Craig A. McKeown

Clinical studies on submicroscopic subtelomeric rearrangements: a checklist

BACKGROUND Submicroscopic subtelomeric chromosome defects have been found in 7.4% of children with moderate to severe mental retardation and in 0.5% of children with mild retardation. Effective clinical preselection is essential because of the technical complexities and cost of screening for subtelomere deletions. METHODS We studied 29 patients with a known subtelomeric defect and assessed clinical variables concerning birth history, facial dysmorphism, congenital malformations, and family history. Controls were 110 children with mental retardation of unknown aetiology with normal G banded karyotype and no detectable submicroscopic subtelomeric abnormalities. RESULTS Prenatal onset of growth retardation was found in 37% compared to 9% of the controls (p<0.0005). A higher percentage of positive family history for mental retardation was reported in the study group than the controls (50%v 21%, p=0.002). Miscarriage(s) were observed in only 8% of the mothers of subtelomeric cases compared to 30% of controls (p=0.028) which was, however, not significant after a Bonferroni correction. Common features (>30%) among subtelomeric deletion cases were microcephaly, short stature, hypertelorism, nasal and ear anomalies, hand anomalies, and cryptorchidism. Two or more facial dysmorphic features were observed in 83% of the subtelomere patients. None of these features was significantly different from the controls. Using the results, a five item checklist was developed which allowed exclusion from further testing in 20% of the mentally retarded children (95% CI 13-28%) in our study without missing any subtelomere cases. As our control group was selected for the “chromosomal phenotype”, the specificity of the checklist is likely to be higher in an unselected group of mentally retarded subjects. CONCLUSIONS Our results suggest that good indicators for subtelomeric defects are prenatal onset of growth retardation and a positive family history for mental retardation. These clinical criteria, in addition to features suggestive of a chromosomal phenotype, resulted in the development of a five item checklist which will improve the diagnostic pick up rate of subtelomeric defects among mentally retarded subjects.

Heterozygous mutations of the kinesin KIF21A in congenital fibrosis of the extraocular muscles type 1 (CFEOM1).

Congenital fibrosis of the extraocular muscles type 1 (CFEOM1; OMIM #135700) is an autosomal dominant strabismus disorder associated with defects of the oculomotor nerve. We show that individuals with CFEOM1 harbor heterozygous missense mutations in a kinesin motor protein encoded by KIF21A. We identified six different mutations in 44 of 45 probands. The primary mutational hotspots are in the stalk domain, highlighting an important new role for KIF21A and its stalk in the formation of the oculomotor axis.

Validity of the convergence insufficiency symptom survey: a confirmatory study.

Purpose. The objectives of the present study were to evaluate whether investigator bias influenced the Convergence Insufficiency Symptom Survey (CISS) scores of children with normal binocular vision (NBV) in our original validation study, reevaluate the usefulness of the cutoff score of 16, and reexamine the validity of the CISS. Methods. Six clinical sites participating in the Convergence Insufficiency Treatment Trial (CITT) enrolled 46 children 9 to <18 years with NBV. Examiners masked to the child’s binocular vision status administered the CISS. The mean CISS score was compared with that from the children with NBV in the original, unmasked CISS study and also to that of the 221 symptomatic convergence insufficiency (CI) children enrolled in the CITT. Results. The mean (±standard deviation) CISS score for 46 subjects with NBV was 10.4 (±8.1). This was comparable with our prior unmasked NBV study (mean = 8.1 (±6.2); p = 0.11) but was significantly different from that of the CITT CI group (mean = 29.8 ± 9.0; p < 0.001). Eighty-three percent of these NBV subjects scored <16 on the CISS, which is not statistically different from the 87.5% found in the original unmasked study (p = 0.49). Conclusions. Examiner bias did not affect the CISS scores for subjects with NBV in our prior study. The CISS continues to be a valid instrument for quantifying symptoms in 9 to <18-year-old children. These results also confirm the validity of a cut-point of ≥16 in distinguishing children with symptomatic CI from those with NBV.

Retinal structure of birds of prey revealed by ultra-high resolution spectral-domain optical coherence tomography

PURPOSE To reveal three-dimensional (3-D) information about the retinal structures of birds of prey in vivo. METHODS An ultra-high resolution spectral-domain optical coherence tomography (SD-OCT) system was built for in vivo imaging of retinas of birds of prey. The calibrated imaging depth and axial resolution of the system were 3.1 mm and 2.8 μm (in tissue), respectively. 3-D segmentation was performed for calculation of the retinal nerve fiber layer (RNFL) map. RESULTS High-resolution OCT images were obtained of the retinas of four species of birds of prey: two diurnal hawks (Buteo platypterus and Buteo brachyurus) and two nocturnal owls (Bubo virginianus and Strix varia). These images showed the detailed retinal anatomy, including the retinal layers and the structure of the deep and shallow foveae. The calculated thickness map showed the RNFL distribution. Traumatic injury to one birds retina was also successfully imaged. CONCLUSIONS Ultra-high resolution SD-OCT provides unprecedented high-quality 2-D and 3-D in vivo visualization of the retinal structures of birds of prey. SD-OCT is a powerful imaging tool for vision research in birds of prey.

Foveal Structure–Function Correlation in Children With History of Retinopathy of Prematurity

PURPOSE To correlate visual acuity to macular spectral-domain optical coherence tomography (SD OCT) anomalies detected in children with a history of retinopathy of prematurity (ROP). DESIGN Retrospective cohort study. METHODS All charts of children with a history of ROP between 2 and 18 years of age and with SD OCT performed between 2010 and 2012 were reviewed. Central foveal thickness was measured and correlated with visual acuity. Secondary outcome measures included temporal parafoveal thickness, presence of the inner nuclear layer and outer segment, gestational age at birth, sex, spherical equivalent, history of laser treatment, and developmental delay. RESULTS The study included 44 better-seeing eyes of 44 patients. Sixty-four percent (28/44) of patients in our study had 20/40 or better visual acuity despite an abnormal foveal morphology in 91% of total eyes. CONCLUSION Patients with a history of ROP demonstrate a high frequency of macular morphologic abnormalities, including retention of inner retinal layers and absent foveal depression, on SD OCT. These structural changes do not always correlate to visual acuity. Instead it appears that cone maturation may be a better indicator of visual acuity. In addition, there is a significant correlation between best-corrected visual acuity and myopia.

Diplopia after glaucoma drainage device implantation

PURPOSE To determine incidence of diplopia after glaucoma drainage device (GDD) surgery and to report treatment outcomes. METHODS Financial claims data were used to identify patients who underwent GDD surgery (CPT [Current Procedural Terminology] 66180) at the Bascom Palmer Eye Institute from January 2, 1991, through December 31, 2005. After a second claims data search, the medical records of patients diagnosed with diplopia (International Classification of Diseases, 9th Revision code 368.2) and those who underwent extraocular muscle surgery (CPT-4 code 67311-67335) after GDD implantation were reviewed retrospectively. RESULTS A total of 2,661 patients underwent GDD surgery during the study period. Charges were submitted for 59 patients for strabismus surgery or office visits relating to diplopia. Of these, 27 patients were excluded because medical records did not document diplopia or included pre-existing diplopia, cranial nerve palsy, or diplopia attributed to another ocular procedure. The remaining 32 patients developed diplopia secondary to GDD. Superotemporal quadrant GDDs were identified in 23 eyes and inferonasal quadrant placement in 9 eyes. The 1-year cumulative incidence of diplopia was 1.4%. No patient developed diplopia after 1 year. The mean follow-up after diagnosis for patients with diplopia was 48 ± 27 months (range, 1-124 months). The mean time of onset of diplopia after GDD implantation was 66 ± 62 days, with median onset of 42 days (range, 8-278 days). Treatment of diplopia included prisms in 17 cases (53.1%), no treatment in 13 (40.6%), other therapies in 2 (6.3%), and surgery after prismatic treatment failed in 3 (9.4%). CONCLUSIONS The incidence of diplopia after GDD surgery is low, and most patients are treated with prisms.

The Use of Titanium T-Plate as Platform for Globe Alignment in Severe Paralytic and Restrictive Strabismus

PURPOSE To evaluate the long-term effectiveness of improved ocular alignment using a suture/T-plate anchoring platform system. DESIGN Retrospective, noncomparative, interventional case series. METHODS setting: Institutional. study population: Seven consecutive patients with large angle deviations attributable to paralytic and/or restrictive strabismus managed jointly by orbital and strabismus surgeons. intervention procedure: The T-plate base is anchored to the orbital rim with the shaft projecting toward the orbital apex to simulate the origin of the affected muscle. A nonabsorbable suture serves as the coupling element linking the muscle insertion to the tip of the T-plate such that the suture coincides with the axis of the dysfunctional muscle and yields a pull vector to simulate the passive tensile force of the muscle. Information analyzed included patient demographics, etiology of strabismus and characteristics, prior muscle surgeries, secondary interventions, subjective appraisal of diplopia, and final ocular alignment measurements. main outcome measures: Subjective appraisal of diplopia, final ocular alignment in primary gaze, and late stability. RESULTS All 7 patients showed marked reduction in ocular deviation with a median change of 33 prism diopters (PD) and a range of 7 to 72 PD. For the 6 patients with medial rectus dysfunction, the final ocular alignment ranged from 6 to 18 PD of residual exotropia in primary gaze. The patient with sixth nerve palsy had 5 PD of residual esotropia. There were no failures after an average of 59.4 months of follow-up. CONCLUSIONS A globe tethering technique using a suture/titanium T-plate anchoring platform system effectively treats refractory cases of paralytic and restrictive strabismus with large angles of deviation.

Strabismus Surgery Reoperation Rates With Adjustable and Conventional Sutures

PURPOSE To determine the association of strabismus surgery reoperation rates with adjustable or conventional sutures. DESIGN Retrospective cross-sectional study. METHODS setting: Review of a large national private insurance database. STUDY POPULATION Adults aged 18-89 having strabismus surgery between 2007 and 2011. INTERVENTION Adjustable vs conventional suture strabismus surgery. OUTCOME MEASURE Reoperation rate in the first postoperative year. RESULTS Overall, 526 of 6178 surgical patients had a reoperation (8.5%). Reoperations were performed after 8.1% of adjustable suture surgeries and after 8.6% of conventional suture surgeries (P = .57). Of the 4357 horizontal muscle surgeries, reoperations were performed after 5.8% of adjustable suture surgeries, and after 7.8% of conventional suture surgeries (P = .02). Of the 1072 vertical muscle surgeries, reoperations were performed after 15.2% of adjustable suture surgeries and after 10.4% of conventional suture surgeries (P = .05). Younger age (18-39 years) was associated with a lower reoperation rate (P ≤ .02). The significant multivariable predictors of reoperation for horizontal surgery were adjustable sutures (odds ratio [OR] 0.69, 95% confidence interval 0.52-0.91), monocular deviation (OR 0.64), complex surgery (OR 1.63), and unilateral surgery on 2 horizontal muscles (OR 0.70, all P ≤ .01). Adjustable sutures were not significantly associated with reoperation rates after vertical muscle surgery (multivariable OR 1.45, P = .07). CONCLUSIONS Adjustable sutures were associated with significantly fewer reoperations for horizontal muscle surgery. Adjustable sutures tended to be associated with more reoperations for vertical muscle surgery, but this observation was not statistically significant in the primary analysis after controlling for age.

Successful treatment of juvenile xanthogranuloma using bevacizumab

Juvenile xanthogranuloma (JXG) is an uncommon non-Langerhans cell histiocytic disorder that occurs predominantly in infants. Traditional treatment of ocular JXG involves the administration of topical or local corticosteroids. We treated 2 children with JXG refractory to local corticosteroid therapy with off-label intraocular bevacizumab. To our knowledge, this is the first report of successful use of bevacizumab for ocular JXG.

Atypical Teratoid/Rhabdoid Tumor Arising From the Third Cranial Nerve

An otherwise healthy 6-week-old girl who presented with an isolated left third cranial nerve palsy underwent MRI that revealed an enhancing mass intrinsic to the left third cranial nerve. Rapid enlargement of the lesion over 1 month led to subtotal neurosurgical resection of an atypical teratoid/rhabdoid tumor (AT/RT), a rare, highly aggressive malignancy of infancy closely related histologically to medulloblastoma and primitive neuroectodermal tumor. Despite aggressive chemotherapy, the patient died within 6 months of presentation. This is the first report of an AT/RT presenting as an isolated third cranial nerve palsy caused by tumor arising from within the nerve.