Surrendering control, or nothing to lose: Parents' preferences about participation in a randomised trial of childhood strabismus surgery.

BACKGROUND: Intermittent exotropia is the most common form of divergent strabismus (squint) in children. Evidence regarding its optimum management is limited. A pilot randomised controlled trial has recently been completed (Surgery versus Active Monitoring in Intermittent Exotropia trial) to determine the feasibility of a full randomised controlled trial. PURPOSE: To identify drivers for and barriers against parents' participation in Surgery versus Active Monitoring in Intermittent Exotropia and to seek their views on information received, the need for randomisation, and enhancing acceptability. METHODS: Multiple method qualitative study using semi-structured telephone interviews to explore parents' motivations and trial screening logs to provide an indication of common barriers. Exploratory thematic analysis identified key themes. RESULTS: A total of 48 interviews were conducted (14 participants; 34 non-participants). Barriers included no desire for surgery/preference to 'wait and see', wanting surgery immediately, feeling uncomfortable about 'surrendering control' over decision-making/being managed 'at random', lack of confidence in the effectiveness of surgery, believing the risks outweighed the benefits, and lack of trust. Drivers included desiring surgery, 'nothing to lose', benefits offsetting the risks, and being in a trial would result in better care. Some also mentioned 'doing their bit' for research. Suggestions for enhancing acceptability included allowing choice of treatment group, giving more time for decision-making, expanding on information given, and improving communication. Many felt the necessity of randomisation was adequately explained, but there was some indication that it was misunderstood. Information extracted from the screening logs of 80/89 eligible non-participants indicated the most prevalent barrier was not wanting surgery/preferring to observe (56%), followed by desiring surgery straightaway (15%). Opposition to randomisation/wanting to retain control was recorded in 9% of cases as was the belief that the child's squint was not severe enough to warrant surgery. LIMITATIONS: Interviews were not audio-recorded. Not all who consented to interview could be contacted, although the response/contact rate was good (48/62). A few parents did not provide reasons for refusing the trial. CONCLUSION: Opposition to surgery and concerns about surrendering control were common obstacles to participation, whereas parents keen for their child to undergo the operation but happy to defer tended to embrace a 'nothing to lose' attitude. Many non-participants would have consented if allowed to choose group, although most of these would have chosen observation. While most parents felt happy with information given and that randomisation was adequately explained, it is of concern that there may be some misunderstanding, which should be addressed in any trial. These findings will inform future trials in childhood exotropia, for example, consideration of preference arms and improving communication. Lessons learnt from the Surgery versus Active Monitoring in Intermittent Exotropia trial could prove valuable to paediatric and surgical trials generally.

Combined exome and whole-genome sequencing identifies mutations in ARMC4 as a cause of primary ciliary dyskinesia with defects in the outer dynein arm.

BACKGROUND: Primary ciliary dyskinesia (PCD) is a rare, genetically heterogeneous ciliopathy disorder affecting cilia and sperm motility. A range of ultrastructural defects of the axoneme underlie the disease, which is characterised by chronic respiratory symptoms and obstructive lung disease, infertility and body axis laterality defects. We applied a next-generation sequencing approach to identify the gene responsible for this phenotype in two consanguineous families. METHODS AND RESULTS: Data from whole-exome sequencing in a consanguineous Turkish family, and whole-genome sequencing in the obligate carrier parents of a consanguineous Pakistani family was combined to identify homozygous loss-of-function mutations in ARMC4, segregating in all five affected individuals from both families. Both families carried nonsense mutations within the highly conserved armadillo repeat region of ARMC4: c.2675C>A; pSer892* and c.1972G>T; p.Glu658*. A deficiency of ARMC4 protein was seen in patient's respiratory cilia accompanied by loss of the distal outer dynein arm motors responsible for generating ciliary beating, giving rise to cilia immotility. ARMC4 gene expression is upregulated during ciliogenesis, and we found a predicted interaction with the outer dynein arm protein DNAI2, mutations in which also cause PCD. CONCLUSIONS: We report the first use of whole-genome sequencing to identify gene mutations causing PCD. Loss-of-function mutations in ARMC4 cause PCD with situs inversus and cilia immotility, associated with a loss of the distal outer (but not inner) dynein arms. This addition of ARMC4 to the list of genes associated with ciliary outer dynein arm defects expands our understanding of the complexities of PCD genetics.

A prospective study of binocular visual function before and after successful surgery to remove a unilateral epiretinal membrane.

OBJECTIVE: To examine the effect of a unilateral epiretinal membrane (uERM) on visual acuity, stereopsis, and motor fusion in patients before and after successful surgery to remove the membrane. DESIGN: Cohort study. PARTICIPANTS: Twenty-seven consecutive patients undergoing surgery to remove an idiopathic uERM and 30 normal control subjects. METHODS: Patients underwent full orthoptic examination before and between 3 and 6 months after surgery to remove a uERM. Stereoacuities were analyzed statistically using the Wilcoxon signed-rank test, Mann-Whitney U test, and Spearman correlation. Motor fusion ranges and visual acuities were compared using paired and unpaired t tests, with correlations examined by linear regression. MAIN OUTCOME MEASURES: Snellen visual acuity, TNO (stereoscopic acuity test of the Netherlands; Netherlands Organisation for Applied Scientific Research; Laméris Ootech BV, Nieuwegein, the Netherlands) and Titmus stereoacuity, motor fusion range. RESULTS: Postoperative acuity and improvement in visual acuity after removal of a uERM were better in patients with a shorter duration of symptoms. Stereoacuity was substantially reduced in the presence of a uERM (TNO, P<0.001; Titmus, P<0.001; Mann-Whitney U test), as were total motor fusion ranges at near and distance (near P = 0.002; distance P = 0.015; t test). Stereoacuity was worse in patients with symptoms of longer duration (TNO, P = 0.21; Titmus, P = 0.045; Spearman rank correlation). After successful surgery, stereoscopic function improved. This improvement occurred mainly in those patients with better preoperative stereoacuity and a shorter duration of symptoms. CONCLUSIONS: Improvement in visual acuity after surgery was greater in patients with visual symptoms of shorter duration. A uERM adversely affected stereoscopic function, an effect that increased with time. The best monocular and binocular visual outcomes occurred in those patients who had earlier surgery.

A worldwide survey of retinopathy of prematurity screening.

BACKGROUND: To ascertain which countries in the world have retinopathy of prematurity (ROP) screening programmes and guidelines and how these were developed. METHODS: An email database was created and requests were sent to ophthalmologists in 141 nations to complete an online survey on ROP screening in their country. RESULTS: Representatives from 92/141 (65%) countries responded. 78/92 (85%) have existing ROP screening programmes, and 68/78 (88%) have defined screening criteria. Some countries have limited screening and those areas which have no screening or for which there is inadequate knowledge are mainly Southeast Asia, Africa and some former Soviet states. DISCUSSION: With the increasing survival of premature babies in lower-middle-income and low-income countries, it is important to ensure that adequate ROP screening and treatment is in place. This information will help organisations focus their resources on those areas most in need.

Differential changes of magnocellular and parvocellular visual function in early- and late-onset strabismic amblyopia.

PURPOSE: Studies in nonhuman primates show that monocular visual deprivation starting at different ages has different effects on cells in the parvocellular and magnocellular laminae of the lateral geniculate nucleus. The present study used color and luminance contrast sensitivity (CS) measurements to look for differences in parvocellular- and magnocellular-related visual function in human subjects with strabismic amblyopia. METHODS: Fifteen subjects with early- and 14 with late-onset strabismic amblyopia and similar ranges of visual acuity were studied, together with 15 subjects with normal vision. Contrast sensitivities were measured to an equiluminant (L-M cone-modulated) grating with slow onset and an achromatic (L+M cone-modulated) 0.8-cpd grating with rapid onset using an adaptive RESULTS: Luminance and color CS were lower in the amblyopic eyes than in the fellow eyes of all amblyopes. For luminance CS, this was due both to an increase in sensitivity of the fellow eye and to a reduction in sensitivity in the amblyopic eye. Color CS was greatly reduced in the amblyopic and fellow eyes of subjects with strabismic amblyopia of early- and late onset compared with subjects with normal vision. The reduction in color CS compared with luminance CS was significantly greater in eyes with late- rather than early-onset amblyopia. CONCLUSIONS: Parvocellular and magnocellular function are differentially affected in the amblyopic and fellow eyes of subjects with strabismic amblyopia. The difference is more marked in late-onset amblyopia than in early-onset amblyopia.

Electrophysiological and psychophysical differences between early- and late-onset strabismic amblyopia.

PURPOSE: To compare visual evoked potentials (VEPs) and contrast sensitivity in adults with early- or late-onset strabismic amblyopia. METHODS: Twelve adults with early- and 12 with late-onset strabismic amblyopia with similar ranges of visual acuity were studied. Pattern-onset VEPs to 30-minute checks were recorded at a range of contrast levels. Contrast sensitivity (CS) was measured at 3.2 cyc/deg using a two-alternative, forced-choice staircase method. RESULTS: There was no significant difference in VEP CII latency or amplitude between amblyopic and fellow eyes across all contrast levels for the early-onset group, but in the late-onset group, CII latencies were significantly longer and amplitudes smaller in the amblyopic eye. CII responses in both amblyopic and fellow eyes of the early-onset amblyopes were of significantly shorter latency and smaller amplitude than normal. In the late-onset group the CII responses from the amblyopic eye were of significantly increased latency and reduced amplitude compared with normal, whereas latency and amplitude of fellow eye responses did not differ significantly from normal. Late-onset amblyopes showed reduced CS across the central field for the amblyopic eye, but increased CS for the fellow eye compared with normal. In the early-onset group, central CS did not differ between amblyopic and fellow eyes or from normal. CONCLUSIONS: There are significant differences in the electrophysiological and psychophysical characteristics of adults with early- and late-onset strabismic amblyopia.

Visual evoked potentials in successfully treated strabismic amblyopes and normal subjects.

PURPOSE: To assess electrophysiological recovery in successfully treated strabismic amblyopes. METHODS: Pattern reversal visual evoked potentials were recorded from 11 successfully treated strabismic amblyopes 7 to 11 years of age and 10 age-matched normal children using 12.5' and 50' checks. RESULTS: Nine amblyopic eyes had recovered to a Snellen acuity of 6/6 or better, and the remaining 2 were 6/9 after patching. Comparison between the amblyopic and the fellow eyes showed significantly lower P100 amplitude for the amblyopic eyes with small checks (difference -16.7%; P <.02) and significantly longer latency with larger checks difference (+5.0%; P <.02). The P100 latencies to stimulation of both the amblyopic and fellow eyes by 12.5' checks were markedly longer than in normal subjects (amblyopic eye, +11.7%, P <.0001; fellow eye, +7.7% P <.002). CONCLUSIONS: Successfully treated amblyopic eyes showed significantly longer latency than did normal eyes with small check stimulation. However, the nonamblyopic fellow eyes also showed significantly longer latency than did normal eyes, suggesting altered central processing.

Quantitative changes in the field of binocular single vision following a fadenoperation to a vertical rectus muscle.

PURPOSE: To quantify the effect of a fadenoperation to a vertical rectus muscle on the field of binocular single vision (BSV). PATIENTS AND METHODS: BSV was assessed quantitatively in 32 patients before and after a fadenoperation to a single vertical rectus muscle by measuring the vertical extent of single vision in the midline and a score for the total field of BSV. Patients were aged from 14 to 72 years. All patients had diplopia in either downgaze or upgaze before surgery. In 11 patients, this was due to a fourth cranial nerve palsy, and in 8 patients it followed an orbital floor fracture. RESULTS: The 15 patients who had an inferior rectus fadenoperation alone showed a significant mean increase in downward and total vertical extent of BSV and in their field of BSV. The 9 patients who underwent a superior rectus fadenoperation alone showed a significant increase in total vertical extent of BSV and field of BSV score. Three of the 8 who underwent a fadenoperation combined with another strabismus procedure at the same time had a substantial improvement in their score, but after the other 5 showed little change. Patients with a paretic deficit showed substantially more improvement than those with an upgaze deficit after a blowout fracture. CONCLUSION: The fadenoperation to a vertical rectus muscle produced a significant functional expansion in the field of BSV in approximately two thirds of patients. The procedure was more effective in incomitant squints of paretic rather than mechanical etiology.

Age- and stereovision-dependent eye-hand coordination deficits in children with amblyopia and abnormal binocularity.

PURPOSE: To examine factors contributing to eye-hand coordination deficits in children with amblyopia and impaired stereovision. METHODS: Participants were 55 anisometropic or strabismic children aged 5.0 to 9.25 years with different degrees of amblyopia and abnormal binocularity, along with 28 age-matched visually-normal controls. Pilot data were obtained from four additional patients studied longitudinally at different treatment stages. Movements of the preferred hand were recorded using a 3D motion-capture system while subjects reached-to-precision grasp objects (two sizes, three locations) under binocular, dominant eye, and amblyopic/nonsighting eye conditions. Kinematic and "error" performance measures were quantified and compared by viewing condition and subject group using ANOVA, stepwise regression, and correlation analyses. RESULTS: Movements of the younger amblyopes (age 5-6 years; n = 30) were much slower, particularly in the final approach to the objects, and contained more spatial errors in reaching (∼×1.25-1.75) and grasping (∼×1.75-2.25) under all three views (P < 0.05) than their age-matched controls (n = 13). Amblyopia severity was the main contributor to their slower movements with absent stereovision a secondary factor and the unique determinant of their increased error-rates. Older amblyopes (age 7-9 years; n = 25) spent longer contacting the objects before lifting them (P = 0.015) compared with their matched controls (n = 15), with absence of stereovision still solely related to increases in reach and grasp errors, although these occurred less frequently than in younger patients. Pilot prospective data supported these findings by showing positive treatment-related associations between improved stereovision and reach-to-grasp performance. CONCLUSIONS: Strategies that children with amblyopia and abnormal binocularity use for reach-to-precision grasping change with age, from emphasis on visual feedback during the "in-flight" approach at ages 5 to 6 years to more reliance on tactile/kinesthetic feedback from object contact at ages 7 to 9 years. However, recovery of binocularity confers increasing benefits for eye-hand coordination speed and accuracy with age, and is a better predictor of these fundamental performance measures than the degree of visual acuity loss.

Visual acuity, crowding, and stereo-vision are linked in children with and without amblyopia.

PURPOSE: During development, the presence of strabismus and anisometropia frequently leads to amblyopia, a visual disorder characterized by interocular acuity differences. Although additional deficits in contrast sensitivity, crowding (the impaired recognition of closely spaced objects), and stereoacuity are common, the relationship between these abilities is unclear. METHODS: We measured the covariation between these four abilities in children 4 to 9 years of age (n = 72) with strabismus, anisometropia, or mixed strabismus/anisometropia, and unaffected controls. Children reported the orientation of a target (a modified "Pac-Man," similar to Landolt-C stimuli) using four "ghosts" as references. Using a modified staircase procedure we measured threshold size (acuity), contrast detection, foveal crowding (the minimum separation between target and ghost-flankers supporting accurate identification), and stereoacuity (with random-dot stereogram ghosts). RESULTS: Group averages revealed significant interocular differences (IODs) in acuity for all three clinical groups (0.2-0.3 log minutes), and significant crowding IODs for the strabismic and mixed groups (0.6 and 0.4°, respectively). Nonetheless, crowding IODs were correlated with acuity IODs in all four groups (r values between 0.43 and 0.59 and P < 0.05; P = 0.07 in the mixed group). Similarly, the occurrence of stereo-blindness (most common in strabismic and mixed groups) was associated with a significant increase in IODs for both acuity and crowding (each P < 0.05). No correlations were found with contrast detection. CONCLUSIONS: Our results demonstrate an association between IODs in acuity and crowding and, furthermore, between these IODs and the presence of stereo-vision. We suggest that the deficits derived from strabismus and anisometropia lay along a continuum with abilities observed during normal development.

Surgical intervention in childhood intermittent exotropia: current practice and clinical outcomes from an observational cohort study.

PURPOSE: To describe surgical outcomes in intermittent exotropia (X(T)), and to relate these to preoperative and surgical characteristics. METHODS: 87 children (aged <11 years) underwent surgery in 18 UK centres; review data (mean 21 months post-surgery) were available for 72. The primary outcome measure was motor/sensory outcome (angle and stereoacuity). The secondary outcome measure was satisfactory control assessed by Newcastle Control Score (NCS). RESULTS: 35% of patients had excellent, 28% had fair and 37% had poor primary outcome. Preoperative and surgical characteristics did not influence primary outcome. Satisfactory control was achieved in 65% of patients, while X(T) remained/recurred in 20%. Persistent over-correction occurred in 15% of children. There was no relationship between over-correction and preoperative characteristics or surgical dose/type. Median angle improved by 12 prism dioptres (PD) at near and 19 PD at distance (p<0.001). Median NCS improved by 5 (p<0.001). 40% of those initially over-corrected remained so by last postoperative assessment; no relationship was found between an initial over-correction and good outcome. CONCLUSIONS: Whilst excellent motor/sensory outcome was achieved in one-third and satisfactory control in two-thirds of patients, the 37% poor outcome and 15% persistent over-correction rate is of concern. Surgical dose was similar in those under- and over-corrected, suggesting that over-corrections cannot be avoided merely by getting the dosage right: a randomised controlled trial (RCT) would shed light on this issue. Initial over-correction did not improve the chance of a good outcome, supporting the growing literature on this topic and further highlighting the need for randomised controlled trials of X(T) surgery.

Eye-hand coordination skills in children with and without amblyopia.

PURPOSE: To investigate whether binocular information provides benefits for programming and guidance of reach-to-grasp movements in normal children and whether these eye-hand coordination skills are impaired in children with amblyopia and abnormal binocularity. METHODS: Reach-to-grasp performance of the preferred hand in binocular versus monocular (dominant or nondominant eye occluded) conditions to different objects (two sizes, three locations, and two to three repetitions) was quantified by using a 3D motion-capture system. The participants were 36 children (age, 5-11 years) and 11 adults who were normally sighted and 21 children (age, 4-8 years) who had strabismus and/or anisometropia. Movement kinematics and error rates were compared for each viewing condition within and between subject groups. RESULTS: The youngest control subjects used a mainly programmed (ballistic) strategy and collided with the objects more often when viewing with only one eye, while older children progressively incorporated visual feedback to guide their reach and, eventually, their grasp, resulting in binocular advantages for both movement components resembling those of adult performance. Amblyopic children were the worst performers under all viewing conditions, even when using the dominant eye. They spent almost twice as long in the final approach to the objects and made many (1.5-3 times) more errors in reach direction and grip positioning than their normal counterparts, these impairments being most marked in those with the poorest binocularity, regardless of the severity or cause of their amblyopia. CONCLUSIONS: The importance of binocular vision for eye-hand coordination normally increases with age and use of online movement guidance. Restoring binocularity in children with amblyopia may improve their poor hand action control.

Improvement in the field of binocular single vision following bilateral phacoemulsification with toric intraocular lens implantation in a patient with a partial third nerve palsy.

A 44-year-old female teacher with partial third (oculomotor) nerve palsy had a small central field of binocular single vision (BSV) following three strabismus procedures. Over several years her field of BSV constricted further, coincident with the development of myopia in one eye secondary to early lens change and in the presence of significant astigmatism. Following bilateral lens extraction with toric intraocular lens implants, her field of BSV reexpanded.

Differential changes in color and motion-onset visual evoked potentials from both eyes in early- and late-onset strabismic amblyopia.

PURPOSE: To examine changes in color- and motion-related visual function in patients with strabismic amblyopia. METHODS: Motion-onset and color visual-evoked potentials (VEPs) were recorded in 16 adult patients with strabismic amblyopia which had an early onset, before 18 months of age, and 14 patients with amblyopia of later onset. The results are compared with those from 21 normal adults. RESULTS: The peak times of motion-onset VEPs in the amblyopic eye were longer those than in the fellow eye in patients with both early- and late-onset strabismic amblyopia, but peak times in both amblyopic and fellow eyes were shorter than those in normal eyes. In patients with late- but not early-onset amblyopia, the peak times for color VEPs were significantly longer in amblyopic than in fellow and normal eyes. CONCLUSIONS: The patterns of abnormality for motion-onset and color VEPs in patients with strabismic amblyopia are different, probably indicating differential changes in function in magno- and parvocellular pathways. These abnormalities affect both the amblyopic and fellow eyes and are different in patients with an onset of amblyopia before or after 18 months of age.

Early midline interactions are important in mouse optic chiasm formation but are not critical in man: a significant distinction between man and mouse.

The optic chiasm is one of the most popular models for studying axon guidance. Here axons make a key binary decision either to cross the midline to innervate the contralateral hemisphere or to remain uncrossed. In rodents, midline interactions between axons from the two eyes are critical for normal development, as early removal of one eye systematically disrupts hemispheric projections from the remaining eye, increasing the crossed projection at the expense of the uncrossed. This is similar to the abnormal decussation pattern seen in albinos. This pattern is markedly different in marsupials where early eye removal has no impact on projections from the remaining eye. These differences are related to the location of the uncrossed projection through the chiasm. In rodents these axons approach the midline whereas in marsupials they remain segregated laterally. We provide anatomical evidence in man suggesting that, unlike in rodents, uncrossed axons are confined laterally and do not mix in each hemi-chiasm, which is a pattern similar to that found in marsupials. Further, we demonstrate electrophysiologically, using visual cortical evoked potentials, that the failure of one eye to develop in man has no impact on the hemispheric projections from the remaining eye. These data demonstrate that the mechanisms regulating chiasmal development in man differ from those in rodents but may be similar to those in marsupials. We suggest that mouse models of the organization and development of the optic chiasm are not common to placental mammals in general.

Optic chiasm formation in humans is independent of foveal development.

A failure of human foveal development only occurs in two genetically determined conditions; aniridia (Pax6 mutation) and albinism (tyrosinase mutation). The chiasmatic pathways from this region are disrupted in albinism and central retinal blood vessel patterns are abnormal. It is assumed that these three abnormalities have a common mechanism. Here we investigate whether similar abnormalities are present in subjects with aniridia. Using fundus photographs it is shown that abnormal blood vessel patterns are present in aniridia, but these significantly differ from those in albinos. Using electrophysiological techniques, abnormal hemispheric projections through the chiasm are demonstrated in albinos, but aniridics do not differ from normal subjects. These results demonstrate that although mutations in Pax6 and tyrosinase both affect central retinal development, they have a fundamentally different impact on the formation of the retinal vasculature and the projections from this region. This strongly suggests that separate mechanisms regulate the development of the central retina and decussation patterns at the optic chiasm.

Age-related changes in the dynamics of human albino visual pathways.

A deficiency of melanin in the retinal pigment epithelium, which regulates the development of neural retina, leads to chiasmal misrouting such that the uncrossed pathway (to the ipsilateral hemisphere) is reduced relative to the crossed pathway (to the contralateral hemisphere). This study examines age-related changes in the flash and pattern appearance visual evoked potentials (VEP) of human albinos. Scalp recorded cortical VEPs to flash (FVEP) and pattern appearance stimulation were recorded in 58 albino (8 months to 60 years) and 34 normal subjects (4-55 years). VEPs were analysed by amplitude and latency. The contralateral hemisphere FVEP amplitude decreased with age in albino subjects, as in both hemispheres in normals. However, the ipsilateral hemisphere FVEP amplitude was significantly lower in young albino subjects, initially giving a marked interhemispheric asymmetry, but this normalized with age. Significant interhemispheric FVEP latency asymmetries were not observed. The contralateral pattern appearance VEP latency in albino subjects decreased with age, as in both hemispheres in normals; the ipsilateral latency increased significantly with age. Significant interhemispheric pattern appearance VEP amplitude asymmetries were not observed. These novel and unexpected observations indicate significant age-related changes in the retinocortical pathways of the human albino. These changes have implications for our understanding of development and plasticity of the central visual pathways.