The relationship of central corneal thickness with the status of diabetic retinopathy.

BACKGROUND: To compare central corneal thickness (CCT) values measured by three different devices: slit-scanning topography (SST), ultrasonic pachymetry (UP), and optical coherence tomography (OCT) in diabetic eyes and compare the CCT values in patients with and without diabetic retinopathy. METHODS: Ninety-six patients with diabetes mellitus were included in this prospective study and divided into two groups according to the presence of diabetic retinopathy, as Group I with retinopathy and Group II without. The CCT of 96 eyes was measured by three different devices; SST (Orbscan II), UP and OCT. The results of CCT measurements with three different devices were compared. Also, the intergroup differences in CCT measurements were evaluated. RESULTS: The CCT was statistically insignificantly different between the two groups. Although the three methods of CCT measurements correlated well with each other, SST showed significantly (p < 0,0001) higher CCT results compared to both UP and OCT. CONCLUSIONS: According to our results, neither the duration of DM nor the presence of diabetic retinopathy did have a significant effect on the CCT. The CCT values obtained with three devices were all in correlation. However, the results of SST were significantly higher compared to the other two. Our findings emphasize the value anterior segment OCT in CCT measurements, since it is a non-contact method and correlate very well with UP.

Influence of glycosylated hemoglobin on the choroidal thickness.

PURPOSE: The aim of the study reported here was to assess the influence of serum HbA1c levels on foveal choroidal thickness in diabetic patients. METHODS: A total of 122 eyes from 122 patients who had type 2 DM were studied in this prospective, cross-sectional study. Patients were divided into three groups: 43 patients (43 eyes) without diabetic retinopathy (NDR), 39 patients (39 eyes) with diabetic retinopathy and no macular edema (DR/ME-), 40 patients (40 eyes) with diabetic retinopathy and macular edema (DR/ME+). Central foveal thicknesses and subfoveal choroidal thicknesses were noted. Subfoveal choroidal thickness measurement was taken perpendicularly from the outer part of the retinal pigment epithelial layer to the line corresponding to the choroidal-scleral junction. Serum glycosylated hemoglobin (HbA1c) levels were evaluated. RESULTS: No significant differences in age, gender, pseudophakia were observed between the groups. There was no significant difference in HbA1c value among the three diabetic groups. Mean foveal choroidal thickness was 270.09 ± 42.41 in NDR group, 243.18 ± 30.21 in DR/ME- group and 250.90 ± 40.06 in DR/ME+ group. Mean foveal choroidal thickness in NDR group was significantly different from DR/ME- group. There was no statistically significant difference between the other groups among foveal choroidal thicknesses. There was no correlation between HbA1c and foveal choroidal thickness. Multiple regression analyses of two diabetic retinopathy groups showed no significant correlation between foveal choroidal thickness and HbA1c and also no significant correlation between foveal choroidal thickness and duration of diabetes. CONCLUSIONS: Serum HbA1c levels were not correlated with foveal choroidal thickness. Choroidal thickness is effected by several factors as axial length, age and systemic diseases.

Age-Related Differences in the Clinical Patterns of Ocular Graft-Versus-Host Disease.

Objectives: To evaluate age-related differences in clinical patterns of ocular graft-versus-host disease (GVHD). Materials and Methods: In this cross-sectional study, patients diagnosed with ocular GVHD were evaluated in two groups: Group I included those aged 18 years or younger and Group II included those over 18 years of age. Demographic and clinical information were recorded and compared between the groups. Results: Forty eyes of 20 patients were included (11 patients were in Group I and 9 patients were in Group II). Follow-up was at least 6 months. All patients had burning, dryness, and foreign body sensation. Conjunctival hyperemia, cicatricial conjunctivitis, and limbal stem cell disease (LSCD) was observed more frequently in Group II. In addition to non-preserved artificial tears, cyclosporine A 0.05% (65%) and autologous/allogeneic serum eye drops (80%) were given and silicone plugs were inserted (28%). In Group I, an improvement in GVHD scoring and best corrected visual acuity was observed after 6 months of treatment (p<0.0005). Conclusion: In ocular GVHD, conjunctival cicatrization and limbal stem cell deficiency might be observed more often in adults. Topical cyclosporine, autologous/allogenic serum drops, and punctal plugs are helpful in moderate or more severe cases. With early diagnosis and treatment, an improvement in clinical signs and visual acuity might be observed, particularly in younger patients.

Prevalence of Ocular Surface Disease and Associated Risk Factors in Glaucoma Patients: A Survey Study of Ophthalmologists.

Objectives: This survey study of ophthalmologists investigated the prevalence and clinical manifestations of ocular surface disease (OSD) in glaucoma patients, assessment methods used, risk factors, glaucoma drugs considered responsible, and treatment approaches. Materials and Methods: A questionnaire prepared jointly by the Turkish Ophthalmological Association Cornea and Ocular Surface Society and Glaucoma Society using SurveyMonkey was sent to ophthalmologists via e-mail. The distribution of parameters was compared with chi-square test and p<0.05 was considered statistically significant. Results: Forty-five percent of the ophthalmologists reported that OSD was evident in least 25% of their patients. The most common symptom was redness (91.9%), while the most common ocular surface finding was conjunctival hyperemia (75.6%). The tests considered to be the most important in ocular surface assessment were ocular staining (38.7%) and tear film break-up time (TBUT) (21.9%). Ninety percent of the physicians stated that the main cause of OSD was benzalkonium chloride (BAC) in medications. Prostaglandin analogs and alpha-2 agonists were reported to be the most common medications causing OSD. In case of OSD, the ophthalmologists often switch to a glaucoma drug from a different group (38%), a non-preservative glaucoma drug (33.7%) or a drug with a preservative other than BAC (20.4%). Most physicians prescribed artificial tears (84.6%). Conclusion: In this cross-sectional survey study, ophthalmologists detected varying rates of OSD in glaucoma patients depending on chronic drug use and BAC exposure. Although ocular surface examination was performed by physicians, tests such as TBUT and ocular surface staining were rarely used. Detecting OSD in glaucoma patients and planning personalized treatment increase patient comfort, drug compliance, and treatment effectiveness. For this reason, it is important to prepare an algorithm for the management of comorbid OSD in glaucoma patients.

Management of facial disfigurement in orbitotemporal neurofibromatosis.

A 19-year-old woman with type I neurofibromatosis requested reconstruction of her severe facial disfigurement caused by the plexiform neurofibroma of the right upper eyelid. Previously, she had glaucoma surgery for buphthalmus and enucleation with dermis fat transplantation. She was unable to wear prosthesis in the last year. Transverse palpebral resection of the lesion, lateral canthal reconstruction, and frontal sling ptosis surgery were performed at the same session. Postoperatively, the cosmetic appearance of the patient was markedly improved. No complication or progression was observed during 2 years follow-up. We believe that an individual-based surgical plan may give acceptable results in these challenging cases.

Clinical features and surgical management of orbitotemporal neurofibromatosis: a retrospective interventional case series.

PURPOSE: To evaluate the clinical features and surgical preferences of patients with neurofibromatosis. METHODS: Histologically confirmed neurofibromatosis cases that underwent surgery during a 15-year period were retrospectively evaluated. The patients' demographics, severity of periorbital involvement, aim of surgery, surgery types, postoperative outcome, and complications were recorded. RESULTS: Nineteen patients with a mean age of 24.7 ± 21.2 years were included in the study. Nine were younger and 10 were older than 16 years. Seventeen patients had unilateral and two had bilateral involvement. Patients were followed for a mean of 5.8 ± 5.7 years. A total of 35 surgeries were performed. In 22 times the surgery was performed to improve vision, and in others to get a cosmetically acceptable appearance. Although there was an improvement in visual acuity, the difference was not significant (P = 0.085). Debulking of the tumor was performed in 100%, ptosis surgery in 90%, and lateral canthal fixation in 50% of surgeries. All patients showed improvement: at the last examination, six eyes had no ptosis, in 13 eyes ptosis not covering the pupil in primary gaze was observed on the involved side, and in only one eye the pupil was half covered. CONCLUSION: In neurofibromatosis the treatment should be customized to each patient. As confirmed in our study, an open visual axis is the main goal in surgery, followed by cosmetic appearance. The authors believe that, with possibly multiple surgeries an acceptable result can be achieved.

Nasolacrimal duct obstruction: clinicopathologic analysis of 205 cases.

PURPOSE: To investigate the histopathological results of lacrimal sac biopsies in patients with primary acquired nasolacrimal duct obstruction. METHODS: In this prospective non-comparative study, 205 consecutive patients, who were diagnosed as primary acquired nasolacrimal duct obstruction, were included. Patients with history of trauma and/ or surgery in the periorbital area, punctum or canalicular obstruction were excluded from the study. Patients were evaluated for age, gender, history, and presenting symptoms. Lacrimal drainage system abnormalities were assessed. Lacrimal system irrigation, dacryocystography, and in selected cases dacryoscintigraphy was performed. All patients underwent external dacryocystorhinostomy. Biopsy specimens were obtained from the posterior inferior flap and examined by the same pathologist. RESULTS: Forty-seven male and 158 females with age ranging from 6 to 81 years (mean 47.5 ± 16.2 years) were included in the study. Only one patient had the diagnosis of chronic leukemia, others had no preexisting history of systemic disease. Pathologic examination revealed chronic inflammation (n= 178), fibrosis without inflammation (n= 19), normal mucosa (n= 4), and lymphoid hyperplasia (n= 1). Three patients had abnormal pathology: Lymphoproliferative disease in the patient with chronic leukemia, granulomatous inflammation, and basosquamous cell carcinoma. CONCLUSION: In primary nasolacrimal duct obstruction, pathological examination of the lacrimal sac revealed chronic inflammatory changes in most patients. Even though rare, malignant or systemic disease in patients with neither specific history nor clinical or radiological finding might be observed in these cases. Thus, we recommend taking biopsy if any suspicion of abnormality of the lacrimal sac exists.

Clinical factors associated with floppy iris signs: a prospective study from two centers.

BACKGROUND AND OBJECTIVE: To evaluate the relationship of intraoperative floppy iris syndrome with pseudoexfoliation, diabetes mellitus, hypertension, and alpha-1 adrenergic blocker (A1AB) use. PATIENTS AND METHODS: Five hundred patients were included in this prospective study. Intraoperative adverse events, such as pupillary constriction, iris billowing, and iris prolapse from the wound, were noted. Multinomial regression analysis was used to evaluate the relationship of intraoperative floppy iris syndrome with pseudoexfoliation, diabetes mellitus, hypertension, pupil diameter, and A1AB use. RESULTS: Pupil constriction was significantly associated with pseudoexfoliation (P < .001). Diabetes mellitus was associated with pupil constriction and iris billowing (P = .005 and .003, respectively). Hypertension was associated with pupil constriction (P = .021). Intraoperative floppy iris syndrome was strongly associated with A1AB use and male gender (P < .001 and .039, respectively). CONCLUSION: Intraoperative floppy iris syndrome was observed in 2.8% of patients and was strongly related to A1AB use, particularly in smaller pupil diameters. Pseudoexfoliation, diabetes mellitus, and hypertension were not associated with intraoperative floppy iris syndrome.

An Unusual Case with Unilateral Epithelial Basement Membrane Detachment.

Purpose: To present a case with unusual epithelial basement membrane detachment.Methods: A 29-year-old female presented with blurred-vision and pain in left-eye for 2 months. Slit-lamp showed almost total bullous epithelial detachment with subepithelial fluid, and intraocular pressure rise. Recurrences were observed, despite repeated epithelial debridement and topical medication.Results: Decrease in corneal endothelial cell density and changes resembling cytomegalovirus (CMV) keratitis were noted on specular microscopy. PCR for CMV came negative; however, we had success with topical gancyclovir and steroids, in addition to topical antiglaucomatous agents and artificial tears. During the following 12 months, no recurrence was observed.Conclusion: According to her clinic and response to medication, we believe that this case represents an atypical form of CMV endotheliitis.

Effect of diluted povidone iodine in adenoviral keratoconjunctivitis on the rate of subepithelial corneal infiltrates.

AIM: To evaluate the clinical characteristics of adenoviral keratoconjunctivitis, the management modalities, as well as the incidence of subepithelial corneal infiltrates (SEI). METHODS: Patients with characteristic clinical symptoms and signs, who presented to our clinic within the first week of symptoms and received the diagnosis of adenoviral keratoconjunctivitis between January 2013 and April 2016, were included in the study. A total of 211 patients were included in the study. Patients were evaluated for the incidence of clinical signs, late complications, management preferences, and the effect of diluted povidone-iodine (d-PVP-I) 2%. RESULTS: Patients' mean age was 33.03±14.76y. We observed an increase in the number of cases according to the years. At presentation and/or early follow-up, the clinical signs were conjunctival hyperemia (100%), conjunctival follicules (79.1%), edema of the eyelids (39.3%), chemosis (16.1%), pseudomembrane formation (16.6%), and corneal epitheliopathy (29.9%). During late follow-up 13.3% patients developed conjunctival subepithelial fibrosis, and 39.8% developed SEI. A significant decrease in the incidence of SEI development was observed in patients who used d-PVP-I 2% (P=0.032; 33.3% vs 45.9%, respectively in patients who received d-PVP-I 2% and who did not). CONCLUSION: Adenoviral keratoconjunctivitis has a tremendous effect on patient's comfort and abilities in short-term. Additionally, almost half of the patients develop visual problems related to SEI. According to our clinical experience, using d-PVP-I 2% in the first days of adenoviral keratoconjunctivitis might be helpful in reducing the risk of SEI as a complication.

Comparison of the inhibitory effect of different doses of subconjunctival bevacizumab application in an experimental model of corneal neovascularization.

AIM: To evaluate the inhibitory effect of subconjunctival bevacizumab as single- and multiple-dose application, and compare their effects on corneal neovascularization in a rat model. METHODS: Thirty adult Sprague-Dawley rats were used in this experimental study. The central cornea of the rats was cauterized chemically. The rats were randomly enrolled into three groups. All groups received subconjunctival injections. In Group 1 (control group, n=10), 0.05 mL 0.9% NaCl solution was injected on the first day. In Group 2 (single-dose group, n=10), 0.05 mL bevacizumab (1.25 mg) was injected on the first day. In Group 3 (multiple-dose group, n=10), four doses of 0.05 mL bevacizumab (1.25 mg) were injected on the first, third, fifth and seventh day. Slit-lamp examination of all rats was performed at the third and ninth day. Digital images of the corneas were taken and analyzed using image analysis software to calculate corneal neovascularization area. All rats were sacrificed on the tenth day. In corneal sections, the number of blood vessels, state of inflammation and collagen formation was evaluated histopathologically. RESULTS: In Group 3, corneal edema grades were significantly lower than Group 1 and Group 2 (P=0.02, and P=0.035, respectively). The mean percentage of neovascularized corneal area in Group 3 was significantly lower than Group 2 (P=0.005). On histopathological examination, Group 2 and Group 3 showed significantly less number of blood vessels than Group 1 (P=0.005, and P=0.001, respectively). Additionally, Group 3 showed significantly less number of blood vessels compared to Group 2 (P=0.019). Inflammation and edema grades were significantly lower in Group 3 compared to Group 1 (P=0.001). CONCLUSION: Subconjunctival bevacizumab injection is effective in inhibition of newly formed corneal neovascularization. The multiple-dose bevacizumab treatment seems to be more effective compared to single-dose treatment.

Bilateral disciform keratitis of presumed adenoviral etiology.

Adenoviral conjunctivitis may lead to subepithelial corneal infiltrates as a late complication. Herein, we aim to present a 19-year-old healthy female, who developed bilateral disciform keratitis three weeks after suffering adenoviral conjunctivitis. She presented with widespread subepithelial corneal infiltrates in addition to central corneal edema with white distinct border resembling immune stromal ring, as well as Descemet's folds and keratic precipitates in the central area. Following topical corticosteroid and ganciclovir for 10 days, her condition improved. After 1 month, she had another episode. Short-term topical corticosteroids in addition to long-term topical cyclosporine and nonpreserved artificial tears were able to prevent further recurrences.

Measurements of Retinal Nerve Fiber Thickness and Ganglion Cell Complex in Neurofibromatosis Type 1, with and Without Optic Pathway Gliomas: A Case Series.

PURPOSE: The aim of this study was to investigate differences in retinal nerve fiber layer (RNFL) and ganglion cell complex (GCC) thicknesses in neurofibromatosis 1 (NF1) cases, with and without optic pathway gliomas (OPGs). MATERIALS AND METHODS: In total, 33 eyes of 33 subjects were evaluated in this prospective observational case series. Twenty-one patients with a diagnosis of NF1 were enrolled. Patients with NF1 and OPGs were included in Group 1 (n = 9), and patients with NF1 without OPGs were included in Group 2 (n = 12). The control group (Group 3) was comprised of 12 age- and sex-matched subjects with no history of ophthalmic or systemic diseases. All of the subjects underwent complete ophthalmic examinations, including best-corrected visual acuity (BCVA), slit lamp microscopy, and indirect ophthalmoscopy. Additionally, optical coherence tomography (OCT) measurements were obtained. RESULTS: There were no statistically significant between-group differences in age and sex (p = 0.227 and 0.986, respectively). The average RNFL thickness in Group 1 (NF1 patients with OPGs) was significantly lower than in Groups 2 and 3 (86.6 ± 22.5, 107.4 ± 6.65, and 108.4 ± 5.05 µm, respectively; p = 0.001). Furthermore, the average GCC thickness in Group 1 was significantly lower than in Groups 2 and 3 (78.6 ± 16.3, 94.8 ± 3.55, and 94.9 ± 3.82 µm, respectively; p < 0.001). CONCLUSIONS: Both RNFL and GCC thicknesses were significantly lower in NF1 patients with OPGs. The use of OCT to quantify damage to the visual pathway may enable earlier detection of OPGs in NF1 patients.

The effects of two systemic alpha1-adrenergic blockers on pupil diameter: a prospective randomized single-blind study.

Our aim was to investigate the effects of two alpha(1)-adrenergic blockers-tamsulosin and alfuzosin-on pupil diameter (PD). In this prospective randomized single-blind clinical trial, 64 patients with benign prostatic hyperplasia received treatment with either tamsulosin or alfuzosin. The same ophthalmologist, masked to the given medication, evaluated patients prior to, 4 weeks after and 6 months after the start of the medication (day 0, day 28 and month 6). Best corrected visual acuity and PD under mesopic, scotopic, and dilated conditions were measured. t-test, ANOVA, and Dunnett's multiple comparison post-test were used for statistical analysis. With tamsulosin treatment, both mesopic and scotopic PD decreased, respectively, from 3.9 +/- 0.7 and 5.7 +/- 0.6 mm at day 0 to 3.6 +/- 0.9 and 5.5 +/- 0.8 mm at day 28, and 3.6 +/- 0.7 and 5.4 +/- 0.7 mm at month 6 (ANOVA; P = 0.021 and = 0.040, respectively). However, the difference in dilated PD was not significant (day 0 7.8 +/- 0.6 mm, day 28 7.7 +/- 0.7 mm, and month 6 7.6 +/- 0.6 mm, P = 0.379). In the alfuzosin group, PD did not differ significantly from the baseline except for the scotopic measurements, which decreased from 5.6 +/- 0.6 mm at day 0 to 5.5 +/- 0.6 mm at day 28 and 5.2 +/- 0.8 mm at month 6 (P = 0.004). Compared to baseline values, small but statistically significant decreases were detected in mesopic and scotopic illumination in patients treated with tamsulosin and in scotopic PD in patients treated with alfuzosin. The clinical significance of these differences needs further evaluation.

Effect on astigmatism of the location of clear corneal incision in phacoemulsification of cataract.

PURPOSE: To investigate the refractive results of clear corneal incision performed at the steepest meridian of pre-existing corneal astigmatism. METHODS: One hundred eighty-two patients with astigmatism > 0.75 diopters (D) were evaluated. Superior, temporal, nasal, superotemporal, or superonasal clear corneal incisions were performed at the steep meridian. Refraction, visual acuity, and topography values were evaluated, and changes in surgically induced astigmatism were calculated by vector analysis using the Fourier formula. Paired t test was used to compare mean values. RESULTS: Postoperative cylinder values showed minor changes in all groups, except the nasal group. Nasal incision increased preoperative cylinder from 1.13 D to 1.83 D 6 months after surgery. Temporal and superotemporal incisions resulted only in small astigmatic changes. Conversely, superior, superonasal, and nasal incisions induced more pronounced astigmatism. CONCLUSIONS: Performing clear corneal incision for phacoemulsification of cataract at the steep meridian resulted in small changes with temporal incisions, whereas nasal incisions resulted in higher surgically induced astigmatism.

The effects of systemic alpha-1 adrenergic antagonists on pupil diameter in rats.

PURPOSE: To investigate the effects of alpha-1 adrenergic blockers on pupil diameter (PD) in rats. METHODS: Four groups, with 10 rats each, were designed to receive terazosin, tamsulosin, doxazosin, and no medication. Dilated pupil diameter (PD) measurements were performed 24 hr before, 24 hr after, and 30 days after the initiation of medication, and after 30 days of washout. The intergroup and intragroup differences in PD were evaluated using one-way ANOVA and Wilcoxon signed rank test, respectively. RESULTS: In day 1, PD decreased in both eyes significantly only in tamsulosin and doxazosin groups, but these effects became insignificant at 30 days of treatment (p > 0.05). The control group showed no significant difference in PD (p > 0.05). PD values returned to baseline after the washout period in all groups. CONCLUSIONS: A significant reduction in PD occurred in two of the three groups with alpha-1 adrenergic blockers (tamsulosin and doxazosin), but this effect was not sustained at 30 days. Further functional and structural studies of the iris are needed to determine the clinical significance of these findings.

Otologic T-tube in endonasal dacryocystorhinostomy: a new approach.

CONCLUSION: Otologic T-tubes had a success rate of 73% if implanted during endoscopic dacryocystorhinostomy (DCR). We suggest that they can be used successfully in endoscopic DCR, and are promising as an alternative to silicone stent intubations. OBJECTIVE: To evaluate the efficacy of endoscopic DCR using otologic T-tube. MATERIALS AND METHODS: Twenty patients (22 eyes) with nasolacrimal duct obstruction underwent endoscopic DCR. After creating an aperture in the medial wall of the lacrimal sac, the otologic T-tube (1.15 mm diameter, Invotec, Jacksonville, FL, USA) was inserted into the sac transnasally. The T-tube was left in the lacrimal sac for between 3 and 6 months. The patients were followed up for between 6 and 24 months (mean 12.4 months). The improvement in patients' epiphora complaint was grouped as very good, good, or no change. RESULTS: Eleven eyes (50%) proved to be 'very good', whereas five eyes (23%) were good, and six eyes (27%) had no change. Of six eyes that were reported to have no change after the operation, three experienced spontaneous tube loss in the early period, one eye was a recurrent case, and the other two were primary cases.

Astigmatism induced by oblique clear corneal incision: right vs. left eyes.

BACKGROUND: To compare the induced astigmatism after phacoemulsification in the right vs. the left eye. METHODS: An oblique clear corneal incision was made in a superotemporal location in the right (n = 344) and a superonasal location in the left (n = 292) eye. Retrospectively, patient characteristics, pre- and postoperative visual acuity, and induced astigmatism values were compared. Statistical analysis was performed with the Student t , chi2, and Mann-Whitney U tests. RESULTS: The proportion of against-the-rule astigmatism and surgically induced astigmatism values were significantly larger in the left-eye group (p < 0.001). INTERPRETATION: Surgically induced astigmatism occurred to a greater extent in the left eyes compared with the right, possibly because of structural differences.

Intravitreal Ranibizumab Injection in Peripapillary CNVM Related to Idiopathic Intracranial Hypertension.

Peripapillary choroidal neovascular membrane (CNVM) may develop in papilledema related to idiopathic intracranial hypertension. The authors present a teenaged boy who responded well to one dose of intravitreal ranibizumab injection. [J Pediatr Ophthalmol Strabismus. 2017;54:e27-e30.].

Amniotic membrane transplantation for treatment of symblepharon in a patient with recessive dystrophic epidermolysis bullosa.

PURPOSE: To report the surgical treatment of a case with epidermolysis bullosa. METHODS: A 12-year-old girl with dystrophic epidermolysis bullosa presented to our clinic with a symblepharon connecting the lateral half of the left upper lid to the upper temporal quadrant of the cornea. The central cornea exhibited diffuse opacity and vascularization. RESULTS: During surgery, the symblepharon was lysed, and lamellar keratectomy was performed. The operated portion of cornea and palpebral conjunctiva was covered with amniotic membrane to promote healing. Fourteen months later, the operated eyelid margin was normal and the eye was fully mobile. The temporal portion of the corneal stroma was still thinner than normal and showed mild superficial vascularization and opacification. CONCLUSION: We believe that amniotic membrane transplantation is a valuable way to treat symblepharon in cases of epidermolysis bullosa.