Mizuka Kamoi

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.

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.

Spontaneous lacrimal punctal occlusion associated with ocular chronic graft-versus-host disease

Purpose: To investigate the clinical features of spontaneous lacrimal punctal occlusion (SLPO) after allogeneic hematopoietic stem cell transplantation (HSCT). Methods: One hundred nineteen recipients after HSCT who visited Keio University between 2001 and 2004 were examined. The condition of the lacrimal punctum, severity of dry eye, meibomian gland secretion, and presence of systemic chronic graft-versus-host disease (cGVHD) were determined with or without SLPO by retrospective chart review. Results: Among the 119 recipients, SLPO was diagnosed in 8. All the patients with SLPO after HSCT had meibomian gland dysfunction (MGD), dry eye, and systemic cGVHD. The percentage of patients with dry eye, MGD, and systemic cGVHD were significantly higher in recipients with SLPO than non-SLPO recipients (p < 0.0013, p < 0.00015, p < 0.0008, respectively). Conclusions: SLPO is a clinical presentation of ocular cGVHD and may be an indicator of the severity of dry eye and systemic cGVHD after HSCT.

Accumulation of Secretory Vesicles in the Lacrimal Gland Epithelia Is Related to Non-Sjögren's Type Dry Eye in Visual Display Terminal Users

Previous observations in a rat model of a non-Sjögrens syndrome (non-SS) type of dry eye seen in users of visual display terminals (VDT) indicated that secretory vesicle (SV) accumulation in the lacrimal gland epithelia contributes to the condition. Here, to examine this possibility in humans, we compared the lacrimal gland histology and percent SV area in the cytoplasm of acinar epithelial cells using light microscopy and transmission electron microscopy, in patients with VDT work-related non-SS dry-eye (VDT group), SS-induced dry-eye, and autopsied normal controls. In addition, the VAMP8 (vesicle-associated membrane protein 8, an exocrine-pathway molecule) and Rab3D (mature vesicle marker) were histochemically examined in lacrimal gland tissue sections. The lacrimal gland acini were larger in the VDT group than in the SS group, and the percent SV area was significantly higher in the VDT group than in the normal controls (P = 0.021) or SS group (P = 0.004). Immunostaining revealed abnormal distributions of VAMP8 in the VDT and SS groups. Rab3D was more strongly expressed in the cytoplasm of acinar epithelial cells in the VDT group than in that of normal controls. The duration of VDT use was significantly longer in the VDT group than in the other groups. These findings suggest that excessive SV accumulation in the acinar epithelia may contribute to the reduced tear secretion in VDT users.

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.

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.

Long-term rebamipide and diquafosol in two cases of immune-mediated dry eye.

Purpose Two new drugs with mucin-inducing and secretion-promotive effects, rebamipide and diquafosol, were recently approved as topical dry-eye treatments. We report two cases in which the long-term use of mucin-inducing eye drops improved chronic ocular graft-versus-host disease (cGVHD)–related dry eye and ocular cicatricial pemphigoid (OCP)-like disease. Case Reports Case 1. A 61-year-old woman had cGVHD-related dry eye that resisted traditional medications. Next, we use topical diquafosol in addition to conventional treatments. The patient used diquafosol for 6 months without experiencing any side effects. The symptoms, including dry-eye sensation, ocular pain, foreign body sensation, and photophobia, as well as ocular surface findings including fluorescein and rose bengal scores and tear break-up time (TBUT), partly improved. To further improve the clinical signs and symptoms and decrease chronic inflammation, rebamipide was added to diquafosol. The symptoms, TBUT, and fluorescein and rose bengal scores markedly improved after long-term dual treatment without any side effects for 6 months. Case 2. A 77-year-old woman had OCP-like disease with dry eye. The patient did not improve using the currently available conventional treatments. Next, we use topical rebamipide in addition to conventional treatments. Symptoms including asthenopia, dry-eye sensation, ocular pain, and dull sensation, as well as fluorescein and rose bengal scores and TBUT, partly improved. Specifically, functional visual acuity was markedly improved after commencement of rebamipide. To further improve the clinical signs and symptoms and increase tear film stability and tear film volume, diquafosol was added to rebamipide. The combination of diquafosol and rebamipide worked for the patient. Improvements were seen in several symptoms, fluorescein and rose bengal scores, Schirmer test value, and TBUT without any side effects for 12 months. Conclusions Long-term treatment with topical rebamipide and diquafosol can improve dry eye in patients with cGVHD or OCP-like disease.

In Vivo Confocal Microscopy Evaluation of Ocular Surface with Graft-Versus-Host Disease-Related Dry Eye Disease

Dry eye disease (DED) is often elicited by graft-versus-host disease (GVHD), an extensive complication of hematopoietic stem cell transplantation (HSCT). To unravel the mechanism of this type of DED, in vivo confocal microscopy (IVCM) was used to investigate alterations in the state of the sub-basal nerves, dendritic cells (DCs) and globular immune cells (GICs) in the central cornea and limbal epithelia. In this study, we examined 12 HSCT recipients with GVHD-caused DED and 10 HSCT recipients without GVHD-associated DED and evaluated the clinical parameters in the 2 groups. Analysis of the central cornea and limbal epithelia using IVCM was conducted to investigate the density of the corneal sub-basal nerves, DCs and GICs as well as the tortuosity and branching of the sub-basal nerves. As suggested by our data, the clinical variables in the GVHD group were significantly different from those in the non-GVHD group. Additionally, GVHD-triggered DED conceivably increased the density of DCs and GICs in the central cornea and the density of DCs in limbal epithelia and altered the morphology of the sub-basal nerves. These phenomena are presumably correlated with the degree of inflammation. Thus, our findings may be translated into non-invasive diagnostic methods that indicate the severity of inflammation on the ocular surface in HSCT recipients.

Reduced Expression of VAMP8 in Lacrimal Gland Affected by Chronic Graft-versus-Host Disease

Purpose To investigate whether the SNARE protein vesicle-associated membrane protein 8 (VAMP8) was implicated in the development of chronic ocular graft-versus-host disease (GVHD). Methods Firstly, the chronic GVHD (cGVHD) and Sjögrens syndrome (SS)-impaired lacrimal gland (LG) tissue sections from humans for diagnostic purpose were evaluated for VAMP8 expression by histopathology and immunohistochemistry. Next, serial changes of tear secretion and VAMP8 expression at both protein and mRNA level of LG in an animal cGVHD model compared with the syngeneic control. Results Decreased VAMP 8 expression in the cGVHD-affected human LG was detected in comparison with SS-affected LG. Tear secretion in the murine cGVHD model was significantly reduced compared with that in the syngeneic controls 8 weeks after BMT. Protein expression of VAMP8 in the cGVHD-affected LG in murine cGVHD was decreased in comparison with that in the controls. Gene expression of VAMP8 in the cGVHD-affected murine LG was significantly less than that in the syngeneic control 3 weeks after BMT. Conclusions Our results suggested that expression of VAMP8 in the cGVHD-affected LG was decreased and accordingly tear secretion in cGVHD was reduced. Collectively, the reduction of VAMP8 expression in the cGVHD-affected LG can be involved in the pathogenic processes of cGVHD-induced dry eye disease.