Ординатура / Офтальмология / Учебные материалы / Uveitis Text and Imaging Text and Imaging Text and Imaging 2009

Figure 9: Schematic diagram of the pharmacology of cystoid macular oedema. The growth factors involved in increasing BRB permeability are derived from membrane lipid and arachidonic acid breakdown. Steroids inhibit Phospholipase A, whereas NSAIDS inhibit Cyclooxygenase 1 and 2. This in turn leads to a decrease in the permeability factors PGF2-alpha, and Leukotriens

On the basis of these scientific findings topical NSAIDs have become a mainstay in the treatment of inflammatory CMO.68 The clinical efficacy of topical NSAIDs has been shown in several studies both for the prevention72-75 and the treatment68,76-78 of inflammatory CMO more particularly related to cataract surgery.

Two double-masked, placebo-controlled studies in which corticosteroids were not used demonstrated that ketorolac 0.5 percent ophthalmic solution, administered for up to 3 months, improves vision in some patients with chronic CMO after cataract surgery.79,80 A meta-analysis of the results from randomized controlled trials suggest that NSAIDs are beneficial as a medical prophylaxis for aphakic and pseudophakic CMO and medical treatment for chronic CMO.75

On the basis of these findings it has been suggested to employ topical NSAIDs in the treatment of inflammatory CMO68 especially when related to ocular surgery.

The most common local adverse reactions following instillation of topical NSAIDs comprise transient burning, stinging and conjunctival hyperaemia. Less commonly local complications include superficial punctuate keratitis, epithelial defects, corneal melting, delayed wound healing and rarely infiltrates and ulcerative keratolysis.69

Carbonic Anhydrase Inhibitors

Medical treatment of cystoid macular oedema with CAIs has been used for over a decade. The initial

observation on its therapeutic efficacy was reported by Cox and Alan Bird in 1988 in a study of 41 patients with CMO of various etiologies.81 It appears that CAIs modulate the polarized distribution of carbonic anhydrase at the level of the RPE and thus the fluid resorption from the retina to the choroid.82,83

Several studies have investigated the effect of CAIs on CMO in uveitis.84-87 Farber et al84 studied 30 patients with CMO due to idiopathic chronic iridocyclitis in a prospective double-blind, placebo controlled, crossover study and found a statistically significant improvement of visual acuity and fluorophotometry measurements after 14 days of treatment. Younger patients responded better to therapy than older individuals. Schilling et al88 looked at the long-term efficacy of CAIs for CMO in uveitis and pseudophakia. Forty-one eyes were followed-up for on average of 3.1 years. A 50 percent success rate was observed in the uveitis group, but only half of these patients could be weaned off the drug in the long run. The remaining cases needed a maintenance dosage of 125-500 mg/d for an average of 2.3 years. Whitcup et al86 also reported a decrease in cystoid macular oedema in patients with chronic uveitis, but not improvement on visual acuity. Additional single case reports describing CMO in association with retinal surgery have also hinted at a positive effect of treatment with CAI.89,90

The major side effects of acetazolamide treatment incurred during these trials included nausea, dizziness and paraesthesia in the arms and legs. Some patients with CMO who responded well to acetazolamide were not able to continue on the drug because of these associated side effects.87 If long-term administration of CAIs is planned, regular renal function monitoring should be carried out and daily supplementation with potassium chloride is advisable to counteract the excessive loss of potassium through the urine.87 It appears that some people develop a tachyphylaxis to the CAIs meaning that the therapeutic efficacy of the treatment starts to wane after some time.91 An increase in drug dose is usually not successful in overcoming this situation. It has been speculated that this tachyphylaxis may be associated with the presence of anti-carbonic anhydrase antibodies in the serum.92

Corticosteroids

Corticosteroids inhibit the enzyme cyclo-oxygenase, but they also have a multitude of other anti-inflam-

matory effects by acting, among others, on interleukine-1 and by reducing vascular permeability. Their additive anti-inflammatory effect to NSAIDs was shown for the treatment of a postoperative inflammatory reaction.93 Both these drops are thus used in the treatment of any inflammatory CMO. Steroid treatment may also be used in association with carbonic anhydrase inhibitors.68,81,86 One of the mode of action is most probably the increased resportion of fluid through the retinal pigment epithelium.82,83 Another action of steroids is the downregulation of vascular endothelial growth factor production, which will in turn render the blood-retinal barrier tighter.94

Corticosteroids may be administered topically, by periocular injection, orally and parenterally. Topical corticosteroids penetrate the corneal epithelium and reach the anterior chamber. Significant potential complications of topical steroid use may thus include glaucoma, posterior subcapsular cataracts, exacerbations of infections, and recurrence of herpetic keratitis.1,95 Corticosteroids may be administered as sub-tenon or peribulbar injections, which allows the deposition of a substantial single dose of drug permitting a more sustained drug release while minimizing the systemic side effects. Possible adverse effects include globe penetration, elevation of intraocular pressure (IOP), and cataract formation. It has been estimated that the risk for a temporary IOP elevation after subtenon injection of Triamcinolone is about 30 percent, but most of these patients can be managed with temporary topical anti-glaucoma drops.96

Only 1 percent of patients carry to risk of having to submit themselves to a surgical procedure to equilibriate the intraocular pressure.

Systemic corticosteroids are also used for the treatment of inflammatory CMO primarily in bilateral or resistant cases. Initial high doses, to achieve control of the inflammatory process, followed by a slow taper, in an attempt to prevent recurrences, are usually needed. Ophthalmic and systemic side effects are common following systemic administration of steroids including osteoporosis, exacerbation of diabetes and hypertension, Cushingoid state, and adrenal suppression. Due to these potentially severe systemic complications, oral steroids should be used with caution and if long-term high-dose corticosteroids are required, the treatment should always be planned after consultation with an internist.1

Many recent studies have reported positive results in the treatment of inflammatory oedema with intravitreal injections of steroids.97-102 Antcliff et al102 injected 2 mg of triamcinolone acetonide (TA) in six patients with refractory uveitic CMO. They reported a complete anatomic resolution in five of the six patients at 1 week as evaluated by OCT. However, between 6 weeks and 3 months after the injection, all five patients had recurrent CMO. In another study, Young et al101 injected 4 mg of TA in six patients with uveitic CMO resistant to other forms of therapy. Resolution of CMO was evident in all patients by 6 weeks post-injection, but four patients had recurrent CMO at 6 months postinjection. Androudi et al100 studied 20 eyes with macular oedema secondary to non-infectious uveitis which were treated with intravitreal TA injections and VA improvement was reported in 55 percent of the cases and complete resolution of the CMO in 50 percent of the cases. Potential adverse effects of intravitreal TA include glaucoma, cataract and endophthalmitis.99

Intraocular sustained drug release via implantable devices or injectable microparticles has also been investigated for treating uveitis and CMO.2,103,104 In 2005, the fluocinolone acetonide intravitreal implant (Retisert®), was FDA-approved for non-infectious uveitis affecting the posterior segment of the eye.103,105 Retisert will likely continue to aid in the effective treatment of uveitic cystoid macular oedema.99 A biodegradable polymer implant providing the sustained release of dexamethasone (Posurdex®) is undergoing phase 3 clinical trials. Data from 6-month phase II clinical trial studies showed that patients with CMO (associated with diabetes, retinal vein occlusions, uveitis, and postcataract surgery) experienced a significant increase in vision after being surgically implanted.99

Anti-vascular Endothelial Growth Factor Agents

Anti-VEGF agents have recently come to the forefront as another promising treatment option for macular oedema.106,107 Anti-VEGF drugs inhibit vascular endothelial growth factor, which has been implicated as a major angiogenic stimulus responsible for neovascularization. VEGF is also involved in the pathomechanisms of inflammation and endothelial dysfunction and is a potent enhancer of blood-retinal barrier permeability.107

A recent study108 evaluated the short-term safety and efficacy of an intravitreal injection of the antiVEGF agent bevacizumab for the treatment of cystoid macular oedema secondary to uveitis. It was concluded that a single intravitreal injection of bevacizumab is well tolerated and is associated with short-term improvement in VA and decreased OCT retinal thickness in a considerable proportion of patients with uveitic CMO otherwise resistant to conventional therapy.108 Another pilot study has reported foveal thickness reduction and visual acuity improvement following intravitreal bevacizumab as a treatment for refractory macular oedema in patients with uveitis.106

Controversy exists, however, regarding the exact role of anti-VEGF substances in the treatment of postoperative CMO. Two studies have so far addressed the issue of intravitreal bevacizumab for postoperative CMO, with conflicting results. One study reported a significant improvement of VA and a decrease of macular thickness,109 while the other found no improvement.110

Immunosuppressive Drugs and Somatostatin Analogues

Steroid-sparing immunosuppressive drugs are frequently used as additional, second-line agents in patients with severe intraocular inflammation and CMO.1

Promising results have been reported using Interferon (INF) alfa-2a as a treatment for long lasting refractory cystoid macular oedema in uveitis.111 In addition, a beneficial effect of IFNb on inflammatory CMO was noted in a retrospective study with multiple sclerosis-associated intermediate uveitis.112 Nussenblatt et al113 reported comparable efficacy of cyclosporine A to prednisolone in the treatment of macular oedema in patients with endogenous uveitis. Anti-TNF Therapy has also been demonstrated as a promising therapy for uveitic macular oedema.114 Somatostatin analogues such as octreotide may also be effective in the treatment of CMO by blocking the local and systemic production of growth hormone, insulin-like growth factor and VEGF.2 Octreotide, resulted in marked improvement or complete resolution of CMO in a study of uveitic patients.115

Figure 10: Schematic diagram depicting the treatment algorithm for inflammatory macular oedema. The induction dose consists of acetazolamide 2 x 250 mg p.o. as well as topical steroid and NSAIDs. If there is no improvement within 3 weeks a subtenon injection of triamcinolone is applied, which can be repeated 2- 3 times as a function of therapeutic response. If the intial therapy is successful, the doses can be tapered slowly

THERAPEUTIC STRATEGY FOR THE MEDICAL TREATMENT OF INFLAMMATORY CMO

The initial treatment of straight forward postoperative and inflammatory CMO consists of topical NSAIDs and steroids 3-4 times per day. In most cases this is coupled with a systemic carbonic anhydrase inhibitor. Such as acetazolamide 250-500 mg/day. If the CMO does not respond to this kind of treatment, a series of 3 subtenon injections with triamcinolone are administered with a three week interval in between the injections and a discontinuation of the steroid drops. A maintenance therapy of NSAIDs and acetazolamide at reduced doses (125-250 mg/d) may have to be continued indefinitely by titrating the dose according to objective and subjective observations. Using this approach more than 50 percent of postoperative and simple inflammatory CMOs are responding favorably. The use of subtenon injections is indicated in practically all cases of more severe inflammatory CMO. This treatment is successful in about 90 percent of non-chronic CMO (< than 6 months duration).68 In refractory cases other alternatives such as Anti-VEGF drugs may be considered (Figure 10).

SURGICAL TREATMENT

The role of vitreous surgery in uveitic macular oedema is not yet completely defined, although there have been several sporadic reports on the outcome of pars plana vitrectomy (PPV) in cases unresponsive to medical

treatment.116-124 Dugel et al122 reported the efficacy of PPV in improving VA and reducing the CMO in 11 eyes of nine patients with intraocular inflammationrelated CMO that was unresponsive to corticosteroids. Other retrospective, non comparative studies have also suggested that PPV maybe associated with a beneficial effect in CMO attributable to intermediate uveitis or sarcoidosis.119,121 Tranos et al116 however found angiographic improvement in only one third of the patients that underwent PPV for macular oedema secondary to chronic uveitis.

Although, there is limited evidence regarding the role of PPV in the treatment of uveitic oedema it has to be kept in mind as a useful alternative in the management of refractory inflammatory CMO particularly in combination with intraocular pharmacological therpies.1

Regarding postoperative macular oedema the Vitrectomy-Aphakic-Cystoid Macular Oedema Study, a prospective, multicenter study of patients with chronic aphakic CMO, showed significant improvement in visual acuity following vitrectomy.125,126 Harbour et al in a study of 24 eyes with chronic, unresponsive to medical treatment, pseudophakic CMO, performed vitrectomy with removal of vitreous adhesions to anterior segment structures. Visual acuity improved in all patients with 71 percent of subjects experiencing postoperative visual improvement of three or more lines. Postoperative visual outcome in this study was not associated with the duration of CMO or the preoperative levels of visual acuity127 (Figures 11A-E).

Figure 11A: Fundus photography of the right eye of a 43-year old patient with longstanding posterior uveitis of unknown origin. There is moderate vitritis and signs of previous chorioretinal involvement are visible. Visual acuity 6/60

Figure 11C: Fundus photography of the right eye 1 day after pars plana vitrectomy and injection of 4 mg of Triamcinolone. Note the accumulation of the whitish steroid crystals on the retinal surface

Figure 11B: Optic coherence tomography of the macula showing marked cystoid macular oedema as well as a serous retinal detachment

Figure 11D: Fundus photography of the right eye 3 months after pars plana vitrectomy and injection of 4 mg of Triamcinolone. Note the clearer view of the fundus which shows scars of previous chorioretinal involvement by the uveitis.Visual acuity has increased to 6/12

Figure 11E: Optical coherence tomography of the macula showing a complete disappearance of the cystoid macular oedema and the serous retinal detachment

SUMMARY

The management of inflammatory macular oedema remains a challenging problem. Diagnostic possibilities have grown tremendously in the last decades with the arrival of new imaging techniques like OCT. Initial treatment guidelines include a graded approach. First line therapies include topical NSAIDs and steroids and oral CAIs. In case of a non-reponse, subtenon injections of steroids are indicated. The exact role of anti-VEGF agents and systemic immunomodulators has not been clearly established yet, but their crucial future role in the treatment of inflammatory macular oedema is undisputed.

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A

Acute annular occult outer retinopathy 509

Acute idiopathic blind spot enlargement 445

Acute posterior multifocal placoid pigment epitheliopathy 447

clinical findings 448 differential diagnosis 454

disease mechanism and physiopathology 448

electroretinography 454 fluorescein angiography (FA) 451 fundus autofluorescence (FAF) 452 general aspects 448

historical aspects 447 ICG angiography 450

optical coherence tomography (OCT) 452

symptoms 448 treatment 455

visual field testing 452

Acute zonal occult outer retinopathy (AZOOR) 500

clinical features 500 investigation 500

autofluorescence 501, 502 electroretinogram (ERG) 501, 502 fluorescein angiography 500 indocyanine green (ICG) angio-

graphy 501, 502 visual field 503

pathogenesis 503 autoimmunity 506

treatment 507

Anatomic basis of imaging in uveitis 3 Angiographic technique 91

angiographic system 91

standard angiographic protocol 91 Anterior granulomatous uveitis 335

fungal granulomas 343 leprosy 337

presumed trematode induced anterior chamber granuloma 343

lens protein uveitis 344 Vogt-Koyanagi-Harada disease

and sympathetic ophthalmia 346

sarcoidosis 335 tuberculosis 337 viral infections 340

cytomegalovirus (CMV) anterior uveitis 342

Epstein-Barr virus (EBV) uveitis 343

HSV infection 340 Vericella-zoster virus (VZV) 342

Anterior segment ICG angiography 144 angiographic interpretation and

semiology 146 clinical use 148 principles 144

angiographic protocol 146 angiography systems 145 AZOOR complex disorders 509

B

Basal lamina 6

Basic principles of indocyanine green angiography 89

macromolecular behaviour 90 pharmacology of indocyanine green

89

physicochemical properties of indocyanine green (ICG) 89

infrared fluorescence 89 Behçet’s disease 262, 397

clinical symptoms and signs 398 colour Doppler ultrasonography 407 epidemiological aspects 397 fluorescein angiography 404 history 397

indocyanine green (ICG) angiography 406

laser flare-cell photometry 404 ocular complications 403

optical coherence tomography (OCT) 407

prognosis and treatment 409 ultrasound biomicroscopy (UBM) and

ultrasonography 408 Behçet’s uveitis 135

Birdshot chorioretinopathy 552 clinical symptoms and signs 553

electroretinography and pathophysiological implications 560

epidemiological aspects 553 evolution, prognosis and treatment

560

fundus fluorescein angiography 554 indocyanine green (ICG) angiography

557

laser flare photometry 554 visual field testing 560

Blood-aqueous barrier 12 Blood-ocular barriers 11 Bruch’s membrane 6 Busacca’s nodules 25

C

Cat scratch disease 611

adnexal and anterior segment manifestations 611

chorioretinal involvement 612 diagnosis 615

differential diagnosis 615 epidemiology 611 neuroretinitis 612

ophthalmic manifestations 611 pathogenesis 612

prognosis 616 systemic disease 611 treatment 615

Cataract extraction in pars planitis 359 Cataract in uveitis 759

complications and management 766 cystoid macular edema 766 hyphaema 766

hypotony 768

immediate postoperative 766 persistent inflammation 767 posterior capsular opacification

(PCO) 768

secondary glaucoma 767 uveitis flare-up 767

intraocular lens implantation in uveitis 764

indications and contraindications 765

IOL designs and biocompatibility 765

preoperative assessment 759 diagnosis and type of uveitis 759 indications for surgery 760

laser flare photometry 762 preoperative control of inflamma-

tion 762

preoperative examination 759 surgical techniques 762

intracapsular extraction 763 manual small incision cataract

surgery 763

pars plana lensectomy and vitrectomy 763

pars plana vitrectomy 764 Chikungunya 706

diagnosis 709 management 709

ocular manifestations 707 pathogenesis 709 prevention 709

Choroid 82

choriocapillaris non-perfusion 82 choroidal folds 84

choroidal neovascularization 85 drawbacks 86

Choroidal neovascularization 789 anatomophysiology 789

choriocapillaris 789 Haller’s layer 789 sattler’s layer 789

pathophysiology 790 Clinical use of ICGA 137

diagnostic contribution 138

monitor disease evolution and response to therapy 139

precise assessment of choroidal involvement 137

Concepts of inflammatory choriocapillaropathy and stromal choroiditis 103

choriocapillaris choroiditis 103 primary inflammatory choriocapil-

laropathies 103

secondary inflammatory choriocapillaropathy 103

stromal choroiditis 105

Concepts of inflammatory choriocapillaropathy and stromal choroiditis 433

primary inflammatory choriocapillaropathy 433

primary stromal choroiditis 433 secondary inflammatory choriocapil-

laropathy 433

secondary stromal choroiditis 434 Concepts of inflammatory choriocapil-

laropathy and stromal choroiditis 515

primary inflammatory choriocapillaropathy 516

primary stromal choroiditis 516 secondary inflammatory choriocapil-

laropathy 516

secondary stromal choroiditis 516 Confocal microscopy 223

confocal analysis of normal cornea 226 qualitative morphometric analysis

226

quantitative morphometric analysis 227

confoscan 2 in vivo confocal microscope 224

z-scan 225

distance immersion principle 224 drawbacks 230

history 223

in vivo confocal microscopy in uveitis 227

endothelial blebs 229 endothelial dusting 229 fresh keratic precipitates 228

height of keratic precipitates 228 keratic precipitates 228 resolving keratic precipitates 228

instrumentation and methodology 223 technique of acquiring confocal images

225

Correlation between slit lamp flare evaluation and laser flare photometry 32

CSLO autofluorescence in inflammatory diseases 149

D

Dengue fever 699 demographics 699 diagnosis 700 epidemiology 699

fundal fluorescein angiography 701 indocyanine green angiography 701 ocular manifestations 699

anterior segment findings 700 ocular symptoms 699 posterior segment findings 700

subconjunctival haemorrhage 700 optical coherence tomogram 701 pathophysiology 700

treatment 705 Descemet’s membrane 229

E

Electrophysiology and inflammatory disease 232

clinical applications 235

Birdshot chorioretinopathy 235 other forms of uveitis 235

effects of pathology 234 tests 232

Endogenous fungal infections of the eye 645

causative organisms 645 clinical features 646 signs 646

symptoms 646 differential diagnosis 650

endogenous aspergillus endophthalmitis 646

endogenous candida endophthalmitis 646

endogenous histoplasma endophthalmitis 647

epidemiology and predisposing factors 645

histopathology 647 investigations 650

microbiology analysis of the vitreous fluid 650

polymerase chain reaction 650 systemic cultures including blood

and urine cultures 650 ultrasonography 650

medical treatment 651 prognosis 651 surgical treatment 651

F

Flare to measure intraocular inflammation 35

Fluorescein angiography 61 analog versus digital 62 dye 63

hardware 61

historical perspective 61

technique of fluorescein angiography 63

adverse reactions 65 Bruch’s membrane 66 choroid 66

ciliary body 66 dye injection 64

fundus photography 65 macula 66

mydriasis 64

ocular tissue response to fluorescein 66

optic nerve 66 patient preparation 64 patient selection 63

performing the fluorescein angiography 65

positioning 64 precautions 63 retina 66

retinal pigment epithelium (RPE) 66

sclera 66

steps in filming 65 test dose 65 vitreous body 66

Fluorescein angiography in uveitis 72 Fuchs’ uveitis 323

angiographic findings 328 diagnostic criteria 329

differential diagnosis, evolution, therapy and prognosis 328