Dana R, Farid M, Gupta PK, Hamrah P, Karpecki P, McCabe CM, Nijm L, Pepose JS, Pflugfelder S, Rapuano CJ, Saini A, Gibbs SN, Broder MS. Expert consensus on the identification, diagnosis, and treatment of neurotrophic keratopathy. BMC Ophthalmol 2021;21(1):327.Abstract
BACKGROUND: Neurotrophic keratopathy (NK) is a relatively uncommon, underdiagnosed degenerative corneal disease that is caused by damage to the ophthalmic branch of the trigeminal nerve by conditions such as herpes simplex or zoster keratitis, intracranial space-occupying lesions, diabetes, or neurosurgical procedures. Over time, epithelial breakdown, corneal ulceration, corneal melting (thinning), perforation, and loss of vision may occur. The best opportunity to reverse ocular surface damage is in the earliest stage of NK. However, patients typically experience few symptoms and diagnosis is often delayed. Increased awareness of the causes of NK, consensus on when and how to screen for NK, and recommendations for how to treat NK are needed. METHODS: An 11-member expert panel used a validated methodology (a RAND/UCLA modified Delphi panel) to develop consensus on when to screen for and how best to diagnose and treat NK. Clinicians reviewed literature on the diagnosis and management of NK then rated a detailed set of 735 scenarios. In 646 scenarios, panelists rated whether a test of corneal sensitivity was warranted; in 20 scenarios, they considered the adequacy of specific tests and examinations to diagnose and stage NK; and in 69 scenarios, they rated the appropriateness of treatments for NK. Panelist ratings were used to develop clinical recommendations. RESULTS: There was agreement on 94% of scenarios. Based on this consensus, we present distinct circumstances when we strongly recommend or may consider a test for corneal sensitivity. We also present recommendations on the diagnostic tests to be performed in patients in whom NK is suspected and treatment options for NK. CONCLUSIONS: These expert recommendations should be validated with clinical data. The recommendations represent the consensus of experts, are informed by published literature and experience, and may improve outcomes by helping improve diagnosis and treatment of patients with NK.
Ruan Y, Jiang S, Musayeva A, Pfeiffer N, Gericke A. Corneal Epithelial Stem Cells-Physiology, Pathophysiology and Therapeutic Options. Cells 2021;10(9)Abstract
In the human cornea, regeneration of the epithelium is regulated by the stem cell reservoir of the limbus, which is the marginal region of the cornea representing the anatomical and functional border between the corneal and conjunctival epithelium. In support of this concept, extensive limbal damage, e.g., by chemical or thermal injury, inflammation, or surgery, may induce limbal stem cell deficiency (LSCD) leading to vascularization and opacification of the cornea and eventually vision loss. These acquired forms of limbal stem cell deficiency may occur uni- or bilaterally, which is important for the choice of treatment. Moreover, a variety of inherited diseases, such as congenital aniridia or dyskeratosis congenita, are characterized by LSCD typically occurring bilaterally. Several techniques of autologous and allogenic stem cell transplantation have been established. The limbus can be restored by transplantation of whole limbal grafts, small limbal biopsies or by ex vivo-expanded limbal cells. In this review, the physiology of the corneal epithelium, the pathophysiology of LSCD, and the therapeutic options will be presented.
Chen Y, Dana R. Autoimmunity in dry eye disease - An updated review of evidence on effector and memory Th17 cells in disease pathogenicity. Autoimmun Rev 2021;20(11):102933.Abstract
The classic Th1/Th2 dogma has been significantly reshaped since the subsequent introduction of several new T helper cell subsets, among which the most intensively investigated during the last decade is the Th17 lineage that demonstrates critical pathogenic roles in autoimmunity and chronic inflammation - including the highly prevalent dry eye disease. In this review, we summarize current concepts of Th17-mediated disruption of ocular surface immune homeostasis that leads to autoimmune inflammatory dry eye disease, by discussing the induction, activation, differentiation, migration, and function of effector Th17 cells in disease development, highlighting the phenotypic and functional plasticity of Th17 lineage throughout the disease initiation, perpetuation and sustention. Furthermore, we emphasize the most recent advance in Th17 memory formation and function in the chronic course of dry eye disease, a major area to be better understood for facilitating the development of effective treatments in a broader field of autoimmune diseases that usually present a chronic course with recurrent episodes of flare in the target tissues or organs.
Ung L, Chodosh J. Urgent unmet needs in the care of bacterial keratitis: An evidence-based synthesis. Ocul Surf 2021;Abstract
Bacterial corneal infections, or bacterial keratitis (BK), are ophthalmic emergencies that frequently lead to irreversible visual impairment. Though increasingly recognized as a major cause of global blindness, modern paradigms of evidence-based care in BK have remained at a diagnostic and therapeutic impasse for over half a century. Current standards of management - based on the collection of corneal cultures and the application of broad-spectrum topical antibiotics - are beset by important yet widely underrecognized limitations, including approximately 30% of all patients who will develop moderate to severe vision loss in the affected eye. Though recent advances have involved a more clearly defined role for adjunctive topical corticosteroids, and novel therapies such as corneal crosslinking, overall progress to improve patient and population-based outcomes remains incommensurate to the chronic morbidity caused by this disease. Recognizing that the care of BK is guided by the clinical axiom, "time equals vision", this chapter offers an evidence-based synthesis for the clinical management of these infections, underscoring critical unmet needs in disease prevention, diagnosis, and treatment.
Cox SM, Kheirkhah A, Aggarwal S, Abedi F, Cavalcanti BM, Cruzat A, Hamrah P. Alterations in corneal nerves in different subtypes of dry eye disease: An in vivo confocal microscopy study. Ocul Surf 2021;22:135-142.Abstract
PURPOSE: To evaluate corneal subbasal nerve alterations in evaporative and aqueous-deficient dry eye disease (DED) as compared to controls. METHODS: In this retrospective, cross-sectional, controlled study, eyes with a tear break-up time of less than 10 s were classified as DED. Those with an anesthetized Schirmer's strip of less than 5 mm were classified as aqueous-deficient DED. Three representative in vivo confocal microscopy images were graded for each subject for total, main, and branch nerve density and numbers. RESULTS: Compared to 42 healthy subjects (42 eyes), the 70 patients with DED (139 eyes) showed lower total (18,579.0 ± 687.7 μm/mm2 vs. 21,014.7 ± 706.5, p = 0.026) and main (7,718.9 ± 273.9 vs. 9,561.4 ± 369.8, p < 0.001) nerve density, as well as lower total (15.5 ± 0.7/frame vs. 20.5 ± 1.3, p = 0.001), main (3.0 ± 0.1 vs. 3.8 ± 0.2, p = 0.001) and branch (12.5 ± 0.7 vs. 16.5 ± 1.2, p = 0.004) nerve numbers. Compared to the evaporative DED group, the aqueous-deficient DED group showed reduced total nerve density (19,969.9 ± 830.7 vs. 15,942.2 ± 1,135.7, p = 0.006), branch nerve density (11,964.9 ± 749.8 vs. 8,765.9 ± 798.5, p = 0.006), total nerves number (16.9 ± 0.8/frame vs. 13.0 ± 1.2, p = 0.002), and branch nerve number (13.8 ± 0.8 vs. 10.2 ± 1.1, p = 0.002). CONCLUSIONS: Patients with DED demonstrate compromised corneal subbasal nerves, which is more pronounced in aqueous-deficient DED. This suggests a role for neurosensory abnormalities in the pathophysiology of DED.
Jowett N, Pineda R. Seeing through the evidence for corneal neurotization. Curr Opin Otolaryngol Head Neck Surg 2021;29(4):252-258.Abstract
PURPOSE OF REVIEW: Trigeminal anesthesia causes neurotrophic keratopathy, which may yield facial disfigurement and corneal blindness. RECENT FINDINGS: We summarize approaches and evidence for corneal neurotization. SUMMARY: Regional sensory nerve transfer appears safe and effective for therapeutic management of neurotrophic keratopathy. Prospective randomized clinical trials are necessary to confirm the utility of corneal neurotization.
Putra I, Shen X, Anwar KN, Rabiee B, Samaeekia R, Almazyad E, Giri P, Jabbehdari S, Hayat MR, Elhusseiny AM, Ghassemi M, Mahmud N, Edward DP, Joslin CE, Rosenblatt MI, Dana R, Eslani M, Hematti P, Djalilian AR. Preclinical Evaluation of the Safety and Efficacy of Cryopreserved Bone Marrow Mesenchymal Stromal Cells for Corneal Repair. Transl Vis Sci Technol 2021;10(10):3.Abstract
Purpose: Mesenchymal stromal cells (MSCs) have been shown to enhance tissue repair as a cell-based therapy. In preparation for a phase I clinical study, we evaluated the safety, dosing, and efficacy of bone marrow-derived MSCs after subconjunctival injection in preclinical animal models of mice, rats, and rabbits. Methods: Human bone marrow-derived MSCs were expanded to passage 4 and cryopreserved. Viability of MSCs after thawing and injection through small-gauge needles was evaluated by vital dye staining. The in vivo safety of human and rabbit MSCs was studied by subconjunctivally injecting MSCs in rabbits with follow-up to 90 days. The potency of MSCs on accelerating wound healing was evaluated in vitro using a scratch assay and in vivo using 2-mm corneal epithelial debridement wounds in mice. Human MSCs were tracked after subconjunctival injection in rat and rabbit eyes. Results: The viability of MSCs after thawing and immediate injection through 27- and 30-gauge needles was 93.1% ± 2.1% and 94.9% ± 1.3%, respectively. Rabbit eyes demonstrated mild self-limiting conjunctival inflammation at the site of injection with human but not rabbit MSCs. In scratch assay, the mean wound healing area was 93.5% ± 12.1% in epithelial cells co-cultured with MSCs compared with 40.8% ± 23.1% in controls. At 24 hours after wounding, all MSC-injected murine eyes had 100% corneal wound closure compared with 79.9% ± 5.5% in controls. Human MSCs were detectable in the subconjunctival area and peripheral cornea at 14 days after injection. Conclusions: Subconjunctival administration of MSCs is safe and effective in promoting corneal epithelial wound healing in animal models. Translational Relevance: These results provide preclinical data to support a phase I clinical study.
Jowett N, Pineda R. Corneal and Facial Sensory Neurotization in Trigeminal Anesthesia. Facial Plast Surg Clin North Am 2021;29(3):459-470.Abstract
Trigeminal anesthesia may yield blindness and facial disfigurement, secondary to neurotrophic keratopathy and trigeminal trophic syndrome. This article summarizes contemporary medical and emerging surgical approaches for the therapeutic management of this rare and devastating disease state.
Patel S, Yuan A, Pineda R. Acute Benign Paroxysmal Positional Vertigo After Endothelial Keratoplasty-A Unique Cause of Postoperative Nausea and Headache. Cornea 2021;40(7):926-929.Abstract
PURPOSE: To describe a case of new-onset benign paroxysmal positional vertigo (BPPV) after uncomplicated Descemet stripping automated endothelial keratoplasty. METHODS: Case report and review of literature. RESULTS: A 61-year-old woman with a history of steroid-induced glaucoma and penetrating keratoplasty for Fuchs endothelial dystrophy, and no history of BPPV or other vertigo, underwent Descemet stripping automated endothelial keratoplasty for penetrating keratoplasty graft failure. On the third postoperative day, she developed acute spinning vertigo, nausea, and headache on sitting up after 3 days of strict supine positioning. Her ophthalmic examination was benign, with no evidence of a pupillary block, and she was diagnosed by an otologist with BPPV. Her symptoms resolved after 1 week without further intervention. CONCLUSIONS: BPPV is a benign but rare complication of nonotologic surgery and has not been previously reported with ophthalmic surgery. The overlap in symptomatology between BPPV and other serious and potentially vision-threatening causes of postoperative nausea and headache, such as pupillary block glaucoma, makes this a relevant etiology to consider in the spectrum of postendothelial keratoplasty complications.
Soeken TA, Ross AE, Kohane DS, Kuang L, Legault GL, Caldwell MC, Brundridge WL, Merkley MB, Ciolino JB, Townley RJ. Dexamethasone-Eluting Contact Lens for the Prevention of Postphotorefractive Keratectomy Scar in a New Zealand White Rabbit Model. Cornea 2021;40(9):1175-1180.Abstract
PURPOSE: To evaluate the safety and efficacy of an experimental dexamethasone-eluting contact lens (DCL) for the prevention of postphotorefractive keratectomy (PRK) corneal haze in a New Zealand White (NZW) rabbit model. METHODS: Both eyes of 29 NZW rabbits underwent PRK. The rabbits were randomized to one of the 5 study arms for 4 weeks: tarsorrhaphy only, tarsorrhaphy and bandage contact lens (BCL) replaced weekly, tarsorrhaphy and BCL for 1 week plus topical 0.1% dexamethasone ophthalmic solution (drops) for 4 weeks, tarsorrhaphy and BCL replaced weekly plus topical dexamethasone for 4 weeks, and tarsorrhaphy and DCL changed weekly for 4 weeks. Each week for 4 consecutive weeks postoperatively, the tarsorrhaphies were opened, the eyes underwent evaluation and imaging, and the tarsorrhaphies were replaced. Contact lenses were cultured on removal. Central corneal haze was assessed weekly with corneal densitometry. After 4 weeks, the animals were killed, and the eyes were enucleated for histopathologic analysis. RESULTS: The tarsorrhaphy only group displayed more haze with a greater change in optical densitometry from pre-op compared with the other treatment groups. There was no difference between the DCL group and the groups receiving a BCL and dexamethasone drops in densitometry or histopathology. No NZW rabbits developed clinical signs of infection, and cultures from DCLs and BCLs grew similar organisms. CONCLUSIONS: In the post-PRK rabbit model, DCLs worn weekly for 4 weeks were safe and as effective at preventing corneal haze as 0.1% dexamethasone drops applied 4 times a day for 4 weeks.
Lee SJ, Kim S-T, Wu J, Cho CS, Jo DH, Chen Y, Dana R, Kim JH, Lee S-M. Corneal lymphangiogenesis in dry eye disease is regulated by substance P/neurokinin-1 receptor system through controlling expression of vascular endothelial growth factor receptor 3. Ocul Surf 2021;22:72-79.Abstract
PURPOSE: To evaluate the role of substance P (SP)/neurokinin-1 receptor (NK1R) system in the regulation of pathologic corneal lymphangiogenesis in dry eye disease (DED). METHODS: Immunocytochemistry, angiogenesis assay, and Western blot analysis of human dermal lymphatic endothelial cells (HDLECs) were conducted to assess the involvement of SP/NK1R system in lymphangiogenesis. DED was induced in wild-type C57BL/6 J mice using controlled-environment chamber without scopolamine. Immunohistochemistry, corneal fluorescein staining, and phenol red thread test were used to evaluate the effect of SP signaling blockade in the corneal lymphangiogenesis. The expression of lymphangiogenic factors in the corneal and conjunctival tissues of DED mouse model was quantified by real-time polymerase chain reaction. RESULTS: NK1R expression and pro-lymphangiogenic property of SP/NK1R system in HDLECs were confirmed by Western blot analysis and angiogenesis assay. Blockade of SP signaling with L733,060, an antagonist of NK1R, or NK1R-targeted siRNA significantly inhibited lymphangiogenesis and expression of vascular endothelial growth factor (VEGF) receptor 3 stimulated by SP in HDLECs. NK1R antagonist also suppressed pathological corneal lymphangiogenesis and ameliorated the clinical signs of dry eye in vivo. Furthermore, NK1R antagonist effectively suppressed the lymphangiogenic factors, including VEGF-C, VEGF-D, and VEGF receptor 3 in the corneal and conjunctival tissues of DED. CONCLUSIONS: SP/NK1R system promotes lymphangiogenesis in vitro and NK1R antagonism suppresses pathologic corneal lymphangiogenesis in DED in vivo.
Carreno-Galeano JT, Dohlman TH, Kim S, Yin J, Dana R. A Review of Ocular Graft-versus-Host Disease: Pathophysiology, Clinical Presentation and Management. Ocul Immunol Inflamm 2021;:1-10.Abstract
Graft-versus-host disease is a common complication following allogeneic hematopoetic stem cell transplantation that can affect multiple organ systems, including the eyes. Ocular GVHD (oGVHD) is characterized by a T cell-mediated immune response that leads to immune cell infiltration and inflammation of ocular structures, including the lacrimal glands, eyelids, cornea and conjunctiva. oGVHD has a significant negative impact on visual function and quality of life and successful management requires a multi-disciplinary approach with frequent monitoring. Here, we review the pathophysiology and clinical presentation of oGVHD, along with current therapeutic strategies based on our clinical experience and the reported literature.