Evidence of central sensitisation in those with dry eye symptoms and neuropathic-like ocular pain complaints: incomplete response to topical anaesthesia and generalised heightened sensitivity to evoked pain.

OBJECTIVE: To evaluate how closely neuropathic-like ocular pain (NOP) symptoms align with a metric of central sensitisation (ie, the presence of persistent ocular pain after topical anaesthetic placement) in individuals with dry eye (DE) symptoms. DESIGN: Cross-sectional study of 224 individuals with DE symptoms seen in the Miami Veterans Affairs eye clinic. An evaluation was performed consisting of questionnaires regarding DE symptoms, NOP descriptors and evoked pain sensitivity testing on the forehead and forearm, followed by a comprehensive ocular surface examination including corneal mechanical sensitivity testing. Subsequent analyses were performed to examine for differences between those with and without ocular pain after topical anaesthetic placement. RESULTS: The mean age was 62 years with 91% being men. DE symptoms and NOP symptoms were higher in subjects with persistent ocular pain after anaesthesia. Most DE signs were not related to persistent pain, with the exception of meibum quality. Individuals with persistent ocular pain also demonstrated greater sensitivity to evoked pain at testing sites on the forehead and forearm. When examining receiver operator characteristic curves considering persistent pain as a gold standard for central sensitisation within the corneal pathway, intensity of ocular pain ratings, Ocular Surface Disease Index scores and sensitivity to light provided the most robust relationships, each with an area under the curve of 0.72. CONCLUSIONS: Individuals with DE symptoms and persistent ocular pain after topical proparacaine (a marker of central sensitisation to pain) more frequently report NOP-like symptoms and demonstrate increased sensitivity to evoked pain.

Compliance and Subjective Patient Responses to Eyelid Hygiene.

OBJECTIVES: Lid hygiene is a commonly prescribed first-line therapy in patients with lid margin disease, yet compliance with therapy is not well characterized. The goals of this study were to assess patient compliance with lid hygiene and evaluate which factors predict a favorable symptomatic response to treatment. METHODS: This was a cross-sectional study of patients seen in the Miami Veterans Affairs eye clinic between August and December 2014. An evaluation was performed to assess dry eye symptoms and lid margin signs. All patients were then instructed to perform warm compresses and lid scrubs. A follow-up phone survey assessed compliance and subjective therapeutic response 6 weeks later. RESULTS: Two hundred seven of 211 (98%) patients (94% male, 60% white) completed the survey. Of the 207 patients, 188 (91%) completed the follow-up survey. Compliance with therapy was reported in 104 patients (55%); 66 reported complete improvement, 30 partial improvement, and 8 no improvement in symptoms. Patients who self-reported dry eye symptoms at first visit (n=86, 74%) were more likely to be compliant with lid hygiene than those who did not report symptoms (n=18, 25%) (P<0.0005). The only factor associated with poorer response to lid hygiene was longer time of self-reported dry eye symptoms. None of the other signs studied, including the presence of skin rosacea and lid margin telangiectasia, were associated with a differential response to lid hygiene. CONCLUSIONS: Patients with dry eye symptoms were moderately compliant with lid hygiene, and patients who performed the routine noted improvement in symptoms.

Gene Therapy for Leber Hereditary Optic Neuropathy: Initial Results.

PURPOSE: Leber hereditary optic neuropathy (LHON) is a disorder characterized by severe and rapidly progressive visual loss when caused by a mutation in the mitochondrial gene encoding NADH:ubiquinone oxidoreductase subunit 4 (ND4). We have initiated a gene therapy trial to determine the safety and tolerability of escalated doses of an adeno-associated virus vector (AAV) expressing a normal ND4 complementary DNA in patients with a G to A mutation at nucleotide 11778 of the mitochondrial genome. DESIGN: In this prospective open-label trial (NCT02161380), the study drug (self-complementary AAV [scAAV]2(Y444,500,730F)-P1ND4v2) was intravitreally injected unilaterally into the eyes of 5 blind participants with G11778A LHON. Four participants with visual loss for more than 12 months were treated. The fifth participant had visual loss for less than 12 months. The first 3 participants were treated at the low dose of vector (5 × 10(9) vg), and the fourth participant was treated at the medium dose (2.46 × 10(10) vg). The fifth participant with visual loss for less than 12 months received the low dose. Treated participants were followed for 90 to 180 days and underwent ocular and systemic safety assessments along with visual structure and function examinations. PARTICIPANTS: Five legally blind patients with G11778A LHON. MAIN OUTCOME MEASURES: Loss of visual acuity. RESULTS: Visual acuity as measured by the Early Treatment Diabetic Retinopathy Study (ETDRS) eye chart remained unchanged from baseline to 3 months in the first 3 participants. For 2 participants with 90-day follow-up, acuity increased from hand movements to 7 letters in 1 and by 15 letters in 1, representing an improvement equivalent to 3 lines. No one lost vision, and no serious adverse events were observed. Minor adverse events included a transient increase of intraocular pressure (IOP), exposure keratitis, subconjunctival hemorrhage, a sore throat, and a transient increase in neutralizing antibodies (NAbs) against AAV2 in 1 participant. All blood samples were negative for vector DNA. CONCLUSIONS: No serious safety problems were observed in the first 5 participants enrolled in this phase I trial of virus-based gene transfer in this mitochondrial disorder. Additional study follow-up of these and additional participants planned for the next 4 years is needed to confirm these preliminary observations.

Neurostimulation of the lacrimal nerve for enhanced tear production.

PURPOSE: To design a proof-of-concept study to assess the effect of lacrimal nerve stimulation (LNS) with an implantable pulse generator (IPG) to increase aqueous tear production. METHODS: Experimental animal study design of 6 Dutch Belted rabbits. Ultra high-resolution optical coherence tomography (UHR-OCT) quantified tear production by measuring the baseline tear volume of each rabbit's OD and OS. A neurostimulator was implanted adjacent to the right lacrimal nerve. After 2 minutes of LNS (100 µs, 1.6 mA, 20 Hz, 5-8 V), the tear volumes were measured with UHR-OCT. The change in tear volume was quantified and compared with the nonstimulated OS. Three rabbits underwent chronic LNS (100 µs, 1.6 mA, 10 Hz, 2 V) and their lacrimal glands were harvested for histopathologic analysis. RESULTS: The UHR-OCT imaging of the OD tear volume showed a 441% average increase in tear production after LNS as a percent of baseline. After stimulation, OD had statistically significant greater increase in tear volumes than OS (p = 0.028, Wilcoxon test). Poststimulation OD tear volumes were significantly greater compared with baseline (p = 0.028, Wilcoxon test). Histopathologic examination of the lacrimal glands showed no discernible tissue damage from chronic neurostimulation. In addition, there were no gross adverse effects on the general well-being of the animals due to chronic stimulation. CONCLUSIONS: LNS with an IPG appears to increase aqueous tear production. Chronic LNS showed no histopathologic lacrimal gland damage. This study suggests that LNS is a promising new treatment strategy to increase aqueous tear production.

Effect of a Mediterranean dietary pattern and vitamin D levels on Dry Eye syndrome.

PURPOSE: The aim of this study was to evaluate the association between a Mediterranean dietary pattern (MeDi) and Vitamin D levels on dry eye syndrome (DES). METHODS: This was a cross-sectional study. Male patients seen in the Miami Veterans Affairs eye clinic with normal eyelid, corneal, and conjunctival anatomy were recruited to participate in the study. The patients filled out the 2005 Block Food Frequency Questionnaire and the Dry Eye Questionnaire 5 and underwent measurement of tear film parameters. The serum level of 25-hydroxy vitamin D was also measured. The main outcome measures included the association among MeDi, Vitamin D levels, and DES. RESULTS: Two hundred forty-seven men underwent DES testing. The mean patient age was 69 years (range, 55-95). Using latent class analysis to categorize the presence or absence of disease and quantify its severity, we found that adherence to the MeDi was positively associated with the risk of having DES (odd ratio 1.25, 95% confidence interval, 1.06-1.47, P = 0.007) and with increasing disease severity. Vitamin D levels were not significantly associated with the presence or severity of disease. However, higher levels of vitamin D were associated with decreased DES symptoms, with a -1.24 decrease in median Dry Eye Questionnaire 5 score for every 10-U increase in Vitamin D levels (P = 0.01). CONCLUSIONS: Adherence to the MeDi was not associated with a beneficial effect on DES. Higher vitamin D levels had a small but favorable effect on DES symptoms.

Ocular decompression with cotton swabs lowers intraocular pressure elevation after intravitreal injection.

OBJECTIVE: To determine the effect of preinjection ocular decompression by cotton swabs on the immediate rise in intraocular pressure (IOP) after intravitreal injections. METHODS: Forty-eight patients receiving 0.05 mL ranibizumab injections in a retina clinic were randomized to 2 anesthetic methods in each eye on the same day (if bilateral disease) or on consecutive visits (if unilateral disease). One method utilized cotton swabs soaked in 4% lidocaine applied to the globe with moderate pressure and the other 3.5% lidocaine gel applied without pressure. IOPs were recorded at baseline (before injection) and at 0, 5, 10, and 15 minutes after the injection until the IOP was ≤30 mm Hg. The IOP elevations from baseline were compared after the 2 anesthetic methods. RESULTS: The preinjection mean IOP (SD, mm Hg) was 15.5 (3.3) before the cotton swabs and 15.9 (3.0) before the gel (P=0.28). Mean IOP (SD, mm Hg) change immediately after injection was 25.7 (9.2) after the cotton swabs and 30.9 (9.9) after the gel (P=0.001). Thirty-five percent of gel eyes had IOP≥50 mm Hg compared with only 10% of cotton swab eyes immediately after the injection (P<0.001). CONCLUSION: Decompressing the eye with cotton swabs during anesthetic preparation before an intravitreal injection produces a significantly lower IOP spike after the injection.

Predictors of ocular surface squamous neoplasia recurrence after excisional surgery.

PURPOSE: To identify predictors of ocular surface squamous neoplasm (OSSN) recurrence after operative resection. DESIGN: Retrospective case series. PARTICIPANTS: Three hundred eighty-nine consecutive patients who underwent excisional biopsy for OSSN lesions at the Bascom Palmer Eye Institute from January 1, 2001, to September 20, 2010. METHODS: Review of pathology records and patient charts. MAIN OUTCOME MEASURES: Identification of factors predictive of OSSN recurrence. RESULTS: Of 389 excised OSSN lesions, 44 recurred during follow-up. The 1-year recurrence rate was 10% and the 5-year recurrence rate was 21%, with a mean time to recurrence in those with a recurrence of 2.5 years (standard deviation, 3.4). Using the American Joint Committee on Cancer (AJCC) clinical staging system, T3 and T2 lesions portended a higher risk of recurrence compared with T1 (T2/T1 hazard ratio [HR], 2.05 [P = 0.04]; T3/T1 HR, 2.31 [P = 0.07]). In addition, a location characteristic that increased the risk of tumor recurrence was tarsal involvement (AJCC T3 stage lesion; HR, 4.12; P = 0.007). Nasal location was associated with a decreased risk of tumor recurrence (HR, 0.41; P = 0.008). Pathologic characteristics significantly associated with tumor recurrence were the presence of positive margins (HR, 2.73; P = 0.008) and higher grade lesions (carcinoma in situ and squamous cell carcinoma versus dysplasia; HR, 2.55; P = 0.02). Treatment with adjuvant cryotherapy significantly decreased the risk of tumor recurrence (HR, 0.51; P = 0.03). In those patients with positive margins, the use of postoperative topical interferon therapy lowered the recurrence rate to a level similar to that of patients with negative margins. CONCLUSIONS: Certain patient and tumor factors are associated with a higher risk of OSSN recurrence after operative excision, such as tarsal tumor location and positive surgical margins. Postoperative adjuvant therapy should be considered in patients with high-risk OSSN characteristics.

Five-year follow-up optic disc findings of the Collaborative Initial Glaucoma Treatment Study.

PURPOSE: To determine the effect of intraocular pressure (IOP) lowering on the optic disc in patients of the Collaborative Initial Glaucoma Treatment Study (CIGTS) after 5 years. DESIGN: Randomized clinical trial. METHODS: The baseline and 5-year stereoscopic optic disc photographs of 348 eyes (patients) randomized to medical or surgical treatment of open-angle glaucoma (OAG) were assessed by 2 independent readers for change in a masked side-by-side comparison, and confirmed by an independent committee. RESULTS: Three hundred and three (87.1%) eyes showed no change, 22 (6.3%) showed enlargement of the cup along any meridian (progression), and 23 (6.6%) showed a reduction in the cup along any meridian (reversal of cupping). Incidence of optic disc progression was higher (P = .007) in the medicine group, 18/185 (10%) than in the surgical group 4/163 (3%); and the incidence of reversal of cupping was higher (P < .001) in the surgical group, 21/163 (13%), than the medicine group, 2/185 (1%), (P < .001). Visual field (VF) worsening (mean deviation) was significantly associated with progression of optic disc cupping (P < .001). Reversal of cupping was also associated with lower postoperative IOP (P < .001). Reversal of cupping was not associated with improvement of either visual acuity or central VFs. CONCLUSIONS: Surgery prevents or delays glaucomatous progression as measured by optic disc criteria in patients with early OAG. Reversal of cupping occurs more frequently in the surgical group than in the medical treatment group. Reversal is associated with lower IOP, but is not associated with improved visual function.

Reproducibility of pattern electroretinogram in glaucoma patients with a range of severity of disease with the new glaucoma paradigm.

PURPOSE: To determine the reproducibility of the pattern electroretinogram with the new Pattern Electroretinogram for Glaucoma (PERGLA) recording paradigm in glaucoma patients with a range of severity. DESIGN: Experimental study. PARTICIPANTS: Fifty-three glaucoma patients were recruited for the study (mean age +/- standard deviation [SD], 69+/-11 years). Their mean deviation (MD) global indices on static automatic perimetry ranged from 2.16 to -31.36 decibels (mean MD, -9.05). INTERVENTION: All patients had pattern electroretinogram recordings done 5 times by the same operator, on 5 different days with the standardized PERGLA paradigm. MAIN OUTCOME MEASURES: Pattern electroretinogram amplitude (microvolts), phase (pi radians), response variability (coefficient of variation [CV] = SD/mean x 100) of amplitude and phase of 2 partial averages that build up the pattern electroretinogram waveform, interocular asymmetry in amplitude and phase (in terms of the CV generated by the pattern electroretinogram software), signal-to-noise (S/N) ratio, SDs, CV, and intraclass correlation coefficient (ICC). All analyses were done on one eye of each subject, except when interocular asymmetry was studied. RESULTS: The CVs of intrasession variabilities in amplitude and phase were 12.08% and 2.20%, respectively, and those of intersession variabilities were 20.82% and 4.17%. The pattern electroretinogram produced intersession ICCs in amplitude and phase of 0.791 and 0.765, respectively. These ICCs were significantly higher than the ICCs for pattern electroretinogram interocular asymmetry in amplitude and phase (0.659 [P<0.05] and 0.571 [P<0.05], respectively). On average, the pattern electroretinogram S/N ratio in glaucomatous patients was about 5:1. CONCLUSIONS: The reproducibility of PERGLA in glaucomatous patients is sufficiently good for it to be considered a useful complementary clinical tool. Being more reproducible, direct measures of amplitude and phase should be more useful in monitoring progression than interocular asymmetry comparisons.

Detection of psychophysical and structural injury in eyes with glaucomatous optic neuropathy and normal standard automated perimetry.

OBJECTIVE: To compare the prevalence of structural and psychophysical abnormalities in normal eyes and eyes with glaucomatous optic neuropathy (GON) and normal standard automated perimetry (SAP). METHODS: Complete examination, SAP, short-wavelength automated perimetry (SWAP), frequency doubling technology (FDT), scanning laser polarimetry (GDx-VCC), and optical coherence tomography (OCT) of the peripapillary retinal nerve fiber layer (RNFL), optic disc, and macula were performed. Glaucomatous optic neuropathy was defined as cup-disc asymmetry between fellow eyes of greater than 0.2, rim thinning, notching, excavation, or RNFL defect. All eyes had normal SAP. Abnormal measurements on OCT, GDx-VCC, SWAP, and FDT were defined as those outside 95% normal limits. Eyes were stratified into 3 groups based on the OCT-generated vertical cup-disc ratio: mild, moderate, and advanced cupping (cup-disc ratio of <0.4, 0.4-0.7, and >0.7, respectively). Receiver operating characteristic curves were developed to assess sensitivity and specificity of structural and functional assessments. RESULTS: Forty-seven eyes of 47 patients (25 with GON and 22 normal) were enrolled (mean +/- SD age, 58 +/- 16 years; range, 25-83 years). Compared with normal eyes, eyes with GON had significantly worse mean deviation and pattern standard deviation by means of SWAP and FDT (P = .02-.05); OCT-derived mean and superior and inferior RNFL thickness (P = .008, <.001, and .05, respectively); mean macular thickness (P = .01), rim volume, rim area, cup-disc ratio, and cup area (all P<.001); and GDx-VCC nerve fiber indicator and inferior average (P = .03). There was a significantly (P = .008, .002, .003, and .01, respectively) greater prevalence of abnormalities identified by SWAP, FDT, OCT and GDx-VCC in eyes with advanced cupping (43%, 43%, 57%, and 57%, respectively) compared with mild cupping (0%) and moderate cupping (9%, 5%, 19%, and 33%, respectively). CONCLUSIONS: Eyes with GON and normal results of SAP have significantly greater structural and psychophysical abnormalities than do normal eyes evaluated by means of OCT, GDx-VCC, SWAP, and FDT. Eyes with increased vertical cup-disc ratio are more likely to manifest such abnormalities on advanced diagnostic testing.

Pattern electroretinogram abnormality and glaucoma.

PURPOSE: To determine the existence of retinal ganglion cell dysfunction and associated risk factors in glaucoma suspects with increased optic disc cupping and normal visual field. DESIGN: Cross-sectional, observational study. PARTICIPANTS: Two hundred glaucoma suspect (GS) patients were identified based on optic disc abnormalities (vertical cup-to-disc ratios [C/D]>0.5; vertical C/D asymmetry >or= 0.2; disc hemorrhages; notching) in association with known glaucoma risk factors (positive family history, African American descent, increased intraocular pressure [IOP]), but normal visual fields. Forty-two patients had early manifest glaucoma (EMG). Sixteen normal black subjects were added to update previous pattern electroretinogram (PERG) normative data and to establish a normal control (NC) group with a racial breakdown comparable with that of the study groups. METHODS: Pattern electroretinograms were recorded simultaneously from both eyes using skin electrodes and automated analysis; visual fields were monitored with standard white-on-white automated perimetry (SAP) central 24-2 program; vertical C/D was evaluated by an independent reader from stereo disc photographs; and univariate and multivariate statistical analysis between PERG and other outcome measures was evaluated. MAIN OUTCOME MEASURES: Pattern electroretinogram amplitude (microV), phase (pi rad), and interocular asymmetry in amplitude and phase (%); and SAP mean deviation (MD; decibels), vertical C/D, age (years), IOP (mmHg), and race (black vs. nonblack). RESULTS: The PERG results were abnormal in at least 1 of the outcome measures in 52% of GS patients and 69% of EMG patients. The PERG amplitude was correlated weakly with both MD (P<0.01) and vertical C/D (P = 0.05). The correlation between PERG amplitude and MD and C/D was stronger (P<0.001) for interocular differences rather than absolute measures. Interocular PERG amplitude asymmetry increased with severity of disease (EMG>GS>NC; P<0.01). The PERG amplitude decline with age was steeper in patients with a more negative MD (P<0.01) and in patients with a more negative MD and a larger vertical C/D (P = 0.06). Black race (but not family history) was associated with lower PERG amplitude (P = 0.005) in GS and EMG patients, but not in normal controls (P = 0.44). CONCLUSIONS: The correlation between PERG abnormality and known risk factors for glaucoma indicates that PERG has a predictive potential for the development or progression of the disease, or both.