Author: Deirdre Harford (Ireland)
Co-authors: Conor Delaney, Jeffrey O'Callaghan, Natalie Hudson, Sarah Doyle, Mark Cahill, Matthew Campbell
Adult onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) is caused by a dominant acting mutation in the CSF1R gene. CSF1R mutations may drive a disruption in brain endothelial cell and microglial/macrophage crosstalk and has been characterized by blood-brain barrier (BBB) disruption in animal models and human subjects. Like the BBB the inner blood retinal barrier (iBRB) has been shown to be dynamic and tightly regulated. Interestingly, CSF-1R signalling has been associated with diseases of the retina, including Age Related Macular Degeneration (AMD). The sub-retinal location of reticular pseudo-drusen (RPD) suggests inner retinal pathology and there is increasing evidence that the inner retina may have a role in the pathogenesis of AMD. We conducted a thorough analysis of retinal and retinal vascular integrity in a patient with a known mutation in the CSF-1R gene.
All studies were carried out in the Royal Victoria Eye and Ear Hospital, Dublin 2.
ETDRS visual acuity was obtained at four metres and was performed by a clinical nurse specialist. Static automated perimetry was performed using the Humphrey Field Analyzer and a central 30-2 threshold test was carried out. NIDEK LM-970 Auto Lensmeter was used to estimate the patient’s glasses prescription. Autorefraction was performed using the NIDEK ARK-530A Keratometer. Intraocular pressure was measured through Goldman applanation tonometry using Minims Proxymetacaine Hydrochloride 0.5% and Minims Fluorescein Sodium 2% eye drops. Fundus fluorescein Angiography (FFA), Optical Coherence Tomography (OCT) and fundal autofluorescence were performed using the Heidelberg SPECTRALIS. Pupils were dilated using 1 % tropicamide and 2.5 % phenylephrine. Intravenous administration of a standard dose of 2 ml of sodium fluorescein (1 mg/mL) was administered and images obtained at 1 minute, 2 minutes, 4 minutes and 5 minutes post injection. FFA and OCT images were obtained with a 30 degree angle of view and 73 line cuts were acquired. Heidleberg Eye Explorer (HEYEX) was used to capture images. FFA analysis was quantified against a threshold determined from the fluorescein signal of n = 33 normal healthy controls (aged 18 -30).
We report the appearance of localised inner retinal vascular leakage and the appearance of reticular pseudo-drusen in the macula of both eyes in a patient with a mutation in the kinase region of CSF-1R. Fundus autofluorescence imaging demonstrated drusenoid deposits in the superior temporal macula of the left eye and in both the superior and inferior macula of the right eye. FFA images showed a significantly increased fluorescein signal in the peri- and para-foveal regions of the macula. Evidence of stage 3 RPD was observed bilaterally in this patient. Areas of stage 3 RPD exhibited a “haloing” effect on FFA, with conical shaped sub-retinal drusen. Areas of hyper-fluorescence on FFA appeared to associate with stage 2 RPD accumulation.
This report suggests a potential association between localised inner retinal vascular leakage and the appearance of reticular pseudo-drusen in a patient with decreased CSF-1R signalling capacity. We now suggest that the early stages of reticular pseudo-drusen accumulation may be associated with disrupted iBRB integrity and a decrease in CSF-1R signalling. These findings suggest a potential role for the inner retina in RPD development. In effect, stabilising the integrity of the iBRB and enhancing the CSF-1R signalling axis may be beneficial in preventing RPD accumulation and AMD development.
Additional Co-authors: 7. Deirdre Harford - Royal Victoria Eye and Ear Hospital, Adelaide Road, Dublin 2, Ireland & Smurfit Institute of Genetics, Trinity College Dublin, Dublin 2, Ireland. 8. Ruairi Connolly - Department of Neurology, Health Care Centre, Hospital 5, St James's Hospital, Dublin 8, Ireland. & Academic Unit of Neurology, Room 5.41, Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland. 9. Michael Farrell - Department of Neuropathology, Beaumont Hospital, Dublin 9, Ireland. 10. Colin P Doherty - Department of Neurology, Health Care Centre, Hospital 5, St James's Hospital, Dublin 8, Ireland. & Academic Unit of Neurology, Room 5.41, Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland. & FutureNeuro, Science Foundation Ireland Research Centre for Chronic and Rare Neurological Diseases, Royal College of Surgeons in Ireland, University of Medicine and Health Sciences, Dublin, Ireland.