Intraocular Pressure Lowering Associated With Worsening Optic Pit-Like Retinoschisis.

In this article, we present a case of optic pit-like macular retinoschisis in the absence of advanced glaucomatous cupping. Intraocular pressure (IOP)-lowering therapy, which was started due to an early concern for glaucoma, caused a worsening of the retinoschisis, which subsequently resolved on discontinuation of the IOP-lowering therapy. Lower IOP likely triggered intraretinal fluid accumulation by facilitating a translaminar gradient from the subarachnoid to intraretinal space. [Ophthalmic Surg Lasers Imaging Retina 2024;55:100-102.].

A randomized phase 2 clinical trial of phentolamine mesylate eye drops in patients with severe night vision disturbances.

PURPOSE: Dim light vision disturbances (DLD) comprise a wide range of symptoms affecting the quality of vision at low illumination including glare, halos, and starbursts. This exploratory study investigated 1.0% phentolamine mesylate ophthalmic solution (PMOS) as a treatment to improve vision and image quality for patients with DLD. METHODS: In this placebo-controlled, randomized, double-masked clinical trial, 24 adult patients with severe DLD were randomized in a 2:1 ratio to receive either one dose of PMOS or placebo. Subjects were eligible if they reported experiencing severe night vision difficulty that was not eliminated by distance spectacle correction and scored ≥0.3 log units below the normal range of contrast sensitivity assessed under mesopic conditions with glare at ≥2 spatial frequencies. Key efficacy outcomes were change from baseline in pupil diameter, contrast sensitivity, and visual acuity. Safety measures including intraocular pressure, conjunctival hyperemia, and systemic effects were also assessed. RESULTS: Eight subjects were randomized to placebo (63% female; mean age 47 years) and 16 were randomized to PMOS (75% female; mean age 42 years). Mean (SD) pupil diameter of PMOS-treated subjects decreased significantly - 1.3 mm (0 to - 2.8 mm) with p < 0.0001. Mean contrast sensitivity with glare in PMOS-treated subjects improved significantly post-treatment at spatial frequencies 3, 6, 12, and 18 cycles per degree (p ≤ 0.03). PMOS also demonstrated improvements in the numbers of letters read for mesopic and photopic, high- and low-contrast visual acuity (LCVA). Importantly, a statistically greater proportion of PMOS-treated eyes registered mesopic LCVA 5 letter (69% vs. 31%, p = 0.029) and 10 letter (34% vs. 6%, p = 0.04) improvement, with a trend at 15 letters (19% vs. 0%, p = 0.16). PMOS was well tolerated with the only reported side effect being a mild increase in conjunctival hyperemia. CONCLUSION: PMOS was well tolerated and effectively reduced pupil size with improvements in contrast sensitivity and visual acuity in adults with severe DLD. Future Phase 3 studies should be conducted to further evaluate its potential to treat DLD. TRIAL REGISTRATION: The trial registration number is NCT04004507 (02/07/2019). Retrospectively registered.

APE1/Ref-1 as a Novel Target for Retinal Diseases.

APE1/Ref-1 (also called Ref-1) has been extensively studied for its role in DNA repair and reduction-oxidation (redox) signaling. The review titled: "The multifunctional APE1 DNA repair-redox signaling protein as a drug target in human disease" by Caston et. al. summarizes the molecular functions of Ref-1 and the role it plays in a number of diseases, with a specific focus on various types of cancer [1]. Previous studies have demonstrated that Ref-1 plays a critical role in regulating specific transcription factors (TFs) involved in a number of pathways, not only in cancer, but other disease indications as well. Disease indications of particular therapeutic interest include retinal vascular diseases such as diabetic retinopathy (DR), diabetic macular edema (DME), and neovascular age-related macular degeneration (nvAMD). While Ref-1 controls a number of TFs that are under redox regulation, three have been found to directly link cancer studies to retinal diseases; HIF-1α, NF-κB and STAT3. HIF-1α controls the expression of VEGF for angiogenesis while NF-κB and STAT3 regulate a number of known cytokines and factors involved in inflammation. These pathways are highly implicated and validated as major players in DR, DME and AMD. Therefore, findings in cancer studies for Ref-1 and its inhibition may be translated to these ocular diseases. This report discusses the path from cancer to the potential treatment of retinal disease, the Ref-1 redox signaling function as a possible target, and the current small molecules which have been identified to block this activity. One molecule, APX3330, is in clinical trials, while the others are in preclinical development. Inhibition of Ref-1 and its effects on inflammation and angiogenesis makes it a potential new therapeutic target for the treatment of retinal vascular diseases. This commentary summarizes the retinal-relevant research that built on the results summarized in the review by Caston et. al. [1].

Phentolamine Eye Drops Reverse Pharmacologically Induced Mydriasis in a Randomized Phase 2b Trial.

SIGNIFICANCE: After a dilated eye examination, many patients experience symptoms of prolonged light sensitivity, blurred vision, and cycloplegia associated with pharmacological mydriasis. Phentolamine mesylate ophthalmic solution (PMOS) may expedite the reversal of mydriasis in patients, potentially facilitating return to functional vision and reducing barriers to obtaining dilated eye examinations. PURPOSE: The protracted reversal time after pharmacologically induced pupil dilation impairs vision. We tested the hypothesis that PMOS rapidly reduces pupil diameter in this acute indication. METHODS: In this double-masked placebo-controlled, randomized, two-arm crossover phase 2b trial, we evaluated the effects of one drop of 1% PMOS applied bilaterally in subjects who had their pupils dilated by one of two common mydriatic agents: 2.5% phenylephrine or 1% tropicamide. End points included change in pupil diameter, percent of subjects returning to baseline pupil diameter, and accommodative function at multiple time points. RESULTS: Thirty-one subjects completed the study (15 dilated with phenylephrine and 16 with tropicamide). Change in pupil diameter from baseline at 2 hours after maximal dilation with 1% PMOS was -1.69 mm and was significantly greater in magnitude compared with placebo for every time point beyond 30 minutes (P < .05). At 2 hours, a greater percentage of study eyes given 1% PMOS returned to baseline pupil diameter compared with placebo (29 vs. 13%, P = .03), which was this also seen at 4 hours (P < .001). More subjects treated with PMOS in the tropicamide subgroup had at least one eye returning to baseline accommodative amplitude at 2 hours (63 vs. 38%, P = .01). There were no severe adverse events, with only mild to moderate conjunctival hyperemia that resolved in most patients by 6 hours. CONCLUSIONS: Phentolamine mesylate ophthalmic solution at 1% reversed medically induced pupil dilation more rapidly than placebo treatment regardless of which mydriatic was used (adrenergic agonists and cholinergic blockers) with a tolerable safety profile.

Phentolamine Mesylate Ophthalmic Solution Provides Lasting Pupil Modulation and Improves Near Visual Acuity in Presbyopic Glaucoma Patients in a Randomized Phase 2b Clinical Trial.

PURPOSE: Phentolamine mesylate ophthalmic solution (PMOS), applied to the eye topically, was shown previously to have beneficial effects in patients with dim light vision disturbances (DLD), including decreased pupil diameter (PD), improved best-corrected distance visual acuity (BCDVA), as well as lower intraocular pressure (IOP). The ORION-1 trial evaluated the long-term safety and efficacy of PMOS in a glaucomatous, presbyopic population. PATIENTS AND METHODS: In this randomized, double-masked, multi-center, placebo-controlled, multiple-dose Phase 2b trial, 39 patients with elevated IOP were randomized to receive one evening dose of study medication or placebo for 14 days. The primary outcome measure was mean change in diurnal IOP, and the key secondary outcome measures included changes in PD, distance-corrected near visual acuity (DCNVA), and conjunctival hyperemia. RESULTS: Use of 1% PMOS did not lead to a statistically significant decrease in diurnal IOP compared to placebo (P = 0.89) but trended toward a greater decrease in patients with lower IOP baselines. PMOS produced a statistically significant mean 20% PD reduction under both photopic and mesopic conditions that was sustained for 36 hours post-dosing. A statistically significant number of patients with PMOS compared to placebo demonstrated ≥1 line of improvement in photopic DCNVA at day 8 (P = 0.0018), day 15 (P = 0.0072), and day 16 (P = 0.0163), with a trend for 2- and 3-line improvements at all time points. There was no statistical difference in conjunctival hyperemia compared to placebo. CONCLUSION: Although mean IOP was not lowered significantly, daily evening dosing of 1% PMOS was found to be well tolerated with no daytime conjunctival redness and demonstrated improvement in DCNVA with sustained PD reduction in a glaucomatous and presbyopic population. Smaller pupil size can have beneficial effects in improving symptoms of presbyopia and DLD, which will be the focus of further studies.

Dorsal Midbrain Syndrome: Clinical and Imaging Features in 75 Cases.

BACKGROUND: Dorsal midbrain syndrome (DMS) consists of a constellation of clinical features, including reduced upgaze, pupillary light-near dissociation, lid retraction, convergence retraction, and eye misalignment. This syndrome results mostly from intrinsic or extrinsic mesodiencephalic tumors or strokes, obstructive hydrocephalus, failure of cerebrospinal fluid shunting to correct obstructive hydrocephalus, and head trauma. Published reports that include imaging corroboration are based on relatively small cohorts and have not included comprehensive patient self-reports on the impact of these abnormalities on quality of life. METHODS: We conducted a retrospective review of cases of DMS identified between 1998 and 2019 at the University of Michigan using the Electronic Medical Record Search Engine. Patients were included only if they had been evaluated by a neuro-ophthalmologist and had a corroborative imaging abnormality. We collected data on symptoms and on neuro-ophthalmic and neurologic signs. We reviewed brain imaging reports on all 75 patients, and the study neuroradiologist analyzed the imaging in 57 patients. Using a uniform list of questions, we conducted telephone interviews of 26 patients to assess lingering symptoms and their impact on quality of life. RESULTS: There were 75 patients, only 5 of whom were younger than 10 years. Neoplasms accounted for 47%, strokes (mostly thalamic) for 25%, nonneoplastic masses for 12%, nonneoplastic hydrocephalus for 7%, traumatic brain injury for 5%, and demyelination for 4%. Reduced upgaze occurred in 93% of patients, being completely absent or reduced to less than 50% amplitude in 67%. Convergence retraction on attempted upgaze occurred in 52%, horizontal misalignment in 49%, vertical misalignment in 47%, and pupillary light-near dissociation in 37%. Optic neuropathy attributed to chronic papilledema occurred in only 3%. Three or more neuro-ophthalmic signs were present in 84%, and only 4% had a single sign-reduced upgaze. Imaging features did not correlate with the frequency or severity of clinical signs. There was some improvement in the clinical signs among the patients with stroke but no change among the patients with neoplasms. In the 26 telephone interviews, patients with neoplasms reported that imbalance had a greater impact on quality of life than did diplopia. Patients with strokes reported that imbalance had the greatest impact initially but that its effect dissipated. Neither group reported lingering effects of impaired upgaze. CONCLUSIONS: This large series expands on the clinical profile of DMS. Neoplasms and strokes were the most common causes. Obstructive hydrocephalus alone, identified as a major cause in the largest previously published series, was uncommon. At least 3 neuro-ophthalmic signs were present in nearly all patients, with upgaze deficit as predominant. Unlike an earlier report, this study found no correlation between brain imaging and clinical signs. Neuro-ophthalmic signs persisted even after neoplasms were successfully treated and improved only slightly after stroke. Telephone interviews with patients revealed that diplopia and upgaze deficit had less lasting impact on quality of life than did ataxia and concurrent nonneurologic problems.

Predictors of distant metastasis in acinic cell carcinoma of the parotid gland.

BACKGROUND: AiCC is a primarily indolent disease process. Our aim with this study is to determine characteristics consistent with rapidly progressive AiCC of the parotid gland. AIM: To report on patients with metastatic lung disease from AiCC and potential correlative factors. METHODS: Single-institution retrospective review of patients treated at the University of Michigan between 2000 and 2017. Univariate analyses were performed. RESULTS: A total of 55 patients were identified. There were 6 patients (10.9%) with primary AiCC of the parotid gland who developed lung metastases. The mean age at diagnosis for patients with lung metastases was 57.8 years of age, in comparison to 40.2 years for those without metastases (P = 0.064). All 6 of the patients with lung metastases demonstrated gross perineural invasion intraoperatively, in comparison to none of those in the non-lung metastases cohort. Worse disease-free and overall survival were significantly associated with gross perineural invasion, high-grade differentiation, and T4 classification (P < 0.001). CONCLUSION: AiCC of the parotid gland is viewed as a low-grade neoplasm with good curative outcomes and low likelihood of metastasis. With metastasis, however, it does exhibit a tendency to spread to the lungs. These patients thereby comprise a unique and understudied patient population. In this retrospective study, factors that have been shown to be statistically significant in association with worse disease-free survival and overall survival include presence of gross facial nerve invasion, higher T-classification, and high-grade disease.

Predominance of Spinal Metastases Involving the Posterior Vertebral Body.

BACKGROUND: Spinal metastases pose significant morbidity. For many histologies, the spine is a frequent site for bone metastases. This predilection is not fully understood, and there are conflicting reports regarding the distribution within the vertebral body itself. Knowing this distribution will give clues as to the underlying biologic reason for this increased incidence in the spine and lead to a better understanding of tumor dispersion and growth. METHODS: We retrospectively examined magnetic resonance imaging scans of patients undergoing radiation to the spine from 2015 to 2017 for spinal metastases. The anatomical distribution of lesions was categorized. Lesions were sorted along the sagittal plane into 5 groups: anterior only, anterior + middle, middle only, posterior + middle, and posterior only. Lesions that covered all groups were discarded. χ2 and post-hoc analyses were used for statistical analyses. RESULTS: Three hundred metastatic lesions were examined in 89 patients; 203 lesions were used for analysis. Sixty-five percent of all lesions were found in posterior only and posterior + middle aspects of the vertebral body (P < 0.0001). This localization was significant regardless of histology: lung (67%, P < 0.0001), kidney (66%, P < 0.0001), sarcoma (67%, P < 0.0001), prostate (63%, P = 0.01), and breast (63%, P = 0.01). This was consistent across thoracic (n = 96) and lumbar (n = 63) regions (72% and 64%, respectively, P < 0.0001). CONCLUSIONS: Metastatic lesions of the thoracolumbar spine have a greater propensity to localize to the posterior aspect of the vertebral body. These data support the hypothesis that there may be differences within the vertebral body leading to differential tumor dispersion and growth.