Modulation of dopamine tone induces frequency shifts in cortico-basal ganglia beta oscillations.

Βeta oscillatory activity (human: 13-35 Hz; primate: 8-24 Hz) is pervasive within the cortex and basal ganglia. Studies in Parkinson's disease patients and animal models suggest that beta-power increases with dopamine depletion. However, the exact relationship between oscillatory power, frequency and dopamine tone remains unclear. We recorded neural activity in the cortex and basal ganglia of healthy non-human primates while acutely and chronically up- and down-modulating dopamine levels. We assessed changes in beta oscillations in patients with Parkinson's following acute and chronic changes in dopamine tone. Here we show beta oscillation frequency is strongly coupled with dopamine tone in both monkeys and humans. Power, coherence between single-units and local field potentials (LFP), spike-LFP phase-locking, and phase-amplitude coupling are not systematically regulated by dopamine levels. These results demonstrate that beta frequency is a key property of pathological oscillations in cortical and basal ganglia networks.

Early phase of pupil dilation is mediated by the peripheral parasympathetic pathway.

Pupil diameter fluctuates in association with changes in brain states induced by the neuromodulator systems. However, it remains unclear how the neuromodulator systems control the activity of the iris sphincter (constrictor) and dilator muscles to change the pupil size. The present study compared temporal patterns of pupil dilation during movement when each muscle was pharmacologically manipulated in the human eye. When the iris sphincter muscle was blocked with tropicamide, the latency of pupil dilation was delayed and the magnitude of pupil dilation was reduced during movement. In contrast, when the iris dilator muscle was continuously stimulated with phenylephrine, the latency and magnitude of rapid pupil dilation did not differ from the untreated control eye, but sustained pupil dilation was reduced until the end of movement. These results suggest that the iris sphincter muscle, which is under the control of the parasympathetic pathway, is quickly modulated by the neuromodulator system and plays a major role in rapid pupil dilation. However, the iris dilator muscle receives signals from the neuromodulator system with a slow latency and is involved in maintaining sustained pupil dilation.NEW & NOTEWORTHY By pharmacologically manipulating the pupil dilator and constrictor muscles of human eye separately, we found that the pupil constrictor muscle is a primary controller of rapid pupil dilation upon brain arousal. However, the pupil dilator muscle, which is innervated by the sympathetic nervous system and is generally considered as a major regulator of pupil dilation, is not involved in rapid pupil dilation, but was involved in long-lasting pupil dilation.

Role of the pupillometer in the assessment of pain in the sedation of pediatric patients.

OBJECTIVE: Pupillometry has been used to assess pain intensity and response to analgesic drugs in adults. The aim of this study was to verify the usefulness and effectiveness of the pupillometer to assess pain and depth of sedation in pediatric patients undergoing painful procedures and to optimize pain management by observing pupillary variations induced by opioids. PATIENTS AND METHODS: This is a prospective, monocentric study conducted in the sedation room of the Pediatric Intensive Care Unit of Fondazione Policlinico A. Gemelli in Rome. A population of 22 pediatric patients who underwent painful procedures was enrolled. Eleven children were sedated by opioid drugs. Heart rate, systolic blood pressure, diastolic blood pressure, bispectral index, maximum pupil size (Size), pupil change (CH), Neurological Pupil Index (NPi) were collected over four times: before starting the procedure; before the painful stimulus (when the patient was sedated); when the painful stimulus was applied; at the end of the procedure. A NeurOptics NPi-200 pupillometer was used for the study. RESULTS: Statistical significance in the variation of haemodynamic parameters was less significant than the variation obtained by analyzing the pupillary parameters: a significant change in NPi and CH in the transition from wakefulness to sedation and from the application of the painful stimulus to awakening was found in both study populations, patients who have received opioids and patients who have not received opioids. Changes in the mean CH of the pupil diameter correlate with the depth of sedation, and the size values vary in relation to the administration of opioids. CONCLUSIONS: Our findings highlight the potential role of pupillometry as a non-invasive method to objectively quantitate pain response in children to reach an efficient analgesic approach.

Analysis of pupillometer results according to disease stage in patients with Parkinson's disease.

We performed pupillometer testing on 132 patients with Parkinson's disease, stratified into two groups according to the disease stage. Neurological examinations and pupillometry were performed in the ON state. Patients in the Hoehn and Yahr stages 1 and 2 comprised the early group, and patients in stages 3-5 formed the late group. We performed age- and sex-matched (2:1) propensity score matching to compensate for the effect of age on pupil light reflex. Eight pupillometer parameters were measured and compared between the two groups. After the propensity score matching, the early group had 64 patients and the late group had 32 patients. The late group had a longer disease duration and took a higher levodopa equivalent dose than the early group. The constriction velocity (P = 0.006) and maximum constriction velocity (P = 0.005) were significantly faster in the early group than in the late group. Pupil size, minimum diameter, and dilation velocity were similar in both groups. The pupillary contraction velocity decreased with the disease progression, suggesting that the progression of Parkinson's disease could be identified by the pupil constriction velocity.

Ocular surface temperature measurement in diabetic retinopathy.

Infrared thermography provides functional imaging by picturing the temperature pattern of the region imaged. The temperature correlates to the blood flow pattern and is used in the diagnosis of diseases like breast cancer, peripheral vascular disorders, diabetic neuropathy and fever screening. In the present study, the usage of ocular thermography for diagnosis of diabetic retinopathy is explored. Ocular thermograms using infrared imaging camera were obtained for normal subjects (80 volunteers - 40 males and 40 females) age groups 21-30, 31-40, 41-50 and 51-60 years, non-proliferative diabetic retinopathy (NPDR) patients (50 volunteers -25 males and 25 females) and proliferative diabetic retinopathy (PDR) patients (20 volunteers -10 males and 10 females) belonging to age group of 51-60 years. The temperature at various points of interest (POIs) and horizontal temperature profiles were studied. Ocular surface temperature (OST) and effect of eye dilation on OST was studied for control, age matched NPDR and PDR. Statistical analyses were carried out to find the significance of correlation between OST of controls and NPDR and PDR. The global minimum temperature on the ocular surface for controls (21-60 years) was found to be at cornea which is about 34.79 ± 0.68 °C, and maximum at the inner canthus viz. 36.08 ± 0.62 °C. Dilation studies showed an average increase of 0.82 ± 0.13 °C in cornea and 0.75 ± 0.14 °C in conjunctiva and limbus (p < 0.001). The temperature of cornea is around 33.22 ± 0.12 °C and 32.64 ± 0.12 °C for NPDR and PDR patients respectively, in the age group of 51-60 years. OST of NPDR patients was 0.60 ± 0.15 °C lesser than that of age matched normal eyes (p < 0.001) at cornea and limbus regions and 0.71 ± 0.20 °C at inner canthus. The OST of PDR patients was lesser than age matched controls by 1.18 ± 0.12 °C at cornea, 0.9 ± 0.13 °C at inner canthus and 1.0 ± 0.14 °C at other POIs. During dilation studies a positive variation of 0.61 ± 0.12 °C in cornea and 0.48 ± 0.13 °C in conjunctiva and limbus was observed (p < 0.001) in NPDR eyes. Similarly an average increase of 0.62 ± 0.11 °C in cornea and an average increase of 0.47 ± 0.15 °C in conjunctiva and limbus were observed (p < 0.001) in PDR eyes. The OST of NPDR and PDR patients was less compared with age matched counterparts in both pre and post dilation studies. Dilation of eye showed increase in OST for both controls and diabetic retinopathy patients. The degree of increase is less compared with controls. The variation in OST observed during pre and post dilatation studies of diabetic retinopathy patients is a functional marker of pathology, and can be used as a parameter for diagnosis.

Efficacy and effect of intracameral adrenaline infusion on pulse rate and blood pressure during phacoemulsification in patients with dark irides.

OBJECTIVE: Phacoemulsification is the most common cataract surgery that needs optimum circumstances in the field of surgery. This comparative pre- and postoperative study assessed the efficacy and safety of using adrenaline in the irrigating solution as an adjunct to preoperative topical mydriatics in dark irides during Phaco surgery. PATIENTS AND METHODS: This was a prospective observational study that enrolled 421 cataract patients (421 eyes) with dark irides, who were scheduled for Phaco surgery from January 2019 to August 2020. All patients received intraoperative irrigation of a balanced salt solution containing adrenaline. The pulse rate and systolic and diastolic blood pressure of all patients were recorded pre- and postoperatively. In addition, the presence of intraoperative floppy-iris syndrome (IFIS), need for pupil mechanical dilatation, and incidence of posterior capsular rupture were recorded. RESULTS: The sample consisted of 421 patients (421 eyes) all had dark irides. Pulse rate and systolic and diastolic blood pressure did not significantly increase post-operatively (p <0.001). Mechanical dilatation of the pupil was performed in one patient (0.24%) and seven eyes (1.66%) were found to have IFIS. There was no case of posterior capsule rupture. CONCLUSIONS: In comparison with the use of preoperative topical mydriatics alone, adding intracameral adrenaline to the irrigation fluid maintains better pupillary dilatation throughout Phacoemulsification surgery, thereby providing better clinical outcomes in dark irides, even in those with IFIS. Its use has no incremental effect on either blood pressure or pulse rate.

Is it necessary to wait several minutes between applications of different topical ophthalmic solutions? A preliminary study with tropicamide eye drops in healthy dogs.

OBJECTIVE: To evaluate the efficacy of topical tropicamide when placed at different time intervals before or after a saline drop. ANIMALS STUDIED: Eight healthy Labrador and golden retriever dogs. PROCEDURES: The effect of 1% tropicamide on pupillary diameter (PD) was measured over 240 min when administered alone (control) and then 1 and 5 min prior to, or following, application of a saline drop, with 1-week washout between each of the five trials. Data were analyzed using repeated-measures ANOVA and Tukey post hoc test. RESULTS: Only 6/110 pairwise comparisons among the 5 trials were statistically significant (p ≤ .035), with post-hoc analysis showing no significant differences (p ≥ .14) between the overall means of all trials. In all five trials, maximal PD was reached 30 min after tropicamide application and maintained until 210 min for 180 min (p = .0005). CONCLUSIONS: Our results suggest that waiting 1 min between applications of different ophthalmic solutions may be sufficient for maximal drug effect. Care should be taken when extrapolating these results to other species and different ophthalmic formulations.

Opioid Specific Effects on Central Processing of Sensation and Pain: A Randomized, Cross-Over, Placebo-Controlled Study.

Moderate to severe pain is often treated with opioids, but central mechanisms underlying opioid analgesia are poorly understood. Findings thus far have been contradictory and none could infer opioid specific effects. This placebo-controlled, randomized, 2-way cross-over, double-blinded study aimed to explore opioid specific effects on central processing of external stimuli. Twenty healthy male volunteers were included and 3 sets of assessments were done at each of the 2 visits: 1) baseline, 2) during continuous morphine or placebo intravenous infusion and 3) during simultaneous morphine + naloxone or placebo infusion. Opioid antagonist naloxone was introduced in order to investigate opioid specific effects by observing which morphine effects are reversed by this intervention. Quantitative sensory testing, spinal nociceptive withdrawal reflexes (NWR), spinal electroencephalography (EEG), cortical EEG responses to external stimuli and resting EEG were measured and analyzed. Longer lasting pain (cold-pressor test - hand in 2° water for 2 minutes, tetanic electrical), deeper structure pain (bone pressure) and strong nociceptive (NWR) stimulations were the most sensitive quantitative sensory testing measures of opioid analgesia. In line with this, the principal opioid specific central changes were seen in NWRs, EEG responses to NWRs and cold-pressor EEG. The magnitude of NWRs together with amplitudes and insular source strengths of the corresponding EEG responses were attenuated. The decreases in EEG activity were correlated to subjective unpleasantness scores. Brain activity underlying slow cold-pressor EEG (1-4Hz) was decreased, whereas the brain activity underlying faster EEG (8-12Hz) was increased. These changes were strongly correlated to subjective pain relief. This study points to evidence of opioid specific effects on perception of external stimuli and the underlying central responses. The analgesic response to opioids is likely a synergy of opioids acting at both spinal and supra-spinal levels of the central nervous system. Due to the strong correlations with pain relief, the changes in EEG signals during cold-pressor test have the potential to serve as biomarkers of opioid analgesia. PERSPECTIVE: This exploratory study presents evidence of opioid specific effects on the pain system at peripheral and central levels. The findings give insights into which measures are the most sensitive for assessing opioid-specific effects.

Pharmacologic interventions for mydriasis in cataract surgery.

BACKGROUND: Cataract surgery is one of the most common surgical procedures performed worldwide. Achieving appropriate intraoperative mydriasis is one of the critical factors associated with the safety and performance of the surgery. Inadequate pupillary dilation or constriction of the pupil during cataract surgery can impair the surgeon's field of view and make it difficult to maneuver instruments. OBJECTIVES: To evaluate the relative effectiveness of achieving pupillary dilation during phacoemulsification for cataract extraction using three methods of pupillary dilation: topical mydriatics, intracameral mydriatics, or depot delivery systems. We also planned to document and compare the risk of intraoperative and postoperative complications following phacoemulsification for cataract extraction, as well as the cost-effectiveness of these methods for pupillary dilation. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), which contains the Cochrane Eyes and Vision Trials Register) (2021, Issue 1); Ovid MEDLINE; Embase.com; PubMed; Latin American and Caribbean Health Sciences Literature Database (LILACS); ClinicalTrials.gov; and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP). We did not use any date or language restrictions in the electronic search for trials. We last searched the electronic databases on 22 January 2021. SELECTION CRITERIA: We included only randomized controlled trial (RCTs) in which participants underwent phacoemulsification for cataract extraction. DATA COLLECTION AND ANALYSIS: We followed standard Cochrane methodology. MAIN RESULTS: We included a total of 14 RCTs (1670 eyes of 1652 participants) in this review. Of the 14 trials, 7 compared topical versus intracameral mydriatics, 6 compared topical mydriatics versus depot delivery systems, and 1 compared all three methods. We were unable to calculate overall estimates of comparative effectiveness for most outcomes due to statistical heterogeneity among the estimates from individual studies or because outcome data were available from only a single study. Furthermore, the certainty of evidence for most outcomes was low or very low, due primarily to imprecision and risk of bias. Comparison 1: topical mydriatics versus intracameral mydriatics Four RCTs (739 participants, 757 eyes) of the 8 RCTs that had compared these two methods reported mean pupillary diameters at the time surgeons had performed capsulorhexis; all favored topical mydriatics, but heterogeneity was high (I2 = 95%). After omitting 1 RCT that used a paired-eyes design, evidence from three RCTs (721 participants and eyes) suggests that mean pupil diameter at the time of capsulorhexis may be greater with topical mydriatics than with intracameral mydriatics, but the evidence is of low certainty (mean difference 1.06 mm, 95% confidence interval (CI) 0.81 mm to 1.31 mm; I2 = 49%). Four RCTs (224 participants, 242 eyes) reported mean pupillary diameter at the beginning of cataract surgery; the effect estimates from all trials favored topical mydriatics, with very low-certainty evidence. Five RCTs (799 participants, 817 eyes) reported mean pupillary diameter at the end of cataract surgery. Data for this outcome from the largest RCT (549 participants and eyes) provided evidence of a small difference in favor of intracameral mydriasis. On the other hand, 2 small RCTs (78 participants, 96 eyes) favored topical mydriatics, and the remaining 2 RCTs (172 participants) found no meaningful difference between the two methods, with very low-certainty evidence. Five RCTs (799 participants, 817 eyes) reported total intraoperative surgical time. The largest RCT (549 participants and eyes) reported decreased total intraoperative time with intracameral mydriatics, whereas 1 RCT (18 participants, 36 eyes) favored topical mydriatics, and the remaining 3 RCTs (232 participants) found no difference between the two methods, with very low-certainty evidence. Comparison 2: topical mydriatics versus depot delivery systems Of the 7 RCTs that compared these two methods, none reported mean pupillary diameter at the time surgeons performed capsulorhexis. Six RCTs (434 participants) reported mean pupillary diameter at the beginning of cataract surgery. After omitting 1 RCT suspected to be responsible for high heterogeneity (I2 = 80%), meta-analysis of the other 5 RCTs (324 participants and eyes) found no evidence of a meaningful difference between the two methods, with very low-certainty evidence. Three RCTs (210 participants) reported mean pupillary diameter at the end of cataract surgery, with high heterogeneity among effect estimates for this outcome. Estimates of mean differences and confidence intervals from these three RCTs were consistent with no difference between the two methods. A fourth RCT reported only means for this outcome, with low-certainty evidence. Two small RCTs (118 participants) reported total intraoperative time. Surgical times were lower when depot delivery was used, but the confidence interval estimated from one trial was consistent with no difference, and only mean times were reported from the other trial, with very low-certainty evidence. Comparison 3: Intracameral mydriatics versus depot delivery systems Only one RCT (60 participants) compared intracameral mydriatics versus depot delivery system. Mean pupillary diameter at the time the surgeon performed capsulorhexis, phacoemulsification time, and cost outcomes were not reported. Mean pupil diameter at the beginning and end of cataract surgery favored the depot delivery system, with very low-certainty evidence. Adverse events Evidence from one RCT (555 participants and eyes) comparing topical mydriatics versus intracameral mydriatics suggests that ocular discomfort may be greater with topical mydriatics than with intracameral mydriatics at one week (risk ratio (RR) 10.57, 95% CI 1.37 to 81.34) and one month (RR 2.51, 95% CI 1.36 to 4.65) after cataract surgery, with moderate-certainty evidence at both time points. Another RCT (30 participants) reported iris-related complications in 11 participants in the intracameral mydriatics group versus no complications in the depot delivery system group, with very low-certainty evidence. Cardiovascular related adverse events were rarely mentioned. AUTHORS' CONCLUSIONS: Data from 14 completed RCTs were inadequate to establish the superiority of any of three methods to achieve mydriasis for cataract surgery, based on pupillary dilation at different times during the surgery or on time required for surgery. Only one trial had a sample size adequate to yield a robust effect estimate. Larger, well-designed trials are needed to provide robust estimates for the comparison of mydriasis approaches for beneficial and adverse effects.

Intraocular pressure and pupil diameter in healthy cats anesthetized with isoflurane and pre-medicated with isolated acepromazine or in combination with tramadol / [Pressão intraocular e diâmetro pupilar em gatos saudáveis anestesiados com isoflurano e pré-medicados com acepromazina isolada ou em combinação com tramadol]

The objective of this study was to determine changes on intraocular pressure (IOP) and pupil diameter (PD) in healthy cats anesthetized with isoflurane, and premedicated with acepromazine alone or in combination with tramadol. Thirty cats were allocated in two groups (n=15/each) and were treated with acepromazine (AG) or acepromazine/tramadol (ATG). PD and IOP were assessed before and following 30 (PM1), and 40 minutes (PM2) of treatments. Anesthesia was induced with propofol, and IOP and DP were recorded (A10) at 10 minute intervals until the end of anesthesia (A40). IOP decreased in AG and ATG, when comparing baseline with PM1. IOP decreased only in AG, in comparisons between baseline and PM2. During anesthesia, IOP did not change within and between groups. Comparisons between baseline with those recorded at PM1 and 2 showed that PD increased in the ATG. During anesthesia, PD decreased significantly in AG and ATG. Both protocols maintained the IOP within the reference range to perform corneal or intraocular surgery in healthy cats but did not sustain pre-anesthetic pupil dilation observed in ATG.(AU)

O objetivo do presente artigo é determinar possíveis alterações na pressão intraocular (PIO) e no diâmetro pupilar (DP) em gatos saudáveis anestesiados com isoflurano e pré-medicados com acepromazina isolada ou em combinação com acepromazina/tramadol. Trinta gatos saudáveis foram distribuídos aleatoriamente em dois grupos (n=15/cada) e tratados com acepromazina (GA) ou acepromazina/tramadol (GAT). DP e PIO foram avaliadas antes (basal) e após 30 (PM1) e 40 minutos (PM2) dos tratamentos. A anestesia foi induzida com propofol, e a PIO e o DP foram registrados (A10) a cada 10 minutos até o final da anestesia com isoflurano (A40). Ao se compararem os valores obtidos no basal com PM1, a PIO diminuiu em GA e GAT; com PM2, a PIO reduziu apenas no GA. Durante a anestesia, a PIO não diferiu dentro e entre os grupos. Comparações entre os valores basais e os registrados em PM1 e em PM2 mostraram que a DP aumentou significativamente no GAT. Durante a anestesia, o DP diminuiu significativamente em GA e GAT. Ambos os protocolos mantêm a PIO dentro dos valores de referência para realizar cirurgias corneanas ou intraoculares em gatos saudáveis, mas não sustentam a dilatação pupilar pré-anestésica observada em GAT.(AU)

Effects of Medetomidine, Dexmedetomidine and their combination with Acepromazine on the intraocular pressure (IOP), tear secretion and pupil diameter in dogs.

BACKGROUND: A great number of sedatives and anaesthetics have been used to perform surgeries or routine ophthalmologic examinations in animals and sometimes the combination of these medicines has more suitable effects than each one alone. OBJECTIVES: This paper aims to explore the main effects of Medetomidine + Acepromazine, Dexmedetomidine + Acepromazine on intraocular pressure, tear secretion and pupil diameter. METHODS: To accomplish the aforementioned aim, 32 adult dogs (aged one-to-three-years-old) were clinically examined. Dogs were divided into four groups consisting of group DA, Dexmedetomidine (5 µg/kg) + Acepromazine (0.05 mg/kg); Group D, Dexmedetomidine (5 µg/kg); Group M, Medetomidine (10 µg/kg); Group MA, Medetomidine (10 µg/kg) + Acepromazine (0.05 mg/kg). The ocular factors including tear production, pupil diameter and intraocular pressure of both right and left eyes were first measured and then recorded in each dog at time T0 (-15 min). Afterwards, the drugs were administered intramuscularly, based on which the ocular factors were re-measured at T1 (+5 min), T2 (+15 min) and T3 (+20 min). All four groups showed a reduction in intraocular pressure, which was significant in DA, D and M groups. RESULTS: Furthermore, there was a fluctuation in the amount of tear secretion in DA and D groups (increase and then decrease), as well as a significant reduction in M and MA groups. Decreasing in pupil diameter also occurred in all four groups, but the reduction was significant only in DA and MA groups. CONCLUSION: According to the results obtained, as the changes caused by the systemic administration of the above drug compounds did not exceed the physiological range, it can be concluded that these combinations could be utilized as suitable sedatives or pre-anaesthetic compounds in the eye surgeries.

Assessing the Clinical Requirement of 2.5% Phenylephrine for Diagnostic Pupil Examination.

Purpose: To evaluate whether the standard dilating drop regimen consisting of phenylephrine, tropicamide, and proparacaine produces clinically significant improvement in pupil size compared to tropicamide and proparacaine during diagnostic eye examination. Methods: Sixty-three adult patients at Washington University School of Medicine Eye Clinic were enrolled in this prospective, randomized trial. Each patient received one of two dilating drop regimens: phenylephrine + tropicamide + proparacaine (PE+T+PP), which is considered the standard therapy, or tropicamide + proparacaine (T+PP). Main outcome measures were the proportion of pupils able to achieve successful clinical examination without need for additional dilating drops and change in predilation to postdilation pupil size. Comparisons were made using McNemar's test, repeated measures analysis of variance, and Fisher's test to determine whether PE is a necessary component of the standard eye examination. Results: There were no statistically significant differences between the PE+T+PP and T+PE treatment groups in predilation to postdilation changes in average resting pupil size (1.58 ± 0.66 and 2.61 ± 0.79; P = 0.57) or constricted pupil size (2.52 ± 0.93 and 3.56 ± 0.96; P = 0.15). There was no statistically significant difference between patients who obtained a successful dilated pupil examination between those receiving PE+T+PP and those receiving T+PP as determined by the examining physicians (Fisher's, P = 0.67). Conclusion: The addition of phenylephrine to tropicamide and proparacaine did not improve pupillary dilation size or ability to conduct a clinical examination. A single dilating agent using tropicamide should be considered in clinical practice.

Pupil response is modulated with optokinetic nystagmus in transparent motion.

When two visual patterns moving in opposite directions are superimposed on the same depth plane, they appear to have two transparent surfaces moving independently (transparent motion). Additionally, the direction of the slow phase of optokinetic nystagmus (OKN) corresponds to the direction of motion that dominates the perceptual appearance. This study examines whether pupil changes correspond to the luminance of the dominated objects related to the transition of the slow-phase direction in OKN following objects. Stimuli consisted of two random dot patterns of different luminance that moved in opposite directions. The results showed that pupil size changed in accordance with the luminance of the pattern in the slow phase of OKN immediately after OKN transition. This suggests that pupil size is modulated with OKN in transparent motion.

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.

Orexin-A Intensifies Mouse Pupillary Light Response by Modulating Intrinsically Photosensitive Retinal Ganglion Cells.

We show for the first time that the neuropeptide orexin modulates pupillary light response, a non-image-forming visual function, in mice of either sex. Intravitreal injection of the orexin receptor (OXR) antagonist TCS1102 and orexin-A reduced and enhanced pupillary constriction in response to light, respectively. Orexin-A activated OX1Rs on M2-type intrinsically photosensitive retinal ganglion cells (M2 cells), and caused membrane depolarization of these cells by modulating inward rectifier potassium channels and nonselective cation channels, thus resulting in an increase in intrinsic excitability. The increased intrinsic excitability could account for the orexin-A-evoked increase in spontaneous discharges and light-induced spiking rates of M2 cells, leading to an intensification of pupillary constriction. Orexin-A did not alter the light response of M1 cells, which could be because of no or weak expression of OX1Rs on them, as revealed by RNAscope in situ hybridization. In sum, orexin-A is likely to decrease the pupil size of mice by influencing M2 cells, thereby improving visual performance in awake mice via enhancing the focal depth of the eye's refractive system.SIGNIFICANCE STATEMENT This study reveals the role of the neuropeptide orexin in mouse pupillary light response, a non-image-forming visual function. Intravitreal orexin-A administration intensifies light-induced pupillary constriction via increasing the excitability of M2 intrinsically photosensitive retinal ganglion cells by activating the orexin receptor subtype OX1R. Modulation of inward rectifier potassium channels and nonselective cation channels were both involved in the ionic mechanisms underlying such intensification. Orexin could improve visual performance in awake mice by reducing the pupil size and thereby enhancing the focal depth of the eye's refractive system.

Safety and efficacy of unilateral topical application of rocuronium bromide in healthy scops owls (Otus scops).

OBJECTIVE: To evaluate the safety and efficacy of unilateral topical application of rocuronium bromide in scops owls. ANIMALS STUDIED: Ten healthy adult scops owls. PROCEDURES: Birds weighting between 82-111 g were enrolled. Complete physical and ophthalmic examinations were performed. Each animal received a single dose of 0.15 mg of rocuronium bromide (30 µL) in a randomly selected eye. Static pupillometric evaluations were performed before and after drug instillation at 0, 30, 60, 90, and 120 minutes, in a room with fixed light intensity. Physical and ophthalmic examinations were carried out to evaluate possible adverse effects. RESULTS: Median pupil (95% CI) size at t0 was 7.10 mm (5.51-7.41) for placebo eyes and 7.22 mm (6.93-7.48) for treated eyes, showing no statistical differences (P > .05). When compared to the placebo eye, significant mydriasis was achieved at t30 [8.18 mm (7.22-9.00)] (P = .014) and lasting until t90 [7.35 mm (6.20-9.52)] (P = .004). Maximal mydriasis was obtained at t60 [8.63 mm (7.72-9.81)] (P = .001). During this period, the treated eye no longer responded to direct light stimulation. Complete mydriasis was observed in 5/10 birds (mean weight 97.4 g). Pupil size at t90 and t120 did not differ from baseline (P > .05) in treated eyes. No adverse effects were seen during the study period. CONCLUSION: Single-dose topical rocuronium bromide (0.15 mg) is a safe and effective medium duration mydriatic agent in scops owls. Further studies are needed to evaluate bilateral topical application and standardize the mydriatic protocol.

Safety and efficacy of topically administered netarsudil (Rhopressa™) in normal and glaucomatous dogs with ADAMTS10-open-angle glaucoma (ADAMTS10-OAG).

OBJECTIVE: To evaluate safety and efficacy of topically administered 0.02% netarsudil ophthalmic solution (Rhopressa™; Aerie Pharmaceutical) in normal and glaucomatous dogs with ADAMTS10-open-angle glaucoma (ADAMTS10-OAG). ANIMALS STUDIED: Five normal and 5 glaucomatous Beagle dogs with ADAMTS10-OAG. PROCEDURES: In each dog, left or right eye was randomly selected for netarsudil treatment. Contralateral eyes were sham-treated with balanced salt solution (BSS). Following a 1-week baseline period, dogs were treated once daily (q24h) during week 2, and twice daily (q12h) during week 3; week 4 served as washout period. Efficacy was measured by diurnal intraocular pressure (IOP) and pupil diameter. Safety was assessed by routine ophthalmic examination, gonioscopy, and pachymetry. Differences in least square means of quantitative outcome measures were compared between netarsudil and BSS sham-treated eyes by linear Gaussian model. RESULTS: Baseline IOPs were 18.5 ± 0.5 mm Hg (mean ± SEM) in normal and 27.8 ± 1.0 mm Hg in OAG dogs. Even though mean IOPs were lower in netarsudil- vs sham-treated eyes, the overall differences were neither significant nor clinically relevant, regardless of treatment frequency (q24h-normal: sham 16.4 ± 1.1 mm Hg vs treatment 15.6 ± 1.0 mm Hg; q24hr-OAG: sham 25.8 ± 2.3 mm Hg vs. treatment 25.7 ± 2.4 mm Hg; q12hr-normal: sham 15.4 ± 0.8 mm Hg vs. treatment 14.4 ± 0.8 mm Hg; q12hr-OAG: sham 26.3 ± 1.7 mm Hg vs. treatment 25.4 ± 1.8 mm Hg). Netarsudil administration was well tolerated but resulted in significant, moderate-to-severe conjunctival hyperemia (P < .001). CONCLUSIONS: Once or twice daily administration of netarsudil resulted in marginal and clinically irrelevant IOP decreases in normal and OAG-affected dogs. Except for conjunctival hyperemia, the drug was well tolerated.

Randomised controlled pilot trial comparing low dose and very low- dose microdrop administration of phenylephrine and cyclopentolate for retinopathy of prematurity eye examinations in neonates.

AIMS: To determine ifVery low dose mydriatic eye microdrop regimen sufficiently dilates the pupil (above 4.1 mm) compared with the currently used low dose mydriatic eye microdrop regimen.Cardiovascular, gastrointestinal and respiratory adverse effects occur following eye drop instillation. METHODS: Seventeen premature infants were recruited into this prospective, randomised controlled pilot trial in January 2017 to November 2018. Data were collected from the single-centre Neonatal Intensive Care Unit, Dunedin Hospital, New Zealand. The inclusion criteria were birth weight less than 1500 g or gestational age less than 31 weeks, or any premature infant requiring red reflex testing. Infants were randomised to receive either phenylephrine 1% or 0.5% and cyclopentolate 0.2% or 0.1%, 1 microdrop in both eyes. Efficacy outcome measures were pupil size at retinopathy of prematurity eye examination (ROPEE) and ophthalmologist rating of ease of screen. RESULTS: All participants had sufficient pupillary dilation for a successful ROPEE. Ophthalmologists rated the ROPEE as easy for 90% of all examinations. Pupil dilation measurements at the time of examination, mean±SD, 4.8±0.2 (95% CI 4.5 to 5.2) mm for treatment A and 5±0.2 (95%CI 4.6 to 5.4) mm for treatment B (p=0.61). There were no statistically significant differences between the groups for safety data. CONCLUSIONS: Very low dose microdrop administration of phenylephrine and cyclopentolate appears to be effective at sufficiently dilating the neonatal pupil for ROPEEs. Low dose and very low dose microdrop mydriatic regimens may also reduce the risk of unwanted adverse effects associated with these medicines. TRIAL REGISTRATION NUMBER: Australian New Zealand Clinical Trials Registry (reference ACTRN12616001266459p).

Macular Pigment Optical Density Fluctuation as a Function of Pupillary Mydriasis: Methodological Considerations for Dual-Wavelength Autofluorescence.

PURPOSE OF THE STUDY: Macular pigment (MP), comprising the dietary carotenoids lutein, zeaxanthin and meso-zeaxanthin, is believed to benefit eye health and vision. Numerous clinical and research devices and techniques are currently available to facilitate MP optical density (MPOD) measurement. One of those techniques, dual-wavelength fundus autofluorescence (AF) is being increasingly used for measurement of MP in the eye. There is substantial methodological variation across the published studies that have employed this technique, including in relation to the use of mydriasis, the possible influence of which does not appear to have been addressed in the literature. This prospective cross-sectional study was designed to investigate the effect of mydriasis on MP measurement quality and MPOD values obtained with dual-wavelength AF using the Heidelberg Spectralis HRA+OCT device. MATERIALS AND METHODS: Twenty-one healthy participants were recruited to the study. The mean age of participants was 44.8 years (± 14.63). Pupil size and MPOD were measured in one eye for each participant, initially under natural pupil conditions and subsequently 30 minutes following instillation of one drop of 0.5% tropicamide. RESULTS: Despite providing MPOD measurements for the majority of undilated eyes (85.7% of eyes herein), pupillary dilation resulted in statistically significant changes in MPOD (p < .001 for central eccentricities). Our results indicate that the changes in MPOD were not uniform across the spatial profile. Marked improvements were also observed in image quality post-dilation (p < .002 for central eccentricities). CONCLUSIONS: This study clearly demonstrates that dual-wavelength AF measurements of MPOD in the same eye vary as a function of pupillary dilation status, with MPOD under-estimated across the entire spatial profile of MP for natural relative to dilated pupillary conditions. Mydriasis should, therefore, be used routinely for MPOD measurements using dual wavelength AF, pupil size should be reported and image quality optimized in order to ensure accurate MPOD quantification.