Abstract: This submission will briefly review the anatomy and physiology of the optic nerve, and highlight various ischemic optic neuropathies including anterior ischemic optic neuropathies (non-arteritis and arteritic), diabetic papillopathy, posterior ischemic optic neuropathies, and ischemic optic neuropathies in the setting of hemodynamic compromise.
Abstract: Optical coherence tomography (OCT) is an ocular imaging technique that can complement the neuro-ophthalmic assessment, and inform our understanding regarding functional consequences of neuroaxonal injury in the afferent visual pathway. Indeed, OCT has emerged as a surrogate end-point in the diagnosis and follow up of several demyelinating syndromes of the central nervous system (CNS), including optic neuritis (ON) associated with: multiple sclerosis (MS), neuromyelitis optica spectrum disorder (NMOSD), and anti-myelin oligodendrocyte glycoprotein (MOG) antibodies. Recent advancements in enhanced depth imaging (EDI) OCT have distinguished this technique as a new gold standard in the diagnosis of optic disc drusen (ODD). Moreover, OCT may enhance our ability to distinguish cases of papilledema from pseudopapilledema caused by ODD. In the setting of idiopathic intracranial hypertension (IIH), OCT has shown benefit in tracking responses to treatment, with respect to reduced retinal nerve fiber layer (RNFL) measures and morphological changes in the angling of Bruch’s membrane. Longitudinal follow up of OCT measured ganglion cell-inner plexiform layer thickness may be of particular value in managing IIH patients who have secondary optic atrophy. Causes of compressive optic neuropathies may be readily diagnosed with OCT, even in the absence of overt visual field defects. Furthermore, OCT values may offer some prognostic value in predicting post-operative outcomes in these patients. Finally, OCT can be indispensable in differentiating optic neuropathies from retinal diseases in patients presenting with vision loss, and an unrevealing fundus examination. In this review, our over-arching goal is to highlight the potential role of OCT, as an ancillary investigation, in the diagnosis and management of various optic nerve disorders.
Abstract: Myasthenia gravis (MG) is an autoimmune antibody-mediated disorder which causes fluctuating weakness in ocular, bulbar and limb skeletal muscles. There are two major clinical types of MG. Ocular MG (OMG) affects extra ocular muscles associated with eye movement and eyelid function and generalized MG results in muscle weakness throughout the body. Patients with OMG have painless fluctuating extra ocular muscles weakness, diplopia and ptosis accompanied by normal visual acuity and pupillary function. Frequently, patients with OMG develop generalized MG over 24 months. Pure OMG is more often earlier in onset (<45 years) than generalized MG. It can also occur as part of an immune-genetic disorder or paraneoplastic syndrome related to thymus tumors. Diagnosis is based on clinical manifestations, laboratory findings, electrophysiological evaluation and pharmacologic tests. Therapeutic strategies for MG consist of symptom relieving medications (e.g., acetylcholine esterase inhibitors), immunosuppressive agents, and surgical intervention (e.g., thymectomy).
Background: The expression, localization, and function of the endocannabinoid system has been well characterized in recent years in the monkey retina and in the primary thalamic relay, the lateral geniculate nucleus (dLGN). Few data are available on cortical recipients’ structures of the dLGN, namely the primary visual cortex (V1). The goal of this study is to characterize the expression and localization of the metabotropic cannabinoid receptor type 1 (CB1R), the synthesizing enzyme N-acyl phosphatidyl-ethanolamine phospholipase D (NAPE-PLD), and the degradation enzyme fatty acid amide hydrolase (FAAH) in the vervet monkey area V1.
Methods: Using Western blots and immunohistochemistry, we investigated the expression patterns of CB1R, NAPE-PLD, and FAAH in the vervet monkey primary visual cortex.
Results: CB1R, NAPE-PLD, and FAAH were expressed in the primary visual cortex throughout the rostro-caudal axis. CB1R showed very low levels of staining in cortical layer 4, with higher expressions in all other cortical layers, especially layer 1. NAPE-PLD and FAAH expressions were highest in layers 1, 2 and 3, and lowest in layer 4.
Conclusions: Interestingly enough, CB1R was very low in layer 4 of V1 in comparison to the other cortical layers. The visual information coming from the dLGN and entering layer 4Calpha (magno cells) and 4Cbeta (parvo cells) may be therefore modulated by the higher expression levels of CB1R in cortical layers 2 and 3 on the way to the dorsal and ventral visual streams. This is further supported by the higher expression of NAPE-PLD and FAAH in the outer cortical layers. These data indicate that CB1R system can influence the network of activity patterns in the visual stream after the visual information has reached area V1. These novel results provide insights for understanding the role of the endocannabinoids in the modulation of cortical visual inputs, and hence, visual perception.
Background: Visual deficits, caused by ocular disease or trauma to the visual system, can cause lasting damage with insufficient treatment options available. However, recent research has focused on neural plasticity as a means to regain visual abilities. In order to better understand the involvement of neural plasticity and reorganization in partial vision restoration, we aim to evaluate the partial recovery of a visual deficit over time using three behavioural tests. In our study, a partial optic nerve crush (ONC) serves as an induced visual deficit, allowing for residual vision from surviving cells.
Methods: Three behavioural tests—optokinetic reflex, object recognition, and visual cliff—were conducted in 9 mice prior to a bilateral, partial ONC, then 1, 3, 7, 14, 21, and 28 days after the ONC. The optokinetic reflex test measured the tracking reflex in response to moving sinusoidal gratings. These gratings increase in spatial frequency until a reflex is no longer observed, i.e., a visual acuity threshold is reached. The object recognition test examines the animal’s exploratory behaviour in its capacity to distinguish high versus low contrast objects. The visual cliff test also evaluates exploratory behaviour, by simulating a cliff to observe the animal’s sense of depth perception. All three tests provide an estimate of the rodent’s visual abilities at different levels of the visual pathway.
Results: The partial optic nerve crush resulted in a total loss of visual acuity as measured by the optokinetic reflex. The deficit did not show improvement during the 4 following weeks. Despite the visual cliff test showing a non-significant decrease in deep end preference 1-day post ONC, though this was not the case for subsequent test occasions. The object recognition test showed no significant trends.
Conclusions: In conclusion, the optokinetic reflex test showed a significant loss of function following the visual deficit, but no recovery. However, a complimentary pilot study shows visual recovery using lighter crush intensities. The spatial visual function does not seem to be affected by the ONC, suggesting that the object recognition and visual cliff tests, in their current design, may rely on somatosensory means of exploration.
Background: Exposure to ethanol in utero leads to several brain development disorders including retinal abnormalities whose underlying cellular pathogenesis remains elusive. We have previously reported changes in electroretinogram recordings in moderate fetal alcohol exposure (MFAE) vervet monkeys. The goal of this study is to characterize the anatomical effects of moderate MFAE during the third trimester in the vervet monkey retina.
Methods: Using immunohistochemistry and Western blots, we analyzed changes in the expression of cell-type specific proteins that may occur in the MFAE retina compared to the normal retina. We also compared the basic retinal anatomy across groups by examining retinal layering and thickness.
Results: Our main result indicates that GFAP (a potent marker of astrocytes) immunoreactivity was increased in the MFAE retina indicating strong astrogliosis. There was no obvious change in the overall anatomy in the MFAE retina and no significant differences in the mean thickness of each retinal layer. Furthermore, no significant changes in the morphology of the photoreceptors, horizontal cells, bipolar cells, and amacrines cells was observed.
Conclusions: These data indicate that astrogliosis is a consequence of prenatal alcohol exposure and might explain the reported changes in the electroretinographic responses.
Background: Our national collaborative research initiative is proposing to develop a common infrastructure for Rb research. We are proposing a novel in vivo Rb model using human Rb cells line.
Methods: The rabbit model has advantages over the mouse models: (I) the larger eye size of rabbits, similar to the human infant eye, permits a more accurate injection of the drugs and evaluation of methods of targeted intraocular drug delivery; (II) the rabbit model demonstrated similar fundus appearance and pathologic features to human Rb, including vitreous seeds of viable tumor when the retinal tumor is mid-sized, which are usually found in the late stage in mouse models. The lack of ability to eliminate vitreous seeds is a major reason of current treatment failures in Group C and D tumors; therefore, the rabbit model of Rb may be used as a model to evaluate the effectiveness and various routes of drug delivery.
Results: This is an implementation of an infrastructure for evaluating therapeutic targets. In addition, this finding enables a variety of pharmacokinetic studies, pharmacodynamic and toxicology studies for new therapeutic agents.
Conclusions: This infrastructure meets the growing concern of practitioners and researchers in the field. The common facility is easily accessible to all VHRN members on request, including requests from other sectors.
Background: Pericytes are contractile cells that wrap along the walls of capillaries. In the brain, pericytes play a crucial role in the regulation of capillary diameter and vascular blood flow in response to metabolic demand. During ischemia, it has been suggested that pericytes may constrict capillaries, and that pericytes remain constricted after reperfusion thus resulting in impaired blood flow.
Methods: Here, we used a mouse model of retinal ischemia based on ligation of the central retinal artery to characterize the role of pericytes on capillary constriction. Ischemia was induced in transgenic mice carrying the NG2 promoter driving red fluorescent protein expression to selectively visualize pericytes (line NG2:DsRed).Changes in retinal capillary diameter at 1 hr after ischemia were measured ex vivo in whole-mounted retinas from ischemic and control eyes (n=4–6/group) using a stereological approach. Vessels and pericytes were three-dimensionally reconstructed using IMARIS (Bitplane). Furthermore, we used a novel and minimally invasive two-photon microscopy approach that allowed live imaging of microvasculature changes in the retina.
Results: Our data show a generalized reduction in capillary diameter in ischemic retinas relative to sham-operated controls in all vascular plexus (ischemia: 4.7±0.2 μm, control: 5.2±0.2 μm, student’s t-test, P<0.001). Analysis of the number of capillary constrictions at pericyte locations, visualized in NG2:DsRed mice, demonstrated a substantial increase in ischemic retinas relative to the physiological capillary diameter reductions observed in controls (ischemia: 1,038±277 constrictions at pericyte locations, control: 60±36 constrictions at pericyte locations, student’s t-test, P<0.01). Live imaging using two-photon microscopy confirmed robust capillary constriction at the level of pericytes on retinal capillaries during ischemia (n=6–8/group).
Conclusions: Collectively, our data demonstrate that ischemia promotes rapid pericyte constriction on retinal capillaries causing major microvascular dysfunction in this tissue. To identify the molecular mechanisms underlying the pathological response of pericytes during ischemia, we are currently carrying out experiments in mice and zebrafish to modulate signaling pathways involved in calcium dynamics leading to contractility in these cells.
