing radial widths of the perivascular spaces. The calculated average glymphatic flow through the whole brain is similar to the measured production of new cerebrospinal fluid by the arachnoid villi. Conclusions. When the branching structure of perivascular trees is properly considered, their classical anatomy has surprising emergent properties. Biologically meaningful amounts of advective flow can happen between smaller, distal branches of periarteriolar and perivenous spaces.

Objective. To explore the biophysics of interstitial tissue fluid flow in the brain, based upon the anatomy and mechanics of the perivascular spaces, in order to better understand how glymphatic flow happens. Methods. The dynamics of fluid flow at cardiac frequencies are investigated in rapidly computable, branched, geometric models of brain tissue at multiple scales. The models are supplied by intermingled trees of penetrating arteries and veins. They include pulsatile changes in intracranial pressure and intravascular pressure, elastic expansion of brain tissue, and nonlinear changes in resistance to flow of cerebrospinal fluid along the axis of the Virchow-Robin space. Resulting changes in periarterial and perivenous pressures and the resulting bulk flow of interstitial fluid from arteriolar to venular perivascular spaces are calculated on a laptop computer. Results. Under typical physiological conditions a time averaged positive pressure of ~ 0.5 mmHg develops between the smaller, distal periarteriolar and perivenous branches. Based on tissue geometry and hydraulic resistance, the resulting flow is sufficient to refresh the interstitial fluid once every 1 to 10 hours. The effect is degraded by increasing radial widths of the perivascular spaces. The calculated average glymphatic flow through the whole brain is similar to the measured production of new cerebrospinal fluid by the arachnoid villi. Conclusions. When the branching structure of perivascular trees is properly considered, their classical anatomy has surprising emergent properties. Biologically meaningful amounts of advective flow can happen between smaller, distal branches of periarteriolar and perivenous spaces.

In a previous paper the author presented details of a new mechanism for the perivascular pump driving glymphatic flow—the brain’s waste removal system. The goal was to capture the essence of complex three-dimensional anatomy and physiology of the brain in a reduced order geometric model. The complexity required to make the model even approximately brain-like tended to obscure the most basic features of the perivascular pump. Here a bare-bones, “simplissimo” model of the perivascular pump is presented. It highlights only the most essential features of the pump mechanism. It also reveals components of brain anatomy and physiology that are not strictly necessary to make the pump work. Interestingly, these unnecessary features include pulsatile motion of the vascular walls, pressures inside the arteries and veins within the Virchow-Robin space, differences in arterial and venous compliance, the tapering of vascular branches, and the details of vascular branching. Instead, the softness of surrounding brain tissue and the relative diameters of venous vs. arterial perivascular cuffs are critical. Wave-like deformations of the soft brain tissue can create time averaged positive pressure in periarterial spaces, greater than that in perivenous spaces, owing to differences between antegrade and retrograde resistance to axial fluid flow along the annular channels of Virchow-Robin spaces. This new mechanism is scale independent from mouse to man, and can work despite the widely differing pulse rates of small versus large animals.

This study exercises a new mathematical model to search for unappreciated therapeutic targets in Alzheimer’s disease. The model describes detailed mechanisms underlying the glymphatic pump mechanism, which removes toxic proteins of Alzheimer’s disease from the interstitial fluid of the brain. It shows that the glymphatic pump is driven by the amplitude of intracranial pressure pulsations in the subarachnoid space, which are correlated with the arterial pulse and modulated by many other factors. Implementing ways to increase intracranial pressure pulses quickly comes to mind as a potential treatment strategy. Specific interventions include drugs that increase arterial pulse volume and small devices similar to balloon pumps to create increased subarachnoid pressure pulsations. Computer simulations of such balloon-like pumps, expanding and contracting in synchrony with the heartbeat, show effective enhancement of subarachnoid space pressure pulsations and resulting interstitial fluid flow in the brain. Design concepts for both totally implanted and externally wearable pumps are presented.

Traditionally, the meninges are described as 3 distinct layers, dura, arachnoid and pia. Yet, the classification of the connective meningeal membranes surrounding the brain is based on postmortem macroscopic examination. Ultrastructural and single cell transcriptome analyses have documented that the 3 meningeal layers can be subdivided into several distinct layers based on cellular characteristics. We here re-examined the existence of a 4th meningeal membrane, Subarachnoid Lymphatic-like Membrane or SLYM in Prox1-eGFP reporter mice. Imaging of freshly resected whole brains showed that SLYM covers the entire brain and brain stem and forms a roof shielding the subarachnoid cerebrospinal fluid (CSF)-filled cisterns and the pia-adjacent vasculature. Thus, SLYM is strategically positioned to facilitate periarterial influx of freshly produced CSF and thereby support unidirectional glymphatic CSF transport. Histological analysis showed that, in spinal cord and parts of dorsal cortex, SLYM fused with the arachnoid barrier layer, while in the basal brain stem typically formed a 1–3 cell layered membrane subdividing the subarachnoid space into two compartments. However, great care should be taken when interpreting the organization of the delicate leptomeningeal membranes in tissue sections. We show that hyperosmotic fixatives dehydrate the tissue with the risk of shrinkage and dislocation of these fragile membranes in postmortem preparations., Traditionally, the meninges are described as 3 distinct layers, dura, arachnoid and pia. Yet, the classification of the connective meningeal membranes surrounding the brain is based on postmortem macroscopic examination. Ultrastructural and single cell transcriptome analyses have documented that the 3 meningeal layers can be subdivided into several distinct layers based on cellular characteristics. We here re-examined the existence of a 4th meningeal membrane, Subarachnoid Lymphatic-like Membrane or SLYM in Prox1-eGFP reporter mice. Imaging of freshly resected whole brains showed that SLYM covers the entire brain and brain stem and forms a roof shielding the subarachnoid cerebrospinal fluid (CSF)-filled cisterns and the pia-adjacent vasculature. Thus, SLYM is strategically positioned to facilitate periarterial influx of freshly produced CSF and thereby support unidirectional glymphatic CSF transport. Histological analysis showed that, in spinal cord and parts of dorsal cortex, SLYM fused with the arachnoid barrier layer, while in the basal brain stem typically formed a 1–3 cell layered membrane subdividing the subarachnoid space into two compartments. However, great care should be taken when interpreting the organization of the delicate leptomeningeal membranes in tissue sections. We show that hyperosmotic fixatives dehydrate the tissue with the risk of shrinkage and dislocation of these fragile membranes in postmortem preparations.

Traditionally, the meninges are described as 3 distinct layers, dura, arachnoid and pia. Yet, the classification of the connective meningeal membranes surrounding the brain is based on postmortem macroscopic examination. Ultrastructural and single cell transcriptome analyses have documented that the 3 meningeal layers can be subdivided into several distinct layers based on cellular characteristics. We here re-examined the existence of a 4th meningeal membrane, Subarachnoid Lymphatic-like Membrane or SLYM in Prox1-eGFP reporter mice. Imaging of freshly resected whole brains showed that SLYM covers the entire brain and brain stem and forms a roof shielding the subarachnoid cerebrospinal fluid (CSF)-filled cisterns and the pia-adjacent vasculature. Thus, SLYM is strategically positioned to facilitate periarterial influx of freshly produced CSF and thereby support unidirectional glymphatic CSF transport. Histological analysis showed that, in spinal cord and parts of dorsal cortex, SLYM fused with the arachnoid barrier layer, while in the basal brain stem typically formed a 1–3 cell layered membrane subdividing the subarachnoid space into two compartments. However, great care should be taken when interpreting the organization of the delicate leptomeningeal membranes in tissue sections. We show that hyperosmotic fixatives dehydrate the tissue with the risk of shrinkage and dislocation of these fragile membranes in postmortem preparations., Traditionally, the meninges are described as 3 distinct layers, dura, arachnoid and pia. Yet, the classification of the connective meningeal membranes surrounding the brain is based on postmortem macroscopic examination. Ultrastructural and single cell transcriptome analyses have documented that the 3 meningeal layers can be subdivided into several distinct layers based on cellular characteristics. We here re-examined the existence of a 4th meningeal membrane, Subarachnoid Lymphatic-like Membrane or SLYM in Prox1-eGFP reporter mice. Imaging of freshly resected whole brains showed that SLYM covers the entire brain and brain stem and forms a roof shielding the subarachnoid cerebrospinal fluid (CSF)-filled cisterns and the pia-adjacent vasculature. Thus, SLYM is strategically positioned to facilitate periarterial influx of freshly produced CSF and thereby support unidirectional glymphatic CSF transport. Histological analysis showed that, in spinal cord and parts of dorsal cortex, SLYM fused with the arachnoid barrier layer, while in the basal brain stem typically formed a 1–3 cell layered membrane subdividing the subarachnoid space into two compartments. However, great care should be taken when interpreting the organization of the delicate leptomeningeal membranes in tissue sections. We show that hyperosmotic fixatives dehydrate the tissue with the risk of shrinkage and dislocation of these fragile membranes in postmortem preparations.

Specifying the exact mechanism driving cyclic, oscillatory flows of cerebrospinal fluid (CSF) through the cerebral ventricles and subarachnoid spaces remains an open problem. Here is a new quantitative hypothesis describing how cyclic expansion and contraction of the cerebral blood volume moves CSF within the closed box of the cranium. As whole brain tissue expands with added blood, volume compensation is provided by partial collapse of the superior sagittal and transverse venous sinuses. The magnitude of the expansion and contraction of whole brain tissue volume can be estimated from the changes in intravascular volume, which in turn can be divided into arterial, venous, and capillary fractions. Each of these volume fractions changes cyclically on a separate time scale. Arterial volume changes at the frequency of the heartbeat. Venous volume changes at the frequency of breathing in response to changes in intrathoracic pressure. Capillary volume changes according to temporal patterns of autoregulation, driven by chemical signals resulting from neural activity, especially during sleep. These volume changes can be predicted from principles of classical anatomy and physiology. In turn, using approximate geometric models of CSF filled spaces, local volumetric flows and flow velocities can be calculated. The calculations imply the existence of cyclic changes in CSF flow at three different frequencies and having three different magnitudes, which are in agreement with observational data in normal humans. Such models can be individualized using routine clinical data and imaging. Further, the predicted tidal movements of CSF over the cerebral convexities would continually refresh fluid drawn into and out of the Virchow-Robbins spaces, providing enhanced clearance of waste products during sleep and during strenuous exercise.

Specifying the exact mechanism driving cyclic, oscillatory flows of cerebrospinal fluid (CSF) through the cerebral ventricles and subarachnoid spaces remains an open problem. Here is a new quantitative hypothesis describing how cyclic expansion and contraction of the cerebral blood volume moves CSF within the closed box of the cranium. As whole brain tissue expands with added blood, volume compensation is provided by partial collapse of the superior sagittal and transverse venous sinuses. The magnitude of the expansion and contraction of whole brain tissue volume can be estimated from the changes in intravascular volume, which in turn can be divided into arterial, venous, and capillary fractions. Each of these volume fractions changes cyclically on a separate time scale. Arterial volume changes at the frequency of the heartbeat. Venous volume changes at the frequency of breathing in response to changes in intrathoracic pressure. Capillary volume changes according to temporal patterns of autoregulation, driven by chemical signals resulting from neural activity, especially during sleep. These volume changes can be predicted from principles of classical anatomy and physiology. In turn, using approximate geometric models of CSF filled spaces, local volumetric flows and flow velocities can be calculated. The calculations imply the existence of cyclic changes in CSF flow at three different frequencies and having three different magnitudes, which are in agreement with observational data in normal humans. Such models can be individualized using routine clinical data and imaging. Further, the predicted tidal movements of CSF over the cerebral convexities would continually refresh fluid drawn into and out of the Virchow-Robbins spaces, providing enhanced clearance of waste products during sleep and during strenuous exercise.

Intrathecal anesthesia is an effective method to provide anesthesia for patients undergoing total knee arthroplasty. Hypotension, bradycardia, and albeit rare asystole can occur following intrathecal anesthesia. These deleterious consequences can lead to poor outcomes for the patient. Effective methods at mitigating the effects of hypotension and bradycardia following intrathecal anesthesia have been studied extensively. Proper examination of the patient and health history can identify risk factors for developing bradycardia or hypotension post neuraxial blockade. Administration of ondansetron or glycopyrrolate prior to intrathecal anesthesia have been shown to be an effective strategy to prevent hemodynamic changes in the patient. Frequently an excessive amount of intrathecal local anesthetic is given to patients for their procedures leading to these adverse hemodynamic changes. Appropriate dosing of intrathecal local anesthetics can decrease the incidence of these changes.

Background and Purpose Reported cutoff values of the optic nerve sheath diameter (ONSD) for the diagnosis of elevated intracranial pressure (ICP) are inconsistent. This hampers ONSD as a possible noninvasive bedside monitoring tool for ICP. Because the influence of methodological differences on variations in cutoff values is unknown, we performed a narrative review to identify discrepancies in ONSD assessment methodologies and to investigate their effect on reported ONSD values. Methods We used a structured and quantitative approach in which each ONSD methodology found in the reviewed articles was categorized based on the characteristic appearance of the ultrasound images and ultrasound marker placement. Subsequently, we investigated the influence of the different methodologies on ONSD values by organizing the ONSDs with respect to these categories. Results In a total of 63 eligible articles, we could determine the applied ONSD assessment methodology. Reported ultrasound images either showed the optic nerve and its sheath as a dark region with hyperechoic striped band at its edges or as a single dark region surrounded by lighter retrobulbar fat. Four different ultrasound marker positions were used to delineate the optic nerve sheath, which resulted in different ONSD values and more importantly, different sensitivities to changes in ICP. Conclusions Based on our observations, we recommend to place ultrasound markers at the outer edges of the hyperechoic striped bands or at the transitions from the single dark region to the hyperechoic retrobulbar fat because these locations yielded the highest sensitivity of ONSD measurements for increased ICP.

Background and Purpose Reported cutoff values of the optic nerve sheath diameter (ONSD) for the diagnosis of elevated intracranial pressure (ICP) are inconsistent. This hampers ONSD as a possible noninvasive bedside monitoring tool for ICP. Because the influence of methodological differences on variations in cutoff values is unknown, we performed a narrative review to identify discrepancies in ONSD assessment methodologies and to investigate their effect on reported ONSD values. Methods We used a structured and quantitative approach in which each ONSD methodology found in the reviewed articles was categorized based on the characteristic appearance of the ultrasound images and ultrasound marker placement. Subsequently, we investigated the influence of the different methodologies on ONSD values by organizing the ONSDs with respect to these categories. Results In a total of 63 eligible articles, we could determine the applied ONSD assessment methodology. Reported ultrasound images either showed the optic nerve and its sheath as a dark region with hyperechoic striped band at its edges or as a single dark region surrounded by lighter retrobulbar fat. Four different ultrasound marker positions were used to delineate the optic nerve sheath, which resulted in different ONSD values and more importantly, different sensitivities to changes in ICP. Conclusions Based on our observations, we recommend to place ultrasound markers at the outer edges of the hyperechoic striped bands or at the transitions from the single dark region to the hyperechoic retrobulbar fat because these locations yielded the highest sensitivity of ONSD measurements for increased ICP.

Background and Purpose Reported cutoff values of the optic nerve sheath diameter (ONSD) for the diagnosis of elevated intracranial pressure (ICP) are inconsistent. This hampers ONSD as a possible noninvasive bedside monitoring tool for ICP. Because the influence of methodological differences on variations in cutoff values is unknown, we performed a narrative review to identify discrepancies in ONSD assessment methodologies and to investigate their effect on reported ONSD values. Methods We used a structured and quantitative approach in which each ONSD methodology found in the reviewed articles was categorized based on the characteristic appearance of the ultrasound images and ultrasound marker placement. Subsequently, we investigated the influence of the different methodologies on ONSD values by organizing the ONSDs with respect to these categories. Results In a total of 63 eligible articles, we could determine the applied ONSD assessment methodology. Reported ultrasound images either showed the optic nerve and its sheath as a dark region with hyperechoic striped band at its edges or as a single dark region surrounded by lighter retrobulbar fat. Four different ultrasound marker positions were used to delineate the optic nerve sheath, which resulted in different ONSD values and more importantly, different sensitivities to changes in ICP. Conclusions Based on our observations, we recommend to place ultrasound markers at the outer edges of the hyperechoic striped bands or at the transitions from the single dark region to the hyperechoic retrobulbar fat because these locations yielded the highest sensitivity of ONSD measurements for increased ICP.

Background: The classical view of cerebrospinal fluid (CSF) production posits the choroid plexus as its major source. Although previous studies indicate that part of CSF production occurs in the subarachnoid space (SAS), the mechanisms underlying extra-choroidal CSF production remain elusive. We here investigated the distributions of aquaporin 1 (AQP1) and Na+/K+/2Cl- cotransporter 1 (NKCC1), key proteins for choroidal CSF production, in the adult rodent brain and spinal cord. Methods: We have accessed AQP1 distribution in the intact brain using uDISCO tissue clearing technique and by Western blot. AQP1 and NKCC1 cellular localization were accessed by immunohistochemistry in brain and spinal cord obtained from adult rodents. Imaging was performed using light-sheet, confocal and bright field light microscopy. Results: We determined that AQP1 is widely distributed in the leptomeningeal vasculature of the intact brain and that its glycosylated isoform is the most prominent in different brain regions. Moreover, AQP1 and NKCC1 show specific distributions in the smooth muscle cell layer of penetrating arterioles and veins in the brain and spinal cord, and in the endothelia of capillaries and venules, restricted to the SAS vasculature. Conclusions: Our results shed light on the molecular framework that may underlie extra-choroidal CSF production and we propose that AQP1 and NKCC1 within the leptomeningeal vasculature, specifically at the capillary level, are poised to play a role in CSF production throughout the central nervous system.

Background: The classical view of cerebrospinal fluid (CSF) production posits the choroid plexus as its major source. Although previous studies indicate that part of CSF production occurs in the subarachnoid space (SAS), the mechanisms underlying extra-choroidal CSF production remain elusive. We here investigated the distributions of aquaporin 1 (AQP1) and Na+/K+/2Cl- cotransporter 1 (NKCC1), key proteins for choroidal CSF production, in the adult rodent brain and spinal cord. Methods: We have accessed AQP1 distribution in the intact brain using uDISCO tissue clearing technique and by Western blot. AQP1 and NKCC1 cellular localization were accessed by immunohistochemistry in brain and spinal cord obtained from adult rodents. Imaging was performed using light-sheet, confocal and bright field light microscopy. Results: We determined that AQP1 is widely distributed in the leptomeningeal vasculature of the intact brain and that its glycosylated isoform is the most prominent in different brain regions. Moreover, AQP1 and NKCC1 show specific distributions in the smooth muscle cell layer of penetrating arterioles and veins in the brain and spinal cord, and in the endothelia of capillaries and venules, restricted to the SAS vasculature. Conclusions: Our results shed light on the molecular framework that may underlie extra-choroidal CSF production and we propose that AQP1 and NKCC1 within the leptomeningeal vasculature, specifically at the capillary level, are poised to play a role in CSF production throughout the central nervous system.

Transport of solutes through brain involves diffusion and convection. The importance of convective flow in the subarachnoid and paravascular spaces has long been recognized; a recently proposed 'glymphatic' clearance mechanism additionally suggests that aquaporin-4 (AQP4) water channels facilitate convective transport through brain parenchyma. Here, the major experimental underpinnings of the glymphatic mechanism were re-examined by measurements of solute movement in mouse brain following intracisternal or intraparenchymal solute injection. We found that: (i) transport of fluorescent dextrans in brain parenchyma depended on dextran size in a manner consistent with diffusive rather than convective transport; (ii) transport of dextrans in the parenchymal extracellular space, measured by 2-photon fluorescence recovery after photobleaching, was not affected just after cardiorespiratory arrest; and (iii) Aqp4 gene deletion did not impair transport of fluorescent solutes from sub-arachnoid space to brain in mice or rats. Our results do not support the proposed glymphatic mechanism of convective solute transport in brain parenchyma.

Transport of solutes through brain involves diffusion and convection. The importance of convective flow in the subarachnoid and paravascular spaces has long been recognized; a recently proposed 'glymphatic' clearance mechanism additionally suggests that aquaporin-4 (AQP4) water channels facilitate convective transport through brain parenchyma. Here, the major experimental underpinnings of the glymphatic mechanism were re-examined by measurements of solute movement in mouse brain following intracisternal or intraparenchymal solute injection. We found that: (i) transport of fluorescent dextrans in brain parenchyma depended on dextran size in a manner consistent with diffusive rather than convective transport; (ii) transport of dextrans in the parenchymal extracellular space, measured by 2-photon fluorescence recovery after photobleaching, was not affected just after cardiorespiratory arrest; and (iii) Aqp4 gene deletion did not impair transport of fluorescent solutes from sub-arachnoid space to brain in mice or rats. Our results do not support the proposed glymphatic mechanism of convective solute transport in brain parenchyma.

BACKGROUND: We previously reported that infants who developed autism spectrum disorder (ASD) had increased cerebrospinal fluid (CSF) in the subarachnoid space (i.e., extra-axial CSF) from 6 to 24 months of age. We attempted to confirm and extend this finding in a larger independent sample. METHODS: A longitudinal magnetic resonance imaging study of infants at risk for ASD was carried out on 343 infants, who underwent neuroimaging at 6, 12, and 24 months. Of these infants, 221 were at high risk for ASD because of an older sibling with ASD, and 122 were at low risk with no family history of ASD. A total of 47 infants were diagnosed with ASD at 24 months and were compared with 174 high-risk and 122 low-risk infants without ASD. RESULTS: Infants who developed ASD had significantly greater extra-axial CSF volume at 6 months compared with both comparison groups without ASD (18% greater than high-risk infants without ASD; Cohens d = 0.54). Extra-axial CSF volume remained elevated through 24 months (d = 0.46). Infants with more severe autism symptoms had an even greater volume of extra-axial CSF from 6 to 24 months (24% greater at 6 months, d = 0.70; 15% greater at 24 months, d = 0.70). Extra-axial CSF volume at 6 months predicted which high-risk infants would be diagnosed with ASD at 24 months with an overall accuracy of 69% and corresponding 66% sensitivity and 68% specificity, which was fully cross-validated in a separate sample. CONCLUSIONS: This study confirms and extends previous findings that increased extra-axial CSF is detectable at 6 months in high-risk infants who develop ASD. Future studies will address whether this anomaly is a contributing factor to the etiology of ASD or an early risk marker for ASD.

BACKGROUND: Cerebral amyloid angiopathy (CAA) has been reported to present as convexity subarachnoid hemorrhage (cSAH). Lesser known is that cSAH can herald intracerebral hemorrhage (ICH) and ischemic lesions. We present seven new cases with 11C-Pittsburgh compound B (PiB) positive positron emission tomography (PET) scans including two with biopsy, review the literature and comment on clinical and radiological findings. METHOD(S): Patients with cSAH identified on CT, underwent MR imaging and MR angiography to exclude intracranial aneurysm. Nonaneurysmal cSAH were further prospectively evaluated for amyloid angiopathy using PiB. Clinical and radiological features of cSAH, subsequent ICH and ischemic lesions were characterized. RESULT(S): Seven patients with nonaneurysmal cSAH fulfilled the Boston criteria for probable CAA. All had PiB PET scans consistent with CAA. Of the 4 patients who had contrast MR Imaging all had enhancement overlying the cSAH, followed by ICH in three cases. All patients presented with transient sensory symptoms. All patients had small punctate subcortical and cortical infarcts on diffusion-weighted MR imaging. Literature review revealed subsequent ICH in approximately 11/79 patients. CONCLUSION(S): The finding of cSAH and PiB binding in our patients suggest underlying CAA. cSAH may be associated with ischemic lesion as well as future ICH occurrence.Copyright © 2014 by the American Society of Neuroimaging.

BACKGROUND: Cerebral amyloid angiopathy (CAA) has been reported to present as convexity subarachnoid hemorrhage (cSAH). Lesser known is that cSAH can herald intracerebral hemorrhage (ICH) and ischemic lesions. We present seven new cases with 11C-Pittsburgh compound B (PiB) positive positron emission tomography (PET) scans including two with biopsy, review the literature and comment on clinical and radiological findings. METHOD(S): Patients with cSAH identified on CT, underwent MR imaging and MR angiography to exclude intracranial aneurysm. Nonaneurysmal cSAH were further prospectively evaluated for amyloid angiopathy using PiB. Clinical and radiological features of cSAH, subsequent ICH and ischemic lesions were characterized. RESULT(S): Seven patients with nonaneurysmal cSAH fulfilled the Boston criteria for probable CAA. All had PiB PET scans consistent with CAA. Of the 4 patients who had contrast MR Imaging all had enhancement overlying the cSAH, followed by ICH in three cases. All patients presented with transient sensory symptoms. All patients had small punctate subcortical and cortical infarcts on diffusion-weighted MR imaging. Literature review revealed subsequent ICH in approximately 11/79 patients. CONCLUSION(S): The finding of cSAH and PiB binding in our patients suggest underlying CAA. cSAH may be associated with ischemic lesion as well as future ICH occurrence.Copyright © 2014 by the American Society of Neuroimaging.

Purpose: To compare the extent and intensity of FLAIR CSF flow related artefacts with and without BLADE (motion correction with multiple radial blade acquisition). Methods and materials: Retrospective review of 22 patients who received FLAIR with and without BLADE. Patients were scanned on three different scanners, two of which are 1.5T, the remainder being 3T. The CSF spaces in the pre-pontine cistern were evaluated for presence of flow related artefact. The cases were blindly assessed by an experienced neuroradiologist (SS) and an MRI fellow (CF). Extent/ Intensity of artefact was assessed on a four point scale (ranked 0-3). Result(s): Flow related artefact was identified on 17 of 22 BLADE studies and 16 of 22 rectilinear FLAIR. The average score based on the four point scale was 1.67 for BLADE and 0.81 for rectilinear FLAIR. The effect was much more pronounced at 3T. Average scores for 3T BLADE was 2.13 compared to 1.00 on rectilinear FLAIR. At 1.5T average scores were 0.43 for BLADE and 0.29 for FLAIR. Conclusion(s): Despite being widely regarded as having less pulsation, ghosting and movement artefacts when compared to conventional FLAIR sequences; BLADE FLAIR images demonstrate increased CSF flow related artefact extent and intensity in the prepontine cistern. The FLAIR with BLADE appearances may mimic the appearance of subarachnoid haemorrhage whereas conventional FLAIR on modern MRI equipment is less likely to result in this appearance. This effect is more pronounced on 3T field strengths when compared to 1.5T. Awareness of this difference may assist in avoiding a false positive subarachnoid haemorrhage diagnosis when FLAIR has been acquired with the BLADE technique.

Background. Intrathecal administration of 5-hydroxytryptamine (5-HT) is antinociceptive to noxious heat and electrical stimuli. The contributions of different receptor subtypes to the antinociceptive effects of 5-HT are controversial. The main reasons for this are the poor receptor subtype selectivity of some agonist drugs and the difficulty of restricting drug action to the spinal cord in some experimental paradigms. This study investigated the roles of different 5-HT receptor subtypes involved in the spinal cord control of the nociception produced by these two nociceptive testing paradigms. Methods. Tail-flick latency and electric current threshold for nociception were measured in an acute pain model that allowed the study of the antinociceptive effects of intrathecally administered drugs that were due to actions of these drugs at spinal cord receptors. Experiments were performed in male Wistar rats with chronically implanted lumbar subarachnoid catheters. Dose-response curves for spinally mediated antinociceptive effects of agonists selective for 5-HT receptor subtypes were constructed. Results. The 5-HT1 agonist 1-(3-chlorophenyl)-piperazine dihydrochloride caused a dose-dependent antinociceptive effect, measured by both nociceptive tests. However, 8-hydroxy-DPAT (selective 5-HT1A agonist) produced antinociception assessed by electric current but not tail flick. A 5-HT1A-selective antagonist, 4-[3-(benzotriazol-1-yl)propyl]-1-(2-methoxyphenyl)-piperazine, reversed the antinociception in the electrical test produced by both of these agonists but the tail-flick latency effects after intrathecal 1-(3-chlorophenyl)-piperazine were not suppressed by this antagonist. Conclusions. We conclude that 5-HT1A receptors in the spinal cord are involved in the nociceptive mechanisms assessed by noxious electrical stimuli. Other 5-HT1 receptors (non 5-HT1A receptors) are involved in the spinally mediated antinociception assessed by thermal noxious stimuli.

Purpose: To compare the conspicuity of subarachnoid blood on CT with MRI FLAIR and susceptibility weighted imaging (SWI) sequences in the setting of acute subarachnoid haemorrahge. Methods and materials: Retrospective, blinded review of 20 patients presenting with aneurysmal subarachnoid haemorrhage has been performed by two experienced neuroradiologists (WC and MH). Patients who presented with aneurysmal subarachnoid haemorrhage and underwent CT and MRI prior to undergoing craniotomy were included. Each modality/sequence was evaluated independently at two week intervals. The subarachnoid space was divided into 7 sections: interhemispheric, frontoparietal, occipitotemporal, sylvian fissure, perimesencephalic, posterior fossa, intra-ventricular. Result(s): When the subarachnoid space was considered in its seven sections blood was detected in 358 instances on either CT, SWI or FLAIR - 97 for CT, 115 for FLAIR and 146 for SWI. Haemorrhage was seen on all three on 57 occasions. It was detected on only one on 73 occasions - 18 for CT, 19 for FLAIR and 36 for SWI. Blood was detected only on MRI on 88 occasions - 19 FLAIR exclusively, 36 SWI exclusively, 33 both FLAIR and SWI. In addition there were 6 instances where blood was identified on CT and FLAIR only and 19 instances of blood on CT and SWI only. Overall blood was detected the most on SWI, followed by FLAIR and then CT. When considering individual patients blood was identified in all modalities in 17 cases. Of the remaining patients one had blood only on CT, one only on FLAIR and one on both CT and SWI. In the interhemispheric region, cerebral convexity sulci and intraventricular locations SWI and FLAIR appeared to outperform CT. Conclusion(s): There are instances where aneurysmal subarachnoid haemorrage may be detected on MRI, but not CT. This was seen more frequently with SWI than FLAIR. SWI and FLAIR appear more sensitive in the interhemispheric region, cerebral convexity sulci and intraventricular locations. Thi

The propensity of canine distemper virus (CDV) to spread to the central nervous system is one of the primary features of distemper. Therefore, we developed a reverse genetics system based on the neurovirulent Snyder Hill (SH) strain of CDV (CDVSH) and show that this virus rapidly circumvents the blood-brain and blood-cerebrospinal fluid (CSF) barriers to spread into the subarachnoid space to induce dramatic viral meningoencephalitis. The use of recombinant CDVSH(rCDVSH) expressing enhanced green fluorescent protein (EGFP) or red fluorescent protein (dTomato) facilitated the sensitive pathological assessment of routes of virus spread in vivo. Infection of ferrets with these viruses led to the full spectrum of clinical signs typically associated with distemper in dogs during a rapid, fatal disease course of approximately 2 weeks. Comparison with the ferret-adapted CDV5804Pand the prototypic wild-type CDVR252showed that hematogenous infection of the choroid plexus is not a significant route of virus spread into the CSF. Instead, viral spread into the subarachnoid space in rCDVSH-infected animals was triggered by infection of vascular endothelial cells and the hematogenous spread of virus-infected leukocytes from meningeal blood vessels into the subarachnoid space. This resulted in widespread infection of cells of the pia and arachnoid mater of the leptomeninges over large areas of the cerebral hemispheres. The ability to sensitively assess the in vivo spread of a neurovirulent strain of CDV provides a novel model system to study the mechanisms of virus spread into the CSF and the pathogenesis of acute viral meningitis.

Purpose: To compare the extent and intensity of FLAIR CSF flow related artefacts with and without BLADE (motion correction with multiple radial blade acquisition). Methods and materials: Retrospective review of 22 patients who received FLAIR with and without BLADE. Patients were scanned on three different scanners, two of which are 1.5T, the remainder being 3T. The CSF spaces in the pre-pontine cistern were evaluated for presence of flow related artefact. The cases were blindly assessed by an experienced neuroradiologist (SS) and an MRI fellow (CF). Extent/ Intensity of artefact was assessed on a four point scale (ranked 0-3). Result(s): Flow related artefact was identified on 17 of 22 BLADE studies and 16 of 22 rectilinear FLAIR. The average score based on the four point scale was 1.67 for BLADE and 0.81 for rectilinear FLAIR. The effect was much more pronounced at 3T. Average scores for 3T BLADE was 2.13 compared to 1.00 on rectilinear FLAIR. At 1.5T average scores were 0.43 for BLADE and 0.29 for FLAIR. Conclusion(s): Despite being widely regarded as having less pulsation, ghosting and movement artefacts when compared to conventional FLAIR sequences; BLADE FLAIR images demonstrate increased CSF flow related artefact extent and intensity in the prepontine cistern. The FLAIR with BLADE appearances may mimic the appearance of subarachnoid haemorrhage whereas conventional FLAIR on modern MRI equipment is less likely to result in this appearance. This effect is more pronounced on 3T field strengths when compared to 1.5T. Awareness of this difference may assist in avoiding a false positive subarachnoid haemorrhage diagnosis when FLAIR has been acquired with the BLADE technique.

Background. Intrathecal administration of 5-hydroxytryptamine (5-HT) is antinociceptive to noxious heat and electrical stimuli. The contributions of different receptor subtypes to the antinociceptive effects of 5-HT are controversial. The main reasons for this are the poor receptor subtype selectivity of some agonist drugs and the difficulty of restricting drug action to the spinal cord in some experimental paradigms. This study investigated the roles of different 5-HT receptor subtypes involved in the spinal cord control of the nociception produced by these two nociceptive testing paradigms. Methods. Tail-flick latency and electric current threshold for nociception were measured in an acute pain model that allowed the study of the antinociceptive effects of intrathecally administered drugs that were due to actions of these drugs at spinal cord receptors. Experiments were performed in male Wistar rats with chronically implanted lumbar subarachnoid catheters. Dose-response curves for spinally mediated antinociceptive effects of agonists selective for 5-HT receptor subtypes were constructed. Results. The 5-HT1 agonist 1-(3-chlorophenyl)-piperazine dihydrochloride caused a dose-dependent antinociceptive effect, measured by both nociceptive tests. However, 8-hydroxy-DPAT (selective 5-HT1A agonist) produced antinociception assessed by electric current but not tail flick. A 5-HT1A-selective antagonist, 4-[3-(benzotriazol-1-yl)propyl]-1-(2-methoxyphenyl)-piperazine, reversed the antinociception in the electrical test produced by both of these agonists but the tail-flick latency effects after intrathecal 1-(3-chlorophenyl)-piperazine were not suppressed by this antagonist. Conclusions. We conclude that 5-HT1A receptors in the spinal cord are involved in the nociceptive mechanisms assessed by noxious electrical stimuli. Other 5-HT1 receptors (non 5-HT1A receptors) are involved in the spinally mediated antinociception assessed by thermal noxious stimuli.

Purpose: To compare the conspicuity of subarachnoid blood on CT with MRI FLAIR and susceptibility weighted imaging (SWI) sequences in the setting of acute subarachnoid haemorrahge. Methods and materials: Retrospective, blinded review of 20 patients presenting with aneurysmal subarachnoid haemorrhage has been performed by two experienced neuroradiologists (WC and MH). Patients who presented with aneurysmal subarachnoid haemorrhage and underwent CT and MRI prior to undergoing craniotomy were included. Each modality/sequence was evaluated independently at two week intervals. The subarachnoid space was divided into 7 sections: interhemispheric, frontoparietal, occipitotemporal, sylvian fissure, perimesencephalic, posterior fossa, intra-ventricular. Result(s): When the subarachnoid space was considered in its seven sections blood was detected in 358 instances on either CT, SWI or FLAIR - 97 for CT, 115 for FLAIR and 146 for SWI. Haemorrhage was seen on all three on 57 occasions. It was detected on only one on 73 occasions - 18 for CT, 19 for FLAIR and 36 for SWI. Blood was detected only on MRI on 88 occasions - 19 FLAIR exclusively, 36 SWI exclusively, 33 both FLAIR and SWI. In addition there were 6 instances where blood was identified on CT and FLAIR only and 19 instances of blood on CT and SWI only. Overall blood was detected the most on SWI, followed by FLAIR and then CT. When considering individual patients blood was identified in all modalities in 17 cases. Of the remaining patients one had blood only on CT, one only on FLAIR and one on both CT and SWI. In the interhemispheric region, cerebral convexity sulci and intraventricular locations SWI and FLAIR appeared to outperform CT. Conclusion(s): There are instances where aneurysmal subarachnoid haemorrage may be detected on MRI, but not CT. This was seen more frequently with SWI than FLAIR. SWI and FLAIR appear more sensitive in the interhemispheric region, cerebral convexity sulci and intraventricular locations. Thi

The case of an adult patient who was treated for 3 years with a diagnosis of chronic low back pain, has a history of laminectomy surgery plus transpedicular fixation L5-S1, however the symptoms persists for which TC is requested from the lumbar region, and shows the deformation of vertebral body L4 with cord duct expansion to that level, MRI shows compatible findings with remaining arachnoiditis with cyst formation in lumbar spinal duct bone.frecuency, etiology, diagnosis and medical management of this condition will be reviewed. The patient went to surgery for spinal lesion biopsy, has a good postoperative evolution and the anatomical pathology report concludes: The removal of lumbar spinal injury, spinal cysticercosis. We emphasize in the diagnostic imaging data, which includes several findings that are classified according to the stage where the disease is. From the radiological point of view the technique of choice in clinical practice is MRI, although CT serves for the diagnosis of neurocysticercosis in nodular calcified stage., Se presenta el caso de un paciente adulto que fue tratado durante 3 años con el diagnóstico de lumbalgia crónica, tiene el antecedente quirúrgico de Laminectomía más Fijación Transpedicular L5-S1. Sin embargo los síntomas persisten por lo cual se solicita TC de la región lumbar, que evidencia deformación de cuerpo vertebral L4 con ampliación del canal a dicho nivel, la RM informa hallazgos compatibles con secuelas de aracnoiditis con formación de quiste en canal medular óseo lumbar. Es intervenido quirúrgicamente para biopsia de lesión intradural, con buena evolución postoperatoria; el informe de anatomía patológica concluye: extirpación de lesión intradural lumbar, cisticercosis intradural. Enfatizamos los datos de diagnóstico por imagen, que incluyen varios hallazgos que se clasifican de acuerdo a la fase en que se encuentre la enfermedad. Desde el punto de vista radiológico la técnica de elección en la práctica clínica es la RM, aunque la TC nos sirve para el diagnóstico de neurocisticercosis en el estadio nodular calcificado.

We report herein an unusual case of diffuse infiltrating retinoblastoma involving the brain, which caused a patient’s death 27 months after enucleation. An eight-year-old boy complained of blurred vision in his right eye (OD) in October 2006. Funduscopic examination showed optic disc swelling, dense whitish vitreous opacity, and an orange-colored subretinal elevated lesion adjacent to the optic disc. Fluorescein angiography revealed hyperfluorescence in the peripapillary region at an early-phase OD. Because the size of the subretinal lesion and vitreous opacity gradually increased, he was referred to us. His visual acuity was 20/1000 OD on June 20, 2007. Slit-lamp biomicroscopy showed a dense anterior vitreous opacity. Ophthalmoscopically, the subretinal orange-colored area spread out until reaching the mid peripheral region. A B-mode sonogram and computed tomography showed a thick homogeneous lesion without calcification. Gadolinium-enhanced magnetic resonance imaging showed a markedly enhanced appearance of the underlying posterior retina. Enucleation of the right eye was performed nine months after the initial presentation. Histopathology demonstrated retinal detachment and a huge choroidal mass invading the optic nerve head. The tumor was consistent with diffuse infiltrating retinoblastoma. The patient died due to brain involvement 27 months after enucleation. Ophthalmologists should be aware that diffuse infiltrating retinoblastoma may show an unfavorable course if its diagnosis is delayed.

The case of an adult patient who was treated for 3 years with a diagnosis of chronic low back pain, has a history of laminectomy surgery plus transpedicular fixation L5-S1, however the symptoms persists for which TC is requested from the lumbar region, and shows the deformation of vertebral body L4 with cord duct expansion to that level, MRI shows compatible findings with remaining arachnoiditis with cyst formation in lumbar spinal duct bone.frecuency, etiology, diagnosis and medical management of this condition will be reviewed. The patient went to surgery for spinal lesion biopsy, has a good postoperative evolution and the anatomical pathology report concludes: The removal of lumbar spinal injury, spinal cysticercosis. We emphasize in the diagnostic imaging data, which includes several findings that are classified according to the stage where the disease is. From the radiological point of view the technique of choice in clinical practice is MRI, although CT serves for the diagnosis of neurocysticercosis in nodular calcified stage., Se presenta el caso de un paciente adulto que fue tratado durante 3 años con el diagnóstico de lumbalgia crónica, tiene el antecedente quirúrgico de Laminectomía más Fijación Transpedicular L5-S1. Sin embargo los síntomas persisten por lo cual se solicita TC de la región lumbar, que evidencia deformación de cuerpo vertebral L4 con ampliación del canal a dicho nivel, la RM informa hallazgos compatibles con secuelas de aracnoiditis con formación de quiste en canal medular óseo lumbar. Es intervenido quirúrgicamente para biopsia de lesión intradural, con buena evolución postoperatoria; el informe de anatomía patológica concluye: extirpación de lesión intradural lumbar, cisticercosis intradural. Enfatizamos los datos de diagnóstico por imagen, que incluyen varios hallazgos que se clasifican de acuerdo a la fase en que se encuentre la enfermedad. Desde el punto de vista radiológico la técnica de elección en la práctica clínica es la RM, aunque la TC nos sirve para el diagnóstico de neurocisticercosis en el estadio nodular calcificado.

We report herein an unusual case of diffuse infiltrating retinoblastoma involving the brain, which caused a patient’s death 27 months after enucleation. An eight-year-old boy complained of blurred vision in his right eye (OD) in October 2006. Funduscopic examination showed optic disc swelling, dense whitish vitreous opacity, and an orange-colored subretinal elevated lesion adjacent to the optic disc. Fluorescein angiography revealed hyperfluorescence in the peripapillary region at an early-phase OD. Because the size of the subretinal lesion and vitreous opacity gradually increased, he was referred to us. His visual acuity was 20/1000 OD on June 20, 2007. Slit-lamp biomicroscopy showed a dense anterior vitreous opacity. Ophthalmoscopically, the subretinal orange-colored area spread out until reaching the mid peripheral region. A B-mode sonogram and computed tomography showed a thick homogeneous lesion without calcification. Gadolinium-enhanced magnetic resonance imaging showed a markedly enhanced appearance of the underlying posterior retina. Enucleation of the right eye was performed nine months after the initial presentation. Histopathology demonstrated retinal detachment and a huge choroidal mass invading the optic nerve head. The tumor was consistent with diffuse infiltrating retinoblastoma. The patient died due to brain involvement 27 months after enucleation. Ophthalmologists should be aware that diffuse infiltrating retinoblastoma may show an unfavorable course if its diagnosis is delayed.