Systemic diseases of old age

Ophthalmic manifestations Part 1

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This article describes the most common
systemic disorders associated with
ophthalmic manifestations in an older
population. In addition, the more specific
characteristics of these manifestations in
the ageing eye, as compared to the younger
one, will be emphasised.

Hypertension

Epidemiology and pathogenesis
Hypertension is a major public health
problem due to its high prevalence and
severe consequences. It is a risk factor for
coronary artery disease, which is the
number one cause of death in the United
States. It is also the most important risk
factor for cerebral vascular disease. The
mortality and morbidity associated with
hypertension also include renal and
ophthalmic end-organ damage.

The diagnosis and categorisation of

hypertension has historically been based on
diastolic blood pressure readings. It has
long been recognised, however, that both
systolic and diastolic blood pressures
contribute to morbidity and mortality. The
term systolic defines the pressure exerted on
the walls of the arteries during the
contraction phase of the heart; the term
diastolic defines the pressure exerted on the
walls of the arteries when the heart is in the
relaxation phase (diastole). In general,
hypertension is diagnosed with a blood
pressure of 140/90 (systolic/diastolic)
mmHg or greater.

Approximately 30% of the population of

the United States between the ages of 18
and 74 years have elevated blood pressure.
It is notable that increasing age represents a
major risk factor for the presence of the
disease and it is well known from

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epidemiological studies that the prevalence
of hypertension increases with each decade
of life. It is characteristic that over half of
the population above 60 years of age in
most industrialised countries are
hypertensive. Moreover, in the seventh and
eighth decades, three-quarters of African
Americans and two-thirds of white
Americans are hypertensive. Hypertension
is more common in men than in women
and the prevalence of the disease in people
of African descent is substantially higher
than in Caucasians (38% versus 29%). In
addition, the hypertension found in
patients of African descent is more severe
with greater cardiovascular morbidity and
mortality.

Hypertension may be divided into

primary and secondary. Primary (or
essential) hypertension is by far the most
common type, representing more than 90%
of cases. Secondary hypertension may be
iatrogenic (oral contraceptives, steroid
therapy) or may be caused by renal
parenchymal disease, renal artery stenosis,
and endocrine causes such as primary
aldosteronism (in patients with primary
aldosteronism, there is an overproduction
of aldosterone either from an adrenal
adenoma or from bilateral adrenal
hyperplasia which leads to sodium
retention and an expanded intravascular
volume), Cushing’s syndrome, and
pheochromocytoma (a tumour of the
adrenal gland which produces
catecholamines; excess catecholamines act
on

α-adrenergic receptors, causing

vasoconstriction, which leads to
hypertension).

Ophthalmic manifestations (Table 1)

Hypertensive retinopathy
The ocular fundus picture in hypertension
is related directly to the status of the retinal
arteries and the rate of rise and degree of
systemic blood pressure. The term
hypertensive retinopathy refers to any
retinal vascular change related directly to
the systemic hypertension.

Changes in typical chronic hypertension

include focal narrowing and dilation of the
retinal vessels as well as generalised
narrowing of the retinal vessels, leading to
‘copper wire’ or ‘silver wire’ appearance.

About the author

Panagiotis Karadimas is a

Consultant Ophthalmic Surgeon in

the 1st Department of

Ophthalmology, Henry Dunant

Hospital, Athens, Greece.

S

ystemic diseases may affect the eye at any age. However,
the manifestations of systemic diseases in the ageing eye
represent, in general, a more significant problem. Firstly,
certain systemic diseases are much more common in old age

and secondly, even disorders which manifest from an early age can
deteriorate in the ageing eye as a result of accumulative damage over
the years.

Panagiotis Karadimas MD

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Module 5 Part 11 of

the ageing eye series

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Hypertensive retinopathy
Hypertensive choroidopathy
Hypertensive optic neuropathy
Risk factor for:

- branch retinal vein occlusion
- central retinal vein occlusion
- retinal artery occlusion
- retinal arterial macroaneurysms
- anterior ischaemic optic neuropathy
- ocular motor nerve palsies
- deterioration of diabetic retinopathy

Table 1

Ophthalmic manifestations

of systemic hypertension

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These vessel colour changes are considered
to result from diffusion of the normal light
reflex secondary to diminution of the size
of the vascular lumen. Arteriovenous
crossing changes (nicking) due to the
pressure from the sclerotic artery to the
crossing vein (Gunn’s sign) is a specific
finding (Figure 1). It is a result of venous
compression by the atherosclerotic
enlarged arterial wall, given that there is a
common adventitial sheath at the
crossings.

When the hypertension is severe,

additional retinal changes may develop.
These include arteriolar closure, retinal
haemorrhages, cotton-wool spots, and lipid
exudates.

Several classification systems have been

proposed in the past, in order to categorise
the retinal findings. The two most
commonly used in the past were Scheie
and Keith-Wagener-Barker classifications.
However, both classifications had been
developed before the widespread use of
hypertensive medications and therefore,
they are not very clinically useful. For
clinical practice today, the general trend is
to record each feature of the hypertensive
retinopathy, without trying to apply a
degree of severity derived from one of the
older classification systems.

However, given that signs of

hypertensive retinopathy are associated
with severity and duration of the disease, it
is clear that these are encountered much
more commonly in older people.

Hypertensive choroidopathy
Hypertensive choroidopathy is usually seen
in younger patients. It is characterised by
patchy non-perfused areas of the
choriocapillaris due to fibrinoid necrosis.
The overlying retinal pigment epithelium
appears yellow in the acute phase and later
becomes irregularly pigmented with
depigmented halos. This sign is called
Elschnig’s spot and is typically observed in
the mid-periphery or close to the optic
disc.

Siegrist streaks are sometimes seen in

patients with chronic hypertension and
represent lines of hyperpigmentation
(retinal pigment epithelium hyperplasia
and hypertrophy) over sclerosed choroidal
arteries; these lesions imply advanced
generalised vascular sclerosis with poor
prognosis.

Rarely, in severe cases, exudative

detachments may also develop. These are
reversible, after the hypertension is brought
under control.

Hypertensive optic neuropathy
In cases of very high blood pressure, optic
disc swelling may occur. This clinical
picture is called malignant hypertension
and it is usually accompanied by lipid
exudates in the macula forming a macular
star. The pathogenesis of the optic disc
swelling is not clear. It is uncertain if it

represents papilloedema secondary to
hypertensive encephalopathy, or if it is
secondary to local ischaemic changes of the
optic disc.

Other manifestations
Systemic hypertension has been associated
with, or it is considered as a risk factor for,
various ophthalmic conditions. In these
conditions, vascular alterations play a
major pathogenetic role. These include
branch retinal vein occlusion, central
retinal vein occlusion (Figure 2), retinal
artery occlusion, retinal arterial
macroaneurysms, anterior ischaemic optic
neuropathy, ocular motor nerve palsies,
and deterioration of diabetic retinopathy.
All of these conditions may be encountered
at increased frequency in older people.

Treatment
The treatment of hypertensive retinopathy,
choroidopathy and optic neuropathy
consists of blood pressure control. No
specific ocular therapies exist to reverse the
changes. Treatment of the underlying
systemic condition usually stops the
progression of the retinal changes, but
arteriolar narrowing and arteriovenous
crossing signs are usually permanent.

A wide range of medications may be

used to treat hypertension. These include
diuretics (their anti-hypertensive action
seems to be due to modest reduction in
plasma volume),

β-blockers, calcium

channel blockers (potent peripheral
vasodilators), angiotensin-converting
enzyme (ACE) inhibitors (vasodilators),
angiotensin receptor blockers (ARBs),
or

α-blockers. Medications such as

hydralazine, minoxidil, diazoxide,
or nitroprusside may be required if the
blood pressure is very high.

Diabetes mellitus

Epidemiology and pathogenesis
Diabetes mellitus is a clinically and
genetically heterogeneous group of
disorders which share hyperglycaemia as
the common clinical feature. Persistent
hyperglycaemia, caused by a lack of insulin
secretion and/or increased insulin
resistance, particularly in muscle and the
liver, is a central feature in the disease.

Diabetes is increasing globally at a rate

that suggests the 1994 prevalence will have
doubled by 2010. The two more common
types of diabetes are Type 1 diabetes
(insulin-dependent diabetes mellitus,
IDDM) and Type 2 diabetes (non-insulin-
dependent diabetes mellitus, NIDDM).

Type 1 diabetes mellitus is the most

prevalent type of diabetes among children
and young adults. However, it represents
only 5-10% of all diagnosed cases of
diabetes. The pathogenesis of Type 1
diabetes is unclear; genetic factors,
environmental factors and autoimmunity
have been implicated.

Type 2 diabetes mellitus is the most

prevalent form of diabetes, constituting
90-95% of all diagnosed cases of diabetes.
It usually develops in older people, most
often between 50 and 70 years. Patients
with Type 2 diabetes tend to develop
symptoms insidiously and are not
dependent on insulin for immediate
survival. Most patients with Type 2 diabetes
are both insulin deficient and insulin
resistant.

In addition to these two main types,

other more rare specific types of diabetes
also exist.

From this classification, it is clear that

diabetes is not exclusively a problem of
older people, at least in relation to the age
of presentation. However, at an older age,
the consequences of the disease are more
evident, reflecting the accumulating
damage over the years.

Ophthalmic manifestations

Diabetic retinopathy
Diabetic retinopathy (DR) describes the
retinal vascular complications of both Type
1 and Type 2 diabetes mellitus.

Epidemiology
Diabetic retinopathy is the leading cause of
blindness in the western population aged

Figure 1

Fluorescein angiography of a hypertensive

patient (note the arteriovenous crossing

changes – white arrow)

Figure 2

Central retinal vein occlusion. Hypertension is a

risk factor for the condition

‘

microangiopathy which affects other organs
in diabetic patients. The main pathogenetic
events are microvascular occlusion and
microvascular leakage.

Microvascular occlusion is the result of

capillary changes and changes in the red
blood cells and platelets leading to
capillary non-perfusion and hypoxia. As a
result, arteriovenous shunts and
neovascularisation develop. Hypoxia results
in neovascularisation through the release of
‘vasoproliferative factors’, the most
prominent being vascular endothelial
growth factor (VEGF).

Microvascular leakage is the result of

alterations in the normal anatomy of
retinal capillaries (loss of pericytes) and
results in intraretinal haemorrhages and
retinal oedema that may be either localised
or diffuse.

Clinical findings (Table 2)

Non-proliferative diabetic retinopathy
The signs of non-proliferative diabetic
retinopathy are microaneurysms,
haemorrhages, hard exudates, and retinal
oedema (Figure 3).

Microaneurysms represent the first

ophthalmoscopically detectable change in
diabetic retinopathy. These are seen as
small red dots in the middle retinal layers.
In fluorescein angiography,
microaneurysms are seen as
hyperfluorescent dots (Figure 4).

Intraretinal haemorrhages may be round

or oval (dot and blot) if located in the
middle retinal layers, or flame-shaped if
located superficially in the nerve fibre
layer.

Hard exudates have a waxy yellow

appearance ophthalmoscopically and
represent lipid accumulation in the retina.
The middle layers of the retina are affected
first. In certain cases, lipid accumulates in a
ring around a group of leaking
microaneurysms. This pattern is called

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Panagiotis Karadimas MD

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20 to 65 years. However, this figure does
not imply that DR is a problem only for
the middle-aged population. It actually
represents the fact that at middle age, other
causes of severe visual loss are uncommon,
which is not the case after 65 years of age.
If one was to consider the diabetic
population as a group, it is clear that visual
impairment and disability are more
common at an older age, reflecting the
accumulating vascular damage due to
increasing diabetes duration.

It is well-known from epidemiological

studies that duration of diabetes is the
most important factor for the development
of DR; 98% of patients with Type 1
diabetes and about 60% of patients with
Type 2 diabetes will develop DR after 20
years. This explains the frequency and the
severity of the disease at increasing age.

Other risk factors include poor

metabolic control, hypertension, elevated
triglycerides and lipids, renal disease with
proteinuria and elevated creatinine and
pregnancy.

The United Kingdom Prospective

Diabetes Study found that 39% of men and
35% of women, who were newly diagnosed
patients with NIDDM, had retinopathy at
the time of diagnosis.

Pathogenesis
The retinal changes observed in DR are the
result of microangiopathy, affecting the
retinal vessels in a way similar to the

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N

Noonn--pprroolliiffeerraattiivvee ddiiaabbeettiicc rreettiinnooppaatthhyy

• Microaneurysms
• Hard exudates
• Haemorrhages
• Retinal oedema

SSeevveerree nnoonn--pprroolliiffeerraattiivvee ddiiaabbeettiicc rreettiinnooppaatthhyy

• Venous beading
• Intraretinal microvascular

•

abnormalities (IRMA)

• Cotton-wool spots

PPrroolliiffeerraattiivvee rreettiinnooppaatthhyy

• Neovascularisation of the disc (NVD)
• Neovascularisation elsewhere (NVE)
• Fibrous proliferation

C

Coonnsseeqquueenncceess ooff nneeoovvaassccuullaarr pprroolliiffeerraattiioonn
–– aaddvvaanncceedd ddiiaabbeettiicc eeyyee ddiisseeaassee

• Preretinal/vitreous haemorrhage
• Retinal detachment
• Rubeosis iridis – neovascular glaucoma

Table 2

Clinical findings in diabetic retinopathy

Figure 3

Non-proliferative diabetic retinopathy. Multiple

haemorrhages (dot and blot, flame-shaped) and

hard exudates

Figure 4

Microaneurysms are seen as hyperfluorescent

dots in fluorescein angiography

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‘circinate retinopathy’ (Figures 5 and 6).

Retinal oedema is the result of leaking

fluid from defective capillaries. It may be
localised or generalised.

Severe non-proliferative
diabetic retinopathy
In advanced non-proliferative diabetic
retinopathy, the increasing retinal hypoxia
leads to the formation of severe multiple
retinal haemorrhages, cotton-wool spots,
venous beading and loops, and intraretinal
microvascular abnormalities. On
fluorescein angiography, large areas of
capillary non-perfusion are evident
(Figure 7).

Venous beading is a term used to

describe an irregular increase in the calibre
of the vessels. It is an important sign of a
sluggish retinal circulation. In severe cases,
the vessels appear segmented (similar to a
string of sausages). Venous beading is
nearly always seen adjacent to large areas of
capillary non-perfusion.

Cotton-wool spots (also called soft

exudates) are white, fluffy lesions in the
nerve fibre layer. These lesions are caused by
occlusion of the precapillary arterioles and
represent accumulated material due to
impaired axoplasmic flow. Fluorescein
angiography shows no capillary perfusion in
the area of a cotton-wool spot. Resolution
of cotton-wool spots may take eight to 17
months in patients with diabetic
retinopathy; it is significantly more
extended than the period required for
cotton-wool spot resolution in hypertension
(which takes about six weeks).

Intraretinal microvascular abnormalities

(IRMA) are dilated capillaries within the
retina that seem to function as collaterals.
IRMA are frequently difficult to
differentiate from surface retinal
neovascularisation. Fluorescein
angiography is very useful in order to
differentiate the two, as IRMA do not leak
while new vessels leak profusely.

According to the Early Treatment

Diabetic Retinopathy Study (ETDRS),
venous beading and loops, intraretinal
microvascular abnormalities, multiple
severe retinal haemorrhages, and
widespread capillary non-perfusion on
fluorescein angiography, represent
significant risk factors for the development
of proliferative diabetic retinopathy (PDR).

The rates of progression of non-

proliferative diabetic retinopathy (NPDR)
to proliferative disease are summarised in
Table 3.

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Macular oedema
Macular oedema (retinal thickening) is an
important manifestation of diabetic
retinopathy and represents the leading
cause of registrable blindness in diabetics.
The intercellular fluid comes from leaking
microaneurysms, or from diffuse capillary
incompetence (Figure 8).

Clinically, macular oedema is best

detected by slit lamp biomicroscopy with a
contact, 60D, 78D or 90D lens. The
oedema causes scattering of light by the
multiple interfaces it creates in the retina by
separated retinal cells. This decreases the
retina’s translucency such that the normal
retinal pigment epithelial and choroidal
background pattern is blurred. Finally, the
pockets of fluid in the outer plexiform
layer, if large enough, can be seen as cystoid
macular oedema. Usually, cystoid macular
oedema is seen in eyes which have other
signs of severe non-proliferative diabetic
retinopathy, such as numerous
haemorrhages or exudates. In rare cases,
cystoid macular oedema due to generalised
diffuse leakage from the entire capillary
network can be seen in eyes which have
very few other signs of diabetic retinopathy.

Proliferative diabetic retinopathy
Neovascularisation is the hallmark of
proliferative diabetic retinopathy.
Proliferative vessels usually arise from
retinal veins. Neovascularisation is usually
sub-classified into neovascularisation of the
disc (NVD, when the new vessels arise at or
within one disc diameter of the optic disc)
(Figure 9) or neovascularisation elsewhere
in the retina (NVE, when the new vessels
arise further than one disc diameter away).
Fluorescein angiography shows dye leakage
from the pathologic new vessels, in contrast
to the normal vessels, which do not leak
(Figure 7).

Figure 5

Massive deposition of hard exudates,

in a circinate pattern

Figure 6

Deposition of hard exudates

in a circinate pattern

Figure 7

Extensive areas of capillary non-perfusion in

fluorescein angiography (note fluorescein

leakage due to active neovascularisation)

Figure 8

Fluorescein angiography showing leaking

microaneurysms and capillaries at the macular

area in a patient with clinically significant

macular oedema (CSMO)

Table 3

Rates of progression of NPDR

RReettiinnooppaatthhyy lleevveellss

A. Mild NPDR
B. Moderate NPDR
C. Severe NPDR
D. Very severe NPDR

PPD

DRR iinn oonnee yyeeaarr

5%

12-27%

52%
75%

H

HRRC

C iinn ffiivvee yyeeaarrss

15%

33%
60%
75%

Figure 9

Neovascularisation of the disc (NVD)

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Neovascular tissue also has a fibrous

component. It has a whitish appearance,
tends to increase with time, and leads to
contraction, which may be the source of
significant morbidity. The fibrovascular
variety is usually found in association with
vessels which extend into the vitreous
cavity, or with abnormal new vessels on the
surface of the retina or disc.

Consequences of
neovascular proliferation
Advanced diabetic eye disease
Vitreous and preretinal haemorrhage:
Vitreous detachment usually begins in the
posterior pole on either side of the vascular
arcades, over the fovea, or temporal to the
macula. Progression of detachment of the
vitreous is halted whenever a tuft of
neovascularisation or a particularly strong
attachment to a retinal vessel is

encountered. The vitreous detachment will
continue to the periphery but it usually
remains attached at the disc if fibrovascular
proliferations are present. This partial
vitreous detachment is a significant cause
of preretinal and vitreous haemorrhage in
diabetic eyes.

Preretinal haemorrhage is located

between the retina and the incompletely
detached posterior hyaloid face. It has a
characteristic boat-shaped appearance. If it
is dense and premacular, there is a high risk
for early macular tractional detachment.

Vitreous haemorrhage occurs as a result

of vitreous traction on preretinal
neovascular proliferation and may obscure
the view of the fundus. B-scan
ultrasonography is valuable in this
situation to exclude any associated retinal
detachment.

Retinal detachment: The fibrous

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Panagiotis Karadimas MD

Table 4

Recommended eye examination schedule for patients with diabetes

(adapted from the recommendations of the American Academy of Ophthalmology)

AAggee ooff oonnsseett ((yyeeaarrss))

ooff ddiiaabbeetteess m

meelllliittuuss

0 to 29

30 and older

Prior to pregnancy

RReeccoom

mm

meennddeedd ttiim

mee

ooff ffiirrsstt eexxaam

m

Five years after onset

At time of diagnosis

Prior to conception or early

in the first trimester

RReeccoom

mm

meennddeedd

ffoolllloow

w--uupp**

Yearly
Yearly

No retinopathy to non-severe NPDR:

every three to 12 months.

Other stages of diabetic

retinopathy: every one to three months

** Abnormal findings may dictate more frequent follow-up examinations

Table 5

Management recommendations for patients with diabetes

(adapted from recommendations of the American Academy of Optometry)

RReettiinnooppaatthhyy lleevveellss

A. Mild NPDR

B. Moderate NPDR

C. Severe NPDR

D. Very severe NPDR
E. Early PDR

F. PDR with high risk

characteristics

FFuunndduuss ffiinnddiinnggss

At least 1 Ma, mild HE,
CWS, H (criteria not met
for B)
H , CWS, VB, IRMA
present (criteria not met
for C)
Any one of the following:
H/Ma in all four quads
VB in 2 or more quad
IRMA in one or more
quad
Any two or more of C
NV present (criteria not
met for E)
Any one of the following:
NVD with VH
NVD>1/4, 1/3 DD, even
without VH
NVE>1/2 DD, with VH

FFoolllloow

w--uupp ((m

miinniim

muum

m))

Nine to 12 months

Six months

Four months

Two to three months
Two to three months

Two to three months

TTrreeaattm

meenntt

Consider PRP

Consider PRP
Consider PRP

Immediate PRP

NPDR (non-proliferative diabetic retinopathy); PDR (proliferative diabetic retinopathy);
Ma (microaneurysms); HE (hard exudates); CWS (cotton-wool spots); H (retinal
haemorrhages); VB (venous beading); IRMA (intraretinal microvascular abnormalities);
DD (disc diameter); NV (neovascularisation); NVD (neovascularisation within one DD of the
disc); NVE (neovascularisation elsewhere in the retina); PRP (panretinal photocoagulation);
VH (vitreous haemorrhage)

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component of the fibrovascular tissue is
responsible for contraction and distortion
of the normal retinal tissue and (in
conjunction with the process of vitreous
detachment) may progress to a tractional
retinal detachment.

The temporal arcades are usually the

first to detach. Peripheral tractional
detachments may remain localised,
without a significant consequence on
vision. The rate of progression of an
extramacular tractional detachment is
approximately 15% in a single year. In
contrast to rhegmatogenous retinal
detachments, tractional detachments are
typically concave, localised, and do not
extend to the ora serrata.

Tractional retinal detachments may also

develop retinal breaks, either atrophic or
tractional. The result is a combined
tractional-rhegmatogenous detachment,
which typically progresses quickly.

When the retinal detachment involves

the fovea, there is a significant drop of
vision. Other causes of reduced vision
include the growth of fibrovascular tissue
obscuring the fovea without actual foveal
detachment, and contraction of extrafoveal
fibrovascular tissue leading to horizontal
displacement of the macula (tangential
traction).

Rubeosis iridis – neovascular

glaucoma: Iris neovascularisation or
rubeosis iridis is a complication of
proliferative retinopathy. Rubeosis is
characterised by pathological new vessels
over the surface of the iris and into the
anterior chamber angle. When the angle is
obstructed, a significant rise of the
intraocular pressure follows and the eye
becomes painful (neovascular glaucoma).
Rubeosis is observed in the setting of
proliferative changes and is usually a result
of extended retinal ischaemia and/or
long-standing retinal detachment. Rubeosis
also develops in almost all cases of retinal
detachment after unsuccessful vitrectomy;
in this setting it progresses rapidly.

Classification and follow-up
Appropriate follow-up is of paramount
importance in patients with diabetic
retinopathy. Time intervals between
follow-up visits are determined by the
severity of the disease. The
recommendations of the American
Academy of Ophthalmology, regarding
classification of the disease and follow-up,
are summarised in Tables 4 and 5.

Medical treatment
Several pharmacological agents have been
tried in diabetic retinopathy. The results, in
general, are rather disappointing until now.

Aspirin, theoretically, may be of benefit

in diabetic retinopathy through the
inhibition of platelet secretion and
aggregation. However, ETDRS showed that
it does not influence the progression of
retinopathy, visual acuity (VA), or the
incidence of vitreous haemorrhages. These

results, on the other hand, show that there
is no ophthalmic contraindication for the
use of aspirin for other medical reasons in
diabetic patients.

Ticlopidine (like aspirin) inhibits

platelet aggregation. It has been shown to
decrease the risk of stroke in patients who
have transient ischaemic attacks. According
to one study, it may retard the progression
of non-proliferative diabetic retinopathy.

Sorbinil is an inhibitor of aldose

reductase, leading to reduced production of
sorbitol. The Sorbinil Retinopathy Trial
Research Group reported that sorbinil leads
to a slightly slower progression rate in the
microaneurysm count, but it did not
observe any clinically important effect in
the course of retinopathy.

Laser treatment
Laser treatment represents the mainstay of
treatment in diabetic retinopathy.

Treatment of macular oedema
The ETDRS defined clinically significant
macular oedema as (Table 6):
a. thickening of the retina located <500µm

from the centre of the macula; or

b. hard exudates with thickening of the

adjacent retina located <500 µm from
the centre of the macula; or

c. a zone of retinal thickening, one disc

area or larger in size located <1 disc
diameter from the centre of the macula.

The ETDRS showed that after three years of
follow-up, 15% of eyes with laser treated
clinically significant macular oedema had
moderate visual loss as opposed to 32% of
untreated control eyes.

The treatment strategy depends on the

presence of focal or diffuse macular
oedema. In focal maculopathy, the aim of
treatment is to prevent leakage after focal
treatment of leaking microaneurysms. In
diffuse maculopathy, a grid of 100-200µm
burns in areas of diffuse capillary leakage is
applied.

Good prognostic signs include circinate

retinopathy of recent duration or focal,
well-defined leaking areas and good
capillary perfusion surrounding the foveal
avascular zone. Bad prognostic signs
include dense lipid exudate in the centre of
the foveola, diffuse oedema with multiple
leaking areas, extensive central capillary
non-perfusion, increased blood pressure,
and cystoid macular oedema. However,
even eyes with bad prognostic signs will
benefit from treatment when compared
with control eyes, according to ETDRS.

Panretinal photocoagulation
Panretinal photocoagulation (PRP)
significantly decreases the likelihood of an
eye with high risk characteristics (HRC) to
progress to severe visual loss. HRC are
defined as: a) neovascularisation of the disc
greater than or equal to one-fourth to one-
third disc in area; b) any neovascularisation
of the disc and vitreous haemorrhage; or c)

neovascularisation elsewhere greater than
half the disc area and vitreous or preretinal
haemorrhage (Table 7).

The goal of PRP is to arrest or cause

regression of the neovascularisation.
The current recommended therapy is
1200-2000 burns, 500µm in diameter,
when delivered through the Goldmann
lens, or 200µm in diameter when delivered
through a panfunduscopic lens, with a
duration of 0.1s, and intensity enough to
whiten the overlying retina (Figure 10).
About two thirds of eyes with HRC that
receive PRP have regression of HRC by
three months after treatment.

Complications of PRP include pain

during treatment, accidental foveal burn,
increased macular oedema, choroidal
detachment, vitreous haemorrhage, loss of
visual field, decrease in colour vision and
dark adaptation, and an increased risk of
tractional detachments.

The exact mechanism by which PRP

works remains unknown. Proposed
theories include a decrease in the
production of vasoproliferative factors by
eliminating some of the hypoxic retina and
stimulation of the retinal pigment
epithelium to produce inhibitors of
vasoproliferation.

1. Thickening of the retina located ≤500µm

from the centre of the macula; or

2. Hard exudates with thickening of the

adjacent retina located ≤500 µm from the
centre of the macula; or

3. A zone of retinal thickening, one disc area

or larger in size located ≤1 disc diameter
from the centre of the macula

Table 6

Clinically significant diabetic

macular oedema (CSMO)

1. Neovascularisation of the disc greater than

or equal to one-fourth to one-third disc
in area; or

2. Any neovascularisation of the disc and

vitreous haemorrhage; or

3. Neovascularisation elsewhere greater than

half the disc area and vitreous or preretinal
haemorrhage

Table 7

High risk characteristics

Figure 10

Fluorescein angiography after panretinal

photocoagulation (PRP)

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in diabetics than in non-diabetics under
65, and up to two times in older patients.
The incidence of cataract surgery reflects
this; estimates of 10-year cumulative
incidence of cataract surgery is 44% in
older-onset diabetics (>75 years of age),
and 27% in younger-onset diabetics (>45
years of age).

Cataract surgery may be a significant

challenge in diabetic patients. The best
known predictive factor of post-operative
success is the pre-operative severity of
retinopathy. Patients who have diabetes
mellitus without co-existing retinopathy
have excellent results from cataract surgery;
90-95% of them will achieve a final VA of
6/12 or better.

Both anterior and posterior segment

complications are more common in
diabetic patients. The most significant
anterior complication is neovascularisation
of the iris. Other anterior segment
complications include severe iritis, posterior
synechiae formation, pupillary block and
pigmented precipitates on the implant.

Posterior segment complications include

macular oedema and ischaemia,
proliferative retinopathy, vitreous
haemorrhage, and tractional retinal
detachment. Macular oedema is a
significant cause of reduced vision after
cataract surgery. For patients who have
active NPDR with no signs of macular
oedema pre-operatively, as many as
50-75% will develop macular oedema
post-operatively. If macular oedema is
present prior to the surgery, it nearly always
becomes worse. In total, only
approximately 50% will achieve a final VA
of 6/12 or better. The risk of the
development, or progression of, macular
oedema is nearly doubled in patients who
are older than 63 years. Laser treatment of
the macular oedema must be undertaken
prior to cataract surgery, if possible.
However, evaluation and treatment of
macular oedema may be extremely difficult
or impossible in the presence of cataract.
For these reasons, the current trend is for
earlier surgical intervention for cataract
removal to diabetic patients.

Cataract surgery in patients with active

PDR often results in a poor post-operative
visual outcome because the risk of both
anterior and posterior segment
complications is even higher.

Intraocular pressure – glaucoma
Considerable debate exists in the literature
regarding the possible association between
diabetes, increased intraocular pressure and
glaucoma. However, it is generally accepted
that glaucoma has a faster course of
deterioration in diabetic patients, with more
rapid visual field loss and optic disc changes.
Moreover, diabetics are more susceptible to
elevation of intraocular pressure after topical
corticosteroid administration.

Neovascularisation of the iris and

neovascular glaucoma have already been
described.

Optic nerve pathology
Many diabetics have sub-clinical optic
neuropathy, demonstrated by increased
latency and decreased amplitude of the
visual evoked potentials. In addition,
diabetes is a risk factor for anterior
ischaemic optic neuropathy.

Other neuro-ophthalmic
manifestations
Isolated cranial nerve palsies, involving the
III, VI, and rarely the IV cranial nerves,
occasionally occur in diabetics. The
mechanism is unclear but it is believed to
occur secondary to focal ischaemia
affecting the vasa vasorum of the involved
nerve. Pain may or may not be
experienced.

Cranial nerve palsies may be the first

indication of a latent diabetic condition.
When the III nerve is involved, pupillary
function usually remains normal. It is a
significant diagnostic feature,
distinguishing it from other causes of
oculomotor involvement such as
intracranial tumour or aneurysm, where
the pupillary function is impaired.
Extraocular muscle function usually
recovers in one to three months. If
recovery does not occur, other causes of
nerve palsies have to be considered.

Mucormycosis
Mucormycosis is a rare fungal infection
caused by fungi of the family Mucoraceae.
It typically affects patients with diabetic
ketoacidosis. The infection starts as
nasopharyngytis due to inhalation of
spores, and subsequently involves the
paranasal sinuses.

Spread of the infection to the orbit

results in orbital cellulitis, loss of
extraocular muscle function and, often,
proptosis with failing vision. Finally, the
destruction of cranial nerves III, IV, VI, and
the ophthalmic branch of cranial nerve V
leads to a complete orbital apex syndrome.
The manifestations include: complete
ophthalmoplegia; a fixed, dilated pupil;
corneal and upper facial anesthesia;
chemosis and conjunctival haemorrhage;
and blindness resulting from retinal artery
thrombosis, which is caused by direct
invasion by fungal elements. Fungi may
also invade the cavernous sinus and
internal carotid artery, causing thrombosis.
Cerebral infarction as a result of vascular
compromise is common. Proper anti-
fungal treatment has to be initiated
because the disease has a high mortality.

Conclusion

Hypertension and diabetes mellitus are
classic examples of systemic diseases
affecting the eye. Both are very common
and both are accompanied frequently be
ophthalmic manifestations. Both diseases
represent a more significant problem for
older people, given their long duration
and the accumulating damage that both
create.

Panagiotis Karadimas MD

Peripheral retinal cryotherapy
Peripheral retinal cryotherapy is used to treat
eyes with HRC in which the media are too
hazy for PRP. The main complication is the
development or acceleration of tractional
retinal detachment in 25-38% of eyes.

Vitrectomy
The major indications for vitrectomy in
diabetic patients are non-clearing vitreous
haemorrhage, tractional retinal detachment
involving or threatening the macula, and
combined tractional-rhegmatogenous retinal
detachment. Less common indications are
macular oedema with a thickened and taut
posterior hyaloid, macular heterotopia
(change to the position of the macula due to
the tractional), epiretinal membrane, dense
preretinal macular haemorrhage, and
neovascular glaucoma with cloudy media
precluding panretinal photocoagulation.

Objectives of surgery are removal of

vitreous gel and haemorrhage, release of
anteroposterior and tangential traction,
repair of retinal detachment, peeling of
membranes, treatment of retinal breaks,
and application of endolaser.

Visual results depend on indication,

with vitreous haemorrhage having the most
favourable prognosis and combined
traction and rhegmatogenous detachment
the worst. In general, 70% of eyes will show
improved VA, 20% will reveal no difference,
and 10% will show a decline in VA.

Complications of the procedure include

progressive rubeosis iridis (especially with
residual areas of persistent retinal
detachment), cataract, glaucoma, and
recurrent vitreous haemorrhage.

Extraretinal ophthalmic
pathology of diabetes

Cornea
Corneal abrasions are more common in
diabetics compared to normals; the
adhesion between the basement membrane
of the corneal epithelium and the corneal
stroma is not as firm in diabetics as that in
normal corneas. Endothelial corneal cells
also present significant differences in size
(polymegethism) and shape
(pleomorphism). Corneal sensitivity is also
reduced in diabetic patients in accordance
with the duration of the disease. In
addition, it is even more reduced in the
presence of retinopathy. After vitrectomy,
recurrent corneal erosion and corneal
oedema are more common in diabetics.

Transient refractive changes
Transient changes in refraction may occur
in diabetic patients. The mechanism is not
absolutely understood, but it is believed to
be secondary to osmotic swelling of the
lens, leading to subsequent myopia.

Cataract
Diabetes is the most common risk factor
for cataract in the western population. The
risk of cataract is three to four times greater

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October 31

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2003 OT

The eye is a significant organ at risk,

and early diagnosis and treatment of
the systemic disease may protect visual
function as well. Recognition of ocular
problems, and timely application of
treatment, is crucial – especially in the
case of diabetes mellitus.

Further reading

• Aiello LM, Cavallerano J, Aiello LP

(1999) Diagnosis, management,
and treatment of nonproliferative
diabetic retinopathy and macular
edema. In Albert D, Jacobiec FA
(eds) Principles and Practice of
Ophthalmology Second edition.
Saunders, Philadelphia.

• Benson W (1998) Diabetic

retinopathy. In Yanoff M & Duker J
(eds) Ophthalmology. Mosby,
Philadelphia.

• Dowler J, Hamilton AMP (2000)

Clinical features of diabetic
retinopathy. In van Bijsterveld OP
(ed) Diabetic Retinopathy. Dunitz,
London.

• Early Treatment Diabetic

Retinopathy Study Research Group
(1991) Fundus photographic risk
factors for progression of diabetic
retinopathy. ETDRS Report Number
12. Ophthalmology 98 (5 Suppl):
823-33.

• Eye Disease Case Control Study

Group (1996) Risk factors for
central retinal vein occlusion. Arch.
Ophthalmol. 114: 545-54.

• Early Treatment Diabetic

Retinopathy Study Research Group
(1987) Treatment techniques and
clinical guidelines for
photocoagulation of diabetic
macular edema. ETDRS Report
Number 2. Ophthalmology 94: 761-
74

• Ferris FL, Davis MD, Aiello LM

(1999) Treatment of diabetic
retinopathy. N. Eng. J. Med. 341:
667-78.

• Kim SK, Christlieb AR, Mieler WF,

Jakobiec FA (1999) Hypertension
and its ocular manifestations. In
Albert D, Jacobiec FA (eds)
Principles and Practice of
Ophthalmology Second edition.
Saunders, Philadelphia.

• Miller JW, D’Amico DJ (1999)

Proliferative diabetic retinopathy. In
Albert D, Jacobiec FA (eds)
Principles and Practice of
Ophthalmology Second edition.
Saunders, Philadelphia.

• Stanga PE, Boyd SR, Hamilton AM

(1999) Ocular manifestations of
diabetes mellitus. Curr. Opin.
Ophthalmol. 10: 483-9.

• Territo C (1998) Hypertensive

retinopathy. In Yanoff M & Duker J
(eds) Ophthalmology. Mosby,
Philadelphia.

1. Manifestations of hypertension include

all of the following except which one?

a. Retinopathy
b. Choroidopathy
c.

Optic neuropathy

d. Rubeosis iridis

2. Systemic hypertension has been

associated with, or it is considered as a
risk factor for, all of the following except
which one?

a. Retinal arterial macroaneurysms
b. Deterioration of diabetic retinopathy
c.

Ocular motor nerve palsies

d. Retinal detachment

3. How many cases of hypertension are

classified as primary (or essential)
hypertension?

a. 10%
b. 50%
c.

75%

d. >90%

4. What is the percentage of hypertensive

patients in the population above 60
years of age in industrialised countries?

a. 5%
b. 10%
c.

25%

d. >50%

5. What is the usual treatment of

hypertensive retinopathy?

a. Grid laser
b. Panretinal photocoagulation
c.

Vitrectomy

d. Medical control of systemic blood pressure

6. How many patients with newly

diagnosed non-insulin-dependent
diabetes mellitus have retinopathy at the
time of diagnosis?

a. 5-10%
b. 20-25%
c.

35-40%

d. 60-70%

7. Which one of the following is not a sign

of non-proliferative diabetic
retinopathy?

a. Microaneurysms
b. Hard exudates
c.

Neovascularisation of the disc (NVD)

d. Retinal haemorrhages

8. Which one of the following is not

defined as clinically significant macular
oedema?

a. Thickening of the retina located <500µm

from the centre of the macula

b. Hard exudates with thickening of the

adjacent retina located <500µm from the
centre of the macula

c.

A zone of retinal thickening, one disc area
or larger in size located <1 disc diameter
from the centre of the macula

d. Hard exudates located <500µm from the

centre of the macula

9. Panretinal photocoagulation (PRP)

significantly reduces the likelihood of an
eye with high risk characteristics (HRC)
progressing to severe visual loss. Which
one of the following is not a part of the
definition of HRC?

a. Cotton-wool spots in four quadrants
b. Neovascularisation of the disc greater than

or equal to one-fourth to one-third of the
disc area

c.

Any neovascularisation of the disc and
vitreous haemorrhage

d. Neovascularisation elsewhere greater than

half the disc area and vitreous or
preretinal haemorrhage

10. In the case of co-existence of cataract

and clinically significant macular
oedema, when is the optimal time for
laser treatment for macular oedema?

a. Prior to cataract surgery
b. During the cataract surgery
c.

The first month after the cataract surgery

d. The first year after the cataract surgery

11. Which one of the following is the

leading cause of registrable blindness
in diabetics?

a. Vitreous haemorrhage
b. Macular oedema
c.

Neovascularisation of the disc (NVD)

d. Retinal detachment

12. Which one of the following is not a

manifestation of advanced diabetic eye
disease?

a. Vitreous haemorrhage
b. Retinal detachment
c.

Cotton-wool spots

d. Neovascular glaucoma

MCQs

An answer return form is included in this
issue. It should be completed and returned to:

CPD initiatives (c4397k), OT, Victoria House,
178-180 Fleet Road, Fleet, Hampshire,
GU51 4DA by November 26, 2003.

Under no circumstances will forms received
after this date be marked
– the answers to the module will have
appeared in our November 28 issue and scores
sent electronically to the accrediting bodies.

Systemic diseases of old age: Ophthalmic manifestations Part 1

Please note there is only
ONE correct answer

Module 5 Part 11
of the ageing eye series