Search

Purpose: To report a rare case of dematiaceous fungal keratitis caused by Cladophialophora boppii (C. boppii) in an immunocompromised patient. Observations: An 83-year-old male with chronic renal failure was referred to the Department of Ophthalmology, Kyoto Prefectural University of Medicine, Kyoto, Japan due to persistent corneal epithelial defects (PEDs) in his left eye. Initial examination revealed decreased central corneal sensitivity and decreased tear secretion in that eye, both thought to be associated with herpetic keratitis. Permanent punctal-plug surgery combined with therapeutic soft contact lens wear was performed to treat the PED, which initially healed, yet recurred. Follow-up examination revealed a 1.0-mm-diameter black lesion consistent with the PED site, which subsequently increased in size, so treatment with miconazole solution eye drops, natamycin ophthalmic ointment, and systemic itraconazole was initially performed. Since the region of the lesion had progressed to corneal perforation, corneal transplantation surgery under general anesthesia was scheduled, yet the patient refused to undergo surgery. Mycological testing via DNA sequencing of the internal transcribed spacer of ribosomal DNA regions revealed that the isolate or pathogen was C. boppii. Mycotic keratitis caused by C. boppii was found to be resistant to antifungal drugs. Conclusion and importance: This is a rare case of fungal keratitis caused by C. boppii in an elderly immunocompromised patient.

Purpose: To report a rare Ocular Cicatricial Pemphigoid (OCP) case in a patient taking a Dipeptidyl Peptidase-4 Inhibitor (DPP-4 inhibitor), a medication used for the management of type 2 diabetes, for at least six years. Observations: A 64-year-old male presented with refractory bilateral conjunctival inflammation and ocular discharge that had persisted for two months, despite multiple prior therapies for presumed bacterial conjunctivitis. Upon initial examination, clinical findings strongly suggested OCP, and he had elevated levels of anti-BP180 antibodies. Despite receiving systemic treatments such as steroid pulse therapy and therapeutic plasma exchange after discontinuing DPP-4 inhibitors, his condition progressively worsened, with manifestations such as forniceal shortening in his left eye. Consequently, the patient required keratoepithelioplasty, amniotic membrane transplantation in his left eye, and bilateral eyelid entropion surgery. His condition initially worsened for a time after discontinuing the DPP-4 inhibitor, but it gradually improved over time, and ocular surface surgical intervention was not required in the right eye. Conclusions and Importance: The findings in this study demonstrate that severe refractory OCP may occur while taking the DPP-4 inhibitor, thus indicating that a detailed interview regarding medications is essential for patients with ocular pemphigoid, especially those with type 2 diabetes.

Ophthalmic nanoemulsions that can treat the deficiencies of meibum (MGS) in Meibomian gland disease and restore its functionality in the tear film are greatly sought. The Rohto Dry Aid (RDA) formulation employs TEARSHIELD TECHNOLOGYTM, which uses a multicomponent oil phase of polar and non-polar lipid-like molecules selected to mimic the profiles of healthy meibum. Thus, the interactions of RDA with “diseased” Meibomian (dMGS) films merit deeper analysis, as these interactions might offer important clues for both the development of new ocular formulations and the processes behind the therapeutic action of the nanoemulsions. Pseudobinary dMGS/RDA films were spread at the air–water surface of the Langmuir trough. Surface pressure-area isocycles and stress relaxations were used to access the layer’s response to blink-like cycling and dilatational viscoelasticity, respectively, while film morphology was recorded via Brewster angle microscopy. It was found that RDA is able to reverse the brittleness and to restore the stability of “diseased” MGS films and thus to revert the layer’s properties to the functionality of healthy Meibomian lipids. Therefore, in order to effectively treat dry eyes with MGS-oriented therapy, ophthalmic nanoemulsions warrant more research.

Meibomitis-related keratoconjunctivitis (MRKC) is characterized by meibomitis with corneal epithelial abnormalities, and can be divided into two types: MRKC accompanied with phlyctenular keratitis, and MRKC accompanied with keratoepitheliopathy that is similar to superficial punctate keratopathy (SPK). The purpose of this retrospective study was to investigate the characteristic features of keratoepitheliopathy and treatment outcomes for MRKC. This study involved 27 eyes of 18 MRKC patients (3 males and 15 females). National Eye Institute (NEI) scores and visual acuity were compared at pre and post treatment. All subjects were treated with a small-dose administration of clarithromycin. Keratoepitheliopathy characteristic to MRKC, yet different in appearance from SPK, was noted in 24 of the 27 eyes. Fluorescein staining revealed granular epithelial lesions generally larger than SPK that coexisted with small dark spots. In 17 eyes, keratoepitheliopathy was located within the pupillary zone, and the visual acuity in 12 eyes was less than 1.0. Our findings showed significant improvement in the NEI score in MRKC (p < 0.0001) and in visual acuity (p = 0.0157) post treatment, and the characteristic features of keratoepitheliopathy in MRKC that are often associated with decreased visual acuity were elucidated. The treatment of clarithromycin was found to be effective for MRKC with keratoepitheliopathy.

The pre-lens tear film (PLTF) over (i) delefilcon A silicone hydrogel water gradient (WG; 33–80% from core to surface) contact lenses (CLs) (SHWG-CLs) and (ii) subjects’ own non-WG soft CLs (SCLs) (SO-SCLs) was studied in 30 eyes of 30 subjects to assess the hypothesized PLTF stabilization over SHWG-CLs. In both eyes, delefilcon A SHWG-CLs (DAILIES TOTAL1®; Alcon, Fort Worth, TX, USA) or SO-SCLs were worn. After 15 min of wearing each lens, the tear meniscus radius (TMR, mm), lipid-layer interference grade (IG) and spread grade (SG), and non-invasive breakup time (NIBUT, seconds) were evaluated and compared between the SHWG-CLs and the SO-SCLs. The comparison between the SHWG-CL and SO-SCL groups (SHWG-CL and SO-SCL, mean ± SD) revealed that TMRs temporarily decreased and reached a plateau value after 15 min (0.21 ± 0.06; 0.21 ± 0.06) compared to the value prior to CL insertion (0.24 ± 0.08; 0.25 ± 0.08), with no significant difference between the two groups. The NIBUT, IG, and SG values after 15 min of wearing the CLs were (9.7 ± 3.7; 4.7 ± 4.2), (1.0 ± 0.2; 1.8 ± 1.0), and (1.1 ± 0.4; 1.9 ± 1.5), respectively, and all values were significantly better in the SHWG-CL group (p < 0.0001, p = 0.0039, and p < 0.0001, respectively). We found that compared to the SO-SCLs, the maintenance of the PLTF on the SHWG-CLs was supported by the thicker and more stable PLTF.

Bitot’s spots (BS) are the buildup of superficially located keratin in the conjunctiva and are early indicators of vitamin A deficiency (VAD), primarily due to malnutrition and malabsorption, thus leading to xerophthalmia. BS are particularly prevalent in developing countries, and their presence necessitates prompt vitamin A supplementation to avert blindness, with the immunohistochemical characteristics of BS aiding in understanding the extent of epithelial abnormalities and the efficacy of vitamin A supplementation. We describe the case of a 34-year-old male with persistent BS despite extensive vitamin A supplementation and topical treatments who underwent surgical excision of the BS followed by amniotic membrane transplantation, thus resulting in symptom relief and epithelialization, with no recurrence observed during follow-up. Histopathologic and immunohistochemical evaluations revealed expression of keratinization-related proteins, along with an absence of mucin-5AC-positive cells, suggesting impaired differentiation into goblet cells due to VAD. This case highlights the potential age-related disparity in the efficacy of vitamin A supplementation, emphasizing the need for early detection and a multidisciplinary approach in the management of VAD, especially in young adults. The favorable outcome of surgical intervention highlights its viability in the management of persistent BS and encourages further investigation to optimize therapeutic strategies for VAD-related ocular manifestations.

Punctal occlusion (PO) is considered to improve both tear-film instability and increased friction during blinking and may consequently affect blinks. The purpose of this study was to investigate the effect of PO on blinks. This study involved 16 eyes of 16 severe aqueous deficient dry eye (ADDE) patients (mean age: 65.7 years). In all eyes, tear meniscus radius (TMR), spread grade (SG) of the tear-film lipid layer (i.e., SG 1-5: 1 being the best), fluorescein break-up time (FBUT), corneal epithelial damage score (CED), conjunctival epithelial damage score, corneal filament (CF) grade, lid-wiper epitheliopathy (LWE) grade, and superior limbic keratoconjunctivitis (SLK) grade were evaluated at before and at more than 1-month after PO. Moreover, using a custom-made high-speed blink analyzer, palpebral aperture height, blink rate, upper-eyelid closing-phase amplitude/duration/maximum velocity, and upper-eyelid opening-phase amplitude/duration/maximum velocity were measured at the same time point. After PO, TMR, SG, FBUT, CED, and the CF, LWE, and SLK grades were significantly improved, and upper-eyelid opening/closing-phase amplitude and maximum velocity significantly increased (all p < 0.04). The findings of this study suggest that PO improves ocular surface lubrication and that blink-related parameters can reflect the friction that occurs during blinking in eyes with severe ADDE.

In this study, the severity of eye pain (EP) and associated objective findings were evaluated in aqueous-deficient dry eye (ADDE) patients using PainVision®, a quantitative pain-measuring device. This study involved 53 eyes of 53 ADDE patients (6 males and 47 females; mean age: 64.4 ± 13.4 [mean ± SD] years). Of those, 18 eyes of 18 patients underwent punctal occlusion, and EP and objective findings in those patients were evaluated before and after treatment. In all patients, the severity of EP as measured by PainVision® was assessed using the Pain Degree (PD). The median PD for the 53 patients was 30.6 µA/µA (interquartile range, 16.9–93.2), and the nasal and central corneal staining score and the upper lid-wiper epitheliopathy score were significantly correlated with PD (R = 0.33, 0.33, and 0.28, respectively) (all: p < 0.05). Using the least squares method, the central corneal staining score most significantly affected PD. In the 18 cases that underwent punctal occlusion, PD was significantly reduced (median PD: 24.8 to 7.1 µA/µA; p < 0.0001). Using the least squares method, the central corneal staining score and tear meniscus radius were significantly more influential as factors contributing to PD before and after treatment, and central corneal epithelial damage was the factor most associated with ADDE-related EP.

We previously reported on ‘Tear Film Oriented Diagnosis’ (TFOD), a method for the dry eye (DE) subtype classification using fluorescein staining and an examination of fluorescein breakup patterns via slit-lamp biomicroscopy. Here, we report ‘AI-supported TFOD’, a novel non-invasive method for DE subtype classification using videokeratography (VK) and “Blur Value” (BV), a new VK indicator of the extent of blur in Meyer-ring images and deep learning (DL). This study involved 243 eyes of 243 DE cases (23 males and 220 females; mean age: 64.4 ± 13.9 (SD) years)—i.e., 31 severe aqueous-deficient DE (sADDE) cases, 73 mild-to-moderate ADDE (m/mADDE) cases, 84 decreased wettability DE (DWDE) cases, and 55 increased evaporation DE (IEDE) cases diagnosed via the fluorescein-supported TFOD pathway. For DL, a 3D convolutional neural network classification model was used (i.e., the original image and BV data of eyes kept open for 7 s were randomly divided into training data (146 cases) and the test data (97 cases), with the training data increased via data augmentation and corresponding to 2628 cases). Overall, the DE classification accuracy was 78.40%, and the accuracies for the subtypes sADDE, m/mADDE, DWDE, and IEDE were 92.3%, 79.3%, 75.8%, and 72.7%, respectively. ‘AI-supported TFOD’ may become a useful tool for DE subtype classification.

In this study, we evaluated the effectiveness of a single-dose oral pilocarpine administration on tear film (TF), as well as dry eye and dry mouth symptoms, in 53 eyes of 27 Sjögren syndrome (SS) patients who were experiencing dry mouth. To evaluate the changes in tear volume, a digital video-meniscometer was used to measure the radius of the lower central tear meniscus curvature (R, mm) of each eye at prior to the administration of 5 mg oral pilocarpine, and at 15 (R:(15)), 30 (R:(30)), and 60 (R:(60)) minutes after administration. The fluorescein breakup time (FBUT, seconds) and ocular and oral dryness symptoms were evaluated before and at 60 min after administration using a visual analogue scale (VAS, mm). A significant increase in R was observed at 15 and 30 min after administration compared to that at prior to administration. FBUT showed significant improvement at 60 min after administration, and the VAS score for ocular and oral dryness symptoms was found to have decreased significantly at 60 min after administration. A single-dose administration of 5 mg oral pilocarpine had a beneficial effect on TF, as well as on ocular and oral dryness symptoms, in patients with SS.

Abstract A relationship between ocular sarcoidosis (OcSar) and dry eye (DE) has previously been reported. Here we investigated the tear function in OcSar, and the other uveitis, Vogt–Koyanagi–Harada disease (VKH), to elucidate the association between OcSar and DE. This study involved 27 eyes of 27 female OcSar patients [mean age: 67.3 ± 13.5 (SD) years], 18 eyes of 18 female VKH patients (53.1 ± 14.1 years), and 17 eyes of 17 female healthy control subjects (59.7 ± 9.6 years). In all examined eyes, tear meniscus height (TMH, mm), fluorescein breakup time (FBUT, s), scoring of keratoconjunctival epithelial damage (ED), and the Schirmer 1 test (ST1, mm/5 min) were analyzed. In the OcSar patients, VKH patients, and control subjects, the respective TMH, FBUT, ED, and ST1 values (mean ± SD) were 0.26 ± 0.10, 0.24 ± 0.09, and 0.24 ± 0.08, 4.3 ± 2.5, 7.3 ± 2.9, and 6.3 ± 3.1, 1.1 ± 1.1, 0.7 ± 0.8, and 0.1 ± 0.3, and 12.9 ± 10.5, 21.5 ± 12.1, and 24.3 ± 10.5. Statistically, the ST1 values were significantly lower in the OcSar patients than in the VKH patients (P = 0.004) and control subjects (P = 0.001). ST1 findings revealed that the neural reflex arc and lacrimal gland system, which attenuate the vicious cycle between the tear film and ocular surface epithelium in DE, are significantly impaired in OcSar cases, thus indicating a possible association between OcSar and DE.

Analysis of higher-order aberrations (HOAs) is one reported method for evaluating dry eye disease (DED)-related loss of visual function. Tear film (TF) instability and corneal epithelial damage (CED) are both reportedly responsible for HOAs in DED, although, to the best of our knowledge, there are no reported methods that allow concurrent evaluation of their effects. In this study, we used a videokeratographer (VK) to continuously measure HOAs in DED after eye opening and investigated factors of ocular surface abnormalities that determine HOAs. This study involved 96 DED cases that underwent DED symptom assessment with a questionnaire and examination of tear volume, TF abnormalities (i.e., TF lipid-layer interference grades and spreading grades, and non-invasive breakup time and fluorescein breakup time), and CED, and their correlation with HOAs evaluated via VK. The results show that HOAs at 1 or 2 s after eye opening can reflect TF instability and CED within the central 4-millimeter-diameter area of the optical zone in DED eyes concurrently. This finding may be useful for the rapid and non-invasive detection and evaluation of degraded visual function in DED cases with a variety of clinical features.

Soft contact lens (SCL) perturbs the intimate connection between the pre-lens tear film (PLTF) and the ocular surface in various ways, i.e., (i) decrease in tear meniscus radius and aqueous tear thickness, (ii) attenuation of tear film lipid layer spread, (iii) limited wettability of SCL surface, (iv) increased friction with eyelid wiper, etc. This often results in SCL-related dry eye (SCLRDE) manifested as PLTF instability and contact lens discomfort (CLD). In this review, the individual contributions of factors (i–iv) to PLTF breakup patterns (BUP) and CLD are considered via the tear film-oriented diagnosis framework adopted by the Asia Dry Eye Society from a clinical and basic science perspective. It is shown that SCLRDE (due to aqueous deficiency, increased evaporation, or decreased wettability) and BUP of PLTF classify within the same types as the ones observed for the precorneal tear film. The analysis of PLTF dynamics reveals that the inclusion of SCL enhances the manifestation of BUP associated with (i) decreased thickness of PLTF aqueous layer and (ii) limited SCL wettability as shown by the rapid expansion of BUP area. PLTF thinness and instability result in increased blink-related friction and lid wiper epitheliopathy as major contributor to CLD.

Spot break (SB), a tear film breakup (TFBU) subtype seen in decreased wettability dry eye (DE), is characterized by a spot-like TFBU that appears immediately after eye opening. It is sometimes difficult to detect using currently available devices for evaluating non-invasive TFBU. The purpose of this study was to investigate the effectiveness of using a newly developed videokeratography indicator for detecting SB. The study involved 44 eyes of 44 DE patients (21 eyes with SB (SB group) and 23 eyes with random break in which fluorescein breakup time was ≤ 5 s (s) (RB group)). All eyes were examined using videokeratography, with digital Meyer-ring images being obtained. By calculation of the degree of luminance blur on the cornea in the Meyer-ring images, termed ‘disturbance value’ (DV), DVs at 0 s (DV(0)]), 2 s (DV(2)), and 5 s (DV(5)) after eye opening, and the changes of DV between each time, were compared between the SB and RB groups. Results: No significant differences in DV(2) and DV(5) and the rate of change between DV(2) and DV(5) were found between the two groups. However, DV(0) and rate of change between DV(0) and DV(2) in the SB group were significantly greater (p < 0.001) than those in the RB group. SB characteristics were successfully detected by videokeratography using a new videokeratography DV indicator.

Summary: What percentage of the protein function is required to prevent disease symptoms is a fundamental question in genetic disorders. Decreased transsynaptic LGI1-ADAM22 protein complexes, because of their mutations or autoantibodies, cause epilepsy and amnesia. However, it remains unclear how LGI1-ADAM22 levels are regulated and how much LGI1-ADAM22 function is required. Here, by genetic and structural analysis, we demonstrate that quantitative dual phosphorylation of ADAM22 by protein kinase A (PKA) mediates high-affinity binding of ADAM22 to dimerized 14-3-3. This interaction protects LGI1-ADAM22 from endocytosis-dependent degradation. Accordingly, forskolin-induced PKA activation increases ADAM22 levels. Leveraging a series of ADAM22 and LGI1 hypomorphic mice, we find that ∼50% of LGI1 and ∼10% of ADAM22 levels are sufficient to prevent lethal epilepsy. Furthermore, ADAM22 function is required in excitatory and inhibitory neurons. These results suggest strategies to increase LGI1-ADAM22 complexes over the required levels by targeting PKA or 14-3-3 for epilepsy treatment.

Meibomian gland disease is associated with quantitative or qualitative deficiencies of meibum (MGS) that result in tear film instability. Thus, there is great demand for ophthalmic nanoemulsions that can replenish MGS and recover its performance at the air/tear surface. Rohto Dry Aid (RDA) utilizes TEARSHIELD TECHNOLOGYTM implementing a complex oil phase of non-polar and polar lipid-like molecules. Therefore, the interactions of RDA with MGS surface films deserve further study as they may provide valuable insights (i) into the mechanisms behind the nanoemulsion therapeutic action and (ii) for the design of novel ophthalmic formulations. Pseudobinary meibum/RDA films were formed at the air–water surface of the Langmuir trough. Surface pressure-area isocycles and stress relaxations were employed to probe the layer (i) reorganization upon cycling and (ii) dilatational elasticity, respectively. Film morphology was accessed by Brewster angle microscopy and the spreading properties of RDA-supplemented meibum were also probed. The diverse ingredients of the nanoemulsion oil phase complemented the non-polar and polar lipid constituents of the meibomian layers, which resulted in enhanced continuity of the MGS duplex film structure and facilitated the MGS spread and viscoelasticity. Nanoemulsions deserve further study as a potent tool for MGS-oriented therapy for dry eyes.

A possible approach for the treatment of meibomian gland disease (MGD) can be the supplementation of meibomian gland secretion (MGS) with nonpolar lipids (NPL) rich plant oils. Sesame oil (SO), approximately equal in monounsaturated fat (oleic acid, 40% of total) and polyunsaturated fat (linoleic acid, 42% of total), has shown multiple health benefits due to its anti-inflammatory and antioxidant effects. Thus, the interactions between SO and MGS in surface layers deserve further study. Therefore, pseudobinary films were formed with controlled MGS/SO molar ratios (0%, 10%, 30%, 50%, and 100% SO) at the air/water surface of the Langmuir trough over phosphate buffered saline (pH 7.4) subphase. Surface pressure (π)-area (A) isotherms and Brewster angle microscopy observations showed nonideal interactions where SO aggregates with MGS and complements the NPL stratum of the meibomian layers. The analysis of stress relaxation transients with Kohlrausch–Williams–Watts equation revealed that the supplementation of fixed amount of MGS with excess lipids via SO altered the dilatational elasticity of the films as reflected by the increase of the exponent β. Thus, SO with its unique combination of high oxidative stability and abundance of long polyunsaturated acyl chains might be a useful supplement to MGS layers.

The small GTPase Cdc42 exists in the form of two alternatively spliced variants that are modified by hydrophobic chains: the ubiquitously expressed Cdc42-prenyl and a brainspecific isoform that can be palmitoylated, Cdc42-palm. Our previous work demonstrated that Cdc42-palm can be palmitoylated at two cysteine residues, Cys188 and Cys189, while Cys188 can also be prenylated. We showed that palmitoylation of Cys188 is essential for the plasma membrane localization of Cdc42-palm and is critically involved in Cdc42-mediated regulation of gene transcription and neuronal morphology. However, the abundance and regulation of this modification was not investigated. In the present study, we found that only a minor fraction of Cdc42 undergoes monopalmitoylation in neuroblastoma cells and in hippocampal neurons. In addition, we identified DHHC5 as one of the major palmitoyl acyltransferases that could physically interact with Cdc42-palm. We demonstrate that overexpression of dominant negative DHHC5 mutant decreased palmitoylation and plasma membrane localization of Cdc42-palm. In addition, knockdown of DHHC5 significantly reduced Cdc42-palm palmitoylation, leading to a decrease of Cdc42-mediated gene transcription and spine formation in hippocampal neurons. We also found that the expression of DHHC5 in the brain is developmentally regulated. Taken together, these findings suggest that DHHC5-mediated palmitoylation of Cdc42 represents an important mechanism for the regulation of Cdc42 functions in hippocampus. [ABSTRACT FROM AUTHOR]