© 2023 Delhi Journal of Ophthalmology | Published by Wolters Kluwer - Medknow 45 Abstract Case Report Introduction Development of the human eye involves complex interplay between the neuroepithelium, surface ectoderm, and the extraocular mesenchyme. It starts in the 4th week of gestation and is complete by 7th week of embryonic development.[1] This process is tightly regulated by a network of genes and any disruption owing to environmental or genetic defects can disturb this morphogenesis, leading to structural anomalies. Microphthalmia is characterized by unilateral or bilateral abnormally small eyeballs. It may or may not result in serious vision loss and is frequently associated with coloboma. Colobomas may involve the iris, retina, choroid, or optic nerves and may affect vision.[1] Microphthalmia may co-occur with microcornea, cataract, and narrowed palpebral fissure. Anophthalmia or complete absence of eyeball represents the severe end of this clinical spectrum. Microphthalmia can occur as part of a syndrome or may be an isolated pathology involving the eyes only, i.e., nonsyndromic microphthalmia. It is a genetically heterogeneous condition with pathogenic variations detected in more than 90 genes.[2] Such anophthalmia/microphthalmia (A/M) can be detected by prenatal high-resolution ultrasonography during the 2nd–3rd trimester. However, at birth, A/M requires detail ophthalmic examination and also complete examination of the baby to rule out other systemic associations. Apart from genetic tests like whole exome sequencing (WES) to determine the exact molecular etiology, an ophthalmic ultrasound is must to determine axial length of eyeballs and comment on internal structures to delineate the complete disease spectrum. Here, we describe the phenotype of two siblings with microphthalmia who were found to harbor a novel disease causing variant in SIX homeobox 6 (SIX6) gene. Case Reports Patients and methods Two brothers with microphthalmia born to consanguineous healthy parents from North India (4th degree consanguinity) Microphthalmia is an ocular anomaly with wide genetic heterogeneity. Many monogenic causes have been identified recently by next‑generation sequencing. Here, we describe the genotype and phenotype of two siblings with complex microphthalmia. The siblings had bilateral cataracts, and a persistent hyperplastic primary vitreous was additionally noted in the younger sibling. Exome sequencing performed in the elder sibling detected a novel missense variant (c.549C>G [p.Asp183Glu]) in SIX homeobox 6 (SIX6) gene in homozygous state. On targeted Sanger sequencing, this variant was also present in homozygous state in the similarly affected younger sibling. In silico structural modeling showed that the c.549C>G variant which lies in the homeobox domain might alter the SIX6 protein structure. Both the affected siblings also had dental anomalies. This feature has not been reported in the three published reports describing biallelic SIX6-related ocular phenotype. SIX6 disease-causing variants are a very rare cause of microphthalmia/anophthalmia. Keywords: Dental anomaly, microphthalmia, nonsyndromic, novel, sine oculis homeobox six Address for correspondence: Dr. Mayank Nilay, Department of Medical Genetics, Post Graduate Institute of Child Health, Sector 30, Noida ‑ 201 303, Uttar Pradesh, India. E‑mail: [email protected] This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution‑NonCommercial‑ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non‑commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms. For reprints contact: [email protected] How to cite this article: Nilay M, Moirangthem A. Complex microphthalmia due to a homozygous novel variant in SIX homeobox 6 gene. Delhi J Ophthalmol 2023;33:45‑9. Complex Microphthalmia due to a Homozygous Novel Variant in SIX Homeobox 6 Gene Mayank Nilay1,2, Amita Moirangthem1 1 Department of Medical Genetics, Sanjay Gandhi Post Graduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India, 2 Department of Medical Genetics, Post Graduate Institute of Child Health, Noida, Uttar Pradesh, India Access this article online Quick Response Code: Website: https://journals.lww.com/djo DOI: 10.4103/DLJO.DLJO_17_23 Submitted: 10-Mar-2023 Revised: 15-Apr-2023 Accepted: 29‑Apr‑2023 Published: 05-Jul-2023
46 Delhi Journal of Ophthalmology ¦ Volume 33 ¦ Issue 1 ¦ January-March 2023 Nilay and Moirangthem: Complex microphthalmia involving SIX6 gene [Figure 1a] were recruited for diagnostic evaluation and associated genetic counseling. Written informed consent was taken from the parents for participation in the study. This study was approved by the institutional ethics committee. The genomic DNA was isolated from their blood leucocytes using standard procedures of QIAamp DNA blood Mini Kit (Qiagen, Hilden, Germany). Exome sequencing was performed following enrichment and capture using TruSeq exome library preparation kit (Illumina, CA, USA). The library was sequenced to mean ~100X coverage on Illumina Novaseq 6000 sequencing platform following the manufacturer’s instructions. The raw sequences obtained were aligned to human reference genome GRCh37/hg19 and variants were called using DRAGEN™ software (Illumina, CA, USA). An in‑house bioinformatics pipeline based on ANNOVAR (https://annovar.openbioinformatics.org/en/latest/) was utilized for annotation. Variant prioritization was based on allele frequencies in population databases, variant location and effect, in silico prediction tools, and phenotype. Standard polymerase chain reaction and Sanger sequencing was performed to confirm the presence of the candidate variant and also for segregation analysis [Figure 1b]. Sequencing results were aligned with the reference sequence of the SIX6 gene (NM_007374.3) and were analyzed using FinchTV software 1.4.0 (Geospiza, Inc.; Seattle, WA, USA; http:// www.geospiza.com). In silico prediction of this novel variant on protein structure was done using HOPE tool.[3] Project HOPE (Have [y] Our Protein Explained) is a web tool that builds structure of protein of interest based on homologous structures and predicts effect of the novel sequence variation on protein conformation and interactions with other proteins. Patient 1 An 8‑year‑old boy presented with congenital bilateral microphthalmia. He was born full term by lower segment caesarean section (LSCS) due to prolonged labor with a birth weight of ~4250 g (>90th percentile). Neonatal period was otherwise uneventful. At the time of examination, his weight was 17 kg (−3.18 Z-score), height: 112 cm (−2.77 Z-score), and occipitofrontal circumference (OFC): 50 cm (−1.0 Z-score). Ophthalmological examination showed bilateral microphthalmia, microcornea, cataract, and narrow palpebral fissures [Figure 2a and d]. He did not have any light perception. Ultrasonography could not be done as he was not cooperative. Dental crowding, caries teeth, and diastema were noted [Figure 2f]. The developmental milestones were achieved as per age with normal intellect and no other chronic health issue. Patient 2 This 6-year-old boy was the younger sibling of proband with similar complaints. He was also born full term by LSCS with a birth weight of ~4000 g (>90th percentile). Neonatal period was otherwise uneventful. At the time of examination, his weight was 15.5 kg (−2.19 Z‑score), height: 103 cm (−2.63 Z-score), OFC: 48.5 cm (−1.75 Z-score). He was also found to have similar eye [Figure 2b and 2e] and dental anomalies[Figure 2g] as his elder brother. Ophthalmic evaluation revealed the presence of perception to light in both eyes. Both eyes also showed cataract and an echogenic thick band passing from the lens to the posterior pole was seen with vitreous appearing membranous [Figure 2j and k]. Ocular ultrasound showed bilateral short axial length (right eye: 13.7 mm [Figure 2h] and left eye: 14.2 mm [Figure 2i]). His psychomotor development was normal as per age with no other systemic abnormalities. Patient 3 This 42-year-old unmarried maternal uncle (IV: 3) of the proband had microphthalmia with cataract in the left eye and microcornea in the right eye [Figure 2c]. He also had dental crowding. He was having diminished vision but had never sought clinical evaluation as he could perform most of his activities independently. He had normal intellect with no other chronic health problem. He was not available for a detailed ophthalmological examination and genetic testing. Results Molecular report Variant detected and interpretation WES was performed for patient 1. Filtering of the WES variants and prioritization as per the phenotype of the proband narrowed down the disease causing variant to a homozygous missense variant in the SIX6 gene (NM_007374.3): c.549C>G(p.Asp183Glu). This missense variant is absent in the population databases like 1000Genomes (https://www.internationalgenome.org/), Exome Variant Server (EVS, https://evs.gs.washington. edu/EVS/), in‑house databases, and Genome Aggregation Database (gnomAD, https://gnomad.broadinstitute.org/). It is also not reported in disease-specific databases. Furthermore, it is predicted to be disease causing by in silico analyses performed using Mutation Taster2 (http://www.mutationtaster.org/), PolyPhen-2 (Polymorphism Phenotyping v2), FATHMM (Functional Analysis through Hidden Markov Models, v2.3), PROVEAN (Protein Variation Effect Analyzer), LRT (Likelihood ratio test), and SIFT (Sorting Intolerant From Tolerant) tool. This variant has a CADD score of 21. This variant is also highly conserved across species (phyloP conservation score: 9.661 [http://compgen.cshl.edu/phast/]). The variant c.549C>G was found to cosegregate within the family. It was detected in homozygous state in the younger affected sibling and in heterozygous state in the parents by Sanger sequencing [Figure 1b]. Hence, this variant is classified as likely pathogenic (PM1, PM2, PP1, and PP2) according to the ACMG/AMP 2015 criteria.[4] The accession number in ClinVar (https://www.ncbi.nlm.nih. gov/clinvar/) for this novel variant is VCV000870595.1.
Delhi Journal of Ophthalmology ¦ Volume 33 ¦ Issue 1 ¦ January-March 2023 47 Nilay and Moirangthem: Complex microphthalmia involving SIX6 gene Figure 2: Phenotype of the proband (a, d, and f); similarly affected younger sibling (b, e and g); phenotype in maternal uncle (c); ocular ultrasound findings in younger sibling (h‑k) d a b c h e f g i j k Figure 1: (a) Pedigree and (b) genotyping results of the family. Chromatograms showing a fragment of the SIX6 gene, with the variant c.549C>G (p.Asp183Glu), homozygous in the proband (V: 1) and similarly affected younger sibling (V: 2); and in the heterozygous state in their parents (IV: 1 and IV: 2) a b
48 Delhi Journal of Ophthalmology ¦ Volume 33 ¦ Issue 1 ¦ January-March 2023 Nilay and Moirangthem: Complex microphthalmia involving SIX6 gene In silico prediction of the novel variant on protein structure using HOPE tool As exact three‑dimensional structure of our protein of interest is not known, HOPE built a homologous model using the Yasara and WHAT IF Twinset [Figure 3a]. Structural information was collected using information from WHAT IF Web services, the UniProt database, and the Reprof software. As a possible modeling template, HOPE identified PDB: 4EGC (http://www. rcsb.org/pdb/explore/explore.do? structureId=4EGC). However, the amount of sequence identity between our sequence and a possible modeling template was low. It was found that the mutated residue is located in an important functional domain of SIX6 protein (homeobox domain [HD]) that is important for binding of other molecules. Mutation of the residue might disturb this function and is probably damaging. Furthermore, the mutant residue is bigger than the wild-type residue [Figure 3b]. Close-up view of this mutation from different angles [Figure 3c] also shows altered protein structure as the resulting side chain may lead to bumps, thus probably hampering protein interactions. Discussion The A/M spectrum is a severe developmental anomaly of the human eye accounting for 3%–12% of visual deficits in children.[5,6] They can be unilateral or bilateral and may be associated with other ocular anomalies, like cataract, coloboma, persistence of primary vitreous, or retinal dysplasia. Both patients in this study had bilateral cataract and patient 2 had persistent hyperplastic primary vitreous in addition. Developmental anomalies like A/M are mostly genetic in origin, though environmental factors may be a rare etiology. TORCH infections, drugs like retinoids and thalidomide, and maternal smoking have been reported to cause such ocular anomalies.[1] Genetic causes may manifest as syndromic or isolated A/M. Syndromic association (occurring with a chromosomal abnormality or malformation syndrome) has been reported around 50% of the A/M cases.[7] The same study found trisomy 13 to be the most common chromosomal abnormality in a large cohort of A/M cases. Submicroscopic chromosomal imbalances (like 4p-syndrome, duplication of 3q, 4p, or 10q) are seen in 10%–15% of such syndromic ocular anomalies.[8,9] There is a long list of putative genes for A/M and these are mainly grouped as transcription factors(e.g. SOX2, PAX6, and SIX6); expression regulators (e.g. YAP1 and BCOR); those involved in signaling pathways(e.g. BMP4, BMP7); and genes involved in retinoic acid metabolism (STRA6 and RARB). WES was performed for our proband considering the genetic heterogeneity in such ocular anomalies and probability of autosomal recessive or X‑linked disorder based on the family history. These high-throughput tests give rapid results and are cost effective, being widely employed for genetic diagnostics. However, exact molecular etiology can only be determined in around 20%–30% of A/M patients,[1] with greater diagnostic yield seen in severe and/or bilateral cases. The novel missense variant (c.549C>G [p.Asp183Glu]) in the SIX6 gene identified in the present study lies in the functionally important HD. Structural protein modeling predicted probable deleterious change in structure. SIX6 (cytogenetic location: 14q23.1) is a member of SIX protein family, which are transcription factors and have been implicated in A/M. The phenotype in OMIM related to pathogenic variations in this gene is colobomatous optic disc-macular atrophy‑chorioretinopathy syndrome (OMIM#212550), which is an autosomal recessive disorder. To the best of our knowledge, only three reports have previously described biallelic variations in SIX6 with structural eye anomalies. Aldahmesh et al. [10] identified a homozygous SIX6 pathogenic variant(c.532_536del) in a consanguineous Syrian family with isolated complex microphthalmia. This frameshift variant is predicted to cause elongation of the wild type protein by 72 amino acids. The same variant was detected in another unrelated Syrian family with microphthalmia recently.[11] Growth retardation as seen in the affected siblings in our cohort has also been reported by Deepthi et al. [11] Hence, this can be a possible feature associated with SIX6 mutations. Yariz et al. [12] reported a homozygous missense variant (c.110T>C) in a consanguineous family with affected individuals showing optic disc anomalies and macular atrophy but no microphthalmia. The variant c.110T>C lies in the N-terminal SIX6 domain (upstream SIX domain), whereas the variants c.532_536del and c.549C>G lie in the DNA binding homeobox nucleic acid recognition domain (HD). Whether the location of the variants is responsible for the variable presence of microphthalmia remains to be seen with additional reports and functional studies. All the patients reported till date including the present study are from consanguineous families. Moreover, testing for SIX6 gene variants in A/M cohorts have failed to identify pathogenic variants in this gene.[13,14] Hence, Figure 3: (a) Overview of the wild protein in ribbon‑presentation. The protein is colored by element; α‑helix = blue, β‑strand = red, turn = green, 3/10 helix = yellow and random coil = cyan. (b) Overview of the mutated protein in ribbon‑presentation. The protein is colored gray, the side chain of the mutated residue is colored magenta and shown as small balls. (c) Close‑up view of the mutation from different angles showing the change in 3D protein conformation and resulting bumps which may possibly hamper protein interactions. The protein is colored gray, the side chains of both the wild‑type and the mutant residue are shown and colored green and red respectively. 3D: Three‑dimensional a b c
Delhi Journal of Ophthalmology ¦ Volume 33 ¦ Issue 1 ¦ January-March 2023 49 Nilay and Moirangthem: Complex microphthalmia involving SIX6 gene SIX6‑related microphthalmia is likely to be very rare. Additional reports of SIX6 variants and microdeletions involving SIX6 have also been described in individuals with A/M spectrum[15] and SIX6 has also been associated with glaucoma.[16] However, conclusive evidence is lacking in these reports. The maternal uncle (IV: 3) of the brothers also had a milder phenotype. Information about consanguinity of his parents was not available and he could not be tested for the SIX6 variant. Extraocular features have been frequently associated even in nonsyndromic microphthalmia. These are mainly related to craniofacial anomalies, skeletal malformations, and cognitive impairment. Dental anomalies have never been reported with SIX6 pathogenic variations. The dental phenotype seen in our study may be an extension of the phenotype or may be a chance association. Noteworthy is the absence of pituitary features in our siblings as also in the previous studies. Management of such severe A/M is mainly supportive with no curative treatment at present. Ophthalmological care involves use of prosthetics to enhance symmetrical socket growth, surgery for cataract, and other ocular anomalies. Such children are supposed to develop psychosocial issues due to the visual impairment and hence require a proper support team involving the family and doctors. Growth monitoring, hearing, motor, and cognitive assessment is paramount on follow-up visits. Identification of molecular etiology helps in providing accurate genetic counseling. SIX6‑related A/M as in the present family has a 25% risk of recurrence. Molecular diagnosis in the fetus is possible by genetic tests in future pregnancies. However, complexities may be seen in A/M caused by aberrations in other genes such as OTX2 and SOX2, which have autosomal dominant inheritance with variable penetrance. Complexity is also true for SIX6 mutations as demonstrated by variable expressivity of ocular involvement in the reported cases. Anophthalmia/microphthalmia spectrum involves a large number of putative genes which result in severe ocular phenotype. SIX6 is one of the very rare causes of microphthalmia. Easy availability of genomic tests helps in exact molecular diagnosis aiding in proper management and surveillance of the individual along with genetic counseling, overall family care through prenatal testing, and preimplantation genetic diagnosis. Acknowledgment The authors thank the patients and their family for their cooperation in this study. The authors also thank CSIR-Centre for Cellular and Molecular Biology, Hyderabad, for performing the WES. Author contributions MN: Drafting the first version of manuscript, procuring patient details, sanger sequencing, and management; AM conceived the idea of study with critical revision, intellectual input, editing the manuscript, and final approval and will act as guarantor. All authors discussed the results and contributed to the final manuscript. Declaration of patient consent The authors certify that they have obtained all appropriate patient consent forms. In the form, the patients’ parents have given their consent for their images and other clinical information to be reported in the journal. The patients’ parents understand that the patients names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest. References 1. Plaisancié J, Ceroni F, Holt R, Zazo Seco C, Calvas P, Chassaing N, et al. Genetics of anophthalmia and microphthalmia. Part 1: Non-syndromic anophthalmia/microphthalmia. Hum Genet 2019;138:799‑830. 2. Harding P, Moosajee M. The molecular basis of human anophthalmia and microphthalmia. J Dev Biol 2019;7:16. 3. Venselaar H, Te Beek TA, Kuipers RK, Hekkelman ML, Vriend G. Protein structure analysis of mutations causing inheritable diseases. An e‑science approach with life scientist friendly interfaces. BMC Bioinformatics 2010;11:548. 4. Richards S, Aziz N, Bale S, Bick D, Das S, Gastier‑Foster J, et al. Standards and guidelines for the interpretation of sequence variants: A joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 2015;17:405‑24. 5. Llorente‑González S, Peralta‑Calvo J, Abelairas‑Gómez JM. Congenital anophthalmia and microphthalmia: Epidemiology and orbitofacial rehabilitation. Clin Ophthalmol 2011;5:1759‑65. 6. Verma AS, Fitzpatrick DR. Anophthalmia and microphthalmia. Orphanet J Rare Dis 2007;2:47. 7. Chambers TM, Agopian AJ, Lewis RA, Langlois PH, Danysh HE, Weber KA, et al. Epidemiology of anophthalmia and microphthalmia: Prevalence and patterns in Texas, 1999‑2009. Am J Med Genet A 2018;176:1810‑8. 8. Balikova I, de Ravel T, Ayuso C, Thienpont B, Casteels I, Villaverde C, et al. High frequency of submicroscopic chromosomal deletions in patients with idiopathic congenital eye malformations. Am J Ophthalmol 2011;151:1087‑94.e45. 9. Delahaye A, Bitoun P, Drunat S, Gérard‑Blanluet M, Chassaing N, Toutain A, et al. Genomic imbalances detected by array-CGH in patients with syndromal ocular developmental anomalies. Eur J Hum Genet 2012;20:527‑33. 10. Aldahmesh MA, Khan AO, Hijazi H, Alkuraya FS. Homozygous truncation of SIX6 causes complex microphthalmia in humans. Clin Genet 2013;84:198‑9. 11. DeepthiA, FakhouryO, DaherM, GambariniA, El‑HayekS, MegarbaneA. SIX6-related anophthalmia/microphthalmia: Second report on a deletion in a consanguineous family. Ophthalmic Genet 2021;42:88‑91. 12. Yariz KO, Sakalar YB, Jin X, Hertz J, Sener EF, Akay H, et al. A homozygous SIX6 mutation is associated with optic disc anomalies and macular atrophy and reduces retinal ganglion cell differentiation. Clin Genet 2015;87:192‑5. 13. Aijaz S, Clark BJ, Williamson K, van Heyningen V, Morrison D, Fitzpatrick D, et al. Absence of SIX6 mutations in microphthalmia, anophthalmia, and coloboma. Invest Ophthalmol Vis Sci 2004;45:3871‑6. 14. Vidya NG, Rajkumar S, Vasavada AR. Genetic investigation of ocular developmental genes in 52 patients with anophthalmia/microphthalmia. Ophthalmic Genet 2018;39:344‑52. 15. Gallardo ME, Lopez‑Rios J, Fernaud‑Espinosa I, Granadino B, Sanz R, Ramos C, et al. Genomic cloning and characterization of the human homeobox gene SIX6 reveals a cluster of SIX genes in chromosome 14 and associates SIX6 hemizygosity with bilateral anophthalmia and pituitary anomalies. Genomics 1999;61:82‑91. 16. Yang X, Sun NN, Zhao ZN, He SX, Zhang M, Zhang DD, et al. Coinheritance of OLFM2 and SIX6 variants in a Chinese family with juvenile‑onset primary open‑angle glaucoma: A case report. World J Clin Cases 2021;9:697‑706.
Abstract Pictorial CME Introduction Macular coloboma is a rare entity with lesser data available on pathogenesis. It is hypothesized that macular coloboma develops due to incomplete differentiation of arcuate bundle of horizontal raphe and not due to anomalous closure of optic fissure.[1] They can present unilaterally or bilaterally with varying sizes. Many disease entities can mimic a coloboma at macula and they should be differentiated from congenital macular coloboma. Optical coherence tomography (OCT) plays an important role as it shows defect in the neurosensory retina and deficient choroid. Case Report A 15‑year‑old boy born out of nonconsanguineous marriage presented to our hospital with complaints of defective vision since childhood. Medical or family history was nonsignificant and no syndrome was detected. Best-corrected visual acuity in both eyes was 20/100 as measured by the Snellen’s visual acuity chart. He was trichromatic in both eyes. On examination, jerk horizontal nystagmus with fast component toward the right side was noted. The anterior segment examination was within normal limits. Fundus examination of both eyes revealed a large 9–10-disc diameter of well-demarcated excavation at the macula with baring of the underlying sclera and thin rim of pigmentation at the margins and findings were consistent with coloboma. Coloboma was spanning between temporal arcades where vessels followed the course along the edges of coloboma. The optic nerve head of both eyes was small and slightly tilted. The rest of the retina periphery was within normal limits [Figure 1a and b]. OCT demonstrated a large excavation at the macula with atrophic neurosensory retina and an absence of retinal pigment epithelium and choroid in the lesion [Figure 1c and d]. Multifocal electroretinogram (ERG) reveals depressed waveforms within 15° which was more marked within 10° [Figure 2]. The patient was rehabilitated with low-vision aids. Discussion The incidence of ocular coloboma ranges from 0.5 to 2.2/10,000 births, whereas the incidence of macular coloboma ranges from 0.5 to 0.7/10,000 births.[2] Macular coloboma is known as atypical coloboma. Mann[3] classified macular coloboma into three types as follow: (1) pigmented macular coloboma; (2) nonpigmented macular coloboma; and (3) macular coloboma associated with abnormal vessels. Macular coloboma is a congenital atypical coloboma which appears as well-demarcated lesion on the macula, it can be unilateral or bilateral. We report one such case of a 15‑year‑old boy who presented to us with horizontal jerk nystagmus. His fundus examination revealed a bilateral large 9–10-disc diameter of well-demarcated excavation at the macula with baring of the underlying sclera and thin rim of pigmentation at the margins. Coloboma was spanning between temporal arcades where vessels followed the course along the edges of coloboma. Large macular colobomas are rare and cause nonprogressive decrease in visual acuity. Keywords: Bilateral coloboma, macular coloboma, temporal dragging Address for correspondence: Dr. Shivraj Tagare, Department of Vitreoretinal Services, Aravind Eye Hospital, Puducherry ‑ 605 007, India. E‑mail: [email protected] This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution‑NonCommercial‑ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non‑commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms. For reprints contact: [email protected] How to cite this article: Singh S, Tagare S. Multimodal imaging in rare case of bilateral macular coloboma. Delhi J Ophthalmol 2023;33:50‑2. Multimodal Imaging in Rare Case of Bilateral Macular Coloboma Shivangi Singh, Shivraj Tagare Department of Vitreoretinal Services, Aravind Eye Hospital, Puducherry, India Access this article online Quick Response Code: Website: https://journals.lww.com/djo DOI: 10.4103/DLJO.DLJO_15_23 Submitted: 05‑Mar‑2023 Revised: 15-Apr-2023 Accepted: 29‑Apr‑2023 Published: 05-Jul-2023 50 © 2023 Delhi Journal of Ophthalmology | Published by Wolters Kluwer - Medknow
Singh and Tagare: Bilateral macular coloboma Congenital macular coloboma needs to be differentiated from other acquired macular pathologies such as macular scarring following toxoplasma retinochoroiditis, North Carolina macular dystrophy, and Leber’s congenital amaurosis. Toxoplasmosis retinochoroiditis scar contains a central region of glial and pigmented material connected by pigmented strands to a peripheral ring of pigment at the edge of the lesion and also known as “wagon-wheel appearance.” OCT of toxoplasmosis retinochoroiditis scar will show thinning of inner layers, choroid, and fibrosed tissue with focal traction point.[4] North Carolina macular dystrophy is autosomal dominantly inherited macular disorder with incomplete penetrance. Fundus feature can range from small drusen-like parafoveal deposits to large coloboma-like excavation. This excavation has surrounding fibrosis and drusen in periphery, positive family history can help in differentiating it from congenital macular coloboma.[5] Leber’s congenital amaurosis is genetically and phenotypically heterogeneous characterized by severe congenital/early infancy visual loss, nystagmus, amaurotic pupils, and markedly reduced/absent full‑field ERGs. Fundus feature includes peripheral pigmentary changes Delhi Journal of Ophthalmology ¦ Volume 33 ¦ Issue 1 ¦ January-March 2023 51 Figure 2: OD and OS multifocal ERG reveals depressed waveforms within 15° which was more marked within 100. ERG: Electroretinograms Figure 1: (a and b) OD and OS large, well‑demarcated excavation at the macula, spanning both the temporal arcades with baring of the underlying sclera, consistent with a coloboma. The coloboma in the left eye is smaller, thus explaining better visual acuity in the left eye. (c and d) OD and OS‑OCT demonstrating a large excavation at the macula with atrophic neurosensory retina and an absence of retinal pigment epithelium and choroid in the lesion. OCT: Optical coherence tomography c d a b
Singh and Tagare: Bilateral macular coloboma and macular atrophy. It also shows a typical marbled fundus appearance. OCT findings are characterized by thinning of the outer nuclear layer, loss of integrity in the ellipsoid zone, and disorganized macular atrophy.[6] Clinical differentiation is possible when disease is bilateral and presents with large colobomas. Smaller and unilateral coloboma poses a problem in differentiation. Mathew showed important clinical finding of temporal dragging of disc with normal nasal vasculature in cases of large macular coloboma.[7] OCT findings described by various authors are consistent with findings of crater‑like depression in macular region with atrophic neurosensory retina, lack of choriocapillaris, and RPE in macular coloboma.[8,9] This helps in differentiating macular coloboma from other causes of macular pathology such as macular dystrophies and macular degeneration secondary to inflammation. Multifocal ERG allows for rapid assessment of retinal function from multiple areas in the retina at the same time. It used contrast-reversing stimulus to record multiple retinal responses simultaneously. The study by Zhang et al. showed that no significant peak value was obtained on multifocal ERG in bilateral congenital coloboma.[10] This was concurrent to our study which showed depressed waveforms within 15° which was more marked within 10°. Macular coloboma is a rare entity, which needs to be differentiated from others. Thus, specific clinical and investigation features as mentioned in our case can help in diagnosis and better rehabilitation of the patient. Declaration of patient consent The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given his consent for his images and other clinical information to be reported in the journal. The patient understands that his name and initials will not be published and due efforts will be made to conceal his identity, but anonymity cannot be guaranteed. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest. References 1. Satorre J, López JM, Martinez J, Piñera P. Dominant macular colobomata. J Pediatr Ophthalmol Strabismus 1990;27:148‑52. 2. Mandura RA, Radi RE. Optical coherence tomographic finding in a case of congenital macular coloboma at King Abdulaziz university hospital, Jeddah. Cureus 2021;13:e14034. 3. Mann IC. On certain abnormal conditions of the macular region usually classed as colobomata. Br J Ophthalmol 1927;11:99‑116. 4. Kamal Gerges T. Ocular Toxoplasmosis: An Update on Diagnosis, Multimodal Imaging and Therapy. Infectious Eye Diseases: IntechOpen; 2021. 5. Tandon M, Barnett C, Taranath D. Case report: North Carolina macular dystrophy misdiagnosed as congenital ocular toxoplasmosis. Mol Vis 2019;25:731‑3. 6. Miyamichi D, Nishina S, Hosono K, Yokoi T, Kurata K, Sato M, et al. Retinal structure in Leber’s congenital amaurosis caused by RPGRIP1 mutations. Hum Genome Var 2019;6:32. 7. Mathew DJ. Bilateral macular colobomata: Temporal dragging of optic disc. Indian J Ophthalmol 2015;63:348‑50. 8. Oh JY, Yu YS, Hwang JM, Park KH. Optical coherence tomographic finding in a case of macular coloboma. Korean J Ophthalmol 2007;21:175‑7. 9. Sharma S, Naqvi A, Cruess AF. Bilateral macular colobomas. Can J Ophthalmol 1996;31:27‑8. 10. Zhang C, Wu P, Wang L, Gao J, Huang X, Jiang Y. Bilateral congenital macular coloboma and cataract: A case report. Medicine (Baltimore) 2019;98:e14803. 52 Delhi Journal of Ophthalmology ¦ Volume 33 ¦ Issue 1 ¦ January-March 2023
Photo Essay Counseling is an integral part of patient care, and it is crucial to provide patients with the necessary information and support to cope with their health problems. The postoperative period can be challenging for patients, and they may face various issues such as anxiety, fear, discomfort, emotional distress, and communication barriers.[1] It is essential to address these concerns to ensure that patients receive the best possible care and support during their recovery period. One area where counseling is particularly critical is cataract surgery. Cataract surgery is a safe and effective procedure associated with certain risks and complications.[2] Patients undergoing cataract surgery require adequate counseling to understand the postoperative instructions, medications, and potential complications. One-on-one counseling can be time-consuming and challenging, especially in a high-volume center. A new approach called “Coffee with Counseling” has been introduced to overcome this challenge. Coffee with Counseling is an innovative approach to postoperative counseling for cataract surgery patients. This approach involves a daily group counseling session from 4 to 5 p.m. after the surgeries. Patients who have undergone surgery and their caregivers are invited to assemble in a hall to attend the postoperative counseling session and collect their discharge sheets. The counseling session is delivered through a 4-min video that explains the postoperative advice and instructions in detail. The video is displayed on a TV monitor, and patients can use the facility for drinking coffee while listening to the instructions. After the video, a nurse explains the postoperative medications, and patients can ask questions and clear their doubts. Cutting-Edge Care: Innovative Approaches to Cataract Surgery Counseling Akshay Wagh1 , Shivraj Tagare2 , Swati Upadhaya3 , Rengaraj Venkatesh4 1 Department of General Ophthalmology, 2 Department of Vitreoretinal Services, 3 Department of Glaucoma Services, 4 Chief Medical Officer, Aravind Eye Hospital, Pondicherry, India This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution‑NonCommercial‑ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non‑commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms. Access this article online Quick Response Code: Website: https://journals.lww.com/djo DOI: 10.4103/DLJO.DLJO_19_23 How to cite this article: Wagh A, Tagare S, Upadhaya S, Venkatesh R. Cutting-edge care: Innovative approaches to cataract surgery counseling. Delhi J Ophthalmol 2023;33:53‑4. © 2023 Delhi Journal of Ophthalmology | Published by Wolters Kluwer - Medknow Submitted: 13-Mar-2023 Accepted: 25-Apr-2023 Published: 05-Jul-2023 Abstract Counselling is an essential part of patient care, especially during the post-operative period, which can be challenging for patients. Cataract surgery patients require adequate counselling to understand the post-operative instructions, medications, and potential complications. However, one-on-one counselling can be time-consuming, especially in high-volume centers. To address this issue, a new approach called “Coffee with Counselling” has been introduced, which involves daily group counselling sessions for patients who have undergone surgery and their caregivers. The sessions include a 4-minute video that explains post-operative advice and instructions, displayed on a TV monitor while patients can drink coffee. After the video, a sister explains post-operative medications, and patients can ask questions and clear their doubts. The approach has several advantages over one-on-one counselling, including reduced counselling time, patients’ ability to ask questions in a group setting, creating a sense of community, and allowing family members to understand post-operative instructions and medications. The Coffee with Counselling approach is an innovative and practical way to provide patients with the necessary information and support during their recovery in a group setting. Healthcare professionals should consider adopting this approach to improve patient care and support. Keywords: Post-op Counselling, Cataract surgery, video counselling Address for correspondence: Dr. Shivraj Tagare, Aravind Eye Hospital, Cuddalore Main Road, Thavalakuppam, Puducherry ‑ 605 007, India. E‑mail: [email protected] © 2023 Delhi Journal of Ophthalmology | Published by Wolters Kluwer - Medknow 53
Wagh, et al.: Cutting‑Edge Care: Innovative Approaches to Cataract Surgery Counseling members to understand the postoperative instructions and medications, as this video can be scanned as a QR code and played whenever required [Figure 1]. In conclusion, postoperative counseling is a crucial aspect of patient care. Providing patients with the necessary information and support to cope with their health problems is essential. The Coffee with Counseling approach is an innovative and practical approach to postoperative counseling that provides patients with the necessary information and support in a group setting. This approach has several advantages over one-on-one counseling, and it can be used for various procedures that require postoperative counseling. Health-care professionals should consider adopting this approach to provide patients with the best possible care and support during their recovery. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest. References 1. Yeola M, Jaipuriya P. Effect of preoperative counselling on postoperative outcome in hernia surgery patients. Internation Journal of Science and Research 2013;5:762-7. 2. Preoperative Counselling of the Cataract Patient. CRSTG | Europe Edition. Available from: https://crstodayeurope.com/articles/2009‑nov/ crsteuro1109_10-php/. [Last accessed on 2023 Feb 20]. 54 Delhi Journal of Ophthalmology ¦ Volume 33 ¦ Issue 1 ¦ January-March 2023 The Coffee with Counseling approach has several advantages over one-on-one counseling. First, it reduces the time required for counseling each patient, allowing health-care professionals focus on other critical aspects of patient care. Second, it allows patients to ask questions and share their concerns in a group setting, which may help alleviate their anxiety and fear. Third, it allows patients to interact with other patients who have undergone similar procedures, creating a sense of community and support. Lastly, it allows family Figure 1: (a) Postoperative video counseling in a group, (b) QR code and YouTube link of the counseling video, (c) Instructions about counseling b c a
Abstract Photo Essay Introduction Pterygium is an abnormal wing-shaped fibrovascular conjunctival growth that encroaches over the cornea in the interpalpebral fissure. The underlying changes are due to the chronic ultraviolet (UV) ray exposure that causes insufficiency in limbal stem cells of the cornea, leading to activation of tissue growth factors and fibroblast proliferation.[1] The predominance of pterygia on the nasal side in the interpalpebral zone is hypothesized to be due to increased light exposure in the nasal region. In addition, there are higher chances of nasal hyperemia due to the natural pooling of tears. Pterygium has a prevalence rate of 0.3%–36.4%, with the highest in tropical regions.[2] Symptoms mainly include redness, irritation, dryness, tearing, and decreased vision due to corneal astigmatism. Pterygium can be managed both medically and surgically. Early pterygium is mostly asymptomatic, and in case of irritation/inflammation, it can be treated using topical lubricants/nonsteroidal anti‑inflammatories, respectively.[3] Surgical management includes various techniques for the excision of abnormal pterygial tissue. The “bare sclera technique” involves only the excision of pterygium while allowing the scleral bed to re-epithelize.[4] Hence, the recurrence rates are around 24%–89%.[4] The “conjunctival autograft (CAG) technique” and “amniotic membrane grafting” (AMG) aim to remove abnormal tissue along with grafting with sutures or fibrin glue to prevent the recurrence of pterygium. This article depicts the various possible complications that can occur following pterygium surgery. Written informed consent has been obtained from all the patients for the reproduction of images. This research work complies with the Declaration of Helsinki and necessary ethics approval has been obtained from the institutional ethics committee of Aravind Eye Hospital Pondicherry. Residual Pterygium This is a result of an incomplete removal of pterygial tissue during surgery which is usually common in the learning phase of a surgeon. Identifying a proper dissection plane under pterygial tissue and using the resistance-guided lamellar peel technique can prevent this complication.[5] Smoothening of the ocular surface by a motorized burr at the end of pterygium removal can also be helpful. Residual pterygium can lead to poor cosmetic appearance and prevents normal wetting of the corneal surface postoperatively [Figure 1a]. While larger residual tissue needs a re-surgery for removal, minimal residues can be treated conservatively using lubricant gels/ ointments that promote epithelisation. Pterygium is a wing‑shaped fibrovascular growth that occurs due to conjunctival degeneration. Although early pterygia can be conservatively managed with lubricants, progressive or symptomatic ones need surgical excision. Various methods include the bare sclera technique, conjunctival autograft transplantation with sutures or fibrin glue, and amniotic membrane grafting. This article depicts the various possible complications that can occur following pterygium surgery with clinical images. Keywords: Graft necrosis, pterygium complications, pyogenic granuloma Address for correspondence: Dr. Josephine S. Christy, Cornea and Refractive Services, Aravind Eye Hospital, Cuddalore Main Road, Thavalakuppam, Puducherry ‑ 605 007, India. E‑mail: [email protected] This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution‑NonCommercial‑ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non‑commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms. For reprints contact: [email protected] How to cite this article: Christy JS, Nair M. Photo snippet on complications following pterygium surgery. Delhi J Ophthalmol 2023;33:55‑7. Photo Snippet on Complications following Pterygium Surgery Josephine S. Christy1 , Megha Nair1 1 Department of Cornea and Refractive Services, Aravind Eye Hospital, Puducherry, India Access this article online Quick Response Code: Website: https://journals.lww.com/djo DOI: 10.4103/DLJO.DLJO_62_23 Submitted: 22‑Apr‑2023 Revised: 08‑May‑2023 Accepted: 08‑May‑2023 Published: 05-Jul-2023 © 2023 Delhi Journal of Ophthalmology | Published by Wolters Kluwer - Medknow 55
Christy and Nair: Complications postpterygium surgery Recurrence Recurrence is one of the most important complications following a pterygium surgery. The bare sclera technique is associated with 24%–89% recurrence in comparison to 14% with AMG and 10% with CAG [Figure 1b].[6,7] Romano et al., in the Cochrane database of systematic reviews, concluded that using fibrin glue results in <5% recurrences as compared to the usage of sutures.[7] Although recurrences can occur after many years, most happen within the first 3–6 months of surgery.[8] Risk factors for recurrence include incomplete control of postoperative inflammation, younger age, outdoor occupation with high exposure to the dusty environment and UV light, fleshy pterygium, and improper surgical removal of pterygium. Since this is a surgery that is commonly done in the young working-age population, the importance of UV light-protecting sunglasses should be stressed to all patients postoperatively. Surgical management for recurrence includes wider dissection of pterygial tissue along with the use of antimetabolite-Mitomycin C (MMC) 0.02%–0.05% (0.2 mg/mL to 0.5 mg/mL) for 1–5 min.[9] Inverted Graft and Graft Necrosis It occurs due to the improper placement of graft with the anterior epithelial surface sutured/glued onto avascular sclera. It is seen on the 1st postoperative day as a white opaque graft [Figure 2a]. This is followed by necrosis and sloughing of the graft [Figure 2b]. Inverted graft requires immediate management. Viable grafts can be surgically reoriented, with the surface and border facing the right direction within 48 h to prevent inversion‑induced graft failure.[10] Whereas necrosed graft needs surgical removal and replacement with AMG. Graft Retraction Graft sagging is a mild dehiscence seen at the limbal or nasal edge of the graft. Graft retraction is a larger dehiscence that occurs due to improper suturing or gluing of the graft [Figure 3a]. Important tips to avoid graft retraction includes over-sizing the graft by an extra 1 mm, complete dissection of subconjunctival connective tissue, and ensuring adequate adherence intraoperatively.[10] While minimal sag at the nasal edge does not require active intervention, limbal edge sag or graft retraction requires re-suturing or re-grafting as unattended retraction leads to poor tear film surfacing, collection of debris, and incites chronic inflammation. Pyogenic Granuloma It is a conjunctival inflammatory granulation tissue seen at the free conjunctival flap site following pterygium excision with the CAG technique.[11] Excessive intraoperative tissue handling and localized suture irritation are some of the common predisposing risk factors. While small granulomas may spontaneously resolve with frequent application of topical steroids, larger ones require simple surgical excision [Figure 3b]. 56 Delhi Journal of Ophthalmology ¦ Volume 33 ¦ Issue 1 ¦ January-March 2023 Figure 1: (a) Residual pterygium, (b) Recurrent pterygium a b Figure 3: (a) Graft retraction at nasal edge, (b) Pyogenic granuloma a b Figure 4: (a) Scleral thinning, (b) Scleral thinning with uveal show, (c) Scleral melt with corneal infection c a b Figure 2: (a) Inverted graft, (b) Necrosed graft a b
Christy and Nair: Complications postpterygium surgery Scleral Melt/Necrosis This is a rare complication that may develop following pterygium surgery. Possible underlying mechanisms include infection, hypersensitivity response, and ischemia.[12] The use of topical MMC for recurrent pterygium surgeries and excessive cauterization may precipitate ischemia and result in progressive inflammatory melting. Careful application of MMC in the form of soaked wet sponges under the conjunctival edges while protecting the bare sclera, followed by a thorough wash with the balanced salt solution, can prevent this complication. Early scleral melts can be seen as thinned-out areas in the sclera on careful slit lamp examination. It can occur with or without corneal thinning and uveal exposure [Figure 4a and b]. Early scleral thinning can be treated with topical steroids to prevent scleral melt. Progressive scleral melts with corneal infection [Figure 4c] require topical antimicrobials, patch grafts, or keratoplasty. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest. References 1. Di Girolamo N, Chui J, Coroneo MT, Wakefield D. Pathogenesis of pterygia: Role of cytokines, growth factors, and matrix metalloproteinases. Prog Retin Eye Res 2004;23:195‑228. 2. Aziza Y, Inatomi T, Sotozono C, Kinoshita S. Pterygium excision with modified bare sclera technique combined with mitomycin C. Jpn J Ophthalmol 2021;65:89‑96. 3. Hall AB. Understanding and managing pterygium. Community Eye Health 2016;29:54-6. 4. Kaufman SC, Jacobs DS, Lee WB, Deng SX, Rosenblatt MI, Shtein RM. Options and adjuvants in surgery for pterygium: Areport by the American Academy of Ophthalmology. Ophthalmology 2013;120:201‑8. 5. Gulani AC, Gulani AA. Cosmetic pterygium surgery: Techniques and long‑term outcomes. Clin Ophthalmol 2020;14:1681‑7. 6. Nuzzi R, Tridico F. How to minimize pterygium recurrence rates: Clinical perspectives. Clin Ophthalmol 2018;12:2347‑62. 7. Romano V, Cruciani M, Conti L, Fontana L. Fibrin glue versus sutures for conjunctival autografting in primary pterygium surgery. Cochrane Database Syst Rev 2016;12:CD011308. 8. Ghiasian L, Samavat B, Hadi Y, Arbab M, Abolfathzadeh N. Recurrent pterygium: A review. J Curr Ophthalmol 2021;33:367‑78. 9. Martins TG, Costa AL, Alves MR, Chammas R, Schor P. Mitomycin C in pterygium treatment. Int J Ophthalmol 2016;9:465‑8. 10. Figueira EC, Coroneo MT, Francis IC. Preventing conjunctival autograft inversion in pterygium surgery. Br J Ophthalmol 2007;91:83‑4. 11. Zhang Z, Yang Z, Pan Q, Chen P, Guo L. Clinicopathologic characteristics and the surgical outcome of conjunctival granulomas after pterygium surgery. Cornea 2018;37:1008‑12. 12. Lu L, Xu S, Ge S, Shao C, Wang Z, Weng X, et al. Tailored treatment for the management of scleral necrosis following pterygium excision. Exp Ther Med 2017;13:845‑50. Delhi Journal of Ophthalmology ¦ Volume 33 ¦ Issue 1 ¦ January-March 2023 57
Omnibus Humans “For oft, when on my couch I lie In vacant or in pensive mood, They flash upon that inward eye….” The All India Ophthalmological Society had issued a useful 184‑page bilingual booklet consisting of “Consent Forms in Ophthalmic Practice” a couple of years ago. A thought on the publication of these forms is required. It is not only a document with medico-legal aspects to answer questions in a consumer forum court. It is the conversation between the doctor and the patient, which helps in establishing a rapport, which is important. I remember in the seventies my grandfathers had their cataract surgery performed at our house. The surgeon and his team had come home with their equipment, conducted the surgery, and had given the family members instructions before leaving. There was trust on both sides. Today, we are taking consent for a fluorescein study also. Introspection on these aspects is warranted. It behooves every ophthalmologist to develop and practice his own soft skills to deal with patients and situations of all types. This includes taking responsibility, paying attention to even minor things, being helpful and transparent with the patient, and having a holistic approach. No branch in medicine has advanced so rapidly in knowledge and instrumentation at such short intervals of time as ophthalmology. Surgeons of my generation started their life with intracapsular cataract extraction (ICCE), followed by switching over to extracapsular cataract extraction (ECCE) under an operating microscope. I still remember the number of times I used to peep sideways under the microscope oculars rather than through them to better visualize my operating field! By the time operating microscopes improved and ECCE was perfected, Ophthalmology came up with phacoemulsification adding a new skill to be learnt by most surgeons who were now at around presbyopic age! However, most surgeons have been able to cope up with these advancements due to skills such as handling instruments and handling tissue, speed, deftness, and orientation. During ICCE days, the surgeon would concentrate on the superior limbus with the fixation forceps in one hand at the 6 o’clock limbus, waiting for the assistant to place the von Graefe’s knife in the other hand. Ambidexterity, orientation, and bimanual surgery has always been an essential requirement at all times. Some skills need to be developed with practice however difficult that might be. During my college residency, there was a lone slit lamp in the department which used to be placed in the departmental head’s room, for which use permission had to be taken. The HOD would first ask for a corneal loupe. He would then question the purpose of the special requirement of the slit-lamp examination in that particular case because the slit lamp was not an alternative for either a light or magnification source. Along with being trained in the slit lamp, we learned to think before acting, and not to take anything for granted! In most eye centers today, the patient is seen in a conveyor belt fashion. At first the optometrist interacts with the patient. Then a junior specialist sees the patient and orders dilatation of the eyes if necessary. The designated consultant would come after all examination is completed to finally see the patient. There are also opticians who have a consultation chamber in their shops, and in general whatever readings are given by the auto-refractometer, the same is prescribed by the optician with the ophthalmologist putting his signature – a process similar to a laboratory report. The interaction with the patient is scant in the latter model. Ophthalmology starts with a sound knowledge of refraction. During my residency, we were not even allowed to prescribe spectacles. We argued that when we were authorized to prescribe penicillin injections (the usual antibiotic in the hospitals in those days) which could cause fatal reactions, what was the harm in prescribing spectacles? My professor felt that a spectacle reflected the standing of the department and hence it had to be correct and certified by a faculty. It is a sense of responsibility which an ophthalmologist must have for the correctness of prescriptions. A famous glaucoma expert once said that in the present day, ophthalmologists literally smell cataract. This sarcastic statement is not a misplaced one. The evaluation of a case of cataract in isolation should be avoided. The eye is but a part of the body. Sometime back as soon as the 1st-day dressing was completed, a patient started complaining of abdominal pain which was severe enough to warrant a referral to a gastroenterologist. The patient turned out to be having acute calculus cholecystitis warranting another major surgery. But the question asked from me was as to how I missed the jaundice while performing cataract surgery. Preanesthetic checkup for a case of cataract has been varied from center to center with some standardization coming up in recent times. I have had diverse experiences, some surprising. I once had a dilemma at a high-altitude center where a cataract was seen in a 40-years- old lady patient. Due to the nonavailability of trained gynecologists at that place, unattended labor was common, which resulted in a high incidence of vesicovaginal fistulas (VVFs) as a complication of obstructed labor. The urine examination of these patients always showed pus cells. It was a catch-22 situation: to operate for cataract or not? The patients were desperate. They wanted to be back to their villages at their earliest. They had accepted VVF as part of their life but wanted to get rid of their blindness. After a lot of backing by the anesthetist, these patients were operated on with favorable results (later on, there was camp Omnibus Humanus 58 © 2023 Delhi Journal of Ophthalmology | Published by Wolters Kluwer - Medknow
Gurunadh: Omnibus Humanus by urologists who operated on these cases for VVF). I also remember a senior colleague of mine who used to take up cases in cataract camps with only a normal blood sugar report assessed by a glucometer. His contention was that if a patient came walking to his outpatient department (OPD) with a cataract complaint, he was fit enough for cataract surgery barring a normal sugar report. The standard teaching is that the eye should be quiescent for a minimum of 3 months before cataract surgery in any case of uveitic cataract. During my residency days, we had a young patient that had the typical features of a complicated cataract with one odd keratic precipitate. Our consultants felt that despite the frank features of a uveitic cataract, that eye should be observed for 3 months. This patient however approached one of the leading ophthalmic centers in the country and was subjected to lensectomy, followed by postsurgical uveitis with not so favorable outcome. The advent of anti-vascular endothelial growth factors has revolutionized at least the approach to so many macular disorders. However, a case that requires maximum attention is a case of diabetic macular edema with postcapsular opacification. This lytic cocktail and performing YAG capsulotomy in my experience has to be extremely calculated and guided by optical coherence tomography (OCT) monitoring of the macula. In the pre‑Avastin, pre‑OCT era after careful deliberation YAG capsulotomy was performed in one such case only to see a macular hole in the immediate follow-up. The practice of glaucoma and to a large extent that of retina are life-long practices. The rapport with the patient and his family has to be strong. The management of the comorbidities of the patient particularly of diabetes can be taken over by the ophthalmologist. A record of documents is a mandatory practice requirement. In the present days of electronic record keeping, it is a very simple task. I am reminded of my days in RP Centre with the legendary Dr. HK Tewari. Before the OPD started, the files of these old patients would be on Dr. Tewari’s table, who would examine the patient, refer to the records, and note down the present findings as well as new orders. Once in my village, an uncle of mine had features of congestive heart failure. He had undergone open-heart surgery in the early seventies at the then‑only AIIMS however had lost all medical documents. We learned that the doctor who had referred him was still practicing in the city. On visiting the hemiparetic, still busy doctor, he recognized my uncle after almost a gap of three decades. He took us into the adjoining room where there was a pigeonhole cupboard and removed a sheet from one of the pigeonholes which had all the details of my uncle (who incidentally had coarctation of the aorta). A literal lifesaver! We deal with cases of near blindness, particularly those in glaucoma practice or retinal practice. All soft skills are required in dealing with these patients and it would be worthwhile if these surgeons are well versed with low vision aid knowledge. One of my patients once told me that I can only perform the surgery; vision is given by “Sai.” When I see an eye with an ugly incisional scar, an irregular pupil with iris chaffing but with 6/6 unaided vision, then this statement of my patient shines upon me. It is not my mind to preach theism but more than in any specialty there is that hidden hand that delivers the final goal of vision in ophthalmology. Declaration of patient consent The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest. V. S. Gurunadh Professor Ophthalmology and Principal, GSL Medical College, Rajahmundry, Andhra Pradesh, India. E‑mail: [email protected] This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution‑NonCommercial‑ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non‑commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms. How to cite this article: Gurunadh VS. Omnibus humanus. Delhi J Ophthalmol 2023;33:58‑9. Access this article online Quick Response Code: Website: https://journals.lww.com/djo DOI: 10.4103/DLJO.DLJO_73_23 Delhi Journal of Ophthalmology ¦ Volume 33 ¦ Issue 1 ¦ January-March 2023 59
Abstract Theme Section Introduction The COVID-19 pandemic has disrupted daily life in many ways, including the way we approach medical education and training. Many medical students and residents have had to adjust to remote learning and limited access to hands-on training opportunities.[1] In the field of ophthalmology, where surgical skills are crucial, this has presented a unique challenge. However, some ophthalmologists have found a creative solution to this problem: the kitchen ophthalmic surgeon. The term “kitchen ophthalmic surgeon”[2] was coined by Akkara and Kuriakose, consultant ophthalmologists in Kochi, India, to describe a new approach to surgical training. The idea is simple: use household items to simulate surgical procedures and practice techniques at home. They have made a video on the concept available on YouTube.[3] While it may sound unconventional, there is evidence to suggest that this approach can be effective in improving surgical skills and knowledge. They Did Surgery on a Grape This fun video[3] is available at https://www.youtube.com/ watch?v=WPdIj9EBevo, Akkara and Kuriakose demonstrate peribulbar block on a dough face model with boiled eggs for eyes. It is always helpful to have a face model when practicing eye surgeries as this helps in orienting the placement of palms and fingers in the optimal position for surgery. Adding a large nose (especially for left eye surgery) would help simulate real-world problems of beginner surgeons. This is often not considered in the standard wet laboratory practice of The COVID-19 pandemic has disrupted medical education and training, leaving medical students and residents with limited access to hands-on learning opportunities. In the field of ophthalmology, where surgical skills are crucial, a creative solution has been found: the kitchen ophthalmic surgeon. Coined by Dr. John Davis Akkara and Dr. Anju Kuriakose, consultant ophthalmologists in Kochi, India, this approach involves using household items to simulate surgical procedures and practice techniques at home. In a YouTube video, Dr. Akkara and Dr. Kuriakose demonstrate various procedures using items like boiled eggs, tomatoes, onions, and fruits to mimic surgical scenarios. While unconventional, this approach has shown promise in improving surgical skills and knowledge. However, it has limitations, such as the lack of feedback from experienced surgeons and the inability to replicate the feel of the anterior chamber. Despite these limitations, the kitchen ophthalmic surgeon approach offers several benefits. It is accessible, cost-effective, allows for repetition and skill development, and boosts trainees’ confidence. Furthermore, alternative methods like virtual reality (VR) simulations and 3D printing have also emerged as promising tools for surgical training. Although more research is needed to evaluate the effectiveness of home-based surgical simulation, early studies show its potential in maintaining and improving surgical skills. Aspiring kitchen ophthalmic surgeons should prioritize safety, choose appropriate household items, and recognize that this approach complements, but does not substitute, traditional training opportunities. Keywords: Home surgical training, kitchen ophthalmic surgeon, surgical training, three-dimensional printed eyeball, virtual reality surgery, Wet laboratory Address for correspondence: Dr. John Davis Akkara, Department of Glaucoma, Cataract and Refractive Surgery, Westend Eye Hospital, Kochi, Kerala, India and Chaithanya Eye Hospital, Kochi Kerala, India. E‑mail: [email protected] How to cite this article: Akkara JD, Kuriakose A. Kitchen ophthalmic surgeon: Polishing surgical skills at home. Delhi J Ophthalmol 2023;33:60-4. Kitchen Ophthalmic Surgeon: Polishing Surgical Skills at Home John Davis Akkara1,2, Anju Kuriakose3,4 1 Department of Glaucoma, Chaithanya Eye Hospital and Research Institute, Kochi, Kerala, India, 2 Department of Glaucoma, Westend Eye Hospital, Kochi, Kerala, India, 3 Department of Retina, Chaithanya Eye Hospital and Research Institute, Kochi, Kerala, India, 4 Department of Retina, Westend Eye Hospital, Kochi, Kerala, India Access this article online Quick Response Code: Website: https://journals.lww.com/djo DOI: 10.4103/DLJO.DLJO_1_23 This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution‑NonCommercial‑ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non‑commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms. For reprints contact: [email protected] Submitted: 21-Feb-2023 Revised: 20-Mar-2023 Accepted: 25-Apr-2023 Published: 05-Jul-2023 60 © 2023 Delhi Journal of Ophthalmology | Published by Wolters Kluwer - Medknow
Akkara and Kuriakose: Kitchen ophthalmic surgeon Delhi Journal of Ophthalmology ¦ Volume 33 ¦ Issue 1 ¦ January-March 2023 61 using a cadaver eyeball in a simple holder. Another option for simulating the face would be to place the eyeball holder inside a cardboard board with holes for the eyeball holders. A superior rectus bridle suture is placed on a tomato. This is one of the initial steps for a beginner surgeon of extracapsular cataract extraction and manual small incision cataract surgery which many a surgeon struggles with unnecessarily. We can simulate the feel of a microscope by using a smartphone pointing down at a tomato, balanced between two boxes with the camera in video mode and flash on [Figure 1]. This teaches hand-eye coordination since you are looking in one direction when your hands are in another location as for microscope-based surgeries. It also gives you illumination and magnification control and allows you to record your “surgeries” for evaluation by yourself or a mentor. Capsulotomy can be practiced on an onion, intraocular lense box,[4] or tomato (which has been heated in a microwave for 20 s). Both can-opener and continuous curvilinear capsulorhexis can be practiced, and rhexis forceps can also be used. An open staple punched lightly into the circumference of a circle drawn on the tomato acts as a simulation of an incision. Cystotome needle should be passed through the staple and moved diagonally for optimum wound integrity. Incisions and sclero-corneal tunnels can be practiced on boiled eggs, oranges, capsicum, or other fruits and vegetables. Boiled potatoes can be cut into a cataract nucleus to practice chopping in phacoemulsification [Figure 2]. Grapes or tomatoes can be used to practice suturing [Figure 3]. Figure 1: Microscope simulator using a smartphone resting on two bottles Figure 3: Surgery on a grape – Suturing cut grape with 10–0 nylon sutures Complex surgical techniques such as Single Pass Four Throw Pupilloplasty [Figure 4] can be practiced on tomato skin as shown in the video. The sewing machine technique of iridodialysis repair [Figure 5] is also demonstrated on tomato skin.[3] Kaur et al. from the UK demonstrated excellent Face validity and Content validity for practicing cataract surgery steps on grapes, lozenge packet, and cheese.[5] In this article, we will explore the concept of the kitchen ophthalmic surgeon in more detail, examining the benefits and limitations of this approach, as well as the evidence to support its use. Why Kitchen Ophthalmic Surgery? The COVID‑19 pandemic has led to a significant reduction in the number of surgical procedures being performed worldwide. This has had a knock‑on effect on surgical training, with many trainees experiencing a reduction in the number of cases they are able to observe or participate in. This reduction in training opportunities is particularly problematic for surgical specialties such as ophthalmology, where surgical skills are essential. Mishra, et al. have discussed the essentials of setting up a wet laboratory for ophthalmic surgical training during the COVID-19 pandemic and lockdown.[6] They also discussed eyeball fixating devices,[7] preparation of the eye for various types of ocular surgeries, and the role of simulation-based Figure 2: Boiled potato being phaco‑chopped with two instruments Figure 4: Single pass four throw pupilloplasty practiced on tomato skin
Akkara and Kuriakose: Kitchen ophthalmic surgeon training. Odayappan et al. describe an innovative use of intravitreal formalin injection[8] in cadaver eyeballs to make collapsed wet laboratory eyeballs firm and usable for more surgical practice.[9] However, all this may be accessible only to ophthalmic residents who are training in a premier institute. To address this problem, some ophthalmologists have turned to home-based surgical simulation as a way to maintain and improve their surgical skills. The idea is simple: use household items to simulate surgical procedures and practice techniques at home. This approach has a number of benefits, including: Accessibility Simulating surgical procedures at home allows trainees to practice at their own pace and on their own schedule. This can be particularly beneficial for those who have limited access to traditional training opportunities, such as medical students in remote areas or those with limited financial resources. Repetition Repetition is key to improving surgical skills, and practicing at home allows trainees to repeat procedures as many times as they need to to master them. This is particularly important for complex procedures such as cataract surgery, which can be challenging to learn and require a significant amount of practice. Cost-effectiveness Traditional surgical simulation models can be expensive, making them inaccessible to many trainees. Simulating surgical procedures at home using household items is a cost‑effective alternative that can be done using items that are readily available. Improved confidence Practicing at home can help trainees feel more confident in their surgical skills, which can be particularly important for those who are just starting out in their careers. By practicing in a low-pressure environment, trainees can build their skills and confidence without the stress of being in an actual operating room. The Limitations of Kitchen Ophthalmic Surgery While there are many benefits to practicing ophthalmic surgery at home, there are also some limitations to this approach. The most significant limitation is the lack of feedback that trainees receive when practicing at home. Without the guidance of an experienced surgeon, trainees may not know if they are performing procedures correctly or may be developing bad habits that could be difficult to correct later on. Even though the fruits and vegetables provide an easily accessible substitute for animal eyes, the feel of the anterior chamber could not be replicated with the materials used. Another limitation of this technique is the failure to provide practice for the foot and hand coordination required for phacoemulsification training. Another limitation is the potential for injury. Simulating surgical procedures at home can be dangerous if proper safety measures are not taken. For example, using sharp instruments such as scalpels or needles can result in accidental injury if the trainee is not careful. Therefore, it is important for trainees to take appropriate safety precautions when practicing at home. The Evidence Supporting Kitchen Ophthalmic Surgery While the concept of the kitchen ophthalmic surgeon is still relatively new, there is already some evidence to support its use. One study published in the Indian Journal of Ophthalmology in 2021 examined the use of a low-cost, at-home surgical simulator for cataract surgery training.[10] The simulator, which was made using household items such as grapes, potatoes, and plastic tubing, was found to be effective in improving trainees’ surgical skills and confidence. The study concluded that the simulator could be a useful tool for trainees who have limited access to traditional training opportunities. However, the improvement in surgical skills was not studied objectively. While these studies are small and more research is needed to fully evaluate the effectiveness of home‑based surgical simulation, they suggest that this approach has the potential as a way to maintain and improve surgical skills in the current challenging environment. How to Get Started with Kitchen Ophthalmic Surgery If you are interested in practicing ophthalmic surgery at home, there are a few key things you should keep in mind. First and foremost, it is important to ensure that you are practicing safely. This means taking appropriate safety precautions when using sharp instruments, such as wearing gloves and using a sterile technique when necessary. You should also be sure to choose appropriate household items to use for simulation. For example, you might use a grapefruit or an orange to simulate the eye, and plastic tubing or a drinking straw to simulate the instruments used in surgery. You can find more detailed instructions and ideas for home-based surgical simulation in the references listed at the end of this article. Figure 5: Sewing machine technique of iridodialysis repair practiced on tomato skin 62 Delhi Journal of Ophthalmology ¦ Volume 33 ¦ Issue 1 ¦ January-March 2023
Akkara and Kuriakose: Kitchen ophthalmic surgeon It is also important to remember that while practicing at home can be a valuable tool for improving surgical skills, it is not a substitute for traditional training opportunities. If you are a medical student or resident, be sure to take advantage of any opportunities for hands-on training that are available to you. Novel Methods for Surgical Training In addition to the concept of Kitchen Ophthalmic Surgeon, other novel methods for surgical training include the use of virtual reality (VR) simulations and three-dimensional (3D) printed eye models. Both these methods are available as commercial models as well as low-cost Do-It-Yourself formats. Let us look at these in detail. Virtual Reality Eye Surgical Training VR has emerged as a promising tool for ophthalmic surgical training in recent years. Commercial tools such as EyeSi simulator (VRmagic, Mannheim, Germany) and HelpMeSee simulator (HelpMeSee, NewYork, NY, USA)[11] simulate steps of ocular surgeries with binocular 3D visualization and force feedback. Nair et al. evaluated the face and content validity of the HelpMeSee simulator which they found sufficient for cataract surgery training.[11] These devices are currently quite expensive, so only large training institutes and organizations have access to them. To reduce the cost barrier, Jayakumar et al. [12] from Amrita Vishwa Vidyapeetham, Kerala developed a low-cost VR cataract simulator using a leap motion controller (UltraLeap, California, USA) and programmed the virtual cataract surgery simulator in Unity 3D. At the low complexity end, there are even simple smartphone apps to help practice capsulorhexis and steps of phacoemulsification such as Cataract Mobile[13] and Cataract Droid. Ambidexterity is a useful surgical skill for ophthalmologists,[14] and so Eltanamly et al. from Cairo showed that VR surgical simulator can improve the skill of nondominant hand for eye surgeons.[15] VR technology allows trainees to practice surgical techniques in a simulated environment that closely resembles the real surgical setting. The use of VR in ophthalmic surgical training offers several potential benefits, including: Improved surgical skills Studies have shown that VR training can improve surgical skills and reduce the learning curve for trainees. VR simulations allow trainees to perform surgical procedures repeatedly and without the risk of causing harm to patients. This helps trainees to develop their skills and confidence before performing the actual surgery. Objective assessment VR technology can provide objective feedback on trainee performance, allowing trainers to identify areas for improvement and adjust training accordingly. This can be particularly useful in identifying and addressing weaknesses in trainee skills before they progress to the actual surgery. Remote access VR technology can be used to provide training to trainees in remote or underserved areas where access to traditional training opportunities may be limited. Cost-effective Although the initial investment in VR technology may be high, once implemented, it can be cost‑effective in the long run. VR training can reduce the need for expensive equipment and supplies, and also reduce the need for operating room time. Overall, the use of VR in ophthalmic surgical training has shown promising results and has the potential to be a valuable tool in improving surgical skills and reducing the learning curve for trainees. However, the implementation of VR training programs requires specialized equipment and training, which may limit its use in some training programs. Further research is needed to better understand the effectiveness of VR training and to identify areas for improvement. Three‑dimensional Printing for Ophthalmic Surgical Training 3D printing[16] has emerged as another promising tool for ophthalmic surgical training in recent years. 3D printing technology allows the creation of patient‑specific anatomical models that closely resemble the structures of the human eye, which can be used to simulate surgical procedures. The use of 3D printing in ophthalmic surgical training offers several potential benefits, including: Realistic simulation 3D-printed models closely resemble the anatomy of the human eye, which makes them an ideal tool for simulating surgical procedures. Trainees can use these models to practice surgical techniques repeatedly and in a controlled environment, which can help them to develop their skills and confidence. Customization 3D printing technology allows the creation of patient‑specific models, which can be used to train trainees on specific surgical procedures that are unique to individual patients. This can help trainees to develop the necessary skills and knowledge to perform these procedures more efficiently and effectively. Reduced cost 3D printing technology can significantly reduce the cost of surgical training by reducing the need for expensive equipment and supplies. In addition, the use of 3D-printed models can also reduce the need for operating room time. Improved patient outcomes The use of 3D-printed models can help surgeons to plan and prepare for complex procedures, which can lead to improved patient outcomes and reduced surgical complications. Overall, the use of 3D printing in ophthalmic surgical training has shown promising results and has the potential to be a valuable tool in improving surgical skills and reducing the Delhi Journal of Ophthalmology ¦ Volume 33 ¦ Issue 1 ¦ January-March 2023 63
Akkara and Kuriakose: Kitchen ophthalmic surgeon learning curve for trainees. However, the implementation of 3D printing in training programs requires specialized equipment and training, which may limit its use in some training programs. Further research is needed to better understand the effectiveness of 3D printing in surgical training and to identify areas for improvement. Dr. Roshni Mohan, Dr. Mimansaa Agasti, and Dr. Megha Nair from Aravind Eye Hospital Pondicherry describe two 3D printed models RETInal LAser and Photography Practice[17] and RetiSurge,[18] for Retinal LASER training and Retinal Surgical training respectively. These models were designed and built with the help of Dr. Ganne Pratyusha, Dr. Rajesh Vedachalam, and Mr Sulaiman.[18] Dr. John Davis Akkara, Dr. Narayanan Balakrishnan, and Dr. Anju Kuriakose also developed a 3D printed Glaucoma Drainage Device which can be used for wet laboratory training.[19] Multiple designs were made and tested and implanted in a cadaver goat eye, including suturing of the plate to sclera and insertion of tube into anterior chamber as shown in https://www.youtube.com/watch? v = 6s8NiV4tYyY. Conclusion The kitchen ophthalmic surgeon is a new and innovative approach to surgical training that has emerged in response to the challenges posed by the COVID‑19 pandemic. While this approach has some limitations, it may be effective in improving surgical skills and confidence. If you are interested in practicing ophthalmic surgery at home, be sure to take appropriate safety precautions and choose appropriate household items for simulation. And remember, while practicing at home can be a valuable tool for improving surgical skills, it is not a substitute for traditional training opportunities. Acknowledgment OpenAI’s ChatGPT was used for the preparation of parts of this article as a writing experiment. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest. References 1. Kaushik J, Chaitanya YV, Kumar A, Jakhar P, Shetty R, Singhal A, et al. Prevalence and effectiveness of innovative techniques in ophthalmic surgical training during COVID-19 pandemic in India. Indian J Ophthalmol 2021;69:3704‑8. 2. Akkara JD, Kuriakose A. Kitchen ophthalmic surgeon: Recipe for operation success in work-from-home era. Indian J Ophthalmol 2021;69:2851‑2. 3. Kitchen Ophthalmic Surgeon. 2021. Available from: https://www. youtube.com/watch?v=WPdIj9EBevo. [Last accessed on 2021 Dec 24]. 4. Shukla A, Gupta P. Flash Box – A pragmatic tool to hone surgical skills of residents during postgraduate curriculum in ophthalmology. TNOA J Ophthalmic Sci Res 2020;58:17‑9. Available from: https:// www.tnoajosr.com/article.asp?issn=2589‑4528;year=2020;volume=58; issue=1;spage= 17;epage=19;aulast=Shukla. [Last accessed on 2023 Feb 20]. 5. Kaur S, Shirodkar AL, Nanavaty MA, Austin M. Cost‑effective and adaptable cataract surgery simulation with basic technology. Eye (Lond) 2022;36:1384‑9. 6. Mishra D, Bhatia K, Verma L. Essentials of setting up a wet lab for ophthalmic surgical training in COVID-19 pandemic. Indian J Ophthalmol 2021;69:410-6. 7. Ramakrishnan S, Baskaran P, Fazal R, Sulaiman SM, Krishnan T, Venkatesh R. Spring‑action Apparatus for Fixation of Eyeball (SAFE): A novel, cost‑effective yet simple device for ophthalmic wet‑lab training. Br J Ophthalmol 2016;100:1317‑21. 8. Odayappan A, Sulaiman SM, Nachiappan S, Venkatesh R. Formalin-assisted training eyes for ophthalmic wet lab practice. Indian J Ophthalmol 2021;69:3752‑5. 9. Akkara JD, KuriakoseA. Commentary: Intravitreal injection of formalin as a life hack for ophthalmic wet lab training. Indian J Ophthalmol 2021;69:3755‑6. 10. Golash V, Kaur S, Naveed H, Nanavaty MA. Low‑tech intraocular ophthalmic microsurgery simulation: A low‑cost model for home use. Indian J Ophthalmol 2021;69:2846‑50. 11. Nair AG, Ahiwalay C, Bacchav AE, Sheth T, Lansingh VC. Assessment of a high‑fidelity, virtual reality‑based, manual small‑incision cataract surgery simulator: Aface and content validity study. Indian J Ophthalmol 2022;70:4010‑5. 12. Jayakumar A, Mathew B, Uma N, Nedungadi P. Interactive Gesture Based Cataract Surgery Simulation. Kochi: In 2015 Fifth International Conference on Advances in Computing and Communications (ICACC). IEEE; 2015. p. 350‑3. Available from: https://ieeexplore.ieee.org/ document/7433879/. [Last accessed on 2021 Dec 24]. 13. Cataract Mobile. App Store; 2018. Available from: https://apps. apple.com/by/app/cataractmobile/id482568096. [Last accessed on 2023 Feb 21]. 14. Akkara JD, Kuriakose A. Commentary: Ambidextrous practice makes eye surgeon perfect. Indian J Ophthalmol 2022;70:1799‑800. 15. Eltanamly RM, Elmekawey H, Youssef MM, Hassan LM. Can virtual reality surgical simulator improve the function of the non-dominant hand in ophthalmic surgeons? Indian J Ophthalmol 2022;70:1795‑9. 16. Akkara J, Kuriakose A. The magic of three‑dimensional printing in ophthalmology. Kerala J Ophthalmol 2018;30:209‑15. 17. GanneP, KrishnappaNC, BaskaranP, SulaimanSM, VenkateshR. Retinal laser and photography practice eye model: A cost‑effective innovation to improve training through simulation. Retina 2018;38:207‑10. 18. Chhabra K, Khanna V, Vedachalam R, Sindal M. RetiSurge – Enabling “Dry Lab” vitreoretinal surgical training during COVID-19 pandemic. Indian J Ophthalmol 2021;69:982‑4. 19. AIOC2022 GP55 Topic Dr John Davis Akkara Designing and Making 3D Printed Glaucoma Drainage Devices; 2022. Available from: https://www.youtube.com/watch?v=6s8NiV4tYyY. [Last accessed on 2023 Feb 21]. 64 Delhi Journal of Ophthalmology ¦ Volume 33 ¦ Issue 1 ¦ January-March 2023
Abstract Theme Section Introduction Corneal astigmatism is a frequent accompaniment in patients undergoing cataract surgery.[1] The introduction of toric intraocular lenses (IOLs) for the management of these patients has provided anterior segment surgeons a simple and reliable one-step solution. These have stood the test of time really well in terms of reliable postoperative outcomes as well as both surgeon and patient satisfaction rates. Studies have shown that these lenses are rotationally stable once implanted within the capsular bag underneath a well-centered capsulorrhexis.[2,3] The shift from manual marking to the use of various image-guided systems such as the Callisto eye (Carl Zeiss Meditec, Jena, Germany) and the VERION (Alcon, Fort Worth, TX, USA) played a significant role in minimizing the errors related to IOL positioning by ensuring accurate placement on the desired axis. Despite these advances, a lot of times the refractive astigmatism attained is not absolutely zero. A meta‑analysis by Kessel et al. showed the average residual astigmatism following toric IOL implantation to range between 0.18 and 0.77 D.[4] Postoperative refractive outcome involves a multiplay of various factors including precise measurement of preoperative corneal astigmatism, accurate estimation of cylindrical power and axis of toric IOL, as well as ensuring its optimal Toric intraocular lenses(IOLs) have been a game‑changer for addressing patients with cataract and significant preexisting corneal astigmatism. With increasing demands and expectations of the patients, there is now a greater responsibility on part of anterior segment surgeons to offer a postoperative uncorrected visual acuity of 6/6. At present, majority of surgeons rely on the “measured” values of anterior corneal astigmatism and “predicted” values of posterior corneal astigmatism to calculate the final IOL power and the axis of the toric IOL. Such a practice, at times, has been shown to result in unexpected postoperative refractive outcomes. We have had situations where the anterior corneal curvature values suggested using a spherical IOL, while the measured total corneal astigmatism values suggested implanting a toric IOL to minimize the postoperative residual astigmatism. Not only this, we also encountered situations where the axis of the anterior corneal curvature is not in concordance with that of the total corneal power. Differences as high as 8° have been witnessed. Implanting a toric IOL solely based on the magnitude and axis of the anterior corneal astigmatism would have resulted in residual astigmatic errors. In this article we intend to elaborate on the available literature regarding the contribution of the posterior corneal surface toward the total corneal power. We would also provide some of our clinical scenarios which changed our practice pattern for IOL calculations and discuss future applications of this information. Keywords: Posterior corneal astigmatism, toric intraocular lens, total corneal astigmatism Address for correspondence: Dr. Sanjay Chaudhary, Eye7 Eye Hospitals Private Limited, New Delhi, India. E‑mail: [email protected] How to cite this article: Chaudhary S, Pandey A, Sharma A, Chaudhary R, Mehra H, Khurana N, et al. Calculating the power of toric intraocular lens using total corneal astigmatism measured by a swept-source optical coherence tomography‑based device: An observation which changed our practice pattern. Delhi J Ophthalmol 2023;33:65‑9. Calculating the Power of Toric Intraocular Lens using Total Corneal Astigmatism Measured by a Swept-Source Optical Coherence Tomography-Based Device: An Observation which Changed our Practice Pattern Sanjay Chaudhary, Alka Pandey, Anju Sharma, Rahil Chaudhary, Hema Mehra, Nishtha Khurana, Divya Vermani, Ritu Nagpal Cornea and Refractive Surgery Services, Eye7 Eye Hospitals Private Limited, New Delhi, India Access this article online Quick Response Code: Website: https://journals.lww.com/djo DOI: 10.4103/DLJO.DLJO_14_23 This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution‑NonCommercial‑ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non‑commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms. For reprints contact: [email protected] Submitted: 03-Mar-2023 Accepted: 25-Apr-2023 Published: 05-Jul-2023 © 2023 Delhi Journal of Ophthalmology | Published by Wolters Kluwer - Medknow 65
Chaudhary, et al.: Toric IOL power calculation using measured total corneal astigmatism positioning during cataract surgery.[5] As far as the accuracy of determination of IOL power and axis is concerned, a reliable assessment of biometry is the prerequisite. Of all the parameters assessed preoperatively, corneal power is one of the most pertinent variables. After the realization of the contribution of the posterior surface toward total corneal power, there has been a shift toward the use of IOL power calculation methods based on the Barrett’s algorithm. The Barrett toric calculator has been consistently shown to produce lower residual astigmatism prediction errors in various studies and therefore has been widely accepted as a reliable tool for toric IOL calculations.[6,7] Since the past few years, observations from various authors and their studies have diverted our attention toward the contribution of the posterior corneal surface and various methods to directly image the posterior corneal surface. Identifying and appropriately quantifying this link might help to further fine‑tune the postoperative refractive outcomes in our subset of patients. Our standard practice As a part of routine protocol, for all patients planned for cataract surgery, we perform biometry using both optical and ultrasound techniques (immersion scan) taking into account that the values are concordant among the two methods. For optical biometry, we have been relying on Lenstar LS 900 (Haag-Streit AG, Koeniz, Switzerland), an optical low‑coherence reflectometry‑based method, and the VERION image‑guided system (Alcon, Fort Worth, TX, USA) as the standard routine for obtaining keratometry readings. Both these imaging devices have been shown to reliably measure the magnitude as well as the axis of the anterior corneal surface astigmatism.[8,9] The toric IOL power and the axis to be implanted were then calculated using the Barrett toric calculator available on https:// ascrs.org/tools/barrett-toric-calculator. Until recently, we have been relying only on measured anterior keratometric values for selecting our cases suitable for toric IOL implantation. Recently, we changed our practice to utilizing the total keratometry values measured using a swept-source optical coherence tomography (SS-OCT)-based device (ANTERION [Heidelberg Engineering, Heidelberg, Germany]). The cataract application of this device provides important biometry measurements for surgical planning including anterior, posterior as well as total corneal astigmatism (TCA), anterior chamber depth, lens thickness, and axial length. The optimized SS-OCT technology allows for accurate measurements besides providing high-resolution imaging‑based visual confirmation. The device’s inbuilt IOL calculator helps to conveniently plan and perform toric IOL calculations on a busy practice day. The high-resolution OCT images provide a visual display of the entire anterior segment, spanning from the anterior surface of the cornea to the posterior surface of the lens, further helping in precise surgical planning. The repeatability and reliability of this device have been demonstrated in various studies.[10,11] Astigmatism being a vector quantity carries a magnitude as well as a direction. The magnitude as well as the axis of anterior corneal astigmatism might be significantly different from the measured TCA. Herein, we highlight two scenarios wherein a significant difference between the anterior corneal astigmatism and the measured TCA was noted in terms magnitude as well as axis. Case selection and toric IOL power calculation were performed using the TCA values measured by the ANTERION cataract application. Case Scenarios Case I A 66‑year‑old male presented to our practice with complaints of gradual blurring of vision in his eyes over the previous 6 months. At presentation, the uncorrected visual acuity (UCVA) was 6/18 in both eyes. Slit‑lamp examination revealed dense nuclear sclerosis in both eyes along with posterior subcapsular opacities. Biometry was performed using the ANTERION platform [Figure 1]. Right eye Sim K values at 3 mm were 45.50 at 161° and 44.96 at 71°. The anterior corneal astigmatism was 0.54 D at 161° while the measured TCA was 1.01 at 168° [Figure 1]. We decided to place a toric IOL in the right eye based on TCA values. A spherical power of +23.5 D was chosen from the device’s inbuilt IOL power calculation formula based on Barrett’s algorithm [Figure 2]. The toric IOL cylindrical power and the axis to be implanted were calculated based on the actual measured value of TCA rather than the predicted one using the device’s inbuilt toric calculator. A toric IOL with cylindrical power of 1.5 D (T3) was chosen for placement at 166 via a main surgical incision placed at 180° [Figure 2]. The surgically induced astigmatism value used for calculation was 0.2 D. The predicted residual astigmatism was 0.13 D at 76° [Figure 2]. On postoperative day 1 and at 1-month follow-up visit, the patient’s UCVA was 6/6. Case II A 65‑year‑old female presented to us with complaints of gradual blurring of vision in her right eye for the past 4 months. Clinical examination revealed early nuclear sclerosis with posterior subcapsular changes. The anterior corneal astigmatism as measured using the ANTERION platform was 0.99 D at 143° while the measured TCA was 1.13 at 151° (a difference of 8°) [Figure 3]. Cylindrical power of the toric IOL and its final axis (1.50 D at 150°) was decided based on the values of TCA. The anticipated residual astigmatism was 0.12 D at 150°. Postoperatively, the patient’s UCVA was 6/6 at day 1 and at 1‑month follow‑up visit. Planning the IOL position according to the axis of anterior astigmatism might have resulted in a higher residual error keeping in mind the assumption that a 10° displacement of toric IOL from the intended axis leads to a 33% reduction in the astigmatism‑reducing effect. 66 Delhi Journal of Ophthalmology ¦ Volume 33 ¦ Issue 1 ¦ January-March 2023
Chaudhary, et al.: Toric IOL power calculation using measured total corneal astigmatism Discussion The posterior surface of the cornea has been shown to induce a certain degree of astigmatism, which in majority of cases has been shown to be against the rule (ATR).[12] Several studies have been used to quantify the magnitude of posterior corneal astigmatism (PCA), approximately amounting to 0.24–0.42 D.[13‑15] The study by LaHood and Goggin evaluated PCA using SS‑OCT‑based IOLMaster 700, to range between 0 and 1.21 D.[16] In about 5% of cases, this value is higher than 0.50 D. Ahigh with‑the‑rule (WTR) astigmatism on the anterior corneal surface has been shown to be accompanied by a greater ATR astigmatism of the posterior corneal surface, overall resulting in a lower total value of corneal astigmatism.[12,17] Delhi Journal of Ophthalmology ¦ Volume 33 ¦ Issue 1 ¦ January-March 2023 67 Figure 1: Various biometry measurements including a detailed analysis of anterior, posterior as well as TCA, axial length, axial length, anterior chamber depth, lens thickness as provided by the cataract application of the ANTERION imaging platform (Heidelberg Engineering). The left half shows high‑resolution OCT imaging of the anterior segment spanning from the anterior surface of the cornea to the posterior surface of the lens. OCT: Optical coherence tomography, TCA: Total corneal astigmatism Figure 2: The results of various IOL calculation formulas including the Barrett formula on the left half while the toric IOL calculator based on actual measured value of PCA on the right half, as provided by the cataract application of the ANTERION. The calculations belong to the same patient, as shown in Figure 1. IOL: Intraocular lens, PCA: Posterior corneal astigmatism
Chaudhary, et al.: Toric IOL power calculation using measured total corneal astigmatism Studies in the recent past have diverted our attention toward measuring the TCA rather than solely relying on the anterior corneal surface values. This was contributed in part by the published observations of overestimation of cylindrical power in eyes with WTR astigmatism eyes and underestimation in eyes with ATR astigmatism.[17‑20] The PCA can be either predicted using measurements obtained from the anterior corneal surface assuming a fixed relationship between the two surfaces,[17] or it can be directly imaged using various platforms such as the SS‑OCT‑based devices, Scheimpflug imaging, and combined Scheimpflug and placido‑based methods.[13-16] In 2009, Ho et al. were the first to compare keratometric astigmatism with TCA in a large study of 493 subjects.[21] Using a rotating Scheimpflug camera (Pentacam, Oculus), they found 10.3% of their study candidates requiring toric IOL implantation to have a corneal astigmatism magnitude that differed by more than 0.50 D from the magnitude of TCA or an angle between the two components that differed by more than 10°. The study concluded that ignoring the posterior corneal surface might lead to significant deviations in the measurement of corneal astigmatism. Savini and Næser[19] in their prospective comparative study found that of all the factors investigated for their contributory role in predicting the residual refractive astigmatism following toric IOL implantation, PCA had the highest influence. The authors concluded basing calculations on TCA rather than keratometric astigmatism to better predict postoperative residual refractive astigmatism. Goggin et al. also noted significant errors in predicting the astigmatic outcome, especially in eyes receiving IOLs with <2 D cylindrical power. The study found overcorrection by a factor of 1.38 in eyes with preexisting WTR astigmatism and under correction by a factor of 0.65 in eyes with ATR astigmatism.[20] Although the utilization of both measured PCA and predicted PCA has been shown to improve the accuracy of toric IOL calculations, studies directly comparing the two variables have reported mixed results. Reitblat et al. [22] in their study of 115 eyes suggested using methods that take into account the effect of the posterior cornea in toric IOL calculations based on their observation of reduced residual astigmatism in eyes where both surfaces were taken into consideration compared to eyes wherein only the anterior surface was measured. This is in contrast to the study by Lukewich et al. [23] who compared residual astigmatism prediction errors with Barrett toric calculations performed using predicted PCA and the PCA measured using IOLMaster 700. No significant differences in mean absolute residual astigmatism prediction error was observed across different calculation methods. Barrett toric calculations using predicted as well as measured PCA values produced comparable residual astigmatism prediction errors. Overall, both predicted as well measured values of PCA significantly affect postoperative refractive outcomes, but it still needs to be determined which value is more impactful.[24-26] What we need to have is the search of an ideal imaging platform or establish the utility of currently available devices for providing reliable assessment of true corneal power. The Figure 3: Biometry measurements on the right half and toric IOL calculation performed using the magnitude and the axis of TCA on the left half using the ANTERION platform. IOL: Intraocular lens, TCA: Total corneal astigmatism 68 Delhi Journal of Ophthalmology ¦ Volume 33 ¦ Issue 1 ¦ January-March 2023
Chaudhary, et al.: Toric IOL power calculation using measured total corneal astigmatism coming few years will be an eye-opener in this regard and will provide us more evidence regarding the measurement precision of the currently available imaging platforms. Alarge prospective study with well‑defined inclusion and exclusion criteria, including patients with varying ranges of corneal astigmatism, across different age groups might help to elucidate a clear answer to this question. Declaration of patient consent The authors certify that they have obtained all appropriate patient consent forms. In the form the patient (s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initial s will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest. References 1. Ferreira TB, Hoffer KJ, Ribeiro F, Ribeiro P, O’Neill JG. Ocular biometric measurements in cataract surgery candidates in Portugal. PLoS One 2017;12:e0184837. 2. Gyöngyössy B, Jirak P, Schönherr U. Rotational stability and patient satisfaction after implantation of a new toric IOL. Eur J Ophthalmol 2016;26:321‑7. 3. Sasaki K, Eguchi S, Miyata A, Nishimura T, Miyata K, Hasegawa Y, et al. Anterior capsule coverage and rotational stability of an acrylic toric intraocular lens. J Cataract Refract Surg 2021;47:618‑21. 4. Kessel L, Andresen J, Tendal B, Erngaard D, Flesner P, Hjortdal J. Toric intraocular lenses in the correction of astigmatism during cataract surgery: A systematic review and meta‑analysis. Ophthalmology 2016;123:275‑86. 5. Hirnschall N, Findl O, Bayer N, Leisser C, Norrby S, Zimper E, et al. Sources of error in toric intraocular lens power calculation. J Refract Surg 2020;36:646‑52. 6. Carmona‑González D, Castillo‑Gómez A, Palomino‑Bautista C, Romero-Domínguez M, Gutiérrez-Moreno MÁ. Comparison of the accuracy of 11 intraocular lens power calculation formulas. Eur J Ophthalmol 2021;31:2370‑6. 7. Iijima K, Kamiya K, Iida Y, Shoji N. Comparison of Predictability Using Barrett Universal II and SRK/T Formulas according to Keratometry. J Ophthalmol 2020;2020:7625725. doi: 10.1155/2020/7625725. 8. McAlinden C, Gao R, Yu A, Wang X, Yang J, Yu Y, et al. Repeatability and agreement of ocular biometry measurements: Aladdin versus Lenstar. Br J Ophthalmol 2017;101:1223‑9. 9. Nemeth G, Szalai E, Hassan Z, Lipecz A, Berta A, Modis L Jr. Repeatability data and agreement of keratometry with the VERION system compared to the IOLMaster. J Refract Surg 2015;31:333‑7. 10. Schiano‑Lomoriello D, Hoffer KJ, Abicca I, Savini G. Repeatability of automated measurements by a new anterior segment optical coherence tomographer and biometer and agreement with standard devices. Sci Rep 2021;11:983. 11. Oh R, Oh JY, Choi HJ, Kim MK, Yoon CH. Comparison of ocular biometric measurements in patients with cataract using three swept-source optical coherence tomography devices. BMC Ophthalmol 2021;21:62. 12. Koch DD, Ali SF, Weikert MP, Shirayama M, Jenkins R, Wang L. Contribution of posterior corneal astigmatism to total corneal astigmatism. J Cataract Refract Surg 2012;38:2080‑7. 13. Royston JM, Dunne MC, Barnes DA. Measurement of posterior corneal surface toricity. Optom Vis Sci 1990;67:757‑63. 14. Zhang L, Sy ME, Mai H, Yu F, Hamilton DR. Effect of posterior corneal astigmatism on refractive outcomes after toric intraocular lens implantation. J Cataract Refract Surg 2015;41:84‑9. 15. Miyake T, Shimizu K, Kamiya K. Distribution of posterior corneal astigmatism according to axis orientation of anterior corneal astigmatism. PLoS One 2015;10:e0117194. 16. LaHood BR, Goggin M. Measurement of posterior corneal astigmatism by the IOLMaster 700. J Refract Surg 2018;34:331‑6. 17. Koch DD, Jenkins RB, Weikert MP, Yeu E, Wang L. Correcting astigmatism with toric intraocular lenses: Effect of posterior corneal astigmatism. J Cataract Refract Surg 2013;39:1803‑9. 18. Tonn B, Klaproth OK, Kohnen T. Anterior surface‑based keratometry compared with Scheimpflug tomography‑based total corneal astigmatism. Invest Ophthalmol Vis Sci 2014;56:291‑8. 19. Savini G, Næser K. An analysis of the factors influencing the residual refractive astigmatism after cataract surgery with toric intraocular lenses. Invest Ophthalmol Vis Sci 2015;56:827‑35. 20. Goggin M, Zamora‑Alejo K, Esterman A, van Zyl L. Adjustment of anterior corneal astigmatism values to incorporate the likely effect of posterior corneal curvature for toric intraocular lens calculation. J Refract Surg 2015;31:98‑102. 21. Ho JD, Tsai CY, Liou SW. Accuracy of corneal astigmatism estimation by neglecting the posterior corneal surface measurement. Am J Ophthalmol 2009;147:788‑95, 795.e1‑2. 22. Reitblat O, Levy A, Kleinmann G, Abulafia A, Assia EI. Effect of posterior corneal astigmatism on power calculation and alignment of toric intraocular lenses: Comparison of methodologies. J Cataract Refract Surg 2016;42:217‑25. 23. Lukewich MK, Murtaza F, Somani S, Tam ES, Chiu HH. Comparison of Barrett toric calculations using measured and predicted posterior corneal astigmatism in cataract surgery patients. Clin Ophthalmol 2022;16:1739‑51. 24. Ribeiro FJ, Ferreira TB, Relha C, Esteves C, Gaspar S. Predictability of different calculators in the minimization of postoperative astigmatism after implantation of a toric intraocular lens. Clin Ophthalmol 2019;13:1649‑56. 25. Abulafia A, Hill WE, Franchina M, Barrett GD. Comparison of methods to predict residual astigmatism after intraocular lens implantation. J Refract Surg 2015;31:699‑707. 26. Park DY, Lim DH, Hwang S, Hyun J, Chung TY. Comparison of astigmatism prediction error taken with the Pentacam measurements, Baylor nomogram, and Barrett formula for toric intraocular lens implantation. BMC Ophthalmol 2017;17:156. Delhi Journal of Ophthalmology ¦ Volume 33 ¦ Issue 1 ¦ January-March 2023 69
Theme Section Frequency Based Phacoemulsification, and Calibrated Phacoemulsification Probe Tip: A Journey of Innovations Taru Dewan Department of Ophthalmology, Atal Bihari Vajpayee Institute of Medical Sciences and Dr. Ram Manohar Lohia Institute, New Delhi, India This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution‑NonCommercial‑ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non‑commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms. Access this article online Quick Response Code: Website: https://journals.lww.com/djo DOI: 10.4103/DLJO.DLJO_13_23 How to cite this article: Dewan T. Frequency based phacoemulsification, and calibrated phacoemulsification probe tip: A journey of innovations. Delhi J Ophthalmol 2023;33:70‑2. Submitted: 01-Mar-2023 Revised: 25-Apr-2023 Accepted: 25‑Apr‑2023 Published: 05-Jul-2023 Nuclear management is the most demanding step for phacoemulsification for all trainees and adding objectivity to that has always been a dream.[1,2] It was 2007 when the idea of calculating preoperatively the exact depth of penetration of phacotip required for a successful vertical chop started taking shape at our hospital, a premier institute of Delhi. The geometric calculations had to keep in mind the unique shape of nucleus and angulated path of tip as it traversed to reach the sweet spot where crack would happen. As the length would vary according to distance of entry point from the center of anterior lens surface as well as depth of the sweet spot, a model was created and with help of students from Indian Institute of Technology (IIT Delhi) a scientific calculator for ellipsoid structures was used [Figure 1]. Mathematical Assumption The cross section of a lens nucleus is ellipsoidal. Ageometrical estimate of the radius of the ellipse traversed by the phacotip to reach the centre can be made preoperatively. The calculation would depend largely on three parameters. 1. The major axis of the ellipse (namely the lens diameter[b]) 2. The minor axis of the ellipse (namely lens thickness [a]) 3. The point of entry on the surface of the lens. This defines an angle “theta” which this radius makes with the vertical axis and in turn can be approximated by the length of the arc from centre of lens surface to entry point [y]. It is known that the adult human crystalline lens varies in thickness from 4.2 ± 0.5 mm and has a diameter of 9.6 ± 0.4 mm. Assuming the lens diameter(b) to be from 9.2 to 10.0mm, the lens thickness (a) varying from 3.7 to 4.7 mm and the point of entry of phacotip 2.0–3.0 mm from centre of anterior lens surface (y), this distance (x) would vary from 2.54 to 3.2 mm (using online Wolfram calculator) in thinnest to thickest nuclei. Higher values are linked with increase in (a), (b) as well as (y). In cataractous lens, the harder a nucleus the deeper, it may be required to penetrate to achieve a full thickness crack. While the lens diameter was not measured, the rest were easy to determine using biometry and nuclear grading preoperatively and entry point peroperatively. It was proposed that if a note of all three variables, i.e., lens thickness, nuclear hardness, and point of entry at the time of surgery is made then one may be able to recommend an effective and safe phacodepth for achieving full-thickness nuclear crack in various grades of hard cataract. Address for correspondence: Dr. Taru Dewan, Department of Ophthalmology, Atal Bihari Vajpayee Institute of Medical Sciences and Dr. Ram Manohar Lohia Institute, Baba Kharak Singh Marg., New Delhi ‑ 110 001, India. E‑mail: [email protected] 70 © 2023 Delhi Journal of Ophthalmology | Published by Wolters Kluwer - Medknow Abstract In today’s era, when instruments and machines decide what kind of ophthalmic advances would come up in the future, doctors have silently given the baton to engineers and industry. Even the geniuses among us fall prey to being merely the best users of what the industry offers. No wonder there are only a handful of patent holders among Ophthalmologists. We must not underestimate the innovative and intuitive streak in all of us and reclaim the position of being the driving force in Ophthalmology. Through this article, a small glimpse of the journey to the final development of a calibrated tip and the concept of frequency-based phacoemulsification is presented. Keywords: Phacoemulsification, patent, calibrated phacotip, frequency based phacoemulsification
Dewan: Innovations, patent, phacoemulsification Once the above-mentioned variable is known surgeon can safely bury, the tip to required depth during surgery and achieve the required goal. Having calculated an expected required range for the length of phacotip penetration, the next challenge was how to measure as one operates and buries the phacotip. Markings on the tip was an intuitive suggestion and novice attempts to mark the tip were started. It was unethical to use any external paints, etc., and the scratching of tip was difficult, imprecise, and damaging. The weight of the tip and oscillatory movements required to be balanced. That was the time when industry (Appasamy associates) was contacted to help in laser etching of phacotips, first prototypes, SRF CP1 and SRFCMP1 for conventional phacoemulsification and microincision phacoemulsification, respectively. Each tip had 4 bands 0.2 mm wide and 0.2 mm apart starting 2 mm from the leading edge of the phaco tip. Once the calibrated phacotip was ready, an observational study was designed in 200 patients, after appropriate ethical approvals, where it was found that the approximate average phacodepth required was 2.8 mm in grades 6.0–6.9, 2.6 mm in grades 4.5–5.9 and 2.4 mm in grades 2.0–4.4 Lens Opacity Classification System III ( LOCSIII) cataracts. Thus, with a proper scientific preoperative assessment one could use the calibrated phacotip which would help in performing an anxiety free vertical chop in various grades of cataract. Subsequently, a patent of design for the calibrated tip was filed (Everyone should learn how to do it). As it was realized that there was no usage of calibrations beyond 2.8 mm, the design was improved to have only two bands from 2.2–2.4 mm to 2.6–2.8 mm from the leading edge. This was named SRF CMP2 [Figure 2]. A series of studies followed assessing the safety and efficacy of calibrated tip in comparison with the conventional tip. The nuclear management became safe, fast, and efficient. Starting from the first video presentation of SRF CMP 1 at ASCRS in 2011, the evolution has gone to the final design SRF CMP2.[3,4] In addition further studies were presented on incisional fluid loss and nuclear cleavage time with presentations at ASCRS, ESCRS, ARVO, and NHGEI‑IOC.[5‑8] Performing a safe and effective vertical chop is what every phacosurgeon desires, but in the absence of an objective guide, they all learn after trial and error to get that right depth of impalement of the nucleus. A simple design as this can make the whole process so much easier and predictable that it would be welcomed by all users including the new phaco surgeons as well as those converting to chopping techniques. Not only does this new design make chopping a great experience but also serves as a measuring tool for any intracameral or peroperative measurements. Studies favorably evaluated the nucleus emulsification time, incisional fluid loss as well as number of attempts for a successful chop.[8‑10] Working from conceptualisation to execution of the successful model brought satisfaction. It was an exhilarating moment when the patent office informed about the grant of patent to the researchers. First in our institute and being among counted few ophthalmologists with a patent, it felt thrilling. Even though the materialization of an idea into a simple and extremely useful tool was fulfilling in itself, it was also good to set an example that doctors can be successful innovators and not passive recipients of advancements by biomedical engineers. As much change that the thinking was bringing to the innovation, the journey itself was bringing greater transformations to the mindset. The materialising of thoughts empowers every individual and there were no exceptions here either. Another ongoing innovation was on OCTOPUS, an acronym for “Our Co‑MICS technique of one percent ultrasound.” The endothelial salvaging effects of this method, drastically reduced power usage of phaco.[11] It was presented at ASCRS in 2011 and 2013, how the hardest of nuclei could be emulsified using one percent ultrasound.[12,13] It was real and happening across many different machines and there were videos of surgeries to prove it but the reason behind it was to be explained. It was in one of those fortunate evenings at Encinitas when looking at a larger picture with a clear mind, everything around seemed to be Delhi Journal of Ophthalmology ¦ Volume 33 ¦ Issue 1 ¦ January-March 2023 71 Figure 1: Diagrammatic representation of lens as an ellipsoid Figure 2: Calibrated phacotip SRF CMP2
Dewan: Innovations, patent, phacoemulsification made up of tiny particles. Athought dawned that anything can be resolved to constituent molecules upon application of a correct frequency. Be it an obstinate mind or a hard rock. It just has to match the resonant frequency of the matter to make it vibrate. And there it was, the code was broken. The resonant frequency of the lens had to be matched to make it dissolve. Sifting through scientific theories, quantum physics had it all sorted. To find the same, one could either take lens samples and analyze them for their resonant frequency, or keep applying different frequencies to lens and note the most effective one. Once again IIT Delhi came to the rescue for the work on lens samples with nanoindentation and Raman spectroscopy.[14,15] However, for the second approach, the major impetus came when it was discovered that in a world where every phacomachine had handpieces with its own fixed frequency, noncomparable to others. One company offered different frequency handpieces, namely Geuder. This became a game changer and a pilot study followed by randomised controlled trial proved the 42 KHz to be better than 28 KHz frequency handpiece.[16-19] The industry was requested to make a still higher frequency handpiece to allow one to inch closer to the desired frequency for hard cataracts. It was successfully designed by Geuder and incorporated in their Megatron S4 phacomachine. The trial that followed evaluated the effective phacoemulsification time (EPT) and estimated fluid usage (EFU) with 53 KHz, 42 KHz and 28 KHz frequency probes for hard cataracts. Endothelial parameters were observed for 6 months. Higher frequency ultrasound was associated with a lower EPT and EFU as well as better endothelial preservation than lower frequencies in hard cataracts. The names of both researchers were included as co-innovators along with the engineering team from Geuder in German patent register for the high frequency hand piece and the study was published.[20] It was a strenuous journey but never tiring. Fresh entrants in ophthalmology always brought hope and renewed energy. The direction it gave, opened up avenues for further improvements of an essential technique. The novel concept of frequency based phacoemulsification can be a panacea for hard cataracts. Even if the industry is driven by economically profitable projects, it won’t be able to ignore the change for long. The beautiful part about this journey is that it does not end. The path never fails to surprise as it ramifies and remerges, goes straight or meanders. However, only one thing alone is certain that it goes on irrespective of who walks the path. Wishing that all readers get to walk the path of meaningful and intuitive innovations as they take on their journey. I wish to acknowledge and thank Dr. Praveen Kumar Malik for not only envisaging the concept of phacotip and being the guide and senior co-researcher for both projects but also for giving meaning to the journey. Links 1. https://register.dpma.de/DPMAregister/pat/ register?AKZ=1020172146796andCURSOR=0 2. https://ipindiaservices.gov.in/PublicSearch/ PublicationSearch/Eregister with Patent No. 20352293. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest. References 1. Dooley IJ, O’Brien PD. Subjective difficulty of each stage of phacoemulsification cataract surgery performed by basic surgical trainees. J Cataract Refract Surg 2006;32:604‑8. 2. Taravella MJ, Davidson R, Erlanger M, Guiton G, Gregory D. Characterizing the learning curve in phacoemulsification. J Cataract Refract Surg 2011;37:1069‑75. 3. Malik PK, Dewan T. CalibChop Technique for Effective Vertical Chop in Various Grades of Cataract Using a Calibrated Phacotip. Video Presentation. San Diego, USA: ASCRS ASOA; 2011. 4. Malik PK, DewanT, Kashyap J, GuptaOP. Calib Chop: Asafe and effective vertical chop with calibrated phaco tip. DOS Times 2011;17:25‑6. 5. Malik PK, Taru Dewan T, Kashyap J. Evaluation of Phacodepth Required to Achieve Full Thickness Nuclear Crack in Various Grades of Cataract and to Determine a Correlation between the Two. Poster Presentation. NHGEI 4th International Ophthalmology Congress, Suntec Singapore; 2011. 6. Vohra V, Malik PK, Dewan T, Gupta M. Evaluation of Customised Tip Exposure for a Safe and Effective Vertical Chop in Various Grades of Cataract using a Calibrated Phacotip: Paper Presentation, XXXI Congress of ESCRS, Amsterdam, Netherlands; 2013. 7. Vohra V, Malik PK, Dewan T, Gupta M, Gupta P.Evaluation of Incisional Fluid Loss using different Sleeve Positions on Calibrated Phacotip During Coaxial Phacoemulsification: A One year Comparative Observational Study. Paper Presentation. New Delhi: Asia ARVO; 2013. 8. Malik PK, Taru Dewan T, Shekhar S. Comparison of Nuclear Cleavage Time Using Calibrated and Conventional Phacotips During Coaxial Microincisional Cataract Surgery. Paper presentation. San Diego, USA: ASCRS ASOA; 2015. 9. Malik PK, DewanT, Kashyap J, Gupta P. Safe and effective vertical chop in different grades of cataract using a calibrated phacotip. OJO 2017;10:63‑9. 10. Shekhar S, Malik P, Kumar A, Singh R. Comparing the number of attempts required for complete nuclear chop using calibrated and conventional phacotip. Int J Res Med Sci 2020;8:1994‑8. 11. Dewan T, Malik PK, Anind A, Gupta SK. OCTOPUS: Our Co‑MICS technique of one percent ultrasound. Delhi J Ophthalmol 2013;23:305‑6. 12. Dewan T, Malik PK, Anind A. Evaluation of Efficacy and Safety of High Vacuum Micropulse Phacoemulsification Using Minimal Versus Routine Ultrasound Power Settings: Paper Presentation. San Francisco, USA: ASCRS; 2013. 13. Dewan T, Malik PK, Chaudhary N. A Prospective Randomized Study to Compare the Corneal Endothelial Status in Phacoemulsification with Different Powers in Hard Cataract: Paper Presentation. ASCRS ASOA. San Diego, USA; 2015. 14. Dewan T, Malik PK. Let’s talk in frequencies. Delhi Ophthalmol Soc Times 2015;26:204‑7. 15. Malik PK, Dewan T, Nishad A, Gupta P. Exploring the universe within the human lens through Raman spectroscopy. Off Sci J Delhi Ophthalmol Soc 2017;27:281‑3. 16. Dewan T, Malik PK, Hasan S. Variable ultrasonic frequency affects emulsifying efficiency: A pilot study. 65th Annual Conference of DOS Ophtha Vaganza. New Delhi, India; 2014. 17. Dewan T, Malik PK, Hasan S. Ultrasonic frequency affects Emulsifying Efficiency: A Pilot Study of Variable Frequency Phacoemulsification. 27th Annual Meeting of APACRS. Jaipur, India; 2014. 18. Dewan T, Malik PK, Kumari R. Comparison of effective phacoemulsification time and corneal endothelial cell loss using 2 ultrasound frequencies. J Cataract Refract Surg 2019;45:1285‑93. 19. Dewan T, Malik PK, Kumari R. Redefining the optimal frequency for more efficient phacoemulsification: A randomised controlled trial comparing different ultrasound frequencies for phacoemulsification. XXXV Congress of the ESCRS. Lisbon, Portugal; 2017. 20. DewanT, MalikPK, TomarP. Comparison of effective phacoemulsification time and corneal endothelial cell loss using three different ultrasound frequencies: Arandomized controlled trial. Indian J Ophthalmol 2022;70:1180‑5. 72 Delhi Journal of Ophthalmology ¦ Volume 33 ¦ Issue 1 ¦ January-March 2023
Abstract Theme Section Introduction Micropulse laser trans-scleral cyclophotocoagulation (MP-TSCPC) has opened a new paradigm in the management of glaucoma. Glaucoma is being managed till now with the topical antiglaucoma medications and invasive surgeries. With the advent of this technology, ophthalmologists have got a new option in their management of this disease. In contrast to the conventional diode laser cyclophotocoagulation, a micropulse laser is not a destructive procedure.[1-3] The advantage of micropulse laser transscleral cyclophotocoagulation (MP-TSCPC) is that it is noninvasive, almost free from the nightmare complications such as malignant glaucoma, hypotony, and endophthalmitis.[4] It also can be repeated again as per patient’s requirements.[5] How it Works • In contrast to conventional diode laser delivery, where a continuous train of high-intensity energy is delivered,[6] micropulse laser application delivers a series of repetitive short pulses of energy with rest periods in between pulses.[6] Micropulse application of laser allows energy to build up with each subsequent pulse to result in photocoagulation, whereas adjacent nonpigmented tissue cools during the off‑cycle and remains below its coagulation threshold.[6] Case Selection MP‑TSCPC can be offered to any patient suffering from glaucoma or on maximum medical therapy where the aim is to reduce the medicine load.[3‑5] It can also be used as a time gap procedure in cases where the patient is not suitable because of systemic parameters for filtering surgery. It can also be done before going for shunt/filtration surgery to decrease intraocular pressure (IOP). It can also be offered to postpenetrating keratoplasty and postvitreoretinal surgery secondary glaucoma patients. Procedure Every case should be considered a surgical procedure and all the necessary preoperative investigations should be done. Electrocardiogram and blood sugar are important as we need to give peribulbar block and during conjunctival holding may result in subconjunctival hemorrhage. Corneal traction suture may be required in the cases where there is difficulty in exposure, more so commonly in the inferonasal quadrant. Topical steroids like loteprednol can be given in the cases of aggressive conjunctiva due to previous multiple anti-glaucoma medications. The author usually does not stop prostaglandin The article describes the efficacy and safety of micropulse transscleral cyclophotocoagulation (MP‑TSCPC) in glaucoma patients. It also describes the pearls of doing this technique. The rare side effects, complications, and future challenges in the use of this technology are also discussed. Keywords: Diode laser TSCPC, glaucoma, intraocular pressure, MP-TSCPC Address for correspondence: Dr. Vineet Sehgal, Glaucoma Services, Sharp Sight Eye Hospitals, New Delhi, India. E‑mail: [email protected] This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution‑NonCommercial‑ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non‑commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms. For reprints contact: [email protected] How to cite this article: Sehgal V. Micropulse laser transscleral cyclophotocoagulation (MP‑TSCPC) for glaucoma management: An overview. Delhi J Ophthalmol 2023;33:73‑5. Micropulse Laser Transscleral Cyclophotocoagulation (MP‑TSCPC) for Glaucoma Management: An Overview Vineet Sehgal Glaucoma Services, Sharp Sight Eye Hospitals, New Delhi, India Access this article online Quick Response Code: Website: https://journals.lww.com/djo DOI: 10.4103/DLJO.DLJO_63_23 Submitted: 26‑Apr‑2023 Accepted: 29‑Apr‑2023 Published: 05-Jul-2023 © 2023 Delhi Journal of Ophthalmology | Published by Wolters Kluwer - Medknow 73
Sehgal: Micropulse laser transscleral cyclophotocoagulation (MP‐TSCPC) for glaucoma management: An overview analogs before the procedure but usually does not give them in the postoperative period. Peribulbar anesthesia is preferred, though can be done under topic anesthesia as well. Patients experience pain during the procedure if they are done under inadequate anesthesia/analgesia. The notch of the probe should be in the direction of the limbus, as shown in Figure 1. The use of hydroxypropyl methylcellulose viscoelastic is advocated over the surface where the probe has to be applied. 3 and 9 o’ clock positions on the limbus are marked and spared during the laser procedure [Figure 2]. Painting motion in one hemisphere is made, followed by another eye to be done [Figure 3]. The author usually follows an 80 s cycle in each hemisphere with an energy of 2000 mW. In cases of small deep-seated eyes, a corneal traction suture to move the eye can be given. The position of the probe should be 2 mm from the limbus. Visualization of the ciliary body through the illuminator probe also and can then customize your position. It is advocated to avoid the position/site where the trabeculectomy is done earlier. As the probe can be used only once, it can be used for 5–6 cases in one go. The probe should be disinfected by the alcohol swab in between two cases. Postoperative Regimen Topical steroids are given four times daily, and the tapering is done weekly. As the ciliary body is involved, cycloplegic like homatropine is usually started. All the anti‑glaucoma medications are continued postoperatively and tapered according to the response. Prostaglandin analogs and miotics are usually avoided. Side Effects and Complications Though almost free from severe vision-threatening complications of Diode laser TSCPC and filtering surgeries,[5,6] the MP‑TSCPC can also have certain side effects which should be kept in mind. Complications that are reported in the literature are a decline in visual acuity, surface keratopathy, persistent mydriasis, hyphema, hypotony, macular edema, scleritis, and choroidal effusion.[7,8] Efficacy The main concern remains regarding the efficacy and duration to which MP‑TSCPC maintains the IOP reduction. Although Western literature has shown a good amount of IOP reduction for a considerable period of time, not much data are available right now in the context of Indian patients. Challenges Although the MP‑TSCPC is easy to perform with fewer risks, its efficacy and use are still restricted because of its high cost and unpredictable clinical course and efficacy. There is no clinically evident endpoint as evident in diode TSCPC. Conclusion Micropulse diode TSCPC is a promising, safe alternative procedure with potential advantages like minimizing further complications compared to conventional diode TSCPC. It should be properly explained to the patient the nature of the procedure and should not be an escape to perform filtering 74 Delhi Journal of Ophthalmology ¦ Volume 33 ¦ Issue 1 ¦ January-March 2023 Figure 1: Notch should be pointing towards the limbus Figure 3: Micropulse Laser going on in a patient with notch of MP3 probe pointing towards the limbus Figure 2: 3 and 9 o’clock positions are spared
Sehgal: Micropulse laser transscleral cyclophotocoagulation (MP‐TSCPC) for glaucoma management: An overview surgeries which still remains the treatment of choice in advanced glaucoma with inadequate IOP control. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest. References 1. Gupta N, Weinreb RN. Diode laser transscleral cyclophotocoagulation. J Glaucoma 1997;6:426‑9. 2. Dastiridou AI, Katsanos A, Denis P, Francis BA, Mikropoulos DG, Teus MA, et al. Cyclodestructive procedures in glaucoma: A review of current and emerging options. Adv Ther 2018;35:2103‑27. 3. Tan AM, Chockalingam M, Aquino MC, Lim ZI, See JL, Chew PT. Micropulse transscleral diode laser cyclophotocoagulation in the treatment of refractory glaucoma. Clin Exp Ophthalmol 2010;38:266‑72. 4. Ma A, Yu SWY, Wong JKW. Micropulse laser for the treatment of glaucoma: A literature review. Surv Ophthalmol. 2019;64:486-497 5. Sarrafpour S, Saleh D, Ayoub S, Radcliffe NM. Micropulse transscleral cyclophotocoagulation: A look at long‑term effectiveness and outcomes. Ophthalmol Glaucoma 2019;2:167‑71. 6. LimEJ, AquinoCM, LunKW, LimDK, SngC, LoonSC, etal. Efficacy and safety of repeated micropulse transscleral diode cyclophotocoagulation in advanced glaucoma. J Glaucoma 2021;30:566‑74. 7. Philip R, George R. Micropulse diode cyclophotocoagulation: A review of the literature. Kerala J Ophthalmol 2020;32:136-42. 8. Nivash A, Mohan S, Anand N, Ariga M. Diffuse anterior scleritis following micropulse transscleral laser: A case report. Indian J Ophthalmol Case Rep 2023;3:80‑2. Delhi Journal of Ophthalmology ¦ Volume 33 ¦ Issue 1 ¦ January-March 2023 75
Abstract Theme Section Introduction Clustered Regularly Interspersed Short Palindromic Repeats(CRISPR), short for CRISPR, is a gene editing strategy described by scientists Jennifer Doudna and Emmanuel Charpentier who received the Nobel Prize in 2020 for it.[1] Pertinent to ophthalmology and specifically the retina, CRISPR can be potentially utilized to develop therapies for patients with inherited retinal dystrophies(IRDs), many of whom experience progressive blinding vision loss with no definitive therapy. India has a relatively high incidence of IRDs as compared to the world. Prevalence studies have found the global prevalence to be 1 in 4000.[2] While a large‑scale Indian study found IRDs to be prevalent in 1 in 372 in rural population, and 1 in 930 in urban population.[3] A large part of this can be attributed to the high degree of consanguinity in our population in India. Further, the landscape of mutations seen in India, tend to be different as compared to elsewhere in the world. Therefore, therapies which need to be devised would need to be tailored to our population. Clustered regularly interspersed short palindromic repeats gene editing The gene-editing tool CRISPR is actually a derivative of the bacterial immune system. In essence, the bacteria once infected by the viral bacteriophage, would integrate a part of the viral genome into their own. On subsequent attack by the virus, the bacteria recognize the viral genome and are able to lyse or cut the viral genome using a Cas enzyme [Figure 1]. Utilizing the molecular tool for therapeutic applications, broadly, CRISPR consists of the Cas9 enzyme, which can cause a double‑strand break in the DNA, along with a single Personalized medicine with the development of targeted therapies toward clinical disorders is predicted to be the future of medicine. Ophthalmology is at the forefront of the development of newer therapies, as the eye forms an excellent target for the development of such therapies given the accessibility of eye to interventions, the immune privilege, and ability to directly monitor response to interventions. Within ophthalmology, inherited retinal dystrophies (IRDs) form a dynamic area of research, as no definitive therapy exists for such a blinding eye condition. There are various approaches in research, and in early clinical trials for treating IRDs including Food and Drug Administration approved gene therapy Voretegene neparvovec for retinal pigment epithelium 65 gene associated Leber’s Congenital Amaurosis, Argus II bionic eye, and regenerative therapies such as stem cells. This narrative review delves deeper into Clustered Regularly Interspersed Short Palindromic Repeats gene editing-based therapies for the management of IRDs, the advantages, limitations, current research, and future direction. Keywords: Adenine base editor, clustered regularly interspersed short palindromic repeats, homology‑directed repair, nonhomologous end joining Address for correspondence: Dr. Mayank Bansal, MD, MRCSEd, FRCS(Glasg), Department of Ophthalmology, Fortis Memorial Research Institute, Gurgaon, India. E‑mail: [email protected] This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution‑NonCommercial‑ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non‑commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms. For reprints contact: [email protected] How to cite this article: Bansal M. Clustered regularly interspersed short palindromic repeats gene editing: Precision medicine and newer therapies for retinal dystrophies. Delhi J Ophthalmol 2023;33:76‑8. Clustered Regularly Interspersed Short Palindromic Repeats Gene Editing: Precision Medicine and Newer Therapies for Retinal Dystrophies Mayank Bansal Department of Ophthalmology, Fortis Memorial Research Institute, Gurgaon, Haryana, India Access this article online Quick Response Code: Website: https://journals.lww.com/djo DOI: 10.4103/DLJO.DLJO_16_23 Submitted: 09-Mar-2023 Accepted: 05-Jun-2023 Published: 05-Jul-2023 76 © 2023 Delhi Journal of Ophthalmology | Published by Wolters Kluwer - Medknow
Bansal: CRISPR gene editing for retinal dystrophies guide RNA (sgRNA), which directs the part of the DNA to localize. The sgRNA can be designed to have the sequence complementary to the desired area of DNA editing. The Protospacer Adjacent Motif(PAM) is a defined sequence which helps the Cas9‑sgRNA complex to identify and bind to the desired part of the DNA. This sgRNA‑Cas9 enzyme complex, essentially the ribonucleoprotein, causes cuts in the DNA, and can thus be strategized to direct targeted gene editing. The inherent DNA repair mechanism of the cell, homology‑directed repair, and non-homologous end joining, are thereafter utilized to introduce desired DNA sequences.[1] This, however, is not without limitations. The Cas9 enzyme may cause cuts in other parts of the genomic DNA as well, called off‑target effects. Further, the desired PAM sequence may not be available close to the target mutation. To overcome these limitations, CRISPR modifications have been developed. Clustered Regularly Interspersed Short Palindromic Repeats Base Editing This consists of a catalytically deactivated Cas9 enzyme, along with a deaminize domain, which is able to target transition point mutations. The deaminaze converts an adenine base to guanine (adenine base editor); or a cytosine base to thymidine (cytosine base editor). Since there are no double‑strand breaks of DNA involved, the chances of insertion–deletion mutations are negligible. Further, the base editors have been found to have a higher editing efficiency. However, they may potentially cause bystander mutations by inadvertently targeting the base adjacent to the desired edit.[4] Clustered Regularly Interspersed Short Palindromic Repeats Prime Editing Prime editing theoretically can target all mutations. It consists of a prime editing guide RNA (pegRNA) along with the Cas9 enzyme with a reverse transcriptase along with it. Broadly, the Cas9 and pegRNA cause a nick in the DNA, which is followed by the synthesis of the desired sequence by reverse transcriptase, for which the pegRNA forms the template.[5] As compared to gene therapy or gene augmentation/ replacement therapy, CRISPR effector molecules can be particularly designed to target: (a) dominant mutations – where gene augmentation therapy may not be able to provide a sufficient quantity of the desired protein; or (b) where the size of the target gene is large, beyond the packaging capacity of the virus. Applications of clustered regularly interspersed short palindromic repeats in retinal dystrophies IRDs are caused by an extensive list of genes and mutations responsible for the structure and functioning of photoreceptors and retinal pigment epithelium (RPE) [Figure 2]. The only CRISPR-based therapy in clinical trials is to target the Centrosomal Protein 290 gene mutations causing Leber’s congenital amaurosis. The therapy called EDIT-101 removes an aberrant splice donor mutation site, using CRISPR so that a functional protein can form. The BRILLIANCE clinical trial using EDIT-101 found an improvement in visual acuity and positive changes in full‑field stimulation testing.[6] The USH2A gene forms an excellent target using CRISPR gene editing as compared to gene therapy since the size of the gene exceeds the packaging capacity of viral vectors used in gene therapy. To this effect, a therapy in development is the EDIT-102, targeting the USH2A gene. The CRISPR effector molecules in EDIT-102, remove a part of the mutated exon 13. This leads to a shorter, yet functional protein, currently being studied in preclinical models.[7] Another potential therapy under research using CRISPR has been to target the gain of function autosomal dominant mutations in the RHO gene. The strategy called “knock-out-and-replace” Figure 1: Depicting components of CRISPR/ Cas9 enzyme (peach color), with the guide RNA (in dark grey), double stranded break in DNA (light green); PAM - Protospacer adjacent motif; Source: from wikimedia commons https://commons.wikimedia.org/wiki/File:GRNA-Cas9.png Under the Creative Commons v4 license Figure 2: a. Layers of the retina including the photoreceptors and retinal pigment epithelium. b. Magnified view of the photoreceptor, showing the genes responsible for various parts of the cell structure. Source: Diakatou M, Manes G, Bocquet B, Meunier I, Kalatzis V. Genome Editing as a Treatment for the Most Prevalent Causative Genes of Autosomal Dominant Retinitis Pigmentosa. Int J Mol Sci. 2019 May Creative Commons License; https://doi.org/10.3390/ijms20102542 a b Delhi Journal of Ophthalmology ¦ Volume 33 ¦ Issue 1 ¦ January-March 2023 77
Bansal: CRISPR gene editing for retinal dystrophies consists of removal of a part of the gene, and replacing it with a correct or wild‑type copy of the DNA. Currently in preclinical studies, the therapy in development is called the EDIT-103.[8] Another strategy has been to change the morphology of photoreceptors, from rods to cones, which has been hypothesized to be protective against retinal dystrophy-associated damage to rods. Neural retina‑specific leucine zipper protein, coded by the NRL gene is a rod fate determinant during photoreceptor development. In rodent model studies, it was found that NRL gene disruption using CRISPR gene editing led to rods gaining partial features of cones. Rod photoreceptors showed improved survival in the presence of mutations in rod‑specific genes consequently preventing secondary cone degeneration.[9] Above we have broadly summarized some of the early techniques and strategies being researched using CRISPR gene editing for IRDs. There are many other IRD causative genes and mutations being targeted and studied using CRISPR, including the ABCA4, GUCY2D, RPE65, RPGR genes, mostly in the preclinical stage at present.[10,11] Conclusion and Future Direction Effective treatment of IRDs is likely to encompass a multitude of treatment modalities. Individuals with advanced retinal changes wherein a significant number of photoreceptors have undergone degeneration may benefit from regenerative therapy solutions such as stem cell therapy, or artificial implants such as the bionic eye. However, individuals diagnosed early in the disease, with preservation of photoreceptors and/or vision are likely to benefit more from gene augmentation, and/or gene editing therapies. Gene editing approach using CRISPR brings in a new treatment strategy which is being developed for managing patients with IRDs. This “genomic surgery” technique of CRISPR also needs to be tailored to our population base in India, since the IRD mutations seen here are much different from those seen in the western part of the world. While in its early stages, as the technique of CRISPR evolves including CRISPR base editing and prime editing, it’s likely we will see newer gene editing therapies for our patients. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest. References 1. Jennifer A. Doudna Emmanuelle Charpentier, The new frontier of genome engineering with CRISPR-Cas9.Science346,1258096(2014). DOI:10.1126/science.12580-96. 2. Yohe S, Sivasankar M, Ghosh A, Ghosh A, Holle J, Murugan S, et al. Prevalence of mutations in inherited retinal diseases: A comparison between the United States and India. Mol Genet Genomic Med 2020;8:e1081. 3. Sen P, Bhargava A, George R, Ve Ramesh S, Hemamalini A, Prema R, et al. Prevalence of retinitis pigmentosa in South Indian population aged above 40 years. Ophthalmic Epidemiol 2008;15:279‑81. 4. Huang TP, Newby GA, Liu DR. Precision genome editing using cytosine and adenine base editors in mammalian cells. Nat Protoc 2021;16:1089‑128. 5. Anzalone AV, Koblan LW, Liu DR. Genome editing with CRISPR‑Cas nucleases, base editors, transposases and prime editors. Nat Biotechnol 2020;38:824‑44. 6. Editas Medicine, Inc. Open‑Label, Single Ascending Dose Study to Evaluate the Safety, Tolerability, and Efficacy of EDIT‑101 in Adult and Pediatric Participants With Leber Congenital Amaurosis Type 10 (LCA10), With Centrosomal Protein 290 (CEP290)‑Related Retinal Degeneration Caused by a Compound Heterozygous or Homozygous Mutation Involving c.2991+1655A>G in Intron 26 (IVS26) of the CEP290 Gene (“LCA10‑IVS262021; Report No.: NCT03872479. Available from: https://clinicaltrials.gov/ct2/show/ NCT03872479. [Last accessed on 2022 Mar 10]. 7. Pendse ND, Lamas V, Pawlyk BS, Maeder ML, Chen ZY, Pierce EA, et al. In vivo assessment of potential therapeutic approaches for USH2A‑associated diseases. Adv Exp Med Biol 2019;1185:91‑6. 8. Meng D, Ragi SD, Tsang SH. Therapy in rhodopsin‑mediated autosomal dominant retinitis pigmentosa. Mol Ther 2020;28:2139‑49. 9. Yu W, Mookherjee S, Chaitankar V, Hiriyanna S, Kim JW, Brooks M, et al. Nrl knockdown by AAV‑delivered CRISPR/Cas9 prevents retinal degeneration in mice. Nat Commun 2017;8:14716. 10. McCullough KT, Boye SL, Fajardo D, Calabro K, Peterson JJ, Strang CE, et al. Somatic gene editing of GUCY2D by AAV‑CRISPR/ Cas9 alters retinal structure and function in mouse and macaque. Hum Gene Ther 2019;30:571‑89. 11. Cremers FP, Lee W, Collin RW, Allikmets R. Clinical spectrum, genetic complexity and therapeutic approaches for retinal disease caused by ABCA4 mutations. Prog Retin Eye Res 2020;79:100861. 78 Delhi Journal of Ophthalmology ¦ Volume 33 ¦ Issue 1 ¦ January-March 2023