Maria Theodorou

Ocular and neurodevelopmental features of Duchenne muscular dystrophy: a signature of dystrophin function in the central nervous system

Multiple isoforms of dystrophin (Dp427, Dp260, Dp140, Dp71) are expressed differentially in the central nervous system (CNS) including the retinal layers. Disruption of these protein products is responsible for cognitive dysfunction, electroretinogram (ERG) abnormalities and behavioural disorders in Duchenne muscular dystrophy (DMD). We studied the ocular characteristics and neuropsychiatric profile of 16 DMD boys. The ISCEV standard, full-field flash ERGs were assessed. Intellectual ability and behavioural disturbances were measured. All genotypes were associated with mildly abnormal photopic ERG a:b-wave amplitude ratios. In addition, we identified the following genotype/phenotype correlations: boys with mutations upstream of exon 30 (ie, isolated Dp427 altered expression) showed normal scotopic a:b ratios, abnormal photopic oscillatory potential OP2 and normal scotopic OP2. Conversely, all boys with DMD mutations downstream of exon 30 showed profoundly ‘negative’ scotopic ERGs (a:b ratios >1). In these patients, the involvement of Dp260 isoform resulted in the absence of slow rod pathway signalling in15 Hz scotopic flicker ERGs. These boys had abnormal scotopic OP2 and normal photopic OP2. Finally, children with mutations also affecting Dp71 were associated with more pronounced electronegative ERGs. When correlating ERGs to neurodevelopmental outcome, we found a positive correlation between negative scotopic ERGs and neurodevelopmental disturbances, and the most severe findings were in boys with Dp71 disruption. These findings suggest a strong association between DMD mutations affecting different DMD isoforms with characteristically abnormal scotopic ERGs and severe neurodevelopmental problems. The role of the ERG as a potential biomarker for dystrophin function in the CNS and response to novel genetic therapies warrants further exploration.

The development of infantile nystagmus.

Purpose To obtain quantitative measurements of the development of infantile nystagmus in children. This task is challenging because the eye movement recording requires some cooperation. Method The oscillations in short duration eye movement recordings were identified by the method of close returns and the characteristics of the saccadic main sequence were used to calibrate the oscillations. These techniques were applied to 11 subjects, aged 0–4 years, who were all tested on more than one occasion. Results The range of waveforms could be described by a sum of asymmetric pendular and pseudocycloid components. The amplitude of the nystagmus decreased from 0 to 1.5 years and then increased again. The foveation associated with the nystagmus increased up to 1.5 years and then remained approximately constant. The average visual acuity of the subjects increased steadily from 0 to 4 years. Conclusions These findings imply that developmental waveform changes are associated with improved visual acuity but only until 1.5–2 years of age.

Botulinum toxin chemodenervation for childhood strabismus in England: National and local patterns of practice

Background Botulinum toxin injection chemodenervation is a well-established intervention for adult strabismus, and has also been recognised as an effective alternative to routine incisional surgery for paediatric disease. We aimed to investigate the temporal patterns of practice, indications and outcomes of chemodenervation for paediatric strabismus at national and tertiary centre level. Methods Retrospective study using routinely collected patient data: Hospital Episode Statistics (HES) data were used to identify children undergoing non-incisional strabismus procedures in England from 2007 to 2016. Single–centre retrospective data on children undergoing botulinum toxin injections (Dysport® 2.5 units/ 0.1ml) as an isolated intervention (not involving incisional procedures) was undertaken to identify indications and outcomes. Successful outcome was defined as deviation <11 prism dioptres (PD). Results Between 2007 and 2016, there was no increase in the proportion of childhood strabismus involving non-incisional procedures. Amongst 150 children undergoing chemodenervation for strabismus within the tertiary centre, the most common diagnoses were acute onset esotropia (n = 34), infantile esotropia (n = 16) and consecutive exotropia (n = 15). Median age at injection was 8.5 years (range 0.9–15 years), and median follow up 12 months (6 months—11 years). Success rates differed by diagnosis, from 66% (non or partially accommodative esotropia) to 0% (congenital cranial disorders). Adverse events were seen in 62/150, 41%, most commonly transient ptosis (39%, n = 58). Overcorrection was seen in 14/119, 13%. Mild subconjunctival haemorrhage (n = 2) was the only other adverse event. Conclusions Botulinum toxin for childhood strabismus has an acceptable safety profile, and considerable potential therapeutic benefit. However, nationally there has been no increased uptake of chemodenervation non-incisional procedures. Further prospective studies are necessary to understand the predictors of outcome within the separate clinical subgroups, to guide clinical decision making.

Childhood Lensectomy Is Associated with Static and Dynamic Reduction in Schlemm Canal Size: A Biomechanical Hypothesis of Glaucoma after Lensectomy

PURPOSE To compare Schlemm canal (SC) and trabecular meshwork (TM) in children with healthy eyes and those with and without glaucoma after lensectomy. DESIGN Cross-sectional observational study. PARTICIPANTS Fifty children 4 to 16 years of age with healthy eyes and 48 children who underwent lensectomy (124 healthy and 72 postlensectomy eyes). METHODS Anterior segment (AS) OCT (Tomey SS-1000 CASIA; Tomey, Nagoya, Japan) of the nasal iridocorneal angle at 2 levels of accommodative effort (2.5 diopters [D] and 15 D). For each parameter and state of accommodation, a random effects model was fitted to estimate differences between healthy eyes and eyes with history of lensectomy. MAIN OUTCOME MEASURES Dimensions of SC and TM and conventional AS OCT iridocorneal angle measurements. RESULTS The horizontal diameter of SC and its cross-sectional area (CSA) are significantly smaller in eyes that have undergone lensectomy versus healthy eyes. Accommodative effort increases SC size in healthy eyes, but not in eyes that have undergone lensectomy. CONCLUSIONS Lensectomy is associated with a reduction in SC size and a loss of physiologic SC dilatation during accommodative effort, which may reflect a reduction in outflow facility and may contribute to the development of glaucoma after lensectomy.

Eye injuries in children – incidence and outcomes: An observational study at a dedicated children’s eye casualty

Purpose: Trauma is an important cause of visual loss in children and may affect their quality of life. Prevention and legislation can reduce the incidence of trauma, and appropriate and timely treatment can improve prognosis. We aimed to describe incidence of eye injuries in children and the adherence to national and local management guidelines. Methods: Retrospective service evaluation at a tertiary hospital (Moorfields Eye Hospital, London, UK) which operates a dedicated children’s eye casualty. The electronic patient administration system and electronic patient record system (Openeyes) were used to identify children who presented with eye injuries between January 2015 and December 2015. Results: Of 2397 first-time attendances to our children’s casualty, 508 were for injuries (estimated incidence 21.1%, 95% confidence interval: 19.5%–22.7%). Mean age at presentation was 7.51 (standard deviation: 7.97) years; boys were more commonly affected than girls (69%). The most common injury was corneal abrasion, followed by blunt and chemical injury; severe injuries such as penetrating trauma were rare. Injuries were sustained mostly during play or sports. Two children sustained permanent loss of vision in the affected eye. Conclusion: Our findings are comparable to other published reports. Adherence to management guidelines is high, but documentation of advice given to families can be improved. Regular training of staff and collaboration with organisations outside the hospital can increase awareness of eye injuries in children.

Magnetic Oculomotor Prosthetics for Acquired Nystagmus

Purpose Acquired nystagmus, a highly symptomatic consequence of damage to the substrates of oculomotor control, often is resistant to pharmacotherapy. Although heterogeneous in its neural cause, its expression is unified at the effector—the eye muscles themselves—where physical damping of the oscillation offers an alternative approach. Because direct surgical fixation would immobilize the globe, action at a distance is required to damp the oscillation at the point of fixation, allowing unhindered gaze shifts at other times. Implementing this idea magnetically, herein we describe the successful implantation of a novel magnetic oculomotor prosthesis in a patient. Design Case report of a pilot, experimental intervention. Participant A 49-year-old man with longstanding, medication-resistant, upbeat nystagmus resulting from a paraneoplastic syndrome caused by stage 2A, grade I, nodular sclerosing Hodgkins lymphoma. Methods We designed a 2-part, titanium-encased, rare-earth magnet oculomotor prosthesis, powered to damp nystagmus without interfering with the larger forces involved in saccades. Its damping effects were confirmed when applied externally. We proceeded to implant the device in the patient, comparing visual functions and high-resolution oculography before and after implantation and monitoring the patient for more than 4 years after surgery. Main Outcome Measures We recorded Snellen visual acuity before and after intervention, as well as the amplitude, drift velocity, frequency, and intensity of the nystagmus in each eye. Results The patient reported a clinically significant improvement of 1 line of Snellen acuity (from 6/9 bilaterally to 6/6 on the left and 6/5–2 on the right), reflecting an objectively measured reduction in the amplitude, drift velocity, frequency, and intensity of the nystagmus. These improvements were maintained throughout a follow-up of 4 years and enabled him to return to paid employment. Conclusions This work opens a new field of implantable therapeutic devices—oculomotor prosthetics—designed to modify eye movements dynamically by physical means in cases where a purely neural approach is ineffective. Applied to acquired nystagmus refractory to all other interventions, it is shown successfully to damp pathologic eye oscillations while allowing normal saccadic shifts of gaze.