Corneal nerve and nerve conduction abnormalities in children with type 1 diabetes.

OBJECTIVE: In vivo corneal confocal microscopy (CCM) is a novel, rapid, and non-invasive technique that identifies early small fiber damage and can predict the progression and development of clinical neuropathy in adults with type 1 diabetes. However, its usefulness in children is not well established. This study compared corneal confocal microscopy with neuropathic symptoms, signs, and objective measures of neuropathy for the diagnosis of diabetic neuropathy in children with type 1 diabetes. RESEARCH DESIGN AND METHODS: A total of 83 children with type 1 diabetes and 83 healthy participants of similar age underwent assessment of neuropathy symptoms, signs, nerve conduction studies, quantitative sensory and autonomic function testing, and in vivo CCM. RESULTS: Only of 3/83 (4%) children with type 1 diabetes had subclinical neuropathy. However, corneal nerve fiber density (p = 0.001), branch density (p = 0.006), fiber length (p = 0.002), tibial motor nerve amplitude and conduction velocity, and sural sensory nerve amplitude and conduction velocity (all p < 0.004) were lower in participants with type 1 diabetes than in the controls. Vibration, cooling, and warm perception thresholds and deep breathing heart rate variability were not found to be different (all p > 0.05) between children with type 1 diabetes and healthy controls. Multivariate regression analysis identified a possible association between body mass index and decreased corneal nerves. CONCLUSIONS: Decreased corneal nerves and abnormal nerve conduction were found in children with type 1 diabetes. CCM may allow rapid objective detection of subclinical diabetic neuropathy in children and adolescents with type 1 diabetes.

Corneal confocal microscopy for identification of diabetic sensorimotor polyneuropathy: a pooled multinational consortium study.

AIMS/HYPOTHESIS: Small cohort studies raise the hypothesis that corneal nerve abnormalities (including corneal nerve fibre length [CNFL]) are valid non-invasive imaging endpoints for diabetic sensorimotor polyneuropathy (DSP). We aimed to establish concurrent validity and diagnostic thresholds in a large cohort of participants with and without DSP. METHODS: Nine hundred and ninety-eight participants from five centres (516 with type 1 diabetes and 482 with type 2 diabetes) underwent CNFL quantification and clinical and electrophysiological examination. AUC and diagnostic thresholds were derived and validated in randomly selected samples using receiver operating characteristic analysis. Sensitivity analyses included latent class models to address the issue of imperfect reference standard. RESULTS: Type 1 and type 2 diabetes subcohorts had mean age of 42 ± 19 and 62 ± 10 years, diabetes duration 21 ± 15 and 12 ± 9 years and DSP prevalence of 31% and 53%, respectively. Derivation AUC for CNFL was 0.77 in type 1 diabetes (p < 0.001) and 0.68 in type 2 diabetes (p < 0.001) and was approximately reproduced in validation sets. The optimal threshold for automated CNFL was 12.5 mm/mm2 in type 1 diabetes and 12.3 mm/mm2 in type 2 diabetes. In the total cohort, a lower threshold value below 8.6 mm/mm2 to rule in DSP and an upper value of 15.3 mm/mm2 to rule out DSP were associated with 88% specificity and 88% sensitivity. CONCLUSIONS/INTERPRETATION: We established the diagnostic validity and common diagnostic thresholds for CNFL in type 1 and type 2 diabetes. Further research must determine to what extent CNFL can be deployed in clinical practice and in clinical trials assessing the efficacy of disease-modifying therapies for DSP.

Corneal Confocal Microscopy Predicts the Development of Diabetic Neuropathy: A Longitudinal Diagnostic Multinational Consortium Study.

OBJECTIVE: Corneal nerve fiber length (CNFL) has been shown in research studies to identify diabetic peripheral neuropathy (DPN). In this longitudinal diagnostic study, we assessed the ability of CNFL to predict the development of DPN. RESEARCH DESIGN AND METHODS: From a multinational cohort of 998 participants with type 1 and type 2 diabetes, we studied the subset of 261 participants who were free of DPN at baseline and completed at least 4 years of follow-up for incident DPN. The predictive validity of CNFL for the development of DPN was determined using time-dependent receiver operating characteristic (ROC) curves. RESULTS: A total of 203 participants had type 1 and 58 had type 2 diabetes. Mean follow-up time was 5.8 years (interquartile range 4.2-7.0). New-onset DPN occurred in 60 participants (23%; 4.29 events per 100 person-years). Participants who developed DPN were older and had a higher prevalence of type 2 diabetes, higher BMI, and longer duration of diabetes. The baseline electrophysiology and corneal confocal microscopy parameters were in the normal range but were all significantly lower in participants who developed DPN. The time-dependent area under the ROC curve for CNFL ranged between 0.61 and 0.69 for years 1-5 and was 0.80 at year 6. The optimal diagnostic threshold for a baseline CNFL of 14.1 mm/mm2 was associated with 67% sensitivity, 71% specificity, and a hazard ratio of 2.95 (95% CI 1.70-5.11; P < 0.001) for new-onset DPN. CONCLUSIONS: CNFL showed good predictive validity for identifying patients at higher risk of developing DPN ∼6 years in the future.

Early corneal nerve fibre damage and increased Langerhans cell density in children with type 1 diabetes mellitus.

Corneal confocal microscopy (CCM) has been used to identify corneal nerve damage and increased Langerhans cell (LC) density in adults with Type 1 diabetes mellitus (T1DM). The purpose of this study was to evaluate whether corneal confocal microscopy can identify early corneal nerve damage and change in LC density in children and adolescents with T1DM. 64 participants with T1DM (age-14.6 ± 2.5 years, duration of diabetes-9.1 ± 2.7 years, HbA1c-75.66 ± 2.53 mmol/mol [9.1 ± 1.8%]) and 48 age-matched healthy control subjects underwent CCM. Sub-basal corneal nerve morphology and the density of mature and immature LCs was quantified. Corneal nerve fibre length and branch density were lower, whilst fibre density and tortuosity did not differ and both immature and mature LC density was significantly higher in T1DM compared to control subjects. There was no association between HbA1c and duration of diabetes with nerve fibre parameters or LC's density. Children and adolescents with T1DM demonstrate early immune activation and nerve degeneration.

Ophthalmic findings in Setleis syndrome: two new cases in a mother and son.

CASE REPORT: Setleis syndrome is a rare ectodermal dysplasia with characteristic ophthalmic findings. We describe the first 2 reported cases in Canadian individuals of Aboriginal descent. COMMENTS: Although most ophthalmic findings are benign, it is important to recognize the clinical significance for management and genetic counselling. We postulate an autosomal dominant inheritance in our cases.

Indoor soccer-related eye injuries: should eye protection be mandatory?

BACKGROUND: Our objectives were to present the spectrum of eye injuries caused by indoor soccer, as seen at our institution, and to initiate discussion as to whether eye protection should become mandatory for this indoor sport. METHODS: Chart review of patients presenting to our institution with eye injuries from indoor soccer. RESULTS: Five cases were identified from 2001-2005, all occurring during the winter or late fall. Each injury was due to contact with the soccer ball itself. Initially, all 5 patients presented with commotio retinae (1 with a prominent retinal and vitreous hemorrhage and 2 with smaller retinal hemorrhages), 2 with hyphema and traumatic mydriasis, 1 with subconjunctival hemorrhage, and 1 with upper lid edema and ecchymosis. Three resolved uneventfully with 20/20 or better vision; however, in 2 there were findings of choroidal rupture with chorioretinal scarring. One of these had 20/20 vision and a discontinuous choroidal rupture peripherally, and the other had 20/40 vision and extensive chorioretinal scarring. One patient also showed a peculiar persistent iris scar. INTERPRETATION: Soccer-related eye injuries have been recognized as an important ophthalmologic problem in Europe and now increasingly so in North America. With the increasing popularity of indoor soccer in Canada, serious eye injuries have become more prevalent. On the basis of the prevalence and the nature and mechanism of the ocular trauma, we believe there may be a need to make eye protection mandatory for all forms of soccer.

Diffraction-enhanced imaging of a porcine eye.

BACKGROUND: Diffraction-enhanced imaging (DEI) is a synchrotron-based x-ray imaging technique that has dramatically improved contrast over standard x-ray imaging techniques. It is possible to acquire images that analyze the x-ray refraction and the apparent absorption (elimination of small-angle scattering) of the object. METHODS: Three formalin-fixed porcine eyes were studied at the National Synchrotron Light Source using DEI. Conventional absorption-type radiography was conducted for comparison. RESULTS: Conventional absorption radiography did not yield significant detail of the eye anatomy. DEI showed excellent characterization of many ocular structures. The cornea, iris, lens, retina, optic nerve, as well as choroidal vasculature and the ampullae of the vortex veins could all be visualized. INTERPRETATION: DEI represents a novel, high-resolution imaging technique that has excellent characterization of ocular anatomy. Further application of this imaging modality will be undertaken to study cataract and choroidal tumors and to examine ocular surface structures, such as the extraocular muscle insertions, more closely.

Optic neuropathy in the context of leukemia or lymphoma: diagnostic approach to a neuro-oncologic emergency.

BACKGROUND: Optic neuropathy in the context of leukemia or lymphoma has a broad differential diagnosis, including infiltration, infection, inflammation, compression, and medication effects. Confirming the underlying etiology in a timely manner is crucial as, while infiltration carries a poor prognosis, treatment modalities can have serious consequences themselves. METHODS: A review of the literature was conducted for cases of isolated optic neuropathy in the context of leukemia or lymphoma, in which the underlying etiology remained unclear following initial clinical examination and neuroimaging. Clinical, radiological, and pathological characteristics of the cases are summarized. RESULTS: Ninety-two cases meeting inclusion criteria were identified. Leukemic or lymphomatous infiltration was the presumed diagnosis in 72% of the reports, indicating this is the most likely etiology in such cases. The remaining reports were attributed to inflammation, infection, or drug toxicity. For illustrative purposes, the previously unpublished case of an 11-year-old girl with remitted T lymphoblastic lymphoma is presented. She suffered recurrence in the form of isolated left optic nerve infiltration that required transconjunctival biopsy to confirm diagnosis. CONCLUSIONS: Optic nerve infiltration by leukemia or lymphoma requires both diagnostic certainty and urgent management. Recommendations are made for a step-wise, yet rapid investigative approach that may ultimately require biopsy of the optic nerve.

The natural history of surgically untreated intermittent exotropia-looking into the distant future.

PURPOSE: We studied patients with distance intermittent exotropia with at least 5 years follow-up before any surgical therapy, to determine how often amblyopia developed, whether there was progressive worsening in the angle or control of the exodeviation, whether there was deterioration in binocular vision, and other parameters. METHODS: Retrospective review of charts of patients with exodeviations examined consecutively over 17 years. RESULTS: There were 109 patients followed for a mean of 9 years (range 5 to 25). Amblyopia was mild (20/25 in 33, 20/30 in 15, and 20/40 in 2). There was no significant change in the mean exoangle from initial to final visit (20.6 to 20.9 PD), but the initial to final exoangle decreased by more than 10 PD in 19%, remained stable in 58%, and increased by more than 10 PD in 23%. There was no statistically significant trend for worsening or improving when serial measurements were plotted and the aggregate slopes were analyzed. Change in control in the distance from initial to final visit was favorable in 26%, showed no change in 51%, and was unfavorable in 23%, with 17% deteriorating to a constant distance exotropia. Mean near stereoacuity at the final visit was 88 seconds of arc. Strabismus surgery was performed in 14% of patients from 5 to 18 years (mean 9) after their initial visit. CONCLUSIONS: Visual acuity and near stereoacuity were generally good. There was little change in the mean angle of deviation from initial to final visit for the group, with a nearly chance occurrence for the distance deviation to progressively worsen or improve, perhaps explaining why strabismologists have had difficulty definitively prognosticating about the long-term stability of intermittent exotropia.

Long-term refractive change after intraocular lens implantation in childhood.

BACKGROUND: To determine refractive change occurring with age in children who had cataract removal with intraocular lens implantation and in whom the immediate postoperative refraction was targeted either to match the refractive error of the opposite eye in unilateral cases, or for only a small refractive error when surgery was bilateral. METHODS: Retrospective review of the refractive error over time in 36 eyes of 25 children who underwent cataract removal (11 bilateral) with insertion of an intraocular lens from 1987 to 1998 and who had at least 4 years follow-up, but no glaucoma. RESULTS: Mean age at surgery was 5.5 years (median 5.7 y, range 1.3-12 y), with a mean follow-up of 8 years (median 6 y, range 4-16 y). The average refraction followed a logarithmic decline with age. Although eyes with unilateral surgery had a slightly faster rate of change and lower final refraction than did eyes with bilateral surgery, this difference was not statistically significant. Variation from this trend was also observed in 3 patients. When the hyperopic refractive error created immediately after surgery was small, children usually became significantly myopic when older, often creating anisometropic myopia in unilateral cases. INTERPRETATION: When implanting intraocular lenses bilaterally one should aim for a significant but balanced hyperopic correction immediately postoperatively in young patients, anticipating that there will be emmetropization with aging. Parents should be warned that variations can occur.

Punctiform and Polychromatophilic Dominant Pre-Descemet Corneal Dystrophy.

PURPOSE: To describe the slit-lamp appearance and corneal confocal microscopy of autosomal dominant punctiform and polychromatophilic pre-Descemet corneal dystrophy in 3 members of the same family. METHODS: Slit-lamp examination of a 9-year-old boy showed bilateral polychromatophilic corneal opacities in a pre-Descemet membrane location evenly deposited limbus to limbus, both horizontally and vertically, with an intervening clear cornea. The corneal endothelium was normal on corneal confocal microscopy, with hyperreflective opacities of various sizes located pre-Descemet membrane. Slit-lamp examination of the patient's father and brother revealed identical crystalline deposition in the pre-Descemet corneal stroma. The remainders of the eye examinations were otherwise normal in all 3 individuals, and all were asymptomatic. RESULTS: The general physical examination and laboratory investigations of the patient were all normal, as were the laboratory investigations of the other 2 family members. There was no progression in the corneal findings over 6 months of follow-up. CONCLUSIONS: These patients likely illustrate a rare autosomal dominant pre-Descemet crystalline keratopathy that has been reported only once previously.

Evidence for small fiber neuropathy in early Parkinson's disease.

INTRODUCTION: Parkinson's disease (PD) is neurodegenerative movement disorder affecting primarily the central nervous system with several recognized non-motor symptoms that can occur at various stages of the disease. Recently it has been shown that patients with PD may be prone to peripheral nervous system pathology in the form of a peripheral neuropathy (PN). It is unclear if PN is an inherent feature of PD or if it is an iatrogenic effect of the mainstay PD treatment Levodopa. METHODS: To determine if peripheral neuropathy occurs in early untreated PD we employed a case-control study design using gold standard tests for PN, including neurological examination according to the Utah Early Neuropathy Scale (UENS) and nerve conduction studies, as well as new, more sensitive and informative tests for PN including the skin biopsy and corneal confocal microscopy (CCM). RESULTS: We studied 26 patients with PD and 22 controls using the neurological examination and nerve conduction studies (NCS) and found no significant difference between groups except for some reduced vibration sense in the PD group. Epidermal nerve densities in the skin biopsies were similar between our cohorts. However, using CCM - a more sensitive test and a surrogate marker of small fiber damage in PN, we found that patients with PD had significantly reduced corneal nerve fiber densities and lengths as compared to controls. CONCLUSIONS: We conclude that our positive CCM results provide evidence of preclinical PN in newly diagnosed PD patients.

The Reliability and Reproducibility of Corneal Confocal Microscopy in Children.

PURPOSE: To assess the image and patient level interrater agreement and repeatability within 1 month for corneal nerve fiber length (CNFL) measured using in vivo corneal confocal microscopy (IVCCM) in children. METHODS: Seventy-one subjects (mean [SD] age 14.3 [2.6] years, range 8-18 years; 44 with type 1 diabetes and 27 controls; 36 males and 35 females) were included. 547 images (∼6 images per subject) were analyzed manually by two independent and masked observers. One-month repeat visit images were analyzed by a single masked observer in 21 patients. Automated image analysis was then performed using a specialized computerized software (ACCMetrics). RESULTS: For CNFL, the ICC (95% CI) were 0.94 (0.93-0.95) for image-level, 0.86 (0.78-0.91) for patient-level, and 0.88 (0.72-0.95) for the 1-month repeat assessment, and the Bland-Altman plots showed minimal bias between observers. Although there was excellent agreement between manual and automated analysis according to an ICC 0.89 (0.82-0.93), the Bland-Altman plot showed a consistent bias with manual measurements providing higher readings. CONCLUSIONS: In vivo corneal confocal microscopy image analysis shows good reproducibility with excellent intraindividual and interindividual variability in pediatric subjects. Since the image-level reproducibility is stronger than the patient-level reproducibility, refinement of the method for image selection will likely further increase the robustness of this novel, rapid, and noninvasive approach to detect early neuropathy in children with diabetes. Further studies on the use of IVCCM to identify early subclinical neuropathy in children are indicated.

Normative values for corneal nerve morphology assessed using corneal confocal microscopy: a multinational normative data set.

OBJECTIVE: Corneal confocal microscopy is a novel diagnostic technique for the detection of nerve damage and repair in a range of peripheral neuropathies, in particular diabetic neuropathy. Normative reference values are required to enable clinical translation and wider use of this technique. We have therefore undertaken a multicenter collaboration to provide worldwide age-adjusted normative values of corneal nerve fiber parameters. RESEARCH DESIGN AND METHODS: A total of 1,965 corneal nerve images from 343 healthy volunteers were pooled from six clinical academic centers. All subjects underwent examination with the Heidelberg Retina Tomograph corneal confocal microscope. Images of the central corneal subbasal nerve plexus were acquired by each center using a standard protocol and analyzed by three trained examiners using manual tracing and semiautomated software (CCMetrics). Age trends were established using simple linear regression, and normative corneal nerve fiber density (CNFD), corneal nerve fiber branch density (CNBD), corneal nerve fiber length (CNFL), and corneal nerve fiber tortuosity (CNFT) reference values were calculated using quantile regression analysis. RESULTS: There was a significant linear age-dependent decrease in CNFD (-0.164 no./mm(2) per year for men, P < 0.01, and -0.161 no./mm(2) per year for women, P < 0.01). There was no change with age in CNBD (0.192 no./mm(2) per year for men, P = 0.26, and -0.050 no./mm(2) per year for women, P = 0.78). CNFL decreased in men (-0.045 mm/mm(2) per year, P = 0.07) and women (-0.060 mm/mm(2) per year, P = 0.02). CNFT increased with age in men (0.044 per year, P < 0.01) and women (0.046 per year, P < 0.01). Height, weight, and BMI did not influence the 5th percentile normative values for any corneal nerve parameter. CONCLUSIONS: This study provides robust worldwide normative reference values for corneal nerve parameters to be used in research and clinical practice in the study of diabetic and other peripheral neuropathies.

Enhanced models for teaching slit-lamp skills.

This article describes enhancements to models previously devised for demonstrating slit-lamp findings to students and physicians. The models can simulate the optical appearance of the anterior segment, "flare" and "cells" in the anterior chamber, hypopyon, gross and microscopic hyphema, the red reflex, cataract, corneal epithelial defects (including fluorescein staining) and superficial corneal foreign bodies, whose removal can be practised.

Two cases of spontaneous filtering blebs, one idiopathic and one associated with Terrien marginal degeneration.

PURPOSE: To report a case of an idiopathic unilateral filtering bleb in an otherwise well patient and a case of bilateral spontaneous filtering blebs in association with Terrien marginal degeneration. METHODS: In this retrospective observational study of 2 cases, clinical notes, ultrasound biomicroscopy and gonioscopy images were reviewed. RESULTS: Case 1: A 32-year-old woman presented with a 1-year history of a gradually growing cyst in her right eye. No changes in vision were reported. The patient had no previous ocular or systemic history, trauma, or surgical interventions. Slit-lamp examination revealed a multilobulated cyst at the supranasal limbus OD. Diagnosis was an idiopathic spontaneous limbal filtering bleb of unclear etiology because there was no inciting event or obvious cause. Case 2: A 31-year-old man, with 2 past episodes of spontaneous filtering bleb development, affecting the left, then the right, eye, presented with his third event in May 2012. The visual acuity was decreased to 20/400 OD. The right eye was hypotonous and ultrasound biomicroscopy confirmed a shallow anterior chamber, a superior peripheral corneal defect, and an echolucent space suggestive of subconjunctival fluid. Limbal thinning was noted bilaterally, consistent with Terrien marginal degeneration. CONCLUSIONS: This is a rare case of an idiopathic filtering bleb occurring in a healthy patient with no precipitating cause, other ocular abnormalities, or physical malformations, and the only reported case of bilateral sequential filtering blebs associated with an atypical presentation of Terrien marginal degeneration.

Intermittent exotropia: facts, opinions, and unknowns.

INTRODUCTION: Intermittent exotropia (IXT) can be a controversial topic, often eliciting lively discussion. This lecture will discuss its definition, incidence, age of onset, presentation, natural variation, criteria for deterioration, goals of treatment, effectiveness of surgical treatment, types of surgical treatment, and unwanted effects of surgical treatment. METHOD: Results from the scientific literature, opinions of respected colleagues, the opinion of the author, and the results of live polling of the audience during the John Pratt-Johnson lecture are presented. RESULTS: IXT is defined as an exotropia that is present intermittently predominantly for distance. Its incidence is about 1% and it usually has an onset before age 5. Patients often present because of concern regarding the appearance of the eye misalignment. There is natural variation in the control of IXT, the angle of IXT, and the amount of stereopsis. Criteria that denote deterioration are increasing frequency of IXT, progressively and consistently increasing angle of IXT, loss of binocular vision, and increasing concern regarding the patient's appearance and its effect on social interaction. Goals of treatment are to retain equal or nearly equal vision, to obtain acceptable cosmesis, and to retain binocular vision. The long-term success of surgical treatment is not well proven. Persistent postoperative overcorrection is an unwanted effect of surgical treatment. CONCLUSION: The inherent biologic variation that occurs when measuring the components of IXT makes it difficult to be dogmatic about IXT, particularly when trying to decide when deterioration is occurring.

Consecutive exotropia following surgically corrected cyclic esotropia.

INTRODUCTION: Cyclic esotropia is a rare form of strabismus consisting of regular intervals of esotropia alternating with periods of orthophoria in a rhythmic/cyclic manner. In the vast majority of cases, surgery appears to permanently correct the esotropia, with no sequelae after years of follow-up. We report a case of consecutive exotropia in a patient five years after bilateral medial rectus recessions for cyclic esotropia. METHODS: A case report involving review of a clinical chart. RESULTS: A two-year-old male presented with right esotropia and mild amblyopia. He was treated with patching and following resolution of the amblyopia he developed a cyclic esotropia. Surgical correction was performed for the full amount measured on a "manifest" day. Following the surgery, he was orthophoric and demonstrated binocular vision. He remained stable for five years, and then returned with occasional diplopia and an intermittent exotropia. CONCLUSION: Cyclic esotropia is a rare disorder of ocular motility that spontaneously appears and disappears at regular intervals. After surgical correction, the deviation disappears and recurrence of esotropia is very infrequent. We present the first reported case of consecutive exotropia following surgical correction of a cyclic esotropia.