The association of early-onset non-progressive ataxia and miosis is an extremely rare phenotypic entity occasionally reported in the literature. To date, only one family (two siblings and their mother) has benefited from a genetic diagnosis by the identification of a missense heterozygous variant (p.Arg36Cys) in the ITPR1 gene. This gene encodes the inositol 1,4,5-trisphosphate receptor type 1, an intracellular channel that mediates calcium release from the endoplasmic reticulum. Deleterious variants in this gene are known to be associated with two types of spinocerebellar ataxia, SCA15 and SCA29, and with Gillespie syndrome that is associated with ataxia, partial iris hypoplasia, and intellectual disability. In this work, we describe a novel individual carrying a heterozygous missense variant (p.Arg36Pro) at the same position in the N-terminal suppressor domain of ITPR1 as the family previously reported, with the same phenotype associating early-onset non-progressive ataxia and miosis. This second report confirms the implication of ITPR1 in the miosis-ataxia syndrome and therefore broadens the clinical spectrum of the gene. Moreover, the high specificity of the phenotype makes it a recognizable syndrome of genetic origin.

Neuronal intranuclear inclusion disease (NIID) exhibits diverse clinical manifestations. Our patient was a 64-year-old woman with bilateral ptosis as the chief complaint. She had bilateral miosis, and the pupil was only slightly dilated 60 min after 1% phenylephrine administration, suggesting autonomic dysfunction secondary to preganglionic sympathetic impairment. A head-up tilt test revealed asymptomatic orthostatic hypotension. She was diagnosed with NIID based on a skin biopsy and genetic testing. This study suggests that blepharoptosis is an early manifestation of NIID. Furthermore, patients with suspected NIID should be examined carefully for autonomic dysfunction.

Background: Presbyopia is an age-related ocular condition, typically affecting individuals aged over 40 years, characterized by a gradual and irreversible decline in the eye\'s ability to focus on nearby objects. Correction methods for presbyopia encompass the use of corrective lenses, surgical interventions (corneal or lens based), and, more recently, the FDA-approved topical administration of 1.25% pilocarpine. While prior research has demonstrated the efficacy of daily pilocarpine eye drop application in enhancing near visual acuity by increasing the depth of focus leveraging the pinhole effect, limited knowledge exists regarding its influence on visual acuity under varying conditions of contrast and ambient luminance. Methods: This study aims to investigate the impact of these variables on visual acuity, employing the VA-CAL test, among 11 emmetropic and 11 presbyopic volunteers who reported subjective difficulties with near vision. This study includes evaluations under natural conditions with a pinhole occluder (diameter of 2 mm), and subsequent administration of 1% pilocarpine (Pilomann, Bausch + Lomb, Laval, Canada). Results: The VA-CAL results demonstrate the expected, statistically significant effects of contrast and ambient luminance on visual acuity in both emmetropic and presbyopic volunteers. Furthermore, in emmetropic individuals, the application of pilocarpine resulted in a statistically significant reduction in visual acuity. In contrast, presbyopes did not exhibit statistically significant differences in the visual acuity space under either the pinhole or pilocarpine conditions when compared to natural conditions. Conclusions: The pharmacological treatment of presbyopia with pilocarpine eye drops, intended to enhance near vision, does not adversely affect visual acuity in presbyopes. This suggests that pilocarpine may offer a viable alternative for individuals averse to wearing corrective eyewear.

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.

Morphine and morphine-6-glucuronide (M6G) produce central nervous system (CNS) effects by activating mu-opioid receptors, while naloxone is used mainly for the reversal of opioid overdose, specifically for the fatal complication of respiratory depression, but also for alleviating opioid-induced side effects. In this study we developed a physiologically-based pharmacokinetic-pharmacodynamic (PBPK-PD) model to simultaneously predict pharmacokinetics and CNS effects (miosis, respiratory depression and analgesia) of morphine as well as antagonistic effects of naloxone against morphine. The pharmacokinetic and pharmacodynamic parameters were obtained from in vitro data, in silico, or animals. Pharmacokinetic and pharmacodynamic simulations were conducted using 39 and 36 clinical reports, respectively. The pharmacokinetics of morphine and M6G following oral or intravenous administration were simulated, and the PBPK-PD model was validated using clinical observations. The Emax model correlated CNS effects with free concentrations of morphine and M6G in brain parenchyma. The predicted CNS effects were compared with observations. Most clinical observations fell within the 5th-95th percentiles of simulations based on 1000 virtual individuals. Most of the simulated area under the concentration-time curve or peak concentrations also fell within 0.5-2-fold of observations. The contribution of morphine to CNS effects following intravenous or oral administration was larger than that of M6G. Pharmacokinetics and antagonistic effects of naloxone on CNS effects were also successfully predicted using the developed PBPK-PD model. In conclusion, the pharmacokinetics and pharmacodynamics of morphine and M6G, antagonistic effects of naloxone against morphine-induced CNS effects may be successfully predicted using the developed PBPK-PD model based on the parameters derived from in vitro, in silico, or animal studies.

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.

Our research letter investigates the potential, as well as the current limitations, of widely available text-to-image tools in generating images for medical education. We focused on illustrations of important physical signs in the face (for which confidentiality issues in conventional patient photograph use may be a particular concern) that medics should know about, and we used facial images of hypothyroidism and Horner syndrome as examples.

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.

BACKGROUND: To date, no study has specifically examined children with acute-onset pupillary motility disorders (APMD). Especially in the Emergency Department (ED), it is crucial to distinguish benign and transient conditions from life-threatening or urgent conditions (UCs). The aim of the study is to describe the clinical characteristics of children with APMD and their association with an increased risk of UCs.
METHODS: We conducted a pediatric retrospective study of APMD referred to ED over a 10-year period. We described the characteristics in the overall sample and in two subgroups divided according to urgency of the underlying condition. Furthermore, we applied a logistic regression model to identify the variables predictive of LT condition.
RESULTS: We analyzed 101 patients. In 59.4%, the APMD was isolated. In patients with extra-ocular involvement, the most frequently associated features were altered consciousness, headache, and vomiting. Exposure to toxic agents was reported in 48.5%. Urgent conditions occurred significantly more frequently in older children, presenting bilateral APMD and/or other ocular or extra-ocular manifestations.
CONCLUSIONS: Our study shows that UCs most commonly occur in patients presenting with bilateral APMD and other associated features. In unilateral/isolated APMD ophthalmological examination, exclusion of toxic exposure and observation until resolution of symptoms should be recommended.

OBJECTIVE: 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.