Yoshiyuki Satake

Surgical Reconstruction of the Ocular Surface in Advanced Ocular Cicatricial Pemphigoid and Stevens-Johnson Syndrome

PURPOSE Ocular cicatricial pemphigoid and Stevens-Johnson syndrome often cause ocular damage and blindness not amenable to surgical correction. We present a new surgical technique for reconstructing affected eyes. METHODS Fourteen eyes of 11 patients with cicatricial keratoconjunctivitis (seven patients with cicatricial pemphigoid and four with Stevens-Johnson syndrome; average age +/- S.D., 55.5 +/- 25.4 years) were treated with a combination of allograft limbal transplantation, amniotic membrane transplantation, and tarsorrhaphy, followed every 15 minutes by artificial tears derived from the patients blood serum. Eight eyes required concomitant penetrating or lamellar keratoplasty because of corneal opacity. RESULTS With a mean follow-up of 143 days (range, 10 to 608 days), we achieved successful ocular surface reconstruction in 12 eyes, with minimal recurrence of symblepharon. Failure occurred in two eyes (one each in 9- and 10-year-old boys) that developed corneal infiltration and vascularization. CONCLUSIONS A combination of allograft limbal transplantation, amniotic membrane transplantation, and tarsorrhaphy, followed by the use of serum-derived tears, can reconstruct the ocular surface in most cases. Although in this study the follow-up period was short and relatively few patients were studied, this approach appears to offer an alternative to keratoprosthesis for treating severe cicatricial keratoconjunctivitis with dry eye.

Treatment of severe ocular-surface disorders with corneal epithelial stem-cell transplantation.

BACKGROUND Conditions that destroy the limbal area of the peripheral cornea, such as the Stevens-Johnson syndrome, ocular pemphigoid, and chemical and thermal injuries, can deplete stem cells of the corneal epithelium. The result is scarring and opacification of the normally clear cornea. Standard corneal transplantation cannot treat this form of functional blindness. METHODS We performed and evaluated 70 transplantations of corneal epithelial stem cells from cadaveric eyes into 43 eyes of 39 patients with severe ocular-surface disorders and limbal dysfunction. Medical treatment had failed in all patients. The patients had a mean preoperative visual acuity of 0.004 (only being able to count the number of fingers presented by the examiner) in the affected eyes, which satisfies the criteria for legal blindness in most countries. In 28 eyes, we also performed standard corneal transplantation. Stem-cell transplantations were performed as many as four times on 1 eye if the initial results were not satisfactory; 19 eyes had multiple transplantations. Patients were followed for at least one year after transplantation. RESULTS A mean of 1163 days after stem-cell transplantation, 22 of the 43 eyes (51 percent) had corneal epithelialization; of the 22 eyes, 7 eyes had corneal stromal edema and 15 eyes had clear corneas. Mean visual acuity improved from 0.004 to 0.02 (vision sufficient to distinguish the largest symbol on the visual-acuity chart from a distance of 1 m) (P<0.001). The 15 eyes in which the cornea remained clear had a final mean visual acuity of 0.11 (the ability to distinguish the largest symbol from a distance of 5 m). Complications of the first transplantation included persistent defects in the corneal epithelium in 26 eyes, ocular hypertension in 16 eyes, and rejection of the corneal graft in 13 of 28 eyes. The epithelial defects eventually healed in all but two of the eyes. CONCLUSIONS Transplantation of corneal epithelial stem cells can restore useful vision in some patients with severe ocular-surface disorders.

A new surgical technique for deep lamellar keratoplasty with single running suture adjustment

PURPOSE To improve the technique of deep lamellar keratoplasty. METHODS For the recipient eye, a divide-and-conquer technique was applied to deep lamellar keratoplasty. After trephinization, the recipient cornea within the trephine was divided into four quadrants to facilitate lamellar dissection at approximately 70% depth. This procedure of division was continued until the Descemet membrane was exposed in the central area. The corneal graft was placed with an adjusted single running suture. Seventeen eyes were treated with this technique. RESULTS In 17 eyes of 15 patients, the mean visual acuity 6 months or more after deep lamellar keratoplasty was 20/52 with eyeglass correction and 20/80 without eyeglass correction. At 6 months or more after deep lamellar keratoplasty, the mean +/- SD keratometric astigmatism in 17 eyes was 3.2 +/- 2.3 diopters. CONCLUSION This technique facilitates deep lamellar keratoplasty and prevents high or excessive astigmatism after surgery.

Application of visante optical coherence tomography tear meniscus height measurement in the diagnosis of dry eye disease

PURPOSE To investigate the applicability of tear meniscus height (TMH) measurement using Visante optical coherence tomography (OCT) in the diagnosis of dry eye disease. DESIGN Prospective, controlled, single-center study. PARTICIPANTS Twenty-four right eyes of 24 patients (6 males, 18 females; mean age, 63.14±13.4 years) with definite dry eye according to the Japanese dry eye diagnostic criteria and 27 right eyes of 27 control subjects (12 males, 15 females; mean age, 56.04±14.22 years) were recruited. METHODS All subjects underwent slit-lamp TMH measurement, OCT upper and lower TMH measurements, tear film breakup time (BUT) measurements, vital stainings, and Schirmer test. The results were compared between the 2 groups by Mann-Whitney test. MAIN OUTCOME MEASURES The correlation between the clinical findings of slit-lamp TMH, strip meniscometry examination, tear functions, vital staining scores, and the OCT upper and lower TMH parameters were tested by Spearmans correlation test. Receiver operating characteristic (ROC) curve technique was used to evaluate the sensitivity, specificity and cutoff values of OCT TMH examination in the diagnosis of dry eye. RESULTS The OCT upper and lower TMH values, slit-lamp TMH, strip meniscometry, tear film BUT, and vital staining scores were significantly lower in the dry eye patients compared with controls (P<0.001). A significant correlation between the OCT upper and lower TMH measurements as well as slit-lamp TMH, strip meniscometry, tear functions, vital staining scores, and the Schirmer test was found. The ROC curve technique analysis of the OCT lower TMH showed that, when the cutoff value was set at <0.30 mm, the sensitivity and specificity of the testing were 67% and 81%, respectively. CONCLUSIONS The Visante OCT is a quick, noninvasive method for assessing the TMH, with acceptable sensitivity, specificity, and repeatability, and may have potential applications for the diagnosis and evaluation of dry eye disease.

Long-term outcome of cultivated oral mucosal epithelial sheet transplantation in treatment of total limbal stem cell deficiency.

PURPOSE To evaluate the long-term outcome of cultivated oral mucosal epithelial transplantation (COMET) in treatment of eyes with total limbal stem cell deficiency. DESIGN Noncomparative, retrospective, interventional case series. PARTICIPANTS Forty eyes in 36 patients with total limbal stem cell deficiency (Stevens-Johnson syndrome in 12 eyes, chemical or thermal burns in 11 eyes, ocular cicatricial pemphigoid [OCP] in 9 eyes, pseudo-OCP in 7 eyes, and gelatinous drop-like dystrophy in 1 eye) were treated at the Department of Ophthalmology, Tokyo Dental College, Chiba, Japan. INTERVENTION Cultivated autologous oral mucosal epithelial sheets were transplanted onto the ocular surface in eyes with total limbal stem cell deficiency. MAIN OUTCOME MEASURES Reconstruction of a stable ocular surface with a clear appearance and no epithelial defects, reduction in fibrovascular tissue invasion of corneal surface, a functional fornix, change in visual acuity, and postoperative complications. RESULTS The mean follow-up period was 25.5 months (range, 6-54.9 months). Kaplan-Meier analysis of a corneal surface stability revealed an early decline in transplanted oral mucosal epithelial stability over the first 6 months, remaining comparatively stable thereafter (1 year, 64.8%; 2 years, 59.0%; and 3 years, 53.1%). Postoperative persistent epithelial failure developed within the first 3 months in 9 eyes. Early epithelial failure was associated closely with preoperative corneal defects. Gradual fibrovascular tissue invasion of the corneal surface was observed in 8 eyes and was marked in cases of OCP. Survival of a functional fornix decreased progressively until approximately 6 months. Postoperative visual acuity seemed to be related to the presence of corneal opacity. Complications included stromal melting or perforation in 8 eyes, infectious keratitis in 2 eyes, glaucoma in 8 eyes, and recurrence of herpetic keratitis in 1 eye. Corneal melting or perforation and infectious keratitis were associated closely with persistent epithelial defects after COMET. CONCLUSIONS The transplantation of cultivated oral mucosal epithelial sheets offers a viable and safe alternative in the reconstruction of a stable ocular surface. Epithelialization of the corneal surface is very important not only in obtaining a satisfactory long-term outcome, but also in achieving a lower incidence of complications. FINANCIAL DISCLOSURE(S) The author(s) have no proprietary or commercial interest in any materials discussed in this article.

Common T cell receptor clonotype in lacrimal glands and labial salivary glands from patients with Sjögren's syndrome.

Sjogrens syndrome (SS) is an autoimmune disease characterized by lymphocytic infiltration into lacrimal and salivary glands leading to symptomatic dry eyes and mouth. Immunohistological studies have clarified that the majority of infiltrating lymphocytes around the lacrimal glands and labial salivary glands are CD4 positive alphabeta T cells. To analyze the pathogenesis of T cells infiltrating into lacrimal and labial salivary glands, we examined T cell clonotype of these cells in both glands from four SS patients using PCR-single-strand conformation polymorphism (SSCP) and a sequencing method. SSCP analysis showed that some infiltrating T cells in both glands expand clonally, suggesting that the cells proliferate by antigen-driven stimulation. Intriguingly, six to sixteen identical T cell receptor (TCR) Vbeta genes were commonly found in lacrimal glands and labial salivary glands from individual patients. This indicates that some T cells infiltrating into both glands recognize the shared epitopes on autoantigens. Moreover, highly conserved amino acid sequence motifs were found in the TCR CDR3 region bearing the same TCR Vbeta family gene from four SS patients, supporting the notion that the shared epitopes on antigens are limited. In conclusion, these findings suggest that some autoreactive T cells infiltrating into the lips and eyes recognized restricted epitopes of a common autoantigen in patients with SS.

Evaluation of lipid oxidative stress status in Sjögren syndrome patients

PURPOSE We evaluated the levels of lipid oxidative stress markers and inflammatory cells from tears and conjunctiva of patients with Sjögren syndrome (SS) and normal subjects. METHODS We examined 31 eyes of 16 patients (16 females) with SS and 15 eyes of 10 healthy controls (2 males and 8 females) in this prospective study. All subjects underwent a Schirmer test, measurement of tear film break-up time, vital stainings, confocal microscopy of the conjunctiva, tear collection for hexanoyl-lysine (HEL), ELISA, and conjunctival brush cytology. Brush cytology samples underwent immunohistochemistry (IHC) staining with HEL and 4-hydroxy-2-nonenal (4HNE). Hematoxylin-eosin and IHC staining with HEL and 4HNE also were performed on conjunctival samples of SS patients and controls. RESULTS The tear stability and vital staining scores were significantly worse in eyes of SS patients compared to the controls. Conjunctival inflammatory cell density was significantly higher in SS subjects compared to controls. The numbers of conjunctival cells stained positively for HEL and 4HNE were significantly higher in SS patients compared to controls. Tear HEL concentrations correlated significantly with staining scores and inflammatory cell density in confocal microscopy. Conjunctival specimens also revealed higher numbers of cells stained positively for inflammatory markers, as well as HEL and 4HNE in the IHC stainings. CONCLUSIONS Increase of the oxidative stress status in the conjunctiva of SS patients appears to have a role in the pathogenesis of dry eye disease. A close relationship may exist between reactive oxygen species (ROS) production, lipid peroxidation related membrane damage, and inflammatory processes in dry eye.

The Contribution of the Posterior Surface to the Corneal Aberrations in Eyes after Keratoplasty

PURPOSE To investigate the contribution of posterior corneal surfaces to higher-order aberrations (HOAs) of the cornea, optical quality, and visual acuity after keratoplasty. METHODS Corneal topography of anterior and posterior surfaces and pachymetry were conducted using anterior segment optical coherence tomography (AS-OCT) in 40 eyes (10 eyes after penetrating keratoplasty [PK], 10 eyes after deep anterior lamellar keratoplasty [DALK], 10 eyes after Descemets stripping automated endothelial keratoplasty [DSAEK], and 10 normal eyes). Anterior, posterior, and total corneal HOAs were calculated using ray-tracing and decomposition into Zernike polynomials and were evaluated as root mean square values. Modulation transfer functions (MTFs) were also evaluated. RESULTS Topography maps of the anterior and posterior surfaces showed reverse patterns in the normal, PK, and DALK eyes, but not in DSAEK eyes. In the normal, PK, and DALK eyes, the total corneal HOAs were significantly smaller (~10%) than were the HOAs of the anterior surface (P < 0.01), whereas there was no significant difference between total and anterior HOAs in the DSAEK eyes (P = 0.483). In the normal, PK, and DALK eyes, the MTFs of the total cornea were slightly better than those of the anterior surface. In the DSAEK eyes, the MTFs of the total cornea were lower than those of the anterior surface. Visual acuity was significantly correlated with total and anterior surface HOAs (P < 0.05). CONCLUSIONS Posterior surfaces compensate for anterior aberrations in normal, PK, and DALK eyes. In DSAEK eyes, the posterior surface increased total corneal HOAs and had a negative influence on MTFs.

Treatment of severe dry eye

SIR—Dry eye syndrome ranges widely in severity from ocular fatigue associated with the use of video display terminals (VDTs) to the destructive changes seen in advanced StevensJohnson syndrome (SJS) or ocular cicatricial pemphigoid (OCP). Whereas patients using VDTs never lose vision, those with OCP frequently go blind. In SJS or OCP, the cornea becomes opaque from vascularisation and is covered by conjunctival epithelium due to depletion of corneal stem cells. The absence of even reflex tears makes these diseases contraindications to corneal transplantation. Since tears supply factors such as epidermal growth factor and vitamin A that are essential for the proliferation and maturation of the corneal epithelium, the cornea cannot survive without tears. We have developed a surgical technique for ocular surface reconstruction in SJS and OCP. We carried out corneal limbus transplantation to replace the corneal epithelial cells, and provided, for frequent use, autologous serum drops as artificial tears to supply growth factors and vitamin A. Although the initial observation period was short, this approach seemed promising. We report here the 18-month follow-up of a patient with SJS who responded well to our treatment. A 37-year-old woman had severe SJS 7 years ago and gradually developed cicatricial keratoconjunctivitis. The left cornea became opaque and keratinised (upper figure); visual acuity was 30 cm for hand motion on Oct 3, 1994. Tear function was completely lost, with no reflex tears. We carried out corneal limbal allograft transplantation and tarsorrhaphy on Oct 13, 1994, and then provided, for frequent use (every 15 min), autologous serum drops. The corneal epithelium was re-established in 2 weeks and visual acuity recovered. Since the Schirmer test, even with nasal stimulation, yielded 0 mm during the initial observation period, autologous serum drops were continued 10 times a day. Low-dose cyclosporin (75 mg/day) was maintained. The corneal epithelium remained clear without any keratinisation or vessel invasion (lower figure), with a final visual acuity of 20/30, with 1·25 D of astigmatism, on March 14, 1996. This report demonstrates the feasibility of combining corneal epithelial stem-cell transplantation with autologous serum drops to treat severe dry eye, such as in SJS or OCP. Our case suggests that serum components can induce proliferation and differentiation of the corneal epithelium, even in the absence of endogenous tear production.

Transplantation of Cultivated Oral Mucosal Epithelium Prepared in Fibrin-Coated Culture Dishes

PURPOSE To compare the clinical results of cultivated oral mucosal epithelial cell sheet transplantation (COMET) of substrate-free sheets with those of COMET of amniotic membrane (AM)-based sheets. METHODS Sixteen eyes receiving COMET of substrate-free sheets (substrate-free group) were studied retrospectively and compared with disease-, age-, and ocular surface status-matched eyes undergoing COMET with AM serving as the substrate (AM group). Each group consisted of six eyes with chemical injury, six with pseudo-ocular cicatricial pemphigoid, two with Stevens-Johnson syndrome, and two with ocular cicatricial pemphigoid. Graft survival rate, best-corrected visual acuity (BCVA), and neovascularization (NV) were assessed. RESULT In all 32 eyes, the entire corneal surface on which the cultivated autologous oral mucosal epithelium sheet had been placed was free of epithelial defects at postoperative day 2. The success rates of COMET at 12 months after surgery were 62.5% in the substrate-free sheet group and 43.8% in the AM group. A Kaplan-Meier curve revealed that the graft survival rate in the substrate-free group was significantly superior to that in the AM group (P = 0.046). Mean postoperative BCVA improved significantly at 1, 3, and 6 months in the substrate-free sheet group, and BCVA was significantly better than that in the AM group at all time points. Postoperative NV improved significantly in the substrate-free group at all time points. CONCLUSIONS A better midterm clinical outcome was achieved with COMET of a substrate-free cell sheet than with COMET of AM as a substrate for treating severe stem cell deficiency.