ORAI1 inhibition as an efficient preclinical therapy for tubular aggregate myopathy and Stormorken syndrome.

Tubular aggregate myopathy (TAM) and Stormorken syndrome (STRMK) are clinically overlapping disorders characterized by childhood-onset muscle weakness and a variable occurrence of multisystemic signs, including short stature, thrombocytopenia, and hyposplenism. TAM/STRMK is caused by gain-of-function mutations in the Ca2+ sensor STIM1 or the Ca2+ channel ORAI1, both of which regulate Ca2+ homeostasis through the ubiquitous store-operated Ca2+ entry (SOCE) mechanism. Functional experiments in cells have demonstrated that the TAM/STRMK mutations induce SOCE overactivation, resulting in excessive influx of extracellular Ca2+. There is currently no treatment for TAM/STRMK, but SOCE is amenable to manipulation. Here, we crossed Stim1R304W/+ mice harboring the most common TAM/STRMK mutation with Orai1R93W/+ mice carrying an ORAI1 mutation partially obstructing Ca2+ influx. Compared with Stim1R304W/+ littermates, Stim1R304W/+Orai1R93W/+ offspring showed a normalization of bone architecture, spleen histology, and muscle morphology; an increase of thrombocytes; and improved muscle contraction and relaxation kinetics. Accordingly, comparative RNA-Seq detected more than 1,200 dysregulated genes in Stim1R304W/+ muscle and revealed a major restoration of gene expression in Stim1R304W/+Orai1R93W/+ mice. Altogether, we provide physiological, morphological, functional, and molecular data highlighting the therapeutic potential of ORAI1 inhibition to rescue the multisystemic TAM/STRMK signs, and we identified myostatin as a promising biomarker for TAM/STRMK in humans and mice.

Pearls & Oy-sters: Ocular Myasthenia Gravis: Central Ocular Motor Signs and Unilateral Visual Loss Caused by the Great Neuro-Ophthalmologic Impersonator.

Myasthenia gravis (MG) has been described as a great mimicker of other neurologic and ocular motility disorders, including centrally mediated ophthalmoplegia. For example, ocular myasthenia gravis (ocular MG) may cause impaired binocular visual acuity for near vision due to reduced accommodation or for distance vision due to accommodative excess. Notably, accommodative excess due to ocular MG is rare, but may occur with exotropia, with or without diplopia. We report 2 cases of ocular MG: First, a 32-year-old man with exotropia, bilateral hypometric and slowed adducting saccades with dissociated abducting nystagmus, miosis, and decreased distance vision in his right eye; second, a 45-year-old man with similar ocular motor deficits, miosis, and myopia. Both patients showed ocular motor deficits which appeared to localize to the pons but were instead due to ocular MG. Ocular MG should be considered in patients who present with reduced visual acuities due to any disruption in accommodation. Any ocular motor deficit, even if appearing to be centrally mediated or occurring without ptosis, may be caused by ocular MG.

Change in three-dimensional choroidal vessel network after AR device assisted 1-hour visual task in 2D/3D mode in young healthy subjects.

PURPOSE: The purpose of the study was to investigate the changes of choroidal blood perfusion in different layers and quadrants and its possible related factors after 1 h visual task by augmented reality (AR) device in two-dimensional (2D) and three-dimensional (3D) mode, respectively. METHODS: Thirty healthy subjects aged 22-37 years watched the same video source in 2D and 3D mode separately using AR glasses for 1 h with a one-week interval. Swept-source optical coherence tomography angiography (SS-OCTA) was performed before and immediately after watching to acquire choroidal thickness (ChT), three-dimensional choroidal vascularity index (CVI) of large- and middle-sized choroidal vessels and choriocapillaris flow voids (FV%) at macular and peripapillary area. Near point of accommodation (NPA) and accommodative facility (AF) were examined to evaluate the accommodative ability. Pupil diameters by infrared-automated pupillometer under scotopic, mesopic and photopic condition were also obtained. RESULTS: Compared with pre-visual task, the subfoveal CVI decreased from 0.406 ± 0.097 to 0.360 ± 0.102 after 2D watching (p < 0.001) and to 0.368 ± 0.102 after 3D watching (p = 0.002). Pupil sizes under different illuminance conditions became smaller after both 2D and 3D watching (all p < 0.001). AF increased after both 2D and 3D watching (both p < 0.05). NPA receded in post-3D watching (p = 0.017) while a not significant tendency was observed in post-2D. CONCLUSION: A reduction in subfoveal choroidal blood flow accompanied with pupil constriction was observed immediately after 1 h visual task using AR glasses in 2D and 3D mode. Accommodative facility improved after 2D and 3D watching with AR glasses, whereas decrease in the maximum accommodation power was only found in 3D mode.

Opioid sensitivity in treated and untreated obstructive sleep apnoea: a prospective cohort study.

BACKGROUND: Opioid administration to patients with obstructive sleep apnoea (OSA) is controversial because they are believed to be more sensitive to opioids. However, objective data on opioid effects in OSA are lacking. We tested the hypothesis that subjects with untreated OSA have increased sensitivity to opioids compared with subjects without OSA, or with OSA treated with continuous positive airway pressure (CPAP) or bilevel positive airway pressure (BIPAP). METHODS: This was a single-centre, prospective cohort study in subjects without OSA (n=20), with untreated OSA (n=33), or with treated OSA (n=21). OSA diagnosis was verified using type III (in-home) polysomnography. Subjects received a stepped-dose remifentanil infusion (target effect-site concentrations of 0.5, 1, 2, 3, 4 ng ml-1). Primary outcome was miosis (pupil area fractional change), the most sensitive opioid effect. Secondary outcomes were ventilatory rate, end-expired CO2, sedation, and thermal analgesia. RESULTS: There were no differences in miosis between untreated OSA subjects (mean=0.51, 95% confidence interval [CI] 0.41-0.61) and subjects without OSA (mean=0.49, 95% CI 0.36-0.62) (mean difference=0.02, 95% CI -0.18 to 0.22); between treated OSA subjects (mean=0.56, 95% CI 0.43-0.68) and subjects without OSA (difference=0.07, 95% CI -0.16 to 0.29); or between untreated OSA and treated OSA (difference=-0.05, 95% CI -0.25 to 0.16). There were no significant differences between subjects without OSA, untreated OSA, and treated OSA in ventilatory rate, end-expired CO2, sedation, or thermal analgesia responses to remifentanil. There was no relationship between OSA severity and magnitude of opioid effects. CONCLUSIONS: Neither obstructive sleep apnoea nor obstructive sleep apnoea treatment affected sensitivity to the miotic, sedative, analgesic, or respiratory depressant effects of the opioid remifentanil in awake adults. These results challenge conventional notions of opioid effects in obstructive sleep apnoea. CLINICAL TRIAL REGISTRATION: NCT02898792 (clinicaltrials.gov).

Surgical time and efficacy of illuminated chopper-assisted cataract surgery involving miosis after femtosecond laser pretreatment.

PURPOSE: To evaluate the efficacy of the illuminated chopper-assisted cataract surgery in terms of shortening the surgical time in eyes with miosis after femtosecond laser pretreatment. METHODS: As retrospective study, three hundred thirty-six eyes of 336 consecutive patients who underwent the femtosecond laser and illuminated chopper-assisted cataract surgery were included. Cases with pupil less than 6 mm after femtosecond laser pretreatment were included in the miosis group. Pupil diameter, surgical time, and improved efficacy (100/surgical time×pupil size) were compared between eyes with and without miosis. RESULTS: Of 336 eyes, 20 were included in the miosis group (6.0%). Pupil diameter was smaller in eyes with miosis than in those without miosis (5.23 ± 0.38 mm vs 7.35 ± 0.64 mm, p < 0.001); however, surgical time was not different (6.86 ± 0.73 min vs 6.60 ± 1.27 min, p = 0.071) between the two groups. Mechanical pupil dilations were not needed in any cases. As a result, improved efficacy was calculated to be higher in patients with miosis (2.83 vs 2.14, p < 0.001). CONCLUSION: In terms of surgical time and improved efficacy, using the illuminated chopper simplified cataract surgery involving miosis after femtosecond laser pretreatment. The use of an illuminated chopper is expected to be a good solution for femtosecond laser-assisted cataract surgeries.

Longitudinal changes in objective accommodative response, pupil size and spherical aberration: A case study.

PURPOSE: Previous transverse and a handful of longitudinal studies have shown that the slope of the static accommodation response/stimulus curve declines as complete presbyopia is approached. Changes in pupillary miosis and ocular spherical aberration (SA) are also evident. This study further investigated longitudinal changes in the relationships between the monocular static accommodative response, pupil diameter and SA of a single adult. METHODS: A wavefront analysing system, the Complete Ophthalmic Analysis System, was used in conjunction with a Badal optometer to allow continuous recording of the aberration structure of the dominant eye in a low myope for a range of accommodative demands (-0.83 to 7.63 D) over a period of 17 years until the age of 50. Monocular accommodative response was calculated as the equivalent refraction minimising wavefront error. The associated longitudinal changes in pupil size and SA with accommodation were also recorded. RESULTS: A decrease in accommodation response with age was found at almost all target vergences, with the changes being greatest for higher vergences. In addition, although absolute pupil diameter decreased with age, the rate of change in pupil diameter with accommodative stimulus remained approximately constant with age. Pupil constriction occurred for near stimuli even in full presbyopia. SA changed linearly with the accommodation response at all ages. CONCLUSIONS: The objective amplitude of accommodation declined linearly with age as complete presbyopia was approached, while the slope of the response/stimulus curve also fell. It was hypothesised that the retinal image blur associated with the larger lags of accommodation at higher accommodative stimuli was reduced by pupil constriction and the resulting lower levels of SA.

Pharmacological management of intra-operative miosis during cataract surgery.

Cataract surgery requires a well-dilated and stable pupil for a good outcome. Unexpected pupillary constriction during surgery increases the risk of complication. This problem is more pronounced in children. There are now pharmacological interventions that help tackle this unforeseen happening. Our review discusses the simple and quick options available to a cataract surgeon when faced with this dilemma. As cataract surgical techniques continue to improvise and get faster, an adequate pupil size is of paramount importance. Various topical and intra-cameral drugs are used in combination to achieve mydriasis. Despite good pre-operative dilation, the pupil can be quite unpredictable during surgery. Intra-operative miosis limits the field of surgery and increases the risk of complications. For example, if the pupil size decreases from 7 mm to 6 mm, this 1 mm change in pupil diameter will lead to a decrease of 10.2 mm2 in the area of surgical field. Making a good capsulorhexis with a small pupil can be a challenge, even for an experienced surgeon. Repeated touching of the iris increases the risk of fibrinous complications. Removal of cataract and the cortical matter becomes increasingly difficult. Intra-ocular lens implantation in the bag also requires adequate dilation. When dealing with challenging cases like lens subluxation, pseudo-exfoliation, and zonular dehiscence, a small pupil further increases the risk and adversely affects the surgical outcome. Hence, achieving and maintaining adequate mydriasis throughout surgery is essential. This review highlights the risk factors for small pupils during surgery and current management strategies.

Pharmacological Accommodative Changes of the Anterior Segment and Its Impact on the Vault in Implantable Collamer Lens Implantation.

PURPOSE: To estimate the accommodative changes of the anterior segment and its impact on the central and peripheral vaults after Visian Implantable Collamer Lens (ICL) (STAAR Surgical) implantation. METHODS: Eighty eyes of 40 consecutive patients (mean age: 28.05 years; range: 19 to 42 years) were examined 3 months after ICL implantation. Eyes were randomly divided into a mydriasis group and a miosis group. Anterior chamber depth (ACD) to crystalline lens (ACD-L), anterior chamber depth to ICL (ACD-ICL), central distance from endothelium to sulcus to sulcus (ASL), central distance from sulcus to sulcus to crystalline lens (STS-L), central distance from ICL to sulcus to sulcus (STS-ICL), and central (cICL-L), midperipheral (mICL-L), and peripheral (pICL-L) vaults were measured by ultrasound biomicroscopy at baseline and after induction with tropicamide or pilocarpine. RESULTS: After tropicamide treatment, cICL-L, mICL-L, and pICL-L decreased from 0.531 ± 0.200, 0.419 ± 0.173, and 0.362 ± 0.150 mm to 0.488 ± 0.171, 0.373 ± 0.153, and 0.311 ± 0.131 mm, respectively. The values decreased from 0.540 ± 0.185, 0.445 ± 0.172, and 0.388 ± 0.149 mm to 0.464 ± 0.199, 0.378 ± 0.156, and 0.324 ± 0.137 mm after pilocarpine administration, respectively. The ASL and STS showed a significant increase in the mydriasis group (all P ≤ .038), but a decrease in the miosis group (all P < .001). The ACD-L increased and STS-L decreased in the mydriasis group (all P < .001), indicating the backward shift of the crystalline lens, whereas crystalline lens forward shift was observed in the miosis group. Additionally, the STS-ICL decreased in both groups (all P ≤ .021), suggesting the ICL backward shift. CONCLUSIONS: Both central and peripheral vaults decreased during the pharmacological accommodation process, and the ciliaris-iris-lens complex contributed to the changes. [J Refract Surg. 2023;39(6):414-420.].

Harlequin syndrome.

A 56-year-old man presented to the clinic with episodic headaches for several years which had been worsening over a few months prior to the presentation. He described headache as sharp, stabbing pain around the left eye associated with nausea, vomiting, photophobia, and phonophobia lasting for hours associated with flushing on the left side of the face. The picture of his face during these episodes showed flushing of the left side of the face, ptosis of the right eyelid, and miosis (panel A). Flushing in his face would resolve with the abortion of the headache. At the time of presentation to the clinic, his neurological exam was only significant for mild left eye ptosis and miosis (panels B and C). Extensive workup including MRI brain, cervical spine, thoracic spine, lumbar spine, CTA head and neck, and CT maxillofacial was unremarkable. He had tried several medications in the past including valproic acid, nortriptyline, and verapamil without significant benefit. He was started on erenumab for migraine prophylaxis and was given sumatriptan for abortive therapy following which his headaches improved. The patient was diagnosed with idiopathic left Horner's syndrome and his migraines with autonomic dysfunction would present with unilateral flushing opposite to the site of Horner's presenting as Harlequin syndrome [1, 2].

A new intraocular lens marker to guide the implantation of toric intraocular lenses in small and mid-dilating pupils.

Insufficient pupillary dilatation is a significant challenge during cataract surgery, as it increases the risk of various intraoperative complications. Implantation of toric intraocular lenses (TIOL) is particularly difficult in eyes with small pupils, as the toric marks are provided in the periphery of the IOL optic, making the visualization of the same difficult for proper alignment. Attempts at visualizing these marks using a second instrument such as a dialler or iris retractor lead to additional manipulations in the anterior chamber resulting in increased chances of postoperative inflammation and intraocular pressure rise. A new intraocular lens (IOL) marker to guide the implantation of TIOLs in eyes with small pupils is described, which can potentially be beneficial in achieving accurate alignment of toric IOLs in small pupils, without the need for additional manipulations, thus improving safety, efficacy, and success rates of TIOL implantation in these eyes.

Brimonidine eye drops reveal diminished sympathetic pupillary tone in comatose patients with brain injury.

BACKGROUND: There is an urgent need for easy-to-perform bedside measures to detect residual consciousness in clinically unresponsive patients with acute brain injury. Interestingly, the sympathetic control of pupil size is thought to be lost in states of unconsciousness. We therefore hypothesized that administration of brimonidine (an alpha-2-adrenergic agonist) eye drops into one eye should produce a pharmacologic Horner's syndrome if the clinically unresponsive patient is conscious, but not if the patient is unconscious. Here, in a first step to explore this hypothesis, we investigated the potential of brimonidine eye drops to distinguish preserved sympathetic pupillary function in awake volunteers from impairment of sympathetic tone in patients in a coma. METHODS: We enrolled comatose patients admitted for acute brain injury to one of the intensive care units (ICU) of a tertiary referral center, in whom EEG and/or neuroimaging for all practical purposes had ruled out residual consciousness. Exclusion criteria were deep sedation, medications with known drug interactions with brimonidine, and a history of eye disease. Age- and sex-matched healthy and awake volunteers served as controls. We measured pupils of both eyes, under scotopic conditions, at baseline and five times 5-120 min after administering brimonidine into the right eye, using automated pupillometry. Primary outcomes were miosis and anisocoria at the individual and group levels. RESULTS: We included 15 comatose ICU patients (seven women, mean age 59 ± 13.8 years) and 15 controls (seven women, mean age 55 ± 16.3 years). At 30 min, miosis and anisocoria were seen in all 15 controls (mean difference between the brimonidine-treated pupil and the control pupil: - 1.31 mm, 95% CI [- 1.51; - 1.11], p < 0.001), but in none (p < 0.001) of the 15 ICU patients (mean difference: 0.09 mm, 95% CI [- 0.12;0.30], p > 0.99). This effect was unchanged after 120 min and remained robust in sensitivity analyses correcting for baseline pupil size, age, and room illuminance. CONCLUSION: In this proof-of-principle study, brimonidine eye drops produced anisocoria in awake volunteers but not in comatose patients with brain injury. This suggests that automated pupillometry after administration of brimonidine can distinguish between the extremes of the spectrum of consciousness (i.e., fully conscious vs. deeply comatose). A larger study testing the "intermediate zone" of disorders of consciousness in the ICU seems warranted.

Morphine and Hydromorphone Effects, Side Effects, and Variability: A Crossover Study in Human Volunteers.

BACKGROUND: Balancing between opioid analgesia and respiratory depression continues to challenge clinicians in perioperative, emergency department, and other acute care settings. Morphine and hydromorphone are postoperative analgesic standards. Nevertheless, their comparative effects and side effects, timing, and respective variabilities remain poorly understood. This study tested the hypothesis that IV morphine and hydromorphone differ in onset, magnitude, duration, and variability of analgesic and ventilatory effects. METHODS: The authors conducted a randomized crossover study in healthy volunteers. Forty-two subjects received a 2-h IV infusion of hydromorphone (0.05 mg/kg) or morphine (0.2 mg/kg) 1 to 2 weeks apart. The authors measured arterial opioid concentrations, analgesia in response to heat pain (maximally tolerated temperature, and verbal analog pain scores at discrete preset temperatures to determine half-maximum temperature effect), dark-adapted pupil diameter and miosis, end-expired carbon dioxide, and respiratory rate for 12 h after dosing. RESULTS: For morphine and hydromorphone, respectively, maximum miosis was less (3.9 [3.4 to 4.2] vs. 4.6 mm [4.0 to 5.0], P < 0.001; median and 25 to 75% quantiles) and occurred later (3.1 ± 0.9 vs. 2.3 ± 0.7 h after infusion start, P < 0.001; mean ± SD); maximum tolerated temperature was less (49 ± 2 vs. 50 ± 2°C, P < 0.001); verbal pain scores at end-infusion at the most informative stimulus (48.2°C) were 82 ± 4 and 59 ± 3 (P < 0.001); maximum end-expired CO2 was 47 (45 to 50) and 48 mmHg (46 to 51; P = 0.007) and occurred later (5.5 ± 2.8 vs. 3.0 ± 1.5 h after infusion start, P < 0.001); and respiratory nadir was 9 ± 1 and 11 ± 2 breaths/min (P < 0.001), and occurred at similar times. The area under the temperature tolerance-time curve was less for morphine (1.8 [0.0 to 4.4]) than hydromorphone (5.4°C-h [1.6 to 12.1] P < 0.001). Interindividual variability in clinical effects did not differ between opioids. CONCLUSIONS: For morphine compared to hydromorphone, analgesia and analgesia relative to respiratory depression were less, onset of miosis and respiratory depression was later, and duration of respiratory depression was longer. For each opioid, timing of the various clinical effects was not coincident. Results may enable more rational opioid selection, and suggest hydromorphone may have a better clinical profile.

A novel Y-shaper and chopper for small pupil management in cataract surgery: The initial experience.

Small pupil is a well-known risk factor for causing cataract surgery complications such as vitreous loss, anterior capsular tear, increased inflammation, and an irregular pupil shape. Because all currently available pharmacological approaches of dilating the pupil before or during cataract surgery cannot guarantee the result, the surgeon sometimes resorts to the use of mechanical pupil-expanding devices. However, these devices can increase the overall surgical cost and operative time. Very frequently, a combination of the two is needed; thus, we present the Y-shaped chopper designed by the authors, which serves the purpose of managing the intra-operative miosis and allows simultaneous nuclear emulsification.

Light- and drug-induced pupillary dynamics in eyes with a retropupillary iris-claw intraocular lens.

PURPOSE: We evaluated the pupillary characteristics and response to light and drugs in eyes with posterior chamber (PC) placement of iris-claw intraocular lens (IC-IOL). METHODS: In this cross-sectional, comparative study, we included adults with an IC-IOL implanted in the PC of a single eye. We excluded patients with ocular trauma, postoperative IC-IOL displacement or complications, and extended iris atrophy. We used anterior segment optical coherence tomography to perform light-controlled pupillography, measure the pupil diameter (PD), and estimated the pupil circularity under mesopic conditions. PD was also assessed under photopic, scotopic, pharmacological mydriasis, and miosis conditions. The results were compared to those of the fellow eye, phakic, or regular pseudophakic. RESULTS: The IC-IOL and control groups included 30 eyes each. The most frequent reasons for IC-IOL implantation were complicated cataract (37%) and dislocated/luxated prior IOL (33%). Compared to the control group, the IC-IOL group had lower visual acuity, a smaller PD under scotopic conditions (p = 0.0010) and after pharmacological mydriasis (p < 0.0001), and a larger PD after pharmacological miosis (p < 0.0001). Mesopic pupil circularity was comparable between the groups. We also considered ongoing extraocular treatments with possible effects on iris motility. CONCLUSIONS: The pupillary size and profile were similar between the groups in mesopic light. Reduced mydriasis was noted in response to light and drugs, while the degree of miosis was reduced in response to inducing drugs in the IC-IOL compared to the control group. This study complements previous results concerning the PC placement of IC-IOLs by adding original observations on drug-induced pupil motility.

Emerging order of anomalous eye movements with progressive drowsiness.

It has been widely recognized that human alertness is reflected in the eyes (e.g., when drowsiness, miosis, slow saccades, divergence, less compensatory vestibulo-ocular reflex, and less-accurate optokinetic response and smooth pursuit emerge). Previous studies that discovered these pupil/oculomotor anomalous behaviors along with lowering alertness evaluated only one or a few of them simultaneously, thus their emergence order is yet unknown. Presently, we focused on the following five pupil/oculomotor behaviors that can be evaluated under a natural stationary environment without giving external sensory stimulations: saccades, slow-phase eye movements, vergence, pupil diameter, and blinks. We demonstrate that their anomalous behaviors emerge in the following order: first: frequent saccades; second: slow saccades; third: divergence & miosis, then slow eye movement, while elongated eyelid closure duration emerges randomly in this sequence. These results provide a basis for the oculo-pupillometry-enabling objective monitoring of progressive drowsiness.

Influence of miosis and laser peripheral iridotomy on intraocular lens power calculation in patients with primary angle closure disease.

OBJECTIVES: To evaluate the effect of miosis and laser peripheral iridotomy (LPI) on intraocular lens (IOL) power prediction and ocular biometry in eyes with primary angle closure disease (PACD). METHODS: In this prospective observational study, primary angle closure suspects (PACS), and subjects classified with primary angle closure (PAC)/primary angle-closure glaucoma (PACG) undergoing LPI were enrolled. Ocular biometric parameters were measured with IOLMaster700 at baseline (T0), one week after pilocarpine instillation (T1), and another week post LPI (T2). Biometric changes and the IOL power predicted for emmetropia using Barrett Universal II, Haigis, Holladay2, Hoffer Q and SRK/T formulae were analysed and compared among different time points. RESULTS: 100 eyes of 50 PACS and 50 PAC/PACG patients were enrolled. Following pilocarpine-induced miosis, lens thickness (LT) increased and anterior chamber depth (ACD) decreased (all groups p < 0.01), while white-to-white diameter decreased and central corneal thickness increased significantly only in the PACS cohort (both p < 0.01). Compared to baseline, LPI induced an increase of ACD and a slight decrease of LT in PACS (both p < 0.01), whereas only axial length changed significantly (p = 0.012) in the PAC/PACG cohort. Regardless of the formula used, no significant difference to the predicted IOL power for emmetropia existed among the three time points in each group (all p > 0.1). CONCLUSION: We report the changes of anterior segment parameters induced by miosis and LPI in PACD. These interventions do not significantly affect the IOL power calculation predicted for emmetropia in Chinese eyes when common third-, fourth-and new generation IOL formulae are used.

Changes to Outflow Structures After Pilocarpine in Primary Open Angle Glaucoma Compared With Healthy Individuals Using Optical Coherence Tomography.

PRCIS: Lower response of aqueous outflow pathway structures after pilocarpine could be observed in primary open angle glaucoma (POAG) patients, which is likely to be helpful for understanding intraocular pressure (IOP) evaluation in glaucoma. PURPOSE: To evaluate the morphologic changes in the trabecular meshwork (TM), Schlemm canal (SC), scleral spur (SS), and ciliary muscle after miosis in patients with POAG and healthy individuals. METHODS: A total of 30 patients with POAG and 26 healthy controls were recruited. All participants underwent complete ophthalmologic examinations, including IOP and swept-source optical coherence tomography (OCT), before and 1 hour after the local administration of pilocarpine (2%). OCT measurements included TM thickness and width, SC diameter and area, SS length, ciliary muscle thickness, and ciliary muscle angle (CMA). RESULTS: Pilocarpine administration induced a decline in IOP (15.6±2.3-14.6±2.2 mm Hg), decrease in nasal SS length (196.31±47.75-171.52±33.93 µm), decrease in TM thickness (90.18±16.43-83.02±13.74 µm), and increase in SC diameter (134.84±32.28-162.08±48.67 µm) and SC area (3851.37±1455.07-4801.39±1762.37 µm 2 ) among healthy controls. In contrast, no significant changes in IOP and OCT measurements were found in patients with POAG. At baseline, CMA was independently correlated with IOP in normal eyes. After miosis, the change in TM thickness was independently correlated with changes in IOP in normal eyes; in eyes with POAG, changes in SS length and CMA were independently associated with changes in IOP. CONCLUSIONS: Topical pilocarpine-induced morphologic changes to outflow pathway structures in healthy individuals without significant changes in POAG. The lower response observed in patients with glaucoma may be relevant to understanding IOP changes.

Coma, Severe Hypotension, and Pinpoint Pupils After Olanzapine Intoxication in the Intensive Care Unit with Symptom Reversal After Administration of Flumazenil.

BACKGROUND Olanzapine is an antipsychotic drug and is used in critical care to treat delirium. There is no known antidote to olanzapine intoxication. Overdosing olanzapine can cause, tremor, bradykinesia, hypotension somnolence, coma, and miosis. CASE REPORT We present the case of a previously healthy 69-year-old man who after routine mitral valve surgery developed pneumonia and severe sepsis requiring several weeks on a ventilator in the Intensive Care Unit. He developed delirium and paranoia and was prescribed olanzapine. After 4 doses, he became hypotensive and nonresponsive and developed pinpoint pupils. The symptoms were reversed minutes after administration of flumazenil. The clinical picture in this case corresponds well with an olanzapine intoxication. No other drugs, such as benzodiazepines or opioids, had been administered that could explain the reaction. Olanzapine intoxication is known to present with hypotension, coma, and miosis. The doses given were normal starting doses for olanzapine in the outpatient setting but much higher than recommended doses in the intensive care setting. CONCLUSIONS This case illustrates a risk for severe adverse effects, even within normal prescription range, when olanzapine is used in the intensive care setting. Finally, it is intriguing that the symptoms were reversed after administration of flumazenil, a selective competitive antagonist of the GABA receptor. Olanzapine mainly effects dopamine, serotonin, a1-adrenergic, histamine, and muscarinic receptors, but a low affinity to GABA and benzodiazepine sites can perhaps explain the observed effect.