Nghiên cứu sử dụng thuốc bevacizumab tiêm nội nhãn phối hợp cắt dịch kính điều trị bệnh võng mạc đái tháo đường giai đoạn tăng sinh có biến chứng xuất huyết dịch kính tt tiếng anh

HA NOIMEDICALUNIVERSITYNGUYEN DIEU LINH STUDY ON USING INTRAVITREAL BEVACIZUMAB INJECTION AND VITRECTOMY IN THE TREATMENT OF VITREOUS HEMORRHAGE COMPLICATION DUE TO PROLIFERATIVE DIABETI

HA NOIMEDICALUNIVERSITY

NGUYEN DIEU LINH

STUDY ON USING INTRAVITREAL BEVACIZUMAB INJECTION AND VITRECTOMY IN THE TREATMENT

OF VITREOUS HEMORRHAGE COMPLICATION DUE

TO PROLIFERATIVE DIABETIC RETINOPATHY

Major : OPHTHALMOLOGY

Code : 62720157

MEDICAL DOCTOR DISSERTATION SUMMARY

HANOI - 2019

HANOI MEDICAL UNIVERSITY

Scientific guidance:

Professor Do Nhu Hon

Reviewer 1: Associate professor Tran Thi Nguyet Thanh

Reviewer 2: Associate professor Hoang Nang Trong

Reviewer 3: Associate professor Nguyen Van Dam

The dissertation presented to the Board of Ph.D dissertation at University level at Hanoi Medical University.

At date month year 2019.

The dissertation can be found at:

- National Library of Vietnam

- Library of Hanoi Medical University

RELATED TO THE DISSERTATION

1 Nguyễn Diệu Linh, Đỗ Như Hơn, (2015), “ Evaluation of treatment results for vitreous hemorrhage in diabetic retinopathy after 1 year by intravitreal Avastin injection in

combination with vitrectomy”, Vietnamese Journal of

Ophthalmology,vol.38, p:37-43.

2 Nguyễn Diệu Linh, Nguyễn Thị Nhất Châu, Đỗ Như Hơn, (2015), “ The effectiveness of intravitreal Avastin injection as

an adjunct to vitrectomy in the management of diabetic

vitreous hemorrhage”, Journal of Practical Medecine, N0

987, November, p:95-98

Diabetic retinopathy is one of the most prevalent and severeocular disorders, which is a major cause of adult blindness Vitreoushemorrhage ( VH) is a common complication of proliferative diabeticretinopathy ( PDR) Vitrectomy is a predominant treatment forproliferative diabetic retinopathy The incidence of postoperativevitreous hemorrhage after vitrectomy is 20%-60%

Bevacizumab (Avastin) is a recombinant humanizedmonoclonal IgG1 antibody that inhibits human vascular endothelialgrowth factor (VEGF) Bevacizumab can induce regression of retinalneovascularization in patients with diabetes; therefore, it was suggestedthat a presurgical administration of intravitreal bevacizumab ( IVB)may reduce intraoperative bleeding during vitrectomy in PDR.Recently, numerous studies have reported clinical outcomes ofintravitreal bevacizumab as an adjunct to vitrectomy in the management

of proliferative diabetic retinopathy

In Vietnam, there are no studies that have been performed Therefore,the study named " Study on using intravitreal Bevacizumab injectionand vitrectomy in the treatment of vitreous hemorrhage complicationdue to proliferative diabetic retinopathy” is conducted with the aims of:1.To evaluate the effect of intravitreal bevacizumab ( IVB) injectionbefore vitrectomy in the management of vitreous hemorrhagecomplication associated with PDR

2.To analyse some associated factors with the results

NEW CONTRIBUTION OF THE THESIS

- Intravitreal Bevacizumab injection and vitrectomy in the treatment ofvitreous hemorrhage due to proliferative diabetic retinopathy help tolimit intraoperative and postoperative complications, improve visualacuity and anatomical results

- Systemic factors, complications during surgery do not affect treatmentresults Complications after surgery, additional surgery affect theoutcome of treatment

STRUCTURE OF THE THESIS

The thesis consists of 139 pages: Introduction (2 pages), Overview(36 pages), subjects and methods (24 pages), Results (28 pages),Discussion (46 pages), Conclusion (2 pages), Recommendation (1

page) New contribution (1 page) The thesis consists of 32 tables, 6charts, 5 pictures, appendix and list of patients.

CHAPTER 1 OVER VIEW 1.1 DIABETIC RETINOPATHY

1.1.1 Epidemiology of diabetic retinopathy: Diabetic retinopathy

( DR) usually occurs after 5 years of having diabetes After 15 years and

20 years more than 50% and most of diabetic patients have retinopathy,respectively

1.1.2.Pathophysiology of diabetic retinopathy: metabolic changes at

the molecular level leading to endothelial cell dysfunction, basementmembrane thickening, endothelial cell and pericyte loss cell changes.Those abnormalities contribute permeability changes, retinal occlusion,formation retinal hypoxia, which stimulates endothelial, pericyte andretinal pigment epithelium to produce VEGF causingneovascularization

1.1.3.Clinical features of diabetic retinopathy

1.1.3.1 Clinical findings: capillary closure, retinal occlusion, retinal

hypoxia, neovascularization New vessels develope on the surface ofretina or optic disc, create a widespread neovascular network that cancause complications of vitreous hemorrhage, tractional retinaldetachment and neovascular glaucoma

1.1.3.2.Classification of DR: According to Alfédiam’s classification

* Non-proliferative diabetic retinopathy: mild, moderate, severe

* Proliferative diabetic retinopathy: mild, moderate, severe andcomplications

* Diabetic macular retinopathy: focal, diffuse, cyst, tractional macularedema

1.1.3.3.Complications of PDR

*Vitreous hemorrhage: The neovascular tissue grows within the outer

cortical vitreous and associate with fibrous tissue proliferation Tractiondue to posterior vitreous detachment lead to vitreous hemohhrage

Classification of vitreous hemohhrage according to MR Romano: Grade0( no hemohhrage, can see fundus clearly in detail), grade 1 (mildhemorrhage, can see fundus), grade 2 (moderate hemorrhage, can notsee the fundus except the disc), grade 3 (severe hemorrhage, unable tosee the fundus).

*Tractional retinal detachment: Neovascular and fibrous tissueadhering to the posterior hyaloid membrane shrink the retina leading toretinal detachment, possibly with retinal tearing

* Neovascular glaucoma: due to response to hypoxia, VEGF diffuses

to the anterior chamber, causing neovascular on iris and anteriorchamber angle

*Pegaptanip: connect to VEGF-A 165 branch

*Ranibizumab: connect to all kinds of VEGF

*Aflibercept: connect to VEGF-A, VEGF-B andplatelet growth factor

*Bevacizumab ( Avastin): is a monoclonal immunoglobulin,combining VEGF through 2 antigen-binding sites

1.1.4.4.Vitrectomy

*Purpose: Removing vitreous , dissecting and removing fibrous

membrane to reattach retina, doing laser photocoagulation to preventneovascular

*Indications: severe vitreous hemorrhage / fibrovascular membrane /

traction macular detachment / traction retinal detachment with retinal tear

*Technique: vitrectomy from the center to the periphery, makingposterior vitreous detachment then segment the fibrovascularmembrane by separating them from the retinal surface, re-attach retina,

laser photocoagulation, using temponade Combined vitrectomy andphaco surgery to put artificial lenses in cases of cataract.

* Complication

- Complications during surgery: bleeding, retinal tear

- Complications after surgery: Hemorrhagic hemorrhage (early, late),

retinal detachment, glaucoma and glaucoma, cataract, infection

1.2 BEVACIZUMAB IN OCULAR TREATMENT

1.2.1.Structure: Bevacizumab (Avastin, Genetech Inc., San Francisco,

CA) is a monoclonal immunoglobulin, combining VEGF through 2antigen-binding sites

1.2.2.Pharmacokinetics: The drug exists in vitreous more than 30 days

after a dose of 1.25mg / 0.05ml

1.2.3 Mechanism: the drug penetrate the blood-retina barrier,

combined with all types of VEGF VEGF inhibitors cause temporaryvasoconstriction, new vessels regress completely within 48 hours andmaintain for 4 weeks After injection, there is a decrease in both thenumber and aperture of new vessels that will then develop fibrosis

1.2.4 Indication: to treat proliferative diabetic retinopathy: reduces

new vessels of iris, optic disc, retina and reduces vascular leakage,hemorrhage

1.2.5 Side effects

1.2.5.1 Systemic side effects: reduced wound healing, hypertension,

myocardial infarction, stroke, even death

1.2.5.2 Ocular side effects after injection (side effects of the drug and injection technique): subjunctival hemorrhage, intraocular

inflammation, retinal tear

1.3 THE COMBINATION OF INTRAVITREAL BEVACIZUMAB AND VITRECTOMY TO TREAT PROLIFERATIVE DIABETIC RETINOPATHY

1.3.1.Indications

Severe vitreous hemorrhage/ fibrovascular membrane/ tractionalmacular detachment/ tractional retinal detachment with retinal tear

1.3.2.Researchs on combination therapy: Increased VEGF

concentration in vitreous of proliferative diabetic retinopathy eye is arisk factor for failure of vitrectomy Intravitreal injection of anti-VEGFdrugs reduces VEGF levels in the vitreous cavity of proliferativediabetic retinopathy eye

* Drugs: Ranibizumab and Bevacizumab are rated equally on the

effectiveness of treatment and safety The larger molecular size ofBevacizumab should have the advantage of treating proliferativediabetic retinopathy

* Dose: the effect of intravitreal injection Bevacizumab for proliferative

diabetic retinopathy is not significantly different with the dose rangingfrom 1.25mg, 2.5mg to 6.2mg Currently the common dosage is 1.25mg/ 0.05ml

* Time between injection and vitrectomy: In the treatment of

proliferative diabetic retinopathy, Bevacizumab is injected before or atthe end of the surgery Preoperative Bevacizumab injection is betterbecause the drugs makes it easily to dissect fibrous proliferativemembrane, laser photocoagulation, limit bleeding during surgery,postoperative complications

* Studies using Bevacizumab (1.25mg / 0.05ml) intraocular injection before vitrectomy: the authors in the world report that

intravitreal Bevacizumab injection (1.25mg / 0.05ml) preoperative 1-2weeks in the treatment of proliferative diabetic retinopathy has goodanatomical results, increased postoperative vision, limiting bleeding andtears in surgery, limiting recurrent bleeding after surgery In Vietnam,the author Nguyen Thi Nhat Chau reports the results of usingBevacizumab in combination with vitrectomy for treatment of diabeticretinopathy, but the study was conducted on a small scale with shortfollow-up time, didn’t analyse related factors to the outcome

1.3.3.Related factors to the outcome of treatment

1.3.3.1.Systemic factors:age, duration of diabetes, high blood sugar,

hypertension, diabetic kidney disease

1.3.3.2.Ocular factors related to treatment outcome

* Diagnosis: vitreous hemorrhage gain the best result after treatment,

vitreous hemorrhage accompanied by fibrosis proliferation also hasgood result if there are no complications or well-treated surgicalprocedures Vitreous hemorrhage with retinal detachment have theworst prognosis results

*Complications: complications during surgery (bleeding, retinal

tear, ), postoperative complications ( vitreous hemorrhage, irisneovascular, retinal detachment, cataract, infection .)

* Additional treatment

- Additional injections: recurrent vitreous hemorrhage, neovascular

glaucoma

- Additional surgery: additional surgery affects the results of anatomy,

visual acuity and visual quality

CHAPTER 2 SUBJECTS AND METHODS 2.1.Subjects: The study was conducted on severe proliferative diabetic

retinopathy patients with vitreous hemorrhage complications who wereexamed and treated Retinal Department of National Institute ofOphthalmology, from January 1, 2012 to December 30, 2016

2.1.1.Selection criteria

- Patients aged 18 years or older

- Diagnosed with proliferative diabetic retinopathy with vitreoushemorrhage:

+ Vitreous hemorrhage does not clarify the fundus (grade II, III)

+ Vitreous hemorrhage with fibrosis proliferation or vitreoushemorrhage with retinal detachment of macula

-Agree to join the research

2.1.2.Exclusion criteria

- Patient has a history of vitrectomy

- Patients currently have other eye diseases such as trauma, progressiveinflammation, new glaucoma, etc

- Patients with severe systemic diseases such as systemic disease,tuberculosis

- If after intravitreal Bevacizumab injection, hemorrhage is fullyabsorbed or there is small amount of hemorrhage (grade I) withoutfibrosis proliferation/ retinal detachment patients move to do laser

2.2.5.2 Clinical examination

* Vision function: best corrected visual acuity with Snellen eye chart

* Evaluation the intraocular pressure

* Examining and evaluating the ocular surface condition, anterior

chamber,iris, pupil, crystal lens

* Examining and evaluating vitreous and retina

2.2.5.3.Tests: blood tests of blood,ultrasound, fluorescence

2.2.5.5.Intravitreal Bevacizumab injection

* Preparing the patient: applying mydriasis medication, antiseptic

skin, anesthetic

* Dosage and method of injection: Using speculum, using a needle

27-30 G, injecting 0.05ml of Bevacizumab solution with the content of1.25mg into the vitreous chamber through pars-plana in the temporalregion below the cornea of the cornea 3.5- 4mm, small antibioticmoxifloxacin (Vigamox) 4 times / day after injection for 5 days

2.2.5.6 Vitrectomy: after injection Bevacizumab vitreous chamber

from 1-2 weeks

* Preparing patients: dilated pupils, antiseptic, anesthesia next to the

eyeball

* Surgery: Open the eyeball through the pars plana 3.5-4mm from the

edge to create a way for infusion, lights, cutters Vitrectomy using a 20

or 23 gauge system under a wide-angle optical system or through anintraocular camera Cut out the hemorrhagic from the center to theperiphery, treat the posterior vitreous membrane, dissect and cut thefibrous membrane, stop bleeding, retinal laser, using tamponadereplacement, close the entrance Cataract surgery if needed

2.2.5.7 Treatment after surgery

* Anti-inflammatory treatment

* Treatment of complications: glaucoma, cataract, vitreous

hemorrhage, retinal detachment, pre-retinal membrane, neovascular glaucoma, macular edema

2.2.6 Evaluation criteria

2.2.6.1 Evaluation the characteristics of the patient

* Systemiccharacteristics

* Ocular characteristics

2.2.6.2 Evaluate the outcome of treatment

* Evaluation after intravitreal injection: time of injection before

surgery, average vision, intraocular pressure, systemic complications,ocular complications

* Surgical evaluation

 Surgical indications: Vitreous hemorrhage, fibrous membrane,

retinal detachment ± tear

*Postoperative evaluation: 1 week, 1 month, 3 months, 6 months, 12

months, 24 months after surgery

- Assessing vision results:

+ Average vision is calculated by logMar

+ Vision group: Good, fair, poor

No increased visual acuity after treatment: visual acuity stays thesame or worse than pre-treatment visual acuity In the case of visualacuity at counting fingers level, if the visual acuity is still between ≤ 1meter between 2 assessments, the visual acuity will not increase.

- Evaluating postoperative surgery results

+ Success: complete clear environment of the components of thefundus, no neovascular and fibrous membranes on the retina, optic disc,retinal attachment, retinal neovascularization does not progress further.+ Failure: opaque vitreous obscures the central retina or the entireretina, the fundus is not illuminated or retinal detachment, there arepersistent retinal fluid shrinkage, neovascular continue to evolve, andneovascular glaucoma

-Complications after surgery: recurrent vitreous hemorrhage, uveitis,endophthalmitis, cataract, retinal detachment, ocular atrophy, and othercomplications

* Additional treatment: additional injections, additional surgery.

* General evaluation

* Successful surgery

- Anatomical results: remove blood in the vitreous chamber, removeall the hyaloids later, remove the fibrous proliferating membrane andcontract

- Vision increased at the time of examination compared with visionbefore treatment

* Surgery failure: when either of the 2 criteria or both criteria on

vision and surgery are missing

2.2.6.3 Evaluate factors related to treatment results

* Systemic factors associated with the outcome of treatment

* Ocular factors associated with the outcome of treatment:

diagnosis, complications, additional treatment

2.2.7 Data processing: SPSS 18.0 statistical software Tested by

T-student algorithm and when squared, test Phi

2.2.8 Research ethics