Juniper Publishers- JOJ Ophthalmology

 Triamacinolone Acetonide Versus Bevacizumab in Treatment of Neovascular Age Related Macular Degeneration-Juniper Publishers

Abstract

Purpose: To evaluate the effects of intravitreal triamacinolone acetonide (IVTA) and bevacizumab injection on visual acuity, electro physiologic response and foveal thickness of patients with neo vascular age related macular degeneration (CNVs).

Methods: The study included three groups. Group 1 included fifty eyes (50 patients) with progressive occult or predominately occult sub foveal choroidal neovascularization treated with intravitreal injection of trimacinolone acetonide. Group 2 included another fifty eyes (50 patients) with progressive macular degeneration of occult or predominately occult sub foveal choroidal neovascularization treated with intravitreal bevacizumab. The patients is followed up every month by bio microscopy, optical coherence tomography (OCT), photography, fluoresce in angiography, Ganzfeld full field electro retinogram(F-ERG), multifocal electro retinogram (MF-ERG) and determination of best corrected visual acuity (BCVA). Group 3 (control group) included 50eyes (50 patients) with neo vascular age related macular degeneration who did not receive treatment for macular degeneration.

Results: Apparent improvement of morphological and functional characteristics were observed in 40/50 eyes after one month after first injection in group1, and in 45/50 in group 2. The mean±SD visual acuity improved significantly (p=0.003) from (0.12 ±0.19 to 0.35±0.25) in group1 and from 0.13±0.2 to 0.40±0.28 in group 2. Visual acuity was highest 1-2 month after intravitreal injection. Central macular thickness decreased from 325±50^m to 275±40^m at one month after first injection in group 1 and decreased from 320±53^m to 255±41^m in group 2 while in control group, there is statistically insignificant increase of the central thickness. The average amplitude of central macular ring of MFERG was improved from 25.5±5.8nv to 31±8.9nv in group 1 and from 26.6±6.1nv to 33±9.9nv in group 2, while no changes in F-ERG response. Intraocular pressure increased significantly (p=0.009) from 14±2.5mmHg to maximal 23±7.6mmHg in group 1. Intraocular pressure decreased significantly (p=0.006) to 16±2mmHg at the end of follow up while in group 2, there was no increase in intraocular pressure. No other serious drug related adverse events (endophthalmitis, retinal detachment, cataract or proliferative vitreo retinopathy) observed during the course of the study in groups 1, 2. In control group, visual acuity, central foveal thickness and function did not change significantly during follow up period (p=0.6, p=0.4, p=0.1 respectively).

Conclusion: Intravitreal injection of trimacinolone acetonide may transiently stabilize or improve visual acuity in some patients with progressive neo vascular age related macular degeneration. Intravitreal injection of bevacizumab led to a more visual improvement than IVTA in treatment CNVs. MFERG had an important role in describing the effect of treatment on retinal function. Intravitreal injection improved MFERG macular function responses with little insignificant change in F-ERG.

Keywords: Electroretinogram; Optical coherence tomography; Choroid neovascularization; Avastin; Triamacinolone acetate

Introduction

None of the present treatment decreases the loss of vision on the central 35° of the retina in macular degeneration. Neovascular age related macular degeneration is a common reason for irreversible reduction and loss of vision in the world [1] . Triamacinolone acetonide is one of the first drugs used for the management of age related choroidal neo vascularization [2] . Triamacinolone acetonide stabilizes blood retinal barrier, decreases the permeability and inflammation, increases the diffusion and reduces vascular endothelial growth factor [3]. Vascular endothelial growth factor (VEGF) plays important role in AMD pathogenesis [4]. Bevacizumab is humanized antibody to human vascular endothelium growth factor (VEGF) which combines to VEGF and hinders it from attachment to its receptors [5]. Electro retinogram of neo vascular macular degeneration gives information about the treatment safety. MF-ERG represents the photopic retinal response to a rapidly changing stimulus on the central 35° of the retina [6]. Neovascular age related macular degeneration decreases the central peak amplitude which is altered by subretinal fluid [7]. MF-ERG is used to monitor the localized change after treatment. Full field ERG response reflects general retinal electrical response and gives information about treatment toxicity [6,7]. The aim of the study was to evaluate and compare the effects of triamacinolone acetonide and bevacizumab on visual acuity and retinal thickness in neovascular age related macular degeneration patients and to study the effects of triamacinolone acetonide and bevacizumab on the retinal function.

Subjects and Methods

This study was carried out on patients attending the Outpatient's Clinic of Mansoura Ophthalmic Center during the period from February 2012 to December 2015. One hundred and fifty patients (150) with neovascular age related macular degeneration were included in the study.

The patients were divided into three group:

a) Group 1: Included progressive occult subfoveal choroidal neovascularization patients who received intravitreal injection of triamcinolone acetonide.

b) Group 2: Included occult subfoveal choroidal neovascularization patients who received intravitreal injection of bevacizumab.

c) Group 3 (control group): Included neovascular age related macular degeneration patients who refused intravitreal injection.

Exclusion criteria

Included patients with classic type of neovascular age related macular degeneration and any other ophthalmological. All patients were examined on the first day after injection, in first week, then every month for 6 months. A repeated injection was performed if there were activity of choroidal neovascularization (CNV). Intra-retinal and sub-retinal fluid accumulation, new intra-retinal and sub-retinal hemorrhage and CNVs growth were signs of CNVs activity. Re-treatment was done if there were signs of CNV activity or decreasing visual acuity. At baseline of the study and at monthly intervals, all patients underwent a routine ophthalmological examination. Goldman applanation tonometry, direct and indirect ophthalmology, optical coherence tomography (OCT), and electroretinogram (ERG) were done. Fluorescein angiography was done using Topcon Corporation 2000, TRC, 50Ix, Japan. Fluorescein angiography was performed for all patients at beginning and after 3months and 6 months.

Optical coherence tomography (OCT)

OCT was done with Topcon, 3 dimensional OCT-1000 (Topcon Corporation, Tokyo, Japan). Internal fixation was chosen because of better reproducibility. It scanned a cube of 6x6mm length. Central macular thickness of a circular 1-mm radius area around the fovea was calculated.

ERG

Full field ERG and MF-ERG were recorded using Roland Consult, (Germany system). ERG was done according to ISCEV standard [8]. After topical corneal anesthesia (Benoxinate hydrochloride 4%), positive electrode (Dawson, Trick and litzkow (DTL) electrode) was placed just contact with corneal limbus, ground electrode was installed on the forehead and negative electrode was placed near orbital rim temporary. The recording was monocular.

Full field ERG

The test was started and recorded in 5 steps, scotopic rod response, scotopic combined response, oscillatory potential then light adaptation for 10 minute then photopic cone response and flicker response recording.

MF-ERG

Patients were positioned 30cm from the stimulus monitor. Stimulus clarity was adjusted by over-refraction. Each hexagon was temporally modulated between light and dark according to binary m-squence [9,10]. Patients fixated a spot in the center of the stimulus. The results of two 8-minute recordings were averaged to improve the signal to noise ratio.

Intravitreal injection of triamacinolone acetonide (IVTA)

In group 1, 25mg of crystalline triamacinolone acetonide (Volona A, Bristol-Myers-Squibb, Munich, Germany, containing 40mg of triamacinolone acetonide in 1ml) was injected intravitreal. The injection of 25mg of crystalline triamacinolone acetonide was performed using sharp 27-gauge needle in inferio-temporal quadrant 3.5mm from limbus.Then antibiotic ointment was applied.

Intravitreal injection of bevacizumab

All patients in group 2 received Intravitreal injection of 1.25mg/0.05 of bevacizumab. A total of 0.05ml Bevacizumab was injected into vitrous cavity 3.5mm from limbus in inferotemporal quadrant using 30 gauge needles. Postoperative antibiotics were used and a light patch was placed. The eye patch is removed the next day.

Statistical Analysis

Statistical analysis was performed using soft ware (SPSS WIN Version11.5, SPSS Inc, Chicago). Non parametric Wilcoxon test was applied for comparison. Spearman rank test and linear correlation analysis were used in order to evaluate the correlation with changes of MFERG, changes of OCT and best correct visual acuity. Significance was set at p=0.05 (2-tailed) for all statistical tests.

Results

The study included one hundred and fifty (150) patients (one hundred and fifty eyes). The patients were divided into three groups. Group 1 included fifty eyes (50) of fifty patients (50) with progressive occult or predominately occult subfoveal choroidal neovascularization who received one or more than one of intravitreal injection of 25mg of triamcinolone acetonide, Mean age was 60±8.6years ,ranged (55 -75 years old). Group 2 included another fifty eyes (50) of fifty patients with progressive occult or predominately occult sub foveal choroidal neovascularization) who received one or more than one of intravitreal injection of 1.25mg/0.05ml of bevacizumab. The Mean age was 62±6.9 years, ranged (58-74 years). Group 3 (Control group) included fifty eyes (50) of fifty patients (50) (with neovascular age related macular but did not receive intravitreal injection of tri amcinolone acetonide for this disease after explanation the importance of treatment for visual acuity and CNVs. The Mean age was 61 ±7.9 years, ranged (58-74 years). There was no significant difference between groups. In group 1, Ten (10) patients received a second intravitreal injection of 25mg of triamcinolone acetonide. According to flourescein angiography, group 1 were further divided into subgroups with occult or mostly (>50%) occult without hemorrhage (n=40, 80%), subgroup with sub-retinal hemorrhage (n=7, 14%) and subgroups with retinal pigment detachment (n=4, 8%). While in group 2, occult CNV without haemorrhage was presented in 35 eyes (70%), with haemorrhage was present in 10 eyes (20%) and retinal pigment detachment was found in 5 eyes (10%) ( Table1). All three subgroups did not vary significantly (p=0.2) at baseline. In control group, all subjects were having occult CNV without sub retinal hemorrhage.

Visual acuity(VA)

All patients complained of decreased visions which were diagnosed by ophthalmologic examination within three months before IVTA. The mean VA at baseline in group 1, group 2 and control Group (0.12±0.19, 0.13±0.05 and 0.14±0.22) respectively. (Range from finger counting to 0.3 in group 1, from finger count to 0. 32 in group 2 and from finger counting to 0.5 in control group. For the Group 1 and Group 2, mean VA increased significantly (p=0.003) after first injection to maximum 0.35±0.25 during the follow up period (Table 2). The maximum postoperative VA was detected 1-2 months after the injection. The increase in VA was statistically significant in 1st month (p=0.003) and 2nd month (p=0.004) after the injection. The preoperative visual acuity and postoperative visual acuity achieved at the end of the follow up period did not differ significantly (p=0.2) in group 1 while in group 2, there is statistically significant difference between VA at the baseline and VA at the end. In group 1, Visual acuity significantly decreased towards the end of the follow up period, parallel to a disappearance of triamacinolone acetate crystals out of vitreous cavity. In group 1, after 1 month, 40eyes (80%) gained in visual acuity and 4eyes (8%) lost visual acuity. Visual acuity was unchanged for 6 eyes (12%). While, in group 2, 45 eyes (90%) gained in visual acuity. There were no significant correlation between postoperative visual acuity and postoperative change in visual acuity (p=0.6). For three subgroups, there were significant difference in gain in visual acuity (p=0.04). Ten eyes received second injection three months after first injection, visual acuity increased in eight eyes about one month after the re-injection and declined again after about 3 month in group 1 while in group 2, fifteen eyes received second injection after 2 months, and fourteen eyes of fifteen improved after reinjection. 

OCT

For group 1, Central subfield OCT thickness was 325±50μm at baseline. The central subfield OCT thickness decreased to 280±55μm at one week and 275± 40μm at one month (Table 3, Figure 1). In group 2, central subfield OCT thickness was 320±53μm at baseline. The Central subfield OCT thickness decreased to 270± 40μm at one week and 255±41μm at one month

ERG

F-ERG data is presented in (Table 4). No significant worsening of FERG response was observed during follow up period in the three groups. Most of the values were within the limits normal variation. For most subjects retested one month with F-ERG, the amplitude returned to baseline after a slight decrease in scotopic and photopic amplitudes at one week. For all subjects who was received either triamacinolone acetate or bevacizumab had an essentially stable F-ERG.

MFERG

In most cases, there was improvement at one week, one month and two months of IVTA, then return to baseline value at 3 months (Table 5, Figure 2 & 3). In group 2, there was increase in amplitude and decrease in latency reach the maximum after 2 months.

Intraocular complications

In group 1, IOP increased significantly (p=0.005) from 14.5±2.5mmHg at baseline of the study to a mean maximal value of 20±5.6mmHg again decreased significantly to 16.5mm Hg at 6 months after IVTA at p=0.001. IOP measurements at the end were slightly and significantly (P=0.05) higher. During the study, IOP was higher than 22mmHg in 30 eyes (60%). In those patients, IOP normalized by topical anti-glaucomatous drugs. Optic nerve damage was not detected. While in group 2, there was no case with increase in intraocular pressure. With respect to other complication of IVTA, three cases of cataract were detected in group 1, while no case of cataract was observed in group 2. No postoperative infectious endophthalimitis, rhegmatogenous retinal detachment or proliferative vitreo-retinopathy was detected in groups 1 and group 2.

Discussion

While, classic type of subfoveal neovascularization, photodynamic therapy with verteporfin stabilizes or increases visual acuity. Photodynamic therapy for occult subfoveal neovascularization is unsuccessful [11,12]. Steroids have antiinflammatory, antiangiogenic, antifibrotic and antipermeability properties, which contribute to stabilization of the blood- retina barrier [13] Penfold et al. [14,15] Chella et al. [16], injected trimacinolone intraviteal to treat exudative macular degeneration. Additionally, Danis et al. [17], detected a beneficial effect of trimacinolone in the study group compared with control group. Also, Ranson et al. [18], treated recurrent subfoveal neovascularization after laser treatment by IVTA. Chella et al. [16] evaluated the efficacy of intravitreal of trimacinolone for one and half year in exudative age related macular degeneration. They reported that a single intravitreal injection of 4mg of trimacinoloneacetate was helpful in treatment of exudative age related macular degeneration. In this study (in group 1), there was increase in visual acuity, reduction of fluorescein angiography leakage, reduction central macular thickness and increase in amplitude of MFERG with reduction of implicit time in 40 eyes of 50eyes (80%) within 2 months. Ten eyes of 40 eyes (25%) receive another intravitreal injection after 3 months (after beginning of reduction of visual acuity with increase macular thickness, reduction of amplitude of MFERG and increase implicit time). There was improvement of six of ten eyes (60%).

There was correlation between visual acuity and central macular thickness (p=0.008, R=0.5) and visual acuity and MFERG amplitude (P=0.006, R=0.55). Also, there was significant correlation between central macular thickness and MFERG amplitude (P=0.001, R=0.65) in group 1. In this study, we injected high dose of triamcinolone acetate intravitreal in group 1, because the results of previous studies were not clear; Jonas et al found significant increase in visual acuity after intravitreal injection of 25mg of trimacinolone acetate [19,20]. while Gillies et al. [21], reported no effect of 4mg of intravitreal injection of trimacinolone acetate on the development of sever visual loss during one year follow up. The Causes for the difference between studies may be the amount of injected trimacinolone acetate Second cause for difference between studies may be related to the effect of development of cataract on vision. Other cause for discrepancy between this study and investigation of Gillies et al. [21] may be that their study included classic subfoveal neovascularization that had a worse prognosis than occult choroidal neovascularization.

There was significant elevation in intraocular pressure in group 1 compared with other groups. There was 30 eyes (60%) had increased intraocular pressure. All cases were controlled with medical anti-glaucomatous treatment. Various studies have reported increase of IOP ranging from11-30% of subjects following IVTA [17,19,22] None of patients had been shown infectious endophthalmitis, rhgmatogenous retinal detachment , or proliferative vitreo retinopathy in this study .

Jonas et al. [19] found the reduction of visual acuity started 4-5 months after initial increase in visual acuity two months after injection. Similarly, in the present study after initial increase of vision two month after injection, visual performance started to decrease again. This may be result from resolving of trimacinolone acetate crystals Vascular endothelial growth factor (VEGF) plays an important role in the pathogenesis of AMD 22 Intravitreal bevacizumab injection was reported to be effective for treatment exudative AMD. Bevacizumab inhibit VEGF, decrease angiogenesis and decrease vascular permeability. [23-25].

In group 2, there were increase in visual acuity, reduction in retinal thickness and improvement of electrophysiological amplitudes and latencies. The improvement was slightly more significant in group 2 than in group 1 (As seen in Table 1) The cause for this improvement in group 2 more than group 2 is that triamcinolone exerted its antiangiogenic effect by enhancing endostatin expression rather than suppressing VEGF expression [26]. While bevacizumab decrease angiogenesis by decreasing VEGF expression and enhancing endostatin [27]. There was correlation between visual acuity and central macular thickness (p=0.006, R=0.55) and visual acuity and MFERG amplitude (P=0.005, R=0.65). Also, there was significant correlation between central macular thickness and MFERG amplitude (P=0.003, R=0.6) in group 2. Similarly, Rosenfeld et al reported that intravitreal injection of bevacizumab cause marked decrease in retinal thickness without toxicity [28]. Ahmadieh et al. observed improvement of vision and reduction of thickness after bevacizumab [29]. Also, Falkenstein et al showed that primary bevacizumab therapy resulted in significantly visual improvement [30]. The bevacizumab preparation is unpreserved and contains no ingredients that are toxic to the eye [28]. Intravitreal bevacizumab is well tolerated in the majority of patients. In this study, there were no complications in group 2. Only subconjuctival heamorrhage in two cases which resolved within a week. While, Ahmadieh et al. [29]. Observed one case with pigment epithelial detachment without any cases of endophalmitis or sub-conjuctival haemorrhage [29]. Also, Cleary et al. [30]. Found endophthalmitis in 1 of 112 eyes, submacular hemorrhage in 3 of 112 eyes and retinal pigment epithelial tears in 3 of112 eyes. Ronan et al. [31], and Avery said that the presence of pigment epithelial detachment was risk factor for retinal pigment epithelial tear after IVB injection [32]. The limitations of this study were the method of measuring visual acuity. Instead of the charts used for the Early Treatment Diabetic Retinopathy [33], visual acuity was determined using Snellen charts. But, the same method was used to three groups. Other limitation of this study was limited follow up and limited number of the patients, the relatively high dose of trimacinolone acetate injected into eye. In summary, intravitreal injection of trimacinolone acetate and bevacizumab improve visual acuity transiently in patients with neovascular age related macular degeneration. Furthermore, intravitreal injection caused anatomical changes and functional improvement of MFERG. Bevacizumab gave more favorable visual outcome and anatomical and functional improvement than triamcinolone acetate. To stabilize visual acuity, repeated intravitreal injection is recommended with 2-3 months apart with take care of complication especially intraocular pressure in cases of IVTA.

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Monocular Optic Neuropathy: Case Unsolved-JOJ Ophthalmology

Case Presentation

Female patient, 58 years old, unremarkable general medical and ophthalmological history, complains about pulsatile headache, with no irradiation, no specific location, and absence of nausea or vomiting. The headache would not aggravate after Valsalva maneuver and faded without medication. Also, refers vision loss in the right eye (RE) since the beginning of the headache, 10 days before. The best corrected visual acuity (BCVA) was hand movement in the (RE) and 9/10 Snellen scale in the left eye (LE). It was observed a relative afferent pupillary defect (RAPD) graded 3+, no color perception on the RE, Ishihara plates fully read in the LE, no eye movement alterations, and no facial proprioception alterations. The anterior segment had no inflammation signs and phacosclerosis was present in both eyes. Posteriorly, therewas no signs of disc inflammation, vitritis, macular or vascular alterations. Intra-ocular pressure (IOP) was 15 mmHg bilaterally.

Investigations

Emergency head Computorized Tomography (CT) and Magnetic Resonance Imaging (MRI) with gadolinium were performed to rule out optic pathway lesions or neuritis. ESR, CRP, blood count were performed to exclude Giant Cell Arteritis, wich all came negative [1]. Furthermore, testing for HIV, Syphilis, Hepatitis B and C, IGRA Quantiferon-TB (Tuberculosis), ACE and urinary calcium (Sarcoidosis), ANCA PR3 and MPO (Autoimunity), HLA-B51 (Behçet's disease) and Anti-NMO Aquaporin 4 antibodies (Devic's disease) was completed, with no positive results [2]. Optic disc and macular spectral domain Ocular Computorized Tomography (sdOCT) had no acute alterations. Computorized static perimetry (CSP) was unreliable due to a high percentage of false positive and negative responses, but revealed a deep and general loss of visual sensitivity across all right visual field.

Differential Diagnosis

At this time, the main differential diagnosis were:

Posterior optic neuropathy (PON)

Although there was no big abdominal or heart surgery previously, an RAPD graded 3+ and deep visual loss were present [3], without optic disc edema.

Optic neuritis (ON)

The patient was not young enough to fit the diagnosis of multiple sclerosis or Devic's disease, plus, there were no lesions revealed by the MRI or neurological symptoms, but due to the profundity of visual loss [4], these options had to be considered.

Anterior Ischemic Optic Neuropathy (AION)

No disc edema was observed, so by definition, this option was excluded [5]. The patient had no risk factors.

Treatment

After exclusion of infectious possibilities, a 1Gr metilprednisone/day was administered for 3 days. After this period [6], she was medicated with oral prednisone 1mgr/Kg/ day for 2 months, and then started to halt it in a slow manner.

Outcome

The patient improved greatly after 2 months. RE BCVA was 9/10, no RAPD was present, Ishihara plates were completely read and equally fast [7]. RE CSP, wich had initially a Visual Function Index of 2%, presented lastly 65%, with a medium deviation of -15.42dB and pattern stand deviation of 8.45dB. LE was considered unremarkable. sdOCT revealed RE optic disc atrophy, as the peripapillary nerve fiber layer had a thickness of 60|im, and an apparent loss of macular nerve fiber layer thickness [8]. The optic atrophy was observed at the slit lamp.

Discussion

Initially, due to the absence of optic disc edema, the options considered were posterior to the optic disc, which lead us to think of Multiple Sclerosis and Devic's disease, but the neuro imaging and blood testing ruled out these possibilities. After 2 months, although RE vision had improved, an optic atrophy was evident. It's curious as there was no optic disc edema observed throughout the follow-up, and no occupying-space lesion was identified. Since there was a clinical response to the steroids, ON is a possible diagnosis, although the study was negative.

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Hemi-Central Retinal Vein Occlusion Secondary to the Habit of Forceful Sneeze Prevention-Juniper Publishers

Introduction

31 year-old man applied to the eye clinic with a complaint of silhouette in the lower paracentral visual field on his left eye. His central visual acuity was 10/10 both on his eyes. Fundus examination revealed hemi-central vein occlusion sparing the macula. A few days later widespread intra-retinal hemorhages fell into macula and visual acuity reduced dramatically. Detailed story of the patient pointed out that he had a lomber disc herniation 3 months ago at L3-L4 levels. Detailed history also showed that the patient had hypertrophic adenoids and hypertrophic nasal conc has which are under treatment by nasal decongestants. The patient did not have a heavy conditional work. But it had been speculated that powerful prevention and keeping the sneeze resulted both the herniation and hemi-central vein occlusion. Vein occlusions are common among olders but systemic disorders must be ruled out in youngers. We intended to share acute intra-ocular pressure increase as an uncommon cause for vein occlusion in this dramatic young man because systemic disease research came clean. Lomber herniation usually occurs secondary to forcing the inter-vertebral discs to high pressures that they can endure. So they can rupture and cause disc herniation. Performing valsalva maneuver by coughing, sneezing or sneeze prevention may increase pressure inside the medulla spinalis so it can result as disc herniation. This maneuver not only affects on the intervertebral discs, but also on all intra- and extra-dural structures and nerves [1]. So optic nerve head may be affected as an intra-dural component.

Hemi-central retinal vein occlusions which are classified in central retinal vein occlusion may result from hypertension, diabetes, atherosclerosis, hyper coagulable states and hypercholesterolemia. Younger patients with hemi-central retinal vein occlusion must be ruled out from diseases mentioned above. Valsalva manoeuver is the forced exhalation against a closed glottis. First described by an Italian anatomist in 17th century Antonio Maria Valsalva, it is now a well known entity amongst medical practitioners. It leads to increased intra- thoracic and intra-abdominal pressure and raised central venous pressure. It is an uncommon condition and has been reported to occur with various forms of Valsalva stress such as weight lifting, physical exercise, balloon blowing, birth labour [2]. Sneezing prevention may be accepted as a rare cause of valsalva stress. Preretinal haemorrhage caused by this sudden rise in venous pressure was first termed as Valsalva haemorrhagic retinopathy by Duane TD in 1972 [3]. Valsalva retinopathy is typically seen in young males. Sometimes it may make a fluid level which's location can be subinternal limiting membrane (ILM) or subhyaloid. Duane [3] first postulated the mechanisms for retinopathies due to distal trauma as alteration in arterial circulation (forward retinopathy), venous circulation (backward retinopathy) or to changes occurring in both systems (mixed retinopathy). Valsalva retinopathy may look like vein occlusions in appearance as spreaded intraretinal haemorrhages but transformation of valsalva retinopathy to vein occlusion related macular edema is a rare antity. Here i report a case about valsalva retinopathy which transformed to complete hemi-central vein occlusion in a week.

Case Presentation

A 31 year-old healthy man complained about a blurry silhouette in the lower para-central visual field in his left eye after a powerfull sneeze prevention. Ophthalmic examination revealed bilateral 10/10 visual acuities and normal ocular tensions. Detailed examination showed a hemi-central vein occlusion sparing macula in the left fundus. There were widespread intra-retinal haemorrhages diffused in the upper hemi- central retina and a pre-retinal and subhyaloid haemorrhage just near the temporal macula. The fundus view is seen in Figure 1. Questioning about heavy work conditions for probable valsalva maneuver indicated a sneeze prevention habit. He had a lomber disc herniation at the L3-L4 levels 3 months ago and hypertrophic adenoids and nasal conchas which were still being treated by nasal decongestants. Lomber disc herniation is seen in Figure 2. Sneeze prevention habit was accused for lomber disc herniation by neuro-surgeon. After a week of rest recommendation and conservative management for valsalva retinopathy, the haemorrhages came to the bottom of macula and clinical macular edema settled upon as his visual acuity decreased to 3/10. Intravitreal bevacizumab injection was performed in other eye center at second week and he had full visual recovery again in two weeks time after the injection.

There were no retinal holes, tears, detachment, perivascular sheathing or snow banking at parsplana. Vein occlusions were not common among youngers so investigations including complete blood counts, clotting parameters such as antithrombin, protein c, protein s, d-dimer, factor 5, biochemical parameters such as urea, creatinine and glucose, crp, sedimentation were normal. Systemic evaluation was carried out by the physician and no abnormality was detected. We diagnosed him as hemi-central vein occlusion secondary to valsalva retinopathy. Systemic clotting abnormalities must be ruled out in hemi-central retinal vein occlusion among youngers. Disc herniation without predisposing factor and vein occlusion after sneeze prevention steered us to think about valsalva retinopathy. Intravitreal bevacizumab injection was performed and laser photocoagulation was performed for the macular edema secondary to hemi-central retinal vein occlusion. Because of the valsalva retinopathy was not limited to the pre-retinal and sub-hyaloid area, a week later the haemorrhages were spreaded widely to the macula and macular edema was settled. The visual acuity of the patient decreased to 3/10 snellen on the left and conservative treatment modality for the valsalva haemorrhagic retinopathy was replaced by the treatment of macular edema secondary to hemi-central retinal vein occlusion.

Results

The visual acuity of the patient is 10/10 on both eyes with complete resolution of macular edema for 2 months. Ghost vessels are seen on fundus examination and retinal haemorrhages are just about to resolve. These are seen in Figure 1. Bed rest and avoiding from valsalva maneuvers were adviced for lumbar disc herniation.

Discussion

Valsalva retinopathy is a unilateral or bilateral condition which occurs by rupture of superficial retinal capillaries. Heavy lifting, straining, coughing or vomiting may cause it. Valsalva maneuvers typically result in superficial retinal haemorrhages(sub-internal limiting membrane, subhyaloid) with a predilection for the macula, but subretinal, retinal and vitreous haemorrhages have been reported. The prognosis is variable, however complete visual recovery is possible [4] Some patients may develop a poor visual outcome due to the presumed toxic effects of dense premacular haemorrhages on the retinal pigment epithelium and/or epiretinal membrane formation. Nd-YAG laser puncture of the posterior aspect of the vitreous may allow drainage of premacular haemorrhage or vitrectomy may be performed in selected cases [4]. It may also managed conservatively with good outcomes. It may Valsalva retinopathy is a self-limited condition. Recurrence of valsalva retinopathy can be encountered if preventing any condition leading to valsalva like stress is not succeeded [2]. Our patient did not know about the harmful effects of sneeze prevention. A careful history is the key to the diagnosis. The prognosis is good and patient needs to be counselled to avoid any such Valsalva manoeuver like stress to prevent recurrence in future. Habits which are against the physiology such as sneeze prevention may be harmful. Patients should be careful in every physical activities which may induce valsalva maneuver. Valsalva retinopathy may be seen as central or hemi-central retinal vein occlusion.

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 Translational Research on BDNF may Lead to New Research Therapy in Glaucoma

Introduction

Glaucoma is a group of eye disorders, currently recognized to be multi factorial, progressive, leading to reduction in vision and eventual blindness. Glaucoma is characterized by progressive degeneration of the retinal ganglion cells (RGCs) and optic nerve (ON) fibers it is one of the leading causes of vision loss. Usually glaucoma affects the older population. Over 60 million people worldwide were estimated to be affected by glaucoma in 2010, and bilateral blindness from the disease was estimated to be present in 4.5 million people with glaucoma [1] . A generally accepted theory suggests an initial insult to the axons of RGCs in the ON head region, where they exit the eye [2] . Glaucoma is characterized by anomalies such as the RGC degeneration and cell death, loss of RGC axons as well as ON atrophy, impairment of visual function with visual field defects and finally loss of neurons in the lateral geniculate nucleus and visual cortex. Several types of glaucoma are known; these can be divided in primary and secondary. Primary open-glaucoma (POAG) is considered the most common subtype of glaucoma. In POAG, ocular hypertension represents the major risk factor for glaucoma onset and progression. Ocular hypertension is a condition in which intraocular pressure (IOP) is consistently greater than normal. In the presence of ocular hypertension, there is no obvious damage to the ON as detected by an eye examination, ON imaging, or evidence of visual field changes. However, retinal responses to patterned visual stimuli (pattern electro retinogram, P-ERG) together with a transcription factor (Brn3) expressed in RGCs are altered during ocular hypertension in a murine model of glaucoma [3]. It is reasonable to think that ocular hypertension applies some stress to RGCs and their circuitry during a phase preceding the degeneration of RGCs and ON atrophy. In addition, it has been reported that the rate of untreated ocular hypertension patients in developing glaucoma was 9.5 percent in 5 years and 22 percent at 13 years [4].

There are limitations to treating IOP exclusively, including:

1. Several glaucoma patients do not show an elevated pressure (normotensive glaucoma).
2. There are patients who continue to progress with controlled low IOP.

Indeed, IOP lowering by means of anti-glaucoma drugs, laser or incisional surgery is unable to arrest the progression of glaucoma till blindness.

These observations suggest that IOP-independent mechanisms contribute to disease progression, and require a new therapeutic approach independent of IOP lowering to prevent vision impairment, RGC death and ON degeneration. Neuro protection by neurotrophic factors was initially investigated for neurodegenerative diseases such as the Alzheimer's disease; evidence suggests that treatments with neurotrophic factors such as the brain-derived neurotrophic factor (BDNF), ciliary neurotrophic factor (CNTF), glial cell line-derived neurotrophic factor (GDNF), neurotrophin-4 (NT-4) increase the survival of neurons in rodent models of injury and disease [5]. BDNF appears to provide the highest level of protection by supporting both protective and regenerative functions. The notion of a neuro protective role for BDNF in retinal degenerations derives from the observation that death of photoreceptors is prevented by intravitreal BDNF administration [6]. BDNF has been shown to protect retinal cells, in particular RGCs, in various models of ON injury and disease [7,8], interestingly, BDNF is effective in a rat glaucoma model as shown by Martin and coworkers [9] using AAV-BDNF transfection. BDNF is a high molecular weight protein locally produced by cells in the ganglion cell and inner nuclear layers [10], its TrkB receptor is expressed in RGCs, amacrine and Müller cells [10,11] that represent the cellular target of BDNF trophic action. RGC take up BDNF and transports it along axons towards target neurons and back to the cell body in the retina [12], BDNF is one of the molecules delivered to the retina by way of retrograde axonal transport [13]. These studies suggest a role for BDNF in retinal injury and diseases. A strong rational supports BDNF treatment in glaucoma. Previous work showed that BDNF delivery to the retina is reduced in glaucoma models [13,14] and BDNF level is reduced in ocular tears [15] and blood [16]. BDNF, but not its receptor TrkB, is reduced in murine models of glaucoma [17,18]. Altogether, these studies suggest that BDNF is expressed in the retina, to help protect neurons maintaining their survival and connections when damaged by injury and diseases. Thus, neuro protection by BDNF in glaucoma can be pursued to protect RGCs. However, the therapeutic approach based on BDNF is promising if the restrictions imposed by complex pharmacokinetic of high molecular weight proteins (for example BDNF low propensity to pass blood- brain barrier following systemic treatment) can be overcome. So far BDNF, as well as other growth factors, has been typically administered to the internal ocular tissues by intravitreous or retrobulbar injection, these methods of treatment are associated with the risk of various complications such as the ocular bulb perforation and infections [19]. Given that glaucoma is a chronic condition, developing over several years, the prospect of chronic, intravitreous administration of BDNF is not realistic. To overcome these obstacles we recently settled a simple method of treatment with BDNF in the form of collyrium. We showed that treatment for a short period with BDNF eye drops was able to increase the retinal level of BDNF in the mouse and rat retina [3]. Remarkably, BDNF topical eye treatment was able to rescue retinal responses to visual stimuli in a murine model of glaucoma during an early phase of degeneration characterized by ocular hypertension, visual impairment and RGC alterations [3] . Thus, the specific anatomical construction of the eye and, possibly, the presence of BDNF carriers offer the possibility for local drug delivery that can avoid the barriers. However, in view of therapeutic approach based on BDNF in glaucoma there are fundamental questions to be answered.

The first question is whether neuro protection by BDNF in glaucoma depends on the stage of retinal degeneration. In our previous work we showed that a short period of treatment with BDNF eye drops was able to restore vision and protect RGCs during an early phase of retinal degeneration in a murine model of glaucoma [3]. However, whether BDNF protects retinal cells at advanced stages of neuro degeneration in glaucoma is still an open question. The second question concerns the durability of BDNF neuro protective effect. Indeed, for glaucoma like other progressive neurodegenerative diseases, it is challenging to identify clinical outcome measures for use in short term proof-of-concept studies. A related question is whether BDNF treatment results in long-term neuro protective effects [20]. Previous results on this issue were contradictory. Interestingly, recent results showed that over expression of BDNF delayed progressive RGC and axon loss in hypertensive eyes [21].

The third question concerns the dose/concentration of BDNF to be used when supplied in the form of eye drops. In other words, does the topical eye application of BDNF represent a safe method of neuroprotection in glaucoma? In a previous work we used high BDNF doses to restore vision in a murine model of glaucoma [3]. This raises concerns over promotion of tumor growth resulting from BDNF taken up from non-retinal tissues; indeed, BDNF, as well as other neurotrophic factors, has been associated with neovascularization and tumor promotion [22]. To reduce the dose/concentration of BDNF we recently formulated BDNF in tamarind seed polysaccharide (TSP) [23], the TSP-BDNF combination appeared to confer a relatively higher bioavailability to BDNF.

Future Directions

Proven neurotrophic factors such as the BDNF should be safe, effective and characterized by long-lasting protection, thus these agents can be taken to clinical trials in glaucoma and other retinal degenerations such as the Retinitis Pigmentosa and age- related macular degeneration (AMD). Drug delivery systems suchas eye drops and, possibly, encapsulated cell technology, AAV-BDNF transfection should be considered for use.

Acknowledgment

Supported by the Department of Biotechnological and Applied Clinical Sciences (DISCAB), University of L'Aquila, and? the scientific consortium IN-BDNF. We thank Ms. S. Wilson for revising the English style.  

Juniper Publishers- JOJ Ophthalmology

 Nasolacrimal Duct Obstruction Review-JOJ Ophthalmology

Introduction

The lacrimal system comprises two components the main and accessory lacrimal glands and their secretions and the lacrimal excretory system [1]. The lacrimal excretory system is divided into the proximal and distal sections. The proximal section includes the punctum, canaliculus, and the common canaliculus [2,3]. The distal lacrimal drainage system consists of the lacrimal sac and the nasolacrimal duct that finally ends under the inferior turbinate and empties into the inferior meatus [2].

The precorneal tear film is composed of aqueous, mucinous and oily components and is necessary for the maintenance of the cornea as well as the maintenance of the ocular surface epithelium. More than 90% of the lacrimal fluid is removed by the excretory system, whereas less than 10% evaporates between blinks. Outflow is mainly regulated by the pumping effect of the orbicularis oculi muscle (Horner muscle) [3,4]. Tears are thus drawn into the lacrimal excretory system after each blink. The passage of tears down the nasolacrimal duct is influenced by gravity, evaporation in the nose, and inspiration and expiration.

Diagnosis

A detailed history of any systemic or topical medication, surgery, trauma or scarring, and infection must be obtained. It is valuable to grade the severity of epiphora using a uniform grading system such as the Munk scale [5]. Slit lamp examination starts with recognizing the papilla, presence of a membrane or fibrosis over the punctum, punctum size, tear meniscus height, eyelid margin, conjunctiva around the punctum, eyelid malposition, position of the punctum in the tear lake, and any sign of previous surgery. The Schirmer test [6], tear break up time [7], ocular surface staining, and tear meniscus height will rule out any associated ocular surface abnormalities. Abnormal dye disappearance test is a very maneuver to assess abnormal tear drainage system and is especially helpful in pediatric patients [7].

Congenital Nasolacrimal Duct Obstruction

Congenital nasolacrimal duct obstruction is the first cause of pediatric epiphora. Other causes include congenital punctum and canaliculus stenosis and/or atresia, nasal malformations and craneofacial abnormalities. It is frequently seen at birth due to lack of perforation of the valve of Hasner or an inferior and distal nasolacrimal duct opening failure. At birth, half of the nasolacrimal new born pathways are not permeable. A spontaneous apoptosis mechanism takes place between 3^rd- 4^th weeks after birth. Nevertheless, the obstruction persists in approximately 20% of the patients. Symptoms of congenital nasolacrimal duct obstruction consist of epiphora and dacryocystitis. The diagnosis is easily made in the office by observing epiphora and mattering of the eyelashes (Figure 1). It can be confirmed by compression over the nasolacrimal sac, which results in regurgitation of mucopurulent material in those patients who have developed chronic dacryocystitis. Instillation of 2% fluorescein dye and observation of abnormally delayed passage from de cul-de-sac is helpful in confirming the diagnosis.

This is a rare entity presented at birth or within the fourth week after birth. The blockage Rosenmüller valve. An edematous, tender and red mass below the medial canthal tendon will be clinically found (Figure 2). Conservative management (medical treatment). If dacryocele is initially sterile, all patients must be treated with warm compresses, local massage and topical antibiotics [8]. Those infected will be treated with broad spectrum intravenous antibiotic therapy [9]. Local massage by pushing down the lacrimal sac is useful and accelerates the lumen duct perforation process (Figure 3). Controversy exists whether conservative management or early probing for decompression are preferable.

Surgical Management of Congenital Nasolacrimal Obstruction

Probing consist by introducing a thin metal probe into the lacrimal punctum trough the nasolacrimal pathway, producing a mechanical opening in the obstruction site. It is an operating room procedure under general anesthesia. The ideal time is controversial, most of the time the procedure is performed around the first year of life for those patients that did not show spontaneous improvement or despite conservative treatment [10].

Close dacryointubation is performed by placement of silicone stents through the superior and inferior canaliculus and down to the nasolacrimal duct. This dilates the inferior meatus. The duration of the stent employment ranges from 6 weeks to 6 months [10]. Dacryocystorhinostomy surgical procedure involves the removal of bone adjacent to the lacrimal sac draining directly into the nasal cavity and it is performed when siliconte intubation have failed.

Differential Diagnosis

Dermoid cyst, dongenital glaucoma, acute conjunctivitis, corneal abrasion, trichiasis, ocular foreign body sensation and meningoencephalocele must be discarded.

Acquired Nasolacrimal Duct Obstruction

The primary acquired nasolacrimal duct obstruction is caused by inflammation or fibrosis without any precipitating cause. Appears in middle age and elderly females in 3:1 ratio. The obstruction site is located in the lower nasolacrimal fossa and middle nasolacrimal duct. The secondary acquired obstruction is caused by inflammation or fibrosis with precipitating causes as infectious, inflammatory, neoplastic, traumatic or mechanical factors [11,12].

Clinical presentation Patients with primary acquired nasolacrimal duct obstruction most commonly present with a history of epiphora. A chronic dacryocystitis owing to tear stasis can show a mucopurulent discharge at the punctum, or pus can be expressed from the punctum by massage of the lacrimal sac. Two stages can be distinguished [13].

Acute Dacryocystitis

Is an acute inflammation of the lacrimal sac due mostly to the obstruction of nasolacrimal duct. In most cases is a clinical diagnosis. Lacrimal sac bacterial overgrowth and inflammation? occludes the superior and the natural drainage creating a true abscess. Symptoms and signs include a no compressible painful and erythematous mass below the medial canthal tendon. Medical treatment must be initiated because of the risk of extension to the periocular tissues and the orbit (Figure 4 ) including topical and systemic antibiotics, analgesics and antiinflammatory measures. Local heat and massages helps drainage and the opening of the obstruction siteLacrimal sac abscess requires sometimes manual percutaneous drainage, material can be collected and cultivated (Figure 5). Avoid irrigation during the acute phase because the risk of dissemination of the infectious process. Definitive treatment is a dacryocystorhinostomy procedure which can be performed as an external or internal endoscopic. It is preferable to postpone two or three weeks after the acute phase resolution.

Chronic Dacryocystitis

Symptoms and signs include recurrent epiphora, swelling and redness at medial canthus and a painless and compressible mass below the medial canthal tendon. The patient usually refers history of previous acute dacryocistitis or chronic unilateral conjunctivitis.

The lacrimal sac is filled with mucoid or purulent discharge that can be expressed frequently with local massage (Figure 6). Medical treatment includes topic and systemic antibiotics and a dacryocystorhinostomy as the surgical first choice. Differential Diagnosis: Preseptal cellulitis, sinusitis, canaliculitis, sebaceous cyst and neoplastic tumours.

Conclusion

For most tearing patients a diagnosis can be arrived at after a thorough history and a few relatively simple office procedures. A small number of cases will require more sophisticated studies to confirm the site of anatomic block. With the various test available, appropriate medical or surgical management can be determined in the vast majority of patient with tear production and drainage imbalance. Nasolacrimal duct obstruction is a common finding and the ophthalmologist must be prepared to recognize signs and symptoms to perform an accurate diagnosis and offer a correct management.

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Posterior Astigmatism: Improving Refractive Outcomes with Toric IOL Implantation-Juniper Publishers

Abstract

Cataract surgery is not only a rehabilitative surgery, but also a refractive procedure, largely because of the intraocular lens (IOL) improves in latest years. However, recent studies showed a significant residual astigmatism after phacoemulsification with toric IOL implantation. There are several factors that can cause astigmatism refractive errors, such as IOL misalignment, factors related to the incision, incorrect calculation of toric IOL and corneal measurement errors. We believe that overlooking posterior corneal power is one of the most relevant reasons for refractive errors after cataract surgery with toric IOL.

Mini Review

Cataract is one of the leading causes of blindness worldwide, and its extraction is one of the most performed surgical procedures nowadays. The improvement of phacoemulsification techniques contributes for an increasingly less invasive procedure. Advances in IOL (intraocular lens) calculation, as well as the evolution of IOL technology increase patient's expectations for better results and postoperative spectacle independence [1}. Astigmatism is responsible for 13% of refractive errors [2]. Approximately 20 to 30% of patients submitted to cataract surgery had corneal astigmatism of 1.25 diopters (D) or higher, and around 10% of the patients have 2,00D or higher [3]. Recent studies demonstrate that residual astigmatism after toric IOL implantation is frequent [1,4]. Therefore, the correct astigmatism measurement is crucial for better post-operative results and, consequently, the patient's satisfaction. Furthermore, in present days, the 'gold standard’ in IOL power calculation is optical coherence biometry associated with keratometry. However, the capacity of this technique to determine the true corneal power is limited [5] because it assumes a fixed posterior-anterior curvature ratio, to estimate the posterior corneal curvature influence in the total corneal power [2]. Ignoring the posterior corneal power was recently highlighted as an important factor that leads to errors in toric IOL [5,6]. Posterior corneal refractive power is low when compared to the anterior surface, but when we take the astigmatic power into account, the posterior cornea surface can represent more than 20% of the total astigmatism power of the cornea [5].

Devices for an accurate measurement of posterior corneal surface have a shorter story when compared to the methods to evaluate the anterior surface. Nevertheless, this data can currently be obtained by several methods such as Scheimplug imaging and optical coherence tomography. This way, total corneal power can be calculated by using ray tracing or Gaussian optics thick-lens formula [2]. Posterior astigmatism has its own clinical importance demonstrated since 1890 by Javal, and recent studies show that posterior astigmatism is usually against the rule and the mean power is around 0.3D (Table 1) [7-10]. When the anterior corneal surface shows with the rule astigmatism, the posterior astigmatism compensates the anterior surface, and consequently reduces the total astigmatism. However, if the anterior surface astigmatism is against the rule, the total astigmatism will increase [9]. Ho et al showed that neglecting posterior astigmatism can cause absolute errors of 0.2±0.16D in astigmatism magnitude and 7.4±10.3 degrees in astigmatism angle [11]. The surgical prognosis related to the reduction of postoperative residual refractive cylinder is influenced by the correct calculation of the total corneal astigmatism and its axis. In conclusion, the efficacy of toric IOL implantation can be enhanced with the measurement of both anterior and posterior astigmatism.

Competing Interest

The authors declare that they have no conflict of interests regarding the publication of this paper.

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