Intravitreal bevacizumab: an analysis of the evidence

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A Case of Intravitreal Bevacizumab Injection for the Treatment of Choroidal Neovascularization in Angioid Streaks

A 56-year-old Korean woman presented with decreased visual acuity of the right eye. She had a history of two photodynamic therapy treatments for choroidal neovascularization (CNV) due to angioid streaks in her left eye with central scarring and low visual acuity. She was diagnosed with subfoveal CNV due to angioid streaks in her right eye and treated with six intravitreal bevacizumab (1.25 mg / 0.05 mL) injections over one year. Best corrected visual acuity improved from 20 / 125 at baseline to 20 / 50 at the final visit. The area of CNV had changed into a fibrotic scar by the final visit, and fluorescein angiography and indocyanine green angiography revealed no evidence of leakage. Optical coherence tomography showed that central macular thickness decreased from 311 µm at baseline to 203 µm with complete resolution of subretinal and intraretinal fluid at the final visit. Intravitreal bevacizumab for CNV associated with angioid streaks prevented the progression of disease and resulted in the improvement of visual acuity after one year of follow-up in our patient

Μηχανισμός ανάπτυξης και θεραπευτική αντιμετώπιση της χοριοειδικής νεοαγγείωσης της ωχράς κηλίδας σε ασθενείς με παθολογικό υπόστρωμα (αγγειοειδείς ταινίες)

Εισαγωγή: Οι αγγειοειδείς ταινίες είναι αποτιτανωμένες ρήξεις της μεμβράνης του Bruch. Η σοβαρότερη επιπλοκή των αγγειοειδών ταινιών είναι η ανάπτυξη χοριοειδικής νεοαγγείωσης της ωχράς κηλίδας, με σχηματισμό αμφιβληστροειδικής ουλής και μη αναστρέψιμη απώλεια της όρασης. Η τρέχουσα θεραπεία εκλογής είναι ενδοϋαλοειδικές εγχύσεις αντιαγγειογενετικών παραγόντων. Όλες οι δημοσιευμένες μελέτες αφορούν μικρές σειρές ασθενών, που περιλαμβάνουν «παρθένους» θεραπευτικά οφθαλμούς και ασθενείς που είχαν προηγηθεί άλλες θεραπείες. Δεν υπάρχει δημοσίευση που να συγκρίνει τα αποτελέσματα θεραπείας μεταξύ του πρώτου και του δεύτερου έτους, δηλαδή σε ποιο βαθμό συνεχίζεται η βελτίωση της οπτικής οξύτητας κατά το δεύτερο έτος θεραπείας. Σκοπός: Η παρούσα μελέτη σχεδιάσθηκε με κύριο σκοπό να συγκρίνει τα αποτελέσματα της θεραπείας με αντιαγγειογενετικούς παράγοντες μεταξύ πρώτου και δεύτερου έτους θεραπείας σε «παρθένους» θεραπευτικά οφθαλμούς. Ασθενείς και Μέθοδοι: Η παρούσα ανοικτή, προοπτική μελέτη περιέλαβε 20 οφθαλμούς 19 διαδοχικών ασθενών που ολοκλήρωσαν θεραπεία και παρακολούθηση για 24 μήνες. Αποτελέσματα: Κατά τη διάρκεια του πρώτου έτους θεραπείας 15 (75%) οφθαλμοί υποβλήθηκαν σε 7, 4 (20%) οφθαλμοί σε 8 και ένας (5%) οφθαλμός σε 10 ενδοϋαλοειδικές εγχύσεις. Κατά τη διάρκεια του δεύτερου έτους θεραπείας 15 (75%) οφθαλμοί υποβλήθηκαν σε 2, 4 (20%) οφθαλμοί σε 1 και ένας (5%) οφθαλμός σε 5 ενδοϋαλοειδικές εγχύσεις. Συγκριτικά με την προ θεραπείας μέτρηση, στο τέλος του πρώτου έτους διαπιστώθηκε μείωση του μέγιστου πάχους αλλοίωσης (382±96 μm vs 287±87μm, αντίστοιχα, pair-T=4,73, p<0,001). Στο τέλος του δεύτερου έτους θεραπείας η μείωση του μέγιστου πάχους αλλοίωσης ήταν επίσης σημαντική (382±96 μm vs 322±98 μm, αντίστοιχα, pair-T=6,44, p<0,001, αντίστοιχα). Δεν υπήρχε όμως στατιστικά σημαντική διαφορά μεταξύ πρώτου και δεύτερου έτους παρακολούθησης (pair-T=1,55, p=0,14). Η προ θεραπείας καλύτερη μέση (mean) διορθούμενη οπτική οξύτητα στους 20 οφθαλμούς ήταν 0,75±0,26, στο τέλος του πρώτου έτους ήταν 0,42±0,26 και στο τέλος του δεύτερου έτους ήταν 0,44±0,22. Οι μεταβολές της προ θεραπείας καλύτερης διορθούμενης οπτικής οξύτητας ήταν στατιστικά σημαντικές στο πρώτο και το δεύτερο χρόνο παρακολούθησης (t=4,74, p<0,001 και t=4,94, p<0,001 αντίστοιχα). Αντίθετα, δεν υπήρχε στατιστικά σημαντική διαφορά της καλύτερης διορθούμενης οπτικής οξύτητας μεταξύ πρώτου και δεύτερου έτους παρακολούθησης (t=0,72, p=0,48). Ειδικότερα, στο 75% και στο 80% των οφθαλμών βελτιώθηκε η καλύτερη διορθούμενη οπτική οξύτητα τουλάχιστον κατά 0,2 LogMAR στο τέλος του πρώτου και δεύτερου έτους παρακολούθησης, αντίστοιχα. Αντίθετα, δεν υπάρχει στατιστικά σημαντική διαφορά στη καλύτερα διορθούμενη οπτική οξύτητα μεταξύ πρώτου και δεύτερου έτους παρακολούθησης (x2=0,18, DF=2, p=0,92), όπου στο 85% των οφθαλμών η οπτική οξύτητα ήταν αμετάβλητη. Συμπεράσματα: Τα αποτελέσματα της παρούσας μελέτης έδειξαν για πρώτη φορά ότι οι ενδοϋαλοειδικές εγχύσεις ranibizumab σε «παρθένους» θεραπευτικά οφθαλμούς με χοριοειδική νεοαγγείωση της ωχράς κηλίδας σε έδαφος αγγειοειδών ταινιών έχει ως αποτέλεσμα τη βελτίωση της οπτικής οξύτητας στο πρώτο έτος θεραπείας, η οποία διατηρείται στην πλειονότητα των οφθαλμών κατά το δεύτερο έτος θεραπείας και παρακολούθησης.Introduction: Macular choroidal neovascularization (CNV) is the most serious complication of Angioid streaks (AS). It has a poor natural course usually resulting in central visual loss. Treatment of CNV in patients with AS with laser photocoagulation, photodynamic therapy and submacular surgery were not effective. Intravitreal injections of vascular endothelial growth factor (anti-VEGF) drugs is currently the most effective treatment. However, published case series report on the final effect of anti-VEGF therapy on the best corrected visual acuity (BCVA). No one study has compared the functional outcomes, i.e., BCVA, by the end of the first and second year of therapy. Purpose: The aim of our study was to compare 12 and 24-month results of intravitreal ranibizumab therapy in the management of choroidal neovascularization (CNV) secondary to angioid steaks (ST). This could be of clinical importance helping us planning optimal dosing strategies. Design: 24-month prospective, open-label, interventional clinical study. Methods: Over a 7-year period, a consecutive series of treatment-naive eyes with macular CNV due to AS were treated with intravitreal ranibizumab (0.5 mg). The main outcome measure was changes in best-corrected visual acuity (BCVA) at 12 and 24 months as compared to baseline. Results: Twenty eyes completed 24-month therapy and regular follow up. Each eye received a median of 7 (7-10) and 2 (1-5) injections during the first and the second year, respectively. BCVA was improved at 12 (0.42±0.26 logMAR) and 24 months (0.44±0.22 logMAR) as compared to baseline (0.75±0.26 logMAR) (p<0.001), but did not change between the 12 and 24-month follow up (p=0.48). BCVA was improved in 15 (75%) and 16 (80%) of the eyes, but in 4 (20%) and 3 (15%) remain unchanged (p=0.92) at 12 and 24 months, respectively. Central retinal thickness was reduced at 12 (287±87 μm) and 24 months (322±98 μm) as compared to baseline (382±96 μm) (p<0.001), but did not change between the 12 and 24-month (p=0.14). No injection or drug-related side-effects were observed. Conclusion: Our 24-month prospective study have clearly shown that intravitreal injections of ranibizumab in patients with macular CNV secondary to AS improves visual acuity during the first year and stabilizes it during the second year of therapy. We can postulate that it is mostly the treatment during the first year that leads to functional and anatomical improvement while, during the second year, treatment mainly preserves the first-year results

Management of neovascular age-related macular degeneration with ranibizumab: Long-term outcomes and second eye outcomes

Background: Intravitreal anti-vascular endothelial growth factor (anti-VEGF) agents are the established standard of care for neovascular age related macular degeneration (nAMD), however there are currently limited data on long-term outcomes of this therapy. Ranibizumab is one such anti-VEGF agent administered to treat nAMD. Patients diagnosed with nAMD undergo regular clinic based follow-up as part of their treatment, often on a monthly basis. Assessment during these appointments includes optical coherence tomography (OCT) scans, which can contribute to the detection of nAMD in the second eye. There is limited data on the symptomatic status, clinical presentation and outcomes of second eye nAMD whilst undergoing regular assessment for the first treatment eye under these conditions. Aims: The first aim of this thesis is to evaluate the long-term (5-year) outcomes of intravitreal ranibizumab (an anti-VEGF agent) in treating nAMD by examining a cohort within a real life clinic setting. The second aim is to compare the clinical presentation and treatment outcomes between the first and second treated eyes in patients that developed nAMD in both eyes, whilst under regular review for unilateral nAMD. Methods: A total of 208 patients (208 eyes) were included in a retrospective case series assessing the 5-year outcomes of nAMD treated with ranibizumab, entitled the long-term ranibizumab study (LTRS) (Chapter 3). Intervention was an individualised treatment model after three initial monthly loading doses. Visual acuity (VA), central macular thickness (CMT), qualitative OCT features, and adverse events (AE) were determined for each visit. Snellen VA was converted to Early Treatment Diabetic Retinopathy Study (ETDRS) letters for analysis. To assess outcomes of second eyes diagnosed with nAMD, a retrospective case series entitled second-eye ranibizumab study (SERS) forms the second part of this thesis (Chapter 4). Forty-five consecutive patients fulfilled the inclusion criteria of commencing treatment with ranibizumab in the first eye for nAMD between July 2007 and March 2011,and subsequently developing nAMD in the second eye with at least 12-months of follow-up in each eye. Treatment was administered under the same conditions as the LTRS. Snellen VA was measured, and OCT examination of both eyes at each visit assessed the presence of intra-retinal fluid (IRF) and sub-retinal fluid (SRF). Patient reported symptoms were recorded at every clinic visit. Paired t-tests were used to assess changes in VA and CMT over the study duration of the LTRS and SERS and two sample t- tests were used to evaluate VA differences between groups. Changes in VA compared to baseline were classified into the three categories: stable VA (loss or gain of ≤15 letters), improved VA (gain of >15 letters), or worse VA (loss of >15 letters). Linear regression was used to assess the effects of age, gender, number of injections, previous treatment, medical history, medications, and baseline VA on both VA and CMT changes. Chi-square test or Fisher’s exact test were used to measure proportions of patients with visual stability and OCT fluid free status at 12-months in the SERS. Results: In the LTRS, mean VA improved by 1.9 letters after 1 year (p=0.020) and decreased by 2.4 letters over 5-years of the treatment (p=0.040). At the end of year 5, 11.1% (23/208) of patients improved VA by more than 15 letters and 68.8% (143/208) of patients had stable VA, while 20.2% (42/208) patients lost more than 15 letters. Patients with VA less than 35 letters (approximate Snellen VA 6/60) at baseline showed significant VA improvement after 5-years of treatment (mean increase 11.5 letters, p=0.01), whilst those that were between 70 and 85 letters (approximate Snellen VA 6/12 to 6/6) at baseline showed a mean decrease (-12.9 letters, p=76 letters, or Snellen VA approximately 6/9)) showed greater stability of vision at 12-months vs. first treated eyes (p=0.05). There was no significant difference in mean VA change between first and second treated eyes. The proportion of OCT - fluid free eyes was higher amongst second treated eyes compared with first treated eyes at 12-months (70% vs. 40%, p=0.02). Intra-retinal fluid (IRF) was seen in 54% of second treated eyes at baseline compared with 84% in first treated eyes (p=0.01). Symptoms were absent in 54% of second treated eyes at baseline. The most common symptoms were “blurred vision” (28% of all patients) and metamorphopsia (11% of all patients). Conclusions: The visual gains achieved were not as significant as clinical trials, likely reflecting the differences in inclusion criteria of patients, and less rigorous follow-up and treatment. Intravitreal ranibizumab was effective in maintaining vision in patients with nAMD and reducing macula thickness over 5-years using an individualised treatment regime in a real-world setting.. Ranibizumab is a safe drug to use over 5-years in a real-world clinical setting. In patients undergoing treatment for nAMD in the first eye, OCT screening of the second eye at each visit may be necessary to detect second eye nAMD in this at-risk population. A large proportion of patients are asymptomatic at diagnosis of second eye disease, and a significant proportion of patients were detected to have treatable subfoveal nAMD with OCT alone. Second eye disease detected and treated by such a protocol showed a lower rate of IRF at baseline, suggesting early detection had occurred. Second eyes showed a higher rate of fluid free status at 12-months compared to the first treated eye, suggesting that early detection and treatment led to improved anatomical outcomes, potentially explaining superior VA outcomes. Patients commencing treatment in their second eye with good VA had better visual outcomes compared to those with worse VA

Clinical Profile of Retinal Vasculitis at a Tertiary Eye Care Centre and Outcomes following Management

INTRODUCTION: Retinal Vasculitis is a group of inflammatory disorders of the eye characterised by retinal vascular inflammation along with intra-ocular inflammation. It preferentially affects the veins, but rarely arteries or arterioles or both veins and arteries can be affected. It is most commonly associated with presence of retinal haemorrhages or vitreous haemorrhages. Recurrence of vitreous haemorrhages is a common feature which might later get complicated by development of retinitis proliferens followed by retinal detachment, complicated cataract and ultimately secondary glaucoma. Ophthalmoscopic examination and fundus fluorescein angiography along with other investigations play a key role in the diagnosis and management of retinal vasculitis. AIM OF THE STUDY: PRIMARY OBJECTIVES: 1. To investigate the aetiologies, association with tuberculosis and other systemic illnesses. 2. Management of retinal vasculitis with either systemic steroids, intravitreal anti VEGF, laser photocoagulation, immunosuppressants, vitrectomy or observation based on the case scenario. 3. Visual outcome following treatment of the vasculitis patient. SECONDARY OBJECTIVES: 1. To look for any complications following treatment. 2. Measures to provide rehabilitation for vasculitis patient. MATERIALS AND METHODS 50 cases of retinal vasculitis which attended the vitreo-retina clinic of Regional Institute of Ophthalmology and Government Ophthalmic Hospital, Egmore , Chennai between August 2015 and August 2016 for a period of 1 year were taken up for the study. It is a prospective study. INCLUSION CRITERIA: 1. Age > 18 years, 2. All cases of Retinal Vasculitis presenting with atleast one of the following features - a. Sheathing, b. Perivascular inflammation, c. Superficial and Deep Hemorrhages, d. Staining of vessel wall on FFA. EXCLUSION CRITERIA: 1. Age < 18 years, 2. Patient with pre existing ocular disease like diabetic retinopathy, vein occlusion, arterial occlusion, glaucoma etc. RESULTS: In this study on 77 eyes of 50 retinal vasculitis patients, 31 cases(62%) were due to Eales Disease, 15 cases (30%) were secondary to systemic disease and the remaining 4 cases (8%) were secondary to ocular disease. Amongst the 50 case of Retinal vasculitis which visited the retina clinic, maximum incidence was in the age group of 18-28 years (44%) followed by 29-38 years (42%) followed by 39-48 years (7%). The mean age was 30.02 + 12 years. In a study by Biswas [et. al], mean age of presentation was found to be 33 + 11. In a study by Donders in 1958 the average age for men was 28 years and for women it was 30 years. In our study, incidence of Retinal Vasculitis is more in males (80%) as compared to females (20%). Out of the 31 patients with Eales’s Disease, 30 were male and only 1 was female. Out of 4 cases with retinal vasculitis secondary to ocular disease, 3 were males and 1 was female. Out of 15 cases with retinal vasculitis secondary to systemic disease, 7 were males and 8 were females. CONCLUSION: Retinal vasculitis is a challenge for an ophthalmologist both to diagnose and to treat. If left untreated it may lead to total loss of vision. Ophthalmologist also play an important role in finding out systemic diseases in a patient who have no other manifestations apart from ophthalmological signs. That aids in timely treatment of the underlying cause. For each patient treatment has to be individualised based on their findings. A multidisciplinary approach is required in cases with systemic involvement. In our study, primary vasculitis is the predominant form of vasculitis accounting for 62% of the cases. Male predilection is noted with 80% cases being males and 20% being females. Most commonly involved age group is between 18-28 years of age (44%). Maximum cases had a bilateral presentation (54%) with defective vision being the chief complaint in most of the cases (88%). Oral corticosteroids were the main modality of treatment in our study. Patients treated with laser photo-coagulation did not show worsening of signs. Observation was helpful in patients with vitreous hemorrhage. Treatment of associated systemic conditions in addition to oral corticosteroids showed improvement in visual acuity. Although systemic steroids are efficacious in controlling active disease and easily administered, adverse systemic complications is a matter of concern. Since the time period of the study was short (1 year), we have kept 3 months as the criteria for assessing the outcome of management. Due to referrals to various departments, patients took time to review with us with all the work up. More long term studies are required to overcome these shortcomings

Haemodynamic studies of the eye

The study of the circulation of the eye has been taxing the imaginations of ocular investigators for 100 years, and has resulted in various and ingenious methods for its assessment. In recent decades technological advances have provided even more scope for examination. In these studies the method of colour Doppler imaging (which has considerably improved the localisation and measurement of blood flow in small blood vessels) was investigated as a means of examining the haemodynamics of the eye. The examination of 95 normal individuals showed that many orbital blood vessels could be examined but that only the Doppler recordings (blood velocities and resistive index) from the ophthalmic artery, central retinal artery and vein were reproducible. Normal ranges for the Doppler measurements from these vessels were defined. The results were influenced by the age of the patient, by systemic blood pressure and by smoking habit. The identity of individual blood vessels was confirmed by examining patients with occlusive vascular disease. According to the Hagen Poiseuille law an increase in the viscosity of a fluid reduces its flow. In a group of normal individuals the interrelationship between blood velocity (from colour Doppler imaging) and systemic blood viscosity was examined. No effect of viscosity on the blood velocities was found but a negative correlation between viscosity and resistive indices (a Doppler measure of resistance to flow) was detected. This result suggested that in normal individuals there was compensation for increased blood viscosity by a reduction in peripheral resistance thereby maintaining blood flow to the eye. The method of colour Doppler imaging was then applied to the examination of 80 patients with central retinal vein occlusion in whom significantly reduced blood velocities were found in the retinal vessels. In fact the values of the velocities (a minimum peak velocity in the central retinal vein of less than 3.0 cm/sec) could be used to predict the development of the blinding and painful complication of iris neovascularisation. Investigation of the systemic blood viscosity in these patients revealed elevated viscosity compared to population based controls and the examination of haemostatic factors demonstrated a thrombotic tendency particularly in those who developed iris neovascularisation. In contrast to normal individuals, the orbital blood velocities from the patients with central retinal vein occlusion were negatively correlated with their blood viscosities whereas resistive indices were unaffected, indicating that a reduction in peripheral resistance did not occur. In these patients therefore not only was blood viscosity elevated but there was no evidence of compensation for this by reduction of peripheral resistance. Potentially therefore retinal blood flow is reduced in eyes with central retinal vein occlusion by increased blood viscosity and poor vascular compensation to such an extent that "occlusion" of flow in the vein occurs