Heritable Risk and Protective Genetic Components of Glaucoma Medication Non-Adherence.

Glaucoma is the leading cause of irreversible blindness, affecting 76 million globally. It is characterized by irreversible damage to the optic nerve. Pharmacotherapy manages intraocular pressure (IOP) and slows disease progression. However, non-adherence to glaucoma medications remains problematic, with 41-71% of patients being non-adherent to their prescribed medication. Despite substantial investment in research, clinical effort, and patient education protocols, non-adherence remains high. Therefore, we aimed to determine if there is a substantive genetic component behind patients' glaucoma medication non-adherence. We assessed glaucoma medication non-adherence with prescription refill data from the Marshfield Clinic Healthcare System's pharmacy dispensing database. Two standard measures were calculated: the medication possession ratio (MPR) and the proportion of days covered (PDC). Non-adherence on each metric was defined as less than 80% medication coverage over 12 months. Genotyping was done using the Illumina HumanCoreExome BeadChip in addition to exome sequencing on the 230 patients (1) to calculate the heritability of glaucoma medication non-adherence and (2) to identify SNPs and/or coding variants in genes associated with medication non-adherence. Ingenuity pathway analysis (IPA) was utilized to derive biological meaning from any significant genes in aggregate. Over 12 months, 59% of patients were found to be non-adherent as measured by the MPR80, and 67% were non-adherent as measured by the PDC80. Genome-wide complex trait analysis (GCTA) suggested that 57% (MPR80) and 48% (PDC80) of glaucoma medication non-adherence could be attributed to a genetic component. Missense mutations in TTC28, KIAA1731, ADAMTS5, OR2W3, OR10A6, SAXO2, KCTD18, CHCHD6, and UPK1A were all found to be significantly associated with glaucoma medication non-adherence by whole exome sequencing after Bonferroni correction (p < 10-3) (PDC80). While missense mutations in TINAG, CHCHD6, GSTZ1, and SEMA4G were found to be significantly associated with medication non-adherence by whole exome sequencing after Bonferroni correction (p < 10-3) (MPR80). The same coding SNP in CHCHD6 which functions in Alzheimer's disease pathophysiology was significant by both measures and increased risk for glaucoma medication non-adherence by three-fold (95% CI, 1.62-5.8). Although our study was underpowered for genome-wide significance, SNP rs6474264 within ZMAT4 (p = 5.54 × 10-6) was found to be nominally significant, with a decreased risk for glaucoma medication non-adherence (OR, 0.22; 95% CI, 0.11-0.42)). IPA demonstrated significant overlap, utilizing, both standard measures including opioid signaling, drug metabolism, and synaptogenesis signaling. CREB signaling in neurons (which is associated with enhancing the baseline firing rate for the formation of long-term potentiation in nerve fibers) was shown to have protective associations. Our results suggest a substantial heritable genetic component to glaucoma medication non-adherence (47-58%). This finding is in line with genetic studies of other conditions with a psychiatric component (e.g., post-traumatic stress disorder (PTSD) or alcohol dependence). Our findings suggest both risk and protective statistically significant genes/pathways underlying glaucoma medication non-adherence for the first time. Further studies investigating more diverse populations with larger sample sizes are needed to validate these findings.

Is Multiple Sclerosis Associated With a Lower Intraocular Pressure?

OBJECTIVE: To determine if multiple sclerosis (MS) is associated with lower intraocular pressure (IOP) compared with individuals without MS. METHODS: Thirty patients with clinically definite MS were identified and a retrospective chart review was conducted. Each patient with MS underwent IOP recording by a single investigator using kinetic applanation tonometry. Measurement of central corneal thickness (CCT) also was obtained. Similarly, 30 study controls were identified and kinetic applanation tonometry and CCT were recorded. Univariate analysis of covariance was conducted to determine a statistically significant difference between IOP between MS and control groups, controlling for age. RESULTS: Analyses were adjusted for age and 2 subjects were excluded because of steroid use. The average IOP in MS group was 12.3 mm Hg (right eye = 12.3 mm Hg, left eye = 12.2 mm Hg) and in the control group was 17 mm Hg (right eye = 16.9 mm Hg, left eye = 17 mm Hg). There was a significant effect of presence of MS on IOP accounting for 53% variability in mean IOP (F(1,55) = 60.7; P < 0.001) when compared with the control group. CONCLUSIONS: This study demonstrated that IOP was significantly lower in patients with MS compared with controls. A more in-depth prospective study design is required, along with further investigation of possible etiologies. Identifying the mechanism of decreased IOP in patients with MS might allow development of new-targeted therapies for the treatment of glaucoma.

Acetazolamide induced noncardiogenic pulmonary edema, an underreported serious adverse event.

Purpose: To report a case of acute noncardiogenic pulmonary edema (NCPE) after administration of acetazolamide post routine cataract surgery. Observations: 30 minutes after administration of oral acetazolamide, the patient experienced abdominal pain, nausea, vomiting, diarrhea, and diaphoresis. The patient was taken to the emergency room where she was found to have pulmonary edema. After life threatening respiratory failure resulting in prolonged intubation, the patient was eventually discharged from the hospital. Conclusions and importance: NCPE is a rare but severe adverse effect of acetazolamide and should be considered when prescribing such agents.

Acute panuveitis after COVID-19 mRNA booster vaccination following cataract surgery.

Purpose: To report a case of presumed COVID-19 Pfizer third dose (booster) vaccination leading to severe panuveitis mimicking acute endophthalmitis in the early postoperative period following routine cataract extraction and intraocular lens implantation. Observations: A 68-year-old female with mild refractive error who previously received 2 doses of the BNT162b2 vaccine underwent routine cataract extraction and intraocular lens implantation in the right eye. On postoperative day (POD) 2 the patient received her BNT162b2 booster vaccination. On POD 3 the patient's vision was hand motion at face with photophobia. Anterior segment examination was significant for 2+ conjunctival injection, mild stromal edema, 4+ cell and flare with trace hypopyon, and 4+ anterior vitreous cell without any wound leak. Subsequent Gram staining, culture for aerobic and anaerobic bacteria, KOH preparation, and PCR testing for infectious organisms were also obtained, all of which were found to be negative. ESR and CRP values were also negative. The patient was started on intravitreal injections of vancomycin and ceftazidime, as well as oral moxifloxacin, fortified vancomycin and tobramycin drops, prednisolone acetate 1%, and atropine 1%. On POD 5 the patient reported significant improvement of her vision and was found to have 20/80 vision. On POD 12 her vision improved to 20/25, and improved further on POD 19 to 20/20 vision with a completely normal examination. Cultures remained negative throughout the entire course. Conclusions and importance: This is the first report to suggest a possible association between the BNT162b2 booster vaccination and development of acute panuveitis in the postoperative period after routine cataract extraction and intraocular lens implantation. This condition may mimic acute bacterial postoperative endophthalmitis and may portend a more favorable prognosis, but the authors believe such cases should nonetheless be treated aggressively as presumed infection.

Uveitis-Glaucoma-Hyphema Syndrome Following iStent Implantation.

Minimally invasive glaucoma surgery (MIGS) is a subset of glaucoma surgery that is known for its low rate of complications both intraoperatively and postoperatively compared to traditional filtering surgery. We present a case of a patient who, after receiving uncomplicated cataract extraction with posterior chamber intraocular lens implantation and concurrent iStent trabecular bypass stent implantation, experienced recurrent episodes of spontaneous microhyphema and inflammation in the late postoperative period. The patient, who had a history of mild asymmetric exfoliative glaucoma but no identifiable sources of trauma, underwent extensive examination to investigate causes of his episodic anterior segment bleeding and mild inflammation with concurrent elevated intraocular pressure. Given the circumstances of the patient's recurrent symptoms and a negative workup for conventional causes of recurrent hyphema, it was suspected that the patient's iStent was interacting with the patient's peripheral iris, causing microtrauma and hyphema. We hypothesized that this contact was potentially exacerbated by pre-existing exfoliation syndrome, which caused zonular weakness and subsequent anterior movement of the lens-iris diaphragm. After the patient's third recurrence of microhyphema and inflammation, the patient underwent removal of iStent and concurrent OMNI canaloplasty for glaucoma. Six months post-iStent explantation, the patient has had complete resolution of symptoms without recurrence of hyphema. In this case report, we outline the course of this patient's symptoms and diagnosis, discuss the potential of MIGS devices such as iStent to cause recurrent hyphema, and explore treatment options following removal.

Efficacy of Selective Laser Trabeculoplasty after iStent Implantation in Primary Open-Angle Glaucoma.

iStent implantation is thought to augment the trabecular outflow channel in the anterior segment of the eye. We hypothesized that iStent with subsequent selective laser trabeculoplasty (SLT) would better control the intraocular pressure (IOP) compared to standalone SLT in patients with primary open-angle glaucoma (POAG). We, therefore, determined if the presence of an iStent combined with SLT was statistically associated with IOP lowering compared to standalone SLT. Through retrospective electronic medical record review, records of 824 eyes from 440 patients who received primary SLT without a history of iStent were considered. Additionally, 42 eyes from 28 patients who received SLT after combined phacoemulsification and iStent implantation that failed to control intraocular pressure (IOP) and/or the progression of the disease were retrospectively reviewed. IOP and number of medications, which were tracked in each patient for up to 12 months post laser, were also examined. Successful outcome was defined as a statistically significant reduction in IOP or number of medications at 6 months. As defined in univariate analysis (p ≤ 0.01), multivariate analysis included iStent, age, sex, race, and initial IOP as variables. IOP reduction was statistically associated with patients pre-SLT IOP (p < 0.001) but not with patients with iStent (p = 0.222). Medication reduction was statistically associated with the pre-SLT number of medications (p < 0.001) and iStent (p < 0.001). In eyes that received SLT, iStent was not statistically associated with a greater reduction in IOP compared to controls, but was associated with a higher reduction in the overall number of medications used 6 months after receiving SLT. The work presented should guide clinicians to consider SLT as an effective therapy after iStent implantation, in terms of glaucoma medication reduction in iStent patients, but clinicians should know that the presence of an iStent does not necessarily make subsequent SLT more effective at lowering IOP.

Pseudoexfoliation and Cataract Syndrome Associated with Genetic and Epidemiological Factors in a Mayan Cohort of Guatemala.

The Mayan population of Guatemala is understudied within eye and vision research. Studying an observational homogenous, geographically isolated population of individuals seeking eye care may identify unique clinical, demographic, environmental and genetic risk factors for blinding eye disease that can inform targeted and effective screening strategies to achieve better and improved health care distribution. This study served to: (a) identify the ocular health needs within this population; and (b) identify any possible modifiable risk factors contributing to disease pathophysiology within this population. We conducted a cross-sectional study with 126 participants. Each participant completed a comprehensive eye examination, provided a blood sample for genetic analysis, and received a structured core baseline interview for a standardized epidemiological questionnaire at the Salama Lions Club Eye Hospital in Salama, Guatemala. Interpreters were available for translation to the patients' native dialect, to assist participants during their visit. We performed a genome-wide association study for ocular disease association on the blood samples using Illumina's HumanOmni2.5-8 chip to examine single nucleotide polymorphism SNPs in this population. After implementing quality control measures, we performed adjusted logistic regression analysis to determine which genetic and epidemiological factors were associated with eye disease. We found that the most prevalent eye conditions were cataracts (54.8%) followed by pseudoexfoliation syndrome (PXF) (24.6%). The population with both conditions was 22.2%. In our epidemiological analysis, we found that eye disease was significantly associated with advanced age. Cataracts were significantly more common among those living in the 10 districts with the least resources. Furthermore, having cataracts was associated with a greater likelihood of PXF after adjusting for both age and sex. In our genetic analysis, the SNP most nominally significantly associated with PXF lay within the gene KSR2 (p < 1 × 10-5). Several SNPs were associated with cataracts at genome-wide significance after adjusting for covariates (p < 5 × 10-8). About seventy five percent of the 33 cataract-associated SNPs lie within 13 genes, with the majority of genes having only one significant SNP (5 × 10-8). Using bioinformatic tools including PhenGenI, the Ensembl genome browser and literature review, these SNPs and genes have not previously been associated with PXF or cataracts, separately or in combination. This study can aid in understanding the prevalence of eye conditions in this population to better help inform public health planning and the delivery of quality, accessible, and relevant health and preventative care within Salama, Guatemala.

Prompt vitrectomy for management of endophthalmitis in setting of unexposed glaucoma drainage implant.

PURPOSE: To highlight a rare case of fulminant endophthalmitis in the late post-operative stage after glaucoma drainage device implantation without evidence of device exposure, and to share the unique management that resulted in successful restoration of vision and intraocular pressure control. OBSERVATIONS: Endophthalmitis after glaucoma drainage implantation (GDI) is a rare complication most often associated with exposure of the device. Management options are limited, but removal of GDI is a common approach in the setting of an exposed implant. Visual acuity outcomes are often significantly reduced despite adequate treatment. There is little in the existing literature about management of late-onset endophthalmitis in the setting of a GDI without implant exposure. Here we present such a case that was successfully managed by prompt pars plana vitrectomy and removal of tube from the anterior chamber with subsequent re-insertion and patch graft. Our case results in a restoration of baseline visual acuity and IOP control at 7 months follow up. CONCLUSIONS AND IMPORTANCE: Endophthalmitis occurring after GDI implantation is a challenging complication to manage. Many physicians resort to removal of device for treatment, and a majority would treat initially with intravitreal antibiotic injection of antibiotics rather than prompt pars plana vitrectomy. This article provides a different approach that avoids removal of the device.

Systemic Disease and Ocular Comorbidity Analysis of Geographically Isolated Federally Recognized American Indian Tribes of the Intermountain West.

BACKGROUND: The American Indian Navajo and Goshute peoples are underserved patient populations residing in the Four Corners area of the United States and Ibupah, Utah, respectively. METHODS: We conducted a cross-sectional study of epidemiological factors and lipid biomarkers that may be associated with type II diabetes, hypertension and retinal manifestations in tribal and non-tribal members in the study areas (n = 146 participants). We performed multivariate analyses to determine which, if any, risk factors were unique at the tribal level. Fundus photos and epidemiological data through standardized questionnaires were collected. Blood samples were collected to analyze lipid biomarkers. Univariate analyses were conducted and statistically significant factors at p < 0.10 were entered into a multivariate regression. RESULTS: Of 51 participants for whom phenotyping was available, from the Four Corners region, 31 had type II diabetes (DM), 26 had hypertension and 6 had diabetic retinopathy (DR). Of the 64 participants from Ibupah with phenotyping available, 20 had diabetes, 19 had hypertension and 6 had DR. Navajo participants were less likely to have any type of retinopathy as compared to Goshute participants (odds ratio (OR) = 0.059; 95% confidence interval (CI) = 0.016-0.223; p < 0.001). Associations were found between diabetes and hypertension in both populations. Older age was associated with hypertension in the Four Corners, and the Navajo that reside there on the reservation, but not within the Goshute and Ibupah populations. Combining both the Ibupah, Utah and Four Corners study populations, being American Indian (p = 0.022), residing in the Four Corners (p = 0.027) and having hypertension (p < 0.001) increased the risk of DM. DM (p < 0.001) and age (p = 0.002) were significantly associated with hypertension in both populations examined. When retinopathy was evaluated for both populations combined, hypertension (p = 0.037) and living in Ibupah (p < 0.001) were associated with greater risk of retinopathy. When combining both American Indian populations from the Four Corners and Ibupah, those with hypertension were more likely to have DM (p < 0.001). No lipid biomarkers were found to be significantly associated with any disease state. CONCLUSIONS: We found different comorbid factors with retinal disease outcome between the two tribes that reside within the Intermountain West. This is indicated by the association of tribe and with the type of retinopathy outcome when we combined the populations of American Indians. Overall, the Navajo peoples and the Four Corners had a higher prevalence of chronic disease that included diabetes and hypertension than the Goshutes and Ibupah. To the best of our knowledge, this is the first study to conduct an analysis for disease outcomes exclusively including the Navajo and Goshute tribe of the Intermountain West.

Outcomes of Micropulse Transscleral Cyclophotocoagulation in Eyes With Good Central Vision.

PRECIS: This study is the first to report micropulse transscleral cyclophotocoagulation (MP-TSCPC) use in only good vision patients. MP-TSCPC significantly reduced intraocular pressure (IOP) and glaucoma medication use without any significant reduction in visual acuity at every postoperative follow-up point. PURPOSE: To evaluate outcomes of MP-TSCPC in eyes with baseline best-corrected visual acuity (BCVA) of ≥20/60. METHODS: A retrospective review of patients who underwent MP-TSCPC at Mayo Clinic and Ross Eye Institute from July 2016 to August 2017 with BCVA of ≥20/60, and a minimum of 3 months follow-up. RESULTS: A total of 61 eyes of 46 patients (68.80±17.12 y) underwent MP-TSCPC with a mean follow-up of 10.2±3.1 months. Mean IOP and mean number of glaucoma medications used were significantly reduced from baseline at every follow-up time point (P<0.0001). At month 12, mean IOP was reduced 40.2% from baseline with 85.4% of the patients having an IOP reduction of ≥20%, and mean glaucoma medication use reduced by 0.82±0.53 with 79.6% of the patients having a reduction of ≥1 medication. There was no significant reduction in BCVA from baseline at any follow-up point (P>0.05), except for 10 eyes with a vision loss of ≥2 lines and 5 out of 10 eyes had cataract progression. The probability of complete success (IOP range, 6 to 21 mm Hg or ≥20% IOP reduction; BCVA loss ≤2 lines, no reoperation for glaucoma) was 74.14%, 83.61%, 84.21%, and 75.0% at months 1, 3, 6, 12, respectively. The probability of qualified success (above criteria for IOP, no reoperation and BCVA loss >2 lines) was 81.03%, 91.80%, 94.74%, and 93.75% at months 1, 3, 6, 12, respectively. CONCLUSIONS: MP-TSCPC should be considered earlier in the management of glaucoma and can possibly be offered as an alternative to incisional glaucoma surgeries.

Posterior displacement of the lamina cribrosa in glaucoma: in vivo interindividual and intereye comparisons.

PURPOSE: We assessed in vivo lamina cribrosa (LC) position within the optic nerve head in glaucoma. METHODS: For interindividual comparison, glaucoma patients at various stages and normal subjects were recruited. For intraindividual, intereye comparison, glaucoma patients with visual field (VF) defects in only one eye were recruited separately. Serial horizontal and vertical enhanced depth imaging optical coherence tomography (EDI OCT) B-scans of the optic nerve head were obtained prospectively from each participant. Mean and maximum anterior LC depths were measured in 11 equally spaced horizontal B-scans, excluding the LC insertion area under the Bruch's membrane and scleral rim. RESULTS: Totals of 47 glaucomatous eyes (47 patients; VF mean deviation, -12.7±8.2 dB) and 57 normal eyes (57 subjects) were enrolled for the interindividual comparison. Mean and maximum LC depths were significantly greater in the glaucomatous than in the normal eyes in all 11 scans (all P<0.03). There were 54 glaucoma patients with VF defects in only one eye (VF mean deviation, -15.6±8.8 dB) included in the intereye comparison. Mean and maximum LC depths were significantly greater in the eyes with VF defects than in the fellow eyes with no VF defects in all 11 scans (all P<0.01). CONCLUSIONS: The central and midperipheral LC is located more posteriorly in glaucomatous than in normal eyes, as well as in eyes with VF defects compared to fellow eyes with no VF defects. These results support the concept of posterior LC displacement in glaucoma and provide the basis for future in vivo human studies.

Urrets-Zavalia syndrome following goniotomy in a child.

Urrets-Zavalia syndrome is a surgical complication in which the pupil remains fixed and dilated after a procedure. It is believed to be caused by brief periods of high intraocular pressure. Although the syndrome was originally associated with penetrating keratoplasty, it has subsequently been associated with other procedures. We report the case of a 13-year-old boy with congenital glaucoma who developed Urrets-Zavalia syndrome after goniotomy. After 2 years of follow-up, the pupil remained fixed and dilated in that eye. To our knowledge this is the first case of Urrets-Zavalia syndrome to be reported following goniotomy and the first to occur in a child.

Decompression Retinopathy after ExPRESS Shunt Implantation for Steroid-Induced Ocular Hypertension: A Case Report.

Purpose. To present a unique case of decompression retinopathy after the implantation of ExPRESS drainage device. Method. A 25-year-old female patient underwent implantation of ExPRESS drainage device in the left eye for the management of steroid-induced ocular hypertension. Results. On the postoperative day one, best-corrected visual acuity in the left eye was 20/50. Fundus examination revealed diffuse intraretinal hemorrhages, some white-centered, throughout the retina. There was also marked tortuosity to the retinal vasculature and no evidence of choroidal effusion. Intravenous fluorescein angiography and indocyanine green did not contribute to the aetiopathogenesis. Conclusion. Decompression retinopathy can occur following the implantation of ExPRESS drainage device. It is very important to be aware of this complication in patients with relatively high intraocular pressure who is planned for filtration surgery, including the ExPRESS implant.