Excessive glutamate receptor activity, principally of theN-methyl-D-aspartate (NMDA) subtype, contributes to neuronal damage in a large number of neurologic disorders, including dementia. Until recently, however, NMDA receptor antagonists had all failed in clinical trials. Stuart Lipton reviews the mechanism of action that led to the clinical approval of the first NMDA receptor antagonist, memantine, which has become the newest and one of the best-selling drugs for Alzheimer's disease. Neuroprotective drugs tested in clinical trials, particularly those that block N-methyl-D-aspartate-sensitive glutamate receptors (NMDARs), have failed miserably in large part because of intolerable side effects. However, one such drug, memantine, was recently approved by the European Union and the US FDA for the treatment of dementia following our group's discovery of its clinically tolerated mechanism of action. Here, we review the molecular basis for memantine efficacy in neurological diseases that are mediated, at least in part, by overactivation of NMDARs, producing excessive Ca2+ influx through the receptor's associated ion channel and consequent free-radical formation.

Paradigm shift in neuroprotection by NMDA receptor blockade: Memantine and beyond

The members of the Management and Therapy Subcommittee undertook an evidence-based review of current dry eye therapies and management options. Management options reviewed in detail included treatments for tear insufficiency and lid abnormalities, as well as anti-inflammatory medications, surgical approaches, dietary modifications, environmental considerations and complementary therapies. Following this extensive review it became clear that many of the treatments available for the management of dry eye disease lack the necessary Level 1 evidence to support their recommendation, often due to a lack of appropriate masking, randomization or controls and in some cases due to issues with selection bias or inadequate sample size. Reflecting on all available evidence, a staged management algorithm was derived that presents a step-wise approach to implementing the various management and therapeutic options according to disease severity. While this exercise indicated that differentiating between aqueous-deficient and evaporative dry eye disease was critical in selecting the most appropriate management strategy, it also highlighted challenges, based on the limited evidence currently available, in predicting relative benefits of specific management options, in managing the two dry eye disease subtypes. Further evidence is required to support the introduction, and continued use, of many of the treatment options currently available to manage dry eye disease, as well as to inform appropriate treatment starting points and understand treatment specificity in relation to dry eye disease subtype.

TFOS DEWS II Management and Therapy Report

OBJECTIVE: We aimed to develop consensus-based recommendations for streamlining medical communication among various health care professionals, to improve accuracy of diagnosis and treatment, and to facilitate future investigations for mucous membrane pemphigoid. PARTICIPANTS: Because of the highly specific nature of this group of diseases, the 26 invited participants included either international scholars in the field of mucous membrane pemphigoid or experts in cutaneous pharmacology representing the 3 medical disciplines ophthalmology, oral medicine, and dermatology. EVIDENCE: The first author (L.S.C.) conducted a literature search. Based on the information obtained, international experts who had contributed to the literature in the clinical care, diagnosis, and laboratory investigation for mucous membrane pemphigoid were invited to participate in a consensus meeting aimed at developing a consensus statement. CONSENSUS PROCESS: A consensus meeting was convened and conducted on May 10, 1999, in Chicago, Ill, to discuss the relevant issues. The first author drafted the statement based on the consensus developed at the meeting and the participants' written comments. The draft was submitted to all participants for 3 separate rounds of review, and disagreements were reconciled based on literature evidence. The third and final statement incorporated all relevant evidence obtained in the literature search and the consensus developed by the participants. The final statement was approved and endorsed by all 26 participants. CONCLUSIONS: Specific consensus-based recommendations were made regarding the definition, diagnostic criteria, pathogenic factors, medical treatment, and prognostic indicators for mucous membrane pemphigoid. A system of standard reporting for these patients was proposed to facilitate a uniform data collection.

The first international consensus on mucous membrane pemphigoid: definition, diagnostic criteria, pathogenic factors, medical treatment, and prognostic indicators.

Background Despite extensive knowledge regarding the diagnosis and management of keratoconus and ectatic corneal diseases, many controversies still exist. For that reason, there is a need for current guidelines for the diagnosis and management of these conditions. Purpose This project aimed to reach consensus of ophthalmology experts from around the world regarding keratoconus and ectatic diseases, focusing on their definition, concepts, clinical management, and surgical treatments. Methods The Delphi method was followed with 3 questionnaire rounds and was complemented with a face-to-face meeting. Thirty-six panelists were involved and allocated to 1 of 3 panels: definition/diagnosis, nonsurgical management, or surgical treatment. The level of agreement considered for consensus was two thirds. Results Numerous agreements were generated in definitions, methods of diagnosing, and management of keratoconus and other ectatic diseases. Nonsurgical and surgical treatments for these conditions, including the use of corneal cross-linking and corneal transplantations, were presented in a stepwise approach. A flowchart describing a logical management sequence for keratoconus was created. Conclusions This project resulted in definitions, statements, and recommendations for the diagnosis and management of keratoconus and other ectatic diseases. It also provides an insight into the current worldwide treatment of these conditions.

Global consensus on keratoconus and ectatic diseases.

Purpose To evaluate femtosecond laser lens fragmentation and anterior capsulotomy in cataract surgery. Methods Anterior capsulotomy and phacofragmentation procedures performed with an intraocular femtosecond laser (LenSx Lasers Inc) were initially evaluated in ex vivo porcine eyes. These procedures were then performed in an initial series of nine patients undergoing cataract surgery. In addition to standard intraoperative assessments (including capsulotomy diameter accuracy and reproducibility), optical coherence tomography was used to evaluate human procedures. Results For an intended 5-mm capsulorrhexis in porcine eyes, average achieved diameters were 5.88+/-0.73 mm using a standard manual technique and 5.02+/-0.04 mm using the femtosecond laser. Scanning electron microscopy revealed equally smooth cut edges of the capsulotomy with the femtosecond laser and manual technique. Compared to control porcine eyes, femtosecond laser phacofragmentation resulted in a 43% reduction in phacoemulsification power and a 51% decrease in phacoemulsification time. In a small series of human clinical procedures, femtosecond laser capsulotomies and phacofragmentation demonstrated similarly high levels of accuracy and effectiveness, with no operative complications. Conclusions Initial results with an intraocular femtosecond laser demonstrate higher precision of capsulorrhexis and reduced phacoemulsification power in porcine and human eyes.

Initial clinical evaluation of an intraocular femtosecond laser in cataract surgery.

PURPOSE The safety and efficacy of corneal collagen cross-linking (CXL) and topography-guided photorefractive keratectomy (PRK) using a different sequence and timing were evaluated in consecutive keratoconus cases. METHODS This study included a total of 325 eyes with keratoconus. Eyes were divided into two groups. The first group (n=127 eyes) underwent CXL with subsequent topography-guided PRK performed 6 months later (sequential group) and the second group (n=198 eyes) underwent CXL and PRK in a combined procedure on the same day (simultaneous group). Statistical differences were examined for pre- to postoperative changes in uncorrected (UCVA, logMAR) and best-spectacle-corrected visual acuity (BSCVA, logMAR), manifest refraction spherical equivalent (MRSE), keratometry (K), topography, central corneal thickness, endothelial cell count, corneal haze, and ectatic progression. Mean follow-up was 36+/-18 months (range: 24 to 68 months). RESULTS At last follow-up in the sequential group, the mean UCVA improved from 0.9+/-0.3 logMAR to 0.49+/-0.25 logMAR, and mean BSCVA from 0.41+/-0.25 logMAR to 0.16+/-0.22 logMAR. Mean reduction in spherical equivalent refraction was 2.50+/-1.20 diopters (D), mean haze score was 1.2+/-0.5, and mean reduction in K was 2.75+/-1.30 D. In the simultaneous group, mean UCVA improved from 0.96+/-0.2 logMAR to 0.3+/-0.2 logMAR, and mean BSCVA from 0.39+/-0.3 logMAR to 0.11+/-0.16 logMAR. Mean reduction in spherical equivalent refraction was 3.20+/-1.40 D, mean haze score was 0.5+/-0.3, and mean reduction in K was 3.50+/-1.3 D. Endothelial cell count preoperatively and at last follow-up was unchanged (P<.05) in both groups. Statistically, the simultaneous group did better (P<.05) in all fields evaluated, with improvement in UCVA and BSCVA, a greater mean reduction in spherical equivalent refraction and keratometry, and less corneal haze. CONCLUSIONS Same-day simultaneous topography-guided PRK and CXL appears to be superior to sequential CXL with later PRK in the visual rehabilitation of progressing keratoconus.

Comparison of sequential vs same-day simultaneous collagen cross-linking and topography-guided PRK for treatment of keratoconus.

PURPOSE\nThe safety and efficacy of corneal collagen cross-linking (CXL) and topography-guided photorefractive keratectomy (PRK) using a different sequence and timing were evaluated in consecutive keratoconus cases.\n\n\nMETHODS\nThis study included a total of 325 eyes with keratoconus. Eyes were divided into two groups. The first group (n=127 eyes) underwent CXL with subsequent topography-guided PRK performed 6 months later (sequential group) and the second group (n=198 eyes) underwent CXL and PRK in a combined procedure on the same day (simultaneous group). Statistical differences were examined for pre- to postoperative changes in uncorrected (UCVA, logMAR) and best-spectacle-corrected visual acuity (BSCVA, logMAR), manifest refraction spherical equivalent (MRSE), keratometry (K), topography, central corneal thickness, endothelial cell count, corneal haze, and ectatic progression. Mean follow-up was 36+/-18 months (range: 24 to 68 months).\n\n\nRESULTS\nAt last follow-up in the sequential group, the mean UCVA improved from 0.9+/-0.3 logMAR to 0.49+/-0.25 logMAR, and mean BSCVA from 0.41+/-0.25 logMAR to 0.16+/-0.22 logMAR. Mean reduction in spherical equivalent refraction was 2.50+/-1.20 diopters (D), mean haze score was 1.2+/-0.5, and mean reduction in K was 2.75+/-1.30 D. In the simultaneous group, mean UCVA improved from 0.96+/-0.2 logMAR to 0.3+/-0.2 logMAR, and mean BSCVA from 0.39+/-0.3 logMAR to 0.11+/-0.16 logMAR. Mean reduction in spherical equivalent refraction was 3.20+/-1.40 D, mean haze score was 0.5+/-0.3, and mean reduction in K was 3.50+/-1.3 D. Endothelial cell count preoperatively and at last follow-up was unchanged (P<.05) in both groups. Statistically, the simultaneous group did better (P<.05) in all fields evaluated, with improvement in UCVA and BSCVA, a greater mean reduction in spherical equivalent refraction and keratometry, and less corneal haze.\n\n\nCONCLUSIONS\nSame-day simultaneous topography-guided PRK and CXL appears to be superior to sequential CXL with later PRK in the visual rehabilitation of progressing keratoconus.

Long Term Comparison of Sequential vs. Same-Day Simultaneous Collagen Cross-Linking and Topography-Guided PRK for Treatment of Keratoconus

Purpose To evaluate the safety and efficacy of higher fluence cornea collagen cross linking (CXL). Methods Twenty-one patients with bilateral keratoconus had randomized CXL in one eye (group A) with 7 mw/cm(2) for 15 minutes; the other eye (group B) had the standard 3 mw/cm(2) for 30 minutes; 50 um PTK with the Eye-Q 400 Hz Excimer laser (Wavelight, Erlagen, Germany) was used for epithelial removal. The patients were evaluated postoperatively at the following intervals: day 1, day 4, month 1, month 3, and then every 6 months. Results FOR GROUPS A AND B RESPECTIVELY, IN MEAN VALUES: uncorrected distance visual acuity (UDVA) improved from 20/60 to 20/38, and 20/62 to 20/40; best corrected visual acuity (BCVA) from 20/30 to 20/25 in both groups; mean sphere was reduced by 2.5 and 2.1 diopters; mean cylinder was reduced by 2.9 and 2.5 diopters on average; Steepest K was reduced from 49.5 to 46.1, and from 48.7 to 45.8 diopters. There was no ectasia progression in any of the cases during the follow-up time studied. There was no change in the endothelial cell count. All patients returned to full activities postoperatively within a month. Four cases from group A and five cases from group B had delayed epithelial healing (completed by postoperative day 9). No other adverse effects were noted in any of the cases studied. Mean follow-up was 46 months (18-56). Corneal optical coherence tomography (OCT) revealed diffused light scattered in anterior two-thirds of the cornea stroma, which was more intense and much broader in diameter in group A than in group B. Conclusion This novel technique offers similar clinical results in ectasia stabilization without any adverse effects noted.

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Long term results of a prospective randomized bilateral eye comparison trial of higher fluence, shorter duration ultraviolet A radiation, and riboflavin collagen cross linking for progressive keratoconus.

PURPOSE To evaluate the safety and efficacy of modified intracorneal ring segment implantation (INTACS) in the management of moderate and advanced keratoconus (KCN). METHODS A modified procedure of intracorneal ring segment (INTACS) implantation was performed in eyes with moderate to advanced keratoconus that were intolerant to contact lens or spectacle correction. The main outcome measures were uncorrected visual acuity (UCVA), best spectacle corrected visual acuity (BSCVA), refraction, and keratometry. The preoperative values were compared with the values 6 and 12 months postoperatively. RESULTS Implantation was performed on 20 eyes of 15 patients; 9 were female and 6 were male. The mean age was 30.2 years (SD +/- 5.44; range, 23-40). At the 6-month follow-up, UCVA improved from 20/154 (SD +/- 0.11) preoperatively to 20/28 (SD +/- 0.21) postoperatively (P < 0.05); BCSVA improved from 20/37 (SD +/- 0.21) preoperatively to 20/22 (SD +/- 0.13) postoperatively (P < 0.05). Spherical refractive error improved from -3.38 D (SD +/- 3.12) to -1.15 D (SD +/- 1.84); cylindrical refractive error improved from -3.75 (SD +/- 2.04) preoperatively to -1.21 (SD +/- 0.84) postoperatively (P < 0.05); average keratometry decreased from 49.50 D (SD +/- 1.64) preoperatively to 46.35 D (SD +/- 1.50) postoperatively. The changes remained stable to the 12-month follow-up. There was 1 case of anterior chamber perforation. There were 6 eyes that had ring exposure secondary to corneal thinning over the implants 3-6 months postoperatively, and a dense corneal infiltrate developed in 1 patient at 7 months postoperatively. CONCLUSIONS The procedure appears to be effective in improving UCVA and BSCVA of patients with clinical keratoconus. In our small study group, however, there were significant (6/20) postoperative problems with regards to thinning and ring exposure.

Modified intracorneal ring segment implantations (INTACS) for the management of moderate to advanced keratoconus: efficacy and complications.

PURPOSE: To evaluate a series of patients with corneal ectasia after LASIK that underwent the Athens Protocol: combined topography-guided photorefractive keratectomy (PRK) to reduce or eliminate induced myopia and astigmatism followed by sequential, same-day ultraviolet A (UVA) corneal collagen cross-linking (CXL).

Management of Corneal Ectasia After LASIK With Combined, Same-day, Topography- guided Partial Transepithelial PRK and Collagen Cross-linking: The Athens Protocol

Anastasios John Kanellopoulos

Papers

Comparison of sequential vs same-day simultaneous collagen cross-linking and topography-guided PRK for treatment of keratoconus.

Long Term Comparison of Sequential vs. Same-Day Simultaneous Collagen Cross-Linking and Topography-Guided PRK for Treatment of Keratoconus

Long term results of a prospective randomized bilateral eye comparison trial of higher fluence, shorter duration ultraviolet A radiation, and riboflavin collagen cross linking for progressive keratoconus.

Modified intracorneal ring segment implantations (INTACS) for the management of moderate to advanced keratoconus: efficacy and complications.

Management of Corneal Ectasia After LASIK With Combined, Same-day, Topography- guided Partial Transepithelial PRK and Collagen Cross-linking: The Athens Protocol