ArticlePDF Available

Progression to macula-off tractional retinal detachment after a contralateral intraoperative intravitreal bevacizumab injection for proliferative diabetic retinopathy

Taylor & Francis
Clinical Ophthalmology
Authors:
Michael W Stewart at Mayo Foundation for Medical Education and Research
Michael W Stewart
Michael L Stewart
Michael L Stewart
Michael L Stewart
  • This person is not on ResearchGate, or hasn't claimed this research yet.
Download full-text PDF
Read full-text
Download citation

Figures

Figures - available from: Clinical Ophthalmology
This content is subject to copyright. Terms and conditions apply.
Access to this full-text is provided by Taylor & Francis.
Learn more
Content available from Clinical Ophthalmology 
This content is subject to copyright. Terms and conditions apply.
© 2015 Stewart and Stewart. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0)
License. The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further
permission from Dove Medical Press Limited, provided the work is properly attributed. Permissions beyond the scope of the License are administered by Dove Medical Press Limited. Information on
how to request permission may be found at: http://www.dovepress.com/permissions.php
Clinical Ophthalmology 2015:9 409–411
Clinical Ophthalmology Dovepress
submit your manuscript | www.dovepress.com
Dovepress 409
LETTER
open access to scientific and medical research
Open Access Full Text Article
http://dx.doi.org/10.2147/OPTH.S81547
Progression to macula-off tractional retinal
detachment after a contralateral intraoperative
intravitreal bevacizumab injection for proliferative
diabetic retinopathy
Michael W Stewart
Michael L Stewart
Department of Ophthalmology,
Mayo Clinic, Jacksonville, FL, USA
Dear editor
In a recent edition of Clinical Ophthalmology, Zlotcavitch et al presented a case
of progressive diabetic traction retinal detachment in the fellow eye 1 week after
vitrectomy with intravitreal bevacizumab.1 This interesting observation extends
previous original work by the same authors in which proliferative diabetic retinopathy
was noted to regress following a bevacizumab injection into the fellow eye.2 Several
points pertaining to this thought-provoking report deserve further discussion.
Bevacizumab exits the eye through the trabecular meshwork and choroidal circulation,
and enters the bloodstream unchanged. Since the intravitreal half-life of bevacizumab
in human eyes is considerably shorter than the intravascular half-life (9.8 days3 vs
20 days4), the drug accumulates in the circulation. Concentrations increase initially, peak
at approximately 2 weeks, and then decrease exponentially as intraocular concentrations
fall further. Bevacizumab circulates to the fellow eye and enters both the vitreous and
anterior chamber, although it remains unclear whether intravitreal or intravascular drug
is primarily responsible for vascular inhibition. Since intravascular bevacizumab contacts
neovascular endothelium directly, the blood concentration of bevacizumab, and not the
intravitreal concentration, may be the primary determinant of contralateral effects.
Rabbit5 and monkey6 models, along with a small human study,7 show that bevaci-
zumab exits the eye more rapidly following vitrectomy. The magnitude of the intra-
vitreal half-life reduction varies between reports, but the 46% decrease contended by
Zlotcavitch et al resulting in a human half-life of 5.3 days, is a reasonable assumption.
With these rates in mind, we mathematically modeled the time-dependent intravitreal
and intravascular bevacizumab concentrations in patients before and after vitrectomy.
Using the half-lives mentioned above, the concentrations of bevacizumab following
a 1.25 mg intravitreal injection are as follows:
Pre-vitrectomy: eye [B]V =0.3125 * e-0.0707t; serum [B]S =0.00078 * (e-0.033t - e-0.0707t)
Post-vitrectomy: eye [B]V =0.3125 * e-0.131t; serum [B]S =0.0005577 * (e-0.033t - e-0.131t)
where [B]V is the intravitreal concentration of bevacizumab and [B]S is the serum
concentration of bevacizumab. The time-dependent concentrations of bevacizumab
in both vitreous and serum can be seen in Figure 1.
Correspondence: Michael W Stewart
Department of Ophthalmology, Mayo
Clinic, 4500 San Pablo Rd, Jacksonville,
FL 32224, USA
Tel +1 904 953 2232
Fax +1 904 953 7040
Email stewart.michael@mayo.edu
Journal name: Clinical Ophthalmology
Article Designation: Letter
Year: 2015
Volume: 9
Running head verso: Stewart and Stewart
Running head recto: Macula-off tractional retinal detachment after contralateral bevacizumab injection
DOI: http://dx.doi.org/10.2147/OPTH.S81547
This article was published in the following Dove Press journal:
Clinical Ophthalmology
27 February 2015
Number of times this article has been viewed
Clinical Ophthalmology 2015:9
submit your manuscript | www.dovepress.com
Dovepress
Dovepress
410
Stewart and Stewart
Several important observations regarding serum concen-
trations and the resultant exposure of the fellow eye to beva-
cizumab can be made from the graph. In a post-vitrectomy
patient, the serum concentration rises faster and peaks earlier
than in a pre-vitrectomy patient, with maximum concentra-
tions at 14 days and 20 days, respectively. More importantly,
the serum concentration at 7 days in a post-vitrectomy patient
is 1.53 times that in a pre-vitrectomy patient and the area
under the curve ratio through 7 days is 1.6 times. Therefore,
a vitrectomy significantly increases the exposure of the fel-
low eye to bevacizumab during the first week, which helps
to explain the observation made by Zlotcavitch et al.
As a monoclonal antibody against vascular endothelial
growth factor (VEGF), bevacizumab works by decreasing
the concentration of unbound (metabolically active) VEGF.
In eyes with proliferative diabetic retinopathy, the degree
of fibrosis depends upon the relative amounts of connective
tissue growth factor and VEGF. The introduction of bevaci-
zumab alters the ratio of connective tissue growth factor to
VEGF in favor of fibrosis,8 as occurred in this case.
Disclosure
The authors report no conflicts of interest in this commun-
ication.
References
1. Zlotcavitch L, Flynn HW Jr, Avery RL, Rachitskaya A. Progres-
sion to macula-off tractional retinal detachment after a contralateral
intraoperative intravitreal bevacizumab injection for proliferative diabetic
retinopathy. Clin Ophthalmol. 2015;9:69–71.
2. Avery RL, Pearlman J, Pieramici DJ, et al. Intravitreal bevacizumab
(Avastin) in the treatment of proliferative diabetic retinopathy.
Ophthalmology. 2006;113:1695.e1–e15.
3. Krohne TU, Eter N, Holz FG, Meyer CH. Intraocular pharmacokinet-
ics of bevacizumab after a single intravitreal injection in humans. Am
J Ophthalmol. 2008;146:508–512.
4. Avastin. Bevacizumab solution for intravenous infusion prescribing
information. Available from: http://www.gene.com/download/pdf/
avastin_prescribing.pdf. Accessed January 21, 2015.
5. Christoforidis JB, Xie Z, Jiang A, et al. Serum levels of intravitreal
bevacizumab after vitrectomy, lensectomy and non-surgical controls.
Curr Eye Res. 2013;38:761–766.
6. Kakinoki M, Sawada O, Sawada T, Saishin Y, Kawamura H, Ohji M.
Effect of vitrectomy on aqueous VEGF concentration and pharmacoki-
netics of bevacizumab in macaque monkeys. Invest Ophthalmol Vis Sci.
2012;53:5877–5880.
7. Beer PM, Wong SJ, Hammad AM, Falk NS, O’Malley MR, Khan S. Vit-
reous levels of unbound bevacizumab and unbound vascular endothelial
growth factor in two patients. Retina. 2006;26:871–876.
8. Van Geest RJ, Lesnik-Oberstein SY, Tan HS, et al. A shift in the balance
of vascular endothelial growth factor and connective tissue growth factor
by bevacizumab causes the angiofibrotic switch in proliferative diabetic
retinopathy. Br J Ophthalmol. 2012;96:587–590.

9LWUHRXVSUHYLWUHFWRP\
6HUXPSUHYLWUHFWRP\
6HUXPSRVWYLWUHFWRP\
9LWUHRXVSRVWYLWUHFWRP\













 
'D\V
9LWUHRXVEHYDFL]XPDEJ/
6HUXPEHYDFL]XPDEJ/×
 
Figure 1 Time-dependent vitreous and serum bevacizumab concentrations in
patients before and after vitrectomy.
Notes: In post-vitrectomy patients, the vitreous concentration falls more rapidly,


Clinical Ophthalmology
Publish your work in this journal
Submit your manuscript here: http://www.dovepress.com/clinical-ophthalmology-journal
Clinical Ophthalmology is an international, peer-reviewed journal
covering all subspecialties within ophthalmology. Key topics include:
Optometry; Visual science; Pharmacology and drug therapy in eye
diseases; Basic Sciences; Primary and Secondary eye care; Patient
Safety and Quality of Care Improvements. This journal is indexed on
PubMed Central and CAS, and is the official journal of The Society of
Clinical Ophthalmology (SCO). The manuscript management system
is completely online and includes a very quick and fair peer-review
system, which is all easy to use. Visit http://www.dovepress.com/
testimonials.php to read real quotes from published authors.
Clinical Ophthalmology 2015:9 submit your manuscript | www.dovepress.com
Dovepress
Dovepress
Dovepress
411
Macula-off tractional retinal detachment after contralateral bevacizumab injection
Authors’ reply
Leonid Zlotcavitch1
Harry W Flynn Jr2
Robert L Avery3
Aleksandra Rachitskaya2
1University of Miami, Miller School of Medicine, 2Bascom Palme r
Eye Institute, Department of Ophthalmology, University of Miami,
Miller School of Medicine, Miami, FL, USA; 3California Retina
Consultants, Santa Barbara, CA, USA
Correspondence: Harry W Flynn Jr
900 NW 17th St, Miami, FL 33136, USA
Tel +1 305 326 6303
Fax +1 305 326 6417
 ynn@med.miami.edu
Dear editor
We read with interest the comments of Stewart et al regarding
our case of progressive diabetic traction retinal detachment
in the fellow eye 1 week after vitrectomy with the use of
intravitreal bevacizumab.1 The letter to the editor estimates
the vitreous and serum time-dependent concentrations of
bevacizumab after an intravitreal injection in vitrectomized
and non-vitrectomized eyes. These calculations support the
clinical course observed in our patient. Further studies are
necessary to quantitatively assess the possible bilateral effect
of intravitreal medications and the effects of vitrectomy
on the pharmacodynamics of anti-vascular growth factor
agents. Although the bilateral response to a unilaterally
injected medication is usually beneficial, one should be
cognizant of potential progression of diabetic traction retinal
detachment.
Disclosure
The authors report no conflicts of interest in this communi-
cation.
Reference
1. Zlotcavitch L, Flynn HW Jr, Avery RL, Rachitskaya A. Progression
to macula-off tractional retinal detachment after a contralateral intra-
operative intravitreal bevacizumab injection for proliferative diabetic
retinopathy. Clin Ophthalmol. 2015;9:69–71.
Available via license: CC BY-NC 3.0
Content may be subject to copyright.
... 25 Geographic atrophy may also be the result of anti-VEGF therapy. 18,26,27 Furthermore, therapeutic 28 and adverse effects [29][30][31] of the intravitreal administration of anti-VEGF or corticosteroids have been documented in the contralateral eye and have been attributed to systemic absorption of the drug. ...
... We also observed in our study some degree of micro-and macroglial reaction not only in the injected retina but also in the contralateral retina; thus it is tempting to suggest that the IVI may itself trigger, at least in part, the micro-and macroglial reaction observed in the ipsi-and contralateral retina and may thus explain some ipsi-and contralateral effects observed after IVI in clinical practice. 18,[26][27][28][29][30][31] Nevertheless, the technique that we use for IVI in rats is not comparable to that used in clinical practice. In rats, in order to avoid injury to the crystalline lens, we inject at 1 to 2 mm from the limbus and, because in rats the distance between the limbus and the retina is shorter than 1 mm, 78 when we enter the eye we perforate the retinal periphery. ...
... This was the case after optic nerve axotomy, 37,63 topical instillation of saline drops, 57 ocular hypertension induced by laser photocoagulation to the limbal tissues, 58,60-62 or after anti-VEGF injection. [29][30][31] At present we do not know the mechanism responsible for the response in the contralateral fellow eyes, but one possibility is the limited systemic absorption of the injected substances, and, alternatively, that retinal or eye injury results in systemic inflammatory or paracrine-mediated effects that reach the fellow eye. 59 In this latter context, the microglial response may be subtle and not reach statistical significance, as in this study, or may be more intense when the insult is clearly damaging, such as after axotomy 37 or elevation of the intraocular pressure. ...
Different Ipsi- and Contralateral Glial Responses to Anti-VEGF and Triamcinolone Intravitreal Injections in Rats
Article
Full-text available
  • Jul 2016
Purpose: To investigate the glial response of the rat retina to single or repeated intravitreal injections (IVI). Methods: Albino Sprague-Dawley rats received one or three (one every 7 days) IVI of anti-rat VEGF (5 μL; 0.015 μg/μL), triamcinolone (2.5 or 5 μL; 40 μg/μL; Trigón Depot), bevacizumab (5 μL; 25 μg/μL; Avastin), or their vehicles (PBS and balanced salt solution) and were processed 7 days after the last injection. Retinas were dissected as whole mounts and incubated with antibodies against: Iba1 (Ionized Calcium-Binding Adapter Molecule 1) to label retinal microglia, GFAP (Glial Fibrillary Acidic Protein) to label macroglial cells, and vimentin to label Müller cells. The retinas were examined with fluorescence and confocal microscopy, and the numbers of microglial cells in the inner retinal layers were quantified using a semiautomatic method. Results: All the injected substances caused an important micro- and macroglial response locally at the injection site and all throughout the injected retina that was exacerbated by repeated injections. The microglial response was also observed but was milder in the contralateral noninjected eyes. The IVI of the humanized antibody bevacizumab caused a very strong microglial reaction in the ipsilateral retina. Two types of macroglial response were observed: astrocyte hypertrophy and Müller end-foot hypertrophy. While astrocyte hypertrophy was widespread throughout the injected retina, Müller end-foot hypertrophy was localized and more extensive with triamcinolone use or after repeated injections. Conclusions: Intravitreal injections cause micro- and macroglial responses that vary depending on the injected agent but increase with repeated injections. This inflammatory glial response may influence the effects of the injected substances on the retina.
View
... [31][32][33] At the same time, studies have reported that the degree of fibrosis depends upon the relative amounts of VEGF in proliferative DR eyes. 34,35 Many prospective randomized clinical trial data have shown that the use of VEGF inhibitors -such as ranibizumab and bevacizumab (Avastin) -is an effective treatment for retinal vascular diseases. [35][36][37] Despite the success of drugs in the treatment of DR, the exact mechanisms have only been partly resolved. ...
... 34,35 Many prospective randomized clinical trial data have shown that the use of VEGF inhibitors -such as ranibizumab and bevacizumab (Avastin) -is an effective treatment for retinal vascular diseases. [35][36][37] Despite the success of drugs in the treatment of DR, the exact mechanisms have only been partly resolved. Previous studies have revealed that VEGF-A is the best-studied inducer of ocular angiogenesis and vascular Drug Design, Development and Therapy 2015:9 submit your manuscript | www.dovepress.com ...
Effects of intravitreal injection of netrin-1 in retinal neovascularization of streptozotocin-induced diabetic rats
Article
Full-text available
  • Dec 2015
Background: In a previous study, we confirmed that netrin-1 acts as an antiangiogenic factor by inhibiting alkali burn-induced corneal neovascularization in rats. Here, we continue working on the role of netrin-1 in retinal neovascularization. Methods: Using an in vitro angiogenesis assay, we detected the effects of netrin-1 on human umbilical vein endothelial cell tube formation, viability and proliferation, migration, and invasion at concentrations of 0.1 μg/mL or 5 μg/mL. We intravitreally injected 0.1 μg/mL or 5 μg/mL netrin-1 into streptozotocin-induced rats to assess retinal neovascularization using retinal electrophysiology and electroretinography, enzyme-linked immunosorbent assay, fundus fluoresce in angiography, measurement of inner blood retinal barrier, retinal hematoxylin-eosin staining, and retinal flat-mount fluorescence assays. Results: Human umbilical vein endothelial cell tube formation, viability and proliferation, migration, and invasion were upregulated by netrin-1 at a concentration of 0.1 μg/mL (P<0.05), while 5 μg/mL netrin-1 had an opposite effect (P<0.05) in our in vitro angiogenesis assay. Retinal electrophysiology testing revealed that intravitreal injection of netrin-1 affected the amplitude of a- and b-waves (a-wave: 0.1 μg/mL netrin-1 =17.67±3.39 μm, 5 μg/mL netrin-1 =28.50±1.31 μm, phosphate-buffered saline [PBS]-treated =17.67±3.39 μm; b-wave: 0.1 μg/mL netrin-1 =44.67±4.80 μm, 5 μg/mL netrin-1 =97.17±9.63 μm, PBS-treated =44.67±4.80 μm) and the expression of VEGF-A (no-treatment rats, 9.29±0.80 pg/mL; PBS-treated rats, 19.64±3.77 pg/mL; 0.1 μg/mL netrin-1 treated rats, 21.37±3.64 pg/mL; 5 μg/mL netrin-1 treated rats, 9.85±0.54 pg/mL, at 6 weeks after induction). By comparing fluoresce in angiography, level of inner blood retinal barrier breakdown (% of control), retinal hematoxylin-eosin staining, and collagen-IV fluorescence assays in the retinas of PBS-treated rats, netrin-1 was found to suppress and reverse retinal neovascularization at a concentration of 5 μg/mL (P<0.05), while 0.1 μg/mL netrin-1 (P<0.05) led to an increase in the number of new retinal blood vessels, after 6 weeks' injection. Conclusion: Netrin-1 could play a significant role in retinal neovascularization by dual-direction regulating angiogenesis dependent on dosage.
View
Mechanistic insights into the alterations and regulation of the AKT signaling pathway in diabetic retinopathy
Article
Full-text available
  • Nov 2023
In the early stages of diabetic retinopathy (DR), diabetes-related hyperglycemia directly inhibits the AKT signaling pathway by increasing oxidative stress or inhibiting growth factor expression, which leads to retinal cell apoptosis, nerve proliferation and fundus microvascular disease. However, due to compensatory vascular hyperplasia in the late stage of DR, the vascular endothelial growth factor (VEGF)/phosphatidylinositol 3 kinase (PI3K)/AKT cascade is activated, resulting in opposite levels of AKT regulation compared with the early stage. Studies have shown that many factors, including insulin, insulin-like growth factor-1 (IGF-1), VEGF and others, can regulate the AKT pathway. Disruption of the insulin pathway decreases AKT activation. IGF-1 downregulation decreases the activation of AKT in DR, which abrogates the neuroprotective effect, upregulates VEGF expression and thus induces neovascularization. Although inhibiting VEGF is the main treatment for neovascularization in DR, excessive inhibition may lead to apoptosis in inner retinal neurons. AKT pathway substrates, including mammalian target of rapamycin (mTOR), forkhead box O (FOXO), glycogen synthase kinase-3 (GSK-3)/nuclear factor erythroid 2-related factor 2 (Nrf2), and nuclear factor kappa-B (NF-κB), are a research focus. mTOR inhibitors can delay or prevent retinal microangiopathy, whereas low mTOR activity can decrease retinal protein synthesis. Inactivated AKT fails to inhibit FOXO and thus causes apoptosis. The GSK-3/Nrf2 cascade regulates oxidation and inflammation in DR. NF-κB is activated in diabetic retinas and is involved in inflammation and apoptosis. Many pathways or vital activities, such as the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) and mitogen-activated protein kinase (MAPK) signaling pathways, interact with the AKT pathway to influence DR development. Numerous regulatory methods can simultaneously impact the AKT pathway and other pathways, and it is essential to consider both the connections and interactions between these pathways. In this review, we summarize changes in the AKT signaling pathway in DR and targeted drugs based on these potential sites.
View
Anti-VEGF Crunch Syndrome in Proliferative Diabetic Retinopathy: A Review
Article
  • Mar 2021
  • SURV OPHTHALMOL
Anti-vascular endothelial growth factor (anti-VEGF) crunch syndrome describes the progression to tractional retinal detachment following intravitreal anti-VEGF therapy in an eye with proliferative diabetic retinopathy (PDR). We reviewed the literature on the anti-VEGF crunch using the PubMed and Cochrane databases. Anti-VEGF crunch typically manifests as sudden vision loss in the affected eye between 1 and 6 weeks following intravitreal anti-VEGF injection, with a mean onset of 13 days. Risk factors for crunch development include the use of a higher anti-VEGF dose and increased severity of diabetic retinopathy with fibrosis. Our review found that intravitreal anti-VEGF, in particular bevacizumab, should be used with caution when treating patients with severe PDR and pre-existing intraocular fibrosis. In patients where anti-VEGF is used before a planned vitrectomy, we recommend close monitoring for crunch symptoms and proceeding promptly with surgery if there is new or progression of TRD. For eyes with minimal preexisting traction that develop crunch after anti-VEGF treatment, surgeons should proceed to vitrectomy within 7 days. The existing literature on the anti-VEGF crunch is limited by heterogeneity in the way crunch is documented and characterized and the presence of PRP as a confounding factor. Because of these methodological flaws, the relative frequency of the anti-VEGF crunch cannot be accurately estimated.
View
Progression to macula-off tractional retinal detachment after a contralateral intraoperative intravitreal bevacizumab injection for proliferative diabetic retinopathy
Article
Full-text available
We report a patient with progression to a macula-off tractional retinal detachment in a fellow eye after a contralateral intraoperative intravitreal bevacizumab injection. A 32-year-old diabetic man noted decreased vision in his left eye 1 week following 25 gauge pars plana vitrectomy, gas tamponade, and intraoperative injection of bevacizumab in his right eye. Left eye visual acuity decreased from 20/80 to 20/200, and macula-off tractional retinal detachment was seen on clinical exam and imaging. Progression of tractional retinal detachment associated with proliferative diabetic retinopathy in a fellow eye after a contralateral intraoperative intravitreal bevacizumab injection may occur.
View
Serum Levels of Intravitreal Bevacizumab After Vitrectomy, Lensectomy and Non-Surgical Controls
Article
Full-text available
  • Apr 2013
  • CURR EYE RES
Purpose: To determine serum level differences of intravitreally-placed bevacizumab after vitrectomy and lensectomy-vitrectomy and to compare these with non-operated eyes in a rabbit model. Methods: Five Dutch-belted rabbits underwent pars plana vitrectomy (PPV), five rabbits underwent pars plana lensectomy (PPL) and five rabbits served as non-surgical controls. Twelve days following the surgical procedures, each operated eye underwent an intravitreal injection consisting of 1.25 mg/0.05 mL bevacizumab. Serum levels from each rabbit were drawn on days 2, 4, 7, 10, 14, 21, 28 and 35 and were measured with ELISA immunoassay. Results: The average peak serum concentration (Cmax) was highest for the PPL group (11.33 μg ± 3.48 mL), and was similar between the PPV (5.35 μg ± 2.69 mL) and non-surgical control groups (5.35 μg ± 0.69 mL). The average time to maximal plasma concentration (Tmax) in days was earliest for the PPL group (2.8 ± 0.47), followed by the PPV (5.6 ± 0.84) and non-surgical control groups (6.4 ± 0.71). The PPL group had higher serum levels than the other two groups until day 7 that was significant only at day 2 (p < 0.0001). After day 4, there were no significant differences or trends between any of the three groups. The half-life (T1/2) was fastest for the PPL group (1.41 ± 0.21 d) followed by the PPV (2.80 ± 3.35 d) and non-surgical control groups (6.69 ± 10.4 d). Conclusions: Serum bevacizumab levels were initially elevated following lensectomy and vitrectomy compared to non-surgical eyes following intravitreal injection. The half-life of bevacizumab was prolonged in non-surgical eyes presumably due to a slower release from the vitreous cavity.
View
A shift in the balance of vascular endothelial growth factor and connective tissue growth factor by bevacizumab causes the angiofibrotic switch in proliferative diabetic retinopathy
Article
Full-text available
  • Jan 2012
  • BRIT J OPHTHALMOL
In proliferative diabetic retinopathy (PDR), vascular endothelial growth factor (VEGF) and connective tissue growth factor (CTGF) may cause blindness by neovascularisation followed by fibrosis of the retina. It has previously been shown that a shift in the balance between levels of CTGF and VEGF in the eye is associated with this angiofibrotic switch. This study investigated whether anti-VEGF agents induce accelerated fibrosis in patients with PDR, as predicted by this model. CTGF and VEGF levels were measured by ELISA in 52 vitreous samples of PDR patients, of which 24 patients had received intravitreal bevacizumab 1 week to 3 months before vitrectomy, and were correlated with the degree of vitreoretinal fibrosis as determined clinically and intra-operatively. CTGF correlated positively, and VEGF correlated negatively with the degree of fibrosis. The CTGF/VEGF ratio was the strongest predictor of fibrosis. Clinically, increased fibrosis was observed after intravitreal bevacizumab. These results confirm that the CTGF/VEGF ratio is a strong predictor of vitreoretinal fibrosis in PDR, and show that intravitreal anti-VEGF treatment causes increased fibrosis in PDR patients. These findings provide strong support for the model that the balance of CTGF and VEGF determines the angiofibrotic switch, and identify CTGF as a possible therapeutic target in the clinical management of PDR.
View
View
View
Effect of Vitrectomy on Aqueous VEGF Concentration and Pharmacokinetics of Bevacizumab in Macaque Monkeys
Article
  • Jul 2012
Purpose: To evaluate the effect of vitrectomy on the concentration of vascular endothelial growth factor (VEGF) and the pharmacokinetics of intravitreally injected bevacizumab in the aqueous humor in cynomolgus macaques. Methods: Pars plana lensectomy and a standard three-port vitrectomy were performed in one eye each of six macaques. After a minimal 12-week healing period, the vitrectomized eyes received an intravitreal injection of bevacizumab (1.25 mg/50 μL). Aqueous humor and venous blood samples were obtained from the macaques just before vitrectomy, just before injection of bevacizumab, on days 1, 3, and 7, and during weeks 2, 4, 6, and 8 after the injection. The bevacizumab and VEGF concentrations were measured by using enzyme-linked immunosorbent assay. Results: The VEGF concentrations in the aqueous humor ranged from 52.6 to 113.9 pg/mL (mean ± standard deviation [SD], 81.7 ± 27.0 pg/mL) before vitrectomy and 20.7 to 72.7 pg/mL (mean ± SD, 51.4 ± 20.5 pg/mL) 3 months after vitrectomy, a difference that reached significance (P = 0.03). The aqueous VEGF concentrations decreased to less than 9.0 pg/mL, the lower limit of detection, in all eyes between 1 and 7 days after injection of bevacizumab. The mean half-life of 1.25 mg intravitreally injected bevacizumab was 1.5 ± 0.6 days (range, 1.0-2.4 days) in the aqueous humor. Conclusions: The VEGF concentration in the aqueous humor decreased and the half-life of the intravitreally injected bevacizumab was shorter in vitrectomized eyes.
View
Intraocular Pharmacokinetics of Bevacizumab After a Single Intravitreal Injection in Humans
Article
  • Oct 2008
To investigate intraocular concentrations and pharmacokinetics of bevacizumab after a single intravitreal injection in humans. Prospective, noncomparative, interventional case series. We included 30 nonvitrectomized eyes of 30 patients (age range, 43 to 93 years) diagnosed with clinically significant cataract and concurrent macular edema secondary to neovascular age-related macular degeneration, diabetic retinopathy, or retinal venous occlusion in the same eye. All patients received an intravitreal injection of 1.5 mg bevacizumab. Between one and 53 days after injection, an aqueous humor sample was obtained during elective cataract surgery. Concentrations of unbound bevacizumab in these samples were quantified by enzyme-linked immunosorbent assay. Concentration of bevacizumab in aqueous humor peaked on the first day after injection with a mean concentration (c(max)) of 33.3 microg/ml (range, 16.6 to 42.5 microg/ml) and subsequently declined in a monoexponential fashion. Nonlinear regression analysis determined an elimination half-time (t(1/2)) of 9.82 days (R(2) = 0.81). No significant differences between diagnosis subgroups were noted. In human nonvitrectomized eyes, the aqueous half-life of 1.5 mg intravitreally injected bevacizumab is 9.82 days.
View
View
Some Structural Features of the Fovea Centralis in the Human Retina
Article
  • Sep 1969
  • ARCH OPHTHALMOL-CHIC
Fovea centralis in the human retina was studied with light and electron microscopes on a glutaraldehyde-osmium tetroxide fixed and epoxy resin embedded specimen. A relatively large amount of Müller cell processes is recognized at the center of the fovea. These cells constitute the floor of the fundus and possess a watery cytoplasm among central cone fibers in an area about 50μ in diameter. The mitochondria of the foveal cone tend to be dispersed in the inner segment and outer cone fiber. At the center, no ellipsoid is discernible in the inner segment of the foveal cone. The basal lamina along the vitreal surface is extremely thin at the fundus of the fovea. The center of the fovea externa, about 80μ in diameter, shows a slight convex elevation.
View
Fluorescein Studies of Normal Choroidal Circulation
Article
  • May 1970
  • AM J OPHTHALMOL
The choroidal circulation has been evaluated, using fluorescein angiography, in a series of human subjects with varying degrees of retinal pigmentation, including four albinos. The angiographic features of the choroidal vessels have been outlined in various areas of the fundus. Fluorescein appears in the choroidal arteries in the posterior eyegrounds, in the cilioretinal artery, and in the papillary vessels, before it does in the branches of the central retinal artery. In the periphery, dye appears at about the same time in the choroidal arteries and retinal arterioles. On the other hand, dye appears in the choroidal veins later than it does in the retinal veins. The transit time of dye through the larger choroidal vessels is much shorter than it is through the retinal vessels. The choriocapillaris initially fills in segmental areas closely related to the choroidal arteries. Eventually, though, these segmental areas become confluent and can no longer be distinguished. It is likely that the choriocapillaris of a normal subject is permeable to fluorescein, but that the larger vessels do not allow passage of the dye.
View