Diabetic retinopathy

Habibah S. MuhiddinDept. of Ophthalmology

Fac. of MedicineHasanuddin University

• Blindness is one of the microangioapathy complications of diabetes, but also one of the most preventable.

• Diabetic retinopathy is the commonest cause of blindness in people aged 30 to 69 years.

• 20 years after the onset of diabetes almost all patients with Type 1

• over 60% of patients with Type 2

Histopathologic findings

- Early signs → leucocytes stasis and adhesion in retinal vasculature

- Loss of pericytes- Thickening of basement membrane- Hyperpermeability- Microaneurysm formation- Microvascular occlusion- Infarct retina- Fibrovascular formation

Hematologic/ biochemical abnormalities

• Increased platelet adhesiveness• Increased erythrocyte aggregation• Abnormal serum lipid• Increased mediator inflammation, ICAM-1,

VEGF, TNF-α ext• Defective fibrinolysis• Abnormalities in serum and whole blood

viscosity

Pathologic changes in diabetic retinopathy

PATHOGENESIS OF DR

• The exact cause is unclear• Several biochemical mechanisms have been

proposed as pathogenic background of DR- inflammatory process- oxidative damage- extensive hyperglycemia- VEGF- growth hormon- renin angiotensin system- genetic factors

Proliferation DR

More inflammation mediators, growth factors(TNF-, 　 ICAM-1, VCAM-1, IL-1, IL-6, IL-18 ) 　　 (VEGF, IGFs, TGF-)

Non Proliferative DR

Protein Kinase C (PKC) activation (AGEs), Polyol accumulation,Hexoamine pathway, oxidative stress Stress Oxidative

Increased inflammation mediators (TNF-, 　 ICAM-1, VCAM-1, IL-1, IL-6, IL-18 )

Retina haemodynamic damage

Vascular endothelial dysfunction

Retinal hypoxia

Biochemical changes

Hyperglycemia

CYTOKINES / MOLECULAR ADHESION

Monocyte Chemotactic Protein-1(MCP-1) ( aqueous humor, vitreous )

Macrophage Migration Inhibitory Factor (MIF) vitreous

Interleukine-6 (IL-6) ( vitreous )Interleukine-8 (IL-8) (vitreous )Tumor necrosis factor α (TNFα) (epiretinal

memb/ aqueous humor)Icam-1 in aqueous humor Tashimoto et al. (Diabetic Med, 2005)Elner et al. (Curr Eye Res, 1995)Abu El-Asrar et al (Am J Ophthalmol, 1997) Capeans et

al (Retina,1998) Mitamura et al (Ophthalmologica, 2001) Tashimo et al. (Diabetic Med, 2005) Mitamura et al. (Br J Ophthalmol, 2000), Funatsu et al. (Retina, 2001), Abu El-Asrar et al. (Am J Ophthalmol, 1997), Elner et al. (Curr Eye Res, 1995), Yuuki et al. (J Diabetic Complications, 2001), Limb et al. (Br J Ophthalmol, 1996), Muhiddin, disertasi, 2007

Classification of DR

• due to microangiopathy affecting the• retinal precapillary arterioles, capillaries, and venules.

Damage is caused by both microvascular leakage due to break down of the inner blood-retinal barrier and microvascular occlusion.

• These two pathological mechanisms can be distinguished from

• each other by fluorescein angiography, which is the “gold• standard” for assessing diabetic retinopathy.

• Hard exudates are yellow lipid deposits with relatively discrete margins.

• Retinal oedema is due to microvascular leakage and indicates breakdown of the inner blood-retinal barrier.

Background retinopathy

• Microaneurysms are small saccular pouches possibly caused by local distension of capillary walls. They are often the first clinically detectable sign of retinopathy, and appear as small red dots commonly temporal to the macula.

• Haemorrhages may occur within the compact middle layers of the retina, and appear as “dot” or “blot” haemorrhages, or

Clinically significant macular oedema (CSMO)

• retinal oedema within 500m (one-third of a disc diameter) of the fovea

• hard exudates within 500m of the fovea, if associated with adjacent retinal thickening

• retinal oedema that is one disc diameter (1500m) or larger,

Exudative maculopathy

Pre-proliferative retinopathy

Signs of ischaemia include:• cotton wool spots, which appear as white patches

with rather feathery margins and represent nerve fibre layer micro infarcts; they become highly significant when there are more than five

• large dark “blot” haemorrhages• venous beading and looping• intraretinal microvascular abnormalities (IRMA).

Pre-proliferative retinopathy with venous bleeding, cotton wool spots and some hard exudates

Proliferative diabetic retinopathy

• More progressive condition,• Retina more ischemic, induced higher

production of VEGF (vascular endothelial growth factor)

• Stimulate formation of neovascular (new vessel) else where (NVE)

• And/or new vessl of the disc (NVD)

Disc new vessels (NVD) New vessels elsewhere (NVE)

Advanced eye disease

• In advanced proliferative diabetic retinopathy, progressive fibrovascular proliferation leads to blindness due to vitreous haemorrhage and traction retinal detachment.

• Rubeosis iridis and neovascular glaucoma occur when new vessels form on the iris and in the anterior chamber drainage angle, leading to a most painful blind eye which occasionally requires enucleation.

Rubeosis iridis

Blindness in diabetic patients

• VITREOUS HEMORRHAGE• RETINAL DAMAGE• HARD EXUDATE• MACULOPATHY,ISCHEMIC AND OEDEma• Traction retinal detachment• Neovascular glaucoma

DR screening

• Visual acuity

• Funduscopy/ fundus photograph• Fundus fluorescein angiography• OCT

Indications for referral to an ophthalmologist

• For adult DM, without regular medical check up : as soon as diagnose

• With anual regular medical check up : after 3 to 5 years.

• DM in children : after 3 to 5 years OR

• Reduced visual acuity from any cause• Presence of proliferative or pre-proliferative changes• Presence of clinically significant macular oedema• Presence of hard exudates near the macula• Presence of any form of progressing or extensive

diabetic• retinopathy especially when the lesions are near the

macula

TREATMENT

The UKPDS/ DCCT• tight control of the diabetes and of

hypertension, with reduction of other “risk factors” : dyslipidemia, smoking

• Even when the complications are established, their progression leading to

serious damage can be delayed.• The Diabetes Control and Complications Trial (DCCT) - 6.5 years of follow-up• * * United Kingdom Prospective Diabetes Study (UKPD) – 9 years of follow-up

Primary interventionGlycemic control Intensive control (HbA1c = 7.2%) vs conventional control (HbA1c = 9.1%)* – Reduction of incidence of DRP by 76% – Reduction of progression of DRP by 54%

Blood pressure controlTight blood pressure (<150/<85 mm Hg) control vs conventional control

(<180/<105 mm Hg) **– 34% reduction in DRP progression– 47% reduction in visual actuity deterioration– 35% reduction in laser photocoagulation

• Lipid-lowering therapyDyslipidemia increases the risk of DRP, especially diabetic macular edema

Secundary intervention

Medical intervention– Anti-platelet agents– Protein Kinase C inhibitors (Ruboxystaurin)

Laser intervention– Severe nonproliferative and proliferative DRP– Diabetic macular edema• Interventions with intravitreal agents– Corticosteroids– Anti-angiogenesis agents

Surgical intervention– Vitrectomy for diabetic macular edema– Vitrectomy for vitreous hemorrhage and proliferatieve DRP

Medical interventionAntiplatelet agents– 650 mg aspirin has no effect on DRP (positive or negative) – ETDRS

– Circumstantial evidence that aspirin may delay the incidence of DRP

Protein kinase C (PKC) inhibitors

Hyperglycemia

Diacylglycerol (DAG)

Protein kinase C activation

• Decreased retinal bloodflow• Thickening of basement memb• Enhancement of capillarypermeability

Non-selective PKC inhibitors: side-effectsRuboxistaurin (PKC-! inhibitor)– Phase II and III– Therapeutically effective:• Preventing visual loss• Resolution of macular edema• No effect on progression from NPDR to PDR– Limited side-effects

Glucose

Aldose reductase

Sorbitol

Contribution to diabetic pathology

Polyol pathway

Octreotride (synthetic analogue of somatostatine)

Aldose reductase inhibitors

– RCTs: sordinil and tolrestat

– No effect on DRP incidence or progression 3-5 years

Nonproliferative and proliferative DRP

Mild and moderate nonproliferative DRP• No photocoagulation (unless for macular edema)

Severe and very severe nonproliferative DRP • Consider panretinal photocoagulation, especially for:– Type II diabetes– Impending cataract surgery– Pregnancy

Proliferative DRP• Panretinal photocoagulation generally indicated. High risk proliferative DRP• Panretinal photocoagulation• Vitrectomy

Severe NPDR

Laser photocoagulation

Reduced ischemic area, reduced oedema, reduced VEGF and other inflammationmediators

Diabetic macular edema

• Clinical significant macular edema (CSME)– Focal laser treatment– Grid laser treatment

Intravitreal injection

• Triamcinolone acetonide (corticosteroid) decrease inflammation mediators, reduced

oedema

• Anti VEGF : prevent new vessels development, obliterate NV, reduced vitreous hemorrhage

Triamcinolon (IVTA)

• Suggestions for use:– In diabetic macula edema– An option in refractory cases– An option in very pronounced, diffuse edema– Consider a combination with focal / grid laser after 4-6

weeks

Triamcinolon (IVTA)• Several small RCTs show improvement in macular edema and visual acuity

• RCT (n=69, follow-up 2 years)– Twice the chance of improved visual acuity– Half the chance of visual loss

• Significant disadvantages– Significant side-effects

• Cataract (50%)• Elevated intraocular pressure (40%)• Medically uncontrollable glaucoma (1-2%)• Endophthalmitis (1:1000)

– Repeat injections may be necessary (duration of effect is approximately 6-9 months for 20 mg – 2-4 months for 4 mg)

Anti-angiogenic agents• Three trials– Finished (phase II) Pegaptanip (Macugen®)- 172 patients with DME- 34% versus 10% improvement of " 10 letters- decrease in macular thickness– Ongoing Ranibizumab (Lucentis®) - RESOLVE study Bevacizumab (Avastin®) - US National Eye Institute

Anti-angiogenic agents

Suggestions for use:

– Perhaps in diabetic macular edema (glaucoma patients / steroid responders)

– In case of very severe proliferationsa. Neovascular glaucomab. Very severe retinal proliferatiesc. Always additional treatment necessary!

1. Tn. L. H. OS

PRE POST

Diabetic macular edema

?

vitrectomy

VITRECTOMY

• Evacuate vitreous bleeding• Evacuate fibrosis• Redetach retina• Endolaser photocoagulation

Vitrectomy

• Guideline indications– Dense nonclearing vitreous hemorrhage– Tractional retinal detachment involving or

threatening the macula

Vitrectomy

• The role of vitrectomy has expanded:– Recurrent vitreous hemorrhage despite maximal PRP– Diabetic macular edema in combination with vitreous

traction– Diabetic macular edema evidence of traction– Progressive PDR despite laser (especially type I)

Vitrectomy

• Important:– Create a posterior vitreous detachmant– In case of traction, consider removing the ILM

to ensure complete removal oftractional membranes

– Consider very peripheral laser

Prognosis

• Mild/ moderate back ground DR : prognosis is good to dubia

• Severe NPDR (preproliferative) : bad• Vitreoretinal fibrosis : very bad• Neovascular glaucoma : the worst

• References• ABC diabetes• AAO 2008

GRAVE’SOPHTHALMOPATHY

Habibah S. Muhiddin

Anatomy of the orbit

Introduction

Graves’ ophthalmopathy : = Thyroid-associated orbitopathy (TOA) = Thyroid Eye Disease

An autoimmune inflammatory disorders whose underlying cause remain unclear

Typically associated with hyperthyroid,May accompany hypothyroidism Hashimoto thyroiditis Euthyroid

The courseof the eye disease doesn’t alwaysParaller the activity of the thyroid gland orThe treatment of thyroid abnormalities

Referred to as :

• Grave’s Disease• Thyroid Orbitopathy• Thyroid Eye Disease (TED)• Thyroid Associated Ophthalmopathy (TAO)

What is it ?

Grave’s Disease is an autoimmune disease, which involves both orbital tissues and the thyroid gland.

Produce a variety of eye problems ranging from periocular swelling to blindness caused by optic nerve compression

Who gets Grave’s Ophthalmopathy ?

• Eye problems are most commonly associated w/ Grave’s Disease (up to 50% of patients may have signs if examined carefully )

• In rare cases it can affect patients with thyroid carcinoma

• Women are much more commonly affected then men

What causes Grave’s Ophthalmopathy ?

Complex and not fully understoodOccurs about 12 -18 month after the development of hyperthyroidsmCan affect → people with Euthyroid or Hypothyroid

Antibodies → like those active against the thyroid → damage the soft tissues in the orbit ( the bony socket of the eye )

producing inflammation with enlargement of the muscle and the fat around the eye

Factors that affect the development Grave’s Ophthalmopathy

1. Heredity ( 30% have a family history )2. Stress3. Smoking4. Environment

ORBITA

• Orbita is a space filed in eye ball extra ocular musclevesselsnervesfat etc

Signs and Symptoms

• Non infiltrative Ophthalmopathy

- widening of the palpebral fissure- lag of the globe on upward gaze, or- lag of the upper lid on downward gaze

cause the eyes to appear exophthalmic, but there is no proptosis

• Infiltrative Ophthalmopathy

- Edema of the palpebra contents- Protrusion of the globe- Infiltration of the extra ocular muscle- Damage to the optic nerve and the retina- Increased IOP

Classification of the Ocular Changes in Grave’s Disease

Many problems from Grave’s Ophthalmopathy

• Lid retraction ( upper lid too high or lower lid too low )

• Double vision• Bulgy eyes• Swelling of the eyelids and

eyeballs• Blurry vision or loss of vision• Trouble closing the eyelids

and dryness of the eyes / watering of the eyes

The photo show a patients with marked upper lid retraction and bulging of the eyes

Bulging red eyes in thyroid eye disease

23 y/o woman presents with

the chief complaint of nervousness.

She has a one month history of increased

nervousness associated with a short temper, crying easily, and tremor. In addition she states she has lost 25 poundswithout dieting, and is always hot. Her eyes protrude and feel dry.

Pathology

Involves histologic abnormalities in orbital tissue including :

- extraocular muscles- orbital fat- lacrimal glands ,and - interstitial connective tissue

Extraocular muscle from a patients with grave’s disease and

infiltrative ophthalmopathy

Edematous orbital fat and cellular infiltrate

Lacrimal gland with

mononuclear infltrate, fibrosis and an increase

in ground substance

End stage in severe involvement of extra ocular muscles in ophthalmopathy

Tests are performed in patients with Grave’s Ophthalmopathy

- Re-check of thyroid function- VA- Assessment of eyelid position /function- Slit lamp exam. of the surface the eye- Pupil test (a test of optic nerve function )- Test of IOP- Color vision test- Eye movement assessment- CT or MRI of orbits (to look at the tissue around

the eyes )- Ultrasound scan of the eye muscles

Enlarged muscle on the left side compared to the right on an MRI scan

Clinical Activity Score ( CAS )( Table 1 )

• To assess treatment of active inflammatory ophthalmopathy

• To predict therapeutic outcome• To select patient for surgical or non surgical

treatment

Table 1. Proposed classification System to assess Disease activity in Grave’s ophthalmopathy

Pain

Painfull, oppresive feeling on or behind the globe

Pain on attempted up, side, or down gaze

Redness

Redness of the eyelids

Diffuse redness of the conjunctiva

Swelling

Chemosis

Edema of the eyelids

Increase proptosis of 2 mm or more during a period between 1 and 3 Months

Impaired function

Decrease in VA OF 1 or more lines on the Snellen Chart during a period between 1 and 3 months

Decrease of the eye movements in any durection equal to or more 5 degrees during a period of time between 1 and 3 months

One point is given for each sign present. The sum of these points defines the activity

score.

Treatment

Depends on the severity of signs and symptomsAcute episodes of inflammation result in double vision and optic nerve compression recommend HIGH DOSE-ORAL STEROIDS ( PREDNISON )

Radiation therapy !!! radiation retinopathy

Surgical procedures :- orbital decompression ( to decrease

proptosis )- strabismus surgery ( to realign the eyes ) repair of double vision- lowering of the upper eyelids- raising the lower eyelids, and- blepharoplasty

3 to 5 years after onset