January-February 2024 DOS Times

www.dosonline.org/dos-times DOS Times Volume 29, Number 7, January-February 2024 49 Subspeciality - Cornea Association for Pediatric Ophthalmology and Strabismus. 2001 Apr 1;5(2):70-5. 26. Vajpayee RB, Angra SK, Honavar SG. Combined keratoplasty, cataract extraction, and intraocular lens implantation after corneolenticular laceration in children. American journal of ophthalmology. 1994 Apr 1;117(4):507-11. 27. Ashar JN, Pahuja S, Ramappa M, Vaddavalli PK, Chaurasia S, Garg P. Deep anterior lamellar keratoplasty in children. American Journal of Ophthalmology. 2013 Mar 1;155(3):570-4. 28. Price Jr FW, Price MO. Descemet’s stripping with endothelial keratoplasty in 200 eyes: early challenges and techniques to enhance donor adherence. Journal of Cataract & Refractive Surgery. 2006 Mar 1;32(3):411-8. 29. Aquavella JV, Qian Y, McCormick GJ, Palakuru JR. Keratoprosthesis: current techniques. Cornea. 2006 Jul 1;25(6):656-62. 30. Sharma N, Priyadarshini K, Agarwal R, Bafna RK, Nagpal R, Sinha R, Agarwal T, Maharana PK, Titiyal JS. Role of microscopeintraoperative optical coherence tomography in pediatric keratoplasty: acomparative study. American journal of ophthalmology. 2021 Jan 1;221:190-8. Dr. Avani Hariani, MS Senior Resident Cornea and Refractive Surgery Services Guru Nanak Eye Centre, Maulana Azad Medical College, New Delhi. Corresponding Author:

DOS Times Volume 29, Number 7, January-February 2024 www.dosonline.org/dos-times 50 Ptosis: A to Z Kasturi Bhattacharjee, MS, DNB, FRCS, FAICO, Gargi Wavikar, MBBS, Deepak Soni, MS, Komal Sawarkar, DNB, Pragya Bhattacharjee, MBBS Sri Sankaradeva Nethralaya, Guwahati. Ptosis of the eyelid, blepharoptosis, is the inferior displacement of the upper eyelid when the eye is in primary position. While often causing superior visual field loss, ptosis can also affect the central visual field depending on the severity. It decreases the amount of light reaching the macula, reducing the visual acuity, particularly at night. In children, ptosis can obscure the visual axis, causing stimulus deprivation amblyopia. The associated cosmetic concern is also an impetus for treatment.[1] Etiology Myogenic Ptosis Congenital myogenic ptosis results from Levator Palpebrae Superioris (LPS) muscle dysgenesis where in normal muscle fibers are replaced by fibrous or adipose tissue. Acquired myogenic ptosis is caused by muscular diseases like Myasthenia Gravis, Chronic Progressive External Ophthalmoplegia (CPEO), Muscular Dystrophy and Oculopharyngeal Dystrophy. In the former, the ability of the levator muscle to contract as well as relax is impaired. This leads to a decrease in ptosis in downgaze, lid lag and lagophthalmos. The eyelid crease is absent or poorly developed. Levator function is poor in both.[2] Aponeurotic Ptosis It is the most common form of ptosis. It is caused by stretching and attenuation, dehiscence, or disinsertion of the levator aponeurosis from its normal position.[3,4] Senile involution, eye rubbing, rigid contact lenses can all cause weakening of the aponeurosis. Intraocular or eyelid surgery can exacerbate this form of ptosis due to trauma to the LPS muscle owing to use of eyelid speculum and postoperative eyelid swelling.[4,5] Clinical features include, high upper lid crease, deep superior sulcus, good LPS function and normally reacting pupils. The ptosis worsens in downgaze and in the evening due to Muller’s muscle fatigue.[3,4] Neurogenic Ptosis It can be broadly classified as congenital or acquired. Congenital form is caused by innervational anomalies occurring during embryonic development. Congenital oculomotor nerve palsy results is elevation, depression, adduction deficit, ptosis, and dilated pupil. Congenital Horner’s syndrome, caused by affliction of the sympathetic nerve chain causes ptosis, miosis, anhidrosis, enophthalmos and ipsilateral decreased iris pigmentation. Inferior tarsal muscle involvement leads to reverse ptosis with an elevated lower lid. Blepharophimosis-Ptosis-Epicanthus inversus Syndrome (BPES) is an autosomal dominant condition with bilateral congenital ptosis, epicanthus inversus, horizontal lid shortening, telecanthus, hypertelorism and hypoplasia of the nasal bridge.[4] Marcus Gunn Jaw Winking Syndrome leads to unilateral ptosis with synkinetic eyelid elevation during mastication which occurs because of aberrant connection between the mandibular division of trigeminal nerve and oculomotor nerve.[6] Acquired oculomotor nerve palsy can occur due to ischemic or compressive causes. Ischemic causes like hypertension and diabetes, spare the pupil and often resolve spontaneously with the control of systemic disease. Pupil involvement warrants urgent radiological investigations, mainly Magnetic Resonance Imaging (MRI) and Magnetic Resonance Angiography (MRA) to rule out compressive neoplastic or aneurysmal lesions.[4] Mechanical Ptosis Upper eyelid can be weighed down by congenital causes likeplexiform neurofibroma or hemangioma-and acquired causes like-chalazion. Post-traumatic or post-surgical edema can also cause mechanical ptosis.[4] Traumatic Ptosis Damage to the LPS, it’s aponeurosis or it’s innervation can occur after trauma, orbital or neurosurgical procedures. Spontaneous recovery can occur, hence prolonged observation before planning surgical intervention is the dictum.[4] Pseudoptosis: The Mimics It is an apparent ptosis without true decreased Marginal Reflex Distance or a ptosis secondary to globe malposition. Dermatochalasis, contralateral lid retraction, enophthalmos, globe asymmetry secondary to phthisis or microphthalmos, hypotropia, spastic disorders like Benign Essential Blepharospasm (BEB) and Hemifacial Spasm, Floppy Eyelid Syndrome can falsely give the impression of ptosis.[7] Subspeciality - Oculoplasty

www.dosonline.org/dos-times DOS Times Volume 29, Number 7, January-February 2024 51 Evaluation of Ptosis[3,4,5,7,8] History • Onset, duration and progression of ptosis • Diurnal variation • Precipitating factors like trauma, surgery • Associated ocular symptoms like diplopia, jaw winking • Associated systemic symptoms like dysphagia, dysarthria (Oculopharyngeal Dystrophy), proximal muscle weakness causing difficulty in climbing up the steps, getting up from lying down position, tiredness (Myasthenia Gravis), heart disease (Kearns Sayre Syndrome) • Family history of ptosis, muscular disease • Severity of ptosis must be quantified in terms of effect on the activities of daily living Examination External examination comprises the assessment of • Abnormal head posture like chin elevation in case of severe bilateral ptosis, head tilt and face turn in case of associated strabismus • Frontalis Overaction: Lifting the eyebrows to compensate for the ptosis • Associated features like epicanthus inversus, telecanthus, hypertelorism, hypoplasia of the nasal bridge and superior orbital rim, ear deformities, horizontal lid shortening Palpation of eyelids and bony orbital margin must be done. Proptosis and Enophthalmos if present must be quantified using Hertel’s Exophthalmometry. Best Corrected Visual Acuity and Cycloplegic Refraction must be done in children to assess amblyopia and associated vision problems. Extraocular Movements can be affected in CPEO, Myasthenia, Oculomotor Nerve Palsy. Squint Evaluation must be done in patients with associated strabismus. Pupillary Assessment is especially important in cases of Oculomotor Nerve Palsy and Horner’s Syndrome. Posterior Segment examination to look for associated disease like Retinitis Pigmentosa in Kearns Sayre Syndrome. Ptosis Evaluation Measurements • Margin Reflex Distance 1 (MRD1): The distance between central corneal light reflex and center of the upper eyelid margin with eyes in primary position. Normal value is 4-5 mm. • The severity of ptosis can be graded based on MRD1 by calculating the difference from the normal eye in cases of unilateral ptosis and difference from normal values in cases of bilateral ptosis. o Mild: 1-2 mm o Moderate: 3 mm o Severe: 4 mm or greater • Margin Reflex Distance 2 (MRD2): The distance between central corneal light reflex and center of the lower eyelid margin with eyes in primary position. Normal value is 5 mm or greater. • Palpebral Fissure Height (PFH): It is the distance between the center of upper and lower lid margin in vertical alignment with the center of the pupil. 9-10 mm is the normal value in primary gaze. • LPS Action: o Berke’s Method: By measuring the upper lid excursion from downgaze to upgaze after negating the frontalis action with the head in the frontal plane. Poor: 0-4 mm Fair: 5-7 mm Good: 8-12 mm Normal: 13-17 mm o Putterman’s Method: By measuring the Marginal Limbal Distance, from the center of upper lid margin to the 6 O’ Clock limbus in extreme upgaze. Normal value is 9 mm. o Iliff Test: It is used to assess LPS action in infants. While the child id looking down, upper eyelid is everted. If the lid reverts on its own, the LPS action is considered good. • Margin Crease Distance (MCD): From the center of the upper eyelid margin to the eyelid crease. It is 7-8 mm in males and 9-10 mm in females. It is higher in aponeurotic ptosis. • Pretarsal Show: Distance between the lid margin and upper eyelid skin fold with eyes in primary gaze. Other Examination To assess Corneal Health: • Bell’s Phenomenon: Good Bell’s is a prerequisite for ptosis surgery to ensure corneal health. • Lagophthalmos: It can be exacerbated by ptosis surgery thus further subjecting the cornea to exposure. • Tear Film Break Up Time (TBUT) and Schirmer’s to assess baseline tear film parameters. Lid Signs • Lid retraction in the other eye which can cause pseudoptosis in the affected eye. • Lid position in downgaze: While congenital ptosis improves in downgaze with associated lagophthalmos and lid lag, aponeurotic ptosis is often worse in downgaze. • Cogan’s Lid Twitch: Overshoot of the upper lid during upward saccade after prolonged downgaze. Seen in Myasthenia Gravis. • Herring’s Law: Manual elevation of the ptotic eyelid can unmask mild ptosis in the contralateral eye. Subspeciality - Oculoplasty

DOS Times Volume 29, Number 7, January-February 2024 www.dosonline.org/dos-times 52 Synkinesis • Ipsilateral eyelid retraction is seen with jaw movements. • Aberrant regeneration after Bell’s palsy can lead to closure of the eyes upon jaw movements due to aberrant neuronal connection between the orbicularis oris and oculi. Ancillary Tests • Fatigue Test: Worsening of the ptosis upon prolonged upgaze for at least 2 minutes. Seen in myopathies, myasthenia, and even aponeurotic ptosis. Quantification is doen using MRD1. • Ice Pack Test: Improvement of ptosis by more than 2 mm after application of ice pack to closed upper lid for 2 minutes. It is positive in Myasthenia with a sensitivity of 96% and specificity of 88%. • Tensilon Test: Done by slow injection of 1 mg Neostigmine i.v. Considered positive if ptosis improves in 5-15 minutes. Alternatively, 2 mg of Edrophonium can be injected i.v. over 15-30s. The remaining 8 mg is injected slowly if no adverse reaction is observed within 1 minute. Positive Tensilon test is seen in Myasthenia. • Phenylnephrine Test: 2.5% or 10% Phenylnephrine or 0.5% apraclonidine is instilled under the eyelid. 2 mm elevation after 5 minutes is considered a positive test. It is used to mainly assess if the patient will benefit from ptosis correction with Muller’s Muscle Conjunctival Resection. Management of Ptosis Algorithm[3] The surgery can be timed at 3-4 years of age in cases of congenital ptosis as it allows better pre-operative assessment and post-operative care, and the tissues are strong enough to withstand surgical trauma.[8] The choice of surgery depends on the laterality and severity of ptosis and the LPS action, as depicted by the above algorithm. Anterior approach surgeries begin with a skin incision and involve Frontalis Sling, Frontalis flap advancement, LPS resection and LPS plication surgery. Posterior approach surgeries approach the lid transconjunctivally and include Mullers Muscle Conjunctival Resection, Fasanella Servat surgery, Posterior white line advancement surgeries and Posterior LPSR. We will briefly discuss some of the important ptosis correction surgeries-their principles and basic steps. Modified Fasanella Servat Surgery[9,10,11] Principle and Mechanism of Ptosis Correction Comprises excision of a Tarso-Conjunctivo-Muller’s muscle fragment from the upper lid. Ptosis correction is proposed to be due to Muller’s muscle resection and shortening of the tarsus. Indications • Upto 2 mm ptosis correction • LPS action more than 10 mm • Phenylnephrine test negative Procedure The position of lid crease is marked. Upper eyelid is everted, and tarsal height is measured. At the folded edge of the everted lid, three 4-0 silk sutures (central, medial, and lateral) are taken. Three 4-0 silk sutures (central, medial, and lateral) are passed through the upper forniceal conjunctiva to emerge just below the lid margin taking care that the sutural pass is not full thickness. 1 mm ptosis correction is achieved with 2 mm resection. Accordingly, the amount of resection needed is marked. Full thickness tarsal incision is made up to the orbicularis. Tissue is excised and conjunctiva is sutured with 6-0 exteriorized catgut sutures. Mullers Muscle Conjunctival Resection[12,13,14] Principle and Mechanism of Ptosis Correction This has been a matter of debate. While some argue that the effect of MMCR is from the advancement of the levator aponeurosis, others propose shortening of the posterior lamella and plication of the levator aponeurosis and muscle, as the possible mechanism of ptosis correction. Indications • Mild ptosis • Good levator function • Phenylnephrine test positive Procedure Lid traction sutures are taken, and the lid is everted over a desmarre’s retractor. The upper edge of tarsus and the midpoint of the muller’s muscle conjunctival strip to be excised is marked. 8 mm excision yields a 2 mm ptosis correction. Traction sutures are taken through the marking and a Putterman’s clamp is placed to delineate the strip. An exteriorized non absorbable suture is passed back and forth, just under the clamp, across the entire width of the strip. The clamped tissue is excised with a blade. The exteriorized sutures are then tied. Subspeciality - Oculoplasty

www.dosonline.org/dos-times DOS Times Volume 29, Number 7, January-February 2024 53 Figure 1: Preoperative and 3 months postoperative photographs of a 21-year-old female with mild left congenital ptosis with good LPS function and positive phenylnephrine test, after MMCR surgery. Figure 2: Preoperative and 6 months postoperative photographs of a 68-year-old male with right senile aponeurotic ptosis with good LPS function, after LPS resection surgery. Levator Resection/Advancement/Reattachemnt[15,16,17,18] Principle and Mechanism of Ptosis Correction Shortening of the Levator aponeurosis is the primary mechanism. In those cases, with dehiscence of the aponeurosis, a simple reattachment to the anterior surface of the tarsus corrects the ptosis. Indications Moderate to severe ptosis with LPS action of more than 4 mm Procedure It is most done via an anterior approach. Eyelid crease incision Frontalis Suspension Surgery[19,20,21,22,23] Principle and Mechanism of Ptosis Correction The mild eyelid elevating action of the Frontalis is enhanced by passing a subcutaneous sling and connecting the frontalis and eyebrow to the eyelid. This can be achieved by autogenous fascia Lata as a gold standard material. However, the fascia must be harvested. This can leave a scar and is not possible up to 3 years of age because of the inadequacy of the fascia. Autogenous Temporalis fascia is also used. Harvested allogenic is given, and blunt dissection is done up to the orbital septum which is then opened. The pre-aponeurotic fat pads are retracted away from the aponeurosis. Once the levator muscle-aponeurosis complex is identified, it is dissected from the muller’s muscle and resected. The amount of resection is given by either the Berke’s or Beard’s method. The former uses upper eyelid excursion to estimate the upper lid height intra-operatively at the end of surgery. The latter estimates the amount of Levator to be resected based on the eyelid excursion and amount of ptosis. fascia Lata is an alternative if autogenous fascia Lata cannot be harvested. Synthetic slings that can be used are Silicon rods and bands, Mersilene, Gore-Tex. Indications Severe ptosis with LPS action less than 4 mm Procedure Eyebrow, eyelid, and forehead incisions are made either according to the Crawford’s two triangle technique or the Fox Subspeciality - Oculoplasty

DOS Times Volume 29, Number 7, January-February 2024 www.dosonline.org/dos-times 54 pentagon technique. The sling material is passed through each of these incisions successively making sure the passage is in the submuscular plane, superficial to the tarsus and the orbital septum. The ends are brought out through the forehead incision, tied, and tightened to achieve the desired eyelid height. Figure 3: Preoperative and 3 months postoperative photographs of a 7-year-old boy with bilateral congenital ptosis with poor LPS function after Frontalis sling surgery. Figure 4: Preoperative and 3 months postoperative photographs of a 20-year-old male with severe left congenital ptosis with poor LPS function after undergoing Frontalis Muscle Flap Advancement surgery. Frontalis Muscle Flap Advancement[25] Principle and Mechanism of Ptosis Correction The vector of Frontalis muscle contraction is transmitted to the tarsus which results in a dynamic correction ptosis. Indications • Severe ptosis with LPS action less than 4 mm • Aesthetically superior outcome Procedure Lid crease is marked across the upper eyelid. The biplanar Posterior White Line Advancement Surgery[26] Principle and Mechanism of Ptosis Correction Ptosis correction is based on the transconjunctival advancement and reattachment of a dehisced levator aponeurosis to the posterior surface of the tarsus. dissection is carried out through subcutaneous tissue and the orbicularis muscle, subcutaneous dissection continues upward and reaches as far as the inferior margin of the eyebrow. In a plane between orbicularis oculi and the orbital septum, dissection is taken superiorly to the supraorbital rim. Frontalis muscle is approached and fashioned. The distal portion of the muscle is advanced and attached to the anterior surface of the tarsus. Indications • Aponeurotic ptosis with LPS action more than 4 mm • Aesthetically superior outcome Procedure After subcutaneous infiltration of the local anaesthetic in the Subspeciality - Oculoplasty

www.dosonline.org/dos-times DOS Times Volume 29, Number 7, January-February 2024 55 Figure 5: Preoperative and 12 months postoperative photographs of a 19-year-old male with left sided ptosis after Posterior White Line Advancement Surgery. Complications of Ptosis Surgery[23,24] Common complications include under or overcorrection of the ptosis, lagophthalmos leading to corneal exposure, lid malposition, lid contour abnormalities like lid notching. Incorporation of a synthetic sling can cause foreign body rection like sling granuloma. During harvesting of the fascia Lata, weakening of the fascia can lead to muscle herniation. Wound hematomas can also occur. References 1. Cahill KV, Bradley EA, Meyer DR, et al. Functional indications for upper eyelid ptosis and blepharoplastysurgery: a report by the American Academy of Ophthalmology. Ophthalmology. 2011;118(12):2510–2517. 2. Allen RC, Zimmerman MB, Watterberg EA, Morrison LA, Carter KD. Primary bilateral silicone frontalis suspension for good levator function ptosis in oculopharyngeal muscular dystrophy. Br J Ophthalmol. 2012;96(6):841–845. 3. Collin J. A Manual of Systematic Eyelid Surgery. 3rd ed. Oxford: Butterworth-Heinemann Elsevier; 2006. p. 85-113. 4. Edmonson BC, Wulc AE. Ptosis evaluation and management. Otolaryngol Clin North Am 2005;38:921-46. 5. Zoumalan CI, Lisman RD. Evaluation and management of unilateral ptosis and avoiding contralateral ptosis. Aesthet Surg J 2010;30:320-8. 6. Demirci H, Frueh BR, Nelson CC. Marcus Gunn jaw¬winking synkinesis: clinical features and management. Ophthalmology. 2010;117(7):1447–1452. 7. Evan B, Frank N, Christopher C, Geoffrey G, Mark L. Smith and Nesi’s Ophthalmic Plastic and Reconstructive Surgery.Third Edition. Springer. 2012. p. 362-370. midpupil pretarsal region, traction sutures are given in the middle of the lid at the grey line and the lid is everted over a desmarre’s retractor. An incision is made on the conjunctiva with no 15 Bard Parker blade superior to the edge of the tarsus. The conjunctiva and muller’s muscle are dissected until the edge of the dehisced aponeurosis, the white line, is identified. Double armed 5-0 vicryl sutures are then passed through the white line and then the posterior surface of the tarsal plate to emerge through the skin in the region of the lid crease. 8. Pauly M, Sruthi R. Ptosis: Evaluation and management. KeralaJOphthalmol 2019;31:11-6. 9. Servat J. The Fasanella-Servat operation. In Bosniak, S. L., and Smith, B. C. (eds.): Advances in Ophthalmic Plastic andReconstructive Surgery. New York, Pergamon Press, 1982, vol. 1, pp. pp. 1961–1981. 10. Pang, Noelene K., et al. “Fasanella—Servat procedure: indications, efficacy, and complications.” Canadian Journal of Ophthalmology 43.1 (2008): 84-88. 11. Chaudhry, Imtiaz A. “Modified fasanella-servat for acquired ptosis: Case report and review of the literature.” Middle East African journal of ophthalmology 16.4 (2009):263. 12. Putterman AM, Urist MJ. Müller’s muscle-conjunctival resection. Arch Ophthalmol.1975;93(8):619-623. 13. Weinstein GS, Buerger GF Jr. Modifications of the Müller’s muscleconjunctival resection operation for blepharoptosis. Am J Ophthalmol. 1982;93(5):647-651 14. Perry JD, Kadakia A, Foster JA. A new algorithm for ptosis repair using conjunctival Müllerectomy with or without tarsectomy. Ophthal Plast Reconstr Surg. 2002;18(6):426-429. 15. Hatt M, Anderson RL. Ptosis surgery: Anterior approach for levator aponeurosis shortening.Ophthalmologica.1979;179:94–8. 16. Jordan DR, Anderson RL. The aponeurotic approach to congenital ptosis.Ophthalmic Surg.1990;21:237–44. 17. Berke RN. Results of resection of the levator muscle in congenital ptosis. ArchOphthalmol 1959;62:177. 18. Beard C, Sullivan JH. Ptosis. Current Concepts. Int Ophthalmol Clin 1978; 18:53-73. 19. Lee MJ, Oh JY, Choung HK, Kim NJ, Sung MS, Khwarg SI. Frontalis sling operation using silicone rod compared with preserved fascia lata Subspeciality - Oculoplasty

DOS Times Volume 29, Number 7, January-February 2024 www.dosonline.org/dos-times 56 for congenital ptosis a three year follow-up study. Ophthalmology. 2009;116:123-9. 20. Betharia SM. Frontalis sling: A modified simple technique.Br J Ophthalmol.1985;69:443–5. 21. Crawford JS. Repair of ptosis using frontalis muscle and fascia lata. Trans Am Acad Ophthalmol Otolaryngol. 1956; 60:672–8. 22. Petroni S, Capozzi P, Parrilla R, Zinzanella G, Buzzonetti L. Surgical treatment of severe congenital ptosis using deep temporal fascia. Orbit 2018;12:1-5. 23. Wagner RS, Mauriello JA, Nelson LB, Calhoun JH, Flanagan JC, Harley RD. Treatment of congenital ptosis with frontalis suspension: a comparison of suspensory materials. Ophthalmology.1984; 91245- 248. 24. Hakimbashi, M., Kikkawa, D.O., Korn, B.S. (2011). Complications of Ptosis repair: Prevention and Management. In:Cohen A., Weiberg, D. (eds) Evaluation and Management of Blepharoptosis. Springer, New York, NY. 25. Zhong, M., Jin, R., Li, Q. et al. Frontalis Muscle Flap Advancement for Correction of Severe Ptosis Under General Anesthesia: Modified Surgical Design with 162 Cases in China. Aesth Plast Surg 38, 503- 509 (2014). Dr. Gargi Wavikar, MBBS Primary DNB, Sri Sankaradeva Nethralaya. Corresponding Author: 26. Patel V, Salam A, Malhotra R. Posterior approach white line advancement ptosis repair: the evolving posterior approach to ptosis surgery. Br J Ophthalmol. 2010 Nov;94(11):1513-8. Subspeciality - Oculoplasty

www.dosonline.org/dos-times DOS Times Volume 29, Number 7, January-February 2024 57 Subspeciality - Oculoplasty Congenital Eyelid Imbrication Syndrome Manisha Subhadarsini, MBBS, DNB, Shreya Gujral, MBBS, MS, Shivangi Kashyap, MBBS, DO, S.M.Zaid, MBBS, DO, N.Z.Farooqui, MS, Jatinder Singh Bhalla, MS, DNB, MNAMS Department of Ophthalmology, DDU Hospital, New Delhi. Introduction Eyelid imbrication syndrome is an idiopathic eyelid malposition disorder and characterized by upper eyelids over riding the lower eyelids.[1] In adults eyelid imbrication is usually associated with floppy eyelid syndrome and affects middle aged obese men presenting as a unilateral or bilateral chronic papillary conjunctivitis. Further evidence suggests that it maybe a sign of sleep apnea in adults.[2] Eyelid imbrication syndrome in adults requires surgical correction. Congenital eyelid imbrication syndrome is extremely rare, benign and self limiting condition and may sometimes be associated with congenital floppy eyelid syndrome.[3] The classic triad of signs in patients with a CEIS consists of bilateral upper eyelids overriding the lower eyelids when child was in sleep, bilateral medial and lateral canthal tendon laxity and tarsal conjunctival hyperemia.[4] We report a case of congenital eyelid imbrication syndrome associated with congenital floppy eyelid syndrome that reduced with conservative management over 70 days. Case Report A full term newborn Indian female born through emergency caesaerean section indicated by MSL and PD was referred to us on next day of delivery for inability to open eyelids completely and spontaneous bilateral upper eyelid eversion on crying that was observed immediately after birth. 1. The parameter at birth were body weight-2.5kg • Crown rump length: 50cm • Head circumference: 34cm • Apgar score: 10\10 2. Ocular measurements • Horizontal palpebral length=18mm • Vertical palpebral fissure=5mm • Horizontal length of upper lid=24mm • Midpoint vertical upper eyelid height=10mm 3. Child was managed conservatively • E\d tobramycin 6 times\day • E\oint HPMC 2% TDS • Night time lid taping. The child was followed on alternate days. B-Scan eyeball and orbit showed normal findings. The child showed improvement in next visit and by 3rd visit (6th day), there was minimal over riding and no spontaneous eversion of upper lids. She was the first born child in the family. There is no family history of ocular malformations, syndromes or consanguinity. Retrospective review of antenatal record did not reveal intake of any teratogenic drugs. Ocular was the first born child in the family. There is no family history of ocular malformations, syndromes or consanguinity. Retrospective review of antenatal record did not reveal intake of any teratogenic drugs. Ocular examination of child showed bulky upper eyelids overlapping on lower eyelids, 4mm. there was spontaneous bilateral upper eyelid eversion while crying. The tarsal conjunctiva of both upper eyelids were hyperemic. The lids required manual repositioning to normal position. The upper eyelids were easily everted by gentle tuck on the skin of upper eyelid towards forehead. The medial canthal tendon and lateral canthal tendon of both eyes were lax. Both cornea were clear and did not show any staining with rose Bengal or fluorescein stain. Upper eyelid margins were faintly stained with rose bengal staining. Digital IOP appeared to be within normal range. Both eye pupillary reactions were brisk. Rest of adnexal, anterior segment and dilated fundus examinations were unremarkable. There was no discharge and no features of Down syndrome or sleep apnea syndrome were found on systemic evaluation. Figure 1: Showing bulky upper eyelids overlapping lower eyelids.

DOS Times Volume 29, Number 7, January-February 2024 www.dosonline.org/dos-times 58 Discussion Congenital Congenital eyelid imbrication syndrome is a rare condition, and the exact cause of which remains unknown.[1] The condition was first reported by Rumelt et al in 2004 who also suggested that the longer and less stretched canthal tendons were the attributing factor, and gradual tightening, possibly related to postnatal growth, may have resulted in its resolution.[3] The spontaneous resolution of congenital EIS must have been a strong causative factor for its scarce literature.[2] This self limiting, bilateral rare condition is associated with lax eyelids in congenital variety while the acquired ones need a definitive surgical correction.[2] An association with Down’s syndrome is suggested but the child being reported here had no suggestive features of Down’s syndrome.[5] On physical examination, this condition is best evaluated by having the patient tip his or her head back and by shining a flashlight toward the upper lid. The physical finding of the upper lid overriding the lower lid is pathognomonic for the disease.[6] As seen from previous reported cases this idiopathic condition usually presents within 48 hrs of birth with no gender predilection usually having lax medial and lateral canthi followed by spontaneous recovery in congenital cases and surgical intervention required in acquired cases. Due to constant direct contact of upper tarsal conjunctiva with the eyelashes of the lower lid, the upper tarsal conjunctiva is hyperemic. This constant source of irritation makes the orbicularis undergo a neuronal spasm thus making the eyelid more prone to spontaneous eversion as orbicularis remains in constant state of subclinical spasm. This hypothesized series of events was explained by chandravanshi et al and odat and hina.[4,7] Treatment with eye ointment like HPMC 2% helps in reducing chronic irritation thereby helping in reliving the subclinical neuronal spasm. Using antibiotic eye drops Tobramycin 0.3% provides added benefit of curbing secondary bacterial infection. Night time lid taping helps in maintaining normal anatomical position of the eyeball. The natural resolution of EIS could best possibly be explained by the thicker lipid layer and more mucin content of tear film in infants as compared to adults.[8,9] The more common eyelid malposition disorders include blepharoptosis, entropion, ectropion, euryblepharon, tarsal kink, epiblepharon, and eyelid eversion. The latter two, like congenital eyelid imbrication syndrome, usually have a benign course and resolve over time.[10] Financial Support and Sponsorship Nil. Conflict of Interest The authors have no conflict of interest. References 1. Karesh JW, Nirankari VS, Hameroff SB. Eyelid imbrication. An unrecognized cause of chronic ocular irritation. Ophthalmology 1993;100:883 9. 2. Kaur M, Singh S, Singh M. Congenital bilateral eyelid imbrication in a neonate: A rare case. J Clin Neonatol 2016;5:137-9. 3. Rumelt S, Kassif Y, Rehany U. Congenital eyelid imbrication syndrome. Am J Ophthalmol 2004;138:499 501. 4. Chandravanshi SL, Rathore MK, Tirkey ER. Congenital combined eyelid imbrication and floppy eyelid syndrome: Case report and review of literature. Indian J Ophthalmol 2013;61:593-6. 5. Rao LG, Bhandary SV, Devi AR, Gangadharan S. Floppy eyelid syndrome in an infant. Indian J Ophthalmol 2006;54:217 8. 6. Eric D. Donnenfeld, MD, Henry D. Perry, Amilia Schrier, Bruce Zagelbaum, and Rodgers Ophthalmology 1994;101:763-766. 7. Odat TA, Hina SJ. Congenital combined eyelid imbrication and floppy eyelid syndrome. J Optom 2010;3:91 3. 8. Isenberg SJ, Del Signore M, Chen A, Wei J, Guillon JP. The lipid layer and stability of the preocular tear film in newborns and infants. Ophthalmology 2003;110:1408 11. 9. Esmaeelpour M, Watts PO, Boulton ME, Cai J, Murphy PJ. Tear film volume and protein analysis in full term newborn infants. Cornea 2011;30:400 4. 10. Hoyt C, Lambert S. Eyelids: In: Taylor D, editor. Pediatric ophthalmology. Boston: Blackwell Scientific, 1990:141–155. Dr. Manisha Subhadarsini, MBBS, DNB Resident Department of Ophthalmology, DDU Hospital, New Delhi. Corresponding Author: Figure 2: Spontaneous eversion of both upper eyelids on crying. Subspeciality - Oculoplasty

www.dosonline.org/dos-times DOS Times Volume 29, Number 7, January-February 2024 59 Subspeciality - Ocular Surface Combination of Cyclosporine and Tacrolimus in Treatment of Vernal Keratoconjunctivitis Vedanshi Pandya, MS, Anwar H. Sipai, MS 1. Senior Resident, Department of Ophthalmology, M.P. Shah Govt Medical College, Jamnagar. 2. Assistance Professor, Department of Ophthalmology, M.P. Shah Govt Medical College, Jamnagar. Introduction • VKC is inflammatory disease of conjunctiva and cornea in young children. • Pathogenesis includes role of IgE, cytokines, chemokines & inflammatory cells with release of granular protein, fibroblast proliferation and laying down exuberant amount of collagen fibres in conjunctival tissues. • In severe VKC diagnostic ‘cobble-stone papillae are seen on upper palpebral conjunctiva and corneal ulcers can occur owing to its constant rubbing. • Topical corticosteroids has serious complications. Signs The signs of VKC can be divided into conjunctival, limbal and corneal signs. • Conjunctival Signs: Include diffuse conjunctival injection and upper tarsal giant papillae. These are discrete >1mm in diameter that characteristically have flattened tops which sometimes demonstrate stain with fluorescein. Additionally, these giant papillae can sometimes be seen near the limbus and, while relatively uncommon, symblepharon formation and conjunctival fibrosis can occur. Symptoms • Itching • Tearing • Discharge • Irritation • Redness • Blepharospasm • Photophobia • Limbal Signs: Include thickening and opacification of the limbal conjunctiva as well as gelatinous appearing and

DOS Times Volume 29, Number 7, January-February 2024 www.dosonline.org/dos-times 60 sometime confluent limbal papillae. Peri-limbal HornerTrantas dots are focal white limbal dots consisting of degenerated epithelial cells and eosinophils. Limbal disease can result in a limbal stem cell deficiency which can lead to pannus formation with corneal neovascularization. • Corneal Signs: Vary according to the severity of the disease process. Punctate epithelial erosions or keratitis can coalesce into macro-erosions of the epithelium. Plaques containing fibrin and mucous can accumulate into macroerosions forming Shield ulcers. Corneal neovascularization can ensue and resolution can leave a characteristic ring-like scar. A waxing and waning gray- white lipid depositing in the peripheral, superficial stroma can occur and is known as pseudogerontoxon. Keratoconus has been shown to be more prominent in VKC patients as well; possibly due to increased eye rubbing of chronically irritated patients. Aim To study the efficacy and remission of symptoms and ocular inflammatory signs in patients provided with combination of Cyclosporine and Tacrolimus. Methods • Children presenting to Ophthalmology OPD with redness, foreign body sensation and itching were identified. • Any papillae, gelatinization or white limbal dots (Horner's Tranta’s spots) were noted. • The size of the papillae and any congestion at the base were recorded by inversion of the eyelids. • 25 children presenting with severe VKC were given combination of Cyclosporine A (0.1%) eye drops thrice a day and Tacrolimus (0.03%) eye ointment twice a day in lower fornix for 1 month removing all other topical applicants and/or systemic medications. • We excluded patients who were already using topical CsA or tacrolimus, and who had ever used a systemic immunosuppressant. • Children were advised to avoid allergens and wear dark glasses and do cold compressions. • They were kept on weekly follow ups for symptomatic and slit lamp examination. • Visual acuity and intraocular pressure were monitored. Subspeciality - Ocular Surface

www.dosonline.org/dos-times DOS Times Volume 29, Number 7, January-February 2024 61 Subspeciality - Ocular Surface Results • Improvement in symptoms were noted in 1st week and Giant papillae were resolved within 15 days in 19 out of 25 patients. • The combination is safe and effective for tarsal form of VKC and can rapidly inhibit the activity of dendritic cells, improve symptoms and reverse damage at palpebral conjunctiva. • Long-term use of steroids can lead to complications like glaucoma and cataract. In addition, patients who are steroid responder can develop acute rise in intraocular pressure (IOP) following steroid use. • Quick resolution of symptoms were noted without any significant side effects in chronic persistent VKC and is safe compared to steroids. • Cyclosporine A is known to have multiple inhibitory effects on T-cells, and allergic conjunctivitis models have shown that cyclosporine A eye drops can effectively inhibit T-cellmediated eosinophil and neutrophil migration. • Tacrolimus is chemically known as a macrolide. In T-cells, activation of the T-cell receptor normally increases intracellular calcium, which acts via calmodulin to activate calcineurin. • Tacrolimus has a higher potency, as it exhibits similar effects to CsA at concentrations 100 times lower. In addition, both these drugs lead to inhibition of calcineurin receptor by binding to different categories of immunophilins (CsA binds mainly to cyclophilin A, the predominant cyclophilin found within T cells, whereas tacrolimus binds to FK-binding proteins, in particular FKBP12). Although, the exact mechanism of this synergistic effect is difficult to explain pharmacologically, with current evidence, it is possible that either of the drugs might not be effective enough to block all the calcineurin receptors when prescribed alone. It may be possible that tacrolimus might also be acting through other pathways of inhibiting inflammation than calcineurin receptor blockade alone. Thus, combination therapy was observed to cause more complete immunosuppression than CsA alone. • Herein, we report cases of steroid intolerant VKC in whom an initial attempt was made to control the disease using CsA only but the response to treatment was below expectation. In all these cases, the disease could be controlled after inclusion of tacrolimus in the treatment regimen. • A combination of these two drugs will have a synergistic effect leading to a rapid resolution of inflammation. Dr. Vedanshi Pandya, MS Senior Resident Department of Ophthalmology, M.P. Shah Govt Medical College, Jamnagar. Corresponding Author:

DOS Times Volume 29, Number 7, January-February 2024 www.dosonline.org/dos-times 62 Trials in Management of Diabetic Retinopathy and complications: A Comprehensive Review Ankur Singh, MBBS, MS, FRCS, FAICO Department of Ophthalmology, UCMS & GTB hospital, New Delhi. Introduction In the intricate landscape of ocular health, diabetic retinopathy stands as a formidable challenge, claiming its rank as the leading cause of blindness among individuals aged 25 to 74 in the industrialized world. Affecting three out of four diabetic patients after 15 years of disease duration, this pervasive condition is intricately linked to chronic hyperglycemia. The pivotal significance of maintaining long-term glycaemic control is underscored by the conclusive findings of landmark clinical trials, notably the Diabetes Control and Complications Trial (DCCT) and the UK Prospective Diabetes Study (UKPDS). These trials not only illuminate the pathogenesis of diabetic retinopathy but also establish a compelling correlation between sustained glycaemic control and the mitigation of this sightthreatening complication. At the forefront of advancing therapeutic strategies for diabetic eye diseases, the Diabetic Retinopathy Clinical Research (DRCR) Retina Network plays a pivotal role. Conducting over 30 multicentre studies in collaboration with more than 160 clinical sites across the United States and Canada, the DRCR Retina Network has significantly shaped the landscape of diabetic retinopathy research. Their impact is evident in the establishment of anti-VEGF therapy as a primary intervention and their ongoing commitment to exploring new horizons in retinal diseases. This article aims to dissect various studies, including those championed by the DRCR Retina Network, delving into their importance for ophthalmologists seeking a comprehensive understanding of diabetic retinopathy. Diabetes Control and Complications Trial (DCCT)[1] Type of Trial: Prospective randomized multicenter clinical trial. Participants: A total of 1441 patients with insulin-dependent diabetes mellitus (IDDM) were enrolled. Among them, 726 patients were categorized into the primary-intervention cohort (PIC), characterized by the absence of retinopathy at baseline, while 715 patients were classified into the secondaryintervention cohort (SIC), exhibiting mild retinopathy. Intervention: The study aimed to evaluate the effect of intensive glycaemic control on the progression of diabetic complications. Intensive glycaemic control significantly reduced the risk of developing retinopathy by 76% in the PIC and decelerated retinopathy progression by 54% in the SIC. Outcome: The combined analysis of both cohorts revealed a substantial reduction in the risk of clinical neuropathy by 60% and albuminuria (nephropathy) by 54% with intensive glycaemic control. Importance: These findings underscore the importance of rigorous glycaemic management in mitigating diabetic complications, particularly retinopathy, neuropathy, and nephropathy. United Kingdom Prospective Diabetes Study (UKPDS)[2] Type of Trial: This study was a 20-year prospective multicenter randomized controlled trial. Participants: The trial enrolled 4209 patients with type 2 diabetes and an additional 1148 patients with concomitant hypertension and newly diagnosed type 2 diabetes. The participants were followed between 1977 and 1997. Intervention: The study investigated the impact of intensive blood glucose and blood pressure control on the risk of microvascular complications, particularly retinopathy progression, in patients with newly diagnosed type 2 diabetes. Intensive control of blood glucose levels and blood pressure was implemented as the intervention strategy. Outcome: The study demonstrated that intensive control of blood glucose levels independently reduced the risk of microvascular complications, including retinopathy progression. Similarly, intensive control of blood pressure in patients with elevated blood pressure and type 2 diabetes also reduced the risk of microvascular complications, including retinopathy progression. Notably, sulfonylureas were not associated with increased cardiovascular risk. Additionally, no clinically or statistically significant differences in retinopathy outcomes were observed when comparing blood pressure reduction using ACE inhibitors versus beta-blockers. Importance: These findings underscore the importance of intensive blood glucose and blood pressure control in mitigating microvascular complications, including retinopathy progression, in patients with type 2 diabetes. Diabetic Retinopathy Study (DRS)[3] Type of Trial: This study was a randomized prospective multicenter clinical trial involving. Participants: The trial enrolled total 1742 participants with Subspeciality - Retina

www.dosonline.org/dos-times DOS Times Volume 29, Number 7, January-February 2024 63 Subspeciality - Retina proliferative diabetic retinopathy (PDR) or bilateral severe nonproliferative diabetic retinopathy (NPDR) and visual acuity of 20/100 or better in each eye. Intervention Arm: Participants were randomized, with one eye assigned to immediate photocoagulation using either argon or xenon arc laser, while the other eye was assigned to follow-up without treatment. Outcome: The primary outcome measure was severe vision loss (SVL), defined as visual acuity < 5/200 in two consecutive followup exams, spaced 4 months apart. Results showed that eyes treated with panretinal photocoagulation (PRP) experienced a notable reduction of 50% or more in SVL rates compared to untreated eyes. This benefit was particularly pronounced in eyes with high-risk proliferative diabetic retinopathy (PDR). Additionally, PRP treatment was associated with a decline in visual acuity by one or more lines in 11% of cases, along with instances of visual field loss. High-risk PDR, was defined as neovascularization of the disc (NVD) ≥ 1/3 disc area, vitreous or pre-retinal hemorrhage with NVD, or neovascularization elsewhere (NVE) ≥ ½ disc area. Findings: This study defined High-risk PDR and underscore the efficacy of pan retinal photocoagulation (PRP) in reducing the risk of severe vision loss in patients with PDR or severe NPDR, particularly those with high-risk PDR. Early Treatment Diabetic Retinopathy Study (ETDRS)[4-7] Type of Trial: A randomized, prospective multicenter clinical trial conducted from December 1979 to June 1985. Participants: The trial enrolled 3711 participants with mild-tosevere non-proliferative diabetic retinopathy (NPDR) or early proliferative diabetic retinopathy (PDR), all with a visual acuity of 20/200 or better in each eye. Interventions: Participants were randomly assigned to receive either aspirin (650 mg per day) or placebo, along with one of the following treatments: • Early Photocoagulation: o Macular photocoagulation (focal/diffuse-grid) o Scatter laser/panretinal photocoagulation (PRP) • Deferred Photocoagulation: o Macular photocoagulation (focal/diffuse-grid) o Scatter laser/PRP (High-Risk Characteristics arm) Moderate visual loss (MVL), defined as a doubling of the visual angle, a drop of 15 or more letters on ETDRS visual acuity charts, or a drop of 3 or more lines of Snellen equivalent. Outcomes: The trial aimed to assess: • The efficacy of argon laser photocoagulation (both macular and scatter laser) and aspirin therapy in deterring the progression of early diabetic retinopathy into more advanced stages. • The optimal timing for initiating photocoagulation treatment when necessary. • The natural history and risk factors for the progression of diabetic retinopathy. Findings: The trial provided valuable insights into the management of diabetic retinopathy. Key findings included: • Defer photocoagulation for eyes with mild to moderate NPDR. • Consideration of scatter treatment, especially in severe NPDR or early PDR, particularly for patients with type 2 diabetes and older age. • Laser-treated eyes with clinically significant macular edema (CSME) showed a significant reduction in rates of MVL. CSME is defined by this study as any one of the following: o Retinal thickening at or within 500 microns or 1/3 disc diameter of center of macula. o Hard exudates at or within 500 microns of the center of the macula with adjacent retinal thickening. o Retinal thickening GREATER than 1 disc diameter in size which is within 1 disc diameter from the center of the macula. • The 4-2-1 rule defined by this study for grading of severe NPDR: o Severe/Very Severe NPDR: As per the 4-2-1 rule (marked hemorrhages/microaneurysms in all 4 quadrants, VB in 2 or more quadrants, or intraretinal microvascular abnormalities (IRMA) in 1 quadrant), Severe if 1 feature present, Very Severe if 2 features present. Diabetic Retinopathy Vitrectomy Study (DRVS)[8] Type of Trial: Prospective Randomized Control Trial conducted in 1985. Participants: The study included 616 eyes with recent vitreous hemorrhage, resulting in a reduction of visual acuity to 5/200 or less for at least 1 month. Interventions: Participants were randomized into two groups: • Early vitrectomy • Deferral of vitrectomy for 1 year Outcome Variable: Visual Acuity (VA) Gain Findings: • Early vitrectomy provided significantly better benefits for patients with type 1 diabetes mellitus compared to those with type 2 diabetes mellitus. • Type 2 diabetics experienced poorer results, with a higher rate of maculopathy. However, recent advancements in micro-incision vitrectomy systems (MIVS) and instrumentation have shown that early vitrectomy offers benefits for visual rehabilitation and reduces the chances of subsequent vitreous hemorrhage even in cases of type 2 diabetes mellitus.

DOS Times Volume 29, Number 7, January-February 2024 www.dosonline.org/dos-times 64 DRCR- Protocol B Intravitreal Triamcinolone vs. Laser Photocoagulation for Diabetic Macular Edema.[9] Design: The study was conducted as a multi-centre randomized controlled trial (RCT). Eligibility: Participants aged 18 years or older with bestcorrected visual acuity (BCVA) of 20/400 or better, diabetic macular edema (DME) within 500 microns, and optical coherence tomography (OCT) thickness exceeding 250 microns were included. Groups: Patients were randomly assigned to one of three treatment groups: laser photocoagulation, 1mg intravitreal triamcinolone acetonide (TA), or 4mg intravitreal TA. Findings: At the two-year mark, it was observed that intravitreal TA injections were not superior to laser photocoagulation. Additionally, intravitreal TA injections were associated with higher rates of adverse events, including increased intraocular pressure (IOP) by 9%-21% and cataract development by 23%- 51%. Visual acuity (VA) gain varied across individuals. DRCR- Protocol I Intravitreal Ranibizumab Or Triamcinolone Acetonide In Combination With Laser Photocoagulation For Diabetic Macular Edema.[10] Design: Multi-center clinical trial comparing intravitreal ranibizumab or triamcinolone acetonide in combination with laser photocoagulation for diabetic macular edema (DME). Eligibility: Participants with type 1 or type 2 diabetes mellitus (DM), clinically significant DME (Ci-DME), and best-corrected visual acuity (BCVA) of 20/32 or worse. Groups: Patients were randomly assigned to one of four treatment groups: Sham injection plus focal (macular) photocoagulation, 0.5 mg intravitreal ranibizumab + focal photocoagulation, 0.5 mg intravitreal ranibizumab + Deferred focal photocoagulation, and 4 mg intravitreal triamcinolone + focal photocoagulation. Outcomes: At 2 years, intravitreal ranibizumab + deferred (≥24 weeks) focal/grid laser photocoagulation was more effective in increasing visual acuity (VA) than focal/grid laser treatment alone or intravitreal triamcinolone + laser photocoagulation. Early focal/grid laser treatment at the initiation of intravitreal ranibizumab was not better and possibly worse. Findings: In Ci-DME, intravitreal ranibizumab with deferred laser improves visual acuity more than early laser treatment, which may be detrimental. DRCR- Protocol S Prompt Panretinal Photocoagulation versus Intravitreal Ranibizumab with Deferred Panretinal Photocoagulation for Proliferative Diabetic Retinopathy.[11] Design: The study was structured as a non-inferiority trial. Eligibility: Participants eligible for inclusion had either type 1 or type 2 diabetes mellitus (DM), with no prior pan retinal photocoagulation (PRP), and a best-corrected visual acuity (BCVA) of 20/320 or better. Groups: Patients were divided into two groups: Prompt pan retinal photocoagulation group and Intravitreal 0.5 mg ranibizumab with deferred pan retinal photocoagulation group with total follow-up period of 5 years Findings: Ranibizumab injections emerged as an effective alternative to pan retinal photocoagulation in treating proliferative diabetic retinopathy (PDR). Notably, ranibizumab was associated with reduced peripheral field loss, lower rates of DME onset, and fewer eyes necessitating vitrectomy. These findings underscore the potential advantages of ranibizumab over traditional PRP in managing PDR. Subspeciality - Retina

www.dosonline.org/dos-times DOS Times Volume 29, Number 7, January-February 2024 65 Subspeciality - Retina PROTEUS Study Ranibizumab Plus Panretinal Photocoagulation versus Panretinal Photocoagulation Alone for High-Risk Proliferative Diabetic Retinopathy.[12] Design: The PROTEUS Study employed a prospective, randomized, multicenter, open-label design. Eligibility: Participants eligible for enrollment had either type 1 or type 2 diabetes mellitus (DM) and were diagnosed with highrisk proliferative diabetic retinopathy (PDR). Intervention: Participants were randomly assigned to one of two treatment arms: • Three monthly intravitreal injections of ranibizumab (RBZ) along with standard panretinal photocoagulation (PRP). • Standard panretinal photocoagulation (PRP) alone administered between day 1 and month 2. The primary outcome measured was the regression of neovascularization (NV) in high-risk PDR participants over a 12-month period. Findings: The study found that treatment with ranibizumab plus panretinal photocoagulation was more effective than standard panretinal photocoagulation alone for regressing neovascularization in individuals with high-risk proliferative diabetic retinopathy (PDR) over the course of 12 months. DRCR- Protocol T A Comparative Effectiveness Study of Intravitreal Aflibercept, Bevacizumab and Ranibizumab for Diabetic Macular Edema.[13] Design: DRCR Protocol T was designed as a three-way superiority study. Eligibility: Participants eligible for inclusion had either type 1 or type 2 diabetes mellitus (DM) with central-involved diabetic macular edema (DME) and a visual acuity ranging from 20/32 to 20/320. Groups: Patients were divided into three treatment groups: (a) 2.0 mg intravitreal aflibercept (b) .25 mg intravitreal bevacizumab (c) 0.3 mg intravitreal ranibizumab. The treatment regimen was a modified PRN protocol based on vision and OCT findings. Total Follow-up: The study spanned a total follow-up period of 2 years. Findings: The study found that when initial visual acuity was 20/50 or worse with baseline retinal thickness was >400 µm aflibercept was more effective at improving vision than bevacizumab. DRCR- Protocol V Treatment for Central-Involved Diabetic Macular Edema in Eyes with Very Good Visual Acuity.[14] Design: Randomized, controlled, phase III multi-center clinical trial. Eligibility: Participants eligible for inclusion had either type 1 or type 2 diabetes mellitus (DM) with central-involved DME and a visual acuity of 20/25 or better. Groups: Patients were divided into two treatment arms: • Prompt intravitreal anti-VEGF (aflibercept) • Prompt focal/grid photocoagulation + deferred intravitreal anti-VEGF Outcome: The primary outcome measured was the rate of vision loss over a 2-year period. Findings: The study found that treatment or observation alone resulted in similar rates of vision loss over 2 years in eyes with good vision and center-involved DME. Noninvasive strategies, such as good systemic control, may be effective in managing center-involved DME with good visual acuity, suggesting that treatment should only be initiated when vision worsens. DRCR- Protocol U Short-term Evaluation of Combination Corticosteroid + AntiVEGF Treatment for Persistent Central-Involved Diabetic Macular Edema Following Anti-VEGF Therapy.[15] Design: Randomized, controlled phase II multi-center clinical trial. Eligibility: Participants eligible for inclusion had either type 1 or type 2 diabetes mellitus (DM) with central-involved diabetic macular edema (DME) and a visual acuity ranging from 20/32 to 20/320. They must have received three intravitreal anti-VEGF injections within the prior 20 weeks. Groups: Patients were allocated to one of two treatment arms: • Sham injection + intravitreal ranibizumab • Intravitreal dexamethasone + ranibizumab Outcome: The primary outcome measured was visual acuity at the end of 2 years. Findings: Despite anatomical improvement, no visual acuity benefit was observed in the group receiving intravitreal dexamethasone + ranibizumab compared to the group receiving ranibizumab + sham injection at the end of the 2-year period. DRCR- Protocol AB Intravitreous Anti-VEGF vs. Prompt Vitrectomy for Vitreous Hemorrhage from Proliferative Diabetic Retinopathy.[16] Design: Multi-center randomized clinical trial. Eligibility: Patients eligible for inclusion had a visual acuity of 20/32 or worse and lacked evidence of rhegmatogenous retinal detachment (RRD) or tractional retinal detachment (TRD) involving or threatening the macula. Groups: Participants were randomly assigned to two groups: one group received intravitreal 2 mg aflibercept injections, while the other underwent prompt vitrectomy combined with panretinal photocoagulation (PRP). Outcomes: The primary outcome measured was visual acuity at both the 24-week and 104-week marks post-treatment. Findings: The study revealed that eyes treated with vitrectomy demonstrated faster early visual recovery compared to those receiving intravitreal aflibercept injections. However, both

DOS Times Volume 29, Number 7, January-February 2024 www.dosonline.org/dos-times 66 groups exhibited similar visual outcomes at both the 24-week and 104-week marks post-treatment. Other Key Important Studies Protocol AA[17]: • Objective: Compare ultra-widefield (UWF) imaging with 7-standard-field imaging for assessing peripheral lesions, diabetic retinopathy (DR) severity, and rates of DR worsening. • Findings: UWF fluorescein angiography (FA) may better predict progression of DR compared with 7-standard-fields imaging. Protocol AC[18]: • Objective: Compare the efficacy of intravitreal aflibercept monotherapy versus intravitreal bevacizumab followed by a switch to aflibercept at week 12. • Findings: No significant difference in visual outcomes was observed over 2 years between the two treatment approaches. Protocol TX[19] (Extension Study of Protocol T): • Objective: Evaluate the long-term efficacy of treatment with anti-VEGF injections. • Findings: 68% of participants received at least one antiVEGF injection between years 2 and 5. Mean visual acuity at 5 years improved by 7.4 letters from baseline but was 4.7 letters less than at year 2. Protocol W[20]: • Objective: Assess the long-term visual acuity benefit of early treatment of non-proliferative diabetic retinopathy (NPDR) with anti-VEGF therapy. • Findings: Early treatment of NPDR with anti-VEGF did not offer any long-term visual acuity benefit. Aflibercept: • DA VINCI Study[21]: Aflibercept demonstrated superior visual gains in diabetic macular edema (DME) compared to laser therapy, offering flexibility in dosing frequency. • VIVID and VISTA Trials[22]: Aflibercept, given every 4 or 8 weeks, outperformed laser treatment in DME, indicating potential for less frequent dosing while maintaining efficacy. Ranibizumab: • RESOLVE Study[23]: Ranibizumab showed superior visual outcomes in treating DME compared to sham injections. • RISE and RIDE Trials[24]: These pivotal studies supported ranibizumab as a first-line treatment for DME, showing significant improvements in visual acuity and anatomical parameters. • RESTORE Study[25]: Combined ranibizumab and laser therapy exhibited superior outcomes for DME compared to laser monotherapy. Dexamethasone: • MEAD Study[26]: Dexamethasone intravitreal implants (0.7 mg and 0.35 mg) effectively improved visual acuity and reduced macular edema in DME, offering an alternative to anti-VEGF therapy. Brolucizumab: • KITE and KESTREL Trials[27]: Brolucizumab maintained non-inferiority to aflibercept in DME over two years, requiring fewer injections and potentially offering improved disease control. Faricimab: • BOULEVARD Study[28]: Faricimab, inhibiting Angiopoietin-2 and VEGF-A, showed higher gains in visual acuity compared to ranibizumab in DME. • YOSEMITE and RHINE Studies[29]: Faricimab, administered every 8 weeks or with personalized treatment intervals, was non-inferior to aflibercept in DME, providing a promising treatment option. These trials contribute significantly to the understanding and management of diabetic retinopathy and its complications, providing evidence-based strategies for clinicians and researchers. References 1. Nathan DM; DCCT/EDIC Research Group. The diabetes control and complications trial/epidemiology of diabetes interventions and complications study at 30 years: overview. Diabetes Care. 2014;37(1):9-16. 2. King P, Peacock I, Donnelly R. The UK prospective diabetes study (UKPDS): clinical and therapeutic implications for type 2 diabetes. Br J Clin Pharmacol. 1999 Nov;48(5):643-8. 3. Diabetic Retinopathy Study Research Group. Photocoagulation treatment of proliferative diabetic retinopathy: the second report of Diabetic Retinopathy Study findings. Ophthalmology 1978; 85:82- 106. 4. The Early Treatment Diabetic Retinopathy Study Research Group: Photocoagulation for diabetic macular edema. Arch Ophthalmol 103: 1796-1806, 1985. 5. The Early Treatment Diabetic Retinopathy Study Research Group: Early Photocoagulation for diabetic retinopathy. ETDRS Report No. 9. Ophthalmology (Suppl) 98: 766-785, 1991. 6. The Early Treatment Diabetic Retinopathy Study Research Group: Effects of Aspirin Treatment on Diabetic Retinopathy. ETDRS Report No. 20. Arch Ophthalmol 113: 52-55, 1995. 7. Flynn HW JR., Chew EY, Simons BD, et al. Pars plana vitrectomy in the Early Treatment Diabetic Retinopathy Study. ETDRS Report No. 17. Ophthalmology 99: 1351-1357, 1992. 8. Two-year course of visual acuity in severe proliferative diabetic retinopathy with conventional management. Diabetic Retinopathy Vitrectomy Study (DRVS) report #1. Ophthalmology. 1985 Apr;92(4):492-502. 9. Diabetic Retinopathy Clinical Research Network. A randomized trial comparing intravitreal triamcinolone acetonide and focal/grid photocoagulation for diabetic macular edema. Ophthalmology. 2008 Subspeciality - Retina

www.dosonline.org/dos-times DOS Times Volume 29, Number 7, January-February 2024 67 Sep;115(9):1447-9, 1449.e1-10. doi: 10.1016/j.ophtha.2008.06.015. Epub 2008 Jul 26. 10. Googe J, Brucker AJ, Bressler NM, et al. Randomized trial evaluating short-term effects of intravitreal ranibizumab or triamcinolone acetonide on macular edema after focal/grid laser for diabetic macular edema in eyes also receiving panretinal photocoagulation. Retina. 2011 Jun;31(6):1009-27. 11. Gross JG, Glassman AR, Jampol LM, et al. Panretinal Photocoagulation vs Intravitreous Ranibizumab for Proliferative Diabetic Retinopathy: A Randomized Clinical Trial. JAMA. 2015 Nov 24;314(20):2137- 2146. doi: 10.1001/jama.2015.15217. Erratum in: JAMA. 2016 Mar 1;315(9):944. 12. Figueira J, Fletcher E, Massin P, et al; EVICR.net Study Group. Ranibizumab Plus Panretinal Photocoagulation versus Panretinal Photocoagulation Alone for High-Risk Proliferative Diabetic Retinopathy (PROTEUS Study). Ophthalmology. 2018 May;125(5):691-700. doi: 10.1016/j.ophtha.2017.12.008. 13. Wells JA, Glassman AR, Ayala AR, et al; Diabetic Retinopathy Clinical Research Network. Aflibercept, Bevacizumab, or Ranibizumab for Diabetic Macular Edema: Two-Year Results from a Comparative Effectiveness Randomized Clinical Trial. Ophthalmology. 2016 Jun;123(6):1351-9. doi: 10.1016/j.ophtha.2016.02.022. 14. Baker CW, Glassman AR, Beaulieu WT, et al.; DRCR Retina Network. Effect of initial management with aflibercept vs laser photocoagulation vs observation on vision loss among patients with diabetic macular edema involving the center of the macula and good visual acuity: a randomized clinical trial. 15. Maturi RK, Glassman AR, Liu D, et al; Diabetic Retinopathy Clinical Research Network. Effect of Adding Dexamethasone to Continued Ranibizumab Treatment in Patients With Persistent Diabetic Macular Edema: A DRCR Network Phase 2 Randomized Clinical Trial. JAMA Ophthalmol. 2018 Jan 1;136(1):29-38. doi: 10.1001/ jamaophthalmol.2017.4914. 16. Antoszyk AN, Glassman AR, Beaulieu WT, et al; DRCR Retina Network. Effect of Intravitreous Aflibercept vs Vitrectomy With Panretinal Photocoagulation on Visual Acuity in Patients With Vitreous Hemorrhage From Proliferative Diabetic Retinopathy: A Randomized Clinical Trial. JAMA. 2020 Dec 15;324(23):2383-2395. doi: 10.1001/jama.2020.23027. 17. Silva PS, Cavallerano JD, Haddad NM, et al. Peripheral Lesions Identified on Ultrawide Field Imaging Predict Increased Risk of Diabetic Retinopathy Progression over 4 Years. Ophthalmology. 2015 May;122(5):949-56. doi: 10.1016/j.ophtha.2015.01.008. 18. Jhaveri CD, Glassman AR, Ferris FL 3rd, et al; DRCR Retina Network. Aflibercept Monotherapy or Bevacizumab First for Diabetic Macular Edema. N Engl J Med. 2022 Aug 25;387(8):692-703. doi: 10.1056/ NEJMoa2204225. 19. Glassman AR, Wells JA 3rd, Josic K, et al. Five-Year Outcomes after Initial Aflibercept, Bevacizumab, or Ranibizumab Treatment for Diabetic Macular Edema (Protocol T Extension Study). Ophthalmology. 2020 Sep;127(9). 20. Maturi RK, Glassman AR, Josic K, et al. Four-Year Visual Outcomes in the Protocol W Randomized Trial of Intravitreous Aflibercept for Prevention of Vision-Threatening Complications of Diabetic Retinopathy. JAMA.2023;329(5):376–385. 21. Ray KK, Molemans B, Schoonen WM, et al; DA VINCI study. EUWide Cross-Sectional Observational Study of Lipid-Modifying Dr. Ankur Singh, MBBS, MS, FRCS, FAICO Associate Professor Department of Ophthalmology UCMS & GTB hospital, New Delhi. Corresponding Author: Therapy Use in Secondary and Primary Care: the DA VINCI study. Eur J Prev Cardiol. 2021 Sep 20;28(11):1279-1289. 22. Heier JS, Korobelnik JF, Brown DM, et al. Intravitreal Aflibercept for Diabetic Macular Edema: 148-Week Results from the VISTA and VIVID Studies. Ophthalmology. 2016 Nov;123(11):2376-2385. 23. Massin P, Bandello F, Garweg JG, et al. Safety and efficacy of ranibizumab in diabetic macular edema (RESOLVE Study): a 12-month, randomized, controlled, double-masked, multicenter phase II study. Diabetes Care. 2010 Nov;33(11):2399-405. 24. Boyer DS, Nguyen QD, Brown DM, et al; RIDE and RISE Research Group. Outcomes with As-Needed Ranibizumab after Initial Monthly Therapy: Long-Term Outcomes of the Phase III RIDE and RISE Trials. Ophthalmology. 2015 Dec;122(12):2504-13.e1. doi: 10.1016/j. ophtha.2015.08.006. 25. Mitchell P, Bandello F, Schmidt-Erfurth U, et al; RESTORE study group. The RESTORE study: ranibizumab monotherapy or combined with laser versus laser monotherapy for diabetic macular edema. Ophthalmology. 2011 Apr;118(4):615-25. 26. Boyer DS, Yoon YH, Belfort R Jr, et al; Ozurdex MEAD Study Group. Three-year, randomized, sham-controlled trial of dexamethasone intravitreal implant in patients with diabetic macular edema. Ophthalmology. 2014 Oct;121(10):1904-14. doi: 10.1016/j. ophtha.2014.04.024. 27. Brown DM, Emanuelli A, Bandello F, et al. KESTREL and KITE: 52- Week Results From Two Phase III Pivotal Trials of Brolucizumab for Diabetic Macular Edema. Am J Ophthalmol. 2022 Jun. 28. Sahni J, Patel SS, Dugel PU, et al. Simultaneous Inhibition of Angiopoietin-2 and Vascular Endothelial Growth Factor-A with Faricimab in Diabetic Macular Edema: BOULEVARD Phase 2 Randomized Trial. Ophthalmology. 2019 Aug;126(8):1155-1170. 29. Wykoff CC, Abreu F, Adamis AP, et al; YOSEMITE and RHINE Investigators. Efficacy, durability, and safety of intravitreal faricimab with extended dosing up to every 16 weeks in patients with diabetic macular oedema (YOSEMITE and RHINE): two randomised, double-masked, phase 3 trials. Lancet. 2022 Feb 19;399(10326):741- 755. Subspeciality - Retina

DOS Times Volume 29, Number 7, January-February 2024 www.dosonline.org/dos-times 68 Overview of Laser Photocoagulation in Diabetic Retinopathy Sanjeev Kumar Nainiwal, MD, DNB, MNAMS, Kavita Bajiya, MBBS, Sunil Kumar Gurjar, MBBS, Pooja Hathiwal, MBBS, Shailendra Singh, MBBS, Prithvi Raj, MS Vitreo Retinal Services, Department of Ophthalmology, Sawai Man Singh Medical College & Hospital, Jaipur, Rajasthan. Diabetic retinopathy is one of the important leading cause of blindness in western and developing countries like India, between 20 to 75 years of age. This feared clinical diagnosis necessitated the establishment of multiple major multicentric trials, namely, the diabetic retinopathy study (DRS), Early Treatment diabetic retinopathy study (ETDRS), and diabetic retinopathy vitrectomy study (DRVS) & DCCT, each of which has been invaluable in providing guidelines for the management of patients with diabetic retinopathy. These and many other studies have demonstrated the statistically significant efficacy of photocoagulation treatment in proliferative diabetic retinopathy (PDR) and diabetic macular edema (DME). By identifying eyes at high risk for visual loss and applying appropriate treatment, we can interfere in natural course of diabetic retinopathy with the hope of halting and even reversing the natural progression from its proliferative stage to its fibrotic end stage. The fundus changes that occur in diabetic retinopathy follow a progressive course from the non-proliferative to the proliferative stage. All the fundus changes which occur, are results of diabetic retinal microangiopathy characterized in early stage by vascular occlusion and in its later stage by fibrovascular proliferation and scar formation. Both pericyte loss and thickening of the basement membrane are early changes in the pathologic evolution of diabetes- induced vascular disease. Clinical findings in Diabetic Retinopathy Microaneurysm A Microaneurysm is generally the first sign of diabetic retinopathy, the location of which indicates areas of capillary closure (a primary step in the pathogenesis of diabetic retinopathy). Microaneurysm can be from 12 to 100 microns in diameter, but only those larger than 30 microns in diameter are clinically visible. Any red spot larger than 125 microns is considered to be a hemorrhage, unless its characteristics such as distinct round shape, smooth borders and central light reflex are specifically consistent with features of microaneurysm. Retinal Hemorrhages Dot hemorrhages with very distinct borders, and blot hemorrhages, with somewhat fuzzier borders, are located deeper within the outer plexiform layer and inner nuclear layers. Flame shaped hemorrhages occur in superficial nerve fiber layer. The tighter organization of the cells and the relative paucity of extracellular space in the nerve fiber layer allows the hemorrhage to follow the configuration of nerve fiber or axons. These intraretinal hemorrhages usually resolve in 6 weeks to 3-4 months without vascular obscurations, unless the hemorrhages are located within the fovea. Hard Exudates Hard exudates are usually located within the outer plexifom layer and glisten, appearing waxy or yellowish-white. These can be reabsorbed either spontaneously or following laser photocoagulation, being phagocytosed by macrophages. Soft Exudates Cotton wool spots, or soft exudates are actually small infarcts of the nerve fiber layers. They are created by either occlusion or by a transient decrease in flow of an arteriole, with consequent axoplasmic stasis and swelling in the retinal tissue supplied by this arteriole. Cotton wool spots are often found on intimate apposition to areas of both arteriolar and capillary non-perfusion and venous beading. Vascular Abnormalities Many vascular abnormalities are noted in diabetics, among them, venous beading which represents focal areas of venous dilation with apparent thinning of the venous wall. In fact, the ETDRS found that venous beading was the most powerful individual predictor for the risk of future proliferative disease when compared with all other individual factors. Other vascular abnormalities, which may occur in diabetic retinopathy include, venous loops which sometimes take the shape of omega symbol, reduplication of a venous segment, and intraretinal microvascular abnormalities (IRMA), in addition to venous sheathing and focal narrowing. ETDRS has classified retinopathy into various stages, ranging from mild non-proliferative diabetic retinopathy (NPDR) to high-risk proliferative diabetic retinopathy based on the severity of the above mentioned clinical findings on ophthalmoscopic examination (Table-1). I. Non-Proliferative Diabetic Retinopathy (NPDR) 1. Mild NPDR • At least one microaneurysm or intraretinal hemorrhage Subspeciality - Retina

www.dosonline.org/dos-times DOS Times Volume 29, Number 7, January-February 2024 69 Subspeciality - Retina • Hard/soft exudates may or may not be present 2. Moderate NPDR • Moderate hemorrhage mioaneurysms/intraretinal • Early mild IRMA • Hard/soft exudates may or may not present 3. Severe NPDR (4-2-1 Rule) Any one of the following: • Four quadrants of severe microaneurisms/intraretinal hemorrhages • Two quadrants of venous beading • One quadrant of IRMA changes 4. Very severe NPDR (4-2-1 Rule) Any two of the following: • Four quadrants of severe microaneurysms/intraretinal hemorrhages • Two quadrants of venous beading • One quadrant of IRMA changes II. Proliferative Diabetic Retinopathy (PDR) 1. Early proliferative diabetic retinopathy • PDR without DRS high-risk characteristics 2. High-risk proliferative diabetic retinopathy • NVD of one fourth to one third disc area with or without preretinal/vitreous hemorrhage • NVD of less than one fourth disc area with vitreous or preretinal hemorrhage • NVE of one third to half disc area with preretinal or vitreous hemorrhage Table 1: Classification of Diabetic Retinopathy. Figure 1: Proliferative Diabetic Retinopathy. Macular Edema Macular edema is the most common cause of decreased vision in patients with NPDR, and is caused partly by dysfunction at the level of the inner blood-retinal barrier. Although fluorescein leakage is often visible in macular edema, it is clinically defined as being present only when the retinal thickening is noted on slitlamp biomicroscopy during the clinical examination, either with a contact lens or hand-held lens. In other words, the diagnosis of macular edema is made on the basis of clinically observed retinal thickening and not by angiography. Pre-Laser Work-up Before undergoing laser photocoagulation, every patient must go through a pre-laser work-up which should include basic evaluation of the patient, adjunctive tests required and formal dialogue with the patient including consent form. The basic work-up includes a detailed history, recording of best corrected visual acuity, anterior segment evaluation by slit-lamp, recording of intraocular pressure (IOP), visual field charting, macular function tests, indirect ophthalmoscopy, contact lens biomicroscopy, and color photography and optical coherence tomography (OCT). The adjunctive diagnostic tests include basic fluorescein angiography and vitreous fluorophotometry (only as a research tool). The most important component of pre-laser work-up and one, to which least attention is paid, is discussion with the patients regarding usefulness and pitfalls of laser. The patient and his/ her attendant should be clearly told that in most instances laser treatment is done to arrest the progress of the disease and that it helps to maintain or prevent serious visual loss over a period of time. He/she should also be educated about the need for periodical follow-up, repeated fluorescein angiography and possibilities of more laser treatment. The patient is then asked to sign a consent form explaining the purpose and scope for treatment.

DOS Times Volume 29, Number 7, January-February 2024 www.dosonline.org/dos-times 70 Figure 2: Proliferative Diabetic Retinopathy on FFA. Laser Procedure After pre-laser workup laser photocoagulation should be done under topical anesthesia with adequate dilation of pupil(s). For adequate and proper laser procedure, the position of the patient at the slit lamp should be appropriate with the doctor and the patient should be comfortable. This not only helps to decrease treatment time but also helps to prevent inadvertent laser mediated complications. Laser photocoagulation requires a contact lens, which is placed on the eye under topical anesthesia with the aid of a viscous solution such as gonisol [hypermellose ophthalmic solution]. The choice of contact lens depends on the region of the fundus being treated, the patient’s anatomy, the desired field of view, image magnification, working distance from the patient’s cornea and also the surgeon’s individual preference. In general, the Goldmann contact lens is an all-purpose lens for treating the retina from macula to the retinal periphery. It has a central region providing a virtual, erect image of the posterior pole. Three angled peripheral mirrors, inclined at 59o , 67o and 73o provide visualization from the ora serrata to the posterior pole, respectively. Due to small field of view obtained with this lens, problems could occur with regard to orientation of the treating doctor, especially one who performs the procedure occasionally. Personally we prefer the volks trans-equator lens, used with different magnifications for photocoagulation of different parts of the fundus. Macular Photocoagulation Photocoagulation of clinical significant macular edema (CSME) should be considered first before performing scatter treatment for proliferative disease in all patients with concomitant macular edema since panretinal photocoagulation (PRP) may worsen macular edema. For CSME, photocoagulation treatment is performed for areas of thickening, and not of fluorescein angiographic leakage, which can often be present without clinical thickening. Focal Photocoagulation Treatment should be carried out of all lesions (microaneurysms) 500 to 3000 microns from the center of macula thought to be leaking and causing CSME. Treatment is initially optional for leaking microaneurysm within 500 microns of the macular center. If macular edema persists on follow-up examination and/or if vision is worse than 6/12 with a good perifoveal capillary network, focal treatment up to 300 microns from the macular center may be considered. Large miceroaneurysms (40 microns or more) can usually be closed with several 50 to 100 micron burns. Treatment of red spots is optional if they thought to be microanurysms that do not fill on fundus fluorescein angiography. However, these should not be treated if they are though to represent hemorrhages. Laser burns for focal macular laser photocoagulation should be moderate in intensity (i.e. grade 2 to 3 burns). Usually a burn size if 50 to 100 microns is used. The end point is darkening of microaneurysm/a blanching of the microaneurysm. Treatment is specific and only of all microaneurysm in the area of CSME which are considered to be leaking and thus the direct cause of the CSME. Grid Photocoagulation The early treatment diabetic retinopathy study (ETDRS) used fluorescein angiograms to classify DME eyes with focal leakage associated with microaneurysms as focal and DME eyes with less leakage associated with microaneurysms as diffuse.[1-2] In the ETDRS, focal laser photocoagulation was directly applied to microaneurysms to obtain closure of the leak, and grid laser photocoagulation was applied to areas of diffuse leakage or thickened retinae[1-3]; these techniques became the gold standard for treating DME until the introduction of anti vascular endothelial growth factors (Anti VEGF agents). The ETDRS suggested that focal/grid laser could prevent severe vision loss compared to observation only.[1] However, focal/grid laser therapy might result in scar atrophy and subretinal fibrosis in the macula in approximately 21% of patients, leading to vision loss.[4] To avoid these complications, DRCR.net (diabetic retinopathy clinical research network) recommended “modified” ETDRS settings, in which the laser spots were slightly smaller (50μm) and lighter (gray), and a color change was not required when treating the microaneurysms.[5] DRCR.net protocol A found the modified ETDRS laser to be better than the Mild Macular Grid laser for DME in terms of optical coherence tomography (OCT)-based retinal thickness measures, but best-corrected visual acuity (BCVA) measures in the two groups were not substantially different.[5] In Protocol A, researchers specifically evaluated the effect of modified ETDRS laser in eyes with non-centre involved clinically significant macular edema (CSME). Vision was stable, and the study concluded that modified ETDRS focal/grid laser therapy was still an appropriate treatment for extrafoveal DME.[6] The EURETINA guideline also recommended laser application as a treatment option, specifically targeting the vasogenic subform of DME, characterized by the presence of focal accumulation of microaneurysms and leaking capillaries.[7] Grid macular photocoagulation should be reserved for patients Subspeciality - Retina

www.dosonline.org/dos-times DOS Times Volume 29, Number 7, January-February 2024 71 Subspeciality - Retina with diffuse diabetic macular edema. Diffuse diabetic macular edema is a specific diagnosis in which there is a diffuse slow pooling of fluorescein dye in the center of macula. The area of pooling does not show leaking microaneurysm. It therefore appears to be part of a hyperpermeability response from capillaries in the macular area. Diffuse diabetic macular area does not refer to cases with multiple microaneurysm which show focal leaks which coalesce to form a large area of retinal leak in the late phase of the fluorescein angiogram. Photocoagulation burns are placed approximately two burn width apart so as to create a final inter burn distance of one burn width apart. Photocoagulation should remain more than 500 microns from the disc margin. Treatment within the papillomacular bundle is usually avoided but may be allowed (if required) if it remains more than 500 microns form the macular center. Focal treatment should be applied to areas of focal leakage within the region of grid photocoagulation. Photocoagulation is clearly beneficial for all types of CSME. However, treatment is most beneficial for eyes with better prelaser visual acuity. Quite obviously, eyes with more extensive macular thickening not involving the center of macula. Immediate treatment must also be considered for retinal thickening part of which extends within 500 microns from the center of macula, as these patients are already likely to have significant visual loss. Grid photocoagulation is applied initially using two or three Figure 3: Lasered Diabetic Maculopathy (Macular Grid). Light: Barely visible retinal blanching. Mild: Faint white retinal burn. Moderate: Opaque, dirty white retinal burn. Heavy: Dense white retinal burn. 1. Clinically Significant Macular Edema (CSME). Definition A. Retinal thickening involving the centre of macula. B. Hard exudates at or within 500 microns from the centre of macula if associated with adjacent retinal thickening. C. Retinal thickening of at least one disc area in extent, any part of which is within one disc diameter from the centre of the macula. 2. Proliferative Diabetic Retinopathy with highrisk characteristics 3. Neovascularisation of Iris (NVI) Table 2: Choreoretinal Burn Intensity Classification. Patient should be examined monthly and 3 months after treatment may be considered for additional supplementation focal and/or grid photocoagulation if CSME persists. As it is known that each additional supplemental treatment causes a cumulative decrease in the paracentral visual field. Our goal is to eliminate the residual central thickening, and residual thickening outside the central FAZ must be reassessed carefully before taking the decision regarding supplemental treatment. A new fluorescein angiography must therefore be obtained before supplemental treatment. The known side effects of macular laser namely paracentral scotoma and the estimate risk of vision loss owing to a misplaced laser spot, especially when treating within 500 microns from the center of fovea, need to be kept in mind when considering for the treatment of eyes with good visual acuity. Nevertheless, those eyes with central involvement and CSME with good visual acuity should be considered for photocoagulation. According to ETDRS, photocoagulation decreased the risk of persistent macular edema and significant visual loss by about 50%, regardless of the baseline vision or fluorescein angiographic characteristics. Panretinal Photocoagulation Panretinal photocoagulation (PRP) is indicated for any eye with diabetic retinopathy study (DRS) high risk characteristics, rubeosis iridis (NVI), neovascular glaucoma (NVG) or in severe non-proliferative diabetic retinopathy under some special circumstances (Table-3). rows of 100microns spots to all areas of perifoveal thickening upto and including the edge of the FAZ. These initial spots are placed 100microns apart. Then 150 to 200 microns spot are placed approximately 200 microns apart to the remaining areas of retinal thickening and capillary nonperfusion. The endpoint of each laser burn used in a grid pattern is a light intensity burn (Table-2) just barely visible at the level of the outer retina or retinal pigment epithelium.

DOS Times Volume 29, Number 7, January-February 2024 www.dosonline.org/dos-times 72 4. Neovascular Glaucoma (NVG) 5. Severe Non-proliferative Diabetic Retinopathy if as-sociated with: • Poor compliance for followup • Before cataract surgery/YAG capsulotomy • Renal failure • One eyed patient • Pregnancy Table 3: Indications for Laser Photocoagulation in Diabetic Retinopathy. Table 4: Laser settings for Macular Grid and Panretinal Photocoagulation. Scatter (Panretinal) Photocoagulation Scatter photocoagulation burns are placed from just within the vascular arcades to anterior to the equator. Laser settings for PRP are given in (Table-4). All wavelengths appear to be equally effective in inducing regression of proliferative disease. However, the red and diode wavelengths are better able to penetrate cataracts and vitreous hemorrhage than the shorter wavelengths. These laser are however more painful than green laser and may require some form of anesthesia. Photocoagulation burns are placed approximately one burn width apart so as to create a final inter burn distance of half burn diameter. The posterior edge of treatment includes an oval area that extends 500 microns nasal to the optic disc margin and 3000 microns above, temporal to, and below from the center of macula (i.e. just adjacent vascular arcades superiorly and inferiorly). It may be possible to decrease the incidence of PRP-induced macular edema by treating from the midperiphery to anterior to the equator, avoiding the posterior pole. However this has not been proved in long term studies. Treating over retinal hemorrhage, major retinal vessels, or chorioretinal scars should be avoided. Direct treatment of a retinal hemorrhage can result in unnecessary inner retinal damage. Vascular occlusion and rupture are potential rare complications when PRP burns are placed over retinal vessels. Overly intense burns can occur when photocoagulation burns are placed over pigmented chorioretinal scars, causing visual field loss. Treatment may extend within the vascular arcades for persistent retinal neovascularization within 3000 microns of the macular center despite full PRP. Treatment should not extend closer than 500 microns from the macular center or disc margin and photocoagulation within the papillomacular bundle should be avoided. The order in which the retina is treated is optional. The Laser Settings Macular Grid Panretinal Photocoagulation Wavelength Argon green, Nd:YAG green, or dye yellow Argon green, Nd:YAG green, or dye yellow, red or diode Duration 0.1 second 0.1 to 0.5 seconds Retinal spot size 50 to 100 microns (200 microns in periphery) 200 to 500 microns Intensity Light retinal burns Moderately intense retinal burns inferior retina is usually treated first, as vitreous hemorrhage if it occurs, tends to settle inferiorly, making photocoagulation of this region difficult. Scatter photocoagulation should be completed in several treatment sessions over a 2 to 6 weeks period. Dividing scatter photocoagulation into multiple sessions decrease the risk of macular edema, exudative retinal detachment, choroidal detachment, and angle closure glaucoma. Complete treatment consists of approximately 1800 to 2200 retinal burns of 200 to 500 micron size. Figure 4: Scatter PRP Laser for Proliferative Diabetic Retinopathy. Subspeciality - Retina

www.dosonline.org/dos-times DOS Times Volume 29, Number 7, January-February 2024 73 Subspeciality - Retina Focal Photocoagulation Treatment consists of nearly confluent scatter photocoagulation applied to areas of flat peripheral neovascualrisation. Disc neovascularization (NVD) or elevated peripheral retinal neovascularization (NVE) should not be treated directly as this practice is associated with an increased risk of optic nerve injury, hemorrhage and secondary subretinal, choreoretinal or choreovitreal neovascularization. Postoperatively, patients are given a mild oral analgesic, such as acetaminophen. Patients are instructed to avoid heavy lifting, bending from the waist, or excessive straining if significant new vessels or pre-retinal or vitreous hemorrhage was noted. If vitreous hemorrhage is present, patients are also instructed to sleep with their head elevated by two to three pillows. They are told to return immediately if severe pain occurs because this could herald angle closure caused by choroidal effusion and anteriorly ciliary body rotation. We give topical non-steroidal anti-inflammatory drugs like flurbiprofen for four weeks following a session of PRP. The first follow-up appointment is scheduled for 6 to 8 weeks following completion of the initial PRP since this is the minimum time taken for regression of neovascularization to occur. The response to treatment is often noted early in follow-up, within the first 6 to 8 weeks. In those eyes that either show no or minimal improvement in their clinical picture, supplemental scatter photocoagulation is indicated. Other indications for supplemental treatment include retinopathy that appears to be progressing, new NVD, new rubeosis, new vitreous or preretinal hemorrhage, and the comparative extent and location of previous photocoagulation. Supplemental or “fill-in” treatment should be performed if there are other clinical indications, or if the previous pattern of treatment is scanty, incomplete, or has large skipped areas. If a patient shows reasonable regression of his/her initially florid retinopathy with fine residual loops of NVD, an immediate supplemental treatment may be needed, provided that adequate treatment already exists and that good follow-up can be maintained. The temporal edge of the initial treatment located two disc diameter from the fovea with marked capillary abnormalities. This area should be carefully retreated using supplemental sessions. Anterior cryo treatment with indirect laser photocoagulation with scleral indentation of the peripheral retina can be employed to treat previously untreated retina anterior to the equator, which could not be easily reached with the slit-lamp delivery system. This additional confluent treatment will usually produce irreversible peripheral visual field defects. PRP is not indicated in eyes with end-stage fibroproliferative disease when the originally perfused neovascular tissue is replaced by an avascular gliotic disease. Obvious signs of this “burnt out” picture are a pale optic disc, attenuated vessels, and a generally featureless retina. As is quite obvious, photocoagulation has added a potent weapon for treatment of various forms of diabetic retinopathy in the ophthalmologist’s armamentarium. New Laser Technologies 1. Navigated laser system 2. Subthreshold laser 3. Pattern scan laser 4. Multimodel imaging- guided laser therapy a) Indocyanine green angiography guided laser therapy b) OCT guided laser c) Multimodel imaging integrated system Role of Laser Photocoagulation in the Era of Intravitreal Drug Administration The efficacy of anti-VEGF therapy has been well established in multiple RCTs[8-10], all of which have demonstrated its superiority over laser photocoagulation. One of the disadvantages of antiVEGF therapy is the burden of frequent injections and clinic visits. In comparison, laser treatment is generally considered more cost-effective than pharmacotherapy, including both anti-VEGF and steroid treatments.[11] Laser treatment also offers the advantage of a longer-lasting effect compared to antiVEGF therapy.[12] Moreover, several studies have demonstrated that the combination of laser photocoagulation with antiVEGF treatment has the potential to reduce the frequency of injections.[13] However, it is important to note that the optimal timing and protocol for combining laser treatment with antiVEGF injections have not yet been firmly established. References 1. Early Treatment Diabetic Retinopathy Study Research Group: Photocoagulation for Diabetic Macular Edema. Early Treatment Diabetic Retinopathy Study report number 1. Arch. Ophthalmol. 1985, 103, 1796–1806. 2. Early Treatment Diabetic Retinopathy Study Research Group. Focal photocoagulation treatment of diabetic macular edema. Relationship of treatment effects to fluorescein angiographic and other retinal characteristics at baseline: ETDRS report no. 19. Arch Ophthalmol. 1995, 113, 1144–1155. 3. McDONALD, H.R.; Schatz, H. Grid photocoagulation for diffuse macular edema. Retina 1985, 5, 65–72. 4. Lövestam-Adrian, M.; Agardh, E. Photocoagulation of diabetic macular oedema; complications and visual outcome. Acta Ophthalmol. Scand. 2000, 78, 667–671. 5. Fong, D.S.; Strauber, S.F.; Aiello, L.P.; Beck, R.W.; Callanan, D.G.; Danis, R.P.; Davis, M.D.; Feman, S.S.; Ferris, F.; Writing Committee for the Diabetic Retinopathy Clinical Research Network; et al. Comparison of the Modified Early Treatment Diabetic Retinopathy Study and Mild Macular Grid Laser Photocoagulation Strategies for Diabetic Macular Edema. Arch. Ophthalmol. 2007, 125, 469–480. 6. Scott, I.U.; Danis, R.P.; Bressler, S.B.; Bressler, N.M.; Browning, D.J.; Qin, H.; Diabetic Retinopathy Clinical Research Network. Effect of focal/grid photocoagulation on visual acuity and retinal thickening in eyes with non–center-involved diabetic macular edema. Retina 2009, 29, 613–617. 7. Schmidt-Erfurth, U.; Garcia-Arumi, J.; Bandello, F.; Berg, K.; Chakravarthy, U.; Gerendas, B.S.; Jonas, J.; Larsen, M.; Tadayoni, R.; Loewenstein, A. Guidelines for the Management of Diabetic Macular

DOS Times Volume 29, Number 7, January-February 2024 www.dosonline.org/dos-times 74 Edema by the European Society of Retina Specialists (EURETINA). Ophthalmologica 2017, 237, 185–222. 8. Mitchell, P.; Bandello, F.; Schmidt-Erfurth, U.; Lang, G.E.; Massin, P.; Schlingemann, R.O.; Sutter, F.; Simader, C.; Burian, G.; Gerstner, O.; et al. The RESTORE Study: Ranibizumab monotherapy or combined with laser versus laser monotherapy for diabetic macular edema. Ophthalmology 2011, 118, 615–625. 9. Bressler, N.M.; Varma, R.; Suñer, I.J.; Dolan, C.M.; Ward, J.; Ehrlich, J.S.; Colman, S.; Turpcu, A.; RIDE and RISE Research Groups. Vision-related function after ranibizumab treatment for diabetic macular edema: Results from RIDE and RISE. Ophthalmology 2014, 121, 2461–2472. 10. Do, D.V.; Schmidt-Erfurth, U.; Gonzalez, V.H.; Gordon, C.M.; Tolentino, M.; Berliner, A.J.; Vitti, R.; Rückert, R.; Sandbrink, R.; Stein, D.; et al. The DA VINCI Study: Phase 2 Primary Results of VEGF Trap-Eye in Patients with Diabetic Macular Edema. Ophthalmology 2011, 118, 1819–1826. 11. Mulligan, K.; Kim, J.; Tysinger, B.; Blim, J.; Emerson, G.; Ferrone, P.J.; Kim, J.E.; Seabury, S.; Hahn, P. The Broader Economic Value of Treatment for Diabetic Macular Edema. Diabetes Care 2023, 46, dc222527. 12. Chen, J.; Wang, H.; Qiu, W. Intravitreal anti-vascular endothelial growth factor, laser photocoagulation, or combined therapy for diabetic macular edema: A systematic review and network metaanalysis. Front. Endocrinol. 2023, 14, 1096105. 13. Everett, L.A.; Paulus, Y.M. Laser Therapy in the Treatment of Diabetic Retinopathy and Diabetic Macular Edema. Curr. Diabetes Rep. 2021, 21, 35. Dr. Sanjeev Kumar Nainiwal, MD, DNB, MNAMS Senior Professor Ophthalmology Sawai Man Singh Medical College & Hospital, Jaipur Rajasthan India. Corresponding Author: Subspeciality - Retina

www.dosonline.org/dos-times DOS Times Volume 29, Number 7, January-February 2024 75 Subspeciality - Retina Ocular Decompression Retinopathy: A Rare Complication After Trabeculactomy Vineet Gour, MBBS, DO MS, FVRS, AC Aggrawal, MBBS, DOMS 1. Netrika Netralaya, Bhopal. 2. Dr AC Agrawal Eye Centre, Raisen. Abstract: Ocular decompression retinopathy (ODR) is rare complication after trabeculactomy surgery. Here we reported the case of a 56-years old lady who presented with diminution of vision after 21 days of trabeculactomy surgery. Introduction Trabeculectomy initially described by Cairns in 1968, It is the most commonly performed surgical procedure to control IOP in those who have failed medical therapy, and till now is the gold standard for controlling intraocular pressure in the treatment of glaucoma. After a successful surgery there is formation of diffuse microcystic, filtering subconjunctival bleb which is caused by the flow of diverted aqueous humour. The aqueous are then absorbed by the conjunctival vessels, lymphatics and tear films.[1] It has post-surgical complications. Case A 56 years old lady presented with diminution of vision in the left eye after glaucoma filtering surgery. She had best corrected visual acuity (BCVA) was OD 6/9, N6 and OS 5/60, N35, IOP were OD 20 and OS 42 mmHg before surgery. She underwent OS Trabeculectomy with Mitomycin 21 days before elsewhere. On presentation BCVA was OD-6/9, N6 and OS-1/60. Her anterior segment examination was normal except early cataractous changes in lens in OD, shallow bleb was present superiorly with PI at 12 O’clock position as well as few iris pigment were present over anterior capsule of lens and early cataractous lens in OS (Figure-1). IOP were 19 and 10mmHg respectively. Non diabetic and non hypertensive. Her routine blood investigation were with in normal limits even BT-CT also normal range. Blood pressure was 118/80mmHg. No history of Covid. Fundus examination revealed with in normal limits in OD and splinter hemorrhage around the optic nerve head and glistening light reflex with dense, dark red, sharply outlined hemorrhage over the fovea, splinter shaped hemorrhages located near the optic disc margin as well as flame-shaped hemorrhage at mid periphery cup disc ratio was not comment able due to splinter hemorrhages in OS (Figure-2). On 1 month follow up BCVA was 6/12 and completely resolved hemorrhage from the fundus whereas disc became pale in OS. Figure 1: OS Anterior segment with trab suture. Figure 2: OS Fundus photo.

DOS Times Volume 29, Number 7, January-February 2024 www.dosonline.org/dos-times 76 Spectral domain optical coherence tomography (SD-OCT) normal in OD (Figure-3a). Horizontal scan OS through the fovea illustrates increased thickness and hyper reflectivity of the inner retinal layers, denoting the presence of sub-hyloid and inner retinal bleed with decreased reflectivity of photoreceptor and retinal pigment epithelial layers because of the shadowing Figure 3: A- Spectral domain optical coherence tomography (SD-OCT) normal in OD. B- Horizontal scan OS through the fovea illustrates increased thickness and hyper reflectivity of the inner retinal layers. A detachment of the neurosensory retina below the fovea. Figure 4: A- Sub-hyloid bleed almost resolved where as intraretinal bleed partial resolved on 10th days of follow up, 4b Intraretinal bleed also resolved on 1 month follow up but lost foveal dip and development of ERM. effect. A detachment of the neurosensory retina below the fovea (Figure-3b). Sub-hyloid bleed almost resolved where as intraretinal bleed partial resolved on 10th days of follow up and intraretinal bleed also resolved on 1 month follow up but lost foveal dip and development of Epi-retinal membrane (ERM) (Figure-4a & b). Subspeciality - Retina

www.dosonline.org/dos-times DOS Times Volume 29, Number 7, January-February 2024 77 Subspeciality - Retina Comments The rate of complications was highly variable among different studies. This is possibly secondary to variability in patient demographics such as race and type of glaucoma, surgical technique including conjunctival incision and closure and the presence of antimetabolite use, type and duration of preoperative glaucoma medication use, varying definitions of complications, surgeon's experience, and duration of follow-up.[2] The term ocular decompression retinopathy was coined by Fechner et al (1992) to describe retinal changes subsequent to iatrogenic lowering of intraocular pressure after glaucoma filtering surgery.[3] ODR presents as retinal hemorrhages following acute lowering of the intraocular pressure. Shri Krisna et al review 32 articles published from 1992 to 2011 and address the pathogenesis, clinical features, management, and outcomes of ODR. ODR is defined as a multifocal hemorrhagic retinopathy that results from acute lowering of IOP and is not explained by another process. Hemorrhages occur in all retinal layers, and most patients are asymptomatic. The mean drop in IOP in ODR is 33.2±15.8mm Hg. Eighty-two percent are diagnosed by the first postoperative day, all within 2 weeks. ODR resolved in a mean of 13±12.4 weeks. Visual outcomes are generally good, with 85% of eyes returning to baseline vision. Although ODR infrequently results in significant ocular morbidity, gradual reduction in IOP might prevent this complication.[ ⁴] Ramona et al found ODR is an early complication of trabeculactomy surgery[ ⁵] but in our case it developed after 21days of surgery. Her BCVA was improve to 6/12 after 1 month without any specific treatment. References 1. Madhuri Akella, T Faisal, Surinder S Pandav, Trabeculectomy: Tips for Better Outcomes. DOS times, Jan- Fab 2021. 2. Incidence of short-term complications and associated factors after primary trabeculectomy in Chiang Mai University Hospital Thidarat Leeungurasatien, Preeyanuch Khunsongkiet, Kassara Pathanapitoon, Damrong Wiwatwongwana, Indian J Ophthalmol 2016; 64:737-42. 3. Jea SY, Jung JH. Decompression retinopathy after trabeculectomy. Korean J Ophthalmol. 2005 Jun;19(2):128-31. doi: 10.3341/ kjo.2005.19.2.128. PMID: 15988929. 4. Mukkamala Sri Krishna; Patel, Amar; Dorairaj, Syril; McGlynn, Robert; Sidoti, Paul A.; Weinreb, Robert N.; Rusoff, Jade; Rao, Sunil; Gentile, Ronald C. (2013). Ocular decompression retinopathy: A review. Survey of Ophthalmology, 58(6), 505–512. doi:10.1016/j. survophthal.2012.11.001. 5. Barac Ramona, Pop Monica, Stanciu Paul-Eduard, Schmitzer Speranta and Tataru Calin-Petru, Intraoperative and postoperative complications in trabeculectomy, Clinical study Rom J Ophthalmol. 2015 Oct-Dec; 59(4): 243–247. Dr. Vineet Gour, MBBS, DO MS, FVRS Netrika Netralaya, Bhopal. Corresponding Author:

DOS Times Volume 29, Number 7, January-February 2024 www.dosonline.org/dos-times 78 Photodynamic Therapy Nishant Yadav, MS, Aswini Devi S.B, MBBS, Shilpa Gupta, DNB, Shaifali Khandpur, MS, DNB, Jatinder Singh Bhalla, MS, DNB, MNAMS Department of Ophthalmology, DDU Hospital, New Delhi. Introduction Photodynamic therapy is a therapeutic procedure which uses photosensitising agents that produces selective tissue damage when activated by light of a specific wavelength. Initially when PDT developed it has mainly role in treating cancers by causing selective destruction of tumor cells and their vasculature but later also approved for non melanoma skin cancers as topical therapy and non small cell lung cancer, esohageal and advanced head and neck squamous cell cancer as systemic therapy. In eye, it is used to treat vascular tissue disorders of choroid and retina includes age related macular degeneration (AMD) and choroidal neovascularisation (CNV). In PDT, main drug which is used is verteporfin, a selective vasoocclusive agent. PDT utilises photosensitive drug verteporfin in combination with a low power, low duration infrared laser. Verteporfin emerged as the optimal agent because of its absorption spectrum, lipophilic characteristics and short serum half-life (minimising the duration of skin photosensitivity). Verteporfin efficacy and selectivity depends on the verteporfin dosage, duration of infrared light dose used and tissue selectivity depends on the inerval between verteporfin administered and light irradiation. As new therapies have evolved, it is now typically used as a second-line treatment for neovascular AMD. It remains useful in three situations: in patients with systemic or ocular contraindications regarding intravitreal administration of antiangiogenic drugs, as an adjuvant, in combination with other drugs, and in the treatment of polypoidal choroidal vasculopathy and central serous chorioretinopathy. Mechanism of Action Verteporfin (marketed as Visudyne), is used as a photosensitizer in Photodynamic Therapy. It has a molar mass of 718.794g and a half-life of 5 to 6 hours with an absorption maxima at approximately 690nm.[4] It is rapidly cleared from the body, minimizing patient photosensitivity to 1 to 2 days. Verteporfin is a broad spectrum but only used for far red i.e 689 nm utilised in practice because far red has good penetration across melanin, blood and fibrotic tissue enabling effective treatment of pigmented or hemorrhagic lesions located in the choroid. It provides localised light irradiation of target lesion. It is a complex photochemical reaction in which light excites the verteporfin from ground to higher energy state. After that activated verteporfin interacts with oxygen and biological substrates leading to a creation of cytologic singlet while oxygen and other free radicals leads to cell death and damage. Verteporfin PDT uses laser which produces a circular spot of light. This spot can be visualised by the help of a slit lamp biomicroscope with help of a standard laser contact lens. The diameter of laser spot can be varied which is adjusted according to the size of target lesion. The laser spot is adjusted so that it exceeds the greatest dimension of the lesion typically by a margin of 500 micrometer, the maximum size of the spot which can be produced is around 7000 micrometer. The mechanisms by which PDT induces tissue destruction are not known completely. Three mechanisms have been proposed: cellular, vascular and immune.[7] The cellular mechanism, which is the most relevant, refers to the cytotoxic effects of free radicals on mitochondria, the endoplasmic reticulum and lysosomes. There is release of free radicals when verteporfin is activated by the laser energy. The interaction between the free radicals and blood vessel endothelial cell membranes leads to release of locally increased histamines, thromboxane and TNF-α, all immune modulation factors. This leads to vasoconstriction, thrombosis, increased vascular permeability, blood stasis and hypoxia.[6] The immune mechanism is based on the high concentrations of cytokines observed after injecting PDT in patients, such as interleukin 2 and TNF–α.[6] Standard treatment consists of intravenous infusion of verteporfin at a dose of 6mg/m2 body surface, for 10 minutes. Fifteen minutes after starting the infusion, the diode laser with wavelength of 689nm and light intensity of 600mw/cm2 , at a radiation dose of 50J/cm2 is applied. An exposure time of 83 seconds and a spot diameter corresponding to the diameter of the largest lesion plus 1mm is applied.[8] It is selectively taken up by the proliferating endothelial cells of the neovascular tissue. This activated Verteporfin induces temporary closure of the choroidal neovascular complex. vPDT has a good safety profile. However, few side effects are associated with it. Visual disturbances (10-15%), photosensitivity reactions (3%), and back pain during the verteporfin infusion (2%), extravasation of verteporfin leading to skin necrosis are seen. All patients should be advised to avoid exposure to sunlight for 48h because of skin photosensitivity after the therapy.[9,10] Various protocols have been developed to improve the efficacy and safety profile of vPDT therapy. The most widely used ‘safetyenhanced' vPDT protocols utilise reduced dose verteporfin (typically verteporfin 3mg/m2 BSA) or reduced fluence vPDT (typically vPDT laser fluence 25 J/cm2 ). Still, the optimum vPDT therapy parameters for different chorioretinal conditions are not known completely.[11-14] Subspeciality - Retina

www.dosonline.org/dos-times DOS Times Volume 29, Number 7, January-February 2024 79 Subspeciality - Retina Indications 1. Neovascular Age-Related Macular Degeneration: vPDT therapy was developed to treat neovascular AMD with subfoveal CNV. The standard therapy protocol was demonstrated by the TAP and VIP studies. There was a shift to Anti-VEGF therapy with Ranibizumab following MARINA and ANCHOR studies.[15-17] Anti-VEGF therapy was considered the standard of care for neovascular AMD because of its better efficacy. Combination therapy of Ranibizumab with PDT was also tried. But, no significant benefit was found with the combination therapy in the MONT BLANC and DENALI studies.[18,19] The RADICAL study also found no significant benefit from triple therapy using vPDT, ranibizumab, and dexamethasone. Currently, there is a very limited role for vPDT therapy in neovascular AMD treatment. It can be used in patients not responding to anti-VEGF monotherapy[20], intolerance to the intravitreal injection procedure required for anti-VEGF therapy. 2. Non-AMD Choroidal Neovascularization: It refers to conditions such as pathological myopia, angioid streaks, presumed ocular histoplasmosis syndrome, and idiopathic CNV.[21] The VIP study done for vPDT therapy for myopic CNV reported a significantly better visual outcome at 12 months[22], but not at 24 months.[23] More recent clinical trials have demonstrated superiority of anti-VEGF therapy than vPDT therapy.[24-26] Anti-VEGF therapy is currently the standard of care for myopic CNV treatment.[27] 3. Choroidal Hemangioma: Treatment for Choroidal haemangiomas is necessary when vision is affected by macular oedema or exudative retinal detachment. vPDT therapy is now considered to be the treatment of choice for this condition. Verteporfin is accumulated in the abnormal large calibre vessels and limited accumulation in normal choriocapillaris. This selective targeting of the tumour vessels causes minimal damage to the overlying neurosensory retina. One vPDT treatment session is required usually for long term tumour control. Multiple case series have been reported which stated that vPDT therapy is associated with minimal complications and high rates of tumour control.[28-30] Radiation therapy remains a useful treatment modality for larger choroidal haemangiomas with extensive exudative retinal detachment that are difficult to treat with vPDT therapy.[31] It is associated with radiation-induced complications (cataract, radiation retinopathy and optic neuropathy). 4. Central Serous Chorioretinopathy: There is spontaneous resolution with visual recovery in many cases. In some cases, corticosteroid usage may be a contributory factor. Hence, stopping treatment should be considered.[41] Laser photocoagulation was used for persistent CSC, but it is associated with adverse effects such as symptomatic scotomas, RPE atrophy, and secondary CNV. Micropulse diode laser with subthreshold therapy is equally effective with reduced adverse effects.[42] vPDT therapy is now generally considered to be the preferred treatment modality because it can directly target the abnormal choroidal hyperpermeability.[43,44] Adverse effects include damage to the normal choriocapillaris and RPE leading to choroidal ischaemia, RPE atrophy and secondary CNV. Two principal safety-enhanced vPDT protocols have been adopted for effective treatment with reduced adverse effects as the photochemical response in the choroid is dose–responsedependent. Half-dose vPDT therapy uses a verteporfin dosage of 3mg/m2 BSA.[12,32-34] Reduced fluence vPDT therapy uses a vPDT laser fluence of 25 J/cm2 (300mW/cm2 for 83 s).[13,14,35,36] The FDA granted orphan drug designation to verteporfin for the treatment of chronic or recurrent CSC in September 2012, which may help to drive future research. 5. Polypoidal Choroidal Vasculopathy: Polypoidal choroidal vasculopathy (PCV) is an exudative maculopathy characterised by an inner choroidal branching vascular network (BVN) with nodular polypoidal lesions.[37] The aetiology is uncertain but arteriosclerosis of the choroidal vessels appears to be an important pathological feature. Spontaneous resolution with visual recovery is seen in some cases.[38] Recommended initial treatment is ICG-guided vPDT monotherapy[39,40] or combination therapy with vPDT and ranibizumab (three intravitreal injections of ranibizumab 0.5mg 1-month apart). If there is incomplete regression of polyps by ICG angiography, then further treatment should comprise vPDT monotherapy or combination therapy with vPDT and ranibizumab. If there is complete regression of polyps and other clinical or anatomical signs of disease activity, then further treatment should comprise ranibizumab. The EVEREST study demonstrated that vPDT therapy, either alone or in combination with ranibizumab, is better than ranibizumab monotherapy.[41] 6. Peripapillary Choroidal Neovascularization: It refers to CNV located within one disc diameter of the optic nerve head. PP-CNV becomes symptomatic owing to macular involvement from fluid exudation or haemorrhage. Asymptomatic cases can be managed conservatively as spontaneous resolution usually occurs. The current treatment modalities comprise vPDT therapy or anti-VEGF therapy.[42] vPDT therapy usually achieves PP-CNV regression following 1 or 2 treatments.[43] Anti-VEGF therapy is also effective but may require multiple injections to achieve PP-CNV regression.[44,45] 7. Malignant Ophthalmic Tumours: They may arise from various eye and orbital structures. The most common primary tumors are melanomas and squamous cell carcinomas. Metastases that appear in and around the eye are usually from breast (in women) or lung carcinoma (in men).

DOS Times Volume 29, Number 7, January-February 2024 www.dosonline.org/dos-times 80 Other less common sites of origin are the prostate, thyroid, kidney and gastrointestinal tract. Photodynamic therapy does not seem to play a crucial role in treatment of these malignancies. 8. Choroid Melanoma: Small and low or non-pigmented melanomas respond favorably to PDT[46-48] (light absorption by melanin and hemoglobin. However, transient increased leakage leading to increased retinal edema or subretinal fluid has been reported following PDT for different types of intraocular tumors, including amelanotic choroidal melanoma.[49] Since melanoma is a highly immunogenic malignancy, PDT combined with immunostimulatory therapies can increase anti-tumor efficacy. 9. Squamous Cell Carcinoma: Currently available treatment options for squamous cell carcinoma (SCC) include surgical excision, cryotherapy and radiation, investigational approaches with topical chemotherapy, interferon and antiviral drugs. Only a few case studies have reported successful v-PDT treatment in SCC (conjunctival ocular surface squamous neoplasia extending into the cornea).[50,51] Future study is needed to investigate the role of PDT in the management of squamous cell carcinoma. 10. Choroid Metastasis: The uvea is the most common site for ocular metastasis- 88% of metastases occur in the choroid. Treatment options of choroidal metastasis include laser photocoagulation, cryotherapy, chemotherapy, radiotherapy or PDT. The main advantage of PDT is intraluminal photothrombosis in endothelial structures by it. Kaliki et al[52] reported a case study on choroidal metastases treated with v-PDT. In which complete control with resolution of subretinal fluid was achieved in 7 of 9 tumors (78%). This study confirmed that PDT could be used to effectively destroy malignant tissue and to induce antitumor activity. But, there is a very limited trials and studies of the PDT in melanoma, for PDT to be accepted as an effective adjuvant treatment in choroidal metastasis. 11. Angioid Streaks Angioid streaks (AS) refer to small breaks in a weakened Bruch's membrane. They may be seen in patients with various systemic diseases, such as pseudoxanthoma elasticum or sickle hemoglobinopathy. There have been few case reports on v-PDT treatment for CNV due to AS and that too with varying results. In one case study, eight patients with subfoveal CNV secondary to AS were treated with v-PDT and their vision was monitored for an average of 8.75 months.[53] Treatment was well tolerated and no deterioration of vision was observed. A review by Gliem et al[54] summarized fifty four relevant studies, which evaluated different therapies for CNV due to AS. Treatment with anti-VEGF compounds improved or stabilized BCVA in all case series. V-PDT slowed down disease progression along with stabilization or a decrease in BCVA. Laser photocoagulation gave comparable results as v-PDT for extrafoveal lesions, but led to frequent recurrences and more retinal damage. But, the overall treatment benefits and improvements in vision loss are not clear. So, better treatment options or combination therapies are required. Study Type Outcome Results TAP report 1 (for classic CNV) Randomized control trial, double masked, placebo controlled Proportion of eyes with fewer than 15 letters lost, adhering to an intent-totreat analysis at the end of 1 year 246 (61%) of 402 verteporfin treated eyes compared with 96 (46%) of 207 placebo treated eyes had lost fewer than 15 letters (p<0.001). However no statistically significant difference was seen in case of subfoveal lesions that were minimally classic (Area > 0 % but < 50% of area of entire lesion) TAP report 2 (for classic CNV) Randomized control trial, double masked, placebo controlled Proportion of eyes with fewer than 15 letters of visual acuity loss at the end of 2 years, adhering to an intent to treat analysis 213 (53%) of 402 verteporfin treated patients compared with 78 (38%) of 207 placebo treated patients lost fewer than 15 letters (p<0.001). However no statistically significant difference was seen in case of subfoveal lesions that were minimally classic. VIP report 2 (for occult lesions) Randomized control trial, double masked, placebo controlled Proportion of eyes with fewer than 15 letters of visual acuity loss at the end of 1 and 2 years, adhering to an intent to treat analysis At the end of 1 year, no significant difference was seen. At the end of 2 years, 121(54%) of 225 verteporfin treated patients compared with 76 (67%) of 114 placebo treated patients had lost atleast 15 letters. (p = 0.023) VIM report 2 (Minimally Classic CNV) Randomized control trial, double masked, placebo controlled Proportion of eyes with fewer than 15 letters of visual acuity loss at the end of 2 years, adhering to an intent to treat analysis 5(14%) of 36 eyes treated with reduced fluence and 10(28%) of 36 eyes treated with standard fluence – no difference in the observed loss of atleast 15 letters at the end of 1 year. However, the results were significant when compared to 18 (47%) of 38 eyes treated with placebo. Subspeciality - Retina

www.dosonline.org/dos-times DOS Times Volume 29, Number 7, January-February 2024 81 Subspeciality - Retina Studies Related to Armd Combined Therapies Related to Pathological Myopia Related to Central Serous Retinopathy Related to Ocular Tumors Study Type Outcome Results Denali Combined PDT (standard and reduced fluence) and ranibizumab vs ranibizumab monotherapy in CNV Mean change in BCVA from baseline at 12 months Non inferiority of either combination regimen to monthly ranibizumab monotherapy was not demonstrated. However the combination regimen decreased the number of injections required. Everest ICG guided PDT/ combined PDT and ranibizumab vs ranibizumab in PCV Polyp regression and mean change in BCVA at 6 months Verteporfin combined with ranibizumab or alone was superior to ranibizumab monotherapy in achieving complete polyp regression (77.8% and 71.4% vs. 28.6%; P < 0.01). Mont Blanc Combine PDT and ranibizumab vs ranibizumab monotherapy in subfoveal CNV Mean change in BCVA at 12 months from basline Combination therapy was well tolerated and the study concluded that combined therapy to was more effective in achieving BCVA gain compared to ranibizumab monotherapy. Study Type Outcome Results Vip Trial D o u b l e - m a s k e d , placebo-controlled, randomized clinical trial Proportion of eyes with fewer than eight letters of visual acuity lost, adhering to an intent-to-treat analysis at the end of 1 year. 58 (72%) of 81 verteporfin-treated patients compared with 17 (44%) of 39 placebo-treated patients lost fewer than eight letters (P < 0.01). Author Year Results Yannuzzi et al 2003 20 eyes of 15 patients were taken. PDT guided by ICG showed complete resolution of exudative macular detachments in 12 patients and incomplete resolution in the remaining 8 eyes. Vision had improved in 6 eyes and remained unchanged in 14 eyes during a follow up 6.8 months. Erikitola et al 2014 A meta-analysis concluded that PDT showed promise in treating chronic CSR in the short term but identified that the studies analyzed lacked large sample sizes and follow ups to determine the long term efficacy of PDT. Author Year Results Boixadera et al ( C h o r o i d a l Hemangiomas) 2009 This study enrolled 31 patients and issued one to four treatments at 3 months intervals over a period of one year. At the end of 1 year, 82.8% of patients required 1 treatment, 13.8% required 2 treatments, and 3.4% required 3 PDT to eliminate associate exudative retinal detachments. Sachdeva et al (Retinal Capillary hemangiomas) 2010 Studied 6 eyes (3 with juxtapapillary and 3 with extrapapillary) of 5 patients. All eyes demonstrated tumor regression or stabilization as well as improvement in SRF; however only 3 eyes experienced an increase in visual acuity.

DOS Times Volume 29, Number 7, January-February 2024 www.dosonline.org/dos-times 82 References 1. Dougherty TJ, Gomer CJ, Henderson BW, Jori G, Kessel D, Korbelik M, et al. Photodynamic therapy. J Natl Cancer Inst. 1998 Jun 17;90(12):889–905. 2. Vrouenraets MB, Visser GWM, Snow GB, van Dongen GAMS. Basic principles, applications in oncology and improved selectivity of photodynamic therapy. Anticancer Res. 2003 Feb;23(1B):505–22. 3. Brown SB, Brown EA, Walker I. The present and future role of photodynamic therapy in cancer treatment. Lancet Oncol. 2004 Aug;5(8):497–508. 4. Josefsen LB, Boyle RW. Photodynamic Therapy and the Development of Metal-Based Photosensitisers [Internet]. Vol. 2008, Metal-Based Drugs. Hindawi; 2008 [cited 2020 Aug 2]. p. e276109. Available from: https://www.hindawi.com/journals/mbd/2008/276109/. 5. Miller JW, Schmidt-Erfurth U, Sickenberg M, Pournaras CJ, Laqua H, Barbazetto I, et al. Photodynamic therapy with verteporfin for choroidal neovascularization caused by age-related macular degeneration: results of a single treatment in a phase 1 and 2 study. Arch Ophthalmol. 1999 Sep;117(9):1161–73. 6. Flores R SR. Photodynamic Therapy [Internet]. www.amdbook.org. Thea Portugal; [cited 2020 Aug 2]. Available from: https://amdbook. org/content/photodynamic-therapy. 7. Macular Photocoagulation Study Group. Krypton Laser Photocoagulation for Idiopathic Neovascular Lesions: Results of a Randomized Clinical Trial. Arch Ophthalmol. 1990 Jun 1;108(6):832– 7. 8. Rishi P, Agarwal V. Current Role of Photodynamic Therapy in Ophthalmic Practice. 2015;(2):3. 9. Bressler NM, Treatment of Age-Related Macular Degeneration with Photodynamic Therapy (TAP) Study Group. Photodynamic therapy of subfoveal choroidal neovascularization in age-related macular degeneration with verteporfin: two-year results of 2 randomized clinical trials-tap report 2. Arch Ophthalmol. 2001 Feb;119(2):198– 207. 10. Verteporfin In Photodynamic Therapy Study Group. Verteporfin therapy of subfoveal choroidal neovascularization in age-related macular degeneration: two-year results of a randomized clinical trial including lesions with occult with no classic choroidal neovascularization--verteporfin in photodynamic therapy report 2. Am J Ophthalmol. 2001 May;131(5):541–60. 11. Azab M, Boyer DS, Bressler NM, Bressler SB, Cihelkova I, Hao Y, et al. Verteporfin therapy of subfoveal minimally classic choroidal neovascularization in age-related macular degeneration: 2-year results of a randomized clinical trial. Arch Ophthalmol. 2005 Apr;123(4):448–57. 12. Chan W-M, Lai TYY, Lai RYK, Tang EWH, Liu DTL, Lam DSC. Safety enhanced photodynamic therapy for chronic central serous chorioretinopathy: one-year results of a prospective study. Retina (Philadelphia, Pa). 2008 Jan;28(1):85–93. 13. Shin JY, Woo SJ, Yu HG, Park KH. Comparison of efficacy and safety between half-fluence and full-fluence photodynamic therapy for chronic central serous chorioretinopathy. Retina (Philadelphia, Pa). 2011 Jan;31(1):119–26. 14. Reibaldi M, Boscia F, Avitabile T, Uva MG, Russo A, Zagari M, et al. Functional retinal changes measured by microperimetry in standardfluence vs low-fluence photodynamic therapy in chronic central serous chorioretinopathy. Am J Ophthalmol. 2011 Jun;151(6):953-960.e2. 15. Rosenfeld PJ, Brown DM, Heier JS, Boyer DS, Kaiser PK, Chung CY, et al. Ranibizumab for neovascular age-related macular degeneration. N Engl J Med. 2006 Oct 5;355(14):1419–31. 16. Brown DM, Kaiser PK, Michels M, Soubrane G, Heier JS, Kim RY, et al. Ranibizumab versus verteporfin for neovascular age-related macular degeneration. N Engl J Med. 2006 Oct 5;355(14):1432–44. 17. Brown DM, Michels M, Kaiser PK, Heier JS, Sy JP, Ianchulev T, et al. Ranibizumab versus verteporfin photodynamic therapy for neovascular age-related macular degeneration: Two-year results of the ANCHOR study. Ophthalmology. 2009 Jan;116(1):57-65.e5. 18. Larsen M, Schmidt-Erfurth U, Lanzetta P, Wolf S, Simader C, Tokaji E, et al. Verteporfin plus ranibizumab for choroidal neovascularization in age-related macular degeneration: twelve-month MONT BLANC study results. Ophthalmology. 2012 May;119(5):992–1000. 19. Kaiser PK, Boyer DS, Cruess AF, Slakter JS, Pilz S, Weisberger A, et al. Verteporfin plus ranibizumab for choroidal neovascularization in age-related macular degeneration: twelve-month results of the DENALI study. Ophthalmology. 2012 May;119(5):1001–10. 20. Tozer K, Roller AB, Chong LP, Sadda S, Folk JC, Mahajan VB, et al. Combination therapy for neovascular age-related macular degeneration refractory to anti-vascular endothelial growth factor agents. Ophthalmology. 2013 Oct;120(10):2029–34. 21. Sickenberg M, Schmidt-Erfurth U, Miller JW, Pournaras CJ, Zografos L, Piguet B, et al. A preliminary study of photodynamic therapy using verteporfin for choroidal neovascularization in pathologic myopia, ocular histoplasmosis syndrome, angioid streaks, and idiopathic causes. Arch Ophthalmol. 2000 Mar;118(3):327–36. 22. Verteporfin in Photodynamic Therapy Study Group. Photodynamic therapy of subfoveal choroidal neovascularization in pathologic myopia with verteporfin. 1-year results of a randomized clinical trial- -VIP report no. 1. Ophthalmology. 2001 May;108(5):841–52. 23. Blinder KJ, Blumenkranz MS, Bressler NM, Bressler SB, Donato G, Lewis H, et al. Verteporfin therapy of subfoveal choroidal neovascularization in pathologic myopia: 2-year results of a randomized clinical trial--VIP report no. 3. Ophthalmology. 2003 Apr;110(4):667–73. 24. Hayashi K, Ohno-Matsui K, Teramukai S, Shimada N, Moriyama M, Hayashi W, et al. Comparison of visual outcome and regression pattern of myopic choroidal neovascularization after intravitreal bevacizumab or after photodynamic therapy. Am J Ophthalmol. 2009 Sep;148(3):396–408. 25. Baba T, Kubota-Taniai M, Kitahashi M, Okada K, Mitamura Y, Yamamoto S. Two-year comparison of photodynamic therapy and intravitreal bevacizumab for treatment of myopic choroidal neovascularisation. Br J Ophthalmol. 2010 Jul;94(7):864–70. 26. Wolf S, Balciuniene VJ, Laganovska G, Menchini U, Ohno-Matsui K, Sharma T, et al. RADIANCE: a randomized controlled study of ranibizumab in patients with choroidal neovascularization secondary to pathologic myopia. Ophthalmology. 2014 Mar;121(3):682-692.e2. 27. Wong TY, Ohno-Matsui K, Leveziel N, Holz FG, Lai TY, Yu HG, et al. Myopic choroidal neovascularisation: current concepts and update on clinical management. Br J Ophthalmol. 2015 Mar;99(3):289–96. 28. Schmidt-Erfurth UM, Michels S, Kusserow C, Jurklies B, Augustin AJ. Photodynamic therapy for symptomatic choroidal hemangioma: visual and anatomic results. Ophthalmology. 2002 Dec;109(12):2284– 94. 29. Jurklies B, Anastassiou G, Ortmans S, Schüler A, Schilling H, Subspeciality - Retina

www.dosonline.org/dos-times DOS Times Volume 29, Number 7, January-February 2024 83 Subspeciality - Retina Schmidt-Erfurth U, et al. Photodynamic therapy using verteporfin in circumscribed choroidal haemangioma. Br J Ophthalmol. 2003 Jan;87(1):84–9. 30. Singh AD, Kaiser PK, Sears JE, Gupta M, Rundle PA, Rennie IG. Photodynamic therapy of circumscribed choroidal haemangioma. Br J Ophthalmol. 2004 Nov;88(11):1414–8. 31. Frau E, Rumen F, Noel G, Delacroix S, Habrand J-L, Offret H. Lowdose proton beam therapy for circumscribed choroidal hemangiomas. Arch Ophthalmol. 2004 Oct;122(10):1471–5. 32. Chan W-M, Lai TYY, Lai RYK, Liu DTL, Lam DSC. Halfdose verteporfin photodynamic therapy for acute central serous chorioretinopathy: one-year results of a randomized controlled trial. Ophthalmology. 2008 Oct;115(10):1756–65. 33. Fujita K, Yuzawa M, Mori R. Retinal sensitivity after photodynamic therapy with half-dose verteporfin for chronic central serous chorioretinopathy: short-term results. Retina (Philadelphia, Pa). 2011 Apr;31(4):772–8. 34. Karakus SH, Basarir B, Pinarci EY, Kirandi EU, Demirok A. Longterm results of half-dose photodynamic therapy for chronic central serous chorioretinopathy with contrast sensitivity changes. Eye (Lond). 2013 May;27(5):612–20. 35. Reibaldi M, Cardascia N, Longo A, Furino C, Avitabile T, Faro S, et al. Standard-fluence versus low-fluence photodynamic therapy in chronic central serous chorioretinopathy: a nonrandomized clinical trial. Am J Ophthalmol. 2010 Feb;149(2):307-315.e2. 36. Smretschnig E, Ansari-Shahrezaei S, Hagen S, Glittenberg C, Krebs I, Binder S. Half-fluence photodynamic therapy in chronic central serous chorioretinopathy. Retina (Philadelphia, Pa). 2013 Feb;33(2):316–23. 37. Gomi F, Tano Y. Polypoidal choroidal vasculopathy and treatments. Curr Opin Ophthalmol. 2008 May;19(3):208–12. 38. Uyama M, Wada M, Nagai Y, Matsubara T, Matsunaga H, Fukushima I, et al. Polypoidal choroidal vasculopathy: natural history. Am J Ophthalmol. 2002 May;133(5):639–48. 39. Eandi CM, Ober MD, Freund KB, Slakter JS, Yannuzzi LA. Selective photodynamic therapy for neovascular age-related macular degeneration with polypoidal choroidal neovascularization. Retina (Philadelphia, Pa). 2007 Sep;27(7):825–31. 40. Otani A, Sasahara M, Yodoi Y, Aikawa H, Tamura H, Tsujikawa A, et al. Indocyanine green angiography: guided photodynamic therapy for polypoidal choroidal vasculopathy. Am J Ophthalmol. 2007 Jul;144(1):7–14. 41. Koh A, Lee WK, Chen L-J, Chen S-J, Hashad Y, Kim H, et al. EVEREST study: efficacy and safety of verteporfin photodynamic therapy in combination with ranibizumab or alone versus ranibizumab monotherapy in patients with symptomatic macular polypoidal choroidal vasculopathy. Retina (Philadelphia, Pa). 2012 Sep;32(8):1453–64. 42. Jutley G, Jutley G, Tah V, Lindfield D, Menon G. Treating peripapillary choroidal neovascular membranes: a review of the evidence. Eye (Lond). 2011 Jun;25(6):675–81. 43. Bernstein PS, Horn RS. Verteporfin photodynamic therapy involving the optic nerve for peripapillary choroidal neovascularization. Retina (Philadelphia, Pa). 2008 Jan;28(1):81–4. 44. Figueroa MS, Noval S, Contreras I. Treatment of peripapillary choroidal neovascular membranes with intravitreal bevacizumab. Br J Ophthalmol. 2008 Sep;92(9):1244–7. 45. Hoeh AE, Schaal KB, Ach T, Dithmar S. Treatment of peripapillary choroidal neovascularization with intravitreal bevacizumab. Eur J Ophthalmol. 2009 Feb;19(1):163–5. 46. Tuncer S, Kir N, Shields CL. Dramatic regression of amelanotic choroidal melanoma with PDT following poor response to brachytherapy. Ophthalmic Surg Lasers Imaging. 2012 May 3;43(3):e38-40. 47. Campbell WG, Pejnovic TM. Treatment of amelanotic choroidal melanoma with photodynamic therapy. Retina (Philadelphia, Pa). 2012 Jul;32(7):1356–62. 48. Donaldson MJ, Lim L, Harper CA, Mackenzie J, G Campbell W. Primary treatment of choroidal amelanotic melanoma with photodynamic therapy. Clin Experiment Ophthalmol. 2005 Oct;33(5):548–9. 49. Mashayekhi A, Shields CL, Shields JA. Transient increased exudation after photodynamic therapy of intraocular tumors. Middle East African Journal of Ophthalmology. 2013 Jan 1;20(1):83. 50. Çekiç O, Bardak Y, Kapucuoğlu N. Photodynamic Therapy for Conjunctival Ocular Surface Squamous Neoplasia. Journal of Ocular Pharmacology and Therapeutics. 2011 Apr;27(2):205–7. 51. Kevany BM, Palczewski K. Phagocytosis of retinal rod and cone photoreceptors. Physiology (Bethesda). 2010 Feb;25(1):8–15. 52. Kaliki S, Shields CL, Al-Dahmash SA, Mashayekhi A, Shields JA. Photodynamic therapy for choroidal metastasis in 8 cases. Ophthalmology. 2012 Jun;119(6):1218–22. 53. M K, S K, H O, C M. Photodynamic therapy with verteporfin for choroidal neovascularization in patients with angioid streaks. Am J Ophthalmol. 2002 Sep 1;134(3):360–6. 54. Gliem M, Finger RP, Fimmers R, Brinkmann CK, Holz FG, Charbel Issa P. Treatment of choroidal neovascularization due to angioid streaks: a comprehensive review. Retina (Philadelphia, Pa). 2013 Aug;33(7):1300–14. Dr. Nishant Yadav, MS Senior Resident, Department of Ophthalmology, DDU Hospital, New Delhi. Corresponding Author:

DOS Times Volume 29, Number 7, January-February 2024 www.dosonline.org/dos-times 84 Pachychoroid Spectrum of Disorders Aswini Devi S.B, MBBS, Nishant Yadav, MS, Shilpa Gupta, DNB, Shaifali Khandpur, MS, DNB, Jatinder Singh Bhalla, MS, DNB, MNAMS Department of Ophthalmology, DDU Hospital, New Delhi. Introduction Pachychoroid is a relatively recent term that has been used to describe a thickened Haller choroidal layer with attenuation of the Sattler and choriocapillaris layers.[1] The term ‘pachy’ is a Greek word ‘παχύ’, which means thick. The pachychoroid is a relatively new concept referring to a group of ophthalmological disorders which has as major characteristics, not only a thickened choroid, but also dilated choroidal vessels and attenuation of choriochapillaris. These alterations of the choroidal structure have as a consequence the dysfunction of the retinal pigment epithelium, a layer of great importance in maintaining the normal retinal metabolism and functions and subsequent development of choroidal neovascularization. The etiology of pachychoroid diseases is controversial. It is assumed that autosomal dominant heredity is implicated, together with endogenous and exogenous factors that trigger the onset of the clinical manifestations.[2] Recently, the following diagnosis criteria has been proposed for pachychoroid: a) reduced fundus tessellation, b) pachyvessels, defined as dilated choroidal vessels seen on optical coherence tomography (OCT) or indocyanine green angiography (ICGA), extending the entire length of the vessel to the vortex vein ampullae, causing choriocapillaris and Sattler layer attenuation, c) a lack of soft- drusen (an exception is made for pachydrusen, which are irregular, scattered yellow-white deposits across the posterior pole), d) the presence of CSCR characteristics, such as retinal pigment epithelium (RPE) abnormalities, choroidal vascular hyperpermeability (CVH), or a prior CSCR diagnosis.[1] The pachychoroid spectrum comprises: 1. Central serous chorioretinopathy, 2. Pachychoroid pigment epitheliopathy, 3. Pachychoroid neovasculopathy, 4. Polypoidal choroidal vasculopathy, 5. Peripapillary pachychoroid syndrome, 6. Focal choroidal excavation And relatively two new entities: 7. Peripapillary pachychoroid neovasculopathy 8. Peripheral exudative hemorrhagic chorioretinopathy.[1] Anatomy of Choroid The choroid represents the vascular layer of the eye and it is part of the uvea together with the iris and ciliary body. It extends from the anterior ora serrata to the posterior optic nerve. The choroid provides vascular supply for the outer third of the retina. Alterations of the choroidal structure have repercussions on retinal function and can lead to the death of retinal pigment epithelial cells and the photoreceptors.[2] The choroid is comprised of 5 layers: Bruch Membrane, choriocapillaris, Sattler Layer - medium diameter blood vessels, Haller's Layer - large diameter blood vessels, supra- choroid lamina - a transitional zone between choroid and sclera. The choriochapillaris is important in the rapid transport of large molecules because in its structure are included large diameter capillaries and fenestrations of 700-800nm diameter. The blood flow of the choroid is higher than that of any other tissue in the organism, 20 times higher than the retinal flow, providing oxygen and nutritive substances to the outer retina, retinal pigment epithelium, avascular fovea and the prelaminar part of the optic nerve.[3] The choroid is best studied by enhanced depth imaging-optical coherence tomography (EDI-OCT) and swept source-optical coherence tomography (SS-OCT), both techniques being able to display the deep layers of this tissue and correlate its structural and functional analysis. Optical coherence angiography (OCTA) is a new, non-invasive, 3D imaging technique, which can reconstruct the blood flow in all the vascular layers of the choroid without using contrast substances.[3] As viewed on OCT, choroid thickness is the greatest in the subfoveal region and it is thinner in the nasal and temporal areas. Choroidal thickness varies with age, gender, ethnical group, refractive error and axial length, but the mean thickness is considered to be between 260-300 microns.[4] Some variations in the thickness of choroid are possible: it decreases with age and with a longer axial length of the eye and it temporary increases in the acute stages of severe posterior uveitis (multifocal choroiditis, multiple white dot syndrome, VogtKoyanagi-Harada syndrome).[4,5] More recently, software based on binarized OCT has been developed to quantify the ratio between the choroidal vascular luminal area to total choroidal area (choroidal vasculature index [CVI]), potentially representng a useful imaging biomarker for choroidal diseases.[6] In pachychoroid disorders, CVI is found high both in diseased eyes and fellow eyes.[7,8] Clinical Entities Included in the Pachychoroid Disease Spectrum 1. Central Serous Chorioretinopathy CSC is characterized by RPE changes, serous PEDs, and Subspeciality - Retina

www.dosonline.org/dos-times DOS Times Volume 29, Number 7, January-February 2024 85 Subspeciality - Retina subretinal fluid and tends to occur unilaterally in young to middle-aged men. While the first attack regresses spontaneously 80% of the time, it can become chronic in the remaining cases. Even if the first attack regresses, the recurrence rate is around 50%. Acute CSC is the most common form of presentation and manifests as localized neurosensory retinal detachment often regresses spontaneously and heals with minimal sequelae while the chronic form is often associated with long-term persistence of fluid (more than 6 months), cystoid macular degeneration, secondary CNV and RPE atrophies and defined as the form in which permanent vision loss can develop.[9] Fundus examinations reveal serous macular detachment and diffuse RPE irregularities in chronic cases. OCT imaging can demonstrate attenuation of the outer retinal layers (related to chronic subretinal fluid) and defects in the external limiting membrane. Descending tract and mottled hyper- autofluorescent areas are observed in FAF imaging. Delayed arterial filling and subsequent capillary and venous hyperemia manifest as capillary and venous congestion are frequently seen in eyes with CSC. These findings suggest that capillary or venous congestion after ischemia in one or more choroidal lobes may be the cause of CSC-related choroidal hyperpermeability. CSC is now proposed as a disease characterized by congestion in the distal vortex vein that developed in eyes with asymmetric vortex veins. Kishi and coworkers evaluated the correlation between the areas of filling delay in early-phase ICG angiography and the regions of dilated vortex veins in en-face OCT imaging and found there was a significant co-localization.[10] In FFA, hyperfluorescence in the form of window defect due to RPE atrophy, and in acute cases leaky foci from the RPE are observed. The enlargement of the leaky area in the later stages of angiography is a typical finding. In ICGA, dilated choroidal vessels in the macular region are observed and in mid phases, patchy areas of choroidal hyperpermeability are revealed. OCT angiography (OCTA) is especially important in detecting the development of secondary CNV. Although treatment options such as risk factor modifications, medical treatments, and anti-vascular endothelial growth factor (VEGF) injections are discussed, the strong benefits of these options have not been proven yet. Mineralocorticoid antagonists, which have been emphasized recently, are not found superior to placebo in a multicenter randomized study.[11] Although applying laser photocoagulation to the focal points maintains its historical importance, the possibility of secondary CNV development in the laser field and its inability to apply it to leaky foci near the fovea makes it far from being an ideal treatment. Two treatment modalities which are agreed on their efficacy in the treatment of chronic CSC are sub-threshold micropulse laser and half-dose or half-fluence photodynamic therapy (PDT). PDT increases the resorption of subretinal fluid by decreasing choroidal hyperpermeability.[12,13] Half-dose Verteporfin Photodynamic Therapy (vPDT) has become a popular treatment choice given its efficacy and improved safety compared to full-dose vPDT.[14,15] However, in one of the prospective randomized control studies; PLACE study, PDT showed superior efficacy with respect to complete resolution of SRF compared with micropulse laser at both short-term and long-term follow-up visits. Moreover, functional outcome was better with respect to both increased retinal sensitivity at the first and final evaluation visits and increased BCVA at the first evaluation visit in PDT group.[16] 2. Pachychoroid Pigment Epitheliopathy PPE refers to a usually asymptomatic condition characterized by RPE changes and choroidal thickening. It differs from CSC by the absence of detectable subretinal fluid, despite the presence of irregularities in the RPE. It is also called the “formae frustae” form of the CSC. It is a finding that is usually seen in the other asymptomatic eyes of the eyes with CSC.[17] Pachychoroid pigment epitheliopathy has been classified into four types: RPE thickening, hyper-reflective RPE spike, RPE elevation with inter-RPE fissures, and PED.[18] Sakurada et al demonstrated decreased choriocapillaris blood flow in areas coinciding with PPE lesions, suggesting that local ischemia may be the basis of this condition.[19] Similarly, Tagawa et al investigated choriocapillaris flow changes in 32 eyes with Figure 1: Optical coherence tomography and angiography images of a case with acute central serous chorioretinopathy: (a) Large neurosensory detachment with subretinal fluid on enhanced depth imaging optical coherence tomography passing through fovea (b and c) Simultaneous fundus fluorescein angiography and indocyanine green angiography (ICGA) showing the smokestack configuration. The leak in ICGA is smaller in size as com- pared to fundus fluorescein angiography. Areas of choroidal hyperpermeability are seen in ICGA along the vascular arcades.

DOS Times Volume 29, Number 7, January-February 2024 www.dosonline.org/dos-times 86 PPE compared to 30 healthy controls, finding that eyes with PPE had significantly larger mean total flow void area and average flow void size compared to healthy controls. Further, PPE eyes tended to exhibit a diffuse decrease in choriocapillaris blood flow area, not necessarily spatially related to pachyvessel location. Interestingly, only 21.3% of flow void areas were present over a pachyvessel, leading these authors to suggest that pachyvessel presence does not directly result in choriocapillaris flow deficits.[20] 3. Pachychoroid Neovascularization (PNV) Choroidal neovascularizations are classified according to whether new vessels are located above or below the RPE on OCT. Type-1 CNV is located under the RPE and is typically characterized by the presence of PED. Although it is frequently seen in neovascular AMD, it can also be observed in pachychoroid diseases such as CSC, PCV, and PNV. Therefore, in cases without classical AMD findings, PNV should be considered in the presence of thick choroid and type-1 CNV. PNV is a relatively new clinical entity defined in 2014 by Pang and Freund. They reported a small case series of patients with type-1 CNV occurring over enlarged choroidal vessels with increased choroidal thickness and defined this entity as “PNV".[21] PNV joined the pachychoroid spectrum after imaging demonstrated that neovascular lesions spatially correspond to areas with common pachychoroid features, such as thickened choroid, pachyvessels, and increased CVH.[22][1] Figure 2: Imaging of pachychoroid pigment epitheliopathy. (A) Multicolour image highlighting two small PEDs. (B) FAF imaging does not demonstrate major changes in RPE autofluorescence. (C) Near infrared image highlights the position of the line scan for the OCT in image D. Two elevated changes are again seen surrounded by haloes of reduced infrared signal. (D) EDI SD-OCT shows two small serous PEDs (arrowheads) with clear pachychoroid (arrow). PED, pigment epithelial detachment; FAF, fundus autofluorescence; OCT, optical coherence tomography; EDI SDOCT enhanced depth imaging spectral domain-OCT. Figure 3: A 58-year-old female with PNV in the right eye. (A) FA demonstrating hyperfluorescence with minimal leakage. (B) OCT showing pigment epithelial detachment (PED) with hyperreflectivity within PED. (C) Early ICG which depicts dilated choroidal vessels and hyperfluorescence. (D) ICG late phase shows diffuse choroidal fluorescence with increasing hyperfluorescence at the lesion site. Some investigators have suggested that PNV is a late complication of preexisting PPE or chronic CSC[22]; however, this link is contentious.[8] In support of this theory, previous authors have suggested that given the extensive metabolic demand of photoreceptor cells and relatively limited oxygen supply of the inner retinal vasculature, choroidal thickening decreases diffusion of available oxygen supply from the choriocapillaris to the outer retina, and may therefore lead to VEGF expression from the RPE and subsequent neovascularization.[22] On OCT, CNV developing on a pachychoroid background typically presents as a flat irregular PED over the dilated Haller layer and according to the activity of the disease, subretinal fluid can be observed. Evaluation of type 1 CNV by dye angiography methods may be difficult due to leak-age in FFA and increased choroidal permeability in ICGA. Whereas, OCTA can show the full size of the neovascular membrane and is not affected by leakage, staining, and increased choroidal permeability, unlike conventional dye angiograms.[23] Pulsation seen in the downstream of the vortex vein on ICGA has recently been proposed as a biomarker for choroidal overload, particularly in eyes with PNV.[24] Many treatment options have been explored for PNV; however, differences in case inclusion between studies somewhat cloud this work. Anti-VEGF treatments are equally effective in both PNV and nAMD, but PNV patients often require a longer treatment interval.[25] Aflibercept has proven more effective than ranibizumab at targeting CVH, reducing fluid, and decreasing choroidal thickness.[26,27] NV and chronic CSCR have recently been shown to respond differently to half-fluence PDT treatment and may require antiVEGF + half-fluence PDT combination therapy.[37] Plausibly, PDT monotherapy may successfully treat the CVH component of PNV; however, the neovascular lesions still require an antiVEGF medication.[28,29] Subspeciality - Retina

www.dosonline.org/dos-times DOS Times Volume 29, Number 7, January-February 2024 87 Subspeciality - Retina 5. Peripapillary Pachychoroid Syndrome (PPS) Peripapillary pachychoroid syndrome (PPS) is a relatively new addition to the pachychoroid spectrum, with few cases reported overall. In PPS, patients demonstrate intra or subretinal fluid in the region nasal to the macula and choroidal thickening near the optic disk, rather than the fovea.[25][37] These patients are characterized by subretinal fluid, intraretinal cyst, and rarely optic disc edema, which often develops in the temporal region of the optic disc. Hyperopia, short axial length, and choroidal folds are other conditions that associated with PPS.[38] 4. Polypoidal Choroid Vasculopathy (PCV) Polypoidal choroid vasculopathy (PCV) has been described as polypoidal vascular dilations overlying a choroidal vascular network.[25] In an enucleated PNV case, CNV was shown to be accompanied by aneurysmal enlargements located between the RPE and Bruch’s membrane. Therefore, some authors argue that it should be named aneurysmal type-1 CNV instead of PCV.[30] Recently, aneurysmal type 1 neovascularization (AT1) or pachychoroid aneurysmal type 1 neovascularization (PAT1) have become common in the literature, removing the “polypoidal” terminology to reflect the idea that the lesions are primarily vascular rather than epithelial.[22][1] Aneurysmal dilation of type 1 CNV might develop over time and might be complicated by lipid leakage and hemorrhage. Fundus examination reveals orange nodules, serous or hemorrhagic PED, subretinal hemorrhage, subretinal fluid, fibrosis, and scarring. The most feared complication and the cause of poor visual prognosis is massive subretinal hemorrhage. On OCT, inverted V-shaped, sharply peaked PED appearance, multilobular PEDs, ring-like lesion inside the PED, and flat irregular PED and double layer sign can be seen in the area where the branching vascular network and polyps are located.[31] ICGA is the gold standard for definitive diagnosis. In ICGA, choroidal hyperpermeability, hyperfluorescent plaque appearance due to branching vascular network, and polyp structures that appear as grape bunches are striking. Polyps show early filling Figure 4: Multimodal fundus images of the right eye of a polypoidal choroidal vasculopathy case: (a) On enhanced depth imaging optical coherence tomography, shallow serous pigment epithelium detachment with a hyperreflective inverted V-shaped pigment epithelium detachment and subretinal fluid. (b) Leakage of the inferior macula in fundus fluorescein angiography (c) Bright hyperfluorescent polyps surrounded by hypofluorescent wall and branching vascular network in indocyanine green angiography. and are observed as a bright hyperfluorescent interior and hypofluorescent wall structure in the early stages. In the later stages, the center of the polyps is hypo, and the wall structure is hyperfluorescent due to staining.[32] Although OCTA is also useful in imaging PCV lesions, it may be insufficient to visualize polyp structures in cases with high-speed turbulent flow or thrombosis within the polyp.[33] Some recent authors suggest that EDI-OCT is crucial in diagnosing this entity, which may demonstrate peaked PEDs containing “thumbprint signs,” or rings of hyperreflectivity with hyporeflective lumens.A “double hump sign” may present where one PED leaks fluid near another PED, while saccular dilations may appear as hyperreflectivity at the RPE level on enface OCT.[34] Photodynamic therapy, anti-VEGF therapy, or a combination of these can be used in the treatment. In the EVEREST II study, the PDT and ranibizumab combination group compared to the ranibizumab therapy and accordingly the rate of final letter gain (8.8 letters; 5.1 letters respectively) and polyp regression (69.3%;34.7% respectively) were higher, while the mean number of injections was lower (5.2; 7.3 respectively) in the combined group.[35] Recently, Vadalà et al evaluated full fluence vPDT + aflibercept in pachychoroid-PCV eyes, finding significant improvement in functional outcomes at 12 months.[36] Initially treating with vPDT before aflibercept injections has been hypothesized to maintain the effects of initial vPDT and reduce retreatment in PCV and PNV patients.[36][1] Recent evidence has led authors to theorize that anastomotic connections may also play a role in PPS pathogenesis.[1] Peripapillary anastomoses, in combination with the lack of RPE around the optic nerve head, may allow for the direct transmission of choroidal hydrostatic pressure to the inner retinal layers in this region.[39] Hyperautofluorescent gravitational tracks of pigmentary abnormalities of chronic fluid localized to the peripapillary area because of gravity on either FFA or FAF can be illustrated.[40]

DOS Times Volume 29, Number 7, January-February 2024 www.dosonline.org/dos-times 88 ICGA illustrates peripapillary dilated choroidal vessels with multifocal hy-perpermeability.[39] Treatment efficacy for PPS varies. Recent cases have resolved spontaneously or with PDT laser.[41] The efficacy of anti-VEGF injections is mixed; some have reported favorable outcomes after aflibercept injections, while others reported cases of PPS that were recalcitrant to multiple anti-VEGF medications. Recalcitrant cases have recently shown improved BCVA after low-fluence PDT.[42] Most recently, some reports have documented the potential utility of topical steroids in these cases with good anatomical outcomes.[43] 6. Focal Choroidal Excavation (FCE) FCE is an imaging finding that describes the localized excavation of choroidal tissue towards the sclera, observed in the absence of a disease-causing thinning of the sclera (posterior staphyloma).[44] Most cases are asymptomatic and fundus examination may reveal non-specific RPE changes or a yellow spot. OCT is the imaging method that best describes this situation. There are two subtypes according to OCT findings; in the conforming type of the photoreceptor tips are in direct contact with the RPE, in the non-conforming type, the photoreceptor ends are separated from the RPE below it with an intermittent hyporeflective cleft.[45] Nonconforming type FCE is like an inverse RPE detachment; it compresses the choriocapillaris and further exacerbates choroidal ischemia. This leads to further focal RPE/Bruch’s membrane complex injury, increasing the pre- disposition to CSC or CNV.[46] Hyperfluorescent window defects can be seen in FFA depending on the condition of the RPE on it. In ICGA, a hypofluorescent area may be observed showing choriocapillaris atrophy. FCE has been reported in pachychoroid cases with Figure 5: Optical coherence tomography images of a case with peripapillary pachychoroid syndrome in both eyes: (a and b) Increasing choroidal thickness from temporal to nasal in both eyes (arrow-head) and dilated Haller veins on enhanced depth imaging optical coherence tomography. Figure 6: Enhanced depth imaging optical coherence tomography of focal choroidal excavation (FCE) in the left eye of a patient with central serous chorioretinopathy who was using long-term systemic corticosteroid therapy for renal transplantation: (a) On optical coherence tomography subretinal fluid, FCE in subfoveal location, shallow pigment epithelium detachment localized nasally, and also thick choroid and dilated Hal-ler veins. increased subfoveal choroidal thickness and hyperpermeability in ICGA. The localization of choroidal hyperpermeability in or near the choroidal hyperperme-ability area in ICGA, and the presence of this finding in both the patient eye and the other eye in the CSC and PCV case series suggested that FCE is a pachychoroid-related condition. FCE leads to atrophy of the overlying RPE and subsequent pump dysfunction, and CSC occurs as a complication. It has also been proposed that CNV and PCV are both the result of choroidal ischemia in areas of anatomic anomalies.[47] Regular observation is recommended to monitor for treatmentrequiring complications, such as neovascularization. New Entities Peripapillary Pachychoroid Neovasculopathy Montero Hernandez et al presented a new entity in the pachychoroid spectrum, peripapillary pachychoroid neovasculopathy (PPN), which describes PPS occurring with peripapillary type 1 CNV. Notable findings included: papillonasal pigmentary changes overlying mottled autofluorescence; an irregular PED and pachyvessels on SD-OCT; a large neovascular network and hyper-flow signal on OCTA; and CVH on ICGA. The patient was given treat-and-extend aflibercept, resulting in a good visual and anatomic outcome.[48] Peripheral Exudative Haemorrhagic Chorioretinopathy Peripheral exudative hemorrhagic chorioretinopathy (PEHCR) is associated with peripheral subretinal fluid and hemorrhaging, typically located between the ocular equator and ora serrata.[49] Imaging studies have found polypoid lesions in the retinal periphery on ICGA, prompting authors to suggest it is similar to PCV. Schroff et al recently proposed PEHCR as an addition to the pachychoroid spectrum after finding that it was associated with a thickened choroid in the temporal periphery.[50] Mantel et al described these cases as being self-limiting, with long-term follow- up demonstrating stability, regression, or full resolution.Importantly, given the similarities in their presentation, these lesions must be distinguished from Subspeciality - Retina

www.dosonline.org/dos-times DOS Times Volume 29, Number 7, January-February 2024 89 Subspeciality - Retina choroidal melanoma which may prevent unneeded radiation or enucleation in these patients.[50,51] Summary Significant advancements in our comprehension of pachychoroidal disease entities, including plausible pathways for their genesis and pathogenesis, have been made possible by retinal and choroidal imaging. Technological developments in imaging are critical for distinguishing the various disease entities on this spectrum, clarifying the pathophysiology of pachychoroid subtypes, and enabling more accurate diagnosis and treatment monitoring. To explain these variations between pachychoroid spectrum disorders, Prospective studies with a large number of patients with long-term folowups are needed. References 1. Brown R, Mohan S, Chhablani J. Pachychoroid Spectrum Disorders: An Updated Review. J Ophthalmic Vis Res [Internet]. 2023 Apr 19 [cited 2024 Feb 12]; Available from: https://knepublishing.com/index. php/JOVR/article/view/13188. 2. Moraru A, Costin D, Moraru R, Costuleanu M, Brănișteanu D. Current diagnosis and management strategies in pachychoroid spectrum of diseases (Review). Exp Ther Med [Internet]. 2020 Aug 4 [cited 2024 Feb 12]; Available from: http://www.spandidospublications.com/10.3892/etm.2020.9094. 3. Mrejen S, Spaide RF. Optical coherence tomography: Imaging of the choroid and beyond. Surv Ophthalmol. 2013 Sep;58(5):387–429. 4. Goldenberg D, Moisseiev E, Goldstein M, Loewenstein A, Barak A. Enhanced Depth Imaging Optical Coherence Tomography: Choroidal Thickness and Correlations With Age, Refractive Error, and Axial Length. Ophthalmic Surg Lasers Imaging Retina. 2012 Jul;43(4):296– 301. 5. Margolis R, Spaide RF. A Pilot Study of Enhanced Depth Imaging Optical Coherence Tomography of the Choroid in Normal Eyes. Am J Ophthalmol. 2009 May;147(5):811–5. 6. Agrawal R, Seen S, Vaishnavi S, Vupparaboina KK, Goud A, Rasheed MA, et al. Choroidal Vascularity Index Using Swept-Source and Spectral-Domain Optical Coherence Tomography: A Comparative Study. Ophthalmic Surg Lasers Imaging Retina [Internet]. 2019 Feb [cited 2024 Feb 13];50(2). Available from: https://journals.healio. com/doi/10.3928/23258160-20190129-15. 7. Demirel S, Özcan G, Yanık Ö, Batıoğlu F, Özmert E. A comparative study of the choroidal vascularity indexes in the fellow eyes of patients with pachychoroid neovasculopathy and central serous chorioretinopathy by binarization method. Graefes Arch Clin Exp Ophthalmol. 2020 Aug;258(8):1649–54. 8. Demirel S, Yanık Ö, Özcan G, Batıoğlu F, Özmert E. A comparative study on the choroidal vascularity index and the determination of cutoff values in the pachychoroid spectrum diseases. Jpn J Ophthalmol. 2021 Jul;65(4):482–91. 9. Pauleikhoff L, Agostini H, Lange C. Chorioretinopathia centralis serosa. Ophthalmol. 2021 Sep;118(9):967–80. 10. Kishi S, Matsumoto H, Sonoda S, Hiroe T, Sakamoto T, Akiyama H. Geographic filling delay of the choriocapillaris in the region of dilated asymmetric vortex veins in central serous chorioretinopathy. Vavvas DG, editor. PLOS ONE. 2018 Nov 9;13(11):e0206646. 11. Lotery A, Sivaprasad S, O’Connell A, Harris RA, Culliford L, Ellis L, et al. Eplerenone for chronic central serous chorioretinopathy in patients with active, previously untreated disease for more than 4 months (VICI): a randomised, double-blind, placebo-controlled trial. The Lancet. 2020 Jan;395(10220):294–303. 12. Piccolino FC, Eandi CM, Ventre L, Rigault De La Longrais RC, Grignolo FM. Photodynamic Therapy for Chronic Central Serous Chorioretinopathy: RETINA. 2003 Dec;23(6):752–63. 13. Silva RM, Ruiz-Moreno JM, Gomez-Ulla F, Montero JA, Gregório T, Cachulo ML, et al. PHOTODYNAMIC THERAPY FOR CHRONIC CENTRAL SEROUS CHORIORETINOPATHY: A 4-Year Follow-up Study. Retina. 2013 Feb;33(2):309–15. 14. Hanumunthadu D, Tan AS, Singh S, Sahu N, Chhablani J. Management of chronic central serous chorioretinopathy. Indian J Ophthalmol. 2018;66(12):1704. 15. Chan WM, Lai TYY, Lai RYK, Tang EWH, Liu DTL, Lam DSC. SAFETY ENHANCED PHOTODYNAMIC THERAPY FOR CHRONIC CENTRAL SEROUS CHORIORETINOPATHY: OneYear Results of a Prospective Study. Retina. 2008 Jan;28(1):85–93. 16. Van Dijk EHC, Fauser S, Breukink MB, Blanco-Garavito R, Groenewoud JMM, Keunen JEE, et al. Half-Dose Photodynamic Therapy versus High-Density Subthreshold Micropulse Laser Treatment in Patients with Chronic Central Serous Chorioretinopathy. Ophthalmology. 2018 Oct;125(10):1547–55. 17. Ersoz MG, Karacorlu M, Arf S, Hocaoglu M, Sayman Muslubas I. Pachychoroid pigment epitheliopathy in fellow eyes of patients with unilateral central serous chorioretinopathy. Br J Ophthalmol. 2018 Apr;102(4):473–8. 18. Karacorlu M, Ersoz MG, Arf S, Hocaoglu M, Sayman Muslubas I. Long-term follow-up of pachychoroid pigment epitheliopathy and lesion characteristics. Graefes Arch Clin Exp Ophthalmol. 2018 Dec;256(12):2319–26. 19. Sakurada Y, Fragiotta S, Leong BCS, Parikh R, Hussnain SA, Freund KB. RELATIONSHIP BETWEEN CHOROIDAL VASCULAR HYPERPERMEABILITY, CHORIOCAPILLARIS FLOW DENSITY, AND CHOROIDAL THICKNESS IN EYES WITH PACHYCHOROID PIGMENT EPITHELIOPATHY. Retina. 2020 Apr;40(4):657–62. 20. Tagawa M, Ooto S, Yamashiro K, Tamura H, Oishi A, Uji A, et al. Choriocapillaris flow deficit in a pachychoroid spectrum disease using en face optical coherence tomography angiography averaging. Grulkowski I, editor. PLOS ONE. 2022 Sep 12;17(9):e0271747. 21. Pang CE, Freund KB. PACHYCHOROID NEOVASCULOPATHY. Retina. 2015 Jan;35(1):1–9. 22. Borooah S, Sim PY, Phatak S, Moraes G, Wu CY, Cheung CMG, et al. Pachychoroid spectrum disease. Acta Ophthalmol (Copenh) [Internet]. 2021 Sep [cited 2024 Feb 14];99(6). Available from: https://onlinelibrary.wiley.com/doi/10.1111/aos.14683 23. Demirel S, Yanık Ö, Nalcı H, Batıoğlu F, Özmert E. The use of optical coherence tomography angiography in pachychoroid spectrum diseases: a concurrent comparison with dye angiography. Graefes Arch Clin Exp Ophthalmol. 2017 Dec;255(12):2317–24. 24. Yamada C, Mukai R, Shinohara Y, Matsumoto H, Akiyama H. Occlusion of a Vortex Vein After Treatment With Half-Fluence Photodynamic Therapy Combined With Intravitreal Aflibercept Injection for Pachychoroid Neovasculopathy. Cureus [Internet]. 2022 Aug 4 [cited 2024 Feb 14]; Available from: https://www.cureus.com/ articles/101759-occlusion-of-a-vortex-vein-after-treatment-withhalf-fluence-photodynamic-therapy-combined-with-intravitrealaflibercept-injection-for-pachychoroid-neovasculopathy.

DOS Times Volume 29, Number 7, January-February 2024 www.dosonline.org/dos-times 90 25. Cheung CMG, Lee WK, Koizumi H, Dansingani K, Lai TYY, Freund KB. Pachychoroid disease. Eye. 2019 Jan;33(1):14–33. 26. Jung BJ, Kim JY, Lee JH, Baek J, Lee K, Lee WK. Intravitreal aflibercept and ranibizumab for pachychoroid neovasculopathy. Sci Rep. 2019 Feb 14;9(1):2055. 27. Padrón-Pérez N, Arias L, Rubio M, Lorenzo D, García-Bru P, Català-Mora J, et al. Changes in Choroidal Thickness After Intravitreal Injection of Anti-Vascular Endothelial Growth Factor in Pachychoroid Neovasculopathy. Investig Opthalmology Vis Sci. 2018 Feb 28;59(2):1119. 28. Lee JH, Lee WK. ONE-YEAR RESULTS OF ADJUNCTIVE PHOTODYNAMIC THERAPY FOR TYPE 1 NEOVASCULARIZATION ASSOCIATED WITH THICKENED CHOROID. Retina. 2016 May;36(5):889–95. 29. Yanık Ö, Demirel S, Batıoğlu F, Özmert E. A Comparative Study of Short-Term Vascular and Stromal Alterations of the Choroid Following Half-Fluence Photodynamic Therapy in Pachychoroid Neovasculopathy and Chronic Central Serous Chorioretinopathy. Life. 2022 Aug 25;12(9):1304. 30. Dansingani KK, Gal‐Or O, Sadda SR, Yannuzzi LA, Freund KB. Understanding aneurysmal type 1 neovascularization (polypoidal choroidal vasculopathy): a lesson in the taxonomy of ‘expanded spectra’ – a review. Clin Experiment Ophthalmol. 2018 Mar;46(2):189–200. 31. Cheung CMG, Lai TYY, Teo K, Ruamviboonsuk P, Chen SJ, Kim JE, et al. Polypoidal Choroidal Vasculopathy. Ophthalmology. 2021 Mar;128(3):443–52. 32. Destro M, Puliafito CA. Indocyanine Green Videoangiography of Choroidal Neovascularization. Ophthalmology. 1989 Jun;96(6):846– 53. 33. Wang M, Zhou Y, Gao SS, Liu W, Huang Y, Huang D, et al. Evaluating Polypoidal Choroidal Vasculopathy With Optical Coherence Tomography Angiography. Investig Opthalmology Vis Sci. 2016 Jul 29;57(9):OCT526. 34. Pereira A, Aldrees S, Pimentel MC, Yan P. Updated review: optical coherence tomography findings of the pachychoroid disease spectrum. Can J Ophthalmol. 2023 Feb;58(1):e33–5. 35. Koh A, Lai TYY, Takahashi K, Wong TY, Chen LJ, Ruamviboonsuk P, et al. Efficacy and Safety of Ranibizumab With or Without Verteporfin Photodynamic Therapy for Polypoidal Choroidal Vasculopathy: A Randomized Clinical Trial. JAMA Ophthalmol. 2017 Nov 1;135(11):1206. 36. Vadalà M, Castellucci M, Guarrasi G, Cillino G, Bonfiglio VME, Casuccio A, et al. Polypoidal choroidal vasculopathy in pachychoroid: combined treatment with photodynamic therapy and aflibercept. Int Ophthalmol. 2022 Feb;42(2):601–10. 37. Hubschman S, Hou K, Sarraf D, Tsui I. An unusual presentation of peripapillary pachychoroid syndrome. Am J Ophthalmol Case Rep. 2022 Mar;25:101338. 38. Phasukkijwatana N, Freund KB, Dolz-Marco R, Al-Sheikh M, Keane PA, Egan CA, et al. PERIPAPILLARY PACHYCHOROID SYNDROME. Retina. 2018 Sep;38(9):1652–67. 39. Xu D, Garg E, Lee K, Sakurada Y, Amphornphruet A, Phasukkijwatana N, et al. Long-term visual and anatomic outcomes of patients with peripapillary pachychoroid syndrome. Br J Ophthalmol. 2022 Apr;106(4):576–81. 40. Kumar V, Azad SV, Verma S, Surve A, Vohra R, Venkatesh P. PERIPAPILLARY PACHYCHOROID SYNDROME: New Insights. Retina. 2022 Jan;42(1):80–7. 41. Bouzika P, Georgalas I, Sotirianakou ME, Karamaounas A, Symeonidis C, Tyrlis K, et al. Peripapillary Pachychoroid Syndrome (PPS): Diagnosing and Treating a Rare Entity. Battaglia Parodi M, editor. Case Rep Ophthalmol Med. 2022 May 28;2022:1–8. 42. Manayath GJ, Verghese S, Ranjan R, Narendran V. Photodynamic therapy for peripapillary pachychoroid syndrome—a case report. Digit J Ophthalmol. 2022 Jan 27;28(1):7–11. 43. Pothof AB, Fernández-Avellaneda P, Behar-Cohen F, Martinez Ciriano JP, Yzer S. POTENTIAL TREATMENT FOR PERIPAPILLARY PACHYCHOROID SYNDROME. Retin Cases Brief Rep. 2023 Jul;17(4):425–9. 44. Lim FPM, Wong CW, Loh BK, Chan CM, Yeo I, Lee SY, et al. Prevalence and clinical correlates of focal choroidal excavation in eyes with age-related macular degeneration, polypoidal choroidal vasculopathy and central serous chorioretinopathy. Br J Ophthalmol. 2016 Jul;100(7):918–23. 45. Margolis R. The Expanded Spectrum of Focal Choroidal Excavation. Arch Ophthalmol. 2011 Oct 1;129(10):1320. 46. Chung H, Byeon SH, Freund KB. FOCAL CHOROIDAL EXCAVATION AND ITS ASSOCIATION WITH PACHYCHOROID SPECTRUM DISORDERS: A Review of the Literature and Multimodal Imaging Findings. Retina. 2017 Feb;37(2):199–221. 47. Lee CS, Woo SJ, Kim YK, Hwang DJ, Kang HM, Kim H, et al. Clinical and Spectral-Domain Optical Coherence Tomography Findings in Patients with Focal Choroidal Excavation. Ophthalmology. 2014 May;121(5):1029–35. 48. Montero Hernández J, Remolí Sargues L, Monferrer Adsuara C, Castro Navarro V, Navarro Palop C, Cervera Taulet E. Peripapillary pachychoroid neovasculopathy: A novel entity. Eur J Ophthalmol. 2022 Jan;32(1):NP149–53. 49. Shroff D, Sharma M, Chhablani J, Gupta P, Gupta C, Shroff C. PERIPHERAL EXUDATIVE HEMORRHAGIC CHORIORETINOPATHY-A NEW ADDITION TO THE SPECTRUM OF PACHYCHOROID DISEASE? Retina. 2021 Jul;41(7):1518–25. 50. Mantel I, Schalenbourg A, Zografos L. Peripheral Exudative Hemorrhagic Chorioretinopathy: Polypoidal Choroidal Vasculopathy and Hemodynamic Modifications. Am J Ophthalmol. 2012 May;153(5):910-922.e2. 51. Goldman DR, Freund KB, McCannel CA, Sarraf D. PERIPHERAL POLYPOIDAL CHOROIDAL VASCULOPATHY AS A CAUSE OF PERIPHERAL EXUDATIVE HEMORRHAGIC CHORIORETINOPATHY: A Report of 10 Eyes. Retina. 2013 Jan;33(1):48–55. Dr. Aswini Devi S.B, MBBS Resident Department of Ophthalmology, DDU Hospital, New Delhi. Corresponding Author: Subspeciality - Retina

www.dosonline.org/dos-times DOS Times Volume 29, Number 7, January-February 2024 91 Case Report Bilateral Corneal Ulcer in Young Diabetic Male Shagun Korla, MBBS, MS, Pallavi kumari, MBBS, MS, Ridhima, MBBS, Ravinder Kumar Gupta MBBS, MS Department of Ophthalmology, Maharishi Markandeshwar Medical College and Hospital, Kumarhatti Solan, Himachal Pradesh, India. Introduction Diabetes mellitus can cause significant ocular surface changes, including abnormal tear film causing dry eye and keratitis.[1] Fungal keratitis is more commonly seen in tropical and subtropical countries, is a major cause of corneal blindness[2], which if treated well and quickly, can severely reduce the ocular morbidity. The prevalence ranges from 25.6 to 36.7% across India[3], which is three times more in males than females. In North India and Northeast India, the prevalence of fungal keratitis ranges from 7.3 to 25.6%; in West India, it is 36.3% while a higher prevalence of 36.7% is reported in Southern India.[4] Case Description A thirty five year diabetic male presented with diminution of vision in both the eyes for 2 months. Systemic history revealed, history of mouth ulcers since 20 days, burning micturition, loose stools since 6 months 3-4 times in day, history of lower limb numbness since 1 year, loss of 3 kgs weight in last 3 months and alcohol intake since last 10 years. There was no history of preceding ocular trauma, contact lens usage, over the counter eye drops usage or ocular surgery. On ocular examination best corrected visual acuity was finger counting close to face and hand movement close to face in right and left eye respectively. Intraocular pressure was digitally high in both the eyes. On anterior segment examination right eye showed diffuse conjunctival congestion (Figure-1 red arrow) with dry looking infiltrate with oval epithelial defect in inferonasal quadrant of 4*6mm (Figure-1 black arrow) with stromal edema and descemets folds. Left eye showed diffuse conjunctival congestion with dry looking infiltrate with feathery margins in centre of cornea (Figure-2 red arrow) with non mobile hypopyon of 2mm with large epithelial defect of 7*10mm (Figure-2 black arrow) suggestive of fungal corneal ulcer bilaterally. Blood Investigations revealed anemia with deranged glucose and renal function tests. Ocular investigation on 10% KOH showed Septate Hyphae, Gram Stain revealed Filamentous fungi. The growth was positive on SDA. B SCAN of both the eyes was Anechoic with Retina on. Patient was managed in multidisciplinary approach by department of medicine, dermatology and ophthalmology. Ocular treatment included Tab. Itraconazole 100mg BD, E/d Natamycin 5% 1 hourly, E/d Timolol 0.5% BD, E/d Atropine 1% TID, E/d Gatifloxacin 0.3% 6times/day, E/d Carboxymethylcellulose 0.5% 4times/day. The patient started showing improvement in 2 weeks. Figure 1: Anterior segment of right eye showing fungal corneal ulcer with severe dry eye. Figure 2: Anterior segment of left eye showing fungal corneal ulcer with fixed hypopyon with severe dry eye. Conclusion It is difficult to diagnose fungal corneal ulcer and treat successfully. The prognosis in cases of fungal keratitis is poor largely because of non availability of antifungal drugs with

DOS Times Volume 29, Number 7, January-February 2024 www.dosonline.org/dos-times 92 Case Report good ocular penetration.[5] Simultaneous bilateral microbial fungal keratitis is rarely reported in literature.[6] References 1. Gao Y, Zhang Y, Ru YS, et al.. Ocular surface changes in type II diabetic patients with proliferative diabetic retinopathy. Int J Ophthalmol 2015;8:358–64. 10.3980/j.issn.2222-3959.2015.02.26. 2. Sharma N, Sahay P, Maharana PK, Singhal D, Saluja G, Bandivadekar P, Chako J, Agarwal T, Sinha R, Titiyal JS, Satpathy G, Velpandian T. Management Algorithm for Fungal Keratitis: The TST (Topical, Systemic, and Targeted Therapy) Protocol. Cornea. 2019 Feb;38(2):141-145. doi: 10.1097/ICO.0000000000001781. PMID: 30334872. 3. Paty BP, Dash P, Mohapatra D, Chayani N. Epidemiological profile of mycotic keratitis in a tertiary care center of eastern Odisha. J Dr NTR Univ Health Sci. 2018;7:23–5. 4. Rautaraya B, Sharma S, Kar S, Das S, Sahu SK. Diagnosis and treatment outcome of mycotic keratitis at a tertiary eye care center in eastern india. BMC Ophthalmol. 2011;11:1–8. 5. Thomas PA, Kaliamurthy J. Mycotic Keratitis: epidemiology, diagnosis and management. Clin Microbial Infect. 2013;19:210-220. 6. Chaniyara MH, Pujari A, Urkude J, Sharma N. Bilateral fungal keratitis with ring infiltrates: a rare scenario. BMJ Case Rep. 2017 Oct 9;2017:bcr2017221226. doi: 10.1136/bcr-2017-221226. PMID: 28993355; PMCID: PMC5652377. Dr. Shagun Korla, MBBS, MS Assistant Professor Department of Ophthalmology, Maharishi Markandeshwar Medical College and Hospital, Kumarhatti Solan, Himachal Pradesh, India. Corresponding Author:

www.dosonline.org/dos-times DOS Times Volume 29, Number 7, January-February 2024 93 Beyond Ophthalmology Shakespeare and Ophthalmology Sunil Gupta, MS Consultant Ophthalmologist (Ant Segment & Glaucoma), RamAvtar Eye Hospital & Glaucoma Pavilion, Tilak Nagar, Jaipur. Disclosure Statement: This article has not been published in any other Journal or magazine or presented in any conference & if accepted, it will not be offered to any other publisher/conference without the consent of the editorial board. Abstract: In this article, an Ophthalmologist with an eye for English literature will discover Shakespeare's thoughts, which can be put to good use & with better effect to describe some aspects of Ophthalmology. Key Words: Shakespeare, Ophthalmology Shakespeare and Ophthalmology The writings of the great English poet, dramatist William Shakespeare (1564-1616) is an ocean of thoughts, in which all can dip & come up with some useful information. His thoughts can be put to good use anywhere, anytime to highlight any issue. That's the beauty of Shakespeare! Here are a few examples : 1. What an infinite mock is this, that a man should have the best use of eyes to see the way of blindness (Cymbeline, Act 4, Scene 2) (Certainly reflects the plight of an Ophthalmologist) 2. "Most pure spirit of sense" (Troilus & Cressida, Act 3, Scene 3) (That's what Vision/Sight/Dristi is!) 3. Men's eyes were made to look, and let them gaze (Romeo & Juliet, Act 3, Scene 1) (Our guiding spirit) 4. He that is strucken blind cannot forget the precious treasure of his eyesight lost (Romeo & Juliet, Act 1, Scene 1) (Truth needs no illustration!) 5. The eye sees not itself, But by reflection by some other things (Julius Caesar, Act 1, Scene 1) (Complexity of the Visual Pathway) 6. To what, my love, shall I compare thine eye? Crystal is muddy (Midsummer Night's dream, Act 3, Scene 2) (A patient with cataract an Ophthalmologist's verdict) 7. Go, clear thy crystals (Henry V, Act 2, Scene 3) (An Ophthalmologist's advice to a patient of cataract) 8. These eyes, like lamps whose wasting oil is spent, wax dim, as drawing to their exigent (Henry VI-1st part, Act 2, Scene 5) (a case of advancing Glaucoma) 9. Thou baleful messenger, out of my sight! upon thy eyeballs, murderous tyranny sits in grim majesty, to fright the world Look not upon me, for thine eyes are wounding (Henry VI-2nd part, Act 3, Scene 2) (Child..... messenger of God always a wounding sight).... with Retinoblastoma 10. One eye thou hast, to look to heaven for grace; The Sun with one eye vieweth all the world (Henry VI-1st part, Act 2, Scene 5) (A real moral-booster for the one-eyeds) 11. His eyes were green as leeks (Midsummer Night's Dream, Act 5, Scene 1) (Eyes with positive fluorescein staining) 12. Things in motion sooner catch the eye Than what not stirs (Troilus Cressida, Act 3, Scene 3) (Isn't that the principle of visual acuity, tests in infants?) 13. Why should others' false adulterate eyes, Give salutation to my sportive blood? (Sonnet CXXI) (An Ophthalmologist's assertion.... Challenging quackery) 14. God be at your table! (Hamlet, Act 4, Scene 5) (Let's wish this to us & our colleagues at their operation tables) 15. Thine eyes that taught the dumb on high to sing

DOS Times Volume 29, Number 7, January-February 2024 www.dosonline.org/dos-times 94 Beyond Ophthalmology And heavy ignorance aloft to fly, Have added feather to the learned's wing, And given grace a double majesty (Sonnet IXXVIII) (A word of gratitude to our patients) References 1. William Shakespeare - The complete works., Oxford Edition, Oxford & IBH Publishing Co., New Delhi, 1980. 2. N.B. Sen : Thoughts of Shakespeare, Jaico Publishing Co., Bombay. 3. Who Said what; Chancellor Press, Bombay, 1988. Dr. Sunil Gupta, MS Consultant Ophthalmologist (Ant Segment & Glaucoma) RamAvtar Eye Hospital & Glaucoma Pavilion, Tilak Nagar, Jaipur. Corresponding Author:

www.dosonline.org/dos-times DOS Times Volume 29, Number 7, January-February 2024 95 Beyond Ophthalmology Perilous Prescription: Dangers of Misleading Advertisements in Medicine Summary: The article by Dr. KV Babu on his persistent crusade against the menace of misleading advertisements with false claims of medicinal value and treatment efficiency is a critical reminder of our collective responsibility to ensure that the health information and products that are endorsed are grounded in truth and scientific evidence. Dr. Jatinder Singh Bhalla MBBS, MS, DNB, MNAMS Senior Consultant & Academic Incharge, Department of Ophthalmology, DDU Hospital, New Delhi. Compiled by: Dr. KV Babu MBBS, DO Member of Kerala Society of Ophthalmic Surgeons Member AIOS Central Working Committee Member, IMA MBBS, Calicut Government Medical College 1982 Batch DO, Guru Nanak Eye Centre, MAMC (1989-91) We wish to hear from you your journey, your mission and your sincere dedicated efforts to get to the root of the problem? Please explain what are your views on the misleading ads which are indiscriminately issued by lot of companies under the garb of Ayurveda unani homeopathy etc? How did you get the inspiration to fight against these unscientific and misleading advertisements? What steps were taken by you to get to root of the problem? a)Did you write letters to central govt/state govt? b)Do you think RTI helped you to get the information to make a strong case against these misleading ads? As a medical practitioner, practising scientific medicine, I am as sensitive as many of you about the issues concerned with the lives of our people around us. Both our professionals and citizens of my country intervened when it affected the lives of the mothers and kids. Though I intervened on lots of issues using communications with the authorities, there are three key issues. 1. This was when junk food was promoted in 2008. https://www.thehindu.com/news/cities/ Thiruvananthapuram/whistleblower-doctor-winsbattle-against-mci/article8329641.ece 2. Oxytocin retail sale ban by the GOI in 2018 https://x.com/drbabukv/status/1392975197859311618 https://www.thehindu.com/news/national/kerala/ order-on-oxytocin-public-health-activists-jubilant/ article25744791.ece 3. Now Patanjali. The turning point was the advertisement to stop insulin https://timesofindia.indiatimes.com/blogs/stayingalive/uttarakhand-state-licensing-body-didnt-registera-single-case-ayush-ministry-did-flip-flops-all-thisemboldened-patanjali/ {JS}: {JS}: {JS}: {JS}: {KV}: Misleading and illegal Advertisements are major public health issues. As rightly pointed out by the Hon'ble SC on March 19th, people will get swayed by the fancy As I said earlier, the lives of our citizens matter. When it is the lives of our kids & mothers it is non-negotiable. The invention of insulin got the Nobel Prize in 1923. Doctors all over the country had to request the parents of our kids NOT TO STOP INSULIN, when they saw the Ad on december 4, 2022. https://x.com/DrAmbrishMithal/ status/1599375176172732416 I wake up early in the morning at 3AM when most of our colleagues are sleeping. I get three hours of quality time. Preparing the properly worded communications to the Union Ayush Ministry & Uttarakhand State Licensing Authorities was the most important part. This is followed by appropriate RTI. I approached the mainstream media, the Press Council of India & the Central Consumer Protection Authority too. As a last advertisement & eminently treatable diseases may go untreated, Patanjali is not the only ayurveda pharma company coming out with such advertisement & my complaints against a Kerala based company is pending with the State Licensing Authority of Kerala. After spending lots of money for the treatment of eminently treatable diseases after seeing the advertisement, people may seek appropriate treatment in an untreatable stage. That is the tragedy. {KV}: {KV}: {KV}:

DOS Times Volume 29, Number 7, January-February 2024 www.dosonline.org/dos-times 96 Beyond Ophthalmology What was the gist of information that you received from DCGI, ministry of ayush, Ayurveda and unani services, State governments, uttarakhand government? What exactly is the role of DCGI and state licensing authorities when companies start issuing advertisements promoting their products without conducting proper trials? Please also educate us about the Madras High Court ruling of 2020 and is provisions? Is it possible to lodge a complaint against self styled babas/practitioners for their claims that that just putting eye drops can totally cure cataract, glaucoma, refractory errors, age-related macular degeneration, diabetic retinopathy and retinitis pigmentosa. There are also some claims being made on social media that it is possible to cure some of the malignancies of the eye lids & retinoblastoma? {JS}: {JS}: {JS}: {JS}: Actually it is not advertising without proper trials. This is what the DMR(OA) Act 1954,3(d) says. 3. Prohibition of advertisement of certain drugs for treatment of certain diseases and disorders. Subject to the provisions of this Act, no person shall take any part in the publication of any advertisement referring to any drug in terms which suggest or are calculated to lead to the use of that drug for- (d) the diagnosis, cure, mitigation, treatment or prevention of any disease, disorder or condition specified in the Schedule, or any other disease, disorder or condition (by whatsoever name called) which may be specified in the rules A plain reading of the statute clearly says, the advertisement of drugs for 54 diseases under the schedule is prohibited even if it is scientifically proven. It is to avoid self medication by citizens. The diseases under the schedule include High BP, diabetes, cataract, glaucoma etc. Extracts from the Judgement of Madras HC in 2020. 10.Perusal of the alleged advertisement clearly shows that the drug is the choice of treatment in management of allergic rhinitis, allergic asthma etc., and it did not say that the drug is the choice of treatment in curing allergic rhinitis, allergic asthma etc., if consumed. http://www.judis.nic.in Crl.O.P.No.26427 of 2013 The object of the Act is that the advertisement in the label of the particular drug should not mis-direct the consumers/ patients. Only when the advertisement in the label of the drug mis-directs the consumers/patients, it would attract the penal provision under the Act." Madras HC judgement said the Advertisement should claim cure & not just as a choice of treatment, though the wordings of the statute of 1954 doesn't say so. As I said earlier most of the RTI responses from the DCGI/Ministry of Ayush/Uttarakhand SLA turned out to be crucial. Though all the complaints were filed under the Drugs and Magic Remedies Act, the SLA insisted on issuing show cause notice citing Rule 170. Rule 170 had been introduced in the Drugs and Cosmetics Act Rules 1945 in December 2018 in response to a Parliamentary Standing Committee report expressing concern over misleading Ayush medicine advertisements. It stipulated that all Ayush advertisements had to be reviewed by the licensing authority before being released to prevent misleading ads from being published. This was important because by the time a company withdrew an ad millions of people would have seen it and the purpose of the ad would be served. But Rule 170 was opposed vehemently by Ayush medicine manufacturers who filed a case against this in Bombay High Court which stayed its implementation. Patanjali claimed in its response that no action could be taken against it because Rule 170 was stayed and the SLA accepted it and informed the Ayush ministry of its inability to act on September 27, 2022. Yet, the very next day the SLA issued Patanjali a show cause notice under Rule 170, knowing it was stayed and totally ignoring the fact that my complaint was specifically against clear-cut violation of DMR(OA) Act, 1954. Ayush ministry which had till then sought action under DMR(OA) Act did a U-turn and concurred with the SLA and Patanjali that no action could be taken as Rule 170 was sub judice. However, after several letters challenging this decision and a letter from an MP seeking action on misleading advertisements, in February 2023, Ayush ministry did an about turn again and told the SLA that only Rule 170 had been challenged in court and that action could be taken under DMRA 1954. This flip-flop seemed to be a deliberate attempt by the authorities to avoid acting against the company which emboldened them. Definitely. Cancer, glaucoma & cataract are the diseases included in the schedule of 1954 Act. resort the Prime Minister's Office too. The 202 Page affidavit filed by the Uttarakhand SLA included most of my communications to them & it was actually an inaction report & not an action taken report. Their affidavit in fact backfired. In more than 30 places it contains written communications about their inaction which turned out to be crucial in the proceedings. {KV}: {KV}: {KV}: {KV}: Many patients have stopped taking the treatment for serious diseases like glaucoma, diabetic retinopathy and are losing precious gift of sight. Your comments on this? {JS}:

www.dosonline.org/dos-times DOS Times Volume 29, Number 7, January-February 2024 97 Beyond Ophthalmology What is your advice a) should we try to do something pro-actively to prevent these so called babas and other people from exploiting the masses by selling such products commercially or b) just leave it to the wisdom of masses? From the whole episode what is the lesson that you wish to be conveyed to general public. a) should they blindly believe & follow the information giving in misleading ads or b) there are means of redressal? Lesson to the ophthalmologist a) should they silently accept the treatments that are propagated for treating cataract, diabetic retinopathy, age related macular degeneration, removing spectacles just by usage of drops that have not been scientifically approved & maintain principle of peaceful co existence or b) they should vehemently oppose this for the welfare of masses? What should be the role of bigger bodies like state ophthalmology society and national ophthalmology society in these kind of situations? {JS}: {JS}: {JS}: {JS}: That is worrying me too. My complaints against the advertisement on eyedrops is part of the affidavit filed by the SLA in the SC (Page 8,12,18 & 56/57 of the affidavit) Though the Magic Remedies Act is not a strong one, we can file complaints with the State Licensing Authorities of the appropriate state & follow up it with the RTI applications. It is very simple. We are not helpless. Believe in science & evidence based medicine. Trust the legal system of our country too. Three important weapons in the present world are a Computer, Internet & RTI. Can spend some quality time on public health & scientific medicine. VICTORY is for the people & science. I think so. I am getting support from Kerala State Society & from the Alumni of GNEC. I believe AIOS have a greater role to play. {KV}: {KV}: {KV}: {KV}: {KV}: Dr. Babu KV, an Ophthalmologist from Kerala, fought a long battle to stop misleading advertising by a leading ayurvedic branded company featuring prominent yoga guru. Even as the state licensing authorities ignored the law for months, Dr. Babu persisted with his efforts-sending over 100 RTIs and related communications, reaching out to lawmakers & even PMO-eventually scoring a win for health of masses. He is an inspiration & role model whose efforts should be applauded & supported by all of us. DOS salutes the indomitable spirit & indefatible attitude of this one man army.

DOS Times Volume 29, Number 7, January-February 2024 www.dosonline.org/dos-times 98 Roth Spots: Risk Factors Anubhav Chauhan, MS, Deepak Kumar Sharma, MS Department of Ophthalmology, Shri Lal Bahadur Shastri Government Medical College and Hospital, Nerchowk, Distt. Mandi, Himachal Pradesh. A Anoxia, anemia B Bacterial endocarditis, B12 vitamin deficiency, birth trauma C Cancer (eg. leukemia), carbon monoxide poisoning, collagen vascular disorders D Diabetic retinopathy E Eclampsia F Fracture skull or trauma to the head G Glaucoma surgery (trabeculectomy) causing sudden decrease in the intraocular pressure H Hypertension, HIV I Intubation during anaesthesia (prolonged), intracranial haemorrhage Source of Support-None The paper being submitted has not been published, simultaneously submitted, or already accepted for publication elsewhere. Conflicts of Interest The authors declare that they have no competing interest. Dr. Anubhav Chauhan, MS Assistant Professor (Designated) Deptt. of Ophthalmology, Shri Lal Bahadur Shastri Government Medical College and Hospital, Nerchowk, Distt. Mandi, Himachal Pradesh, India. Corresponding Author: Financial Disclosure(S) The authors have no proprietary or commercial interest in any material discussed in this article. Tearsheet