3rd Annual Retina Report
An Overview of Intravitreal Injection
Here, we examine the history and process of intravitreal injection as well as review your role in managing potential complications.
Release Date: JUNE 2012
Expiration Date: JUNE 1, 2015
Because of the increased use of anti-VEGF therapy for wet AMD during the last several years, optometrists can expect to comanage these patients more than ever before. Therefore, we must be educated thoroughly about the process of intravitreal injection as well as how to properly manage potential secondary complications.
Jay M. Haynie, O.D.
This course is COPE-approved for 2 hours of CE credit. COPE ID is 34784-PS. Please check your state licensing board to see if this approval counts toward your CE requirement for relicensure.
This continuing education course is joint-sponsored by the Pennsylvania College of Optometry.
Dr. Haynie has no relationships to disclose.
In my practice setting, I have
been fortunate to observe and
manage countless patients with
various sight-threatening retinal
conditions. Many years ago, I was
given the opportunity to participate
in a retinal fellowship in a surgical
practice located in Tacoma, Wash.
This position allowed me to work
with several retinal surgeons as well
as share patients, experience surgical trends, observe outcomes, and
witness the evolution of retina care
Currently, I serve as the clinical director of the practice where
I completed my fellowship. In this
setting, I have found it worthwhile
to consider comanagement as an
evolutionary process. From a historical perspective, it is clear that
the current approach to optometric
comanagement has taken significant
time to emerge and differs greatly
across various practice settings,
states and local communities (for
further reading, see "What is 'Integrated Eye Care?'" March 2012).
So, it seems logical to expect
that the comanagement of intravitreal injections for retinal disease
also will evolve over time and in
different ways. This form of medical care likely will continue between
retinal specialists and optometrists
for several years to come. Therefore, optometrists must be educated
thoroughly about the process of
intravitreal injection as well as how
to properly manage potential secondary complications.
The History of Intravitreal
The administration of intravitreal
injections has revolutionized the
treatment of many visually devastating retinal diseases, including
age-related macular degeneration
(AMD), diabetic retinopathy and
retinal occlusive disease as well
as vitreoretinal surgery. There is
no question that the number of
intravitreal injections performed by
retina specialists has increased dramatically. During the past decade,
there has been a veritable explosion
of new drugs, techniques and indications for intraocular injection.
At one time, intravitreal injection
was limited to antibiotic agents that
were intended to treat a discrete
subset of patients with endophthal-mitis. Today, however, many subtypes of AMD and retinal vascular
disorders are treated with intra-vitreal injections of anti-vascular
endothelial growth factor (VEGF)
agents. Because of the high frequency of reinjection associated with
anti-VEGF therapy, it is inevitable
that optometrists also will interface
increasingly with these patients.
In the past, injections associated
with the eye primarily were administered periocularly (e.g., frequent
sub-Tenon's injections of steroids
and antibiotics delivered following
intraoperative surgery). Periocular
injections of steroidal medications
became a standard method for the
management of uveitis patients.
Additionally, several retina specialists determined that periocular
steroid injections were extremely
useful in the management of wet
AMD (steroids helped limit the
extent of fibrotic and inflammatory disease associated with neo-vascularization).1
Subsequently, intravitreal steroid
injection in an outpatient setting
was attempted for a host of inflammatory conditions, including wet
AMD and diabetic macular edema.
Further, intravitreal ganciclovir
injection also emerged as a technique for treating cytomegaloviral
retinitis in patients with HIV.
Over time, it became apparent that
injection--both in and around the
eye--was safe, efficient, practical
and useful in helping patients with
a variety of ocular conditions.
Anti-VEGF therapy has dramatically changed how eye care
providers treat and manage sight-threatening retinal disease. During
the last 15 years, we have witnessed
a relative explosion in viable treatment options for our patients. Here
is a look at several established and
cutting-edge treatment options for
advanced retinal disease:
* Laser therapy. Some of the
earliest management strategies for
significant retinal disease predominantly included the use of laser
photocoagulation and photody-namic therapy. Although many
clinical trials proved laser therapy
to be beneficial for AMD, patients
often experienced disease recurrence secondary to the continuous
release of VEGF.2
VEGF is a protein produced by
cells that stimulates angiogenesis.
When unregulated by hypoxia,
VEGF is released into the vitreous
cavity, causing vascular permeability and associated retinal edema.
Laser photocoagulation does not
address the release of VEGF, and
therefore underlying retinal disease
continues to smolder in the background. Nonetheless, the ability
to slow or suppress the release of
VEGF has proven to be essential for
long-term visual stability.2
* Macugen. In 2004, Macugen
(pegaptanib sodium, Pfizer and
OSI/Eyetech Pharmaceuticals, Inc.)
was the first anti-VEGF agent
to receive FDA approval for the
treatment of neovascular AMD. Its development marked a clear
breakthrough in modern AMD
Macugen is a selective anti-VEGF
compound that is designed to inhibit one strain of VEGF. It should be
administered via intravitreal injection every six weeks. Although the
use of Macugen has declined with
the release of newer anti-VEGF
agents, such as Lucentis (ranibizum-ab, Roche/Genentech) and Avastin
(bevacizumab, Roche/Genentech), it
appears to be making a comeback
because of its more favorable dosing frequency (e.g., every six weeks
vs. every four weeks). Additionally,
Macugen is associated with a lower
risk of stroke than either Lucentis
* Lucentis. In June 2006, the
FDA approved Lucentis for the
treatment of neovascular AMD and
macular edema secondary to retinal vein occlusion (RVO). Unlike
Macugen, Lucentis is thought to be
effective against several strains of
VEGF. It was the first compound
shown to improve visual acuity
in patients with wet AMD.4 The
recommended dosing schedule for
Lucentis is one injection per month
until the patient stabilizes. Thereafter, Lucentis may be dosed on a
* Avastin. Avastin is FDA-approved for the treatment of
colorectal cancer. However,
because the agent costs substantially less per dose than Lucentis, it
has been widely used off-label since
2004 to treat several retinal diseases, including neovascular AMD.
Recently, a major study supported
by the FDA--the Comparison of
Age-related Macular Degeneration
Treatment Trials (CATT)--compared the safety and therapeutic
efficacy of both Lucentis and Avas-tin for the treatment of neovascular
AMD.5 CATT results confirmed that both compounds exhibit
statistically equivalent safety and
therapeutic benefit in the preservation of visual acuity. Most managing clinicians opt to administer one
intraocular injection of Avastin per
month until the patient's vision
stabilizes, and then on a p.r.n. basis
thereafter (figures 1 and 2), much
|1, 2. Note the multiple pockets of cystoid intraretinal edema seen in this patient with wet age-related macular degeneration (left). Following an injection of Avastin (bevacizumab, Roche/Genentech), the intraretinal edema resolved.
* Eylea. Also known as VEGF
Trap-Eye, Eylea (aflibercept,
Regeneron Pharmaceuticals) is the
latest anti-VEGF agent to receive
FDA approval for the treatment of
neovascular AMD. Unlike Macu-gen, Lucentis and Avastin, Eylea
is administered every other month
(following a loading phase consisting of three monthly injections).
FDA approval for Eylea was
secured following publication of
the VIEW 1 and VIEW 2 clinical
trials, which compared the agent's
safety and efficacy profile to that of
Lucentis.6 The primary endpoints
of VIEW 1 and VIEW 2 were maintenance of visual acuity (defined as
losing fewer than 15 ETDRS letters) for one year. Most importantly, the VIEW researchers concluded
that subjects who revceived 2mg of
Eylea every eight weeks exhibited
comparable visual improvement
to subjects who received 2mg of
Lucentis every four weeks.6 These
results suggest that, when compared
to Lucentis, the reduced dosing
frequency of Eylea likely will save
patients not only time and money,
but also significant discomfort.
* Kenalog. For years, intravitreal
Kenalog (triamcinolone acetonide,
Bristol-Myers Squibb) has been
used either alone or as an adjunct
to anti-VEGF therapy in patients
with a variety of retinal conditions.
Intravitreal Kenalog is especially
effective at treating macular edema
secondary to uveitis, diabetic reti-nopathy and RVO.7,8
To date, the therapeutic impact
of Kenalog on patients with neovas-cular AMD is not well understood.
However, clinical experience suggests that Kenalog may potentially
slow the rate of visual acuity loss,
which could reduce the number of
total anti-VEGF or laser treatments
required to maintain serviceable
vision throughout the patient's lifetime. The primary concern associated with intravitreal Kenalog is an
increased risk of posterior subcap-sular cataract development and/or
* Ozurdex. Ozurdex (dexa-methasone intravitreal implant,
Allergan), a biodegradable steroid
implant, is FDA approved to treat
edema associated with RVO and
non-infectious uveitis. Clinical
studies have shown a rapid reduction in retinal edema secondary to
RVO (figures 3 and 4) as well as
elimination of vitreous haze associated with uveitis within one to two
months after Ozurdex implanta
tion.9 The implant may remain in
place up to four months; however,
the exact duration varies depending on the presentation and/or
therapeutic response. Much like
Kenalog, Ozurdex may increase a
patient's risk for subcapsular cataract development and/or steroid-induced glaucoma.7,8
|3, 4. At left, marked cystoid edema seen in a patient with an underlying central retinal vein occlusion prior to treatment with Ozurdex (dexamethasone intravitreal implant, Allergan). Following Ozurdex implantation, the cystoid edema rapidly cleared.
The Process of Intravitreal
Although slight variations exist
between eye care providers, the
practice of intravitreal injection is
fairly uniform. Notable procedural
differences include: use of gloves by
the clinician, use of a sterile drape,
a preoperative/postoperative measurement of intraocular pressure
and the use of postoperative topical
antibiotics. Here is the standard,
step-by-step process for the administration of intravitreal injection:10
- Instill topical tetracaine and
- Administer a subconjuctival
injection of lidocaine for anesthesia.
- Apply a povidone iodine scrub
to lid margin and lashes.
- Insert the lid speculum.
- Administer a povidone iodine
drop (or apply another swab)
to the conjunctiva in the area of
- Inject the pharmacologic agent
into the superior temporal quadrant.
- Instill a topical antibiotic.
- Remove the lid speculum.
- Confirm hand motion vision
and/or measure the patient's intra-ocular pressure.
- Rinse the eye and lid margin
with sterile saline.
- Prescribe topical antibiotics for
at-home patient use.
It is essential to mention that the
retinal surgeon's primary concern
is avoidance of infectious endo-phthalmitis following intravitreal
injection.11-15 Fortunately, strict
adherence to the aforementioned injection administration protocol is
believed to reduce this risk.11-15
The most common adverse reaction to intravitreal injection is
superficial keratitis associated with
the povidone iodine solution. Without question, this reaction is the
sole reason for triage calls within
the first 24 hours following injection. Patients are encouraged to use
artificial tears regularly for symptoms of discomfort and irritation
immediately following the injection.
More serious complications
include both infectious and psue-do-endophthalmitis, intraocular
hemorrhage, retinal tear, retinal
detachment, cataract formation
and increased intraocular pressure.11,12,16,17
* Infectious endophthalmitis is
the single complication that is most
feared by all ophthalmic surgeons.
Although the risk of endophthalmi-tis following intravitreal injection
remains low, we must familiarize
ourselves with the clinical signs and
The symptoms of endophthalmitis following intravitreal injection may include: increased ocular
discomfort, light sensitivity, pain,
floaters and a marked decrease in
visual acuity.18 The onset of symptoms may vary; however, patients
generally experience such secondary
complications within three to five
days following injection.
Clinical signs of endophthalmitis
include redness; cellular reaction of
the anterior chamber and vitreous;
the abundance or complete absence
of fibrin in the anterior chamber
and/or the vitreous; corneal edema
and keratic precipitates; marked
vitreous haze; and a possible hypo-pyon (figure 5). It is important to
note that a patient does not have
to exhibit all of these complications; just one or more clinical signs
should raise immediate concern
in any individual who recently
received an intravitreal injection.
|5. Anterior segment of a patient with infectious endophthalmitis. Note the global injection and steamy cornea in conjunction with the hypopyon.
* Pseudo-endophthalmitis also
may occur following intravitreal
injection, and it is believed to
be a reaction to a preservative
in the compound or to the compound itself. The signs of pseudo-endophthalmitis typically present
within the first 24 hours following injection and will always be
seen with an associated hypopyon
(however, the vision may be intact
and the level of discomfort usually
Compared to infectious endo-phthalmitis, the clinical appearance
of eyes with pseudo-endophthal-mitis generally is less hyperemic
(figure 6). The differential between
infectious and pseudo-endophthal-mitis can be challenging, and may
require increased clinical experience
to confirm. As a safety measure,
a vitreous tap with an injection of
antibiotics often is performed if
there is any concern that the presentation has an infectious etiology.
To ensure patient safety, immediate
referral back to the retinal surgeon
is strongly advised should any
symptoms of either infectious or
|6. Anterior segment photograph of a patient with pseudo-endophthalmitis. Note how quiet the eye looks, despite the presence of the hypopyon.
* Increased intraocular pressure following intravitreal injection
has been reported in up to 9.4%
of cases; yet, just 5.5% developed
sustained pressure elevation that
required topical or surgical management. Keep in mind, however,
that steroid-associated intra-ocular pressure elevation caused
by inhibited aqueous outflow is
far more common than pressure
increases secondary to anti-VEGF
The management of infectious
endophthalmitis has evolved during recent years, and currently
includes a vitreous biopsy (with or
without vitrectomy) as well as an
intravitreal antibiotic injection (i.e.,
vancomycin hydrochloride and/
or ceftazidime). Some retinal specialists advocate the use of 400mg
gatifloxacin p.o. q.d. and 1gt topical gatifloxacin q.i.d. As a general
guideline, consider the use of topical gatifloxicin for any patient who presents with a suspected case of
Patients who present with
pseudo-endophthalmitis can be
safely and effectively managed in a
similar fashion to those individuals
suspected of infectious endophthal-mitis. In the absence of intraocular
fibrin, however, I will initiate topical fluoroquinolones and topical
steroids q.i.d., and schedule the
patient for 24-hour follow-up. If
the patient experiences a decrease in
visual acuity or an increase in intra-ocular inflammation, you should
make a referral for vitreous biopsy
and intravitreal antibiotics.
When managing increased
intraocular pressure secondary to
intravitreal steroid injection, we
must familiarize ourselves with the
duration/efficacy of the compound
in the vitreous cavity. One study
indicated that at least 0.1cc of tri-amcinolone per 4mg dose was mea
surable in patients' vitreous cavities
for up to three months following
injection.22 In such cases, patients
required the use of topical intra-ocular pressure medications for an
average of eight months following
When deciding how to manage
any elevation in intraocular pressure, it really depends on the status
of the optic nerve, the visual field
and the retinal never fiber layer. A
patient with a healthy optic nerve,
for example, can withstand a transient pressure increase better than
a patient with known compromise
Nonetheless, patients with glaucoma and coexisting retinal disease
should undergo optic nerve head
photography, visual fields testing
and retinal nerve fiber layer analysis at baseline prior to intravitreal
injection. These tests can help predict which patients are at the great
est risk of further damage in the
event of even a modest increase in
Given that the etiology of elevated intraocular pressure is a compromise in aqueous outflow facility,
treatment should include the use of
topical agents that increase aqueous outflow. These agents include
Alphagan P (brimonidine tartrate 0.15%, Allergan), Timoptic (timo-lol 0.5%, Aton Pharma), Trusopt
(dorzolamide 2.0%, Merck) and
Azopt (brinzolamide 1.0%, Alcon).
Keep in mind, however, that pros-taglandin analogues should not be
used in patients with known macu-lar edema, because they may exacerbate the underlying condition.24,25
The concept of measuring intraocular pressure one week following
intravitreal injection is somewhat
controversial, and can be tiring
for the patient given the frequency
of examinations at the retina specialist's office. However, patients
with advanced glaucoma should
be monitored closely for pressure
increases following injection. You
should inform the comanaging
retina specialist of any documented
intraocular pressure spikes.
The O.D.'s Role
So, where do we fit into all of
this? Ultimately, our role in the
comanagement of intravitreal injection still remains undefined; however, we will continue to provide
primary eye care for these patients.
Similar to cataract surgery, we
have the responsibility of discussing potential treatment options
with our patients prior to considering a referral.
Additionally, providing the retina
specialist with pertinent ocular history as well as any documented
contraindications to intravitreal
injection, such as ocular hypertension or glaucoma, is extremely
|7. Intraretinal cystoid edema in a patient with wet AMD (top).
|8. Subretinal fluid seen in a patient who presented with wet AMD.
Further, completing a risk assessment of the patient is becoming
more common, and it should
include the following questions:
- Is there active blepharitis in
- Can the patient cooperate during intravitreal injection and not
interfere with the sterile technique?
- Will the patient recognize
symptoms of endophthalmitis and
report them to you immediately?
- Can the patient instill topical
antibiotics into the eye following
- Is the patient going to return for
scheduled follow-up appointments?
These are just a few baseline
questions that can be asked of every
patient being considered for intra-vitreal injection.
In addition to preparing the
patient for a commitment to intra-vitreal injection, it is equally important to recognize signs of existing
recurrent disease. Fortunately, we
now have access to cutting-edge
diagnostic technology, such as
spectral-domain optical coherence
tomography (SD-OCT) and fundus
autofluorescence, that more easily
enables us to identify subtle characteristics of retinal disease that may
be difficult to see clinically or even
with conventional retinal photography. For example, SD-OCT is vital
in the postoperative management
of patients with AMD, because we
can document intraretinal edema
(figure 7) or subretinal fluid (figure 8), which may help identify a recurrent neovascular membrane in the
absence of new symptoms.
Unlike cataract surgery, intravit-real injection often requires a series
of re-treatments over the course of
the patient's lifetime. For some individuals, this translates into several
years of care with a retina specialist
and comanagining O.D.
Although it is not our job to
decide upon the actual treatment
plan, we certainly can prepare our
patients for what to expect. In this,
we play an essential role in educating the patient about his or her
condition as well as the most effective treatment options that could
help maintain or even restore their
Dr. Haynie is the executive clinical director at Retina & Macula
Specialists, with office locations
in Tacoma, Renton, Olympia and
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