Download The Progression of Diabetic Retinopathy

THE PROGRESSION OF DIABETIC RETINOPATHY: INITIATION AND CONTINUATION OF TREATMENT
AMANDA S LEGGE, B.S.
ABSTRACT
CASE REPORT: A forty-four year-old white male has been experiencing progressive diabetic retinopathy changes for the past
eight years. Retinopathy began as mild and nonproliferative; however because of uncontrolled blood sugars it progressed
to proliferative diabetic retinopathy with clinically significant macular edema. Currently the patient’s fasting blood sugars
and hemoglobin A1C levels are controlled, but the retinopathy continues to progress. Several laser treatments O.U., antivascular endothelial growth factor injections O.D., and a vitrectomy O.S. have been performed in the past. He returns for a
second opinion regarding a recurring vitreous hemorrhage O.S.
DISCUSSION: Diabetic retinopathy has been well studied over the past several decades. Its progression can lead to
microvascular leakage, occlusion, and ischemia which correlate with a progressed deterioration of vision if left untreated.
Therefore it is important to understand the pathology and treatment considerations along the continuum of diabetic
retinopathy to make a prompt diagnosis and begin and continue an appropriate intervention plan.
Diabetic retinopathy is the most prevalent
microvascular complication in the eye and has
the potential to cause irreversible vision loss1.
Chronic hyperglycemia is responsible for
biochemical alterations in the retinal
vasculature such as inflammatory responses
and upregulation of vascular endothelial
growth factor (VEGF)2. These events result in
microaneurysms,
vascular
permeability,
vascular occlusion, and neovascularization. The
progression to retinal ischemia can cause
damaging, permanent vision loss. Therefore
timely diagnosis and intervention is needed.
The following case report illustrates the
progression of diabetic retinopathy in a
formerly noncompliant type 2 diabetic. This
case also highlights the initiation of appropriate
treatment and the on-going efforts to halt the
progression of continuing vision loss in this
young patient.
CASE REPORT
HISTORY
The patient is a 44-year-old white male. His
medical history is positive for type 2 insulin-
dependent diabetes mellitus for 13 years,
hypertension, hyperlipidemia, anemia, chronic
kidney disease, hypothyroidism, and coronary
artery disease. The patient’s diabetes is
managed with 60 units of Lantus in the morning
and 15 units in the evening, 1000mg of
metformin twice per day, 10mg glipizide twice
per day, and NovaLog before each meal per
sliding scale. In addition the patient is
medicated with amlopidine, carvedilol,
furosemide, simvastatin, and ranitidine.
The patient’s most current Hemoglobin A1C
blood level was 6.8% approximately 3 weeks
prior to presentation which is quite well
controlled compared to past levels. At the time
of initial retinopathy diagnosis his A1C levels
varied between 9.5 and 13.4% and fasting
blood sugars ranged between 297 and
356mg/dL. He reported that he was
noncompliant with medication and diet
directives in the past; however recently he has
been much more compliant.
According to previous records, diabetic
retinopathy was first noted in 2004 as mild
nonproliferative diabetic retinopathy (NPDR)
without macular edema (CSME). Visual acuities
were measured to be 20/20 O.D., O.S.
O.S. for a total of 538 spots. The NVD regressed
status post PRP treatments O.U.
Clinically significant macular edema was noted
in 2007 O.S. and focal laser treatment was
warranted. Also at this exam a small area of
disc neovascularization (NVD) was seen O.D.
This was confirmed with fluorescein
angiography. The patient was treated with two
sessions of pan-retinal photocoagulation (PRP)
O.D for a total of 1563 spots.
The NVD O.D. recurred and injections of antiVEGF agents were pursued in early 2010. At
that presentation the vision had deteriorated to
20/60 O.D. and 20/40 O.S. The patient received
3 injections of Lucentis and 2 injections of
Avastin O.D over the course of 6 months at 4
week intervals. The fluorescein prior to these
injections showed the leakage from the NVD as
well as the focal and panretinal laser scars O.U.
(figure 1) Following the injections there was no
leakage that could be detected O.D., O.S.
One year later, 2008, the patient developed
CSME O.D. and NVD O.S. He was then treated
with focal laser O.D. and one session of PRP
Figure 1. Fluorescein Angiography demonstrating the window defects from focal laser treatment,
microaneurysms, and leakage secondary to the disc neovascularization O.D. in later images.
Early 2011 he developed a vitreous hemorrhage
O.S. that was obscuring the macula. He
underwent an additional 930 spots of PRP O.S.
at that presentation; however the vitreous
hemorrhage remained unresolved for 4
months. He underwent a vitrectomy O.S.
approximately 6 months ago at another clinic.
His vision at that time was 20/80 O.D. and
20/100 O.S.
October 2011 a second vitreous hemorrhage
occurred O.S. which decreased his vision to
count fingers at 3 feet. He was told observation
would be appropriate for a time by an outside
ophthalmologist
and
returns
at
this
presentation for a second opinion.
The patient admits that he has been well
educated about the diagnosis, management,
and possible complications of diabetes. He has
improved his management of glucose levels
throughout the day for the past 18 months. He
plans to continue to do this.
His ocular history is also significant for primary
open angle glaucoma O.D., O.S. that is well
controlled with dorzolamide 2% twice per day
O.U. The patient reports good compliance.
DIAGNOSTIC DATA
The patient’s most current exam revealed his
unaided visual acuities were 20/80 O.D. and
20/100 O.S. at distance without improvement
on pinhole. Pupils were equal, round, and
reactive to light with a 1+ afferent defect O.S.
Extraocular motility testing found no
restrictions
of
muscle
movement.
Confrontation visual fields were full to finger
counting O.D., O.S.
Intraocular pressures were measured to be 20
mmHg O.D., O.S. Anterior segment evaluation
was remarkable for mild anterior blepharitis
O.U. and trace off-axis posterior subcapsular
cataracts O.U. The iris was clear without signs
of neovascularization O.U.
Goniscopy revealed the most posterior
structure in all quadrants to be the ciliary body
face. Minimal pigment was noted without signs
of neovascularization.
Posterior segment evaluation O.D. revealed
several microaneurysms throughout the
posterior pole without macular edema. Focal
laser treatment scars were seen temporal to
the macula. The right optic nerve head showed
mild fibrous tissue formation secondary to
receded NVD. The left eye revealed a large,
dense,
preretinal
hemorrhage
with
fibrovascular proliferation in the posterior pole
without clinically significant macular edema.
(figure 2, 3) Residual vitreous from an
incomplete vitrectomy was seen inferiorly with
a resolving vitreous hemorrhage. Extensive PRP
scars were seen in the periphery O.U.
Optical Coherence Tomography (OCT) was
performed to better assess the macula O.S.
Although the image was of poor quality
because of the preretinal hemorrhage, macular
edema was seen. This swelling may be
attributable to diabetic macular edema
pathology or secondary to the preretinal blood
and consequential intrearetinal swelling. No
cystic spaces were seen. (figure 4)
Figure 2. Fundus Photography illustrating the focal laser scars temporal to the macula O.D. and
extensive subretinal blood surrounding the macula O.S. Not pictured is the vitreous hemorrhage that has
settled inferiorly O.S.
Figure 3. Fundus Autofluorescence photography illustrating the extensive preretinal hemorrhage O.S.
and focal laser scars O.U.
Figure 3. Optical coherence tomography illustrating the normal macular thickness O.D. and
macular edema O.S., although this is a poor scan resulting from the preretinal blood
DIAGNOSIS AND FOLLOW-UP
A one-month follow up revealed a resolving
vitreous and pre-retinal hemorrhage O.S. The
right eye remained in stable condition. He
reported the vision was stable.
OCT was repeated and showed no sign of
macular edema O.D., O.S. Subretinal fluid, new
neovascularization, or hemorrhage was not
detected during dilated fundoscopy.
At this time the retinopathy remains stable O.D.
and improving O.S. The patient was once again
advised to maintain tight blood sugar control
and adhere to all primary care physician
directives.
No further intervention at this time was
recommended;
however
the
patient
understands to return to clinic if his vision
worsens. He also understands that future
interventions may be necessary based on the
evolution of the diabetic retinopathy. This
includes a second vitrectomy O.S. to remove
the residual vitreous.
Patient education was critical during this case
with regards to diabetic ocular and systemic
complications. Over the course of 3 years the
patient lost a significant amount of weight and
has much better glycemic control.
The patient now regularly visits his primary care
provider, endocrinologist, diabetic educator,
and diabetic nutritionist to keep tight control of
his blood glucose and HgA1C levels.
The patient was educated to maintain careful
monthly follow ups until his retinal status
stabilizes.
DISCUSSION
Diabetic retinopathy begins and progresses due
to prolonged, uncontrolled, hyperglycemia. In
this state, biochemical alterations result in
damage to the retinal vasculature. This leads to
microaneurysms,
vascular
permeability,
vascular occlusion, and neovascularization
which potentially cause permanent vision loss2.
Diabetic retinopathy is a complex disease with
numerous factors contributing to the overall
progression. Subclinical vascular inflammation
is the first indication of diabetic effects in the
eye. Inflammatory agents intracellular adhesion
molecule 1 (ICAM1) and its receptor, CD18, play
an important role in retinopathy initiation and
progression. ICAM1/CD18 is responsible for
leukocyte adhesion in the pathogenesis of early
diabetic
retinopathy.
Leukocyte
stasis
ultimately causes a breakdown in the bloodretinal barrier and areas of capillary nonperfusion with consequential hypoxia, the
driving force behind retinopathy progression4.
The initiation of the ICAM1/CD18 mechanism
causes capillary wall weakness triggering
microaneurysm formation, the first visible sign
of diabetic retinopathy on fundus examination
or fluorescein angiography5. This vessel wall
weakness is thought to be caused by capillary
pericyte loss secondary to a decrease in platelet
derived growth factor – B (PDGF-B). This is
triggered directly by a hyperglycemic state as
well as indirectly with the initiation of the
ICAM1/CD18 inflammation process6.
Microaneurysms in isolation are benign;
however they can cause capillary closure
resulting in acellular capillaries which
contributes to retinal non-perfusion, initiation
of proliferative retinopathy, and deterioration
of vision7.
Another key molecule in diabetic retinopathy is
VEGF, a well documented protein that
contributes to retinopathy pathogenesis in
diabetes. Typically in the healthy retina VEGF is
found as a small percentage of the retinal
proteins. With increasing hypoxic conditions,
VEGF is released at higher concentrations in
order to increase oxygenation.
VEGF is not only a mediator of new blood
vessel formation, but also of vascular
permeability. Both contribute to the
pathogenesis of visually-impairing forms of
diabetic retinopathy: proliferative retinopathy
and clinically significant macular edema,
respectively8. Additionally some studies link
VEGF to the inflammatory cascade by
upregulating ICAM1, thus creating a cycle
which accelerates the progression of
retinopathy9.
Certainly a multitude of other factors also
contribute to the initiation and progression of
diabetic
retinopathy
including
serum
cholesterol levels, uncontrolled hypertension,
anemia, and other biochemical mediators such
as protein kinase C-beta7,10,11,12. All contribute
to decreased capillary oxygenation, retinal
vessel leakage, and neovasularization, the
major risk factors for severe vision loss in
diabetic retinopathy12.
Understanding the biochemical alterations in
diabetic
retinopathy
allows
for
the
development of appropriate treatment
strategies to prevent progression. Classic
treatment strategies include photocoagulation,
anti-VEGF intravitreal injections, and steroid
intravitreal injections. Possible alternative
treatments
include
non-steroidal
antiinflammatory agents, aldose reductase
inhibitors, growth hormone antagonists, and
protein kinase C inhibitors.
Photocoagulation timing and effectiveness in
diabetic retinopathy was determined by two
major studies: the Diabetic Retinopathy Study
(DRS) and the Early Treatment Diabetic
Retinopathy Study (ETDRS). The DRS qualified
high-risk characteristics of PDR and showed a
50% reduction in severe vision loss when these
eyes were treated with photocoagulation13.
The ETDRS defined the timing for scatter
photocoagulation. It showed that eyes treated
before high-risk characteristics of PDR were
present had no long term benefit14. Therefore it
is important to control serum glucose levels,
hypertension, and cholesterol in NPDR and
monitor closely until these characteristics are
seen10,11. Patient education plays an ever
important role when a patient presents with
NDPR as with any sign of diabetic
complications.
The ETDRS also defined treatment guidelines
for diabetic macular edema. It showed that
treatment with focal or grid photocoagulation
decreased the risk of moderate visual loss for
all eyes with diabetic macular edema by
approximately 50%15. Thus treatment is
warranted for any diabetic patient presenting
with clinically significant macular edema
whether through photocoagulation, or more
recently intravitreal injections.
Both intravitreal triamcinolone and anti-VEGF
agents have been proven to reduce macular
edema and resolve neovascularization in PDR
when
photocoagulation
is
ineffective.
Intravitreal steroids or anti-VEGF agents along
with protein kinase C inhibitors downregulate
VEGF within the retina and reduce vascular
proliferation and leakage, thus reducing
neovascularization and diabetic macular edema
respectively16. Currently anti-VEGF agents are
used more often because they have little
potential to raise intraocular pressure or induce
cataracts as triamcinolone does17.
At present, photocoagulation, intravitreal
steroid, and anti-VEGF injections are the
mainstay of ocular intervention for PDR or
macular edema, although other considerations
are being investigated, such as non-steroidal
anti-inflammatory agents (NSAIDs). In the past
the ETDRS considered aspirin in diabetic
retinopathy patients; however it was concluded
that aspirin was neither beneficial nor harmful
to retinopathy progression18.
Recent research has well established
inflammation and platelet aggregation in the
process of diabetic disease, so NSAIDs are being
closely looked at again. Studies have shown
high-dose aspirin, twice the dose as given
during ETDRS, meloxicam, a cyclo-oxygenase 2
inhibitor, and etaneracept, a soluble tumor
necrosis factor receptor, suppressed diabetic
retinal ICAM-1 expression, leukocyte adhesion,
and blood retinal barrier breakdown in a rodent
model19. This is now being studied in human
trials.
Whether aspirin slows the progression of
diabetic retinopathy or not in humans, it is
known that aspirin reduces morbidity and
mortality by 17% from cardiovascular disease in
the diabetic population18. This makes aspirin a
viable
treatment
adjunct
to
reduce
cardiovascular morbidity and mortality without
negatively affecting the retina.
Oral administration of protein kinase C-β (PKCβ) inhibitors and antagonists of growth
hormone (GH) are also being investigated as
alternative methods to treat diabetic
retinopathy. PKC-β directly activates VEGF20.
GH and insulin-like growth factor have also
been implicated in the VEGF cascade21. Thus
the inhibition of these biochemical mediators
through oral administration may have the same
effect as intravitreal injections with more
convenience and potentially less adverse
effects.
When properly treated, the 5-year risk of
blindness in PDR is reduced by 90% and risk of
visual loss from macular edema is 50%15;
however prevention is the best method to
reduce the risk of visual loss from diabetic
retinopathy.
Several studies have shown that tight glycemic
control prevents or slows the progression of
diabetic retinopathy including the Diabetes
Control and Complications Trial (DCCT),
Epidemiology of Diabetes Interventions and
Complications Trial (EDIC), and the United
Kingdom Prospective Diabetes Study (UKPDS).
This information should be presented to any
patient known to have hyperglycemia or
diabetes. Patient education is the key to
preventative care with regards to diabetic
retinopathy.
Unfortunately the patient in this case did not
tightly control his glycemic levels and diabetic
retinopathy ensued. Several intervention
strategies were employed to slow the
progression; however none have completely
halted it at this point.
Proper patient education and directives were
given and he has since lowered his risk of
progression significantly by controlling his
blood glucose levels and HgA1C. Close
monitoring of the patient’s ocular and systemic
status will continue. Further interventions will
be considered if the patient’s vision or retinal
status decrease over time.
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