Huaizhou Wang

Detection of early neuron degeneration and accompanying glial responses in the visual pathway in a rat model of acute intraocular hypertension

Transsynaptic degeneration has been implicated in patients with primary open angle glaucoma (POAG) and animal models of chronic intraocular hypertension. Whether the sustained intraocular pressure (IOP) elevation is necessary for the induction of transsynaptic changes in the brain remains unclear. The aim of this study is to characterize the effects of acute and transient intraocular hypertension on the visual pathway of rats. Acute intraocular hypertension was induced in the right eye by anterior chamber perfusion. At 1 day, 3 days, 1 week, 2 weeks and 4 weeks after the operation, neuronal degeneration and glial responses in the retina, dorsal lateral geniculate nucleus (dLGN) and superior colliculus (SC) were assessed using Nissl staining and immunohistochemistry. TUNEL staining was also performed to detect the neuronal apoptosis in the brain. At the first day after the operation, no obvious neuronal changes were detected in the retina or the brain. At 3 days, 46% of the retinal ganglion cells (RGCs) were lost. Atrophy of the contralateral optic tract was also observed. Meanwhile, the cross-sectional area of neurons in the contralateral dLGN and SC was decreased, while cell density in the same regions was increased. Glial activation in the retina occurred much earlier than the RGC loss. Co-expression of glial fibrillary acid protein (GFAP) and glutamine synthetase (GS) was observed in the end-feet and processes of Müller cells at 1 day after the operation. GFAP immunoreactivity was remarkably increased in the contralateral dLGN and SC at 3 days. It also showed a good co-localization with GS. All of aforementioned changes gradually progressed and persisted for the whole observation period. No TUNEL-positive cells were detected in the dLGN and SC at any post-operative time point. Taken together, these results illustrate that acute and transient intraocular hypertension is able to induce early onset and long-lasting neurodegenerative changes and the accompanying glial activation in the visual pathway. Brain changes may occur in parallel with the RGC loss. Reactive glial cells in the brain may participate in the clearance of aberrantly released glutamate and may serve as a sensitive marker of neuronal injury. Neuroprotection of the entire visual pathway and glia-target therapies may bring new insights into the glaucoma treatment.

Optic Neuropathy Induced by Experimentally Reduced Cerebrospinal Fluid Pressure in Monkeys

PURPOSE To examine the influence of experimentally reduced cerebrospinal fluid pressure (CSFP) on retinal nerve fiber layer (RNFL) thickness and neuroretinal rim area of the optic nerve head. METHODS This experimental study included nine monkeys that underwent implantation of a lumbar-peritoneal cerebrospinal fluid (CSF) shunt. In the study group (n = 4 monkeys), the shunt was opened to achieve a CSF of approximately 40 mm H2O, while the shunt remained closed in the control group (n = 5 monkeys). At baseline and in monthly intervals thereafter, optical coherence tomographic and photographic images of the optic nerve head and RNFL were taken of all monkeys. RESULTS Two out of four monkeys in the study group showed bilaterally a progressive reduction in RNFL thickness between 12% and 30%, reduction in neuroretinal rim area and volume, and increase in cup-to-disc area ratios. A third monkey developed a splinter-like disc hemorrhage in one eye. The fourth monkey in the study group did not develop morphologic changes during follow-up, nor did any monkey in the control group. CONCLUSIONS Experimental and chronic reduction in CSF in monkeys was associated with the development of an optic neuropathy in some monkeys.

Noninvasive intracranial pressure estimation by orbital subarachnoid space measurement: the Beijing Intracranial and Intraocular Pressure (iCOP) study

IntroductionThe orbital subarachnoid space surrounding the optic nerve is continuous with the circulation system for cerebrospinal fluid (CSF) and can be visualized by using magnetic resonance imaging (MRI). We hypothesized that the orbital subarachnoid space width (OSASW) is correlated with and can serve as a surrogate for intracranial pressure (ICP). Our aim was to develop a method for a noninvasive measurement of the intracranial CSF-pressure (CSF-P) based on MRI-assisted OSASW.MethodsThe prospective observational comparative study included neurology patients who underwent lumbar CSF-P measurement and 3.0-Tesla orbital magnetic resonance imaging (MRI) for other clinical reasons. The width of the orbital subarachnoid space (OSASW) around the optic nerve was measured with MRI at 3, 9, and 15 mm behind the globe. The study population was randomly divided into a training group and a test group. After adjusting for body mass index (BMI) and mean arterial blood pressure (MABP), algorithms for the associations between CSF-P and OSASW were calculated in the training group. The algorithms were subsequently verified in the test group. Main outcome measures were the width of the orbital subarachnoid space (OSASW) and the lumbar cerebrospinal fluid pressure (CSF-P).ResultsSeventy-two patients were included in the study. In the training group, the algorithms for the associations between CSF-P and OSASW were as follows: (a) CSF-P = 9.31 × OSASW (at 3 mm) + 0.48 × BMI + 0.14 × MABP-19.94; (b) CSF-P = 16.95 × OSASW (at 9 mm) + 0.39 × BMI + 0.14 × MABP-20.90; and (c) CSF-P = 17.54 × OSASW (at 15 mm) + 0.47 × BMI + 0.13 × MABP-21.52. Applying these algorithms in the independent test group, the measured lumbar CSF-P (13.6 ± 5.1 mm Hg) did not differ significantly from the calculated MRI-derived CSF-P (OSASW at 3 mm: 12.7 ± 4.2 mm Hg (P = 0.07); at 9 mm: 13.4 ± 5.1 mm Hg (P = 0.35); and at 15 mm: 14.0 ± 4.9 mm Hg (P = 0.87)). Intraclass correlation coefficients (ICCs) were higher for the CSF-P assessment based on OSASW at 9 mm and at 15 mm behind the globe (all ICCs, 0.87) than for OSASW measurements at 3 mm (ICC, 0.80).ConclusionsIn patients with normal, moderately decreased or elevated ICP, MRI-assisted measurement of the OSASW appears to be useful for the noninvasive quantitative estimation of ICP, if BMI and MABP as contributing parameters are taken into account.Trial registrationClinical trial registered with the Chinese Clinical Trial Registry: ChiCTR-OCC-11001271

Valsalva manoeuver, intra-ocular pressure, cerebrospinal fluid pressure, optic disc topography: Beijing intracranial and intra-ocular pressure study

To assess whether a Valsalva manoeuver influences intra‐ocular pressure (IOP), cerebrospinal fluid pressure (CSF‐P) and, by a change in the trans‐laminar cribrosa pressure difference, optic nerve head morphology.

Aqueous Angiography in Living Nonhuman Primates Shows Segmental, Pulsatile, and Dynamic Angiographic Aqueous Humor Outflow

PURPOSE To evaluate the feasibility of safely performing aqueous angiography in intact eyes of living nonhuman primates (NHPs) for evaluating aqueous humor outflow and segmental patterns. DESIGN Cross-sectional, observational study. SUBJECTS Six nonhuman primates. METHODS Aqueous angiography was performed in 6 nonhuman primates. After anesthesia, an anterior chamber (AC) maintainer was placed through a temporal 1-mm side-port wound. Indocyanine green (ICG; 0.4%) or 2.5% fluorescein was introduced (individually or in sequence) into the eye with a gravity-driven constant-pressure system. Aqueous angiography images were obtained with a Spectralis HRA+OCT (Heidelberg Engineering GmbH, Heidelberg, Germany) suspended over the NHP eye using a custom-designed surgical boom arm. Concurrent anterior segment optical coherence tomography (OCT) was performed on distally angiographically positive and negative regions. MAIN OUTCOME MEASURES Angiographic patterns described by location, time-course, choice of tracer, and anterior-segment OCT. RESULTS Aqueous angiography in the living NHP eye demonstrated mostly stable angiographic patterns. With multimodal imaging, angiographically positive signal co-localized with episcleral veins as identified by infrared imaging and intrascleral lumens, as demonstrated by anterior segment OCT. Sequential aqueous angiography in individual eyes with ICG followed by fluorescein showed similar angiographic patterns. A pulsatile nature of aqueous angiographic outflow was sometimes observed. Aqueous angiographic patterns could also dynamically change. In some instances, positive angiographic flow suddenly arose in regions previously without an angiographic signal. Alternatively, an angiographic signal could suddenly disappear from regions in which an angiographic signal was initially documented. CONCLUSIONS Aqueous angiography in living NHPs demonstrated segmental and pulsatile patterns with a newly described ability to dynamically shift. These characteristics further the understanding of live aqueous humor outflow biology and may be useful in improving glaucoma surgeries aimed at trabecular meshwork bypass.

The short-term effects of exercise on intraocular pressure, choroidal thickness and axial length.

Purpose To explore ocular changes in healthy people after exercise. Methods Twenty five volunteers underwent exercise for 15 minutes on a treadmill. Measurements of choroidal thickness, intraocular pressure (IOP), ocular biometry, and blood pressure were taken before and after exercise. Enhanced Depth Imaging optical coherence tomography (EDI-OCT) was used to measure choroidal thickness at the fovea. Intraocular pressure (IOP) was measured by Goldmann applanation tonometry. Ocular biometric measures were collected using A scan ultrasound. Blood pressure was measured concurrently with the acquisition of the scans. Results Twenty five volunteers (25 eyes) with a mean age of 25.44±3.25 years were measured. There was a significant increase in systolic and diastolic pressure after exercise (P<0.05). The IOP showed a significant decrease after exercise (P<0.05). However there was no significant difference in the mean choroidal thickness, ocular axial length, anterior chamber depth, lens thickness, or vitreous length before and after exercise measurements (P>0.05). Conclusion There was a significant decrease in IOP from exercise without a change in choroidal thickness and ocular biometric measures. IOP and choroidal thickness were not correlated, suggesting that the IOP decrease from exercise is not due to changes in choridal thickness.

Pressure balance and imbalance in the optic nerve chamber: The Beijing Intracranial and Intraocular Pressure (iCOP) Study

To determine the interdependence of intracranial pressure (ICP) and intraocular pressure (IOP) and how it affects optic nerve pressures, eight normal dogs were examined using pressure-sensing probes implanted into the left ventricle, lumbar cistern, optic nerve subarachnoid space in the left eye, and anterior chamber in the left eye. This allowed ICP, lumbar cistern pressure (LCP), optic nerve subarachnoid space pressure (ONSP) and IOP to be simultaneously recorded. After establishing baseline pressure levels, pressure changes that resulted from lowering ICP (via shunting cerebrospinal fluid (CSF) from the ventricle) were recorded. At baseline, all examined pressures were different (ICP0.001). As ICP was lowered during CSF shunting, IOP also dropped in a parallel time course so that the trans-lamina cribrosa gradient (TLPG) remained stable (ICP-IOP dependent zone). However, once ICP fell below a critical breakpoint, ICP and IOP became uncoupled and TLPG changed as ICP declined (ICP-IOP independent zone). The optic nerve pressure gradient (ONPG) and trans-optic nerve pressure gradient (TOPG) increased linearly as ICP decreased through both the ICP-IOP dependent and independent zones. We conclude that ICP and IOP are coupled in a specific pressure range, but when ICP drops below a critical point, IOP and ICP become uncoupled and TLPG increases. When ICP drops, a rise in the ONPG and TOPG creates more pressure and reduces CSF flow around the optic nerve. This change may play a role in the development and progression of various ophthalmic and neurological diseases, including glaucoma.

Association of three single nucleotide polymorphisms at the SIX1-SIX6 locus with primary open angle glaucoma in the Chinese population

This study investigated the genetic association of three single nucleotide polymorphisms (SNPs; rs10483727, rs33912345, and rs146737847) at the SIX1-SIX6 locus with primary open angle glaucoma (POAG) in the Chinese population. A total of 866 subjects with POAG (685 high-tension glaucoma (HTG) and 181 normal-tension glaucoma (NTG)) and 266 control individuals were included. Significant genetic association was identified for rs10483727 in HTG (P=0.02; odds ratio (OR)=1.31), NTG (P=7.41×10-6; OR=2.71), and POAG (i.e., HTG and NTG combined; P=0.001; OR=1.44). rs33912345 was also significantly associated with HTG (P=0.008; OR=1.36), NTG(P=2.72×10-6; OR=2.27), and POAG (P=3.84×10-4; OR=1.49). The rare SIX6 mutation, rs146737847, was not found in the subjects enrolled in this study. Stratification by patient age identified that both rs10483727 and rs33912345 were significantly associated with NTG in patients aged above 40 years (P=2.08×10-5; OR=2.28), whereas in patients aged between 20–40 years, rs33912345 was significantly associated with NTG (P=0.017; OR=2.06). In HTG, the genetic associations for both rs10483727 and rs33912345 were significant in patients aged between 20–40 years (P=0.006; OR=1.56) but not in those aged above 40 years (P=0.118, OR=1.21 and P=0.042, OR=1.29, respectively). This study replicated the association of POAG with two SNPs at the SIX1-SIX6 locus and demonstrated that SNPs, rs10483727 and rs33912345, are significantly associated with POAG, especially with NTG in patients aged above 40 years.

Imaging collector channel entrance with a new intraocular micro-probe swept-source optical coherence tomography

To describe the use of a newly developed side‐viewing catheter probe to provide the cross‐sectional images of collector channel entrance (CCE), achieved by swept‐source optical coherence tomography (SS‐OCT).

Comparison of time-domain, spectral-domain and swept-source OCT in evaluating aqueous cells in vitro

Different optical coherence tomography (OCT), both time-domain OCT and spectral-domain OCT, has been used to evaluate anterior chamber cells in previous studies. Recently, commercial swept-source OCT was available. The comparison among three kinds of OCTs have not been done before. Here, we compared their feasibility in discerning aqueous cells in vitro. The peripheral blood was diluted to eight different cell concentrations and was packed into plastic-film bag. Each sample was tested using different scan modes of three OCTs. It was easy to discern aqueous cells from background noise in both Visante AS-OCT and RTVue XR Avanti OCT, but difficult in Casia SS-1000 OCT. The measured blood cell densities in high-resolution corneal cross-sectional scan of Visante AS-OCT, cornea line scan and 3D cornea scan of RTVue XR Avanti OCT were highly correlated with the actual blood cell concentration (Pearson correlation=0.991, 0.989, and 0.993 respectively). The mean adjusted cell densities of cornea line scan (10.46±2.87 spots mm-2) and 3D cornea scan (11.01±2.47 spots mm-2) of RTVue XR Avanti OCT were significantly larger than that of Visante AS-OCT (1.55±1.75 spots mm-2) (P<0.01). Our study demonstrated that RTVue XR Avanti OCT, a spectral-domain OCT, is superior to other two OCTs in evaluating aqueous cells.