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Treatment of Submacular Hemorrhage With Low-Dose Intravitreal Tissue Plasminogen Activator Injection and Pneumatic Displacement
Beth A. Handwerger, MD;
Barbara A. Blodi, MD;
Suresh R. Chandra, MD;
Timothy W. Olsen, MD;
Thomas S. Stevens, MD
Arch Ophthalmol. 2001;119:28-32.
ABSTRACT
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Objective To investigate the safety and efficacy of low-dose intravitreal tissue
plasminogen activator (tPA) and an expansile gas bubble in displacing submacular
hemorrhage in patients with age-related macular degeneration (ARMD).
Patients and Methods We reviewed retrospectively the medical records of 14 consecutive patients
with ARMD from 1 academic center who received low-dose intravitreal tPA (18-50
µg) and expansile gas (0.3-0.4 mL of perfluoropropane) for thrombolysis
and displacement of submacular hemorrhage. After the procedure, patients maintained
face-down positioning for 1 to 3 days.
Main Outcome Measures Displacement of blood from the fovea, early and final visual acuity,
and toxicity of tPA.
Results Submacular blood was completely displaced from the fovea in 10 (71%)
of the 14 patients and partially displaced in 3 (21%). In 1 patient, no displacement
occurred. Early (<2 months) postoperative visual acuity improved by 2 or
more lines in 8 patients (57%). With a mean follow-up of 7.7 months, 2 (15%)
of 13 patients maintained 2 or more lines of improvement and 69% (9 patients)
maintained preoperative visual acuity. No clinical evidence of retinal toxicity
was seen at this low-dose of tPA.
Conclusions Doses of intravitreal tPA ranging from 18 to 50 µg and an expansile
gas bubble are safe and effective in displacing submacular hemorrhage in patients
with ARMD. Final visual acuity was limited by the underlying presence of end-stage
ARMD.
INTRODUCTION
THE VISUAL outcome in patients with age-related macular degeneration
(ARMD) and a submacular hemorrhage is typically poor.1
In patients with submacular hemorrhage, the prognosis is worse when the blood
cover is thick, covers a large area of the macula, and is accompanied by a
choroidal neovascular membrane.2-3
In 1996, Heriot4 presented a new procedure
to lyse and displace submacular blood without intraocular surgery by injecting
intravitreal tissue plasminogen activator (tPA) and a bubble of long-acting
expansile gas into the vitreous cavity. Heriot's technique uses 100 µg
of intravitreal tPA to liquify the submacular blood clot and an intravitreal
gas bubble combined with face-down positioning to directly compress the macula
and displace the submacular blood inferiorly.
Investigators have reported success in displacement of submacular blood
using this procedure in patients with ARMD, macroaneurysms, and trauma.5 However, there is a question of retinal toxicity from
the tPA at a dose of 100 µg.6 We have
modified Heriot's technique by using a lower dose of intravitreal tPA to determine
whether this method is safe and effective in the management of submacular
hemorrhage.
PATIENTS AND METHODS
We reviewed the medical and photographic records of 14 consecutive patients
at the University of Wisconsin, Madison, who underwent intravitreal injection
of low-dose tPA and long-acting expansile gas for thrombolysis and displacement
of submacular hemorrhage between February 1997 and December 1998. Four retinal
specialists (B.A.B., S.R.C., T.W.O., and T.S.S.) performed the 14 procedures.
Inclusion criteria consisted of symptomatic submacular hemorrhage for less
than 3 weeks, thick blood under the fovea resulting in retinal elevation,
and a hemorrhage of at least 3 disc areas. Patients with thick blood beneath
the retinal pigment epithelium were not excluded in this series. Although
the majority of eligible patients elected to undergo this experimental therapy,
the number of patients who refused treatment during this time is not known.
Each patient underwent complete ophthalmologic examination. Visual acuity
was obtained using the patients' current spectacle correction and pinhole.
Visual acuity testing was not standardized and patients were not refracted.
Visual acuity less than 20/400 on the Snellen chart was categorized by the
distance at which a patient was able to count fingers (eg, 1/200, 2/200, 3/200).
For data analysis, these acuities were grouped as "count fingers." For 2 patients,
the final visual acuity was obtained via a telephone call to the referring
ophthalmologists. Stereoscopic color fundus photographs were taken of all
patients at initial presentation except for 1 patient who presented on a weekend.
Fluorescein angiography was performed on 4 patients (29%) and fluorescein
angiography and indocyanine green angiography were performed on 5 patients
(36%). None of the initial angiograms demonstrated choroidal neovascular membranes
that were treatable by conventional photocoagulation.
After obtaining informed consent, the procedure was performed in the
outpatient clinic under retrobulbar anesthesia, using sterile technique. This
was followed by an anterior chamber paracentesis and a pars plana injection
of low-dose tPA (18-50 µg in a concentration of 20-30 µg/0.1 mL)
into the midvitreous cavity. Pure perfluoropropane (0.1-0.3 mL) was injected
into the midvitreous using the same technique. Each patient began prone positioning
within several hours of the procedure and maintained positioning for 24 to
72 hours as directed by the treating ophthalmologist. Follow-up care was determined
on an individual basis by the treating ophthalmologist.
The efficacy of the procedure was assessed by the following outcome
measures: (1) degree of subfoveal blood displacement, (2) best early posttreatment
(<2 months) visual acuity, (3) late posttreatment (>3 months) visual acuity,
and (4) absence of retinal toxicity. Two of us (B.A.H. and B.A.B.) assessed
the degree of blood displacement from the fovea by comparing stereoscopic
color fundus photographs taken prior to and 1 to 2 weeks after the procedure.
The degree of blood displacement from the fovea was graded as complete, partial,
or no displacement. Complete displacement was defined
as more than 90% of blood cleared from the subfoveal space, partial displacement as 20% to 90% clearance of blood, and no displacement as less than 20% displacement.
RESULTS
Fourteen eyes of 14 patients (7 men and 7 women) with ARMD and submacular
hemorrhage underwent intravitreal injection of low-dose tPA and long-acting
expansile gas bubble (Table 1).
Mean follow-up of patients was 7.7 months (range, 1-15 months). One patient
was lost to follow-up 1 month after treatment. The age of the patients ranged
from 71 to 97 years (mean age, 81 years), and the duration of symptoms from
submacular hemorrhage ranged from 1 to 21 days (mean, 9 days). The size of
the hemorrhage ranged from 3.5 to 44 disc areas (mean, 16 disc areas) and,
in all patients, the hemorrhage was thick (defined as elevation of the retina
on stereoscopic clinical examination).
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Data of Patients With Age-Related Macular Degeneration*
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The procedure resulted in complete displacement of blood from the center
of the macula in 10 (71%) of 14 patients (Figure 1). Partial displacement of the blood occurred in 21% (3
patients) and no displacement of the blood occurred in 7% (1 patient), following
the procedure.
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Figure 1. Patient 5. A 76-year-old man with
a thick submacular hemorrhage in the left eye of 12 days' duration. A, Pretreatment
appearance of submacular blood. Visual acuity was 20/200. B, Two days after
injection with 20 µg of tissue plasminogen activator and 0.3 mL of pure
perfluoropropane, the blood has nearly cleared from the center of the macula.
Visual acuity remained at 20/200. C, Six weeks following treatment, this wide-angle
photograph shows the blood has been completely displaced from the macula.
Visual acuity is 20/400 and follow-up fluorescein angiogram revealed a fibrovascular
pigment epithelial detachment.
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Immediately prior to treatment, the visual acuity of all 14 patients
with submacular hemorrhage ranged from 20/80 to 1/200. In 11 patients, the
visual acuity before the hemorrhage ranged from 20/25 to 20/80. The visual
acuity of the remaining 3 patients prior to the hemorrhage is not known. All
patients had signs of ARMD in the fellow eye, consisting of drusen, geographic
atrophy, retinal pigment epithelial changes, or choroidal neovascularization.
Six patients had lost central vision (<20/200) in the other eye due to
exudative macular degeneration.
In the first 2 months of follow-up, 8 (57%) of 14 patients gained 2
or more lines of visual acuity while 5 (36%) did not have any change in visual
acuity. One patient (7%) lost 2 or more lines of visual acuity. With long-term
follow-up, 2 (15%) of 13 patients maintained the improvement of 2 or more
lines in visual acuity, 9 patients (69%) maintained their preoperative visual
acuity, and 2 patients (15%) had a decline of visual acuity of more than 2
lines. One patient did not return after the 1-month visit. Visual loss in
these patients was due to chronic subfoveal choroidal neovascularization and
subretinal fibrosis.
Displacement of the blood uncovered the underlying macular pathology
in 13 (93%) of 14 patients. Of the 14 patients, 12 had a choroidal neovascular
membrane. Ten of these patients had a subfoveal fibrovascular pigment epithelial
detachment (Figure 2 and Figure 3), 1 patient had a juxtafoveal classic
choroidal neovascular membrane, 1 had a poorly demarcated subfoveal occult
choroidal neovascular membrane, and 1 had multiple pigment epithelial detachments.
The remaining patient had geographic atrophy, which was not identified early
in the posttreatment period because there was no displacement of blood. Posttreatment
fluorescein and indocyanine green angiograms were performed on 7 patients
(50%) in an attempt to identify a treatable lesion. None of these patients
had lesions that were deemed treatable with conventional laser.
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Figure 2. Patient 9. An 85-year-old woman
with a thick submacular hemorrhage in the right eye of 21 days' duration.
A, Pretreatment photograph shows subretinal and subretinal pigment epithelial
blood (notice the drusen overlying the blood centrally). Visual acuity was
20/100. B, Nine days after injection with tissue plasminogen activator and
perfluoropropane the subretinal blood has been completely displaced. The central
orange pigment represents persistent subretinal pigment epithelial blood within
the fibrovascular pigment epithelial detachment. Visual acuity improved to
20/80 at this time and declined to 20/400 after 15-month follow-up.
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Figure 3. Patient 14. A 76-year-old man
had 8 days of decreased vision in the right eye. A, Pretreatment photographs
show extensive submacular hemorrhage. Visual acuity was 1/200. B, Two weeks
following tissue plasminogen activator and perfluoropropane injection, the
blood under the fovea has cleared revealing a large subfoveal fibrovascular
pigment epithelial detachment. Visual acuity improved to 20/150. Final visual
acuity decreased to 1/200 after 7-month follow-up.
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There were no complications during the procedure itself. One patient
had corneal edema on the first day after the procedure, presumably from a
transient rise in intraocular pressure. One patient with a massive subretinal
hemorrhage had complete displacement of the blood from the center of the macula
yet developed a vitreous hemorrhage 2 weeks later. The hemorrhage did not
clear from the vitreous and the patient underwent pars plana vitrectomy. One
patient had a posterior retinal tear within the superotemporal arcade and
another patient had a rip in the retinal pigment epithelium, both of which
occurred several days after the procedure. No patient had a recurrent hemorrhage
in the postoperative period. There was no clinical evidence of retinal or
retinal pigment epithelial toxicity from the tPA in any of the 14 patients.
COMMENT
Our results using low-dose tPA and an expansile gas bubble in patients
with ARMD compare favorably with the visual acuity outcomes in 2 series using
higher doses of tPA. In our series, 9 (64%) of 14 patients had a final visual
acuity of 20/400 or better. Heriot7 reported
that 3 (17%) of 18 patients with ARMD had a visual acuity of 20/200 or better
while Hassan and colleagues5 report that 10
(71%) of 14 ARMD patients had a visual acuity of 20/400 or better. Although
initial visual acuity improved in the majority of our patients, with long-term
follow-up their visual acuity stabilized at their preoperative level.
The natural history of submacular hemorrhage in patients with ARMD carries
a worse prognosis than other conditions such as trauma or macroaneurysm. However,
retrospective reports on the visual outcome in untreated eyes with ARMD and
submacular hemorrhage are variable. Bennett and colleagues1
reported only 3 (25%) of 12 ARMD patients had a final visual acuity of 20/400
or better while Berrocal and coworkers3 reported
that 18 (90%) of the 20 ARMD patients had a visual acuity of 20/400 or better.
Animal studies have shown that the most immediate damage from subretinal
blood may be due to the shearing of photoreceptors during clot retraction.
Damage to the retina also occurs when thick subretinal blood forms a mechanical
barrier preventing metabolic exchange between the retina and retinal pigment
epithelium and by iron toxicity.8-9
The destructive effect of subretinal blood has prompted investigation into
new methods of removing submacular blood to minimize retinal damage and to
improve visual prognosis. In theory, removal of the blood should be timely
to decrease the photoreceptor damage caused by clot retraction and to uncover
any choroidal neovascularization that may be treatable by photocoagulation.
Pars plana vitrectomy has been performed in patients with recent submacular
hemorrhages to internally evacuate subretinal blood.10
Subretinal tPA has been used as a surgical adjunct during vitrectomy to dissolve
submacular clots, potentially minimizing photoreceptor cell shearing.11-12
Two studies of ARMD patients undergoing submacular surgery and intraoperative
tPA reported an initial postoperative improvement in visual acuity.11-12 However, at 6-month follow-up, Lim
and colleagues11 reported a deterioration in
visual acuity due to choroidal neovascularization, subretinal fibrosis, and
retinal pigment epithelial atrophy. Only 5 (31%) of 16 eyes with ARMD had
a final visual acuity of 20/400 or better.11
Lewis12 reported a visual outcome of 20/400
or better in 11 (44%) of 25 patients at greater than 6-month follow-up. In
both series, the overall rate of complications was 20% to 30% and included
rhegmatogenous retinal detachment, proliferative vitreoretinopathy, recurrent
subretinal hemorrhage, inadvertent retinectomy, cataract, and macular hole.11-12 Based on these small numbers, the
final visual acuity in our series is similar to those patients undergoing
submacular surgery.
The limited success in final visual outcome and the risk of complications
from surgical intervention has directed efforts toward a less invasive treatment
for submacular hemorrhage. Our experience confirms that the minimally invasive
technique developed by Heriot using intravitreal tPA and a gas bubble combined
with face-down positioning is effective at displacing thick subfoveal blood.
Using tPA and a gas bubble, displacement of blood from the center of the macula
occurred in 19 (95%) of 20 patients in Heriot's7
series and 100% (15 of 15 patients) in the series of Hassan et al.5 In our series, we had no serious complications such
as endophthalmitis, retinal detachment, or proliferative vitreoretinopathy.
Because of our concern for retinal toxicity, we chose to treat patients
with a significantly lower dose of tPA (18-50 µg) compared with that
used by Heriot7 and Hassan et al5
(50-100 µg). In rabbit eyes, 100 µg of tPA treated with expansile
gas can cause toxic retinal damage, including retinal holes, bullous retinal
detachment, attenuation of retinal blood vessels, and marked early reduction
in B-wave amplitude on the electroretinogram. In rabbits receiving 25 to 50
µg of tPA, there were no toxic retinal changes visualized on indirect
ophthalmoscopy, electroretinogram, or light microscopy.13
Although the human eye has a larger vitreous volume than the rabbit eye, a
patient treated with 100 µg of tPA for submacular hemorrhage demonstrated
severe pigmentary changes with marked visual loss (H. Gilbert, MD, unpublished
data presented at the Vitreous Society, 1997). With this lower dose of tPA,
we did not observe any retinal pigmentary changes or unexplained visual loss
in our patients. However, we did not perform electroretinograms on our patients
to measure retinal toxicity.
Despite reports of toxicity in animals and humans, the diffusion of
tPA from the vitreous through the neurosensory retina is not completely understood.
Kamei and colleagues14 reported that intravitreal
tPA labeled with fluorescein isothiocyanate did not diffuse into the subretinal
space in the rabbit. However, albumin (68 kd), a protein with a molecular
weight similar to tPA (70 kd) has been shown to diffuse across the retina
within 1 hour after intravitreal injection in rabbit eyes.15
Clot lysis of submacular hemorrhage in rabbits and pigs was visualized 24
hours after injection of intravitreal tPA while saline-treated eyes showed
no change in clot size.16-17 In
humans, Kimura et al18 treated 6 patients who
had acute (2-4 days) subretinal hemorrhages with intravitreal tPA 12 to 36
hours before surgery and noted liquefied blood at the time of surgery.
Investigators have recently attempted pneumatic displacement of submacular
hemorrhage without tPA. Ohji and colleagues19
reported a series of 5 patients treated with pure perfluoropropane gas and
prone positioning 4 to 18 days after the onset of hemorrhage. Blood displacement
from the fovea occurred partially or completely in all 5 patients. Ohji and
colleagues19 speculate that solid blood clots
that present more than 1 week may not be displaced with gas compression alone.
In our series, we cannot separate the effect of the tPA from the gas bubble
in the displacement of submacular hemorrhage. As a result, there is no direct
evidence that tPA is necessary for the success of the procedure.
In our series, there was no association between the duration of symptoms
or the area of hemorrhage to the final visual outcome. Our retrospective series
is small and did not have a control group or a standardized protocol for visual
acuity measurement and follow-up care. A randomized clinical trial comparing
similar eyes with and without treatment would help determine if this minimally
invasive procedure is beneficial.
At this time, the presence of underlying occult subfoveal choroidal
neovascularization (primarily fibrovascular pigment epithelial detachments)
appears to be the most important contributing factor to the visual prognosis
in patients with submacular hemorrhage. We have shown, however, that the displacement
of submacular hemorrhage with intravitreal low-dose tPA and an expansile gas
bubble is effective and safe. As new treatments for subfoveal choroidal new
vessels are now becoming available, this minimally invasive technique may
be useful in displacing the blood and uncovering previously untreatable lesions.
AUTHOR INFORMATION
Accepted for publication June 16, 2000.
Presented in part at the Association for Research and Vision in Ophthalmology
annual meeting, Fort Lauderdale, Fla, May 11, 1999.
Corresponding author and reprints: Barbara A. Blodi, MD, 2870 University
Ave, Suite 206, Madison, WI 53705.
From the Department of Ophthalmology and Visual Sciences, University
of Wisconsin, Madison (Drs Handwerger, Blodi, Chandra, and Stevens), and Department
of Ophthalmology, University of Minnesota, Minneapolis (Dr Olsen).
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