Gregor P. Jaggi

Cerebrospinal fluid exchange in the optic nerve in normal-tension glaucoma

Aim To report on the cerebrospinal fluid (CSF) exchange between the intracranial spaces (ie, basal cisterns) and the subarachnoid space (SAS) of the optic nerve (ON) in subjects with normal-tension glaucoma (NTG) compared with control subjects without NTG or other forms of glaucoma. Methods CT cisternography of the brain and orbits was performed in 18 patients with NTG (7 women, 11 men; mean age 64.9±8.9 years) and in four patients without glaucoma or intracranial disease (4 women; mean age 62.8±18.4 years). The density of contrast-loaded cerebrospinal fluid (CLCSF) in the intracranial spaces and in the SAS surrounding the ONs was measured in Hounsfield units. Study design Unmasked, prospective series. Statistical analysis was performed using an independent two-tailed t test and the non-parametric Spearman correlation test. Results The density of CLCSF in the SAS surrounding the ONs in the NTG group was significantly reduced compared with its density in the intracranial CSF spaces and in the SAS of ONs measured in the control group (p=0.006). There were no significant differences between men and women within the NTG group (p>0.35). Conclusions The finding of a difference in the concentration gradients between the CLCSF within the intracranial spaces and the SAS of the ONs in this group of NTG patients compared with control subjects supports the hypothesis of a disturbed CSF exchange between the CSF in the intracranial spaces and the CSF in the SAS surrounding the ONs. The disturbance of CSF dynamics in this specific CSF pathway can be explained by ON compartmentation. The clinical importance of this finding warrants further investigation.

Optic nerve sheath diameter in normal-tension glaucoma patients

Background To report on the optic nerve sheath diameter (ONSD) in patients with normal-tension glaucoma (NTG) compared with controls without known optic nerve (ON) or intracranial disease. Methods In 18 patients with NTG (mean age 64.9±8.9 years; 7 women and 11 men), CT of the orbit was performed. 17 age- and gender-matched patients without ON or intracranial disease, who underwent CT of the orbits for non-ophthalmological reasons, served as controls. The widest intraorbital ONSD in axial sections was measured using a standardised technique. Study design: unmasked. Statistical analysis was performed using an independent two-tailed t Test and the non-parametric Spearman correlation test. Results ONSD was significantly (p<0.001) increased in NTG patients (right side: mean 7.9±0.9 mm SD; left: 8.0±1.1 mm) compared with controls (right: 6.3±0.5 mm; left: 6.1±0.6 mm). Neither the NTG nor the control group had a significant difference in ONSD between males and females or between right and left sides. Conclusions An increased ONSD is generally associated with increased intracranial pressure; however, ONSDs in a group of NTG patients also were significantly increased compared with controls. ON sheath compartmentation and thinning of the ON sheath are two possible explanations for an increase in the ONSD in patients with NTG.

Cerebrospinal fluid segregation optic neuropathy: an experimental model and a hypothesis

Aim To describe the histological changes in the optic nerve (ON) after experimental segregation of cerebrospinal fluid (CSF). Methods In seven sheep, a silicone band was placed around one ON to compress the subarachnoid space (SAS) surrounding the nerve, thus blocking the flow of CSF without compressing the ON itself. After 4 or 21 days, both the ligated and untouched ONs were removed and evaluated histologically. Results All treated ONs showed marked loss of axons, destruction of myelin and swelling of meningoepithelial cells, most pronounced in the proximal ON adjacent to the globe at the location most distant to the ligature. There was no significant difference in histological findings between the ONs that were ligated for 4 days and those with 21 days of ligature. Conclusion CSF segregation in the ON by blocking the SAS leads within 4 days to severe nerve damage. The increasing severity of these changes with increasing distance from the site of the ligature argues against simple pressure- or microperfusion-dependent effects and supports the hypothesis that interruption of CSF flow in the SAS of the ON can produce damage due to a change of CSF flow and content.

Papilledema revisited: is its pathophysiology really understood?

The term ‘papilledema’ is used to describe swelling of the optic disc that is thought or known to be associated with increased intracranial pressure (ICP) transmitted to the subarachnoid space (SAS) surrounding the optic nerve (ON). In most cases, the diagnosis of increased ICP is confirmed by lumbar puncture, the results of which are believed to represent the pressure in all of the cerebrospinal fluid (CSF) spaces. Until recently, all CSF spaces were thought to communicate freely and that CSF pressure and composition in one location were the same throughout the central nervous system (CNS) unless there was an acquired structural disturbance. However, the concept of continuous CSF flow and pressure throughout the CNS does not explain why some patients with elevated ICP do not develop papilledema, why some patients have highly asymmetrical papilledema, or why some patients with papilledema have normal ICP during 24‐hour monitoring. In addition, CSF sampling during lumbar puncture and during ON sheath fenestration demonstrates an increased concentration of lipocalin‐like prostaglandin D synthase, a substance toxic to astrocytes, in the SAS of the ON compared with that in the lumbar CSF space, and also a difference in CSF dynamics between the lumbar and ON SAS in some patients with papilledema. We therefore suggest that papilledema does not result from raised ICP alone but in some cases by compartmentation of the SAS of the ON, leading to a toxic milieu around the nerve.

Meningothelial cells react to elevated pressure and oxidative stress

Background Meningothelial cells (MECs) are the cellular components of the meninges enveloping the brain. Although MECs are not fully understood, several functions of these cells have been described. The presence of desmosomes and tight junctions between MECs hints towards a barrier function protecting the brain. In addition, MECs perform endocytosis and, by the secretion of cytokines, are involved in immunological processes in the brain. However, little is known about the influence of pathological conditions on MEC function; e.g., during diseases associated with elevated intracranial pressure, hypoxia or increased oxidative stress. Methods We studied the effect of elevated pressure, hypoxia, and oxidative stress on immortalized human as well as primary porcine MECs. We used MTS (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) bioreduction assays to assess the proliferation of MECs in response to treatment and compared to untreated control cells. To assess endocytotic activity, the uptake of fluorescently labeled latex beads was analyzed by fluorescence microscopy. Results We found that exposure of MECs to elevated pressure caused significant cellular proliferation and a dramatic decrease in endocytotic activity. In addition, mild oxidative stress severely inhibited endocytosis. Conclusion Elevated pressure and oxidative stress impact MEC physiology and might therefore influence the microenvironment of the subarachnoid space and thus the cerebrospinal fluid within this compartment with potential negative impact on neuronal function.

Does Immunohistochemistry Allow Easy Detection of Lymphatics in the Optic Nerve Sheath

We evaluated the validity of anti-D2-40 and anti-LYVE-1 (antibodies against lymphatic endothelium) for IHC diagnosis and semiquantification of lymphatic vessels in the dura mater of the intraorbital portion of the human optic nerve (ON). Fourteen specimens were analyzed using light microscopy within 12 hr postmortem. We found in all specimens that both D2-40 and LYVE-1 stained lymphatic vessels as well as venules and arterioles. Our findings show lymphatic vessels in the meninges of the intraorbital portion of the human ON. Anti-D2-40 and anti-LYVE-1 antibodies, however, are not found to be exclusively specific to the endothelial layer of lymphatics because they also stain the endothelial layer of venules and arterioles. For the unequivocal identification of lymphatics, additional morphological criteria are necessary. Nevertheless, D2-40 and LYVE-1 staining allows rapid identification of endothelial layers.

Is silicone oil optic neuropathy caused by high intraocular pressure alone? A semi-biological model

Background: Silicone oil endotamponade is used for the repair of complicated retinal detachments. Cataract, glaucoma and corneal endothelial dysfunction are the most frequent complications of silicone oil tamponade. Clinical and histopathological studies have revealed that silicone oil can penetrate into the optic nerve and into the brain. The mechanism by which silicone oil moves from intraocular into the optic nerve is still under debate. To investigate the effect of intraocular pressure only, a post-mortem experimental histological study was performed to determine whether silicone oil penetration from the globe into the optic nerve after vitrectomy and silicone oil instillation is a purely pressure-related phenomenon. Although a post-mortem study excludes physiological processes, it serves as a model for the study of pure physical forces onto biological structures. Methods: The study was carried out on 20 human eyes with their optic nerves attached. All specimens had been harvested from patients without known eye disease. The vitreous body was removed with a syringe and the globe was filled with silicone oil. A lipophil fluorescence marker (Bodipy) was added in 8 eyes. The mean intraocular pressure after silicone oil filling measured 40 mm Hg and the globes stayed under pressure for up to 16 weeks. The eyes and optic nerves were stained with H&E and examined with light, phase-contrast and fluorescence microscopy. Results: None of the 20 specimens examined showed silicone oil in the retrolaminar portion of the optic nerve. Conclusions: Migration of silicone oil into the optic nerve was not demonstrated in this human post-mortem study. Therefore other factors, such as pre-existing glaucomatous damage to the disc region and/or active transport mechanisms must be involved in the development of silicone oil-associated optic neuropathy.

Measurement of Optic Nerve Sheath Diameter: Differences between Methods? A Pilot Study.

BACKGROUND Quantification of the optic nerve sheath diameter is a promising approach for the detection of elevated intracranial pressure. The comparability of current methods is unclear. The objective of this study was to assess the relationship between optic nerve sheath diameter as measured with computed tomography, magnetic resonance tomography and ultrasound in patients without known optic nerve disease or increased intracranial pressure. PATIENTS AND METHODS 15 patients (60.8 [years]±16.73 SD; 7 female) with paranasal sinus pathology in whom computed tomography and magnetic resonance imaging were performed underwent optic nerve sheath diameter measurements by ultrasound, as well as an ophthalmological examination. Ultrasound-, computed tomography- and magnetic resonance imaging-derived maximal optic nerve sheath diameter values 3 mm behind the globe were compared. RESULTS Optic nerve sheath diameter measured (n=30) by ultrasound (mean 6.2 [mm]±0.84 SD) was significantly (p<0.01) higher than optic nerve sheath diameter in computed tomography (5.2±1.11) or magnetic resonance imaging (5.3±1.14). There was no significant (p=0.24) difference between optic nerve sheath diameter measured in computed tomography and magnetic resonance tomography. CONCLUSIONS The comparability of optic nerve sheath diameter measurements in patients without known optic nerve disease and assumed normal intracranial pressure appears to be given between computed tomography and magnetic resonance tomography, while comparability between ultrasound and computed tomography or magnetic resonance tomography seems to be less reliable.

Long-term effect of selective laser trabeculoplasty on intraocular pressure in pseudoexfoliation glaucoma.

BACKGROUND Selective laser trabeculoplasty has been found to be effective as an adjunct to topical medical therapy in glaucoma. This analysis examines the intraocular pressure lowering effect of laser trabeculoplasty in eyes with pseudoexfoliation on maximum medical therapy. MATERIAL AND METHODS A retrospective chart review was undertaken of 457 eyes of which 344 underwent a 360° selective laser trabeculoplasty treatment between 2008 and 2013. 94 of these eyes had pseudoexfoliation. Intraocular pressure values were analysed in 3 monthly intervals up to 60 months after selective laser trabeculoplasty. Exclusion criteria were narrow or closed angles as well as uveitic glaucoma and previous intraocular pressure lowering surgery. RESULTS Patients mean age was 71 years±11.0 SD, 42.7% were male. At time point 12 months after selective laser trabeculoplasty the intraocular pressure lowering effect was significantly greater in eyes with pseudoexfoliation than in eyes without pseudoexfoliation (p=0.01; Mann-Whitney test). Up to 21 months after selective laser trabeculoplasty a significant intraocular pressure reduction of 2.76 mmHg±3.72 SD compared to baseline values could be seen in eyes with pseudoexfoliation (p=0.01; Wilcoxon Test). CONCLUSIONS In this retrospective study a significant greater intraocular pressure lowering effect of selective laser trabeculoplasty could be seen in eyes with pseudoexfoliation compared to eyes without pseudoexfoliation only at time point 12 months after selective laser trabeculoplasty. Analyses revealed no significant intraocular pressure reduction compared to baseline values after 21 months in eyes with pseudoexfoliation and after 30 months in eyes without pseudoexfoliation.

Changes in the amygdala produced by viewing strabismic eyes.

PURPOSE The aim of this study was to look for the response to strabismus images in the limbic network (amygdala, hippocampus, parahippocampus) of healthy volunteers and to compare it with their reaction to viewing normal eyes. DESIGN Prospective, observational study. PARTICIPANTS Thirty-one healthy volunteers underwent functional magnetic resonance imaging (fMRI). METHODS Functional magnetic resonance imaging data and blood oxygen level-dependent signal changes were analyzed using the BrainVoyager QX software package (Brain Innovation, Maastricht, The Netherlands). MAIN OUTCOME MEASURES Responses to viewing strabismus images were compared with those observed while viewing normal eye images. RESULTS Strabismus images led to significant activation of the amygdala, hippocampus, parahippocampal, and fusiform gyri in 30 of 31 subjects compared with normal eye images, indicating a negative emotional response. CONCLUSIONS These fMRI results confirm that strabismus influences organically not only the patient with nonparallel eyes but also observers. Treatment of strabismus therefore changes the interpersonal dynamic for patients with strabismus on a demonstrable organic basis. FINANCIAL DISCLOSURE(S) The author(s) have no proprietary or commercial interest in any materials discussed in this article.