Helen V. Danesh-Meyer

Locally administered ocular corticosteroids: benefits and risks.

Corticosteroids, used prudently, are one of the most potent and effective modalities available in the treatment of ocular inflammation. However, they can produce a plethora of adverse ocular and systemic events. In order to optimise and target drug delivery, whilst minimising systemic adverse effects, a diverse range of local ophthalmic preparations and delivery techniques have been developed. Topical drops and ointments remain the primary methods for administration of ocular corticosteroids. However, ocular penetration of topical corticosteroid drops depends upon drug concentration, chemical formulation of corticosteroid, and composition of the vehicle, therefore, apparently small modifications in preparations can produce a more than 20-fold difference in intraocular drug concentration. Periocular injections of corticosteroids continue to have a useful, but limited, therapeutic role and longer acting, intraocular delayed-release devices are in early clinical studies. Although newer corticosteroids with lesser pressure elevating characteristics have been developed, corticosteroid-induced ocular hypertension and glaucoma continue to be significant risks of local and systemic administration. Posterior subcapsular cataract, observed following as little as 4 months topical corticosteroids use, is thought to be due to covalent binding of corticosteroid to lens protein with subsequent oxidation. Inappropriate use of topical corticosteroid in the presence of corneal infections also continues to be a cause of ocular morbidity. Other risks of locally administered ophthalmic corticosteroids include: tear-film instability, epithelial toxicity, crystalline keratopathy, decreased wound strength, orbital fat atrophy, ptosis, limitation of ocular movement, inadvertent intraocular injection, and reduction in endogenous cortisol. This extensive review assesses the therapeutic benefits of locally administered ocular corticosteroids in the context of the risks of adverse effects.

Connexin43 mimetic peptide reduces vascular leak and retinal ganglion cell death following retinal ischaemia

Connexin43 gap junction protein is expressed in astrocytes and the vascular endothelium in the central nervous system. It is upregulated following central nervous system injury and is recognized as playing an important role in modulating the extent of damage. Studies that have transiently blocked connexin43 in spinal cord injury and central nervous system epileptic models have reported neuronal rescue. The purpose of this study was to investigate neuronal rescue following retinal ischaemia-reperfusion by transiently blocking connexin43 activity using a connexin43 mimetic peptide. A further aim was to evaluate the effect of transiently blocking connexin43 on vascular permeability as this is known to increase following central nervous system ischaemia. Adult male Wistar rats were exposed to 60 min of retinal ischaemia. Treatment groups consisted of no treatment, connexin43 mimetic peptide and scrambled peptide. Retinas were then evaluated at 1-2, 4, 8 and 24 h, and 7 and 21 days post-ischaemia. Evans blue dye leak from retinal blood vessels was used to assess vascular leakage. Blood vessel integrity was examined using isolectin-B4 labelling. Connexin43 levels and astrocyte activation (glial fibrillary acidic protein) were assessed using immunohistochemistry and western blot analysis. Retinal whole mounts and retinal ganglion cell counts were used to quantify neurodegeneration. An in vitro cell culture model of endothelial cell ischaemia was used to assess the effect of connexin43 mimetic peptide on endothelial cell survival and connexin43 hemichannel opening using propidium iodide dye uptake. We found that retinal ischaemia-reperfusion induced significant vascular leakage and disruption at 1-2, 4 and 24 h following injury with a peak at 4 h. Connexin43 immunoreactivity was significantly increased at 1-2, 4, 8 and 24 h post ischaemia-reperfusion injury co-localizing with activated astrocytes, Muller cells and vascular endothelial cells. Connexin43 mimetic peptide significantly reduced dye leak at 4 and 24 h. In vitro studies on endothelial cells demonstrate that endothelial cell death following hypoxia can be mediated directly by opening of connexin43 hemichannels in endothelial cells. Blocking connexin43 mediated vascular leakage using a connexin43 mimetic peptide led to increased retinal ganglion cell survival at 7 and 21 days to levels of uninjured retinas. Treatment with scrambled peptide did not result in retinal ganglion cell rescue. Pharmacological targeting of connexin43 gap junction protein by transiently blocking gap junction hemichannels following injury provides new opportunities for treatment of central nervous system ischaemia.

Reduction of optic nerve fibers in patients with Alzheimer disease identified by laser imaging

In this case-control study, we compared the optic nerves (ONs) by clinical examination and scanning laser ophthalmoscopy (SLO) of 40 patients with Alzheimer disease (AD) and 50 controls. There was a reduction in the number of ON fibers in patients with AD, with a threefold greater odds ratio for a larger optic cup-to-disc ratio in patients with AD.

In vivo retinal nerve fiber layer thickness measured by optical coherence tomography predicts visual recovery after surgery for parachiasmal tumors.

PURPOSE Restoration of visual function after neurosurgery for parachiasmal tumors is variable and unpredictable. The current study was conducted to determine whether in vivo retinal nerve fiber layer (RNFL) thickness measurements predict the visual recovery of such patients. METHODS Forty patients undergoing surgical resection of parachiasmal lesions were prospectively assessed before surgery with a neuro-ophthalmic examination, involving standard automated visual field (VF) testing and optical coherence tomography (OCT) measurements of RNFL thickness, which was the prespecified marker for axonal loss. Tests were repeated within 6 weeks after surgery. RESULTS Thinner preoperative RNFL thickness was associated with worse visual acuity (VA) and VF mean deviation (MD). Patients with normal preoperative RNFL had significant improvement in mean VA after surgery, from 20/40 to 20/25 (P = 0.028), whereas patients with thin RNFL did not improve (20/80 to 20/60, P = 0.177). Eyes with normal RNFL showed improvement in MD (-7.0 dB before surgery, -3.5 dB after surgery, P = 0.0007) unlike eyes with thin RNFLs, which had no significant improvement after surgery (-15.3 dB before and -13.3 dB after surgery, P = 0.191). RNFL thickness increased by 1% after surgery among all eyes (P = 0.04). Eyes with severe VF defects (MD </= -10 dB) but normal preoperative RNFL thickness showed a postoperative improvement in MD of 14.6 dB compared with 1.6 dB (P < 0.0001) in eyes with thin RNFL before surgery, despite no difference in MD before surgery (normal RNFL MD, -22.3 dB; thin RNFL MD, -20.8 dB; P = 0.7). CONCLUSIONS Patients who have objectively measurable RNFL loss at the time of surgery for chiasmal compressive lesions are less likely to have return of VA or VF after surgery.

Radiation-induced optic neuropathy.

Radiation-induced optic neuropathy (RION) is a devastating late complication of radiotherapy to the anterior visual pathway resulting in acute, profound, irreversible visual loss. It is thought to be a result of radiation necrosis of the anterior visual pathway. Visual loss may be unilateral or bilateral; simultaneous or sequential. RION occurs commonly between 10-20 months, with an average of 18 months after treatment; but the onset may range from three months to 9 years. Cumulative doses of radiation that exceed 50 Gy or single doses to the anterior visual pathway or greater than 10 Gy are usually required for RION to develop. Several factors are associated with a higher risk for developing RION or for RION occurring with lower total doses of radiation. These include age, pre-existing compression of the optic nerve and chiasm by tumour, concurrent chemotherapy or previous external beam radiation. MRI, the investigation of choice for identifying radiation injury to the visual pathway, may show abnormalities before the loss of vision. Typically, the unenhanced T1- and T2-weighted images show no abnormality, but the optic nerve will show enhancement on T1-weighted images with MRI. Treatment with systemic corticosteroids, anticoagulation and hyperbaric oxygen has been generally unsuccessful and disappointing. If visual dysfunction is detected early, hyperbaric oxygen might be beneficial if treatment is initiated within 72 hours of visual loss. Because of the poor prognosis associated with RION, the risk of its potential development should be factored into the decision to irradiate the brain.

Neuroprotection in glaucoma: recent and future directions.

Purpose of review The concept of neuroprotective therapy for glaucoma is that damage to retinal ganglion cells (RGCs) may be prevented by intervening in neuronal death pathways. This review focuses on strategies for neuroprotection and summarizes preclinical studies that have investigated potential agents over the last 2 years. Recent findings Part of the challenge of studies in neuroprotection has been the utilization of an animal model that resembles human glaucoma. Several models have been utilized including acute and chronic intraocular pressure elevation, the DBA/2J mouse, optic nerve axotomy and crush. NMDA inhibitors continued to be explored however with limited success in human trials. Memantine failed to demonstrate neuroprotection in phase III clinical trials. Although its mechanism of neuroprotection has not been fully elaborated, topical brimonidine has shown some neuroprotective benefits. Exogeneous neurotrophins delay, but do not prevent, RGC death. Bioenergetic neuroprotection that is enhancing the energy supply to RGC has been explored with benefits in animal models. Other strategies include TNF-α, modulation of the immune system and inflammation, and blocking apoptotic signals and stem cells. Summary Animal models of glaucoma and neuroprotective strategies continue to be refined. Establishing consensus guidelines for the execution and design of translational research in neuroprotection may optimize the facilitation of neuroprotection research.

Comparison of intraocular pressure measured by Pascal dynamic contour tonometry and Goldmann applanation tonometry

AimsTo compare the intraocular pressure (IOP) measurements obtained using the Pascal dynamic contour tonometer (PDCT) with the standard Goldmann applanation tonometer (GAT) and to correlate these with central corneal thickness (CCT) in patients with normal corneas.MethodsA prospective, masked, comparative case series of 116 eyes from patients attending a glaucoma clinic. IOP was measured with PDCT by one examiner and with GAT by a masked, independent examiner. A mean of six CCT readings was used for analysis.ResultsIOP measured by the two instruments correlated significantly (r=0.77; P<0.0001). IOP measured by GAT correlated strongly with CCT (r=0.37, P=0.0001) whereas the relationship between IOP measured by PDCT and CCT approached significance (r=0.17, P=0.073). The differences between GAT and PDCT measured IOP also correlated strongly with CCT (r=0.37, P<0.0001). The 95% limits of agreement between GAT and PDCT were ±4.2 mmHg. Dividing the eyes into three groups on the basis of CCT, demonstrated those in the thickest tertile showed a poorer agreement between instruments and the GAT measured significantly higher IOP in this group (P=0.003) while the PDCT showed no significant differences with different CCTs (P=0.37).ConclusionDemonstration of the relative independence of PDCT IOP measurements from CCT supports a potential clinical role for this instrument, particularly for subjects with CCT outside the normal range.

Low diagnostic yield with second biopsies in suspected giant cell arteritis.

Objectives: The clinical diagnosis of giant cell arteritis may be confirmed with a biopsy of the superficial temporal artery. Because of “skip lesions,” a histologic diagnosis of giant cell arteritis may be missed with a unilateral biopsy. The authors report a study that investigates whether a biopsy of the contralateral superficial temporal artery provides any additional information for confirmation of a diagnosis of giant cell arteritis. Methods: Available medical records of 91 consecutive patients who underwent bilateral superficial temporal artery biopsy procedures were reviewed. Information that was abstracted included sequence of biopsy procedures, length specimens, and histologic diagnosis. Microslides from all biopsy specimens were retrieved and reexamined in a masked fashion by the ocular pathologist (RCE) who had made the original diagnoses. Results: Seventy‐two bilateral simultaneous superficial temporal artery biopsies and 19 bilateral sequential biopsies were performed. The mean length of biopsy specimens was 23 mm, and the mean length of the total artery removed from each patient was 33 mm. The pathologists original diagnosis and the diagnosis at reexamination were in 100% agreement. In 90 (99%) of the 91 patients, the histologic diagnoses in the left and right superficial temporal arteries were the same. This is a concordance rate of 98.9% (38 of 39 positive biopsy results) among the positive biopsy results. Conclusion: There is a low yield of information from a second temporal artery biopsy in patients with suspected giant cell arteritis. This suggests that patients who present to the ophthalmologist with possible giant cell arteritis will, in most cases, have a similar diagnosis on both temporal artery biopsies if the specimens are adequate.

Role of connexin43 in central nervous system injury.

Gap junctions are specialized cell-to-cell contacts that provide direct intercellular communication. In the central nervous system (CNS), gap junction coupling occurs between both neurons and glial cells. One of the most abundant gap junction proteins in the CNS is connexin43 (Cx43). The functional syncytium formed by astrocytes via Cx43 gap junction intercellular communication has, for example, been implicated in maintaining the homeostasis of the extracellular milieu of neurons. In particular, astrocytes are involved in the spatial buffering of many ions, signalling molecules and energy sources. In this review, the role of Cx43 following CNS injury is examined by combining evidence surrounding the response of Cx43 to CNS injury and the effects of Cx43 gap junction blockade on neuronal survival in various models of injury. Combined evidence suggests that transient blockade targeting the window of initial Cx43 upregulation observed following injury is potentially therapeutic.

Non-arteritic anterior ischaemic optic neuropathy: A review and update

Non-arteritic anterior ischaemic optic neuropathy (NAION) is the most common acute optic neuropathy in people aged 50 years and older. The condition is caused by infarction of the laminar or retrolaminar portion of the optic nerve head supplied by the short posterior ciliary arteries (SPCAs). The underlying aetiology and pathophysiology is poorly elucidated. Factors that have been implicated include nocturnal hypotension, impaired autoregulation of the microvascular supply, vasculopathic occlusion, and venous insufficiency. These factors are thought to result in axonal oedema causing a compartment syndrome in a structurally crowded optic disc leading to axonal degeneration and loss of retinal ganglion cells via apoptosis. Clinically NAION is characterised by sudden, usually painless, loss of vision in one or both eyes. Examination findings include decreased visual acuity, a visual field defect, decreased colour vision, a relative afferent pupillary defect, and optic disc swelling. Despite significant research, treatment options for NAION remain limited.