Retinal vasculitis is an inflammatory eye disease involving the retinal vessels that can occur due to infectious, neoplastic, or systemic inflammatory disorders. It is detected clinically using fundus fluorescein angiography. It can lead to leakage and exudation from affected vessels, as well as occlusion causing cotton-wool spots, edema, hemorrhages, and retinal infarction. Late sequelae include vitreous hemorrhage, tractional retinal detachment, neovascular glaucoma, and rubeosis iridis. Retinopathy of prematurity is a disease affecting the retinas of premature infants that ranges from mild cases to severe cases causing bilateral blindness. It results from an initial vasocon

1. Retinal Vasculitis
Retinopathy of Prematurity
Sumit Singh Maharjan

2. Introduction
• Sight threatening inflammatory eye disease that involves the retinal
vessels
• It may occur as an isolated idiopathic condition, as a complication of
infective or neoplastic disorders, or in association with systemic
inflammatory disease
• Detection of retinal vasculitis is made clinically, and confirmed with
the help of fundus fluorescein angiography.

3. Natural course
• Leakage – retinal swelling, exudation, and macular edema.
• Occlusive retinal vasculitis affecting the retinal arterioles may cause
cotton-wool spots representing micro infarcts of the retina.
• Occlusive periphlebitis can cause retinal edema, intraretinal
hemorrhages, and hemorrhagic infarction of the retina.
• Late changes secondary to vascular occlusion and remodeling include
- telangiectasis
- microaneurysms
- neovascularization

4. Sequelae
- recurrent vitreous hemorrhage
- tractional retinal detachment
- rubeosis iridis
- neovascular glaucoma

5. Causes
Systemic disorders
• Behcet's disease
• Granulomatosis with polyangiitis (Wegener's)
• Sarcoidosis
• Relapsing polychondritis
• Systemic lupus erythematosus
• Giant cell arteritis
• Polyarteritis nodosa
• Multiple sclerosis
• Whipple's disease
• Crohn's disease
• HLA-B27 associated conditions

7. Infectious disorders
• Toxoplasmosis
• Tuberculosis
• Syphilis
• Herpes simplex
• Herpes zoster
• Acute retinal necrosis
• Cytomegalovirus
• Lyme disease
• Human immunodeficiency virus

8. Ocular disorders
• Birdshot retinochoroidopathy
• Pars planitis
• Eale's disease
• Idiopathic retinal vasculitis ,aneurysms and neuroretinitis.

9. Pathogenesis
• Immune complex
• Autoimmune
• Other mechanisms

10. Immune complex mediated
• Immune complexes are formed by the association of an antibody with
an antigen.
• activate the complement cascade, attracting polymorphonuclear
leukocytes that release proteolytic enzymes causing tissue or vascular
injury.
• Eg:
1 systemic lupus erythematosus (SLE)
2 polyarteritis nodosa,
3 Behcet's disease
4. HLA-B27 uveitis

11. Autoantibodies
• Antibodies may bind directly to surface antigens of cells and tissues,
leading to activation of the complement system and effector cells,
resulting in cell lysis or cytotoxic damage.
• Eg:
1. cancer-related retinopathy (CAR)
2. Wegener's granulomatosis , polyarteritis nodosa
Behcets disease(autoantibodies to endothelial cells)

12. Other mechanisms
• Delayed hypersensitivity in Wegener's granulomatosis, sarcoidosis

13. Clinical features
• The classic symptom of retinal vasculitis is a painless decrease in
vision.
• Other symptoms may include
- floaters (vitritis)
- ischemia-induced scotomas
- metamorphopsia
- altered color perception
- asymptomatic.

14. Fundus examination
• Vascular sheathing
• Vitritis
• Narrowing of the retinal blood vessels
• new blood vessel growth
• Vitreous hemorrhage
• Macular edema

15. Workup
• History and detailed physical examination
• multidisciplinary approach
• laboratory investigation
• discrimination between infectious or noninfectious etiology of retinal
vasculitis is important because treatment is different.

16. • Investigations to be done in all cases of retinal vasculitis
- fluorescein angiogram
- complete blood count
- erythrocyte sedimentation rate
- VDRL
- blood chemistry
- Urinalysis
- tuberculin skin testing
- HIV serology
- chest radiograph.

18. Retinopathy of Prematurity
• Disease affecting the retinas of premature infants
• ROP is unique in that the vascular disease is found only in infants with
incompletely vascularized retinas.
• The spectrum of ROP disease ranges from mild cases without visual
sequelae to advanced cases with bilateral irreversible blindness.

19. Mechanism of oxygen’s effects on the
immature retina
Primary stage of retinal vasoconstriction and vascular occlusion
• primary effect of elevated blood oxygen in any retina is
vasoconstriction, which, if sustained, is followed by some degree of
vascular closure.

20. Vascular caliber is reduced by approximately 50% initially, but then
rebounds to its original dimensions.
Continued oxygen exposure results in gradual vasospasm during the
next 4–6 hours, until the vessels are approximately 80% constricted.
At this stage, constriction is still reversible.
However, if significantly elevated arterial oxygen partial pressure levels
persist for an additional period (e.g., 10–15 hours), some immature
peripheral vessels are permanently occluded
• This occlusion progresses as the duration of hyperoxia increases, and
local vascular obliteration is complete after 2–3 days of exposure

21. Secondary stage of retinal neovascularization
After removal following sustained hyperoxia,
marked endothelial proliferation arises from the residual vascular
complexes adjacent to retinal capillaries ablated during hyperoxia

22. Pathogenesis of ROP
• Alon et al. demonstrated that hyperoxia caused downregulation of
VEGF and death of endothelial cells, suggesting that VEGF is an
endothelial survival factor
• In the time that follows closure of these growing vessels, the
differentiating retina becomes increasingly ischemic and hypoxic and
VEGF is upregulated driving the neovascularization
• (STOP-ROP) trial found that, once the ROP was established, raising the
oxygen saturation mildly did not harm the ROP, but neither was it of
clear benefit.

23. The clinical and histopathologic observations of Flynn and coworkers
led them to postulate the following sequence of events in human ROP
pathogenesis:
1. Endothelial injury occurs where it has just differentiated from
mesenchyme to form the primitive capillary meshwork.
• short duration of hyperoxia resulted in capillary damage limited to the
most recently differentiated vascular complexes.
• It is currently believed that environmental factors other than oxygen
also are involved. For example, nitric oxide may contribute to the
vaso-obliterative stage of ROP, and reduced VEGF may result in death
of endothelial cells because of its role as a survival factor.

24. 2. After this injury to the vascular endothelium, the mesenchyme and
mature arteries and veins survive and merge via the few remaining
vascular channels to form a mesenchymal arteriovenous shunt which
replaces the destroyed or damaged capillary bed.
3. The mesenchymal arteriovenous shunt is located at the demarcation
between the avascular and vascularized retina.
• It consists of a nest of primitive mesenchymal and maturing
endothelial cells that are fed by mature arteries and veins.
• No capillaries are found in the region of the shunt.
• Flynn suggested that this structure represents the pathognomonic
lesion of acute ROP.

25. • Flynn described a dormant period after the injury (days to months),
during which retinal findings are relatively stable.
• The tissues comprising the shunt may thicken, and the gray-white
initial color of the structure turns from pink to salmon to red
• He stated: “during this period when vasculogenic activity resumes in
the retina, the fate of the eye is decided.”
• Flynn pointed out that when the cells inside the shunt divide and
differentiate into normal capillary endothelium, they form primitive
endothelial tubes that send forth a brush border of capillaries that
grows anteriorly into the avascular retina.

26. • This represents ROP involution, which he observed to occur in more
than 90% of cases at this early stage.
• In progressive disease, however, the primitive cells inside the shunt
proliferate and erupt through the internal limiting membrane,
growing on the surface of the retina and into the vitreous body.
• Flynn stated: “it is this lack of differentiation and destructive
proliferation of cells and their invasion into spaces and tissues where
they do not belong that is the chief event in the process of membrane
proliferation leading to traction detachment.

27. • Foos suggested a pathogenesis of ROP based on examination of
histopathologic material.
• He used the terms “vanguard” and “rearguard” to describe cellular
components of the developing retina.
• The vanguard (anterior) component contains spindle shaped cells
thought to be glia, which play a role in nourishing the immature retina
during development.
• The rearguard contains primitive endothelial cells.
• As the retina matures, the endothelial cells aggregate into cords that,
according to Foos, subsequently lumenize and become the primordial
capillaries of the retina.
• It is from the rearguard and primitive endothelial cells that
neovascularization of ROP develops.
• Foos noted that, as the developing vasculature reaches its most anterior
extent and matures, the spindle cells of the vanguard disappear

28. International classification
• The international classification of ROP divided the retina into three
anteroposterior zones and describes the extent of disease by the 30°
meridians (clock-hours) involved

29. Zones of involved retina

30. Extent of retinopathy of prematurity
• The extent of the ROP changes is described according to the 12 30°
sectors involved, labeled as hours of the clock: the nasal side of the
right eye is at 3:00, and the nasal side of the left eye is at 9:00.

31. Staging
• Abnormal peripheral changes are divided into three stages, which
may progress to retinal detachment
Stage 1: demarcation line

32. Stage 2: ridge
• Small tufts of new vessels (“popcorn” lesions) may be seen located
posterior to the ridge structure but not attached to it.

33. Stage 3: ridge with extraretinal fibrovascular proliferation
• proliferating tissue is localized continuous with the posterior and
interior aspect of the ridge, causing a ragged appearance of the ridge
as proliferation increases into the vitreous.
• According to Foos, the stage 3 “extraretinal vascularization” may
appear placoid, polypoid, or pedunculated on histological
examination

34. • The placoid pattern is the most common and also the most important
because it correlates with subsequent development of retinal
detachment.
• Foos demonstrated that these extraretinal vessels are apparently
derived from proliferating endothelial cells and not from the
vasoformative mesenchymal “spindle” cells based on his factor VIII
preparations.
• He also observed significant synchysis and condensation of the
vitreous body in stage 3.
• Foos suggested that a condensation of the vitreous body over the
ridge is related to depolymerization of hyaluronic acid and collapse of
the collagenous framework into optically visible structures

35. “Plus” and “pre-plus” disease
• Increasing dilation and tortuosity of the retinal vessels, iris vascular
engorgement, pupillary rigidity, and vitreous haze indicate progressive
vascular incompetence
• In 2005, the revised international classification defined an
intermediate “pre plus” categorization as abnormal arteriolar
tortuosity and venous dilation of the posterior pole which is
insufficient for diagnosis of plus disease

36. Threshold and pre threshold disease
• ROP of stage 3 plus involving 5 or more contiguous clock hours or 8
cumulative clock hours
• Treatment is mandatory as chances of progression to RD is 50% or
more
Pre threshold disease
• Any stage in zone 1 with plus disease
• Disease with stage 3 plus involving 3 contiguous clock hours or 5
cumulative clock hours
• Involvement of retina in zone 2 with plus disease but less than
threshold

37. Zone I ROP
• ROP located in zone I can be dangerously deceptive, in that the
proliferation signifying stage 3 can appear spread out “flat” on the
retina posterior to the ridge, rather than elevated.
• zone I ROP correlates with vasculogenesis, and is therefore less
sensitive to treatment by laser or cryotherapy because the disease
mechanism is not VEGF-mediated.
• zone II ROP corelates with angiogenesis, is mediated by hypoxia-
induced VEGF-165, and is therefore more sensitive to treatment by
laser or cryotherapy

38. Aggressive posterior ROP
• The 2005 revised international classification of ROP designated an
uncommon, severe form of disease as “aggressive posterior ROP.”
• This rapidly progressive disease variant had been previously termed
“rush disease
• characterized by its location in zone I or posterior zone II, ill-defined
nature of the peripheral retinopathy, and prominent plus disease out
of proportion to the peripheral findings

39. Classification of retinal detachment
Stage 4A: extrafoveal retinal detachment
•The prognosis anatomically and visually is
relatively good in the absence of posterior
extension.
•Frequently these areas will reattach
spontaneously, without affecting macular
function.

40. Stage 4B: partial retinal detachment including the fovea

41. Stage 5: total retinal detachment

42. Involution of retinopathy of prematurity
• typically begins after 38 weeks’ postconceptional/postmenstrual age,
and may be characterized by a downgrading of staging and/or growth
of retinal vessels into a more peripheral zone

43. Regressed ROP: retinal detachment,
strabismus, and amblyopia
• Although active ROP usually involutes without progressing to retinal
detachment, cicatricial sequelae can remain even in those cases.
• The relatively stable state of the eye after retinopathy has run its
course is referred to as regressed ROP.
• The most serious complications of regressed ROP are late
development of retinal detachment and angle closure glaucoma

44. Peripheral changes
• Vascular
Failure to vascularize peripheral retina
Abnormal, nondichotomous branching of
retinal vessels
Vascular arcades with circumferential
interconnection
Telangiectatic vessels
• Retinal
Pigmentary changes
Vitreoretinal interface changes
Thin retina
Peripheral folds
Vitreous membranes with or without
attachment to retina
Lattice-like degeneration
Retinal breaks
Traction or rhegmatogenous retinal
detachment
Posterior changes
• Vascular
Vascular tortuosity
Straightening of blood vessels in temporal
arcade
Abnormal narrowing or widening in the angle
of insertion of major temporal arcade
• Retinal
Pigmentary changes
Distortion and ectopia of macula
Stretching and folding of retina in macular
region leading to periphery
Vitreoretinal interface changes
Vitreous membrane
Dragging of retina over disc

45. Ocular findings of regressed ROP
Myopia
• In the CRYO-ROP study, 20% of infants with birth weight <1251 g were
found to develop myopia in the first 2 years of life.
• The lower the birth weight, the higher the chance of myopia.
• Among infants with ROP, the incidence of myopia increased in direct
relationship to the severity of ROP
• Exact mechanism of the myopia remains unclear.
• Fletcher and Brandon suggested that it might be due to an elongation
of the globe, alteration of the lens or the corneal curvature, or a
combination of these factors

46. Other refractive and binocular defects
• Astigmatism and anisometropia are relatively common in patients
with regressed ROP
• Amblyopia, nystagmus, and strabismus are also common after ROP
has regressed
Lens and corneal changes
• The incidence of cataract among eyes with a history of zone I ROP or
zone II stage 3+ ROP was approximately 2.5%
• At the final 6-year examination of the ETROP study, cataract or
aphakia was found in 4.9% of early-treated eyes and in 7.2% of
conventionally managed eyes in 271 children with symmetric ROP

47. Glaucoma in retinopathy of prematurity
• Glaucoma is a serious complication of ROP in both the acute and
regressed phases of the disease
• In the CRYO-ROP study 1.5% of those control eyes had been noted to
have glaucoma.

48. Differential diagnosis
Unilateral
• PHPV
• Coat’s disease
• Parasitic endophthalmitis
• Trauma
• Retinal vascular abnormalities
Bilateral
• Retinoblastoma
• Retinal dysplasia
• Norrie’s disease
• Walker-Warburg syndrome
• X-linked retinoschisis
• Falciform folds
• Incontinenti pigmenti
• cataract

49. Risk factors
• prematurity, low birth weight, a complex hospital course, and
prolonged supplemental oxygen are today’s established risk factors
for the development of ROP
• Numerous other neonatal health factors have been reported to be
associated with ROP, including cyanosis, apnea, mechanical
ventilation, intraventricular hemorrhages, seizures, transfusions,
septicemia, in utero hypoxia, anemia, patent ductus arteriosus, and
vitamin E deficiency

50. Screening guidelines
• Because ROP can progress to blindness during the first 3 months of
life and treatment is available to arrest it in many cases, a protocol
has been recommended for examining the eyes of premature infants
during that time span
CRYO-ROP study and LIGHT-ROP study
• Initial eye examination should be performed by 31 weeks’
postmenstrual age or 4 weeks from birth, whichever is later, in order
to detect prethreshold retinopathy in a timely fashion

51. • The current recommendations from the American Academies of
Ophthalmology and Pediatrics are that children born at 30 weeks or
less, or at less than 1500 g, should be screened for ROP.
• Specifically those born at a gestational age of 27 weeks or less should
have their first exam at 31 weeks and children born from 28 to 32
weeks should have their first exam 4 weeks after birth.

52. Prophylaxis and therapy
The role of vitamin E
• Vitamin E was considered as a potential agent to prevent ROP due to
its antioxidant properties
• no conclusive evidence either of benefit or harm from vitamin E
administration
• Currently, there is no formal recommendation on the use of vitamin E
in the management of ROP.

53. The role of light
• LIGHT-ROP study concluded that there is no clinically important effect
of light on the occurrence or severity of ROP.
• Neither the American Academy of Ophthalmology nor the American
Academy of Pediatrics has made any recommendations about
restricting ambient light from the eyes of premature infants.

54. Cryotherapy
The multicenter trial of cryotherapy
• CRYO-ROP study was organized in 1985
• The study has been continued for longer-term follow-up, and a final
examination was carried out when the children were about 15 years
old
Treatment
• Infants eligible for the cryotherapy trial had stage 3 ROP, involving five
or more clock-hours of retina posterior to zone III in the presence of a
standardized plus disease
• contiguous, nonoverlapping spots of transscleral cryotherapy were
directed at the entire anterior cuff of avascular retina. No infant
received cryotherapy to both eyes during the study

55. Results
• At the 10-year outcome assessment, 247 of the original randomized
cohort were examined and total retinal detachments had continued
to occur in control eyes that had received cryotherapy, increasing
from 38.6% at 5 and 1/2 years to 41.4% at 10 years, while treated
eyes remained stable at 22%.
• Unfavorable fundus outcomes were present in 27% of treated eyes
versus 48% of control eyes, and visual acuity was 20/200 or worse in
44% of treated eyes versus 62% of control eyes

56. Current concepts in management of ROP
Cryotherapy
• average number of individual freezes used in the CRYO-ROP study was
50.
Laser
• In an effort to reduce the time and stress accompanying cryotherapy,
refinements of ablative therapeutic technique were studied – in
particular, laser therapy, using the binocular laser indirect
ophthalmoscope (LIO) delivery system

57. • In general, ophthalmologists have found that the LIO delivery system
is technically easier than cryotherapy and creates fewer postoperative
sequelae, such as inflammation and swelling.
• Furthermore, it seemed apparent that the outcomes of treatment of
threshold disease in zone I and posterior zone II were superior to
cryotherapy, and at least equivalent to cryotherapy results for zone II
disease
• When LIO delivery systems became available around 1990, the only
laser offered was an argon photocoagulator (488–532 nm).
• Subsequently, the diode laser (810 nm) photocoagulator was
introduced.
• It has become more popular than the argon laser because of its
portability and a lower incidence of postoperative cataract formation.

58. • Photocoagulation burns are distributed in a confluent pattern to
minimize skip areas.
• The objective of the treatment is to apply burns throughout the
entire peripheral nonvascularized retina.
• Treatment is generally started at the anterior edge of the vascularized
retina and applied out to the ora serrata utilizing a Calgiswab or
similar instrument for eye positioning and scleral depression

59. The Early Treatment for Retinopathy
of Prematurity trial
• In this trial, called the ETROP study, eyes were randomized to early
peripheral retinal ablation or conventional management (observation
until threshold criteria developed) once they achieved a high-risk
level of prethreshold ROP.
• The ETROP study showed a significant benefit of earlier treatment
intervention as measured by visual acuity outcome at a corrected age
of 9 months and in the structural outcome of the retina at corrected
ages of 6 and 9 months.
• In the selected high risk eyes that were studied, unfavorable acuity
results were reduced by earlier treatment intervention to 14.5%, from
19.5% in the conventionally treated control group.
• Unfavorable structural outcomes were reduced from 15.6% in the
control group to 9.1% in the early treatment eyes

60. The ETROP indications for treatment
Type 1 ROP (“new threshold”)
Administer peripheral ablation
treatment
• Zone II: plus disease with stage 2
or 3
• Zone I: plus disease with stage 1,
2, or 3
stage 3 without plus disease
Type 2 ROP
Wait and watch for progression
• Zone II: stage 3 without plus
disease
• Zone I: stage 1 or 2 without plus
disease

61. Considering the following schedule for
infants who do not meet criteria for treatment
1-week or less follow-up for type
2 ROP:
• Zone II no plus, stage 3
• Zone I no plus, stage 1 or 2
1–2-week follow-up:
• Zone II no plus, stage 2
• Zone I immature, no ROP
• Zone I, regressing ROP
2-week follow-up:
• Zone II no plus, stage 1
• Zone II, regressing ROP
2–3-week follow-up:
• Zone III, no plus, stage 1 or 2
• Zone II immature, no ROP
• Zone III, regressing ROP.

62. Anti-VEGF therapy for posterior ROP
• A number of recent case series have reported that intravitreal
injections of anti-VEGF antibodies (e.g., bevacizumab) are a very
promising approach for the treatment of aggressive ROP, with the
possibility of easier administration and improved preservation of
peripheral retina compared to laser.
• Although there is the possibility of improved treatment efficacy with
bevacizumab, ROP recurrences have been reported several months
post injection.
• Unlike laser treatment, where the regression is often durable and
permanent, the potential for recurrence after bevacizumab injection
emphasizes the need for prolonged follow-up examinations

63. Surgery for RD
• Scleral buckle
• Vitrectomy and vitrectomy with lensectomy
• In advanced cases, visual results are disappointing.

64. Retinal screening examination can be
discontinued if:
• Zone 3 retinal vasularization is attained without previous zone 1 or 2
ROP
• There is full retinal vascularization
• Post menstrual age of 45 weeks and no prethreshold disease (defined
as stage 3 ROP in zone 2, any ROP in zone 1)
• ROP is regressing, care must be taken to ensure that no abnormal
vascular tissue capable of reactivation and progression present.

65. Cicatricial disease
• 20% of infants with active ROP develop cicatricial complications
• the more advanced or the more posterior the proliferative
disease at the time of involution, the worse the cicatricial
sequelae.
5 stages
• Stage 1 : peripheral retinal pigmentary disturbance and haze at
the vitreous base

66. • Stage 2: temporal vitreoretinal fibrosis and straightening of
vascular arcades followed by ‘dragging’ of the macula and disc
• Stage 3 : more severe peripheral fibrosis with contracture and a
falciform retinal fold
• Stage 4 : incomplete ring of retrolental fibrovascular tissue with
partial RD.

67. • Stage 5 features a complete ring of retrolental fibrovascular tissue
with total retinal detachment, a picture formerly known as
‘retrolental fibroplasia’
• Secondary angle-closure glaucoma may develop due to
progressive shallowing of the anterior chamber caused by a
forward movement of the iris-lens diaphragm and the
development of anterior synechiae.

68. References
• Ryan’s 5th edition
• American academy of Ophthalmology-sec 12, 2013,2014
• Kanski’s clinical ophthalmology 8th edition
• Myron yanoff 4th edition