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125
UHM 2015, VOL. 42, NO. 2 – HBO2 FOR CHOROIDAL NEOVASCULARIZATION: A PILOT STUDY
Copyright © 2015 Undersea & Hyperbaric Medical Society, Inc.
Hyperbaric oxygen therapy for choroidal neovascularization: a pilot study
Fernando K. Malerbi, M.D. 1,2, Eduardo A. Novais, M.D. 1, Emmerson Badaró, M.D. 1,
Pedro Paulo de O. Bonomo, M.D. 1, Adriano J. Pereira, M.D. 2, Claudio L. Lottenberg, M.D. 2,
André Maia, M.D. 1
1 Department of Ophthalmology, Federal University of São Paulo, São Paulo, Brazil
2 Hospital Israelita Albert Einstein, São Paulo, Brazil
CORRESPONDING AUTHOR: Fernando K. Malerbi M.D. – fernandokmalerbi@gmail.com
______________________________________________________________________________________________________________________________________________________
ABSTRACT
Introduction: Choroidal neovascularization (CNV) is
one of the leading causes of blindness worldwide and
affects patients with wet age-related macular degen-
eration (AMD). Its natural course may lead to impaired
central vision and macular brosis. Even VEGF block-
ade, currently the best available treatments for CNV,
may fail to improve vision. Hyperbaric oxygen (HBO2)
therapy may be an alternative or ancillary treatment for
CNV.
Methods: AMD patients with active CNV underwent
10 daily sessions of HBO2 at 2 atmospheres absolute
(atm abs) for 120 minutes each session. After the end of
the sessions, patients with clinical or tomographical
signs of CNV activity underwent standard anti-VEGF
treatment.
Results: Seven patients (average age 73) underwent
10 daily 120-minute sessions of HBO2 at 2 atm abs. After
the sessions, ve patients underwent intravitreal injection
of bevacizumab. Average follow-up was 150 days. Average
CNV area at baseline was 14.42 mm2; average CNV
greatest linear diameter at baseline was 4.56 mm. Stat-
istical analysis of variance (ANOVA) was performed for
central retinal thickness and volume mean percentage
changes post-treatment. At the end of follow up, ve
patients showed anatomical improvement, one patient
maintained anatomical aspect and one patient showed
anatomical worsening.
Conclusion: HBO2 may be a safe and tolerable treat-
ment option for patients with active CNV, potentially
delaying its progression, as monotherapy or in combin-
ation with intravitreal bevacizumab.
______________________________________________________________________________________________________________________________________________________
________________________________________________________
KEYWORDS: age-related macular degeneration, AMD, choroidal
neovascularization, CNV, vascular endothelial growth factor, VEGF,
hyperbaric oxygen therapy
INTRODUCTION
Age-related macular degeneration (AMD) is the lead-
ing cause of irreversible blindness in patients older than
50 years in western countries [1-3]. It is expected that
2.95 million people around the world will have AMD by
the year 2020 [4]. The two presentations of this disease
are “dry” or non-exudative AMD, and “wet” exudative
or neovascular AMD. In dry AMD, a progressive atrophy
of the retinal pigment epithelium (RPE) is present,
causing a decrease in visual acuity. Neovascular AMD
presents with a growth of blood vessels in the subretinal
space, known as choroidal neovascularization (CNV),
and uid, blood or lipid accumulation in the subretinal
space, as well as the presence of scar tissue or brosis;
these features account for visual impairment when the
center of the macula is involved [5,6]. Typically, in-
traocular levels of vascular endothelial growth factor
(VEGF) are increased in wet AMD, leading to increased
vascular permeability [7]. In order to evaluate CNV,
besides thorough clinical ophthalmological evaluation,
patients undergo uorescein angiograms (Figure 1)
and optical coherence tomography (OCT), an imaging
technique that produces high-resolution cross-sectional
images of the retina (Figure 2).
Historically, a variety of treatments have been pro-
posed for wet AMD such as laser photocoagulation,
photodynamic therapy and intravitreal steroid injec-
tion; current treatment for wet AMD is based on intra-
vitreal VEGF blockade [7]. Currently, however, there
are no long-acting drugs, so patients have to undergo
monthly or bimonthly intravitreal injections. Each
126
UHM 2015, VOL. 42, NO. 2 – HBO2 FOR CHOROIDAL NEOVASCULARIZATION: A PILOT STUDY
F.K. Malerbi, E.A. Novais, E. Badaró, et al.
injection carries the risk of serious ocular events such
as endophthalmitis or retinal detachment. Furthermore,
such treatment has a heavy economic burden on the
patient and the health system. Even with the best treat-
ment available, visual acuity gains were modest: Only
34% of patients gained 15 letters in a 12- to 24-month
period, which means that 65% of patients had very
modest visual acuity gains, no gain at all, or their visual
acuity worsened [8].It has been reported that repeated
anti-VEGF injections can increase the odds of geo-
graphic atrophy [9].
VEGF blockade may be partly ineffective because
there are many pathophysiologic steps involved in the
vision loss process caused by AMD — for example,
scar tissue formation or chorioretinal atrophy, which are
not related to VEGF.
Hyperbaric oxygen (HBO2) therapy is a primary or
adjuvant therapeutic method used in the treatment of
various acute or chronic disorders. The Undersea and
Hyperbaric Medical Society (UHMS) approves use of
hyperbaric oxygen for some conditions for which there
is thought to be reasonable scientic evidence or well-
validated clinical experience [10]. HBO2 may be used
in order to enhance healing in refractory wounds such
as diabetic foot ulcers and Fournier’s gangrene, for ex-
ample. The theoretical mechanism of action is through
an increased oxygen delivery to the affected tissue.
Figure 1. Examples of retinal angiograms showing juxtafoveal
(1A) and subfoveal (1B, 1C, 1D) choroidal neovascularization
(CNV).
It has been suggested that HBO2 could be an option
for some ocular diseases caused by tissue hypoxia. The
mechanisms of action proposed are: providing a great-
er efcacy of oxygen delivery, activating endogenous
antioxidants, decreasing lipid peroxidation and regu-
lating inammation [11], and increasing retinal oxygen-
ation [12,13]. Supplementary oxygen has been used
to treat some cases of retinal artery occlusion with
favorable results [12,14].
The choroid provides 85% of ocular blood supply;
impaired choroidal blood ow is related to glaucoma,
diabetic retinopathy and AMD [4,15,16]. Choroidal
blood ow is inversely proportional to AMD severity
in humans [17], and it is postulated that VEGF produc-
tion is increased in wet AMD in response to choroidal
hypoxia [16]. The rationale for HBO2 as a treatment
for CNV is to increase oxygen delivery to the choroid.
The main objective in this pilot study was to eval-
uate safety and efcacy of 10 sessions of 120-minute,
2-atm abs HBO2 for active CNV secondary to AMD.
The main outcome measures would be anatomical
results evaluated by clinical and optical coherence to-
mography (OCT) examinations and functional results
evaluated by visual acuity (VA) measurements.
Our secondary goal was to evaluate the safety and
efcacy of HBO2 and anti-VEGF combination therapy,
with the same outcome measures as stated above.
METHODS
This was an interventional study that treated seven
patients using a monoplace hyperbaric chamber in the
ICU on the premises of Hospital Israelita Albert
Einstein, São Paulo, Brazil.
Inclusion criteria for this study were: active CNV
secondary to AMD, dened as retinal thickening and/or
subretinal hemorrhage or exudates, neurosensory retinal
detachment, recent decrease in visual acuity associated
with clinical features of CNV, presence of subretinal or
intraretinal uid on OCT, or uorescein angiogram
leakage.
Exclusion criteria for HBO2 were: untreated tension
pneumothorax, past history of seizures, impaired
pressure equalization, tympanic membrane disease,
cardiac disease and claustrophobia.
Informed consent was obtained for all patients, and
the Ethics Committee of Hospital Israelita Albert
Einstein approved the study.
Before treatment all patients underwent complete
ophthalmologic examination including best-corrected
UHM 2015, VOL. 42, NO. 2 – HBO2 FOR CHOROIDAL NEOVASCULARIZATION: A PILOT STUDY
127
F.K. Malerbi, E.A. Novais, E. Badaró, et al.
Figure 2. Patient 1, baseline OCT (above) and follow-up OCT (below) showing resolution of subretinal fluid after HBO2.
visual acuity (BCVA), fundus examination, uorescein
angiography and OCT. All patients underwent
standard clinical evaluation for hyperbaric treatment
including otoscopy.
Fluorescein angiography was obtained after a 2-ml
intravenous injection of 25% uorescein sodium;
retinal images were obtained with Heidelberg HRA2
(Heidelberg Engineering, Germany). Image analysis
was performed with HRA software.
Optical coherence tomography (OCT) scans were
obtained with spectral-domain OCT Spectralis (Heidel-
berg Engineering, Germany) and analysis was based
on the automated central retinal thickness protocol
(CRT) and volume protocol.
Hyperbaric sessions were performed in a monoplace
hyperbaric system (model 2500B, Sechrist Industries,
Inc, Anaheim, California, USA). Treatment parameters
were those suggested by UHMS for the treatment of
retinal vascular occlusion: daily 2.0-atm abs sessions
lasting 120 minutes each. Treatment cycle was set as
10 sessions in a 12-day period (with weekend breaks).
After 10 HBO2 sessions, patients underwent the
same ophthalmologic examination protocol as before
treatment. Patients who had a favorable response were
observed and re-evaluated after a 30-day period. Those
who had developed any indication for CNV treatment
– persistence or worsening of uorescein leakage,
intraretinal or subretinal uid on OCT, or new retinal
hemorrhages – would then undergo conventional treat-
ment with intravitreal bevacizumab injections
(1.25 mg/0.05 mL), as detailed elsewhere [7].
Patients who responded poorly or who had no re-
sponse to HBO2 treatment would start anti-VEGF treat-
ment as soon as the hyperbaric sessions were completed.
Only one eye of each patient was taken into account
for results analysis. If both eyes presented with active
CNV, eyes with the higher baseline BCVA and/or a
better anatomical aspect on baseline OCT ndings –
for example, absence of microcystic degeneration,
absence of large membranes – were considered.
Statistical analysis was performed with SPSS for
Windows software version 11; for mean percentage
change, t-test for paired samples and ANOVA analysis
were used. ANOVA was performed after a Kolmo-
gorov-Smirnov test conrmed that distribution was
normal.
RESULTS
A total of 10 patients initiated treatment; seven com-
pleted the 10-session protocol. The three patients who
left treatment were referred for conventional treatment
with anti-VEGF for two different reasons: one patient
presented with otorrhagia after the rst session, and the
other two presented with claustrophobia after one to
two sessions. A total of seven patients (four female,
three male, average age 73 years, median age 74 years,
range 52-85 years) completed the protocol of 10 sessions
in a period of 12 days, with a weekend break. Each
session had duration of 120 minutes and a pressure
of 2.0 atm abs. Follow up ranged from 90 days to
240 days, averaging 150 days, median 150 days.
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UHM 2015, VOL. 42, NO. 2 – HBO2 FOR CHOROIDAL NEOVASCULARIZATION: A PILOT STUDY
F.K. Malerbi, E.A. Novais, E. Badaró, et al.
Baseline visual acuity was equal or worse to 20/60
in ve out of seven patients, ranging from 20/20 to
20/800. At the end of follow-up, ve patients had main-
tained their BCVA, one patient had improved BCVA
(Patient 6), and one had worsened BCVA (Patient 4).
The average CNV area at baseline was 14.42 mm2;
average CNV greatest linear diameter (GLD) at baseline
was 4.56 mm. Area change post-HBO2 was not statis-
tically signicant (p=0.613). Table 1 shows initial
and nal visual acuity, CNV localization, CNV area
pre- and post-HBO2, and GLD.
Soon after the end of HBO2 sessions, ve out of seven
eyes showed an equal or reduced CRT, and three out
of seven eyes showed a reduced retinal cube volume.
At the end of follow up, ve out of seven eyes showed an
equal or reduced CRT, and ve out of seven eyes showed
a reduced retinal cube volume. CRT and volume mean
percentage changes (with 95% condence intervals)
were -8.44% (-25.26%, 8.38%) and -5.47% (-21.68%,
10.74%), respectively. ANOVA analysis (Greenhouse-
Geiser test) showed that CRT and volume changes after
HBO2 and at the end of follow-up were not statis-
tically signicant.
In a qualitative anatomical analysis based on OCT
ndings soon after HBO2 sessions, two eyes out of
seven showed a better anatomical aspect, while
three showed a maintained aspect and two showed
a worsened aspect. After full combined treatment of
HBO2 and anti-VEGF, ve eyes showed improved
anatomical aspect, while one showed a maintained
aspect and one showeda worsened anatomic aspect at
the end of follow-up.
_______________________________________________________________________________________________________________________
Identification Age Baseline Final CNV CNV area CNV area CNV GLD
(years) visual visual localization (mm2) (mm2) (mm)
acuity acuity pre-HBO2 post-HBO2
_______________________________________________________________________________________________________________________
Patient 1 71 20/800 20/800 subfoveal 5.41 12.82 3.15
_______________________________________________________________________________________________________________________
Patient 2 74 20/20 20/20 juxtafoveal 4.52 5.64 3.04
_______________________________________________________________________________________________________________________
Patient 3 74 20/640 20/640 subfoveal 32.71 34.94 7.28
_______________________________________________________________________________________________________________________
Patient 4 71 20/125 20/200 subfoveal 8.59 9.46 3.53
_______________________________________________________________________________________________________________________
Patient 5 52 20/200 20/200 subfoveal 13.06 10.98 4.89
_______________________________________________________________________________________________________________________
Patient 6 85 20/25 20/20 extrafoveal 31.2 27.11 7.28
_______________________________________________________________________________________________________________________
Patient 7 84 20/60 20/60 subfoveal 5.48 5.23 2.76
_______________________________________________________________________________________________________________________
CNV - choroidal neovascularization; GLD - greatest linear diameter; HBO2 - hyperbaric therapy
Table 1. Patient age and visual acuity, choroidal neovascularization (CNV) localization, area
and greatest linear diameter (GLD).
Patient 1, a 71-year-old woman with a large sub-
foveal CNV in the left eye (Figure 1D), underwent
HBO2 treatment alone, with anatomical improvement
(Figure 2). Patient 2, a 74-year-old man with juxta-
foveal CNV in the right eye (Figure 1A), showed
anatomical improvement after combined HBO2 and
anti-VEGF treatment. Patient 3, a 74-year-old woman
with CNV and cystic retinal degeneration in the right
eye (Figure 1B), showed good anatomical response to
combined treatment. Patient 4, a 71-year-old woman
with a large subfoveal CNV in the left eye (Figure 1C),
showed worsened anatomy (cystic retinal degenera-
tion) after combined treatment, at the end of follow-up.
Patient 5, a 52-year-old man with a CNV and subretinal
brosis in the right eye, showed a similar anatomical
pattern after combined treatment, at the end of
follow-up. Patient 6, an 85-year-old man with extra-
foveal CNV in the left eye, showed a good nal
anatomical result after combined treatment, at the end
of follow-up. Patient 7, an 84-year-old woman with
refractory CNV and a large pigment epithelium
detachment in the left eye, maintained anatomical
pattern after HBO2 treatment alone.
DISCUSSION
This study found a favorable anatomical outcome in
CNV patients treated with HBO2 in combination with
intravitreal bevacizumab. Five out of seven patients
who completed the study showed an improved anatom-
ical aspect of the macula, and another patient showed
stability. Only one patient (Number 4) showed a
UHM 2015, VOL. 42, NO. 2 – HBO2 FOR CHOROIDAL NEOVASCULARIZATION: A PILOT STUDY
129
F.K. Malerbi, E.A. Novais, E. Badaró, et al.
worsened anatomical aspect at the end of the study.
We also found HBO2 to be a safe treatment for
CNV patients. Our only side effects were otorrhagia
(one patient) and claustrophobia (two patients); all
three patients left HBO2 treatment.
Our hyperbaric medicine group has previously found
claustrophobia to be the main reason for treatment
discontinuity (up to 40% of patients feel some degree
of claustrophobia in our monoplace cabinets practice).
The most prevalent complications of HBO2 found by
our group were ear pain (20%) and tympanic lesions
(4%) (unpublished data, personal communication).
These ndings are mostly in accordance with pre-
viously published data [18]. HBO2 is considered a safe
treatment [19]. Reported side effects are: seizures;
barotrauma of middle ear, sinuses and lungs; and
claustrophobia in monoplace cabinets. Ocular side
effects include retinal toxicity (caused by very high
oxygen levels – experimental data), transient induced
myopia and cataract formation [10].
In our series, baseline CNV location, area or great-
est linear diameter did not inuence treatment outcome
(Table 1). If the anatomical results of isolated HBO2
are considered, soon after the end of the 10-session
protocol, on a preliminary evaluation, two patients had
improved macular anatomy, three maintained and two
had worsened macular anatomy. CNV area change after
isolated HBO2 treatment was not statistically signi-
cant. However, even though he had shown anatomical
improvement, Patient 6 still showed CNV activity
at the end of HBO2 treatment and underwent fur-
ther treatment with intravitreal bevacizumab. This
prevented a longer follow-up analysis of the isolated
HBO2 effects for this specic patient. At the end
of HBO2 sessions, ve patients underwent addi-
tional therapy with intravitreal bevacizumab.
Both patients treated with HBO2 as a monotherapy
had anatomical and BCVA stability at the end of follow-
up. Patient 1 showed poor prognosis at baseline be-
cause of a large neovascular membrane underneath the
fovea and Patient 7 had showed no response to all other
treatment modalities before. Patient 1 showed a modest
improvement, with diminished subretinal uid, at the
90-day follow-up visit, suggesting a possible sustained
effect of HBO2 even after the end of the sessions
(Figure 2).
When used as a treatment to some well-established
conditions, HBO2 usually shows good results if used in
protocols with a larger number of sessions, averaging
20-40 sessions [20]. Ours was a pilot study and eval-
uated the effects of HBO2 on CNV after 10 sessions
only; the reduced number of sessions may have had
a negative impact on the results. Further studies eval-
uating the effect of HBO2 for CNV with a greater
number ofsessions could provide an answer to this
question.
Five out of seven patients who completed the
study maintained BCVA at the end of treatment;
one had an increased BCVA and another showed
BCVA worsening. In the subgroup of ve patients
who presented with poor prognosis at baseline (micro-
cystic degeneration – Patient 3; large neovascular
membranes underneath the fovea – Patients 1 and 4;
subretinal brosis – Patient 5; failure to respond to
other treatments – Patient 7), four maintained BCVA
and one showed BCVA worsening. Two patients
(Numbers 2 and 6) entered the study with good visual
acuity, one of them with 20/20 and another with
20/25 that eventually improved to 20/20. Because
of the inclusion of these two patients with no de-
creased vision at baseline, we might have had some
negative inuence on the issue of BCVA improvement
since there was no margin for improvement.
Wet AMD is a chronic, aggressive disease. Even
patients treated with VEGF inhibitors still carry the
risk of visual decline and disease activity in the long
term [21]. Since our study included patients with poor
prognosis features at baseline such as microcystic
degeneration, subretinal brosis or large neovascular
membranes underneath the fovea [21], we could
hardly expect great improvements; having included
these patients might have had a negative impact
on the results of this study. Further studies that
include only patients without such poor prognosis
features at baseline could lead to better results.
As a pilot study, one major limitation of this study
is that it was not designed to evaluate the efcacy of
HBO2 treatment for CNV as a monotherapy with a long
follow-up because of ethical concerns: If a patient com-
pleted hyperbaric treatment and remained with clinical
or tomographic signs of CNV activity or CNV worsen-
ing, he or she would have prompt anti-VEGF treatment,
which is the present gold-standard treatment for CNV.
In order to solve this issue, it would be necessary to
perform a study with different inclusion criteria: i.e.,
one that would include only patients with contra-
indications to intravitreal injections (such as scleral
disease, for example) or those not willing to undergo
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UHM 2015, VOL. 42, NO. 2 – HBO2 FOR CHOROIDAL NEOVASCULARIZATION: A PILOT STUDY
F.K. Malerbi, E.A. Novais, E. Badaró, et al.
intravitreal injections. Our follow-up period was not
long enough to determine whether HBO2 monotherapy
showed efcacy because most patients underwent
further treatment with intravitreal bevacizumab after
the end of HBO2 sessions. Due to the lack of a
control group, and to a relatively short follow-up
period (unfortunately, some patients became lost to
follow-up), it was not possible to evaluate whether
HBO2 resulted in less of an anti-VEGF treatment
burden.
There are currently no reported controlled clinical
trials evaluating the efcacy of HBO2 for AMD treat-
ment. However, Weiss [22] evaluated the effects of
HBO2 for 14 AMD patients with both dry and wet
types. In that study, different treatment parameters were
used as compared to the present study, and reported
visual acuity and/or visual eld gains were achieved in
all patients. In that study, all patients were treated with
100% oxygen in a monoplace cabin; eight patients
underwent four daily one-hour 1.75-atm abs sessions,
and six patients underwent six daily one-hour 1.5-atm
abs sessions. One patient from the 1.5-atm abs group
underwent six additional sessions.
Compared to the present study, the duration of each
session was shorter (60 minutes vs. 120 minutes), as
well as the pressure values (1.5 to 1.75 atm abs vs.
2.0 atm abs). Oxygen pressure values in that study
(1.5 to 1.75 atm abs) were inferior to the pressure
suggested by UHMS for retinal artery occlusion
(2.0 atm abs – the value used in the present study),
in order to decrease the risk of cerebral glycolysis and
free-radical damage [23]. Our study treated patients
with longer sessions and with a greater number of
sessions.
Our BCVA outcomes were worse than those found
by Weiss [22]. We hypothesize that some baseline
features of our patients may have inuenced this
different outcome, as discussed above: We enrolled
some patients with poor prognosis at baseline because
of such OCT ndings as microcystic degeneration,
large neovascular membranes underneath the fovea
or subretinal brosis, and we studied patients who
had a very good BCVA at baseline. Furthermore,
only wet AMD patients were included in our study.
CONCLUSION
The present study could determine that, for a small
group of patients with active CNV and a limited
follow-up period, HBO2 was a safe and tolerable
treatment option as monotherapy or in combination
with intravitreal bevacizumab. We believe that HBO2
acts through increased choroidal oxygen delivery.
Further studies could evaluate whether HBO2 therapy
is an option as monotherapy for active CNV: if HBO2
could delay the progression of CNV, alone or in
combination with anti-VEGF agents; if HBO2 could
decrease the burden of intravitreal injections; and
nally, further studies could also determine the best
parameters, such as treatment duration, session dur-
ation and oxygen pressure.
Conict of interest
The authors have declared that no conict of interest exists
with this submission. n
______________________________________________________________________________________________________________________________________________________
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