Corneal Nerve and Epithelial Cell Alterations in Corneal Allodynia: An In Vivo Confocal Microscopy Case Series.

PURPOSE: To investigate morphological changes of the corneal epithelium and subbasal nerves in patients with corneal allodynia using in vivo confocal microscopy (IVCM). DESIGN: Case-control study of patients with corneal allodynia and healthy controls. METHODS: Ten eyes of six patients were diagnosed with corneal allodynia at a single center and compared to fifteen healthy eyes. IVCM of the central cornea was performed on all subjects and controls. Images were retrospectively analyzed numbers of total corneal subbasal nerves, main trunks and branches, total nerve length and density, nerve branching, and tortuosity, superficial and basal epithelial cell densities, and superficial epithelial cell size. RESULTS: Corneal allodynia was seen in patients with dry eye disease, recurrent corneal erosion syndrome, exposure to ultraviolet radiation, and Accutane use. Compared to controls, patients with corneal allodynia had a significant decrease in the total numbers of subbasal nerves (P=.014), nerve branches (P=.006), total nerve length (P=.0029), total nerve density (P=.0029) and superficial and basal epithelial cell densities (P=.0004, P=.0036) with an increase in superficial epithelial cell size (P=.016). There were no statistically significant differences in the number of subbasal nerve main trunks (P=.09), nerve branching (P=.21), and nerve tortuosity (P=.05). CONCLUSIONS: Corneal IVCM enables near-histological visualization and quantification of the cellular and neural changes in corneal allodynia. Regardless of etiology, corneal allodynia is associated with decreased corneal epithelial cell densities, increased epithelial cell size, and decreased numbers and lengths of subbasal nerves despite an unremarkable slit-lamp examination. Therefore, IVCM may be useful in the management of patients with corneal allodynia.

Oculofacial Pain: Corneal Nerve Damage Leading to Pain Beyond the Eye.

The cornea is supplied principally by the ophthalmic branch of the trigeminal nerve and is the most densely innervated organ in the human body. Under normal conditions, the corneal nerve terminals incorporate sensors that monitor the thickness and integrity of the tear film, which are essential for meaningful vision. A disrupted tear film or direct noxious stimulation of these corneal nerves can produce discomfort or pain limited to the affected surface. Damage to these nerves can sometimes lead to a chronic neuropathic condition, where pain persists months following the initial insult, long after the nerves appear to have healed in the cornea itself following treatment. Neuropathic pain appears to persist indefinitely in a few patients.

Ocular neuropathic pain.

As the biological alarm of impending or actual tissue damage, pain is essential for our survival. However, when it is initiated and/or sustained by dysfunctional elements in the nociceptive system, it is itself a disease known as neuropathic pain. While the critical nociceptive system provides a number of protective functions, it is unique in its central role of monitoring, preserving and restoring the optical tear film in the face of evaporative attrition without which our vision would be non-functional. Meeting this existential need resulted in the evolution of the highly complex, powerful and sensitive dry eye alarm system integrated in the peripheral and central trigeminal sensory network. The clinical consequences of corneal damage to these nociceptive pathways are determined by the type and location of its pathological elements and can range from the spectrum known as dry eye disease to the centalised oculofacial neuropathic pain syndrome characterised by a striking disparity between the high intensity of symptoms and paucity of external signs. These changes parallel those observed in somatic neuropathic pain. When seen through the neuroscience lens, diseases responsible for inadequately explained chronic eye pain (including those described as dry eye) can take on new meanings that may clarify long-standing enigmas and point to new approaches for developing preventive, symptomatic and disease-modifying interventions for these currently refractory disorders.

Treatment of persistent corneal epithelial defect with overnight wear of a prosthetic device for the ocular surface.

PURPOSE: To report experience in the treatment of persistent corneal epithelial defect using overnight wear of a prosthetic device for the ocular surface. DESIGN: Retrospective interventional case series. METHODS: A clinical database of patients who underwent prosthetic replacement of the ocular surface ecosystem (PROSE) treatment from March 2003 to August 2008 was searched to identify patients treated for persistent corneal epithelial defect. In early 2003, overnight wear of a PROSE device and addition of commercially available, nonpreserved, topical ophthalmic moxifloxacin to the saline in the device reservoir became standard practice at this center when treating persistent corneal epithelial defect. Medical records were abstracted to obtain underlying diagnoses, previous treatments, days to re-epithelialization, and complications for subsequent analysis. RESULTS: PROSE treatment incorporating overnight wear, with adjunctive use of moxifloxacin, was employed in 20 eyes of 19 patients for a total of 372 days. Re-epithelialization occurred in 17 of 20 eyes. Median duration of treatment incorporating overnight wear was 8.5 days (range = 2-76 days). Healing occurred in ≤7 days in 12 eyes, 8-14 days in 3 eyes, and >14 days in 2 eyes (range = 1-35 days). There were no cases of microbial keratitis. CONCLUSIONS: Overnight wear of a PROSE device is effective in promoting healing of persistent corneal epithelial defect. In comparison to an earlier series from this center, the rate of microbial keratitis as a complication of treatment has been reduced with the use of a nonpreserved topical fourth-generation fluoroquinolone in the device reservoir.

Wavefront-guided scleral lens prosthetic device for keratoconus.

PURPOSE: To investigate the feasibility of correcting ocular higher order aberrations (HOAs) in keratoconus (KC) using wavefront-guided optics in a scleral lens prosthetic device (SLPD). METHODS: Six advanced KC patients (11 eyes) were fitted with an SLPD with conventional spherical optics. A custom-made Shack-Hartmann wavefront sensor was used to measure aberrations through a dilated pupil wearing the SLPD. The position of SLPD, that is, horizontal and vertical decentration relative to the pupil and rotation were measured and incorporated into the design of the wavefront-guided optics for the customized SLPD. A submicron-precision lathe created the designed irregular profile on the front surface of the device. The residual aberrations of the same eyes wearing the SLPD with wavefront-guided optics were subsequently measured. Visual performance with natural mesopic pupil was compared between SLPDs having conventional spherical and wavefront-guided optics by measuring best-corrected high-contrast visual acuity and contrast sensitivity. RESULTS: Root mean square of HOA in the 11 eyes wearing conventional SLPD with spherical optics was 1.17 ± 0.57 µm for a 6-mm pupil. Higher order aberrations were effectively corrected by the customized SLPD with wavefront-guided optics, and root mean square was reduced 3.1 times on average to 0.37 ± 0.19 µm for the same pupil. This correction resulted in significant improvement of 1.9 lines in mean visual acuity (p < 0.05). Contrast sensitivity was also significantly improved by factors of 2.4, 1.8, and 1.4 on average for 4, 8, and 12 cycles/degree, respectively (p < 0.05 for all frequencies). Although the residual aberration was comparable to that of normal eyes, the average visual acuity in logMAR with the customized SLPD was 0.21, substantially worse than normal acuity. CONCLUSIONS: The customized SLPD with wavefront-guided optics corrected the HOA of advanced KC patients to normal levels and improved their vision significantly.

An approach to localizing corneal pain representation in human primary somatosensory cortex.

The cornea has been a focus of animal electrophysiological research for decades, but little is known regarding its cortical representation in the human brain. This study attempts to localize the somatotopic representation of the cornea to painful stimuli in human primary somatosensory cortex using functional magnetic resonance imaging (fMRI). In this case study, a subject was imaged at 3T while bright light was presented in a block-design, which either produced pain and blinking (during photophobia) or blinking alone (after recovery from photophobia). Pain and blinking produced precisely localized activations in primary somatosensory cortex and primary motor cortex. These results indicate that noxious stimulation of the cornea can produce somatotopic activation in primary somatosensory cortex. This finding opens future avenues of research to evaluate the relationship between corneal pain and central brain mechanisms relating to the development of chronic pain conditions, such as dry eye-like symptoms.

The effect of optic asphericity on visual rehabilitation of corneal ectasia with a prosthetic device.

OBJECTIVES: To study the effect of optic asphericity on visual rehabilitation of corneal ectasia with a prosthetic device. METHODS: Subjects with corneal ectasia treated with a fluid-ventilated gas-permeable prosthetic device of diameter 18.0-19.0 mm, who had subjective improvement of good Snellen vision with introduction of optic asphericity, were studied. Best corrected Snellen visual acuity (BCVA) under standard illumination, high contrast visual acuity (HCVA), low contrast visual acuity (LCVA), and wavefront aberrations were measured in a sequence of devices that varied per patient only in presence or amount of ellipsoidal front surface optical eccentricity (FSE). RESULTS: Five eyes of 5 subjects were studied. (M:F = 3:2; Age: 20-76). Mean steepest SimK was 57.72±8.30 D. BCVA was ≥20/30 in all eyes in all prosthetic devices, regardless of FSE. Although FSE improved BCVA, HCVA, and LCVA in each patient, no optimal amount could be identified in this small series. Asphericity in the form of 0.6 or 0.8 FSE improved HCVA, LCVA, or both in each patient. FSE was associated with a trend toward reduction of higher-order aberrations, particularly coma. CONCLUSIONS: Optic asphericity shows promise for optimization of vision in the rehabilitation of corneal ectasia with a prosthetic device.

PROSE treatment of corneal ectasia.

PURPOSE: Prosthetic replacement of the ocular surface ecosystem (PROSE) uses custom designed and fabricated prosthetic devices in a treatment that restores vision, supports healing, reduces symptoms and improves quality of life in patients with complex corneal disease. We report the success rate for PROSE treatment of corneal ectasia. METHODS: Records of 59 patients with corneal ectasia seen in consultation over 6 months were reviewed. Candidacy for treatment, topographic indices, change in visual acuity, achievement of satisfactory fit, device wear status and change in visual function at 6 months were recorded. RESULTS: Sixteen eyes were non-candidates because conventional correction was adequate. Trial devices were inserted but not dispensed for 13 eyes. No eyes were excluded for severity of ectasia. In the remaining 89 eyes, satisfactory fit was achieved and a device was dispensed. Twenty-one eyes (15 patients) had undergone penetrating keratoplasty. Device wear at 6 months was documented in 78/89 eyes (88%). NEI VFQ-25 score improved 27.6 points (p<0.001) on a 100 point scale in patients wearing a device at 6 months. CONCLUSION: All candidate eyes with corneal ectasia could be fitted with a PROSE device. PROSE treatment has a high success rate when measured by ability to achieve satisfactory fit, impact on visual acuity and 6 month data on both rate of continued wear and impact on visual function. PROSE treatment is an alternative to penetrating keratoplasty for patients with corneal ectasia who are contact lens intolerant.

The corneal pain system. Part I: the missing piece of the dry eye puzzle.

The traditional model of dry eye disease based on tear deficiency has presented us with many unanswered questions. Recent studies support the notion that dry eye-like symptoms represent non-specific corneal pain and provide new insights into the mechanisms that sustain the integrity of the optical tear layer. Thus, this enigmatic disease can be viewed with a new perspective, which involves the dysfunctional corneal pain system as a central pathogenetic feature of a series of disorders collectively known today as dry eye.

Chronic (neuropathic) corneal pain and blepharospasm: five case reports.

Pain and focal dystonias have been associated with chronic pain conditions such as complex regional pain syndrome. Corneal pain, frequently known as "dry eye", may be a neuropathic pain condition with abnormalities of the nerve plexus. Here we present 5 case histories of patients with defined corneal pain (with associated neuropathic features) and objective measures of changes in the nerve plexus and associated blepharospasm. A putative relationship between pain and blepharospasm suggests potential involvement of the basal ganglia in both these conditions.

Clinical benefits of the Boston Ocular Surface Prosthesis.

PURPOSE: To evaluate the effects of the Boston Ocular Surface Prosthesis (Boston Foundation for Sight, Needham, Massachusetts, USA) on visual acuity (VA) and visual functioning in patients with severe corneal ectasia, irregular astigmatism, or ocular surface disease. DESIGN: Prospective, interventional case series. METHODS: The study examined the effects of this prosthesis on VA and visual functioning in consecutive patients with corneal ectasia, irregular astigmatism, or ocular surface disease who had failed conventional therapies and were seen at the Boston Foundation for Sight between January 1 and June 30, 2006. Outcomes were best-corrected VA using Snellen charts and visual functioning using the National Eye Institute Visual Functioning Questionnaire (NEI VFQ-25) at 6 months. Clinical data were abstracted from medical records. RESULTS: Of the 101 patients, 80 were fitted with a prosthesis in one or both eyes, and follow-up Visual Functioning Questionnaire data were obtained in 69 eyes. Best-corrected VA improved by a change in mean logarithm of the minimal angle of resolution (logMAR) units of -0.39 (converted from Snellen) with a change of -0.54 logMAR units in patients with ectasia or astigmatism and -0.22 logMAR units in patients with ocular surface disease. Mean composite visual functioning scores increased from 57.0 to 77.8 (P < .0001). Improvements in composite Visual Functioning Questionnaire scores were similar in patients with ectasia or ocular surface disease; but vision-related subscores improved more in patients with ectasia, whereas subscores for ocular pain, role difficulties, and dependency improved more in patients with ocular surface disease. CONCLUSIONS: The Boston Ocular Surface Prosthesis significantly improved VA and visual functioning in patients with corneal ectasia, irregular astigmatism, and ocular surface disease who had failed conventional therapies.

Economic appraisal of the Boston Ocular Surface Prosthesis.

PURPOSE: To perform an economic appraisal of the Boston Ocular Surface Prosthesis in patients with corneal ectasia, irregular astigmatism, or ocular surface disease. DESIGN: Cost, incremental cost-effectiveness, and benefit-cost analyses in a prospective observational study. METHODS: The effects of this scleral lens on visual functioning were measured in 69 patients who received the prosthesis in 2006 and were reassessed 6 months after fitting the prosthesis. Benefits, based on improvements in visual functioning, were converted to quality-adjusted life years (QALYs), and economic values were derived using results from published studies. Costs were estimated from the provider organization's 2006 operating financial statement with additions for donated resources and future scale-up. RESULTS: Mean scores on a 100-point visual functioning questionnaire (VFQ-25) improved from 57.0 to 77.8 (P < .0001). On average, each fitted patient cost $11,841 ($6001 for clinical services and $5840 to produce the prosthesis). Patients' quality of life improved by 0.10 QALYs per year. Assuming that benefits persist for an average of 5 years, the lifetime gain was 0.48 QALYs; the average cost-effectiveness of the prosthesis was $24,900 per QALY (95% confidence interval $19,100 to $29,600), and the average benefit-cost ratio was 4.0 to 1. In patients with the lowest baseline scores (average VFQ score 38.6), results were even more favorable: cost-effectiveness $17,100 per QALY and benefit-cost ratio 5.6 to 1. CONCLUSIONS: The Boston Ocular Surface Prosthesis is cost-effective and cost beneficial in patients with severely compromised visual function attributable to ectasia, irregular astigmatism, or ocular surface disease.

The Boston Ocular Surface Prosthesis as a novel drug delivery system for bevacizumab.

Corneal neovascularization causes deterioration of visual acuity and increases surface irregularities. Various techniques have been employed to help control the progression of corneal neovascularization; bevacizumab is a medication that targets the specific pathway of corneal neovascularization. The Boston Ocular Surface Prosthesis (BOSP) is a large diameter contact lens that aids in maintaining corneal surface integrity and may serve as a delivery system for topical bevacizumab. This paper reviews five patients who were treated with topical bevacizumab in their BOSP. All patients demonstrated improvement in their visual acuity and clinical exam. No adverse reactions were noted.

Corneal pain without stain: is it real?

Clinicians often encounter patients who report corneal pain suggestive of dry eye disease, yet lack equivalent signs. These patients represent a diagnostic and therapeutic challenge that is more easily dismissed than addressed. We review the physiology of pain and the pathophysiological mechanisms of neuropathic corneal pain and speculate on the mechanisms of certain etiopathogenic triggers, such as LASIK, severe dry eye disease, and Sjogren syndrome. Recognizing corneal neuropathic pain as a disease in its own right is the first step toward developing more effective treatments for these severely disabled and presently inadequately served patients.

The Boston Scleral Lens in the treatment of pediatric patients.

PURPOSE: To report the use of a custom-designed, fluid-ventilated, gas-permeable scleral lens in the treatment of patients under 13 years of age. METHODS: We retrospectively reviewed the medical records of all patients under 13 years of age who were fitted with the Boston Scleral Lens at the Boston Foundation for Sight from January 1996 through June 2006. Age, sex, ophthalmic diagnosis, systemic diagnosis, prior surgical intervention, complications, lens fit and wearing failures, and duration of lens use are reported. RESULTS: Boston Scleral Lenses were fitted in 47 eyes of 31 patients referred after failure of conventional therapy. Patients ranged in age from 7 months to 12.92 years (mean, 7.75 years) at time of fitting. There were 16 girls and 15 boys in this group. The mean duration of documented scleral lens use was 24 months (range, 0-85 months). A broad range of refractive and ocular surface disorders was treated with this modality, with the vast majority of patients having ocular surface disease (27/31, 87%) rather than refractive disorders (4/31, 13%). Congenital corneal anesthesia syndromes and Stevens-Johnson syndrome each accounted for over one-third of the patients. CONCLUSIONS: The Boston Scleral Lens is a custom-designed, fluid-ventilated, rigid gas-permeable scleral lens that vaults the cornea retaining a pool of oxygenated artificial tears over the corneal surface. The Boston Scleral Lens is a treatment option, after failure of conventional therapy, for a broad range of ocular surface and refractive disorders in the pediatric age group. Pediatric ophthalmologists should be aware of this treatment modality, particularly in the management of severe ocular surface disease.

Boston scleral lens prosthetic device for treatment of severe dry eye in chronic graft-versus-host disease.

PURPOSE: To determine if the Boston Scleral Lens Prosthetic Device (BSLPD) reduces symptoms and improves quality of life in patients with severe dry eye from chronic graft-versus-host disease (cGvHD). METHODS: This is a noncomparative interventional case series reporting 33 consecutive patients with severe dry eye from cGvHD, unresponsive to conventional therapy, who were fitted with the BSLPD. A patient survey was undertaken after lenses were dispensed and worn regarding the effect of scleral lens wear on their symptoms, quality of life, and activities of daily living. The patient population was characterized from a retrospective chart review. Survey data were tabulated. RESULTS: BSLPD wear resulted in improvement in pain, photophobia, and general quality of life in nearly all patients, with more than half reporting the highest improvement level for pain (52%) and photophobia (63%), and more than two thirds (73%) reporting the highest improvement level for quality of life. There was improvement in reading and driving in >90% of those who reported previous compromise, with >60% reporting the highest improvement level for each of these activities. CONCLUSIONS: The BSLPD mitigates symptoms and improves quality of life in patients with severe dry eye from cGHvD.

Use of fluid-ventilated, gas-permeable scleral lens for management of severe keratoconjunctivitis sicca secondary to chronic graft-versus-host disease.

Keratoconjunctivitis sicca (KCS) occurs in 40%-60% of patients with chronic graft-versus-host-disease (cGVHD) after allogeneic hematopoietic cell transplantation. Although immunosuppressive therapy is the primary treatment of chronic GVHD, ocular symptoms require measures to improve ocular lubrication, decrease inflammation, and maintain mucosal integrity. The liquid corneal bandage provided by a fluid-ventilated, gas-permeable scleral lens (SL) has been effective in mitigating symptoms and resurfacing corneal erosions in patients with KCS related to causes other than cGVHD. We report outcomes in 9 consecutive patients referred for SL fitting for cGVHD-related severe KCS that was refractory to standard treatments. All patients reported improvement of ocular symptoms and reduced the use of topical lubricants after SL fitting resulting from decreased evaporation. No serious adverse events or infections attributable to the SL occurred. The median Ocular Surface Disease Index improved from 81 (75-100) to 21 (6-52) within 2 weeks after SL fitting, and was 12 (2-53) at the time of last contact, 1-23 months (median, 8.0) after SL fitting. Disability related to KCS resolved in 7 patients after SL fitting. The use of SL appears to be safe and effective in patients with severe cGVHD-related KCS refractory to conventional therapies.

Fluid-ventilated, gas-permeable scleral contact lens is an effective option for managing severe ocular surface disease and many corneal disorders that would otherwise require penetrating keratoplasty.

PURPOSE: To examine the diagnostic indications and relative merits of a fluid-ventilated, gas-permeable scleral lens for improving vision impaired by irregular astigmatism and for providing a therapeutic environment for managing severe ocular surface disease. METHODS: After a review of scleral lens development and a description of current design and manufacturing innovations, indications for fitting the Boston Scleral Lens were evaluated based on a retrospective review of all available records of patients fitted with this device, and outcome experiences were described. RESULTS: A total of 875 eyes of 538 patients were fitted with the fluid-ventilated, gas-permeable scleral lens during the past 18 years. Most patients were fitted in the past 4 years. Indications included managing severe ocular surface disease and rehabilitating vision impaired by irregular astigmatism associated with corneal disorders. Rigid gas-permeable contact lenses either were not tolerated or were contraindicated in all eyes. Outcomes included improved vision and reduced ocular pain and photophobia associated with severe ocular surface disease. Scleral lenses promoted healing of persistent epithelial defect (PED) refractory to other treatments and prevented PED recurrence in stem cell-deficient and neurotrophic corneas. Microbial keratitis occurred in 4 of 22 eyes treated with extended scleral lens wear for PED after penetrating keratoplasty. CONCLUSIONS: The fluid-ventilated, gas-permeable scleral lens is an important front-line tool for managing many corneal disorders refractory to other treatment measures or otherwise requiring keratoplasty.