Aberrant regeneration of accommodation in pediatric inferior division oculomotor palsy.

Aberrant regeneration occurs in forms of oculomotor motor nerve palsy and frequently involves the pupil, but the incidence and functional impact of ciliary muscle involvement in pediatric patients is sparsely reported in the literature. A 4-year-old girl presented with inflammatory oculomotor motor nerve paresis affecting the inferior division. Initial treatment focused on her inability to accommodate through her physiologic +2.5 D hyperopia and the prevention and treatment of amblyopia. She subsequently developed aberrant regeneration of the pupil, with miosis on adduction. Following eye muscle surgery for residual exotropia and hypertropia, her dry refraction was noted to be more myopic in the affected eye on adduction, mirroring aberrant pupillary constriction. Recognition of pediatric aberrant regeneration of accommodation may influence surgical planning for oculomotor nerve palsy and/or management of amblyopia.

Temporal Effects of 2% Pilocarpine Ophthalmic Solution on Human Pupil Size and Accommodation.

INTRODUCTION: First responders and those who work with organophosphate (OP) compounds can experience ocular symptoms similar to those caused by exposure to low levels of nerve agents. This study was designed to examine the efficacy of a safe, clinically available, simulant that reproduces ocular symptoms associated with low-level OP exposure. Among these ocular symptoms are a constriction of the pupils (miosis), decreased visual acuity, and changes in accommodation. MATERIALS AND METHODS: Volunteers aged 18-40 were assigned to groups receiving either a two-drop or three-drop dose of FDA approved 2% pilocarpine ophthalmic solution. Baseline visual performance measurements were taken before eye drop instillation and a timer was started following the first drop of pilocarpine. Once eye drops were administered, visual performance including distant and near vision, pupil size, and accommodation were measured every 5 minutes for 2 hours. RESULTS: Both groups experienced significant miosis in excess of 90 minutes. Visual acuity was significantly reduced because of accommodative changes. The three-drop group experienced longer lasting combined effects when compared to the two-drop group. CONCLUSIONS: 2% pilocarpine ophthalmic solution can safely simulate major ocular symptoms of OP exposure for behavioral research studies for at least 60 minutes.

Methods for achieving adequate pupil size in cataract surgery.

PURPOSE OF REVIEW: Cataract surgery is the most common surgical procedure performed worldwide. Small pupils have been an eternal challenge for cataract surgeons; insufficient pupil dilation is associated with increased complication rates, including capsule rupture, vitreous loss, iris trauma or postoperative inflammation. The aim of the current review is to present the methods for pupil dilation and the risk factors for a small pupil in a cataract patient. RECENT FINDINGS: Risk factors for intraoperative small pupil include diabetes, intraoperative floppy iris syndrome, pseudoexfoliation syndrome, receiving glaucoma medications, having undergone previous ocular surgery and iris sphincter sclerosis from aging. There is a wide range of options to manage the small pupil, including pharmacological treatment, mechanical stretching, dilation with iris hooks or pupil expanders. We recommend a stepwise approach for intraoperative pupil dilation, from pharmacological mydriasis to pupil expanders. SUMMARY: The current article discusses risk factors for a small pupil and the methods for pupil dilation in a cataract patient. Every cataract surgeon needs to be ready to cope with a small pupil, both manifesting preoperatively and intraoperatively.

Pharmacological Strategies for Presbyopia Correction.

PURPOSE: To summarize the pharmacological strategies that are being explored for presbyopia correction. METHODS: The review concentrates on pharmacologically induced pupillary miosis to increase depth-of-focus and lens softening or other measures to restore active accommodation. RESULTS: Several studies suggest that near vision improves and distance vision is unaffected for many hours after either monocular or binocular instillation of any one of several drug combinations that cause miosis. Unfortunately, in most studies, measurements were limited to photopic visual acuity for near and distance vision, whereas it is anticipated that pupil constriction may have adverse effects on mesopic and scotopic vision. It is not clear whether improved near vision was due entirely to increased depth-of-focus, or whether, for example, a drug-induced myopic shift in refraction was also involved. Currently, no study has provided direct evidence for drug-induced restoration/enhancement of true accommodation involving an ocular power change. CONCLUSIONS: Although it is possible that, in the future, pharmacological drops may offer a safe and reliable solution for presbyopia correction, more evidence of their effectiveness and limitations is required. [J Refract Surg. 2019;35(12):803-814.].

Ocular surface histopathological insult following sarin and VX exposure and potential treatments in the rat model.

Eye exposure to organophosphate (OP) chemical warfare irreversible acetylcholinesterase inhibitors, results in long-term miosis and impaired visual function. In contrast to the well-documented miotic and ciliary muscle spasm observed following chemical warfare, OP ocular exposure, little is known regarding the ocular surface histopathological insult. The aim of the present study was to determine the degree of the ocular surface insult following sarin or VX ocular exposure and to evaluate potential anti-cholinergic treatments in counteracting this insult. Rats that were whole body exposed to various sarin concentrations (0.049-43 µg/L; 5 min exposure), showed a dose-dependent miotic response and light reflex impairment. Following whole body sarin exposure, a dose dependent ocular surface histopathological insult was developed. A week following exposure to a low concentration of 0.05 µg/L, conjunctival pathology was observed, while corneal insult was noticed only following exposure to a concentration of 0.5 µg/L and above. Both tissues presented poorer outcomes when exposed to higher sarin concentrations. In contrast, eyes topically exposed to 1 µg sarin demonstrated no ocular insult a week following exposure. On the contrary, topical exposure to 1 µg VX resulted in a significant corneal insult. Anticholinergic treatments such as 0.1% atropine or 2% homatropine, given shortly following VX exposure, counteracted this insult. The results of this study show that not only do anti-cholinergic treatments counteract the miotic response, but also prevent the histopathological insult observed when given shortly following OP exposure.

Spinal Subarachnoid Hemorrhage Induced Intractable Miotic Pupil. A Reminder of Ciliospinal Sympathetic Center Ischemia Based Miosis: An Experimental Study.

AIM: To examine ischemic neurodegeneration of the ciliospinal center on permanent miosis following subarachnoid hemorrhage (SAH). MATERIAL AND METHODS: Nineteen rabbits were examined in this study. The animals were divided into three groups, as control (GI, n=5), sham (GII, n=5) and study group (GIII, n=9). Pupil diameters were measured after giving 0.5 mL physiological saline for sham and autologous arterial blood for the study group into the cervico-thoracic subarachnoid space. After three weeks of follow up, the cervico-thoracic cord and bilateral superior cervical sympathetic ganglia were removed. The pupil diameter values were compared with degenerated neuron volumes of sympathetic ganglia and degenerated neuron densities of thoracic sympathetic nuclei which were studied by stereological methods. RESULTS: The mean pupil diameter was 5180 ± 370 µm and the mean degenerated neuron density of the ciliospinal center was 4 ± 1/mm3 in animals of the control group (GI). These values were 9850 ± 610 εm, 10 ± 3/mm3 in sham (GII), and 7.010 ± 440 εm and 98 ± 21/mm3 in the study (GIII) groups. There was an inverse relationship between degenerated neuron density of the ciliospinal nuclei and pupil diameters. CONCLUSION: We showed and reported for the first time that ciliospinal sympathetic center ischemia-induced neurodegeneration may have been responsible for permanent miosis following SAH.

Small-pupil versus multifocal strategies for expanding depth of focus of presbyopic eyes.

PURPOSE: To compare the visually weighted image quality and depth of focus achieved with small-pupil and multifocal strategies for expanding depth of focus of presbyopic or pseudophakic eyes. SETTING: School of Optometry, Indiana University, Bloomington, USA. DESIGN: Computational modeling. METHODS: The visual Strehl ratio was computed from monochromatic optical transfer functions over a wide range of primary spherical aberration and defocus levels for pupil diameters ranging from 1.0 mm to 7.0 mm under high photopic light levels (retinal illuminance >900 trolands) and mesopic light levels (2 candelas/m2). RESULTS: Pupil miosis and added spherical aberration were effective at reducing the impact of spherical defocus. With high light levels at which Weber's law makes neural contrast sensitivity independent of retinal illuminance, small pupils (eg, 1.0 to 3.0 mm) generated higher peak image quality and more effective expansion of depth of focus than the small-pupil multifocal model. However, under low light levels at which the reduced retinal illuminance associated with pupil miosis lowered neural contrast sensitivity, the peak image quality was lower with small pupils (1.0 to 1.5 mm) at all aberration levels. Large pupils and high levels of spherical aberration were most effective at expanding the depth of focus under mesopic light levels. CONCLUSIONS: When reductions in retinal illuminance created by pupil miosis have no effect on neural contrast sensitivity, small pupils produced higher image quality and larger depth of focus than multifocal optics and large pupils. In general, the reverse was true under mesopic light conditions.

Opioid Sensitivity in Children with and without Obstructive Sleep Apnea.

BACKGROUND: Opioids are a mainstay of perioperative analgesia. Opioid use in children with obstructive sleep apnea is challenging because of assumptions for increased opioid sensitivity and assumed risk for opioid-induced respiratory depression compared to children without obstructive sleep apnea. These assumptions have not been rigorously tested. This investigation tested the hypothesis that children with obstructive sleep apnea have an increased pharmacodynamic sensitivity to the miotic and respiratory depressant effects of the prototypic µ-opioid agonist remifentanil. METHODS: Children (8 to 14 yr) with or without obstructive sleep apnea were administered a 15-min, fixed-rate remifentanil infusion (0.05, 0.1, or 0.15 µg · kg · min). Each dose group had five patients with and five without obstructive sleep apnea. Plasma remifentanil concentrations were measured by tandem liquid chromatography mass spectrometry. Remifentanil effects were measured via miosis, respiratory rate, and end-expired carbon dioxide. Remifentanil pharmacodynamics (miosis vs. plasma concentration) were compared in children with or without obstructive sleep apnea. RESULTS: Remifentanil administration resulted in miosis in both non-obstructive sleep apnea and obstructive sleep apnea patients. No differences in the relationship between remifentanil concentration and miosis were seen between the two groups at any of the doses administered. The administered dose of remifentanil did not affect respiratory rate or end-expired carbon dioxide in either group. CONCLUSIONS: No differences in the remifentanil concentration-miosis relation were seen in children with or without obstructive sleep apnea. The dose and duration of remifentanil administered did not alter ventilatory parameters in either group.

STIM1 over-activation generates a multi-systemic phenotype affecting the skeletal muscle, spleen, eye, skin, bones and immune system in mice.

Strict regulation of Ca2+ homeostasis is essential for normal cellular physiology. Store-operated Ca2+ entry (SOCE) is a major mechanism controlling basal Ca2+ levels and intracellular Ca2+ store refilling, and abnormal SOCE severely impacts on human health. Overactive SOCE results in excessive extracellular Ca2+ entry due to dominant STIM1 or ORAI1 mutations and has been associated with tubular aggregate myopathy (TAM) and Stormorken syndrome (STRMK). Both disorders are spectra of the same disease and involve muscle weakness, myalgia and cramps, and additional multi-systemic signs including miosis, bleeding diathesis, hyposplenism, dyslexia, short stature and ichthyosis. To elucidate the physiological consequences of STIM1 over-activation, we generated a murine model harboring the most common TAM/STRMK mutation and characterized the phenotype at the histological, ultrastructural, metabolic, physiological and functional level. In accordance with the clinical picture of TAM/STRMK, the Stim1R304W/+ mice manifested muscle weakness, thrombocytopenia, skin and eye anomalies and spleen dysfunction, as well as additional features not yet observed in patients such as abnormal bone architecture and immune system dysregulation. The murine muscles exhibited contraction and relaxation defects as well as dystrophic features, and functional investigations unraveled increased Ca2+ influx in myotubes. In conclusion, we provide insight into the pathophysiological effect of the STIM1 R304W mutation in different cells, tissues and organs and thereby significantly contribute to a deeper understanding of the pathomechanisms underlying TAM/STRMK and other human disorders involving aberrant Ca2+ homeostasis and affecting muscle, bones, platelets or the immune system.

Diffractive multifocal intraocular lens implantation in eyes with a small-diameter pupil.

Postoperative outcome of diffractive multifocal intraocular lens (MIOL) implantation in eyes with a small-diameter pupil was evaluated. This non randomized case series involved 23 eyes of 23 patients who underwent diffractive MIOL implantation and whose preoperative photopic pupil diameter was ≤3.0 mm [small-diameter pupil (SDP) group], and 79 eyes of 79 patients implanted with the same MIOL whose pupil diameter was >3.0 mm as controls (LDP group). Contrast sensitivity of high spatial frequency (12, and 18 cycle per degree) and both 12.5% and 6% low-contrast visual acuity (VA) were significantly worse in the SDP group than in the LDP group (P = 0.04, 0.05, 0.05, 0.03). However, no significant difference was found between eyes in the SDP group with a postoperative pupil diameter greater than 3.0 mm and LDP group eyes. No significant differences were found in uncorrected and corrected distance VA (UDVA, CDVA), uncorrected and corrected near VA (UNVA, CNVA), contrast sensitivity with low spatial frequency, and defocus curve between the two groups. In conclusion, in eyes implanted with a diffractive MIOL, a pupil diameter of ≤3.0 mm deteriorates contrast sensitivity. This effect was eliminated postoperatively when pupil size was enlarged to >3.0 mm during surgery.

The Tuebingen Scotopic Threshold Test (TSTT).

Measurement of the dark-adaptation threshold plays a key role in the diagnosis and estimation of disease progression of many retinal disorders. Determining the threshold is, however, difficult to perform in young children. We present here a prototype for a dark adaptometer, the Tuebingen Scotopic Threshold Test aimed to ease measurement of photoreceptor thresholds in young subjects. The device consists of two 7 cm ×10 cm fields with either blue or yellow LEDs, for testing rod or cone sensitivity, respectively. Presentation of homogenous field patterns or a flickering stimulus is also possible. The luminance threshold is measured by the method of ascending limits and the stimulus luminance, data recording and analysis are computer controlled. Preliminary results for six adults and two older children were ascertained and the influence of pupil dilation, binocular presentation, and a flickering stimulus examined. The method provides credible and consistent evaluations of the absolute threshold.

Reducing starbursts in highly aberrated eyes with pupil miosis.

PURPOSE: To test the hypothesis that marginal ray deviations determine perceived starburst sizes, and to explore different strategies for decreasing starburst size in highly aberrated eyes. METHODS: Perceived size of starburst images and visual acuities were measured psychophysically for eyes with varying levels of spherical aberration, pupil sizes, and defocus. Computationally, we use a polychromatic eye model including the typical levels of higher order aberrations (HOAs) for keratoconic and post-LASIK eyes to quantify the image quality (the visually weighted Strehl ratio derived from the optical transfer function, VSOTF) with different pupil sizes at both photopic and mesopic light levels. RESULTS: For distance corrected post-LASIK and keratoconic eyes with a night-time pupil (e.g., 7 mm), the starburst diameter is about 1.5 degrees (1 degree for normal presbyopic eyes), which can be reduced to ≤0.25 degrees with pupil sizes ≤3 mm. Starburst size is predicted from the magnitude of the longitudinal spherical aberration. Refracting the eye to focus the pupil margin also removed starbursts, but, unlike small pupils, significantly degraded visual acuity. Reducing pupil diameter to 3 mm improved image quality for these highly aberrated eyes by about 2.7 ×  to 1.7 ×  relative to the natural pupils when light levels were varied from 0.1 to 1000 cd m-2 , respectively. CONCLUSION: Subjects with highly aberrated eyes observed larger starbursts around bright lights at night predictable by the deviated marginal rays. These were effectively attenuated by reducing pupil diameters to ≤3 mm, which did not cause a drop in visual acuity or modelled image quality even at mesopic light levels.

Effect of cervical sympathetic ganglionectomy on facial nerve reconstruction using polyglycolic acid-collagen tubes.

A polyglycolic acid-collagen (PGA-c) tube was used as an artificial nerve guide during facial nerve reconstruction performed in a canine model of stellate ganglion block (SGB). The model was generated using a cervical sympathetic ganglionectomy. We evaluated the effects of blood flow on nerve regeneration. First, we resected the left cervical sympathetic ganglion in beagles (n=6). We assessed buccal mucosal blood flow and nasal skin temperatures once per week for 12weeks and Horner's sign 2, 4, and 6months after resection. We compared these values to those measured prior to resection. Blood flow was increased for 6-11weeks, but sympathetic control remained blocked after 6months. Second, we divided beagles into 3 groups: resection models (negative control), from which 7mm of the left facial nerve buccal branch was resected (n=5); reconstruction models, which underwent nerve reconstruction using PGA-c tubes (n=6); and SGB+reconstruction models, which underwent a left cervical sympathetic ganglionectomy immediately after reconstruction (n=6). The right side of the face served as control (n=17). Nerve regeneration was significantly greater in the SGB+reconstruction model dogs than in the reconstruction model dogs, as measured by both electrophysiological and morphological analyses at postoperative week 12. In particular, motor nerve conduction velocity was increased approximately 2-fold (p=0.018). We were able to generate an SGB model with long-term increased blood flow facilitated by the promotion of facial nerve regeneration by PGA-c tubes.

Choroideremia: melanopsin-mediated postillumination pupil relaxation is abnormally slow.

PURPOSE: To investigate the rod-cone and melanopsin pupillary light response (PLR) pathways in choroideremia. METHODS: Eight patients with choroideremia and 18 healthy age-matched controls underwent chromatic pupillometry by applying blue (463 nm) and red light (643 nm) at 100 lux intensity to the right eye while recording pupil diameters. Absolute baseline pupil size (mm), normalized maximal pupil constriction and the early and late postillumination pupillary dilation, from 0 to 10 seconds and 10 to 30 seconds after the end of illumination, respectively, were determined. Postillumination responses to blue light were considered to be primarily driven by melanopsin activation of the intrinsic photosensitive retinal ganglion cells. RESULTS: Baseline pupil diameters were comparable in patients with choroideremia and control subjects (p = 0.48). The maximum pupil constriction in patients with choroideremia was severely weakened in red light but only mildly weakened in blue light (p < 0.05). Postillumination dilation of the pupil was normal after red illumination but extremely protracted after blue illumination. Also, in contrast to healthy subjects, no abrupt change in the dilation curve was seen in the patients after the end of blue illumination, the early-phase dilation being completely abolished (p < 0.01). CONCLUSION: Rod-cone-driven pupil responses were decreased as expected in an outer retinal degeneration, and near-normal pupil constriction in blue light supports that the melanopsin system is normal. In contrast, the lack of brisk early-phase dilation after blue illumination in choroideremia is remarkable and may be interpreted to mean that the absence of photoreceptor inhibition promotes a tonic contraction of the pupil.

The Effect of Light Level and Small Pupils on Presbyopic Reading Performance.

PURPOSE: To examine the impact of small pupils and light levels on reading performance of distance-corrected presbyopes. To determine whether small pupils would enable presbyopes to read at near even at low light levels. METHODS: To establish the lower range of text luminances, we quantified the space-averaged luminance of text in nine different artificially lit interior environments, and examined the impact of the text characters on space-averaged luminance of electronic and printed displays. Distance and near reading speeds of 20 presbyopes (ages 40-60 years) were measured while viewing through artificial pupils (diameters 1-4.5 mm), natural pupils, or with a multifocal contact lens. Space-averaged text luminance levels varied from 0.14 to 140 cd/m2 (including the range of measured environmental text luminances). RESULTS: Adding black text to a white computer display or paper reduces luminance by approximately 15% to 31%, and the lowest encountered environmental text luminance was approximately 2 to 3 cd/m2. For both distance and near reading performance, the 2- to 3-mm small pupil yielded the best overall reading acuity for space-averaged text light levels ≥ 2 cd/m2. The 2- to 3-mm artificial pupils and the multifocal contact lenses both enabled maximum or near-maximum reading speeds for 0.5 logMAR characters at distance and near, but with natural pupils, reading speeds were significantly reduced at near. CONCLUSIONS: Although photon noise at low luminance reduces the visual benefits of small pupils, the benefits of 2- to 3-mm artificial pupils are sufficient to enable >80% of distance-corrected presbyopes to read proficiently at near, even at the lowest text luminances found in interior environments.

Stabilizing the capsular bag and expanding the pupil with a pupil expansion device.

UNLABELLED: We describe a surgical technique for management of zonular instability and pupillary miosis using a pupil expansion device (Malyugin ring) in patients who need cataract surgery. In this technique, the pupil expansion device is first used in the usual fashion. After a capsulorhexis has been created, lateral scrolls of the pupil expansion device are released and repositioned to entrap both the anterior capsulorhexis and the pupil margin at the against-the-wound meridian (3 o'clock and 9 o'clock position) to fixate the unstable capsular bag to the iris. Phacoemulsification is performed, and the ring is removed after intraocular lens implantation. With this method, capsular stabilization and pupil expansion are achieved simultaneously with the same instrument. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned.

Cilnidipine but not amlodipine suppresses sympathetic activation elicited by isometric exercise in hypertensive patients.

Pupillometry was used to evaluate the effects of the calcium channel blockers cilnidipine (CL) and amlodipine (AM) on changes in autonomic nervous activity induced by isometric exercise in patients with hypertension. After handgrip exercise, the velocity of miosis increased in both the CL and AM groups. However, the velocity of mydriasis increased in only the AM group. Velocity slopes of miosis and mydriasis were smaller in the CL group than in the AM group. The low-to-high frequency ratio obtained from pulse wave analysis increased in only the AM group. Sympathetic activation elicited by isometric exercise was suppressed more effectively by CL than by AM.

Eye movement and pupil size constriction under discomfort glare.

PURPOSE: Involuntary physiological responses offer an alternative means to psychophysical procedures for objectively evaluating discomfort glare. This study examined eye movement and pupil size responses to glare discomfort using new approaches to analysis: relative pupil size and speed of eye movement. METHODS: Participants evaluated glare discomfort using the standard de Boer rating scale under various conditions manipulated to influence glare discomfort. Eye movement was recorded using an electro-oculogram (EOG), and pupil size was recorded using Tobii glasses. Ten young (mean age: 24.5 years old) and 10 senior (mean age: 61 years old) participants were recruited for this experiment. RESULTS: Subjective evaluation of glare discomfort was highly correlated with eye movement (multiple correlation coefficient [R(2)] of >0.94, P < 0.001) and pupil constriction (R(2) = 0.38, P < 0.001). Severe glare discomfort increased the speed of eye movement and caused larger pupil constriction. Larger variations of eye movement were found among seniors. CONCLUSIONS: The two physiological responses studied here to characterize discomfort glare under various lighting conditions had significant correlation with the subjective evaluation. The correlation between discomfort glare and physiological responses suggests an objective way to characterize and evaluate discomfort glare that may overcome the problems of conventional subjective evaluation. It also offers an explanation as to why long-term exposure to discomfort glare leads to visual fatigue and eyestrain.

Safety, tolerability, pharmacokinetics, and pharmacodynamic effects of naloxegol at peripheral and central nervous system receptors in healthy male subjects: A single ascending-dose study.

This randomized, double-blind, placebo-controlled, ascending-dose, crossover study evaluated single oral doses of naloxegol (NKTR-118; 8, 15, 30, 60, 125, 250, 500, and 1000 mg), a PEGylated derivative of naloxone, for safety and tolerability, antagonism of peripheral and central nervous system (CNS) effects of intravenous morphine, and pharmacokinetics. Healthy men were randomized 1:1 to naloxegol or naloxegol-matching placebo administered with morphine and lactulose in a 2-period crossover design. Periods were separated by a 5- to 7-day washout. Assessments included safety, tolerability, orocecal transit time (OCTT), pupillary miosis, and pharmacokinetics. The study was completed by 46 subjects. The most common adverse events were somnolence, dizziness, headache, and nausea. Greater reversal of morphine-induced delay in OCTT occurred with increasing naloxegol dose, demonstrating dose-ordered antagonism of morphine's peripheral gastrointestinal effects. Forty-four subjects showed no reversal of pupillary miosis; 2 showed potential partial reversal at 250 and 1000 mg, indicating negligible antagonism of morphine's CNS effects at doses ≤ 125 mg. Rapid absorption, linear pharmacokinetics up to 1000 mg, and low to moderate between-subject pharmacokinetic variability was observed. The pharmacokinetics of morphine or its glucuronide metabolites were unaltered by concurrent naloxegol administration. Naloxegol was generally safe and well tolerated at single doses up to 1000 mg.