Research Interests and Achievements

My research has centred on the clinical electrophysiology of vision and that continues to be my main focus.

Electrophysiology has a privileged role in the management of the patient with visual system disease as it provides non-invasive functional data that can objectively characterise and quantify the site and nature of dysfunction, thus facilitating accurate diagnosis and enabling management decisions to be taken with greater confidence. Much of my later research was performed at Moorfields Eye Hospital in London, where I was Director of Electrophysiology for 22 years, and UCL Institute of Ophthalmology.

Before moving to Moorfields, I worked in a Regional Clinical Neurophysiology Unit, setting up a diagnostic visual evoked potential (VEP) service, and my initial research was neurologically based, working with multiple sclerosis, intracranial tumours and other disorders, and that interest in neuro-ophthalmology continues to this day. I gradually developed an interest in the retina and extended that service to a regional level ophthalmic diagnostic service. I was working with both retinal disease patients and patients with optic nerve disease and was able to show that the pattern electroretinogram (PERG) has two main components, the earlier P50 component reflecting the function of the macula, and the later N95 component having origins in the retinal ganglion cells. The PERG could thus distinguish between the visual acuity loss due to optic nerve disease and that die to macular disease, which can be challenging clinically. A series of publications resulted examining the relationship between the cortical VEP and the PERG, demonstrating that the PERG can play a crucial role in the accurate interpretation of an abnormal VEP.

In the retina, electrophysiology can separate rod and cone system function, and localise dysfunction to outer or inner retinal structures. It can also distinguish between dysfunction confined to the macula and generalised retinal disease, and further enables the differentiation between generalised retinal dysfunction and restricted loss of function. As with any test in medicine, electrophysiological data should be considered in clinical context and a comprehensive examination and family, medical and surgical history are fundamental to the management of the patient. The findings are usually evaluated in conjunction with imaging techniques, particularly fundus autofluorescence imaging (FAF), with which I have worked since the technique was first described, and optical coherence tomography (OCT). There have been huge advances in imaging in recent years, but imaging techniques provide structural information that can be non-specific in relation to diagnosis, and accurate diagnosis and optimal management often requires both structure and function. Structure-function relationships have been important to my research.

Electrophysiology can also provide insights into underlying pathophysiology, and may direct or inform mutational screening in patients with inherited retinal disease. My research has also focussed extensively on genotype-phenotype relationships, including a number of gene discovery papers. This led to involvement with the first gene therapy trial in a human visual system disease, the RPE65 related Leber Congenital Amaurosis, and with the choroideremia gene therapy trial.

Since moving to Singapore, I have helped establish the Inherited Retinal Disease service at NUH with Prof Adrian Koh and Dr Hwei Wuen Chan and we have now commenced genotyping our Singaporean patients with the clinical and research assistance of Dr Xinyi Su and Dr Wendy Wong in conjunction with the genetics Department at NUS (Prof Poh-San Lai and Dr Grace Tan). Also with Dr Su I have worked on a novel biogel endotamponade and on a model for stem cell rescue of cone photoreceptor damage, both of which should lead to further research and anticipated clinical applications. I have also been continuing an association with Dr Markus Ritter and Profs Christian Windischberger and Ursula Schmidt-Erfurth from the University of Vienna on electrophysiology and functional magnetic resonance imaging in patients with retinal disease.

Selected Publications

• Holder GE. The effects of chiasmal compression on the pattern visual evoked potential. Electroencephalogr Clin Neurophysiol. 1978 Aug;45(2):278 80. https://doi.org/10.1016/0013-4694(78)90011-1 The first to show the importance of stimulus and recording parameters on the lateralisation of pattern VEP abnormalities in chiasmal dysfunction.
• Holder GE, Bartlett JR, Bridges PK, Kantamaneni BD, Curzon G. Correlations between transmitter metabolite concentrations in human ventricular cerebrospinal fluid and pattern visual-evoked potentials. Brain Res. 1980 Apr 28;188(2):582-6. https://doi.org/10.1016/0006-8993(80)90059-1 The only report that examines the relationships between scalp recorded evoked potentials and intraventricular neurotransmitter metabolite levels in humans.
• Holder GE. Significance of abnormal pattern electroretinography in anterior visual pathway dysfunction. Br J Ophthalmol. 1987 Mar;71(3):166-71. https://doi.org/10.1136/bjo.71.3.166 The first clinical demonstration that the N95 component of the PERG reflects the function of the retinal ganglion cells and that the PERG can be used to distinguish macular disease from optic nerve disease. The proposed component nomenclature became internationally accepted.
• Holder GE. Pattern electroretinography in patients with delayed pattern visual evoked potentials due to distal anterior visual pathway dysfunction. J Neurol Neurosurg Psychiatry. 1989 Dec;52(12):1364-8. https://doi.org/10.1136/jnnp.52.12.1364 Shows the importance of PERG in revealing macular dysfunction as a cause of delayed pattern VEPs.
• Holder GE. The incidence of abnormal pattern electroretinography in optic nerve demyelination. Electroencephalogr Clin Neurophysiol. 1991 Jan;78(1):18-26. https://doi.org/10.1016/0013-4694(91)90014-u A large population study of PERGs in MS patients.
• Corbett MC, Shilling JS, Holder GE. The assessment of clinical investigations: the Greenwich Grading System and its application to electrodiagnostic testing in ophthalmology. Eye (Lond). 1995;9 (Pt 6 Su):59-64. Presents the Greenwich Grading scale – a means of evaluating the effectiveness of diagnostic testing.
• Holder GE. The pattern electroretinogram in anterior visual pathway dysfunction and its relationship to the pattern visual evoked potential: a personal clinical review of 743 eyes. Eye (Lond). 1997;11 (Pt 6):924-34. https://doi.org/10.1038/eye.1997.231 A very large population study examining the relationships between PERG and pattern VEPs.
• Arden G, Wolf J, Berninger T, Hogg CR, Tzekov R, Holder GE. S-cone ERGs elicited by a simple technique in normals and in tritanopes. Vision Res. 1999 Feb;39(3):641-50. https://doi.org/10.1016/s0042-6989(98)00182-5 Describes how to measure s-cone ERGs.
• Lois N, Holder GE, Fitzke FW, Plant C, Bird AC. Intrafamilial variation of phenotype in Stargardt mmacular dystrophy-Fundus flavimaculatus. Invest Ophthalmol Vis Sci. 1999 Oct;40(11):2668-75. PMID: 10509664. Defines the grouping by ERG in Stargardt disease and shows 100% sibling concordance even when concordance in clinical parameters is lacking.
• Holder GE. Pattern electroretinography (PERG) and an integrated approach to visual pathway diagnosis. Prog Retin Eye Res. 2001 Jul;20(4):531-61. https://doi.org/10.1016/s1350-9462(00)00030-6 A large regularly cited review of the clinical value of PERG with much novel data.
• Lois N, Holder GE, Bunce C, Fitzke FW, Bird AC. Phenotypic subtypes of Stargardt macular dystrophy-fundus flavimaculatus. Arch Ophthalmol. 2001 Mar;119(3):359-69. https://doi.org/10.1001/archopht.119.3.359 Demonstrates the prognostic value of ERG in Stargardt disease.
• Dorey SE, Neveu MM, Burton LC, Sloper JJ, Holder GE. The clinical features of albinism and their correlation with visual evoked potentials. Br J Ophthalmol. 2003 Jun;87(6):767-72. https://doi.org/10.1136/bjo.87.6.767 A comprehensive study of the diagnostic use of VEPs in albino patients.
• Robson AG, El-Amir A, Bailey C, Egan CA, Fitzke FW, Webster AR, Bird AC, Holder GE. Pattern ERG correlates of abnormal fundus autofluorescence in patients with retinitis pigmentosa and normal visual acuity. Invest Ophthalmol Vis Sci. 2003 Aug;44(8):3544-50. https://doi.org/10.1167/iovs.02-1278 The first description of the significance of the ring of hyperautofluorescence found in many RP patients.
• Newsom RS, Johnston R, Sullivan PM, Aylward GB, Holder GE, Gregor ZJ. Sudden visual loss after removal of silicone oil. Retina. 2004 Dec;24(6):871-7. https://doi.org/10.1097/00006982-200412000-00005 The first reported series of complications following the removal of silicon oil.
• Francis PJ, Marinescu A, Fitzke FW, Bird AC, Holder GE. Acute zonal occult outer retinopathy: towards a set of diagnostic criteria. Br J Ophthalmol. 2005 Jan;89(1):70-3. https://doi.org/10.1136/bjo.2004.042416 Proposals for diagnostic criteria in AZOOR.
• Holder GE, Robson AG, Pavesio C, Graham EM. Electrophysiological characterisation and monitoring in the management of birdshot chorioretinopathy. Br J Ophthalmol. 2005 Jun;89(6):709-18. https://doi.org/10.1136/bjo.2004.047837 Describes and emphasises the way that electrophysiology influences the treatment and management of birdshot chorioretinopathy.
• Coffey PJ, Gias C, McDermott CJ, Lundh P, Pickering MC, Sethi C, Bird A, Fitzke FW, Maass A, Chen LL, Holder GE, Luthert PJ, Salt TE, Moss SE, Greenwood J. Complement factor H deficiency in aged mice causes retinal abnormalities andvisual dysfunction. Proc Natl Acad Sci U S A. 2007 Oct 16;104(42):16651-6. https://doi.org/10.1073/pnas.0705079104 Describes the consequences of CFH deficiency, important in age-related macular degeneration, in a murine model.
• Turney C, Chong NH, Alexander RA, Hogg CR, Fleming L, Flack D, Barnett KC, Bird AC, Holder GE, Luthert PJ. Pathological and electrophysiological features of a canine cone-rod dystrophy in the miniature longhaired dachshund. Invest Ophthalmol Vis Sci. 2007 Sep;48(9):4240-9. https://doi.org/10.1167/iovs.04-0737 Reports the first cone-rod dystrophy to be described in non-humans.
• Audo I, Robson AG, Holder GE, Moore AT. The negative ERG: clinical phenotypes and disease mechanisms of inner retinal dysfunction. Surv Ophthalmol. 2008 Jan-Feb;53(1):16-40. https://doi.org/10.1016/j.survophthal.2007.10.010 A comprehensive clinical survey.
• Bainbridge JW, Smith AJ, Barker SS, Robbie S, Henderson R, Balaggan K, Viswanathan A, Holder GE, Stockman A, Tyler N, Petersen-Jones S, Bhattacharya SS, Thrasher AJ, Fitzke FW, Carter BJ, Rubin GS, Moore AT, Ali RR. Effect of gene therapy on visual function in Leber's congenital amaurosis. N Engl J Med. 2008 May 22;358(21):2231-9. https://doi.org/10.1056/NEJMoa0802268 The first description of gene therapy in human LCA and human visual system disease.
• Burgess R, Millar ID, Leroy BP, Urquhart JE, Fearon IM, De Baere E, Brown PD, Robson AG, Wright GA, Kestelyn P, Holder GE, Webster AR, Manson FD, Black GC. Biallelic mutation of BEST1 causes a distinct retinopathy in humans. Am J Hum Genet. 2008 Jan;82(1):19-31. https://doi.org/10.1016/j.ajhg.2007.08.004 The first description and naming of autosomal recessive bestrophinopathy (ARB).
• Lenassi E, Robson AG, Hawlina M, Holder GE. The value of two-field pattern electroretinogram in routine clinical electrophysiologic practice. Retina. 2012 Mar;32(3):588-99. https://doi.org/10.1097/IAE.0b013e31822059ae Demonstrates the clinical diagnostic value of large field PERG.
• Fujinami K, Lois N, Davidson AE, Mackay DS, Hogg CR, Stone EM, Tsunoda K, Tsubota K, Bunce C, Robson AG, Moore AT, Webster AR, Holder GE, Michaelides M. A longitudinal study of stargardt disease: clinical and electrophysiologic assessment, progression, and genotype correlations. Am J Ophthalmol. 2013 Jun;155(6):1075-1088.e13. https://doi.org/10.1016/j.ajo.2013.01.018 10-year follow up study confirming the prognostic value of ERG in Stargardt disease.
• Vincent A, Robson AG, Neveu MM, Wright GA, Moore AT, Webster AR, Holder GE. A phenotype-genotype correlation study of X-linked retinoschisis. Ophthalmology. 2013 Jul;120(7):1454-64. https://doi.org/10.1016/j.ophtha.2012.12.008 The largest study to date.
• West SK, Hindocha M, Hogg CR, Holder GE, Moore AT, Reddy MA. Electroretinogram assessment of children with sensorineural hearing loss: implications for screening. J AAPOS. 2015 Oct;19(5):450-4. https://doi.org/10.1016/j.jaapos.2015.08.001
• Bainbridge JW, Mehat MS, Sundaram V, Robbie SJ, Barker SE, Ripamonti C, Georgiadis A, Mowat FM, Beattie SG, Gardner PJ, Feathers KL, Luong VA, Yzer S, Balaggan K, Viswanathan A, de Ravel TJ, Casteels I, Holder GE, Tyler N, Fitzke FW, Weleber RG, Nardini M, Moore AT, Thompson DA, Petersen-Jones SM, Michaelides M, van den Born LI, Stockman A, Smith AJ, Rubin G, Ali RR. Long-term effect of gene therapy on Leber's congenital amaurosis. N Engl J Med. 2015 May 14;372(20):1887-97. https://doi.org/10.1056/NEJMoa1414221 Long term follow-up in LCA gene therapy
• Edwards TL, Jolly JK, Groppe M, Barnard AR, Cottriall CL, Tolmachova T, Black GC, Webster AR, Lotery AJ, Holder GE, Xue K, Downes SM, Simunovic MP, Seabra MC, MacLaren RE. Visual Acuity after Retinal Gene Therapy for Choroideremia. N Engl J Med. 2016 May 19;374(20):1996-8. https://doi.org/10.1056/NEJMc1509501 Gene therapy for choroideremia
• da Cruz L, Fynes K, Georgiadis O, Kerby J, Luo YH, Ahmado A, Vernon A, Daniels JT, Nommiste B, Hasan SM, Gooljar SB, Carr AF, Vugler A, Ramsden CM, Bictash M, Fenster M, Steer J, Harbinson T, Wilbrey A, Tufail A, Feng G, Whitlock M, Robson AG, Holder GE, Sagoo MS, Loudon PT, Whiting P, Coffey PJ. Phase 1 clinical study of an embryonic stem cell-derived retinal pigment epithelium patch in age-related macular degeneration. Nat Biotechnol. 2018 Apr;36(4):328-337. https://doi.org/10.1038/nbt.4114 Stem cell transplantation in humans.
• Liu Z, Liow SS, Lai SL, Alli-Shaik A, Holder GE, Parikh BH, Krishnakumar S, Li Z, Tan MJ, Gunaratne J, Barathi VA, Hunziker W, Lakshminarayanan R, Tan CWT, Chee CK, Zhao P, Lingam G, Loh XJ, Su X. Retinal-detachment repair and vitreous-like-body reformation via a thermogelling polymer endotamponade. Nat Biomed Eng. 2019 Aug;3(8):598-610. https://doi.org/10.1038/s41551-019-0382-7 Describes a novel biogel endotamponade with the potential to have a significant influence on VR surgery.
• Lingam S, Liu Z, Yang B, Wong W, Parikh BH, Ong JY, Goh D, Wong DSL, Tan QSW, Tan GSW, Holder GE, Regha K, Barathi VA, Hunziker W, Lingam G, Zeng X, Su X. cGMP-grade human iPSC-derived retinal photoreceptor precursor cells rescue cone photoreceptor damage in non-human primates. Stem Cell Res Ther. 2021 Aug 19;12(1):464. https://doi.org/10.1186/s13287-021-02539-8 Stem cell rescue of cone photoreceptor damage in non-human primates.
• Kleerekooper I, Del Porto L, Dell'Arti L, Guajardo J, Leo S, Robson AG, Trip SA, Petzold A, Plant GT, Holder GE. Pattern ERGs suggest a possible retinal contribution to the visual acuity loss in acute optic neuritis. Doc Ophthalmol. 2022 Dec;145(3):185-195. https://doi.org/10.1007/s10633-022-09896-6 Pattern ERG demonstration that the visual loss in acute optic neuritis has a retinal component.

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