50 Years of Image Analysis

Ocular drug delivery has been a major challenge to pharmacologists and drug delivery scientists due to its unique anatomy and physiology. Static barriers (different layers of cornea, sclera, and retina including blood aqueous and blood–retinal barriers), dynamic barriers (choroidal and conjunctival blood flow, lymphatic clearance, and tear dilution), and efflux pumps in conjunction pose a significant challenge for delivery of a drug alone or in a dosage form, especially to the posterior segment. Identification of influx transporters on various ocular tissues and designing a transporter-targeted delivery of a parent drug has gathered momentum in recent years. Parallelly, colloidal dosage forms such as nanoparticles, nanomicelles, liposomes, and microemulsions have been widely explored to overcome various static and dynamic barriers. Novel drug delivery strategies such as bioadhesive gels and fibrin sealant-based approaches were developed to sustain drug levels at the target site. Designing noninvasive sustained drug delivery systems and exploring the feasibility of topical application to deliver drugs to the posterior segment may drastically improve drug delivery in the years to come. Current developments in the field of ophthalmic drug delivery promise a significant improvement in overcoming the challenges posed by various anterior and posterior segment diseases.

Ocular Drug Delivery

PURPOSE\nTo measure macular choroidal thickness in normal eyes at different points using enhanced depth imaging (EDI) optical coherence tomography (OCT) and to evaluate the association of choroidal thickness and age.\n\n\nDESIGN\nRetrospective, observational case series.\n\n\nMETHODS\nEDI OCT images were obtained in patients without significant retinal or choroidal pathologic features. The images were obtained by positioning a spectral-domain OCT device close enough to the eye to acquire an inverted image. Seven sections were obtained within a 5 x 30-degree area centered at the fovea, with 100 scans averaged for each section. The choroid was measured from the outer border of the retinal pigment epithelium to the inner scleral border at 500-microm intervals of a horizontal section from 3 mm temporal to the fovea to 3 mm nasal to the fovea. Statistical analysis was performed to evaluate variations of choroidal thickness at each location and to correlate choroidal thickness and patient age.\n\n\nRESULTS\nThe mean age of the 30 patients (54 eyes) was 50.4 years (range, 19 to 85 years), and 14 patients (46.7%) were female. The choroid was thickest underneath the fovea (mean, 287 microm; standard deviation, +/- 76 microm). Choroidal thickness decreased rapidly in the nasal direction and averaged 145 microm (+/- 57 microm) at 3 mm nasal to the fovea. Increasing age was correlated significantly with decreasing choroidal thickness at all points measured. Regression analysis suggested that the subfoveal choroidal thickness decreased by 15.6 microm for each decade of life.\n\n\nCONCLUSIONS\nChoroidal thickness seems to vary topographically within the posterior pole. The thickness of the choroid showed a negative correlation with age. The decrease in the thickness of the choroid may play a role in the pathophysiologic features of various age-related ocular conditions.

Enhanced Depth Imaging Optical Coherence Tomography of the Choroid in Normal Eyes

Glaucoma is an optic neuropathy that is characterized by the progressive degeneration of the optic nerve, leading to visual impairment. Glaucoma is the main cause of irreversible blindness worldwide, but typically remains asymptomatic until very severe. Open-angle glaucoma comprises the majority of cases in the United States and western Europe, of which, primary open-angle glaucoma (POAG) is the most common type. By contrast, in China and other Asian countries, angle-closure glaucoma is highly prevalent. These two types of glaucoma are characterized based on the anatomic configuration of the aqueous humour outflow pathway. The pathophysiology of POAG is not well understood, but it is an optic neuropathy that is thought to be associated with intraocular pressure (IOP)-related damage to the optic nerve head and resultant loss of retinal ganglion cells (RGCs). POAG is generally diagnosed during routine eye examination, which includes fundoscopic evaluation and visual field assessment (using perimetry). An increase in IOP, measured by tonometry, is not essential for diagnosis. Management of POAG includes topical drug therapies and surgery to reduce IOP, although new therapies targeting neuroprotection of RGCs and axonal regeneration are under development.

Primary open-angle glaucoma.

"Graefe's Archive" is a distinguished international journal that presents original clinical reports and clinically relevant experimental studies. Founded in 1854 by Albrecht von Graefe to serve as a source of useful clinical information and a stimulus for discussion, the journal has published articles by leading ophthalmologists and vision research scientists for more than a century. With peer review by an international Editorial Board and prompt English-language publication, "Graefe's Archive" provides rapid dissemination of clinical and clinically related experimental information.

Graefe's archive for clinical and experimental ophthalmology

We analysed all of the PubMed publications on ab-interno trabeculectomy (AIT) with the Trabectome (Neomedix, Irvine, California, USA) to determine the reduction in intraocular pressure (IOP) and medications following the procedure. For IOP outcomes, PubMed was searched for ‘trabectome’, ‘ab interno trabeculotomy’ and ‘ab interno trabeculectomy’ and all available papers retrieved. The meta-analysis used a random-effects model to achieve conservative estimates and assess statistical heterogeneity. To investigate complications, we included all abstracts from the American Glaucoma Society, American Academy of Ophthalmology, American Society of Cataract and Refractive Surgery and the Association for Research in Vision and Ophthalmology. The overall arithmetic mean baseline IOP for standalone Trabectome was 26.71±1.34 mm Hg and decreased by 10.5±1.9 mm Hg (39% decrease) on 0.99±0.54 fewer medications. Defining success as IOP ≤21 with a 20% decrease while avoiding reoperation, the overall average success rate after 2 years was 46±34%. For combined phacoemulsification-Trabectome, the baseline IOP of 21±1.31 mm Hg decreased by 6.24±1.98 mm Hg (27% decrease) on 0.76±0.35 fewer medications. The success rate using the same definition at 2 years was 85±7%. The weighted mean IOP difference from baseline to study endpoint was 9.77 mm Hg (95% CI 8.90 to 10.64) standalone and 6.04 mm Hg (95% CI 4.95 to 7.13) for combined cases. Despite heterogeneity, meta-analysis showed significant and consistent decrease in IOP and medications from baseline to end point in AIT and phaco-AIT. The rate of visually threatening complications was

https://bjo.bmj.com/content/bjophthalmol/100/5/594.full.pdf

Review and meta-analysis of ab-interno trabeculectomy outcomes

Aim To analyse ab interno trabeculectomy (AIT) with the trabectome and combined phacoemulsification with AIT (phaco-AIT) by Shaffer angle grade (SG). Methods Prospective study of AIT and phaco-AIT with narrow angles of SG≤2 versus open angles ≥3. Outcomes included intraocular pressure (IOP), medications, complications, secondary surgery and success (IOP 20% reduction without further surgery). Exclusion criteria were missing preoperative data and 0.05). Conclusions SG≤2 is not associated with worse outcomes in AIT or phaco-AIT.

https://bjo.bmj.com/content/bjophthalmol/99/7/914.full.pdf

Outcomes of ab interno trabeculectomy with the trabectome by degree of angle opening.

Aim To evaluate outcomes of ab interno trabeculectomy (AIT) with the trabectome following failed trabeculectomy Methods Prospective study of AITs and phaco-AITs after a failed trabeculectomy The indication for AIT was intraocular pressure (IOP) above target on maximally tolerated therapy, and for phaco-AIT a visually significant cataract and need to lower IOP or glaucoma medications Outcomes included IOP, medications, complications, secondary procedures and success, defined as IOP of less than 21 mm Hg and a greater than 20% reduction from baseline without further surgery Exclusion criteria were trabeculectomy less than 3 months prior to AIT or follow-up under 1 year Results Seventy-three eyes of 73 patients with 1 year follow-up were identified At 1 year, mean IOP in AIT significantly decreased by 28% from 237±55 mm Hg, and medications from 28±12 to 2±13 (n=58) In phaco-AIT, the mean IOP decreased 19% from 20±59 mm Hg and medications from 25±15 to 16±14 (n=15) Transient hypotony occurred in 7%, and further surgery was necessary in 18% For AIT and phaco-AIT, the 1-year cumulative probability of success was 81% and 87%, respectively Conclusions Both AIT and phaco-AIT showed a reduction in IOP and medication use after 1 year, suggesting that AIT with or without cataract surgery is a safe and effective option following failed trabeculectomy

https://bjo.bmj.com/content/bjophthalmol/99/2/258.full.pdf

Outcomes of ab interno trabeculectomy with the trabectome after failed trabeculectomy

Age is an established major risk factor for glaucoma that can be used along with other data to compute chances of developing glaucoma. This leading cause of blindness is becoming increasingly more prevalent in the aging population. The characteristic progressive degeneration of the optic nerve in glaucoma is primarily caused by increased intraocular pressure yet the cause for the reduced outflow is not well understood. Early diagnosis of glaucoma remains difficult. Classic treatment can delay progression of glaucomatous optic neuropathy by lowering intraocular pressure medically or surgically. Recent insights into the age-related molecular changes of the outflow tract and retinal ganglion cells have encouraged search for new treatment approaches. New findings suggest that age related tissue changes themselves contribute significantly and are not just associated. Interdisciplinary research will be necessary to advance understanding, diagnosis and treatment of this neurodegenerative disease that has been known for more than thousand years but to this date remains a challenge.

Glaucoma and Aging

Minimally invasive glaucoma surgeries (MIGS) can improve the conventional, pressure-dependent outflow by bypassing or ablating the trabecular meshwork (TM), or creating alternative drainage routes into the suprachoroidal or subconjunctival space. They have a highly favourable risk profile compared to penetrating surgeries, and lower intraocular pressure with variable efficacy that may depend on the extent of outflow segments accessed. Since they are highly standardised procedures that use clear corneal incisions, they can elegantly be combined with cataract and refractive procedures to improve vision in the same session. There is a growing need for surgeons to become proficient in MIGS to address the increasing prevalence of glaucoma and cataracts in a well-informed, aging population. Techniques of visualisation and instrumentation in an anatomically highly confined space with semitransparent tissues are fundamentally different from other anterior segment surgeries, and present even experienced surgeons with a substantial learning curve. Here, we provide practical tips, and review techniques and outcomes of TM bypass and ablation MIGS.

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Nils A. Loewen

Papers

Review and meta-analysis of ab-interno trabeculectomy outcomes

Outcomes of ab interno trabeculectomy with the trabectome by degree of angle opening.

Outcomes of ab interno trabeculectomy with the trabectome after failed trabeculectomy

Glaucoma and Aging

Techniques and outcomes of minimally invasive trabecular ablation and bypass surgery