DIABETIC RETINOPATHY

1. Can Diabetes make me blind ?
.......Forever
Prof. Dr. Ajay Dudani

2. 1. The Burden of Diabetes
2. DME Patient Journey
3. Diabetic Retinopathy and DME
4. Diagnosis
5. Management
Agenda

3. Global estimates of diabetes: 7th edition of the IDF
world atlas
IDF Diabetes Atlas. 7th Edition, 2015: http://www.diabetesatlas.org/component/attachments/?task=download&id=90 [Accessed December 2015].

4. The cost of diabetes …
In the US, 1 in 5 health care dollars is
spent on the management of diabetes
In the UK, £1 for every £5.50 is
spent on diabetes …
IDF Diabetes Atlas. 7th Edition, 2015: http://www.diabetesatlas.org/component/attachments/?task=download&id=90 [Accessed December 2015].

5. Loss of vision is the most feared complication
of diabetes
Feelings about
complications at
diagnosis:
Complications
patients were most
concerned about:
Strain WD, et al. Diabetes Res Clin Pract 2014;105:302-12.
7%
9%
10%
11%
21%
50%
Other
Problems with
feet/legs
Circulation
problems
Kidney/renal
problems
Heart/cardiac
disease
Problems with
vision/loss of
sight/retinopathy
63% knew these health
problems might affect them in the
future, but risk seemed remote
25%were devastated
they might develop
complications
9%were not
really concerned
3%None of these

6. DME is the most common cause of visual
impairment in patients with diabetes
Patients with DR
General population
Patients with diabetes
Patients with DME with visual impairment
Patients with DME
35% of patients
with diabetes
have DR,2 of
whom 7% have
DME2,3
40% of patients
with DME have
associated
visual impairment3
DR is one of the most
common microvascular
complications of
diabetes, accounting
for >10,000 new cases
of blindness per year in
the US alone4
DME, diabetic macular edema; DR, diabetic retinopathy
1. IDF Diabetes Atlas. 6th Edition, 2013: http://www.idf.org/sites/default/files/EN_6E_Atlas_Full_0.pdf [Accessed October 2015]; 2. Yau JW, et al. Diabetes Care 2012;35:556-64;
3. Minassian D, et al. Br J Ophthalmol 2012;96:345-9; 4. Fong DS, et al. Diabetes Care 2004;27:2540-53.
8.3% of people have diabetes1

7. The principle fears of the person with
diabetes
Self treated hypoglycaemia
Kidney problems
Blindness
Not worried Very worried
Male Female
Male Female
Male Female
Visual analogue scale showing patients’ worries about hypoglycemic events and complications of diabetes, ranging from not worried to very worried
Pramming S, et al. Diabet Med 1991;8:217-22.

8. The prevalence of visual impairment increases
with type and management of diabetes
0
2
4
6
8
10
12
14
Type 2 diabetes
not taking insulin
Type 2 diabetes
taking insulin
DME prevalence differs according to type of
diabetes and treatment1
Prevalence
of
CSME
(%)
The 25-year cumulative
incidences of DME and
CSME were 29% and
17%, respectively, in
patients with
Type 1 diabetes2
11.5
9.1
4.1
CSME, clinically significant diabetic macular edema; defined as the presence of retinal thickening at or within 500 µm of the center of the macula or hard exudates at or within 500 µm of
the center of the macula if associated with thickening of the adjacent retina or zones of retinal thickening 1 disc area in size, at least part of which was within 1 disc diameter of the center
1. Ling R, et al. Eye 2002;16:140-5; 2. Klein R, et al. Ophthalmology 2009;116:497-503
Type 1 diabetes

9. Patients with diabetes are at increased risk of
several comorbid and chronic conditions
Diabetes is a leading cause of
death worldwide1,5
Diabetes caused 5.1 million deaths worldwide in 20135
Every 6 seconds somebody dies from diabetes5
The prevalence of hypertension in
patients with diabetes is 70%4
Diabetes doubles the risk of acute coronary
syndrome and doubles the level of clinical risk
once an event has occurred3
Stroke1,2
Retinopathy1,2
Neuropathy1,2 Nephropathy1,2
Coronary artery disease1,2
Myocardial infarction2
Congestive heart failure1,2
Dyslipidemia2
1. CDC. National Diabetes Fact Sheet, 2011: http://www.cdc.gov/diabetes/pubs/pdf/ndfs_2011.pdf [Accessed August 2015]; 2. Long AN, Dagogo-Jack S. J Clin Hypertens 2011;13:244-51;
3. Kapur A, De Palma R. Heart 2007;93:1504-06; 4. Klein R, et al. Arch Intern Med 1996;156:622-7; 5. IDF Diabetes Atlas. 6th Edition, 2013:
http://www.idf.org/sites/default/files/EN_6E_Atlas_Full_0.pdf [Accessed October 2015].

10. The risk of comorbidities is increased further in
patients with diabetes
Diabetic nephropathy1
Dyslipidemia1
Cardiovascular disease3
Diabetes1
Cerebrovascular accident1-3
Diabetic retinopathy1
Diabetic neuropathy1
Compared with patients with
diabetes without ocular
complications, patients
with DME and/or DR have a
greater risk of stroke2,3 and
myocardial infarction3
Compared with a healthy
control cohort, a larger
proportion of patients with
DME are overweight or obese
(~31%), have hypertension
(66%), and have cardiovascular
disease (25%)1
1. Petrella RJ, et al. J Ophthalmol 2012;159167; 2. Wong TY, et al. JAMA 2002;288:67-74; 3. Nguyen-Khoa BA, et al. BMC Ophthalmol 2012;12:11.

11. Cardiovascular risk is increased in patients
with diabetes
0
50
100
150
200
250
300
<120 120-139 140-159 160-179 180-199 >200
Male patients with diabetes
Male patients without diabetes
Age-adjusted CVD death rate per
10,000 person-years3
Systolic blood pressure, mmHg
50% of people with
diabetes go on to die
of CVD1
Additional risk factors
from: cholesterol,
hypertension,
and smoking
Compared with
healthy individuals,
patients with
diabetes are around
2-6 times more
likely to develop
CVD1 and have a life
expectancy up to
8 years lower2
CVD, cardiovascular disease
1. IDF Diabetes Atlas. 6th Edition, 2013: http://www.idf.org/sites/default/files/EN_6E_Atlas_Full_0.pdf [Accessed October 2015]; 2. Gu K, et al. Diabetes Care 1998;21:1138-45;
3. Stamler J, et al. Diabetes Care 1993;16:434-44.
CVD
death
rate
per
10,000
person-
years

12. Risk of stroke and cardiovascular disease
increased
Presence of DME is
a predictor of
cardiovascular
morbidity and
mortality 6.9
19.7
0
5
10
15
20
25
Patients with
diabetes with no DR*
Patients with DME
Rate
per
1,000
person-years
5.4
13.8
0
4
8
12
16
Patients with
diabetes with no DR*
Patients with DME
Rate
per
1,000
person-years
Acute myocardial infarction Cerebrovascular accident
*Age- and gender-matched patients with diabetes without ophthalmic manifestations, retinal disorders, or vitreous hemorrhage
Nguyen-Khoa BA, et al. BMC Ophthalmol 2012;12:11.

13. Risk of stroke by presence of microvascular
complication
1.4
4.0
4.7
20.0
0
2
4
6
8
10
12
14
16
18
20
Neither Cerebral WMLs Retinopathy Both
Risk
of
stroke
(%)
WMLs, white matter lesions
Wong TY, et al. JAMA 2002;288:67-74.
WMLs are thought to be
associated with cerebral
microvascular disease
Patients with WMLs and
retinopathy had a significantly
higher increased risk of stroke
than patients without WMLs
and/or retinopathy

14. The effects of hyperglycemia on the vascular
system are the major source of morbidity and
mortality in diabetes
Diabetic
nephropathy
Diabetic
neuropathy
Diabetic
retinopathy
Coronary artery
disease
Peripheral arterial
disease
Stroke
The incidence of microvascular
and macrovascular complications
is strongly correlated with extent
and duration of hyperglycemia1,2
Macrovascular
complications
HbA1c, glycated hemoglobin
1. Fowler MJ. Clin Diabetes 2008;26:77-82; 2. Stratton IM, et al. BMJ 2000;321:405-12.
Each 1% reduction in mean HbA1c
reduces the risk of diabetes-
related death by 21%, myocardial
infarction by 14%, and
microvascular complications by
37% (all p < 0.0001)2
Microvascular
complications
Hyperglycemia1

15. Damage to the microvasculature has potential
serious systemic effects
Microcirculatory function is extremely important1
Diabetes can damage the systems that regulate microcirculation,
including the autonomic nervous system (diabetic autonomic neuropathy),
affecting small vessels and organs throughout the body2
Cardiovascular autonomic neuropathy is one of the most important forms of
diabetic autonomic neuropathy3
Clinical manifestations include sudden cardiac death, silent myocardial
ischemia, resting tachycardia, orthostasis, high cardiovascular mortality rate2,3
1. Johnson PC. Overview of the microcirculation. In: Tuma RF, et al., eds. Handbook of Physiology: Microcirculation. 2nd ed USA: Elsevier, 2008: x-xxiv; 2. Dokken BB. Diabetes Spectrum
2008;21:160-5; 3. Boulton AJ, et al. Diabetes Care 2005;28:956-62.

16. The Anatomy of the eye
http://www.eyedefectsresearch.org/mac-degen.html
https://www.ncbi.nlm.nih.gov/pubmedhealth/PMHT0022378/?figure=1
https://www.aapos.org/terms/conditions/22

17. The anatomy of the eye(Layers of Retina)
1) Image: Caspi RR. J Clin Invest. 2010;120:3073-3083

19. • Corneal sensitivity is commonly impaired in diabetes- predispose to bacterial corneal ulcers, neurotropic
ulcers and difficulties with contact lenses
• Decreased reflex tear secretion- dry eye
• Intrinsic abnormalities of the epithelial basement membrane complexes , with impaired barrier function
lead to:
 Superficial punctate keratitis
 Poor healing after trauma
 Prolonged recovery after intraocular surgery
CORNEA

20.  Diabetes is one
of the frequent
etiology of
acquired palsy
 The 3rd, 4th and
6th are affected
(3rd and 6th are
frequently cited)
Extra Ocular Muscles

21. 6th Nerve Palsy
• Most common
• Horizontal diplopia in primary
gaze and in gaze towards same
side

22. Patching either eye or binasal occlusion
Fresnel Prism
 To treat diplopia and alleviate face turn. Can be tried for small eso deviations or
postoperatively if needed
Botolinum toxin A
 Prevent contracture of medial rectus ◦ Successful use of botulinum toxin A in the early
treatment of diplopia caused by 6th nerve palsy in two type 2 diabetic patients. (Anna
Broniarezyk-Loba, 2004)
Eye muscle surgery
 Longstanding esotropia ~ 6 months and above
Control blood pressure and blood sugar
 High sugar and blood pressure not only impact the eye but has increased risk of stroke
Management of 6th Nerve Palsy

23. • Cataract is one of the major cause of vision impairment in people with diabetes
• Diabetics are 60% more likely to be develop cataract
• It occurs 10-20 years after the onset of insulin dependent diabetes
• Control of the diabetes with restoration of normal blood glucose levels stops progression of the
opacity
• True diabetes cataract (snow-flake/snow- storm cataract) Pre-senile cataract
Cataract
Snow-flake Cataract

25. Management of Cataract

26. Anterior Ischemic Optic Neuropathy(AION)
Ischemic optic neuropathy is due to acute ischemia of the optic
nerve.
Based on the pattern of blood supply of the optic nerve, it can be divided
into two distinct regions:
1.The anterior part (optic nerve head) which is supplied primarily by the
posterior ciliary artery circulation
2.The posterior part which is supplied by multiple sources other than
posterior ciliary artery circulation
Abbreviations: A = arachnoid; C= choroid; CRA= central retinal artery; Col. Br.= Collateral
branches; CRV= central retinal vein; D= dura; LC= lamina cribrosa; NFL= surface nerve
fiber layer of the disc; OD= optic disc; ON= optic nerve; P= pia; PCA= posterior ciliary
artery; PR and PLR= prelaminar region; R= retina; RA= retinal arteriole; S= sclera; SAS=
subarachnoid space.
Hayreh 1978 [16]. B Modified From Hayreh, S.S. 1974 [8].

27. Treatment of A-AION is actually treatment of GCA.
It is unlikely that the patient will regain vision with treatment.
 The goal of treatment is to prevent further vision loss, especially in the
contralateral eye.
To prevent bilateral blindness, two things are crucial:
 Early diagnosis
 Immediate and adequate steroid therapy
 The set of clinical criteria most strongly suggestive of GCA in order are:
 Jaw Claudication, CRP > 2.45, Neck pain, ESR > 47
 A combination of the ESR and CRP is 97% specific (best indicator of all).
 If there is a reasonable index of suspicion for GCA, the patient must be treated
ASAP. A biopsy can confirm the diagnosis later.
Management of AION

28. Glaucoma Glaucoma refers to a group of diseases
characterized by
• Optic neuropathy
• Specific pattern of visual field defect
• Higher intraocular pressure
• Damage to optic nerve is irreversible process
• Normal IOP is 10-21mmHg

29. Symptoms
• Photophobia
• Lacrimation
• Blepharospasm
• Enlarged eyeball
Signs
• Corneal edema, corneal enlargement
more than 13mm diameter.
• Sclera become thin and appers blue
• Iris may show iridodonesis and
atrophic patches in late stage
• Lens becomes flat or subluxated
• Optic disc shows increased cup/disc
ratio and atrophy specially after third
year.
• IOP is invariably high.
Symptoms and signs

30. Management of Glaucoma

31. Diabetic Retinopathy
• Progressive dysfunction of the retinal blood vessels
caused by chronic hyperglycemia.
• DR can be a complication of diabetes type 1 or diabetes
type 2.
• Initially, DR is asymptomatic, if not treated though it
can cause low vision and blindness.

32. Cotton Wool Spots
Infarction of the nerve fiber
layer, resulting in fluffy,
white patches
Microaneurism
Outpouchings of the
vessel
Hemorrhage
Vascular
tortuosity
Hard Exudates
lipid byproducts,
appears as waxy,
yellow deposits
Eye with Diabetic Retinopathy
https://webeye.ophth.uiowa.edu/eyeforum/tutorials/diabetic-retinopathy-med-students/Classification.htm

33. • Global prevalence of DR among patients with
diabetes to be 35.4%.
• Prevalence of any DR was higher in those with type
1 diabetes
• A UK study showed prevalence of DR-33.6% and a
study from USA showed 50.3% respectively.
• The incidence and prevalence of DR in India appears
to be lower than that noted in western literature.
Epidemiology of Diabetic Retinopathy

34. Healthy Retina Diabetic Retinopathy
Diabetic Retinopathy and healthy Eye
https://webeye.ophth.uiowa.edu/eyeforum/tutorials/diabetic-retinopathy-med-students/Classification.htm

35. Epidemiology of Diabetic Retinopathy in
INDIA
1) http://bmctoday.net/retinatoday/2013/04/article.asp?f=diabetic-macular-edema-the-indian-perspective
CURES APEDS SN-DREAMS NORTHESTERN
18%
22.40%
18%
28.90%
PREVALENCE OF DR IN INDIA
CURES: Chennai Urban Rural Epidemiological study
APEDS: Andhrapradesh Eye Disease Study
SN-DREAMS:Sankara Nethralaya-Diabetic Retinopathy Epidemiological and Molecular Genetic Study

36. Types of DR
1) Mild nonproliferative
DR
Small areas of balloon-like
swelling in the retina’s tiny
blood vessels.
Occur at this earliest stage of
the disease.
2) Moderate
nonproliferative
retinopathy
Swell and distort blood
vessel
Blood supply to eye reduced
3) Severe nonproliferative
retinopathy.
Many more blood vessels
are blocked, depriving
blood supply to areas of the
retina.
4) Proliferative diabetic
retinopathy (PDR)
Growth factor (VEGF)
released and forms new
tiny,leaky blood vessel.
Risk of permanent vision loss
https://emedicine.medscape.com/article/1224138-overview
5.Watkins PJ. BMJ 2003;326:924-6; 6.Minassian DC, et al. Br J Ophthalmol 2012;96:345-9

37. • Macular edema in diabetes, defined as retinal thickening within 2 disc
diameters of the center of the macula, results from retinal microvascular
changes
• These changes compromise the blood-retinal barrier, causing leakage of
plasma constituents into the surrounding retina and, consequently, retinal
edema.
• DME is a consequence of diabetic retinopathy
Diabetic Macular Edema

38. Clinically significant macular edema (CSME)
https://emedicine.medscape.com/article/1224138-overview
• Retinal thickening within 500 µm of the center of the fovea
• At least 1 disc area of retinal thickening, any part of which is within 1 disc diameter of the center
of the fovea
• Hard, yellow exudates within 500 µm of the center of the fovea with adjacent retinal thickening
CSME as defined by the Early Treatment Diabetic Retinopathy Study (ETDRS):

39. Symptoms of DR
Asymptomatic
Blurred
central vision
Distortion of
objects
Difficult in
reading and
Floaters
! ! ! ! !
!
https://emedicine.medscape.com/article/1224138-overview

40. Diabetes and DR/ DME Pathway

41. Risk Factor for DR
https://www.asrs.org/content/documents/fact_sheet_22_diabetic_retinopathy_new.pdf
Increased total serum cholesterol associated with
increased risk of hard exudates
High blood pressure
Duration of Diabetes and Levels of HbA1C
Teresa,MEDtube Science Mar, 2017; Vol. V (1)
Genetic factors
Pregnant women with diabetes

42. Diagnosis
https://nei.nih.gov/health/diabetic/retinopathy

43. Choice of
therapy
• Anti-VEGF
• Laser
• Steroids
Modifia
ble risk
factors1
• Blood sugar
control
• Blood pressure
• Cholesterol
Disease
stage
• Non-proliferative DR
• Proliferative DR
DME, diabetic macular edema; DR, diabetic retinopathy; VEGF, vascular endothelial growth factor
Ding J, Wong TY. Curr Diab Rep 2012;12:346-54
Factors to consider for treatment

44. https://webeye.ophth.uiowa.edu/eyeforum/tutorials/diabetic-retinopathy-med-students/TreatmentOpts.htm
Treatment
For NPDR:
• Managed by optimizing the patient’s general health.
• Patients should maintain a HbA1c ≤7%.
• patients should be counseled to stop smoking.
• if the patient has clinically significant macular edema (CSME) with NPDR: treat with laser therapy. If
the leakage is more diffuse a grid of light laser burns can slow the edema.
• Finally off-label medical options are available steroids and Anti-VEGF

45. 45
PDR Treatment
PRP:
• Portions of retina are destroyed using thousands of laser burns while
sparing the macula.
• But risk of vision loss. It has been found to be extremely effective,
reducing the risk of severe vision loss by 50%.
• Advised for patients with vitreous hemorrhage and neovascularization.
https://nei.nih.gov/health/diabetic/retinopathy
https://webeye.ophth.uiowa.edu/eyeforum/tutorials/diabetic-retinopathy-med-students/TreatmentOpts.htm

46. Vitrectomy:
• Surgical removal of the vitreous gel in the center of the eye.
• Procedure is used to treat severe bleeding into the vitreous.
• The procedure is also indicated for certain tractional retinal
detachments.

47. Intravitreal Anti-VEGF injections

48. Prior to Anti- VEGF injections , patients lost
vision, But with the advent of Anti- VEGF
injection vision was restored and regained

49. One of the landmark trials shows the gain in
vision by using Anti- VEGF as compared to Laser
and Corticosteroids
49
0
1
2
3
4
5
6
7
8
9
10
11
0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 76 80 84 88 92 96100
104
Sham+prom
pt laser
Ranibizumab
+prompt
laser
Ranibizumab
+deferred
laser
Triamcinolo
ne+prompt
laser
* Values that were ±30 letters were assigned a value of 30
P-values for difference in mean change in visual acuity from sham+prompt laser at the 52-week visit: ranibizumab+prompt laser <0.001; ranibizumab+deferred laser <0.001; and
triamcinolone+prompt laser=0.31.
http://publicfiles.jaeb.org/drcrnet/presentation/protocol_I_Results_slides_4_26_10.ppt
VA
(no.
of
letters
on
ETDRS
chart)
Time (Weeks )

50. 50
DME management Anti-VEGF
• Specifically designed for intraocular use
• Monoclonal antibody fragment (Fab), maximizing biologic activity while
minimizing systemic exposure
• Inhibits the action of VEGF-A in the retina to decrease vascular permeability and
edema
• Very favorable safety profile. Approved for DME.
Ranibizumab
1. Bayer. Eylea SmPC. 2013; 2. Roche. Avastin SmPC. 2014; 3. Avery R, et al. Data presented at ASRS, August 25, 2013, Toronto, Canada;
4. Avery R, et al. Br J Ophthalmol 2014; Epub ahead of print; 5. Matsuyama K, et al. Br J Ophthalmol 2010;94:1215-8

51. 51
Anti-VEGF
• Anti-VEGF-A / PlGF / VEGF-B recombinant fusion protein
containing the FC portion of IgG
• Initially developed for systemic administration in oncology
• Licensed for metastatic colorectal cancer in the EU and US
Aflibercept
1. Bayer. Eylea SmPC. 2013; 2. Roche. Avastin SmPC. 2014; 3. Avery R, et al. Data presented at ASRS, August 25, 2013, Toronto, Canada;
4. Avery R, et al. Br J Ophthalmol 2014; Epub ahead of print; 5. Matsuyama K, et al. Br J Ophthalmol 2010;94:1215-8
• Anti-VEGF-A full-length monoclonal antibody containing the
Fc portion of IgG
• Licensed for multiple oncology indications in the EU and US
• Not licensed for ophthalmology indications or compounding
• Not manufactured for ophthalmic administrations
Bevacizumab (Off-Label)

52. 52
Corticosteroids for DME
• The dexamethasone intravitreal implant 0.7 mg is a long-acting sustained-release,
biodegradable corticosteroid.
• PLACID trial gain in mean BCVA was more in the group receiving Dex compared to
that receiving laser therapy.
• The Dex implant releases the corticosteroid into the vitreous over a period of ≤6
months.
• Risk of IOP rise and cataract formation
Dexamethasone Implant
1Rajendran A, Badole P. DME Management – Current Perspective and Therapeutic Strategies. Journal of Ophthalmology and Related Sciences. 2018;2(1):7–14REVIEW.
Alimera Sciences. Iluvien SmPC. 2014; 2. Campochiaro PA, et al. Ophthalmology 2011;118:626-35
Messenger WB, et al. Drug Des Devel Ther 2013;7:425-34; 2. Al Dhibi HA, Arevalo JF. World J Diabetes 2013;4:295-302; 3. Campochiaro PA, et al. Ophthalmology 2012;119:2125-32;
• Cylindrical polyamide tube containing 190 ug of fluocinolone acetate
• Corticosteroids inhibit inflammation and reduce leakage from blood vessels in the
retina
• Risk of IOP rise and cataract formation
Fluocinolone Acetonide

53. 53
Corticosteroids for DME
• Show short-term efficacy, and effects on visual acuity are transient
• Associated with a high incidence of drug-related cataracts and glaucoma
• Increased incidence of sterile endophthalmitis may be associated with preserved
triamcinolone acetonide
• Not approved for ophthalmology indications
Triamcinolone acetonide IV
DRCR.net. Ophthalmology 2008;115:1447-59; 4. Jonisch J, et al. Br J Ophthalmol 2008;92:1051-54

54. 54

55. 55
Prevention of DR
Take your medicines as prescribed by doctor
T
Reach and maintain a healthy weight
R
Add physical activity to your day
A
Control your ABCs—A1C, B.P, and cholesterol
C
Kick the smoking habit
K
https://www.asrs.org/patients/retinal-diseases/3/diabetic-retinopathy
Do you
know?
DCCT trail shown that
controlling diabetes slows
the onset and worsening
of DR
DCCT: Diabetes control and complication trail

56. Conclusions
Loss of vision is the most feared complication of diabetes1
DME is the most common cause of visual impairment in patients with
diabetes2-4
DME often affects people of working age and therefore requires long-term
management5,6
Patients with diabetes are at increased risk of several comorbid and chronic
conditions,7-9 which is increased further in patients with DME5,10
1. Strain WD, et al. Diabetes Res Clin Pract 2014;105:302-12; 2. Yau JW, et al. Diabetes Care 2012;35:556-64; 3. Minassian DC, et al. Br J Ophthalmol 2012;96:345-9; 4. Fong DS, et al. Diabetes
Care 2004;27:2540-53; 5. Petrella RJ, et al. J Ophthalmol 2012;159167; 6. Zheng Y, He M, Congdon N. Indian J Ophthalmol 2012;60:428-31; 7. IDF Diabetes Atlas. 6th Edition, 2013:
http://www.idf.org/sites/default/files/EN_6E_Atlas_Full_0.pdf [Accessed October 2015]; 8. Kapur A, De Palma R. Heart 2007;93:1504-06; 9. Long AN, Dagogo-Jack S. J Clin Hypertens
2011;13:244-51; 10. Nguyen-Khoa B, et al. BMC Ophthalmol 2012;12:11.