First in man study of intravitreal tripeptidyl peptidase 1 for CLN2 retinopathy.

BACKGROUND/OBJECTIVES: CLN2 Batten Disease is a fatal neurodegenerative condition of childhood associated with retinal dystrophy and blindness. Intracerebroventricular infusion of rhTPP1 greatly slows the rate of neurodegenerative decline but not retinopathy. Intravitreal rhTPP1 is known to slow retinal degeneration in a canine model of CLN2. We report a first-in-man controlled clinical trial of intravitreal rhTPP1 for CLN2 associated retinal dystrophy. SUBJECTS/METHODS: 8 children aged 5-9 with CLN2 Batten Disease were prospectively enroled. Severely affected patients were preferentially selected, provided that vision was better than no perception of light. Children underwent 8 weekly intravitreal injections of rhTPP1 (0.2 mg in 0.05 ml) into the right eye for 12-18 months. The left eye was untreated and acts as a paired control. The primary outcome was safety based on the clinical detection of complications. A secondary outcome was paracentral macular volume (PMV) measured by spectral domain OCT. Linear regression/paired t tests were used to compare rates of decline. RESULTS: No severe adverse reactions (uveitis, raised IOP, media opacity) occurred. The mean baseline PMV was 1.28 mm3(right), 1.27 mm3(left). 3 of the youngest patients exhibited bilateral progressive retinal thinning (p < 0.05), whereas retinal volume was stable in the remaining 5 patients. In the 3 patients undergoing retinal degeneration, the rate of PMV loss was slower in the treated vs. untreated eye (p = 0.000042, p = 0.0011, p = 0.00022). CONCLUSIONS: Intravitreal rhTPP1 appears to be a safe and effective treatment for CLN2 related retinopathy however commencement of treatment early in the course of disease is more likely to be efficacious.

Photopic negative response (PhNR) in the diagnosis and monitoring of raised intracranial pressure in children: a prospective cross-sectional and longitudinal protocol.

INTRODUCTION: Raised intracranial pressure (rICP) can be a consequence of a variety of neurological disorders. A significant complication of rICP is visual impairment, due to retinal ganglion cell (RGC) dysfunction. In children, subjective measurements to monitor this, such as visual field examination, are challenging. Therefore, objective measurements offer promising alternatives for monitoring these effects. The photopic negative response (PhNR) is a component of the flash electroretinogram produced by RGCs; the cells directly affected in rICP-related vision loss. This project aims to assess the clinical feasibility and diagnostic efficacy of the PhNR in detecting and monitoring paediatric rICP. METHODS AND ANALYSIS: Section 1 is a cross-sectional study; group 1 young persons with disorders associated with rICP and a comparator group 2 of age-matched children without rICP. Both groups will undergo a PhNR recording alongside a series of structural and functional ophthalmic investigations, with the rICP group also having measurement of intracranial pressure.Section 2 is a longitudinal study of the relationship between the PhNR and directly recorded intracranial pressure measurements, through repeated measures. PhNR amplitudes and peak times will be assessed against optical coherence tomography parameters, mean deviation of visual fields, other electrophysiology and ICP measurement through regression analyses.Group differences between PhNR measurements in the rICP and control groups will be performed to determine clinically relevant cut-off values and calculation of diagnostic accuracy. Longitudinal analysis will assess PhNR amplitude against ICP measurements through regression analysis. Feasibility and efficacy will be measured through acceptability, practicality and sensitivity outcomes. ETHICS AND DISSEMINATION: Favourable opinion from a research ethics committee has been received and the study approved by Manchester Metropolitan University, the Health Research Authority and the Great Ormond Street Institute of Child Health (GOS-ICH) Research and Development office. This project is being undertaken as a doctoral award (ORM) with findings written for academic thesis submission, peer-reviewed journal and conference publications.

Reduction of severe visual loss and complications following intra-arterial chemotherapy (IAC) for refractory retinoblastoma.

BACKGROUND: Intra-arterial chemotherapy (IAC) for retinoblastoma has been documented as causing visual loss and ocular motility problems. A lack of safety data has precluded its acceptance in all centres. METHODS: Retrospective cohort study of patients with retinoblastoma from 2013 to 2015 who had a healthy foveola and relapsed following systemic chemotherapy. All required IAC. The correlation of complications with doses of melphalan +/- topotecan used and putative catheterisation complications was assessed. Ocular complications were determined using vision, macular (including pattern visual evoked potentials (PVEPs)), retinal electroretinograms (ERGs) and ocular motility functions. Efficacy (tumour control) was also assessed. RESULTS: All eyes had age appropriate doses of melphalan with five having additional doses of topotecan. Severe physiological reactions requiring adrenaline were seen in six patients during the catheterisation procedure. Difficulty was documented in accessing the ophthalmic artery in 7/27 catheterisations. The median/mean number of courses of chemotherapy was three. No child had severe visual loss as assessed by age appropriate tests (median follow-up 20.9 months, range 3.7-35.2 months). One child had nasal choroidal ischaemia and a sixth nerve palsy. Post-IAC PVEPs were performed in eight and reported as normal. All post-IAC ERGs were normal apart from one (total dose 20 mg melphalan 0.8 mg topotecan). Tumour control was achieved in six of nine cases. CONCLUSION: The proportion of visual and ocular motility complications may be reduced by providing age-adjusted doses of melphalan. Dose rather than complications from catheterisation is the most important risk factor for ocular injury.