The Oskar Fehr Lecture.

PURPOSE: The first Oskar Fehr lecture is given in honour of Professor Fehr, a well respected ophthalmologist, who was head physician of the Department of Eye Diseases at the Rudolf Virchow Hospital from 1918. He practiced there until 1938, when he was forbidden to enter the clinic because he was Jewish and subject to the anti-Semitic laws that were instituted after the rise of the Nazi party. Dr. Fehr escaped to Great Britain, where he practiced ophthalmology into his eighties. He was the first to distinguish between granular corneal dystrophy, lattice corneal dystrophy and macular corneal dystrophy. The topic of the first Oskar Fehr lecture is Schnyder corneal dystrophy (SCD), an autosomal dominantly inherited corneal dystrophy associated with abnormal cholesterol deposition in the cornea. METHODS: The clinical, histopathologic and genetic findings of 115 individuals with SCD followed over 18 years are discussed. The impact of systemic cholesterol metabolism on other diseases is reviewed. RESULTS: Corneal findings in SCD are predictable on the basis of patient age. All patients develop progressive corneal haze because of abnormal deposition of corneal lipid, but only half of patients with SCD have evidence of corneal crystals. The prior name for this disease, Schnyder crystalline corneal dystrophy, led me to create the International Committee for the Classification of Corneal Dystrophies, in order to create a more up-to-date and accurate nomenclature for SCD and other corneal dystrophies. The name was then changed to Schnyder corneal dystrophy. Histopathology of excised SCD corneas demonstrates abnormal deposition of only HDL cholesterol. Mutations in the UBIAD1 gene result in SCD. Three dimensional protein modeling shows that mutations result in impaired vitamin K synthesis, suggesting a common link between vitamin K and cholesterol metabolism. UBIAD1 mutations are associated with other diseases, such as bladder carcinoma and Parkinson's disease like findings in Drosophila. CONCLUSIONS: Studies of the cause of SCD have led to the discovery of UBIAD1 gene mutations; further work has demonstrated the systemic importance of this gene. The association of vitamin K metabolism and cholesterol metabolism may give us insight into other diseases, so that SCD research may also have implications beyond ophthalmology.

[The IC3D classification of the corneal dystrophies]. / IC3D-Klassifikation von Hornhautdystrophien.

BACKGROUND: The recent availability of genetic analyses has demonstrated the shortcomings of the current phenotypic method of corneal dystrophy classification. Abnormalities in different genes can cause a single phenotype, whereas different defects in a single gene can cause different phenotypes. Some disorders termed corneal dystrophies do not appear to have a genetic basis. PURPOSE: The purpose of this study was to develop a new classification system for corneal dystrophies, integrating up-to-date information on phenotypic description, pathologic examination, and genetic analysis. METHODS: The International Committee for Classification of Corneal Dystrophies (IC3D) was created to devise a current and accurate nomenclature. RESULTS: This anatomic classification continues to organize dystrophies according to the level chiefly affected. Each dystrophy has a template summarizing genetic, clinical, and pathologic information. A category number from 1 through 4 is assigned, reflecting the level of evidence supporting the existence of a given dystrophy. The most defined dystrophies belong to category 1 (a well-defined corneal dystrophy in which a gene has been mapped and identified and specific mutations are known) and the least defined belong to category 4 (a suspected dystrophy where the clinical and genetic evidence is not yet convincing). The nomenclature may be updated over time as new information regarding the dystrophies becomes available. CONCLUSIONS: The IC3D Classification of Corneal Dystrophies is a new classification system that incorporates many aspects of the traditional definitions of corneal dystrophies with new genetic, clinical, and pathologic information. Standardized templates provide key information that includes a level of evidence for there being a corneal dystrophy. The system is user-friendly and upgradeable and can be retrieved on the website www.corneasociety.org/ic3d .

Review of prevalence and outcome of vascular disease in patients with diabetes mellitus.

OBJECTIVES: Review the literature to determine the prevalence and outcome in patients with diabetes that undergo surgery to correct carotid artery stenosis, lower extremity arterial disease, and abdominal aortic aneurysm (AAA). DESIGN AND MATERIALS: Studies were obtained from searches over the past 15 years on the National Library of Medicine's online search engine. RESULTS: The review demonstrated an equivalent prevalence of carotid artery stenosis requiring surgery in patients with diabetes, it favored no increase risk of post-CEA stroke, and it was split on perioperative morbidity and mortality risk. There was an increase prevalence of lower extremity arterial disease requiring surgery in patients with diabetes, it favored equivalent patency and limb salvage rates, and it was split on the morbidity and mortality risk. The review demonstrated a decrease in AAA prevalence among patients with diabetes, it found an increase in the morbidity risk, and equivalent mortality risk. CONCLUSIONS: Stroke, graft patency, and limb salvage rates in patients with diabetes after surgery are similar to patients without diabetes; however, their risk of complications is increased after surgery and the mortality risk may be higher after CEA.

[Schnyder's crystalline corneal dystrophy. Further narrowing of the linkage interval at chromosome 1p34.1-p36?]. / Schnydersche kristalline Hornhautdystrophie. Weitere Eingrenzung des Kopplungsintervalls auf Chromosom 1p34.1-p36?

BACKGROUND: Schnyder's crystalline corneal dystrophy (SCCD) is a rare autosomal dominant disease and can occur in association with hyperlipoproteinemia. The disease has been mapped to chromosome 1p34.1-p36. CASE REPORT: We report on a 66-year-old woman and her son with Schnyder's crystalline corneal dystrophy. The mother had type IV hyperlipoproteinemia and hypercholesterolemia while her son had hypercholesterolemia with elevated LDL-cholesterol. Analysis of microsatellite markers within the candidate interval of 1p34.1-p36 showed that the affected son and his unaffected brother had inherited different alleles only for the proximal marker D1S228 from their affected mother. CONCLUSIONS: The haplotype analysis suggests that either recombination has occurred, which would allow the candidate interval to be narrowed down, or alternatively, the SCCD in the reported family is not linked to chromosome 1, which would be a first indication of genetic heterogeneity in this disease. To reduce the risk of cardiovascular disease, hyperlipidemia should always be excluded in patients with Schnyder's crystalline corneal dystrophy.

5-fluorouracil 0.5% cream for multiple actinic or solar keratoses of the face and anterior scalp.

Carac (5-fluorouracil 0.5% cream, Aventis Pharma) was approved by the US FDA in October 2000, for the treatment of multiple actinic or solar keratoses involving the face and anterior scalp. The cream should be applied in a thin film once daily to the skin where actinic keratoses (AKs) are present. When it is applied for 1, 2, or 4 weeks, it is significantly more effective than a vehicle in the management of patients with five or more AKs at pretherapy. Pooled data from the two pivotal trials (n=384) indicate that following 4 weeks of therapy the number of subjects with total AK clearance in the Carac and vehicle groups was 52.9% and 1.6% respectively (p<0.001). Furthermore, the corresponding reduction of AK lesion counts in the Carac and vehicle groups was 82.5% and 19.3%, respectively (p<0.001). Treatment should be continued up to 4 weeks as tolerated by the patient. The most common adverse-effect is facial irritation.

A double-blind, placebo-controlled study of topical tetracaine in the treatment of herpes labialis.

BACKGROUND: Before the September 1996 approval of 1% penciclovir cream for the treatment of herpes labialis, no other prescription topical therapy was approved for the treatment of this recurrent viral disease affecting approximately 20% of the adult population of the United States. Local anesthetics, such as tetracaine, have been used in over-the-counter topical products, but are only labeled for the relief of pain and itching associated with cold sores and fever blisters. OBJECTIVE: The purpose of this study was to determine whether a topical preparation of a tetracaine cream is safe and effective in the treatment of recurrent herpes labialis in immunocompetent patients. METHODS: A double-blind, placebo-controlled study was conducted to assess the relative effectiveness and safety of 1.8% tetracaine equivalent in a cream base versus placebo in the treatment of herpes labialis in immunocompetent adults. In this study, patients applied medication up to 6 times daily until the lesions healed (scab loss), but for no more than 12 days. The patients were monitored on the day of enrollment, once during the course of treatment, and at a final visit after the lesions had healed. Patients assessed themselves the day of scab formation and the day the scab fell off. They also graded, on a daily basis, their perception of relief from itching and pain and the overall benefit. RESULTS: The results from 72 patients (35 = placebo; 37 = active) showed that scab formation occurred in a mean of 2.4 +/- 0.27 days for the placebo group and 2. 3 +/- 0.26 days for the active group. Healing time (scab loss) occurred in a mean 7.2 +/- 0.36 days for the placebo group and in 5. 1 +/- 0.35 days in the active group. The difference observed for healing time between the placebo and the active tetracaine cream was statistically significant (P =.0002). This represents an approximately 30% reduction in the healing time for the active group compared with the placebo group. In addition, the study patients ranked the benefit of their treatment on a daily basis and graded the overall benefit of the therapy at their final visit. The ranking was on a 1 to 10 index scale (1 = no benefit at all; 10 = very effective treatment). At the final visit there was a statistically significant difference in the benefit index for active preparation versus placebo for this subjective evaluation (placebo index, 5.9 +/- 0.6; active index, 7.3 +/- 0.48 [P =.0359]). The subjects also evaluated relief from itching and pain on a daily basis. Relief from itching was significantly greater in the active group than in the placebo group on days 2 and 3 after initiation of the treatment. Pain was not found to be severe in either the placebo or active treatment groups. At day 2 of treatment and beyond, pain scores never were greater than 3.2 +/- 0.28 for active on a scale in which 1.0 represented "no pain at all" and 10 represented "most severe pain imaginable." Although mean values for pain were always less for the active therapy, lesional pain scores never reached statistically significant lower values for active compared with placebo. CONCLUSION: Our findings indicate that a 1.8% topical tetracaine cream, when applied frequently, significantly reduces the healing time of recurrent herpes labialis lesions. Additionally, it is perceived by the study subjects to reduce itching of the lesions and to have a beneficial overall effect.

In vivo confocal microscopy of a family with Schnyder crystalline corneal dystrophy.

OBJECTIVE: To analyze corneal morphology in Schnyder crystalline corneal dystrophy (SCCD) in vivo. DESIGN: Observational case series. PARTICIPANTS: Five eyes of four patients of various belonging to the same family were examined. METHODS: The eyes were examined using in vivo confocal microscopy (CM). MAIN OUTCOME MEASURES: The corneal morphology including keratocytes and stromal extracellular matrix, as well as basal epithelial/subepithelial nerves is, described. RESULTS: The right eye of a 48-year-old male patient had been treated with anterior keratectomy and the left eye with phototherapeutic keratectomy (PTK). The right eye presented with increased stromal reflectivity owing to accumulation of extracellular matrix and large subepithelial crystalline deposits. Far fewer crystals could be observed in the left eye. The haze, however, was increased, either because of the dystrophy or the excimer laser treatment. The anterior keratocytes appeared irregular, and the subepithelial nerves were undetectable in both eyes. His 78-year-old mother showed more advanced changes with dense crystals, highly fibrotic stroma, and severely damaged corneal innervation. The partly irregular anterior keratocytes of the 9- and 7-year-old children contained intracellular deposits, although the corneas were clinically clear with only subtle subepithelial crystalline formation. Accumulation of similar reflective material was also observed in association with the prominent subepithelial nerves. CONCLUSIONS: In the early stages of SCCD, highly reflective deposits accumulate intracellularly and around anterior keratocytes and along subepithelial nerves. With time, the normal corneal architecture becomes disturbed by large extracellular crystalline deposits and accumulation of highly reflective extracellular matrix resulting in central opacity and disruption of the subepithelial nerve plexus. Furthermore, neural regeneration after keratectomy appears delayed in SCCD.

Assessment of corneal decompensation in eyes having undergone molteno shunt procedures compared to eyes having undergone trabeculectomy.

PURPOSE: To compare the incidence of corneal decompensation after Molteno shunt to trabeculectomy. METHODS: We conducted a retrospective analysis of the corneal status of 55 patients with primary open angle glaucoma. We compared 24 eyes of 24 patients who underwent Molteno tube shunt placement (Group 1) to fifteen eyes of 14 patients with multiple surgical procedures, including a trabeculectomy (Group 2). We also compared Group 1 to 28 eyes of 17 patients who underwent only one trabeculectomy (Group 3). RESULTS: The three groups were similar with respect to age, sex, and intraocular pressure (IOP). The average follow-up time from the last surgery in Group 1 was 17.9 months (1-90 months), 22.4 months (2-63 months) in Group 2, and 19.6 months (1-37 months) in Group 3. The average number of surgeries was 3.0 (1-4) in Group 1 and 2.53 (1-4) in Group 2. The surgeries included trabeculectomy, cataract extraction, combined procedures, penetrating keratoplasty, pars plana vitrectomy, and scleral buckle. The incidence of corneal edema was 50% (12/24)in Group 1, 6.7% (1/15) in Group 2, and 0% in Group 3 (0/28). The average time to corneal decompensation was 21 months in Group 1 (1-120 months) and 15 months in Group 2. CONCLUSION: Patients undergoing Molteno shunt placement have a higher rate of corneal decompensation compared to patients undergoing trabeculectomy.

An analysis of the accuracy of predicted corneal acuity in the Holladay diagnostic summary program.

PURPOSE: To determine the accuracy of the predicted corneal acuity (PCA) as determined by the Holladay diagnostic summary corneal topography program, if the cornea is the limiting factor in vision and the posterior segment is normal. METHODS: We compared the PCA with the best corrected visual acuity (BCVA) in 10 normal eyes and 10 eyes with corneal abnormalities, including prior penetrating keratoplasty, corneal scarring, and keratoconus. RESULTS: The PCA was consistent with the BCVA in all 10 of the normal eyes. The PCA was less consistent with the BCVA in all eyes with corneal abnormalities. The PCA was least accurate in patients with high amounts of irregular astigmatism and/or low corneal uniformity indices. CONCLUSIONS: The PCA appears to be most useful in predicting the BCVA in patients with normal corneas but is less effective in predicting the BCVA in patients with corneal abnormalities.

Clinical efficacy and safety comparison of adapalene gel and tretinoin gel in the treatment of acne vulgaris: Europe and U.S. multicenter trials.

BACKGROUND: Adapalene is a new chemical entity that exhibits tretinoin-like activities in the terminal differentiation process. OBJECTIVE: We evaluated a dose range effect of two concentrations of adapalene gel as acne treatment and compared adapalene 0.1% gel with tretinoin 0.025% gel in the treatment of acne patients in two large multicenter studies. METHODS: Multicenter, investigator-masked, parallel group studies including 89 acne patients in the dose range study and 591 patients in the concurrent controlled studies were conducted. RESULTS: Adapalene gel 0.1% was significantly more effective in treating acne lesions than 0.03% adapalene gel. Adapalene gel 0.1% was significantly more effective than 0.025% or tretinoin gel in one study and of the same effectiveness in the other study. Adapalene gel was always better tolerated than tretinoin gel. CONCLUSION: Adapalene 0.1% gel is a safe and effective treatment of acne vulgaris.

QT interval dispersion in healthy subjects and survivors of sudden cardiac death: circadian variation in a twenty-four-hour assessment.

Twenty-four-hour acquisition of QT dispersion (QTd) from the Holter and the circadian variation of QTd were evaluated in 20 survivors of sudden cardiac death (SCD), in 20 healthy subjects, and in 14 control patients without a history of cardiac arrest who were age, sex, diagnosis and therapy matched to 14 SCD patients. Computer-assisted QT measurements were performed on 24-hour Holter recordings; each recording was divided into 288 5-minute segments and templates representing the average QRST were generated. QTd was calculated as the difference between QT intervals in leads V1 and V5 for each template on Holter. The 24-hour mean QTd was significantly greater in SCD patients (40 +/- 28 ms) than in healthy subjects (20 +/- 10 ms) and control patients (15 +/- 5 ms) (p <0.05). There was a circadian variation in QTd with greater values at night (0 to 6 A.M.) than at daytime (10 A.M. to 4 P.M.) in healthy subjects (25 +/- 13 vs 15 +/- 8 ms, p <0.001) and control patients (18 +/- 10 vs 12 +/- 4 ms p <0.05), whereas in SCD patients there was no significant difference between night and day values (45 +/- 31 vs 37 +/- 28 ms, p = NS). It is concluded that QTd measured by Holter was greater in SCD patients than in healthy subjects and matched control patients during the entire day. QTd has a clear circadian variation in normal subjects, whereas this variation is blunted in SCD patients. QTd measured on Holter differentiates survivors of cardiac arrest and may be a useful tool for risk stratification.

Current options for the topical treatment of acne vulgaris.

The etiopathogenesis of acne vulgaris, a common disorder of youth and adolescence, includes four primary processes: hyperkeratinization (plugging) of the pilosebacous follicles, increased testosterone levels, bacterial colonization with Propionibacterium acnes, and inflammation. No single agent has yet been developed that addresses all of these factors. Combination regimens, therefore, which usually include an antibiotic and an agent to reduce follicular plugging, have become the mainstay of treatment. Despite a relative dearth of new treatments for almost a decade, recent research has produced a number of new significant oral and topical agents. Azelaic acid, a naturally occurring dicarboxylic acid analogue, has shown promise, and a group of retinoids that include adapalene, tazarotene, and reformulations of tretinoin represent new and forthcoming agents for topical treatment of acne vulgaris. Some studies indicate that several of these agents are associated with less skin irritation than previous formulations while they retain potent comedolytic activity. Adapalene also possesses significant anti-inflammatory activity.

The gene for schnyder's crystalline corneal dystrophy maps to human chromosome 1p34.1-p36.

Schnyder's crystalline corneal dystrophy (SCCD) is an autosomal dominant eye disease characterized by a bilateral clouding of the central cornea, arcus lipoides and/or visible crystalline deposits of cholesterol in the stroma. There is accumulation of phospholipid, unesterified cholesterol and cholesterol ester in the corneal stroma; this is believed to be due to an imbalance in the local factors affecting lipid/cholesterol transport or metabolism. The cellular mechanism of abnormal lipid transport and metabolism in SCCD is of interest due to its potential involvement in atherosclerosis, and its implications for the pathogenesis of cerebrovascular, coronary and peripheral vascular disease as well as corneal opacification. To determine the chromosomal location of the SCCD locus, genome-wide linkage analysis has been performed in two large Swede-Finn kindreds recently identified in central Massachusetts. After analysing 300 microsatellite markers > 90% of the genome was excluded from linkage to the SCCD locus. We now report the chromosomal assignment of the gene for SCCD in both families to be 1p34.1-p36; the maximum multipoint lod-score was 8.48 in the interval between D1S214 and D1S503. From haplotype analysis, the SCCD locus lies in the 16 cM interval between markers D1S2663 and D1S228. Several candidate genes for SCCD have been localized to the 1p34.1-p36 interval.

Accumulation of HDL apolipoproteins accompanies abnormal cholesterol accumulation in Schnyder's corneal dystrophy.

Schnyder's corneal dystrophy is an autosomal dominant disorder that results in clouding of the central cornea and premature development of peripheral arcus in the cornea. Previous studies showed that abnormal lipid accumulation is the basis for the corneal clouding. We examined whether apolipoproteins are involved in this disorder and characterized the lipid accumulation in the central portion of corneas removed from patients with Schnyder's dystrophy. Our findings show that cholesterol and phospholipid contents increased greater than 10-fold and 5-fold, respectively, in affected compared with normal corneas. In addition, the percentage of cholesterol that was unesterified (63% versus 50%) and the molar ratio of unesterified cholesterol to phospholipid (1.5 versus 0.5) were higher in affected compared with normal corneas. Large multilamellar vesicles and electron-dense granules (100 to 300 nm in diameter) as well as cholesterol crystals accumulated in the extracellular matrix of affected corneas. Immunohistochemical analysis showed that apolipoprotein constituents of HDL (apoA-I, apoA-II, and apoE), but not apoB, a marker of LDL, accumulated in the affected cornea. Western blot analysis confirmed the increased amounts of these HDL apolipoproteins in affected corneas and showed that the apparent molecular weights of the apolipoproteins were normal. Our findings show for the first time that HDL apolipoproteins accumulate in the corneas of patients with Schnyder's corneal dystrophy. Thus, this disorder influences the metabolism of HDL in the corneas of these patients.

A comparison of the efficacy and safety of adapalene gel 0.1% and tretinoin gel 0.025% in the treatment of acne vulgaris: a multicenter trial.

BACKGROUND: Adapalene is a new synthetic retinoid analogue developed for the topical treatment of acne vulgaris. OBJECTIVE: The study was designed to compare the efficacy and safety and adapalene gel 0.1% with tretinoin gel 0.025% in the treatment of grade II to II facial acne vulgaris. METHODS: Three hundred twenty-three patients were enrolled in this investigator-masked, randomized, parallel group, multicenter trial. Patients applied the test materials to the entire facial area daily, for a period of 12 weeks. Efficacy and cutaneous tolerance were assessed at baseline and weeks 2,4,8, and 12. Efficacy was determined by investigator counts of noninflammatory open and closed comedones, and inflammatory papules and pustules, as well as global improvement. Cutaneous tolerance was evaluated by erythema, scaling, and dryness, along with burning and pruritus. RESULTS: Staring at weeks 2 and 4, adapalene gel produced numerically greater lesion reductions than did tretinoin gel for all lesion types. At week 12, the mean percent reduction in the different lesion counts was as follow: 49% versus 37% for total lesions (p<0.01); 46% versus 33% for noninflammatory lesions (p=0.02); 48% versus 38% for inflammatory lesions (p=0.06) in adapalene and tretinoin gel treatment groups, respectively. Cutaneous side effects were limited to a mild "retinoid dermatitis" occurring in both treatment groups; however, patients treated with adapalene gel tolerated this therapy significantly better than those treated with tretinoin gel. Laboratory test evaluations (hematology, blood chemistries, urinalysis) were performed in 54 patients before and after 3 months of treatment. No clinically significant changes were observed. CONCLUSION: Adapalene gel 0.1% applied once daily was significantly more effective in reducing acne lesions and was better tolerated than tretinoin gel 0.025% in the treatment of acne vulgaris.

Schnyder crystalline dystrophy sine crystals. Recommendation for a revision of nomenclature.

PURPOSE: To determine the percentage of patients with Schnyder crystal line dystrophy who had corneal crystal deposition. METHODS: Thirty-three patients with Schnyder crystalline dystrophy were identified by the author since 1987. Each patient had a complete ophthalmic evaluation, including slit-lamp examination by the author. RESULTS: Only 51% (17 of 33) of patients with Schnyder crystalline corneal dystrophy actually had clinical evidence of corneal crystalline deposits. CONCLUSIONS: Because of the confusing nomenclature, many ophthalmologists presume that the presence of corneal crystals is an integral part of the diagnosis of Schnyder crystalline dystrophy. The clinician should be aware that despite the fact that the noncrystalline form of the dystrophy has been poorly recognized, it is equally common.

Hinge keratoplasty.

A simple trephination technique is described that allows the surgeon to be prepared to handle an expulsive hemorrhage before it occurs. After trephination is performed, the host button is excised except for a 1 clock hour width of tissue. This hinge allows the attached button to fold over the corneal rim away from the surgical field. There is no interference with subsequent intraocular procedures. Should expulsive hemorrhage develop, the attached button can be immediately flipped into place and the wound quickly sewn closed.

Efficacy and safety of twice-daily augmented betamethasone dipropionate lotion versus clobetasol propionate solution in patients with moderate-to-severe scalp psoriasis.

This 2-week, randomized, multicenter, investigator-blinded, parallel-group study was conducted to compare the efficacy and safety of augmented betamethasone dipropionate 0.05% lotion and clobetasol propionate 0.05% solution in the treatment of moderate-to-severe scalp psoriasis among 197 (193 assessable) healthy adult patients with at least 20% scalp-surface involvement. The patients received one of two treatments applied twice a day for 2 weeks. Signs and symptoms were evaluated at baseline, after 3 days (day 4), and after weeks 1 (day 8) and 2 (day 15) of treatment. As early as 3 days after treatment, scaling and induration were improved significantly faster by betamethasone dipropionate than by clobetasol propionate. Both treatments also reduced erythema and pruritus. Patients receiving betamethasone dipropionate had a significantly greater mean percent improvement in total sign/symptom scores (P < or = 0.015) at all visits and better mean global clinical response scores at the early visits (days 4 and 8) (P < or = 0.017). At the end of the study, only mild disease was present in both groups. Adverse events were reported by 34.0% and 36.4% of patients receiving betamethasone dipropionate and clobetasol propionate, respectively. All events were transient, most were mild and local, and no discontinuations resulted. The effects of treatment on the hypothalamic-pituitary-adrenal axis were not measured. In conclusion, augmented betamethasone dipropionate lotion and clobetasol propionate solution were equally effective, but betamethasone dipropionate lotion provided a faster onset of relief for scaling and induration, which may enhance patient compliance and patient satisfaction with treatment.