Yukako Tatematsu

Ocular surface and tear functions after topical cyclosporine treatment in dry eye patients with chronic graft-versus-host disease

We investigated the effect of 0.05% topical cyclosporine (Cys) on the ocular surface and tear functions in dry eye patients with chronic GVHD (cGVHD) in a prospective comparative study. Thirty eyes of 15 patients refractory to baseline treatment were recruited and the patients assigned for topical Cys treatment group (14 eyes of 7 patients) and control group (12 eyes of 6 patients) respectively. Two patients dropped out because of intolerable irritation while using topical Cys eye drops. Visual analog scale symptom scores, corneal sensitivity, Schirmer I test value, tear film break-up time (TBUT), tear evaporation rate and ocular surface vital staining scores were recorded at baseline and at the end of the following one month. Conjunctival impression and brush cytology were performed before and after the treatment. After topical Cys treatment, significant improvements were found in symptom scores, corneal sensitivity, tear evaporation rate, TBUT, vital staining scores, goblet cells density, conjunctival squamous metaplasia grade, inflammatory cell numbers and the MUC5AC expression. Our study suggests that 0.05% topical Cys may be an effective treatment for dry eye patients with cGVHD. The improvements in the ocular surface and tear functions resulted presumably from the decreased inflammation, increased goblet cell density and MUC5AC mRNA expression.

Baseline profiles of ocular surface and tear dynamics after allogeneic hematopoietic stem cell transplantation in patients with or without chronic GVHD-related dry eye

We evaluated ocular surface alterations in allogeneic hematopoietic stem cell transplantation (HSCT) recipients with or without chronic GVHD-related dry eye in a prospective study. Fifty eyes of 25 post-HSCT patients and 28 eyes of 14 age-matched healthy controls were included. Meibomian gland (MG) obstruction, tear evaporation rate, corneal sensitivity (CS), Schirmer test-I, tear break-up time (BUT) and ocular surface vital staining were examined. Conjunctival impression and brush cytology specimens were collected to evaluate the goblet cell density (GCD) and the inflammatory cell numbers. Obvious MG obstruction, decreased CS and enhanced tear evaporation rate were found in post-HSCT patients compared with normal controls. In addition, decreased conjunctival GCD, increased conjunctival squamous metaplasia and inflammatory cells were noted in cGVHD-related dry eyes compared with normal controls and post-HSCT without dry eye subjects. Furthermore, the conjunctival inflammatory cells were significantly higher in severe dry eyes compared with mild dry eyes (P=0.03). We found comprehensive ocular surface alteration in post-HSCT patients, regardless of whether they had cGVHD-related dry eye or not. The results suggest that the extent of inflammatory process seems to have a pivotal role in the outcome of the cGVHD-related dry eye.

Surgical punctal occlusion with a high heat-energy releasing cautery device for severe dry eye with recurrent punctal plug extrusion.

PURPOSE To report the rate of recanalization and the efficacy of punctal occlusion surgery with a high heat-energy-releasing cautery device in patients with severe dry eye disease and recurrent punctal plug extrusion. DESIGN Prospective, interventional case series. METHODS Seventy puncta from 44 eyes of 28 dry eye patients underwent punctal occlusion with thermal cautery. All patients had a history of recurrent punctal plug extrusion. A high heat-energy-releasing thermal cautery device (Optemp II V; Alcon Japan) was used for punctal occlusion surgery. Symptom scores, best-corrected visual acuity, fluorescein staining score, rose bengal staining score, tear film break-up time, and Schirmer test values were compared before and 3 months after the surgery. Rate of punctal recanalization also was examined. RESULTS Three months after surgical cauterization, symptom score decreased from 3.9 ± 0.23 to 0.56 ± 0.84 (P < .0001). Logarithm of the minimal angle of resolution best-corrected visual acuity improved from 0.11 ± 0.30 to 0.013 ± 0.22 (P = .003). Fluorescein staining score, rose bengal staining score, tear film break-up time, and the Schirmer test value also improved significantly after the surgery. Only 1 of 70 puncta recanalized after thermal cauterization (1.4%). CONCLUSIONS Punctal occlusion with the high heat-energy-releasing cautery device not only was associated with a low recanalization rate, but also with improvements in ocular surface wetness and better visual acuity.

Topical tranilast for treatment of the early stage of mild dry eye associated with chronic GVHD.

Fibrosis and excessive extracellular matrix production are characteristic features of lacrimal gland chronic GVHD (cGVHD). Tranilast (n-[3,4-anthoranilic acid]), used for fibrotic skin disease, inhibits transforming growth factor-β-induced matrix production. We conducted a non-randomized study comparing 8 patients (five men, three women; median age, 47 years) given topical tranilast with 10 patients (three men, seven women; median age, 37 years) receiving therapy with topical artificial tears, sodium hyaluronate and vitamin A for mild ocular cGVHD. The tranilast group instilled topical tranilast and artificial tears q.i.d., beginning the day of dry eye diagnosis. The ocular surface and tear dynamics of each patient were evaluated before hematopoietic stem cell transplant, at the onset of dry eye and after 3 months of treatment. At 3 months, the scores of the Rose Bengal test and Schirmer test with nasal stimulation had significantly improved in the tranilast group compared with that in the control group (P<0.05). Furthermore, although five control patients (50%) developed severe dry eye within the treatment period, only one tranilast-treated patient (12.5%) did; the rest still had mild dry eye (P<0.05). These results suggest the hypothesis that topical tranilast may effectively retard the progression of mild dry eye associated with cGVHD.

Surgical management of lacrimal punctal cauterization in chronic GVHD-related dry eye with recurrent punctal plug extrusion

We investigated the efficacy of lacrimal punctal occlusion surgery with a cautery device in patients with chronic GVHD (cGVHD)-related dry eye, with recanalization of puncta and recurrent punctal plug extrusion. A total of 23 puncta from 14 eyes of 10 patients with chronic GVHD (cGVHD)-related dry eye underwent punctual thermal cauterization with a high-temperature disposable cautery device. All patients were refractory to conventional treatment, including artificial tear eye drops, autologous serum eye drops and vitamin A eye drops, and had a history of recanalization and recurrent punctal plug extrusion. The effect of lacrimal punctal cauterization by thermal cautery device was evaluated by changes in subjective symptom scores, corrected distance visual acuity, Schirmers test values, fluorescein staining scores, rose bengal staining scores, and tear-film break-up time before and 3 months after the surgery. Subjective symptom scores, Schirmers test values, fluorescein and rose bengal scores, and tear-film break-up time improved significantly 3 months after the surgery. Recanalization of puncta was not observed in all the cases (0 of 14 eyes, 0%). Lacrimal punctal cauterization was effective with no recanalization and significant improvements in subjective symptoms and the ocular surface environment in cGVHD-related dry eye patients who had been refractory to conventional treatments.

Mucosal microvilli in dry eye patients with chronic GVHD

The ocular surface is a frequent target tissue of mucosal chronic GVHD (cGVHD). We investigated the histopathological features of the conjunctival microvilli in patients with cGVHD. Conjunctival tissue specimens from patients with cGVHD or Sjögrens syndrome (SS) or from healthy individuals were examined by light microscopy and EM, impression cytology, and immunohistochemistry. The cGVHD conjunctivae showed significantly more metaplasia and fewer goblet cells than the SS and normal conjunctivae. Abundant CD8+ T cells infiltrated the basal epithelia in the cGVHD conjunctiva. The microvilli per standard epithelial unit and the secretory vesicles were counted by analyzing electron micrographs. The mean number of mucosal microvilli was significantly lower in the cGVHD than that in the SS or normal specimens, and the microvilli were significantly shorter, with a smaller height–width ratio. The mean number of secretory vesicles was also significantly lower, and the membrane-spanning mucin thinner, in the cGVHD compared with the SS and normal specimens. Thus, the conjunctival mucosal microvilli of cGVHD patients were significantly different in number and morphology from those of SS and normal subjects. These may be important factors affecting the stability of the tear-film layer and its contribution to cGVHD-related dry eye.

Donor-recipient gender difference affects severity of dry eye after hematopoietic stem cell transplantation.

PurposeTo determine whether the incidence rate and severity of dry eye after hematopoietic stem cell transplantation varies with donor vsrecipient gender.MethodsWe limited this study to patients received bone marrow transplantation (BMT). In all, 172 patients received BMT at Keio University School of Medicine between January 2000 and May 2007. Of them, 136 recipients who survived at least 70 days were studied prospectively. We classified the 136 patients according to the gender of the donor and the recipient (group I: female to female; group II: male to male; group III: male to female; group IV: female to male). The incidence and severity of chronic graft-vs-host disease-associated dry eye were determined for each group. The donor gender was masked when we assessed dry eye and calculate the incidence.ResultsThe incidence of dry eye was 47.4% for group I, 37.5% for group II, 58.6% for group III, and 42.9% for group IV. The percentage of patients with severe dry eye was 44.4, 50.0, 35.3, and 77.8% respectively. There was a significant difference between the percent severe dry eye/total dry eye incidences in groups III and IV (P=0.0375) (odds ratio, 7.6; 95% confidence interval, 1.00–101.01).ConclusionsClose attention must be paid to the development of dry eye in cases of female to male BMTs, because the ratio of severe/total dry eye is more common in cases of female to male BMTs than in other gender combination.

S-1 Induces Meibomian Gland Dysfunction

Dear Editor: S-1 (Taiho Pharmaceutical Co. Ltd., Tokyo, Japan) is an anti-cancer drug containing tegafur, gimeracil, and oteracil potassium that has been approved for use in Japan, Korea, China, and Singapore in large bowel, stomach, breast, and lung cancers as a single oral agent. The drug is still waiting FDA approval in the United States. Reported systemic S-1 toxicity includes myelosuppression, gastrointestinal and renal toxicity, dermatitis, hypotension, and depression. Initial studies from the USA reported mild conjunctivitis and canalicular stenosis. We report in this single-center, prospective clinical study severe obstructive meibomian gland dysfunction (MGD) as an unreported complication of S-1 in patients who experienced ocular symptoms after commencement of S-1. Twenty eyes from 10 patients (5 women, 5 men; mean age: 67.7 11.9 years) receiving solitary oral treatment with S-1, as well as 19 eyes of 10 age and sex-matched healthy control subjects (5 women, 5 men; mean age: 62.3 18.5 years) were studied. One patient had pharyngeal cancer, 2 patients had lung cancers, 3 patients had breast cancers, 2 patients had stomach, and 2 other patients had colon cancers. All patients complained of foreign body sensation, visual discomfort, or epiphora within 4 months after commencement of S-1. The mean total drug dose was 41.0 32.7 (range, 9.0 102.9) grams and the mean duration of treatment was 21.8 17.0 (range, 6 55) months. None of the patients had prior or coexisting treatment with other chemotherapeutics or had radiotherapy. The patients did not have any history of ocular surgery, ocular/systemic diseases, or a history of topical/systemic drug use or contact lens wear that would alter the ocular surface. Informed consents were obtained from all subjects. Examination procedures were ethic board reviewed. The criteria for the diagnosis of MGD were described as follows: (1) occluded meibomian gland (MG) orifices; (2) cloudy/inspissated glandular secretion following digital pressure on the tarsus of the eyelids; (3) presence of keratinization or displacement of the mucocutaneous junction; (4) absence of inflammatory skin disorders such as atopic dermatitis, seborrhea sicca, and rosacea; (5) absence of trachoma, ocular cicatritial pemphigoid, chemical, thermal, or radiation injury; and (6) absence of excessive meibomian lipid secretion (seborrheic MGD). The patients underwent tear lipid layer interferometry, tear evaporation rate measurements from the ocular surface (TEROS), tear collection for tegafur (FT207) concentration assessment by gas chromatography, tear film break-up time (BUT) measurements, vital stainings of the ocular surface, Schirmer test I without anesthesia, in vivo laser confocal microscopy, transillumination of the eyelids with a transilluminator or infrared meibography, and the MG expressibility test. The degree of MG dropout and MG expressibility were scored as described previously. The FT-207 concentrations measured during drug ingestion ranged between 908 and 3631 ng/ml (mean, 2013.2 1014.8 ng/ml). FT-207 was undetectable in tears when the patients were on a rest period from S-1. Slit-lamp microscopy disclosed complete occlusion of MG orifices with numerous pigmentary deposits and unexpressible glands in all patients (Figure 1; available at http://aaojournal.org). Meibography revealed marked loss of glandular structures in patients compared to controls (Figure 2; available at http://aaojournal.org). Three patients had canalicular stenosis/obstruction and 4 eyes had epithelial crack lines. The mean TEROS, corneal fluorescein staining scores, BUT, the mean acinar unit density and the mean acinar unit diameter in in vivo confocal microscopy were significantly worse in S-1 users compared with the controls (Table 1; available at http://aaojournal.org). Such in vivo confocal microscopy findings together with observations of periglandular inflammation, fibrosis, and glandular atrophy provided further evidence on S-1 induced changes in the MGs (Fig 3; available at http://aaojournal. org). Corneal and MG disease did not respond well to conventional MGD treatment for at least 2 months with lid hygiene/warming/nonpreserved artificial tears and sodium hyaluronate eye drops (Table 2; available at http://aaojournal. org). S-1 treatment was observed to induce irreversible MG damage evidenced by lack of improvement in confocal microscopy and infrared meibography even after cessation of S-1 therapy in the 6 patients in remission from their primary disease. The mechanism by which S-1 induces these changes remains unknown but direct toxicity from the drug in tears is a possibility. In summary, oncology and ophthalmology health care personnel should be aware that S-1 may induce MGD, corneal epithelial damage, and evaporative dry eye disease which require careful follow up of cancer patients receiving this treatment.