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To report long-term ophthalmic findings in Wolfram syndrome, including rates of visual decline, macular thinning, retinal nerve fiber layer (RNFL) thinning, and outer plexiform layer (OPL) lamination.Single-center, cohort study.A total of 38 participants were studied, who underwent a complete ophthalmic examination as well as optical coherence tomography imaging of the macula and nerve on an annual basis. Linear mixed-effects models for longitudinal data were used to examine both fixed and random effects related to visual acuity and optic nerve quadrants of RNFL and macula thickness.Participants completed a mean of 6.44 years of follow-up (range 2-10 years). Visual acuity declined over time in all participants, with a mean slope of 0.059 logMAR/y (95% CI = 0.07-0.05 logMAR/y), although nearly 25% of participants experienced more rapid visual decline. RNFL thickness decreased in superior, inferior, and nasal quadrants (β = -0.5 µm/y, -0.98 µm/y, -0.28 µm/y, respectively). OPL lamination was noted in 3 study participants, 2 of whom had autosomal dominant mutations.Our study describes the longest and largest natural history study of visual acuity decline and retinal morphometry in Wolfram syndrome to date. Results suggest that there are slower and faster progressing subgroups and that OPL lamination is present in some individuals with this disease.

Purpose Children with high ametropia who have difficulties with spectacle or contact lens wear benefit from gains in visual function after intraocular collamer lens (ICL) surgery. Here we assess safety by reporting rates and case specifics of peri-operative and longer-term adverse events (AE).[LINE SEPARATOR] SETTING:: St. Louis Children's Hospital at Washington University Medical Center. Design Retrospective Case Series. Methods Clinical data were collated retrospectively for 95 special-needs children (160 eyes) implanted with a Visian ICL over the last 5 years. All surgeries were performed at St Louis Children's Hospital under brief general anesthesia. Follow-up was a mean 2.0 ±1.4 years (range 0.5-5.2). Results Average age at implantation was 9.3 ± 5.2 years (range 1.8-25) and mean pre-operative SEQRE was -11.2 ± 3.9 D (range - 4-22). Sixty-two children (65%) had a neurodevelopmental disorder. The minor AE rate was 2% (3 eyes), consisting of steroid-response ocular hypertension (OHT), which resolved with cessation of topical steroid drops. Endothelial cell loss averaged 8.1 % over 2 years, comparable to that reported in ICL implanted adults. The most common major AE (4%, 7 eyes) was post-operative pupillary block, requiring revision of the peripheral iridotomy. One child (0.6%, 1 eye) with self-injurious behavior required repair of a wound leak. One child (0.6%, 1 eye) with Down syndrome developed a cataract 2.8 years after ICL surgery. And one child (0.6%, 1 eye) with severe Autism Spectrum Disorder experienced traumatic retinal detachment 1.2 years after implantation. Conclusion The most common major AE among our Visian ICL cohort was pupillary block due to closure of the iridotomy. Overall, the AE rate was low in this higher risk, difficult-to-manage population of special-needs children.

BACKGROUNDWolfram syndrome is a rare ER disorder characterized by insulin-dependent diabetes mellitus, optic nerve atrophy, and progressive neurodegeneration. Although there is no treatment for Wolfram syndrome, preclinical studies in cell and rodent models suggest that therapeutic strategies targeting ER calcium homeostasis, including dantrolene sodium, may be beneficial.METHODSBased on results from preclinical studies on dantrolene sodium and ongoing longitudinal studies, we assembled what we believe is the first-ever clinical trial in pediatric and adult Wolfram syndrome patients with an open-label phase Ib/IIa trial design. The primary objective was to assess the safety and tolerability of dantrolene sodium in adult and pediatric Wolfram syndrome patients. Secondary objectives were to evaluate the efficacy of dantrolene sodium on residual pancreatic β cell functions, visual acuity, quality-of-life measures related to vision, and neurological functions.RESULTSDantrolene sodium was well tolerated by Wolfram syndrome patients. Overall, β cell functions were not significantly improved, but there was a significant correlation between baseline β cell functions and change in β cell responsiveness (R2, P = 0.004) after 6-month dantrolene therapy. Visual acuity and neurological functions were not improved by 6-month dantrolene sodium. Markers of inflammatory cytokines and oxidative stress, such as IFN-γ, IL-1β, TNF-α, and isoprostane, were elevated in subjects.CONCLUSIONThis study justifies further investigation into using dantrolene sodium and other small molecules targeting the ER for treatment of Wolfram syndrome.TRIAL REGISTRATIONClinicalTrials.gov identifier NCT02829268FUNDINGNIH/National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (DK112921, DK113487, DK020579), NIH/National Center for Advancing Translational Sciences (NCATS) (TR002065, TR000448), NIH training grant (F30DK111070), Silberman Fund, Ellie White Foundation, Snow Foundation, Unravel Wolfram Syndrome Fund, Stowe Fund, Eye Hope Foundation, Feiock Fund, Washington University Institute of Clinical and Translational Sciences grant UL1TR002345 from NIH/NCATS, Bursky Center for Human Immunology & Immunotherapy Programs.

BACKGROUND Wolfram syndrome is a rare ER disorder characterized by insulin-dependent diabetes mellitus, optic nerve atrophy, and progressive neurodegeneration. Although there is no treatment for Wolfram syndrome, preclinical studies in cell and rodent models suggest that therapeutic strategies targeting ER calcium homeostasis, including dantrolene sodium, may be beneficial. METHODS Based on results from preclinical studies on dantrolene sodium and ongoing longitudinal studies, we assembled what we believe is the first-ever clinical trial in pediatric and adult Wolfram syndrome patients with an open-label phase Ib/IIa trial design. The primary objective was to assess the safety and tolerability of dantrolene sodium in adult and pediatric Wolfram syndrome patients. Secondary objectives were to evaluate the efficacy of dantrolene sodium on residual pancreatic β cell functions, visual acuity, quality-of-life measures related to vision, and neurological functions. RESULTS Dantrolene sodium was well tolerated by Wolfram syndrome patients. Overall, β cell functions were not significantly improved, but there was a significant correlation between baseline β cell functions and change in β cell responsiveness (R2, P = 0.004) after 6-month dantrolene therapy. Visual acuity and neurological functions were not improved by 6-month dantrolene sodium. Markers of inflammatory cytokines and oxidative stress, such as IFN-γ, IL-1β, TNF-α, and isoprostane, were elevated in subjects. CONCLUSION This study justifies further investigation into using dantrolene sodium and other small molecules targeting the ER for treatment of Wolfram syndrome. TRIAL REGISTRATION ClinicalTrials.gov identifier NCT02829268 FUNDING NIH/National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (DK112921, DK113487, DK020579), NIH/National Center for Advancing Translational Sciences (NCATS) (TR002065, TR000448), NIH training grant (F30DK111070), Silberman Fund, Ellie White Foundation, Snow Foundation, Unravel Wolfram Syndrome Fund, Stowe Fund, Eye Hope Foundation, Feiock Fund, Washington University Institute of Clinical and Translational Sciences grant UL1TR002345 from NIH/NCATS, Bursky Center for Human Immunology & Immunotherapy Programs.

BackgroundWolfram syndrome is a rare endoplasmic reticulum disorder characterized by insulin-dependent diabetes mellitus, optic nerve atrophy, and progressive neurodegeneration. Although there is currently no treatment to delay, halt, or reverse the progression of Wolfram syndrome, preclinical studies in cell and rodent models suggest that therapeutic strategies targeting endoplasmic reticulum calcium homeostasis, including dantrolene sodium, may be beneficial.MethodsBased on the results from preclinical studies on dantrolene sodium and ongoing longitudinal studies, our group put together the first-ever clinical trial in pediatric and adult patients with Wolfram syndrome. An open-label phase 1b/2a trial design was chosen. The primary objective of the study was to assess the safety and tolerability of dantrolene sodium in adult and pediatric patients with Wolfram syndrome. Secondary objectives were to evaluate the efficacy of dantrolene sodium on residual pancreatic β-cell functions, visual acuity, quality of life measures related to vision, and neurological functions.ResultsThe results indicate that dantrolene sodium is well tolerated by patients with Wolfram syndrome. Although the study was small, a select few patients seemed to have improvements in β-cell function, which might correlate with a positive trend in other outcome measures, including visual acuity and neurological functions.ConclusionThis study justifies further investigation into using dantrolene sodium and other small molecules targeting the endoplasmic reticulum for the treatment of Wolfram syndrome.Trial registrationClinicalTrials.gov Identifier NCT02829268Key PointsQuestionIs dantrolene sodium safe and effective for the treatment of adult and pediatric patients with Wolfram syndrome?FindingsThe results of this open-label clinical trial show that dantrolene sodium is well tolerated by patients with Wolfram syndrome. Although the study was small, a select few patients seemed to have improvements in β-cell function, which might correlate with a positive trend in other outcome measures, including visual acuity and neurological functions.MeaningDantrolene sodium is well tolerated by patients with Wolfram syndrome. Some patients may experience an increase in β cell function when taking dantrolene.ImportanceWolfram syndrome is a rare endoplasmic reticulum disorder characterized by insulin-dependent diabetes mellitus, optic nerve atrophy, and progressive neurodegeneration. Although there is currently no treatment to delay, halt, or reverse the progression of Wolfram syndrome, preclinical studies in cell and rodent models suggest that targeting endoplasmic reticulum calcium homeostasis, including dantrolene sodium, is an emerging therapeutic strategy.ObjectiveThe primary objective of the study was to assess the safety and tolerability of dantrolene sodium in adult and pediatric subjects with Wolfram syndrome. Secondary objectives were to evaluate the efficacy of dantrolene sodium on residual pancreatic β-cell functions, visual acuity, quality of life measures related to vision, and neurological functions.DesignOpen-label phase 1b/2a trial of dantrolene sodium over a 6-month treatment period.SettingSingle site, academic medical center.ParticipantsAdult and pediatric subjects with a genetically confirmed diagnosis of Wolfram syndrome.InterventionsAll subjects received increasing doses of dantrolene sodium.Main Outcomes and MeasuresThe safety and tolerability of dantrolene sodium administered orally at the upper end of therapeutic dose range for 6 months, and the efficacy of dantrolene sodium on residual pancreatic β-cell functions using a mixed-meal tolerance test, visual acuity using LogMar scores, quality of life measures related to vision using Visual Functioning Questionnaire – 25, and neurological functions using the Wolfram Unified Rating Scale (WURS) and standard neurological assessments.ResultsThe results indicate that dantrolene sodium is well tolerated by subjects with Wolfram syndrome. Although the study was small, a select few subjects seemed to have improvements in β-cell function, which might be correlated with a positive trend in visual acuity.Conclusions and RelevanceThis study justifies further investigation into using dantrolene sodium and other small molecules targeting the endoplasmic reticulum for the treatment of Wolfram syndrome.Trial RegistrationRegistered with clinicaltrials.gov, NCT02829268, (https://clinicaltrials.gov/ct2/show/NCT02829268?term=NCT02829268&draw=2&rank=1)

Purpose To analyze outcomes in a large cohort of spectacle-aversive children with high myopia who were treated by implantation of the Ophtec-Artisan or Visian phakic intraocular lens (pIOL). Methods Outcome data were collated retrospectively in 78 children (115 eyes) implanted with the Ophtec-Artisan iris-enclaved anterior chamber pIOL and 91 children (154 eyes) implanted with the Visian ICL (intraocular collamer lens) sulcus pIOL. All children had difficulties with spectacle or contact lens wear. Mean age at surgery was 9.9 years; mean follow-up was 3.9 years (range, 0.6-14.1 years). Results A total of 248 of 269 eyes (92%) were corrected to within ± 0.5 D of their target value. Spherical correction averaged 12.3 ± 1.0 D. Refractive spherical regression was −0.04 D/year at last follow-up. Uncorrected distance visual acuity improved from an average logMAR 1.8 to 0.4; corrected distance visual acuity improved an average 0.3 logMAR. Of the treated children, 68% had a gain in binocular fusion. Neurobehavioral and/or visuomotor comorbidities were present in 87% of children. Five eyes (2%) developed retinal detachment an average 6 years after implantation. Nine eyes (3%) implanted with the Ophtec-Artisan pIOL required repositioning after trauma. Conclusions Implantation of pIOLs in children is an effective method for correcting high myopia in spectacle noncompliant children. Rates of myopic regression after pIOL surgery are substantially lower than those reported for children treated by excimer laser photorefractive keratectomy (PRK). The prevalence of major complications was relatively low in this high-risk population.

Uncorrected aphakia is as capable as the original lens opacity to limit visual potential. There exist situations where the best and safest option for a patient is to not place an intraocular lens (IOL). In these circumstances, aphakic contact lens fitting after lensectomy can be the preferred means of optical correction. With contact lens correction of aphakia, the image projected on the retina is of normal size and lacks the aberrations and distortion seen with high plus aphakic glasses. Additionally, high plus spectacles can induce a prismatic effect, decrease peripheral vision, and cause anisometropic diplopia. The weight and the thickness of the lenses can render aphakic glasses challenging for babies or children with flat nasal bridges to wear comfortably. With the advent of more materials, better education, and scientific studies, the outcomes with contact lenses are more predictable than a few decades ago. Another advantage of aphakic contact lenses is ease of replacement, especially when needing to adjust the power. Especially in a young eye with rapid axial length elongation, contact lens power adjustments can be made far more readily than new aphakic spectacles. Aphakic rehabilitation requires that the physician, the caregiver, and the patient work together to overcome hurdles leading to amblyopia. The ultimate goal is to provide the child with usable vision and prevent or limit amblyopia by eliminating sight-threatening blur.

Purpose A subset of children with high anisometropia or isoametropia and neurobehavioral disorders have chronic difficulties with spectacle or contact lens wear. We report the results of refractive surgery in a series of these children treated using bilateral or unilateral intraocular collamer lens (Visian ICL) implantation for moderate to high myopia. Design Prospective nonrandomized cohort study. Methods Clinical course and outcome data were collated prospectively for 40 implanted eyes in 23 children (mean age 10.2 ± 5.3 years, range, 1.8–17 years). Myopia ranged from −3.0 to −14.5 diopters (D), mean −9.2 ± 3.5 D. Goal refraction was plano to +1 D. Correction was achieved by sulcus implantation of a Visian ICL (STAAR Surgical, Monrovia, California, USA) under general anesthesia. Mean follow-up was 15.1 months (range, 6–22 months). Results Thirty-five eyes (88%) were corrected to within ±1.0 D of goal refraction; the other 5 (12%) were corrected to within 1.5 D. Uncorrected distance visual acuity improved substantially in all eyes (from mean 20/1050 [logMAR 1.72] to mean 20/42 [logMAR 0.48]). Spherical regression at last follow-up was an average of +0.59 D. Visuomotor comorbidities (eg, amblyopia, nystagmus, foveopathy, optic neuropathy) accounted for residual postoperative subnormal visual acuity. Thirteen of the 23 children (57%) had a neurobehavioral disorder (eg, developmental delay/intellectual disability/mental retardation, Down syndrome, cerebral palsy, autism spectrum disorder). Eighty-five percent (11/13) of those children were reported to have enhanced visual awareness, attentiveness, or social interactions. Endothelial cell density was measureable in 6 cooperative children (10 eyes), showing an average 1% decline. Central corneal thickness, measured in all children, increased an average of 8 μm. Two children (8%) required unplanned return to the operating room on the first postoperative day to alleviate pupillary block caused by a nonpatent iridotomy. No other complications were encounterd. Conclusion Visian ICL implantation improves visual function in special needs children who have moderate to high myopia and difficulties wearing glasses or contact lenses.

Background/aimsTo report alterations in visual acuity and visual pathway structure over an interval of 1–3 years in a cohort of children, adolescents and young adults who have Wolfram syndrome (WFS) and to describe the range of disease severity evident in patients with WFS whose ages differed by as much as 20 years at first examination.MethodsAnnual, prospective ophthalmological examinations were performed in conjunction with retinal nerve fibre layer (RNFL) analysis. Diffusion tensor MRI-derived fractional anisotropy was used to assess the microstructural integrity of the optic radiations (OR FA).ResultsMean age of the 23 patients with WFS in the study was 13.8 years (range 5–25 years). Mean log minimum angle resolution visual acuity was 0.66 (20/91). RNFL thickness was subnormal in even the youngest patients with WFS. Average RNFL thickness in patients with WFS was 57±8 µ or ~40% thinner than that measured in normal (94±10 µ) children and adolescents (PConclusionThe genetic mutation of WFS causes damage to both pregeniculate and postgeniculate regions of the visual pathway. The damage is progressive. The decline in visual pathway structure is accompanied by declines of visual function. Disease severity differs widely in individual patients and cannot be predicted from their age.

Purpose A subset of children with high ametropia and neurobehavioral disorders have chronic difficulties with spectacle or contact lens wear. We report the results of refractive surgery in a series of these children treated using bilateral or unilateral phakic intraocular lenses (IOLs) for ametropia >10 D. Methods Clinical course and outcome data were collated prospectively in a group of 12 children (mean age, 10.1 years; range, 4-17 years) with neurobehavioral disorders exacerbated by poor compliance with spectacles. Myopia in 18 eyes ranged from −10.0 to −22.75 D (mean, −15.2 D) and in 2 hyperopic eyes from +10.25 to +10.75 (mean, +10.5 D). Goal refraction was approximately 0 to +1 D. Correction was achieved by implantation of an iris-enclaved phakic IOL under general anesthesia. Mean follow-up was 9.1 months (range, 3-15 months). Results Myopia correction averaged 14.5 D and hyperopia correction 9.4 D. Eighty-six percent of eyes (17/20 eyes) were corrected to within ± 1 D of emmetropia and the remaining 14% (3 eyes) to within ± 2 D. Uncorrected visual acuity improved substantially in all 20 eyes (60-fold; from a mean of 20/3400 to a mean of 20/57). Ocular comorbidities in each child accounted for residual postoperative, subnormal visual acuity (eg, amblyopia, nystagmus, albinism, regressed retinopathy of prematurity). Visual functions (measured using a 23-item validated survey) improved. One eye required IOL exchange; no other clinically significant complications have been encountered. Conclusions Phakic IOL implantation improves visual function substantially in neurobehaviorally impaired children who have high ametropia and difficulties wearing glasses.

Purpose To describe an ophthalmic phenotype in children at relatively early stages of Wolfram syndrome. Methods Quantitative ophthalmic testing of visual acuity, color vision, automated visual field sensitivity, optic nerve pallor and cupping, and retinal nerve fiber layer (RNFL) thickness assessed by optical coherence tomography (OCT) was performed in 18 subjects 5-25 years of age. Subjects were also examined for presence or absence of afferent pupillary defects, cataracts, nystagmus, and strabismus. Results Subnormal visual acuity was detected in 89% of subjects, color vision deficits in 94%, visual field defects in 100%, optic disk pallor in 94%, abnormally large optic nerve cup:disk ratio in 33%, thinned RNFL in 100%, afferent pupillary defects in 61%, cataracts in 22%, nystagmus in 39%, and strabismus in 39% of subjects. RNFL thinning ( P P = 0.01), strabismus ( P = 0.04), and nystagmus ( P = 0.04) were associated with more severe disease using the Wolfram United Rating Scale. Conclusions Children and adolescents with Wolfram syndrome have multiple ophthalmic markers that correlate with overall disease severity. RNFL thickness measured by OCT may be the most reliable early marker.

Introduction: A subpopulation of children with high myopia and neurobehavioral disorders is noncompliant with spectacle wear and ill-suited to correction using contact lenses. We report the results of refractive surgery in a series of these children treated bilaterally using excimer laser technology. Methods: Clinical course and outcome data were collated prospectively in a group of 9 children (mean age, 10.2 years; range, 3-16 years) with neurobehavioral disorders exacerbated by chronic noncompliance with spectacle wear, causing profoundly low functional vision. Myopia in the 18 eyes ranged from –3.75 to –11.5 D (mean –16.6 D) and the desired refraction was ∼+1D. Correction was achieved by bilateral laser-assisted subepithelial keratectomy (ie, LASEK) performed under brief general anesthesia. Mean follow-up was 17 months (range, 6-36 months). Results: Myopia correction averaged 7.9 D. Eighty-nine percent (16/18 eyes) were corrected to within ±1 D of goal refraction. Uncorrected acuity improved postoperatively in all 18 eyes, with commensurate gains in behavior and environmental visual interaction in 88% (15/17 children). Myopic regression averaged ∼0.8 D/year. The only complication encountered was mild (1+) corneal haze in 35% of treated eyes. Discussion/Conclusions: Bilateral excimer laser surgery is effective for improving functional vision substantially in highly myopic, neurobehaviorally impaired children who have difficulties wearing glasses. Myopic regression is common. Further study is indicated to determine the long-term safety of these and alternative refractive procedures in similar pediatric populations.

Background Wolfram Syndrome (WFS:OMIM 222300) is an autosomal recessive, progressive, neurologic and endocrinologic degenerative disorder caused by mutations in the WFS1 gene, encoding the endoplasmic reticulum (ER) protein wolframin, thought to be involved in the regulation of ER stress. This paper reports a cross section of data from the Washington University WFS Research Clinic, a longitudinal study to collect detailed phenotypic data on a group of young subjects in preparation for studies of therapeutic interventions. Methods Eighteen subjects (ages 5.9–25.8, mean 14.2 years) with genetically confirmed WFS were identified through the Washington University International Wolfram Registry. Examinations included: general medical, neurologic, ophthalmologic, audiologic, vestibular, and urologic exams, cognitive testing and neuroimaging. Results Seventeen (94%) had diabetes mellitus with the average age of diabetes onset of 6.3 ± 3.5 years. Diabetes insipidus was diagnosed in 13 (72%) at an average age of 10.6 ± 3.3 years. Seventeen (94%) had optic disc pallor and defects in color vision, 14 (78%) had hearing loss and 13 (72%) had olfactory defects, eight (44%) had impaired vibration sensation. Enuresis was reported by four (22%) and nocturia by three (17%). Of the 11 tested for bladder emptying, five (45%) had elevated post-void residual bladder volume. Conclusions WFS causes multiple endocrine and neurologic deficits detectable on exam, even early in the course of the disease. Defects in olfaction have been underappreciated. The proposed mechanism of these deficits in WFS is ER stress-induced damage to neuronal and hormone-producing cells. This group of subjects with detailed clinical phenotyping provides a pool for testing proposed treatments for ER stress. Longitudinal follow-up is necessary for establishing the natural history and identifying potential biomarkers of progression.

Background Classically characterized by early onset insulin-dependent diabetes mellitus, optic atrophy, deafness, diabetes insipidus, and neurological abnormalities, Wolfram syndrome (WFS) is also associated with atypical brainstem and cerebellar findings in the first decade of life. As such, we hypothesized that gait differences between individuals with WFS and typically developing (TD) individuals may be detectable across the course of the disease. Methods Gait was assessed for 13 individuals with WFS (min 6.4 yrs, max 25.8 yrs) and 29 age-matched, typically developing individuals (min 5.6 yrs, max 28.5 yrs) using a GAITRite ® walkway system. Velocity, cadence, step length, base of support and double support time were compared between groups. Results Across all tasks, individuals with WFS walked slower (p = 0.03), took shorter (p ≤ 0.001) and wider (p ≤ 0.001) steps and spent a greater proportion of the gait cycle in double support (p = 0.03) compared to TD individuals. Cadence did not differ between groups (p = 0.62). Across all tasks, age was significantly correlated with cadence and double support time in the TD group but only double support time was correlated with age in the WFS group and only during preferred pace forward (rs= 0.564, p = 0.045) and dual task forward walking (rs= 0.720, p = 0.006) tasks. Individuals with WFS also had a greater number of missteps during tandem walking (p ≤ 0.001). Within the WFS group, spatiotemporal measures of gait did not correlate with measures of visual acuity. Balance measures negatively correlated with normalized gait velocity during fast forward walking (rs = −0.59, p = 0.03) and percent of gait cycle in double support during backward walking (rs = −0.64, p = 0.03). Conclusions Quantifiable gait impairments can be detected in individuals with WFS earlier than previous clinical observations suggested. These impairments are not fully accounted for by the visual or balance deficits associated with WFS, and may be a reflection of early cerebellar and/or brainstem abnormalities. Effective patient-centered treatment paradigms could benefit from a more complete understanding of the progression of motor and other neurological symptom presentation in individuals with WFS.