Leukocoria. Khalid Al Husseiny. Lecturer of ophthalmology Kaser Al Ainy, Cairo University 3 rd vitreoretinal school.

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Leukocoria Khalid Al Husseiny Lecturer of ophthalmology Kaser Al Ainy, Cairo University 3 rd vitreoretinal school Side Questions Do u see leukocoria cases? What are u doing when u see retinoblastoma?

1 Leukocoria Khalid Al Husseiny Lecturer of ophthalmology Kaser Al Ainy, Cairo University 3 rd vitreoretinal school Side Questions Do u see leukocoria cases? What are u doing when u see retinoblastoma? What are u doing when u see coats disease? What are u doing when u see ROP? Scleral buckling, ILM peeling Evolving empty field, mandatory needed service Sight saving, life saving You have a role, you are the director 1

disease Practical points in ROP The most common Cataract

2 Objectives Def, Differential dignosis of leukocoria Workup of leukocoria Updates in retinoblastoma Updates in coats disease Practical points in ROP The most common Cataract Out of our scope Happy event in comparison to other causes 2

Retinoblastoma The commonest primary intra ocular malignancy in childhood originating from primitive retinoblasts with tendency towards cone differentiation (from the inner neuroepithelial layers of

3 Retinoblastoma The commonest primary intra ocular malignancy in childhood originating from primitive retinoblasts with tendency towards cone differentiation (from the inner neuroepithelial layers of the embryonic optic cup). 3% childhood cancers 1: 17,000 livebirths Epidemiology In Egypt, the estimated no. of new retinoblastoma cases is cases/year In Jordan 9.32 cases /million children/year In Sudan, retinoblastoma accounts for 4.8% of childhood cancers 3

4 Genetics Heritable 40% vs non-heritable 60% Familial 10% vs non- familial 90% Bilateral 30% vs unilateral vs unilateral multifocal Retinoblastoma gene ( a tumor suppressor gene) anti-oncogene ( misnomer) AD inheritance, 13q14 Knudson's two hit hypothesis. 4

5 5

6 Applications? Restriction fragment length polymorphisms performed on chorionic villus sampling or amniocentisis cultered cells During in vitro fertilization, absence of reimplantation genetic diagnosis of retinoblastoma gene mutation allowed pregnancies of a fetus without retinoblastoma 6

7 Pathology small blue cell tumors" of childhood. Necrosis and dystrophic calcification are commonly seen within this tumor. Growth patterns Spread Invasion of optic nerve Uveal invasion Hematogenous spread 7

8 Retinoblastoma, increasing degrees of retinal differentiation. (a) Primitive Homer Wright rosettes (neuroblastic differentiation). (b) Flexner Wintersteiner rosettes (early retinal differentiation) (c) Photoreceptor differentiation (fleurettes). All figures, hematoxylin and eosin, original magnification 250. How is retinoblastoma diagnosed? Patterns of presentation of retinoblastoma in The Middle East Region differs from that in the Western World Leukocoria 60% Strabismus 20% Glaucoma and buphthalmos Uveitis, pseudohypopyon, spontaneous hyphema, iris neovascularization, heterochroma irides Orbital inflammation, proptosis, orbital invasion Vitreous hge Trilateral retinoblastoma Regressed retinoblastoma 8

9 Endophytic growth pattern Exophytic growth pattern Diffuse infiltrating Ultrasonography Investigations Size and intraocular extent, Intralesion calcifications 9

Retcam fundus picture Fluorescein angiography

Detailed fundus drawings MRI scans extent of

orbital invasion, pineal gland tumors CT scans

10 Retcam fundus picture Fluorescein angiography (early vascularity and late hyperfluorescence) Detailed fundus drawings MRI scans extent of intraocular spread, optic nerve and scleral/ orbital invasion, pineal gland tumors CT scans repeated CT scans is better avoided in bilateral cases 10

11 Laboratory work and audiogram to check the general status of the patient and effects of systemic chemotherapy Genetic studies require fresh tumour tissue from the enucleated eye and a blood sample for DNA analysis. Blood samples from the patient's relatives and a sperm sample from the father may also be useful. Fine needle aspiration or open vitrectomy is contraindicated in any suspected cases High- risk characteristics for recurrence and metastasis (metastatic potential) Clinical factors: Extensively necrotic retinoblastoma Older age and longer lag period Hyphema, pseudohypopyon,staphyloma and orbital cellulitis Delay in enucleation of more than 3 months from diagnosis Increased IOP and buphthalmos Pathological factors: Invasion into postlaminar optic nerve posterior uvea invasion (>3mm in diameter) Scleral invasion Iris neovasularization In presence of histopathological high risk factors, post enucleation chemotherapy use effective in preventing metastasis 11

12 How is retinoblastoma staged? Intraocular retinoblastoma Extraocular retinoblastoma In US, most are diagnosed before they spread outside the eye, so the staging systems that apply only to intraocular retinoblastoma are used most in this country. There are 2 staging systems for intraocular retinoblastomas. It is important to know that regardless of the stage, almost all children with intraocular retinoblastoma can be cured if they are properly treated. Indeed, more than 9 in 10 children with intraocular retinoblastomas are cured. The major challenge is saving their sight. 12

13 International classification for intraocular retinoblastoma IIRC,2003 The Reese-Ellsworth staging system (1-5) 1960 Related to visual prognosis (not mortality ) IIRC,

14 The Reese- Ellsworth staging system (1-5) 1960 Other staging system TNM staging system by The American Joint Commission on Cancer (AJCC) 2009 Clinical TNM Pathological TNM 14

15 How is retinoblastoma treated? Rules Save life Save eye Save vision Unfortunately, with advanced disease, the eye has to be sacrificed by enucleation. This should be carried out with no hesitation in order to save human life. Treatment entails frequent visits during active ttt and lifelong follow up thereafter. Treatment modalities (Menu) Intravenous chemoreduction, Focal therapy Diode laser thermotherapy, Cryotherapy, Plaque radiotherapy, Subtenon chemotherapy Superselective intraarterial chemoyherapy External beam radiotherapy, Enucleation, Orbital exenteration, and systemic chemotherapy for metastatic disease 15

16 Treatment modalities (factors) Staging of the disease, Laterality, Systemic status, Metastatic potential, and Risk of second cancer The socioeconomic status and compliance Conservative treatment modalities in retinoblastoma (Staging) 16

Laterality Unilateral retinoblastoma usually present at a late stage and are generally managed with enucleation if the eye is classified as stage E; for those eyes in groups A to D, chemoreduction

17 Laterality Unilateral retinoblastoma usually present at a late stage and are generally managed with enucleation if the eye is classified as stage E; for those eyes in groups A to D, chemoreduction and focal measures are used. For bilateral retinoblastoma, chemoreduction is utilized in most cases even if one eye is harboring an advanced disease. Enucleation decision is delayed till the end of six cycles and active focal management of the more advanced eye is usually carried out after the second cycle of chemotherapy, along with focal treatment of the less advanced eye. 1. Chemoreduction One, two, three, and even four drug regimen have been used Six cycles given every 3 4 weeks. Two-drug regimen of systemic chemotherapy using carboplatin and etoposide Following two cycles of systemic chemotherapy, most tumors shrink with a mean of 35% in tumor base and 50% in thickness with resolution of subretinal fluid. Focal therapy to the individual tumors is usually delivered at cycle 2. 17

18 With such a regimen, tumor control was achieved in 100% of group A eyes, 93% of group B eyes, 86% of group C eyes, 48.8% of group D eyes and 0% for group E eyes. The child is examined under anesthesia monthly to observe for new tumor development, marginal recurrence or seeds reactivation. Focal therapy is delivered according to the situation, and the follow up is kept monthly as long as active management is performed. Recurrent tumors, new tumors or retinal seeds recur in the first 2 years after treatment and it is crucial to early detect and properly manage recurrences. 18

2. Focal therapy Applied to an eye while the child

enhance the synergistic effect of thermotherapy to

) 42 60 C, a temperature that is below the

19 2. Focal therapy Applied to an eye while the child is receiving chemoreduction, Repeated to each tumor at each chemotherapy session. On the same day or the day before chemotherapy to enhance the synergistic effect of thermotherapy to chemotherapy A) Transpupillary thermotherapy ( TTT ) C, a temperature that is below the coagulative threshold and thus sparing the retinal vessels of photocoagulation. 19

Power settings with diode laser TTT is from 300

indirect ophthalmoscope Aiming at seeing a

ensuring significant indepth tumor penetration

20 Power settings with diode laser TTT is from 300 to 800 mw applied to cover the whole tumor surface with a safety margin around it. Duration : 10 min and the large spot laser indirect ophthalmoscope Aiming at seeing a delayed onset grayish white reaction, thus ensuring significant indepth tumor penetration Note the completely exposed fovea following treatment, thus maximizing visual potential. 20

B) Plaque radiotherapy More commonly as a secondary treatment modality for tumors that fail other focal therapies, Ruthenium/rhodium-106 applicators which are mainly

The radiation dose to the tumor apex is around 50 gy delivered over a period of 2 5 days depending on plaque activity Tumor control rate following plaque radiotherapy

21 B) Plaque radiotherapy More commonly as a secondary treatment modality for tumors that fail other focal therapies, Ruthenium/rhodium-106 applicators which are mainly emitting beta irradiation up to a tumor thickness of 6 7 mm after placing the plaque over the sclera to cover the tumor base with an extra 2 3 mm of safety margin. The radiation dose to the tumor apex is around 50 gy delivered over a period of 2 5 days depending on plaque activity Tumor control rate following plaque radiotherapy as a primary therapy or after failed chemothermotherapy is about 90%. Success decreases to 75% if plaque is used after tumor recurrence following external beam radiotherapy 21

C) Cryotherapy for peripheral tumors under 3 mm in greatest dimension. A triple freeze thaw application is used insisting on seeing the ice ball beyond the apex of the tumor at each application.

Ebrt has fallen out of use because of its local complications effect and associated high incidence of second cancers in the irradiated zone years after cure from the disease in hereditary forms of

22 C) Cryotherapy for peripheral tumors under 3 mm in greatest dimension. A triple freeze thaw application is used insisting on seeing the ice ball beyond the apex of the tumor at each application. for management of recurrent subretinal seeds near the ora serrata. External beam radiotherapy Photons delivered from a remote machine to the eye. Ebrt has fallen out of use because of its local complications effect and associated high incidence of second cancers in the irradiated zone years after cure from the disease in hereditary forms of retinoblastoma. Ebrt is preserved only to bilateral advanced disease with diffuse vitreous seeds as a last globe preserving modality in patients refusing bilateral enucleation after failure of all other conservative treatment modalities A whole eye technique to cover the diffuse vitreous seeds when radiotherapy is required. 22

Subconjunctival chemoreduction for retinoblastoma Chemotherapy has been given as posterior subtenon carboplatin injection (20 mg/2 cc) Local

main drug used is melfalan, at a dose of (0.35 mg/kg) or 5 7.5 mg/injection.

23 Subconjunctival chemoreduction for retinoblastoma Chemotherapy has been given as posterior subtenon carboplatin injection (20 mg/2 cc) Local side effects include inflammation, ptosis, scarring and loss of sight In advanced retinoblastoma in both eyes or in their only remaining eye along with systemic chemoreduction. Selective intraophthlamic artery melfalan injection For advanced disease The minimum age with successful cannulation was 3 months and the main drug used is melfalan, at a dose of (0.35 mg/kg) or mg/injection. Reported complications include transient eyelid edema, blepharoptosis, cilia loss, and orbital congestion with temporary dysmotility. Vascular events are of concern and include ophthalmic artery stenosis (permanent or temporary). Concomitant central or branch retinal artery occlusion (permanent or temporary). 23

Advanced Group E retinoblastoma (A) treated with systemic chemotherapy showing compete tumor regression

regressed tumor and calcified vitreous seeds.

Stage E It is also performed if chemoreduction fails or a normal fellow eye makes aggressive

24 Advanced Group E retinoblastoma (A) treated with systemic chemotherapy showing compete tumor regression (B). Retinoblastoma with extensive vitreous seeds (C) treated with intra-arterial chemotherapy showing regressed tumor and calcified vitreous seeds. (D) Enucleation Indications: if there is rubeosis, vitreous haemorrhage or optic nerve invasion. Stage E It is also performed if chemoreduction fails or a normal fellow eye makes aggressive chemotherapy inappropriate. It is also useful for diffuse retinoblastoma because of poor visual prognosis and high risk of risk of recurrence with other therapeutic modalities. 24

The orbital implant should be as large as possible. Tenon capsule and conjunctiva should be closed separately. Any postoperative chemotherapy should be delayed for at least a week, to allow healing.

Every month until the age of 3 years, After which time every 6 months until the age of about 5 years, Then annually until the age of 10 years.

25 The orbital implant should be as large as possible. Tenon capsule and conjunctiva should be closed separately. Any postoperative chemotherapy should be delayed for at least a week, to allow healing. Follow up After radiotherapy or chemotherapy, tumours regress to a 'cottage-cheese' calcified mass, a translucent 'fish-flesh' mass, a mixture of both, or a flat atrophic scar. Every month until the age of 3 years, After which time every 6 months until the age of about 5 years, Then annually until the age of 10 years. Orbital MRI is indicated in high risk cases for about 18 months. If the child has any risk of developing a second malignant neoplasm, the parents should be educated to be alert to features of pain, tenderness and swelling and to seek medical attention if there is no improvement within a week. 25

26 Differential Diagnosis In an oncology referral practice, 48% of lesions referred to as retinoblastoma proved to be pseudoretinoblastoma. Young males 4-16 yrs Unilateral Late diagnosis, poor prognosis A retinal vascular abnormality resulting in small multifocal outpouchings of the retinal vessels Leucocoria may develop 2ry to exudative RD Such deposits have high concentrations of protein, cholesterol, hemosiderin-laden macrophages, and RPE cells with fibrous metaplasia Coats disease 26

Pathophysiology of coat s disease Mutations in NDP, a gene coding for norrin, have been implicated in diseases involving retinal vasculogenesis, including Coats disease.

(Senior-Loken syndrome). Despite these associations, sporadic cases are the rule, and no hereditary pattern has been consistently identified.

27 Pathophysiology of coat s disease Mutations in NDP, a gene coding for norrin, have been implicated in diseases involving retinal vasculogenesis, including Coats disease. A Coats -like retinopathy has been observed in genetic syndromes such as autosomal dominant facioscapulohumeral muscular dystrophy (Hallermann-Streiff syndrome) and familial renalretinal dystrophy (Senior-Loken syndrome). Despite these associations, sporadic cases are the rule, and no hereditary pattern has been consistently identified. Histopathologic studies of Coats specimens demonstrate pericyte loss, which allows for the formation of aneurysms. Breakdown of the endothelial bloodretinal barrier causes leakage into the vessel wall, leading to dilation and telangiectasis. This pathologic mechanism is similar to that observed in diabetic retinopathy, which has implications in treatment. Fluorescein angiography provides optimal visualization of vascular abnormalities which hyperfluoresce early and leak late helping target treatment Shields classification system proposed in

Laser photocoagulation is the modality of choice for mild to moderate disease with exudation.

Exudation can increase immediately after treatment, especially if a substantial area is involved.

28 Laser photocoagulation is the modality of choice for mild to moderate disease with exudation. In the Shields classification system proposed in 2000, stage 1 and 2, leaking telangiectases and aneurysms, can be directly treated with good Scatter or barricade strategies are generally less efficacious. Multiple sessions are often necessary as new lesions become clinically evident Cryotherapy : If there is significant subretinal fluid, as in stage 3 disease, may be required. Exudation can increase immediately after treatment, especially if a substantial area is involved. Retinal contracture and folds may also occur, and it is generally recommended that only two quadrants be treated at a time, and that sessions be separated by at least one month. Laser photocoagulation to barricade fluid prior to cryotherapy may help limit progression of subretinal fluid Intravitreal injections (e.g., intravitreal triamcinolone or antivascular endothelial growth factor agents before or at the time of ablation) offers the potential benefit of immediate stabilization (or improvement) with longterm control, in stages 2 to 3 Coats disease. 28

$Surgical intervention rarely necessary for late stage or refractory disease. In select cases, patients with extensive retinal detachment may benefit from vitrectomy.$

29 Surgical intervention rarely necessary for late stage or refractory disease. In select cases, patients with extensive retinal detachment may benefit from vitrectomy. In particular, patients with preretinal membranes or contribution from tractional components may require membrane peel, Enucleation may be necessary in stage 4 and 5 disease, where a blind, painful eye may develop. Retinopathy of prematurity ROP Role Of Intravitreal Bevacizumab As Adjuncative Therapy in Retinopathy Of Prematurity: A Randomized Controlled trial My MD thesis 29

30 ROP Prevention better than cure ROP A retinal vascular disease occurring in prematures A preventable blinding disease Evolving condition in Egypt GA BW PMA CRYO ROP International classification of ROP ETROP BEAT ROP 30

31 Practical points In examination Time of 1 st ex Dilatation Speculum Indentor 31

32 In treatment Proper experience or backed up Timing of intervention Different facilities of ttt esp standard ttt indirect laser ophthalmoscopy Follow up 32

33 Standard treatment Indirect laser photocoagulation Type I ROP ( Prethreshold ) 33

34 Complete resolution the LP/IVB group Response pattern according to time of intervention indicated by postmenstrual age at time of treatment in weeks (PMA at ttt) in both groups: Group A (LP/IVB) and Group B (LP) PMA at ttt (weeks) No. of eyes Complete resolution Resolution, fibrous tissue, no traction Resolution, fibrous tissue, traction Reintervention A B A B A B A B A B

Zone Timing (PMA) Treatment modality Outcome Conclusion The addition of intravitreal bevacizumab (IVB) to laser photocogulation in stage 3 ROP (zones I and II) resulted in 1.

Less need for secondary intervention, without exaggeration of the cicatricial response.

35 Zone Timing (PMA) Treatment modality Outcome Conclusion The addition of intravitreal bevacizumab (IVB) to laser photocogulation in stage 3 ROP (zones I and II) resulted in 1. Faster resolution of plus disease, 2. More complete resolution of neovascularization, and 3. Less need for secondary intervention, without exaggeration of the cicatricial response. When IVB was added to supplemental laser treatment, the cicatricial response was more intense than cases where IVB was added to the primary laser treatment, but without the occurrence of retinal detachment. Thus IVB may be useful as an adjunct to primary laser treatment. The late addition of IVB to supplemental laser treatment requires further study. 35

Recommendations Screening system with our guidelines Dissemination of knowledge between ophthalmologists and neonatologists Take care Just an intravitreal Anti VEGF injection >>>>> No it is not <<<<<

36 Recommendations Screening system with our guidelines Dissemination of knowledge between ophthalmologists and neonatologists Take care Just an intravitreal Anti VEGF injection >>>>> No it is not <<<<< Familial exudative vitroretinopathy slowly progressive condition characterized by failure of vascularization of the temporal retinal periphery, similar to that seen in retinopathy of prematurity, but not associated with low birth weight and prematurity. AD inheritance Late childhood Poor prognosis 36

Steroids Vitrectomy Laser photocoagulation to the nematode Retinal

37 Toxocariasis A nematode infection that may appear as Localized granuloma Diffuse endophthalmitis Unilateral, 6-18 yrs Contact with puppies Treatment Steroids Vitrectomy Laser photocoagulation to the nematode Retinal astrocytoma Most difficult No necrosis, No calcifications Ass with tuberous sclerosis, NF1 37

38 PHPV/ PFV A developmental ocular abnormality Cataract and retrolental glial membrane extraction small eye unilateral Others Choroidal coloboma Myelinated nerve fibers 38

39 Retinal dysplasia Incontintina pigmenti History Age Latererality Family history Prematurity Contact with puppies Workup 39

40 Complete ocular ex including Corneal diameter measurement Iris neovasularization Lens Dilated fundus ex and anterior vitreous ex B san ultrasonography RETCAM Fluorescine angiography CT scan or MRI of the orbit and the brain 40

41 Serum ELISA test for Toxocara Systemic ex by a pediatrician AC paracentisis EUA 41

42 Take home message A sign in pediatric age group that is almost always related to vitreoretinal disorder Sight threatening or even life threatening condition Multiple modalities of treatment that needs skills, knowledge, buildup experience and collaboration with other disciplines Thank you for your attention 42

Financial Disclosures

Retinoblastoma Management: Update Jesse L. Berry, MD Associate Director, Ocular Oncology Service Associate Program Director USC/CHLA, Keck School of Medicine Financial Disclosures Research Support: Bright