Longitudinal Changes in Vision and Retinal Morphology in Wolfram Syndrome.

PURPOSE: 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. DESIGN: Single-center, cohort study. METHODS: 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. RESULTS: 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 (ß = -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. CONCLUSIONS: 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.

A phase Ib/IIa clinical trial of dantrolene sodium in patients with Wolfram syndrome.

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 ß cell functions, visual acuity, quality-of-life measures related to vision, and neurological functions.RESULTSDantrolene sodium was well tolerated by Wolfram syndrome patients. Overall, ß cell functions were not significantly improved, but there was a significant correlation between baseline ß cell functions and change in ß 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-1ß, 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.

Safety of phakic intraocular collamer lens implantation in 95 highly myopic special-needs children.

PURPOSE: To assess the safety of intraocular collamer lens (ICL) implantation in children with high ametropia by reporting rates and case specifics of perioperative and longer-term adverse events (AEs).. SETTING: St. Louis Children's Hospital at Washington University Medical Center, St. Louis, Missouri. DESIGN: Retrospective case series. METHODS: Clinical data were collated retrospectively for 95 special-needs children (160 eyes) implanted with a Visian ICL over the past 5 years. All surgeries were performed at St Louis Children's Hospital under brief general anesthesia. The mean follow-up period was 2.0 ± 1.4 years (range, 0.5 to 5.2). RESULTS: The mean age at implantation was 9.3 ± 5.2 years (range, 1.8 to 25) and mean preoperative spherical equivalent refractive error was -11.20 ± 3.90 diopters (range, 4 to 22). 62 children (62/95, 65%) had a neurodevelopmental disorder. 3 eyes (3/160, 2%) reported minor AE, consisting of steroid-response ocular hypertension, which resolved with cessation of topical steroid drops. Endothelial cell loss averaged 8.1% over 2 years, comparable with that reported in ICL-implanted adults. The most common major AE (7 eyes [7/160, 4%]) was postoperative pupillary block, requiring revision of the peripheral iridotomy. 1 child (1 eye [1/160, 0.6%]) with self-injurious behavior required repair of a wound leak. 1 child (1 eye [1/160, 0.6%]) with Down syndrome developed a cataract 2.8 years after ICL surgery, and 1 child (1 eye [1/160, 0.6%]) with severe autism spectrum disorder experienced traumatic retinal detachment 1.2 years after implantation. CONCLUSIONS: The most common major AE among the cohort with Visian ICL 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.

Visual acuity, refractive error, and regression outcomes in 169 children with high myopia who were implanted with Ophtec-Artisan or Visian phakic IOLs.

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.

Visual pathway function and structure in Wolfram syndrome: patient age, variation and progression.

BACKGROUND/AIMS: To 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. METHODS: Annual, 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). RESULTS: Mean 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 (P<0.01). Lower OR FA correlated with worse visual acuity (P=0.006). Subsequent examinations showed declines (P<0.05) in visual acuity, RNFL thickness and OR FA at follow-up intervals of 12-36 months. However, a wide range of disease severity was evident across ages: some of the youngest patients at their first examination had deficits more severe than the oldest patients. CONCLUSION: The 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.

Phakic Intraocular Collamer Lens (Visian ICL) Implantation for Correction of Myopia in Spectacle-Aversive Special Needs Children.

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.

Ophthalmologic correlates of disease severity in children and adolescents with Wolfram syndrome.

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 < 0.001), afferent pupillary defects (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.

Phenotypic characteristics of early Wolfram syndrome.

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.

Early presentation of gait impairment in Wolfram Syndrome.

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.

Phakic intraocular lens correction of high ametropia in children with neurobehavioral disorders.

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.

Refractive surgery for high bilateral myopia in children with neurobehavioral disorders: 1. Clear lens extraction and refractive lens exchange.

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 using lensectomy alone (clear lens extraction), or lensectomy with simultaneous implantation of an intraocular lens (refractive lens exchange). METHODS: Clinical course and outcome data were collated prospectively in a group of 13 children (mean age 10.4 years, range 1 to 18 years) with neurobehavioral disorders exacerbated by chronic noncompliance with spectacle wear, causing profoundly low functional vision. Myopia in the 26 eyes ranged from -14.25 to -26.00 D (mean -19.1 D). Goal refraction was approximately +1 D. Correction was achieved by lensectomy alone in 10 eyes, and lensectomy with intraocular lens implantation in 16 eyes. Primary posterior capsulectomy/subtotal vitrectomy was performed during the primary procedure in 11 eyes (42%). Mean follow-up was 4.5 years (range 1.3 to 7.5 years). RESULTS: Myopia correction averaged 19.9 D. Eighty-one percent (21 eyes) were corrected to within +/-2 D of goal refraction and the remaining 19% (5 eyes) to within +/-4 D. Uncorrected acuity improved substantially (ie, an average 2 log units) in all 26 eyes, with commensurate gains in behavior and environmental visual interaction in 85% [corrected] of children (11/13) [corrected] Myopic regression averaged -0.16 D/year. Capsular regrowth and/or opacification necessitated vitrector or YAG-laser membranectomy in 13 [corrected] eyes (50%) [corrected] Focal retinal detachment (successfully repaired) occurred after eye contusion in one eye (4%) with cicatricial retinopathy of prematurity. CONCLUSIONS: Bilateral refractive lensectomy is effective for improving functional vision in neurobehaviorally impaired children who have high myopia (beyond the range of excimer laser correction: see companion publication) and difficulties wearing glasses. Posterior capsule regrowth/opacification is common, necessitating secondary membranectomy. Further study is indicated to determine the long-term safety of this procedure in similar pediatric populations.

Refractive surgery for high bilateral myopia in children with neurobehavioral disorders: 2. Laser-assisted subepithelial keratectomy (LASEK).

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 approximately +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 approximately 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.