بررسی پروسیجرهای سایکلودیستراکتیو (cyclodestructive) برای گلوکوم غیر‐مقاوم (non‐refractory glaucoma)
چکیده
پیشینه
گلوکوم (glaucoma) عامل اصلی نابینایی در سراسر جهان است. این امر منجر به از دست رفتن پیشرونده بینایی محیطی می‌شود و در مراحل پایانی، از بین رفتن دید مرکزی منجر به نابینایی می‌شود. هدف درمان زودهنگام گلوکوم، پیشگیری یا به تاخیر انداختن از دست دادن بینایی است. افزایش فشار داخل چشم (elevated intraocular pressure; IOP) عامل خطر اصلی قابل اصلاح در گلوکوم است. انسداد محل خروج مایع آبکی، علت اصلی افزایش IOP است که می‌تواند با افزایش جریان خروجی یا کاهش تولید مایع زلالیه (aqueous humor) کاهش یابد. پروسیجرهای سیکلودیستراکتیو (cyclodestructive)، از روش‌های مختلف برای هدف‌گیری و تخریب اپیتلیوم جسم مژگانی (ciliary body epithelium)، محل تولید مایع زلالیه، و در نتیجه کاهش IOP استفاده می‌کند. شایع‌ترین روش لیزر سیکلوفوتوکوآگولاسیون (cyclophotocoagulation) است.
اهداف
ارزیابی اثربخشی و ایمنی پروسیجرهای سیکلودیستراکتیو برای مدیریت گلوکوم غیر‐مقاوم (یعنی، گلوکوم در چشمی که تحت جراحی برشی گلوکوم (incisional glaucoma surgery) قرار نگرفته است). هم‌چنین هدف ما مقایسه تاثیر مسیر‌های مختلف مدیریت درمانی، ابزارهای انجام لیزر و پارامترهای سیکلوﻓﻮﺗﻮﮐﻮﺍﮔﻮﻻﺳﻴﻮﻥ با توجه به کنترل IOP، حدت بینایی، کنترل درد و حوادث جانبی بود.
روش‌های جست‌وجو
پایگاه ثبت مرکزی کارآزمایی‌های کنترل شده کاکرین (CENTRAL) (2017؛ شماره 8) (که شامل پایگاه ثبت کارآزمایی‌های گروه چشم و بینایی در کاکرین بود)؛ MEDLINE Ovid؛ Ovid Embase ؛ LILACS؛ متارجیستری از کارآزمایی‌های کنترل شده(mRCT ؛the metaRegister of Controlled Trials (mRCT) و ClinicalTrials.gov را جست‌وجو کردیم. تاریخ جست‌وجو 7 آگوست 2017 بود. هم‌چنین فهرست منابع گزارش‌های مطالعات وارد شده را جست‌وجو کردیم.
معیارهای انتخاب
کارآزمایی‌های تصادفی‌سازی و کنترل شده‌ای را وارد کردیم که شامل شرکت‌کنندگانی بودند که با سیکلودیستراکشن به عنوان درمان اصلی برای گلوکوم، تحت درمان قرار گرفتند. ما فقط کارآزمایی‌های سر به سر را در نظر گرفتیم که ﺳﻳﮑﻠﻮﻓﻮﺗﻮﮐﻮﺍﮔﻮﻻﺳﻴﻮﻥ را با سایر مداخلات پروسیجرال (Procedural) مقایسه کردند یا به مقایسه ﺳﻳﮑﻠﻮﻓﻮﺗﻮﮐﻮﺍﮔﻮﻻﺳﻴﻮﻥ با استفاده از انواع مختلف لیزر، روش‌های انجام، پارامترها یا ترکیبی از این عوامل پرداختند.
گردآوری و تجزیه‌وتحلیل داده‌ها
دو نویسنده مرور به‌طور مستقل از هم نتایج جست‌وجو را غربالگری کردند، خطرات سوگیری (bias) را ارزیابی نموده، داده‌ها را استخراج و قطعیت شواهد را طبق استانداردهای کاکرین درجه‌بندی کردند.
نتایج اصلی
یک کارآزمایی (92 چشم از 92 شرکت‌کننده) را وارد کردیم که اثربخشی ﺳﻳﮑﻠﻮﻓﻮﺗﻮﮐﻮﺍﮔﻮﻻﺳﻴﻮﻥ ترانس‌اسکلرا دیود (diode transscleral cyclophotocoagulation; TSCPC) را به عنوان درمان جراحی اولیه ارزیابی کرد. ما هیچ کارآزمایی واجد شرایط در حال انجام یا تکمیل شده دیگری را شناسایی نکردیم. کارآزمایی وارد شده به مقایسه TSCPC با انرژی کم در برابر انرژی بالا در چشمانی با گلوکوم اولیه زاویه باز (primary open‐angle glaucoma) پرداخت. این کارآزمایی در غنا انجام شد و دارای میانگین زمان پیگیری 13.2 ماه پس از درمان بود. در این کارآزمایی، TSCPC با انرژی کم که به صورت 45.0 ژول (J) و انرژی بالا که به صورت 65.5 ژول تعریف شد، مورد استفاده قرار گرفت؛ شایان ذکر است که کارآزمایی‌های دیگر انرژی کم و زیاد TSCPC را به طور متفاوت تعریف کردند. این کارآزمایی را در معرض خطر پائین سوگیری انتخاب (selection bias) و سوگیری گزارش‌دهی (reporting bias)، خطر نامشخص سوگیری عملکرد (performance bias) و خطر بالای سوگیری تشخیص (detection bias) و سوگیری ریزش نمونه (attrition bias) ارزیابی کردیم. نویسندگان کارآزمایی، 13 شرکت‌کننده را با داده‌های پیگیری ناقص حذف کردند؛ بنابراین، تجزیه‌وتحلیل‌ها شامل 40 نفر (85%) از 47 شرکت‌کننده در گروه انرژی کم و 39 نفر (87%) از 45 شرکت‌کننده در گروه انرژی بالا بود.
کنترل IOP، که به صورت کاهش IOP به میزان 20% از خط پایه تعریف شد، در 47% از چشم‌ها و با نرخ مشابه در گروه انرژی کم و گروه انرژی بالا، به دست آمد؛ حجم نمونه کوچک مطالعه، سبب عدم قطعیت در مورد معنی‌دار بودن تفاوت، در صورت وجود، بین تنظیمات انرژی شد (خطر نسبی (RR): 1.03؛ 95% فاصله اطمینان (CI): 0.64 تا 1.65؛ 79 شرکت‌کننده؛ شواهد با قطعیت پائین). تفاوت تاثیر بین تنظیمات انرژی بر اساس کاهش میانگین IOP، در صورت وجود، نیز نامطمئن بود (تفاوت میانگین (MD): 0.50‐ میلی‌متر جیوه؛ 95% CI؛ 5.79‐ تا 4.79؛ 79 نفر؛ شواهد با قطعیت پائین).
کاهش بینایی به صورت نسبت شرکت‌کنندگان با کاهش 2 خط یا بیش‌تر از خطوط در نمودار Snellen، یا یک یا چند طبقه‌بندی از حدت بینایی، زمانی که قادر به خواندن نمودار چشم نباشند، تعریف شد. بیست‌وسه درصد از چشم‌ها کاهش دید داشتند. اندازه هر مقدار تفاوت بین گروه انرژی کم و گروه انرژی بالا، نامطمئن بود (RR: 1.22؛ 95% CI؛ 0.54 تا 2.76؛ 79 شرکت‌کننده؛ شواهد با قطعیت پائین). داده‌ها برای میانگین حدت بینایی در دسترس نبود و نسبت شرکت‌کنندگان با تغییر بینایی به میزان بیش از 1 خط در نمودار Snellen تعریف شد.
تفاوت در میانگین تعداد داروهای گلوکوم پس از سیکلوفوتوکوآگولاسیون در مقایسه با گروه‌های درمان مشابه بود (MD: 0.10؛ 95% CI؛ ‐0.43 تا 0.63؛ 79 شرکت‌کننده؛ شواهد با قطعیت متوسط). بیست درصد از چشم‌ها مجددا درمان شدند؛ تاثیر تخمینی تنظیمات انرژی بر نیاز به درمان مجدد غیر‐قطعی بود (RR: 0.76؛ 95% CI؛ 0.31 تا 1.84؛ 79 شرکت‌کننده؛ شواهد با قطعیت پائین). هیچ داده‌ای برای پیامدهای میدان دید، هزینه‐اثربخشی، یا کیفیت زندگی توسط محققان کارآزمایی گزارش نشد.
حوادث جانبی به جای آن‌که برای تفکیک گروه‌های درمان ارائه شود، برای کل جمعیت مطالعه، گزارش شد. نویسندگان کارآزمایی اظهار داشتند که اکثر شرکت‌کنندگان، پس از پروسیجر درد خفیف تا متوسط داشتند و بسیاری از آنها سوختگی‌های موقت ملتحمه (conjunctival) پیدا کردند (درصد گزارش نشد). آماس عنبیه (iritis) شدید در دو چشم و هایفما (hyphema) در سه چشم رخ داد. هیچ نمونه‌ای از هیپوتونی (hypotony) یا phthisis bulbi گزارش نشد. تنها پیامد نامطلوب که توسط گروه درمان گزارش شده بود، مردمک اتونیک (atonic pupil) بود (RR: 0.89 در گروه انرژی کم؛ 95% CI؛ 0.47 تا 1.68؛ 92 شرکت‌کننده؛ شواهد با قطعیت پائین).
نتیجه‌گیری‌های نویسندگان
شواهد کافی برای ارزیابی اثربخشی نسبی و ایمنی پروسیجرهای سیکلودیستراکتیو برای مدیریت پروسیجرال اولیه گلوکوم غیر‐مقاوم وجود ندارد. نتایج حاصل از یک کارآزمایی وارد شده، سیکلوفوتوکوآگولاسیون را با سایر مداخلات پروسیجرال مقایسه نکرد و در مورد هرگونه تفاوت در پیامدها، هنگام مقایسه دیود TSCPC با انرژی کم در برابر انرژی بالا، عدم قطعیت را نشان داد. در مجموع، تاثیر لیزر بر کنترل IOP، نسبتا کم و تعداد چشم‌هایی که بینایی خود را از دست دادند، محدود بود. پژوهش بیشتری برای مدیریت گلوکوم غیر‐مقاوم مورد نیاز است.
PICO
خلاصه به زبان ساده
جراحی لیزری برای گلوکوم (glaucoma) که فشار چشم را با از بین بردن بخشی از چشم که تولید مایعات را در داخل چشم برعهده دارد، کاهش می‌دهد.
هدف از انجام این مرور چیست؟
هدف از این مطالعه مروری کاکرین این بود که پی ببریم پروسیجرهای لیزر در مقایسه با روش‌های دیگر برای کاهش فشار در چشم برای افراد مبتلا به گلوکوم که قبلا تحت جراحی قرار نگرفته‌اند، چگونه عمل می‌کنند. محققان کاکرین همه مطالعات مرتبط با پاسخ این سوال را جست‌وجو و تجزیه‌وتحلیل کردند اما فقط یک مطالعه پیدا کردند.
پیام‌های کلیدی
ما نمی‌دانیم که این نوع جراحی لیزر ایمن‌تر یا موثرتر از جراحی‌های دیگر برای درمان گلوکوم است یا خیر. ما فقط یک مطالعه را در این مرور گنجاندیم. این مطالعه، لیزرهای دیود را با انرژی پائین در برابر انرژی بالا مقایسه کردند، و نتایج به دست آمده از گروه‌های درمان به قدری مشابه بود که نتوانستیم در این مورد نتیجه‌گیری کنیم. علاوه بر این، این مطالعه جراحی لیزر دیستراکتیو را با سایر روش‌های جراحی مقایسه نکرد. برای درک مفید بودن پروسیجرهای لیزر دیستراکتیو در درمان گلوکوم اولیه، پژوهش بیشتری لازم است.
در این مرور چه موضوعی بررسی شد؟
گلوکوم یک بیماری پیشرفته عصب بینایی است که باعث از بین رفتن بینایی می‌شود. این بیماری یک علت شایع نابینایی در سراسر جهان است. چنان‌چه به طور زودهنگام درمان شود، ممکن است سبب پیشگیری یا تاخیر از دست دادن دید شود.
فشار داخل چشم (intraocular pressure; IOP) عامل خطر اصلی قابل درمان برای گلوکوم است. اپیتلیوم جسم مژگانی (ciliary body epithelium)، مایعی را تولید می‌کند که باعث ایجاد فشار در چشم می‌شود. تصور می‌شود پروسیجرهایی که اپیتلیوم جسم مژگانی را از بین می‌برند و با عنوان روش‌های سایکلو دیستراکتیو شناخته می‌شوند، می‌توانند به عنوان درمانی برای گلوکوم، IOP را کاهش دهند. روش‌های مختلفی از پروسیجرهای سایکلودیستراکتیو در دسترس هستند؛ شایع‌ترین آنها لیزر است. هدف از این مرور ارزیابی درمان‌های لیزری است که اپیتلیوم جسم مژگانی را از بین می‌برند. این مرور روی اثربخشی و ایمنی پروسیجرهای وارد شده با ارزیابی کنترل IOP، بینایی، کنترل درد و عوارض جانبی متمرکز شد.
نتایج اصلی مرور چه هستند؟
ما یک مطالعه را یافتیم که شامل 92 فرد مبتلا به گلوکوم بود. این مطالعه ﺳﻳﮑﻠﻮﻓﻮﺗﻮﮐﻮﺍﮔﻮﻻﺳﻴﻮﻥ ترانس‌اسکلرا دیود (diode transscleral cyclophotocoagulation) را که یک پروسیجر لیزری برای پیشگیری از تولید مایعات در چشم است، با انرژی پائین در برابر انرژی بالا با یکدیگر مقایسه کرد. کارآزمایی در غنا انجام شد و شرکت‌کنندگان به طور میانگین 13 ماه پیگیری شدند.
به طور کلی، 47% از چشم‌های درمان شده با ﺳﻳﮑﻠﻮﻓﻮﺗﻮﮐﻮﺍﮔﻮﻻﺳﻴﻮﻥ ترانس‌اسکلرا دیود، کاهش 20% یا بیش‌تر را از IOP تجربه کردند و تفاوتی بین گروه با انرژی پائین و گروه با انرژی بالا برای هیچ یک از پیامدهای گزارش شده وجود نداشت. کنترل IOP در هر دو گروه درمان مشابه بود. تعداد داروها پس از درمان نیز در هر دو گروه مشابه بود. عوارض جانبی به صورت جداگانه در گروه‌های درمان گزارش نشده بود. اطلاعات در مورد پیامدهای مهم دیگر گزارش نشده بود.
بر اساس این مرور، شواهد کافی برای تعیین این‌که ﺳﻳﮑﻠﻮﻓﻮﺗﻮﮐﻮﺍﮔﻮﻻﺳﻴﻮﻥ ترانس‌اسکلرا، یک درمان جراحی اصلی مناسب برای گلوکوم غیر‐مقاوم است و این‌که کدام یک از تنظیمات دیود کم انرژی یا انرژی بالا در درمان گلوکوم ایمن‌تر و موثرتر است، وجود ندارد.
این مرور تا چه زمانی به‌روز است؟
محققان کاکرین در جست‌وجوی مطالعاتی بودند که تا 7 آگوست 2017 منتشر شده بودند.
Authors' conclusions
Summary of findings
| Low‐ versus high‐energy diode transscleralcyclophotocoagulation for non‐refractory glaucoma | ||||||
| Population: people with primary open‐angle glaucoma and no previous glaucoma surgery Settings: ophthalmology clinics Intervention: low energy; 1.5 watts for 1.5 seconds x 20 spots over 360 ° (45.0 J) Comparison: high energy; 1.25 watts for 2.5 seconds x 20 spots over 360 ° (62.5 J) | ||||||
| Outcomes* | Illustrative comparative risks** (95% CI) | Relative effect | No of participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| High‐energy diode transscleralcyclophotocoagulation | Low‐energy diode transscleralcyclophotocoagulation | |||||
| Control of intraocular pressure | 462 per 1000 | 475 per 1000 | RR 1.03 (0.64 to 1.65) | 79 | ⊕⊕⊝⊝ | Control of intraocular pressure defined as a decrease in IOP by 20% from baseline value |
| Mean change in intraocular pressure | On average intraocular pressure in the high energy group dropped by 3 mmHg | On average intraocular pressure in the low‐energy group was 0.5 mmHg lower than the IOP in the high‐energy group (5.79 mmHg lower to 4.79 mmHg higher) | ‐ | 79 | ⊕⊕⊝⊝ | ‐ |
| Decrease in visual acuity | 205 per 1000 | 250 per 1000 | RR 1.22 (0.54 to 2.76) | 79 | ⊕⊕⊝⊝ | Decrease in visual acuity defined as a decrease of 2 or more lines on the Snellen chart or one or more categories of visual acuity if unable to read the eye chart |
| Mean visual field | No visual field outcomes reported | ‐ | ‐ | ‐ | ‐ | ‐ |
| Number of glaucoma medications after treatment | The mean number of glaucoma medications in the high energy group was 1.3 | The mean number of glaucoma medications in the low energy group was 0.10 more (0.43 fewer to 0.63 more) | ‐ | 79 | ⊕⊕⊕⊝ | ‐ |
| Additional glaucoma surgery | 231 per 1000 | 175 per 1000 | RR 0.76 (0.31 to 1.84) | 79 | ⊕⊕⊝⊝ | Additional glaucoma surgery defined as retreatment with cyclophotocoagulation according to randomized assignment |
| Adverse events: atonic pupil | 311 per 1000 | 277 per 1000 | RR 0.89 (0.47 to 1.68) | 92 | ⊕⊕⊝⊝ | Atonic pupil was the only adverse event reported by treatment group. Trial authors noted that most participants had mild to moderate pain for a few days following the procedure and many also had transient conjunctival burns (number not reported). Severe iritis occurred in 2 eyes and hyphema occurred in 3 eyes. No instances of hypotony or phthisis bulbi were reported |
| *All outcomes are reported for participants with at least 3 months follow‐up; mean follow‐up was 13.2 months. | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1Downgraded for risk of bias in the trial (unmasked outcome assessors and 14% attrition). | ||||||
Background
Description of the condition
Glaucoma is a group of diseases that result in a progressive loss of retinal ganglion cells and their axons, leading to characteristic optic nerve head change and retinal nerve fiber layer (RNFL) damage. Visual function deteriorates as a result, with progressive loss of peripheral vision and, in late stages, loss of central vision and blindness. Intraocular pressure (IOP) is the main modifiable known risk factor. The goal of therapy, regardless of the disease mechanism, is reduction of IOP. Several major randomized clinical trials have demonstrated a clear benefit of lowering IOP in the prevention of the development and progression of optic nerve and visual field deterioration (AGIS 2000; CNTGS 1998; Coleman 2004; Garway‐Heath 2015; Leske 2003; Lichter 2001). Currently, IOP can be lowered with medications, laser procedures, and incisional surgery.
Epidemiology
Glaucoma is the leading cause of irreversible blindness worldwide, affecting over 64 million people and causing bilateral blindness in over 8.4 million people (Quigley 2006; Tham 2014). It is estimated that in 2020 about 3.4 million people over the age of 40 in the USA will have open‐angle glaucoma (OAG), the most prevalent form of the disease in North America (Friedman 2004).
Presentation and diagnosis
The glaucomas are a heterogeneous group of diseases, characterized by progressive or impending death of retinal ganglion cells associated with subsequent thinning of the neuroretinal rim of the optic nerve head and progressive visual field loss. Elevation of IOP to a level at which the retinal ganglion cells are susceptible to damage is the main causal risk factor. Aqueous outflow obstruction is the main cause of elevated IOP. Glaucoma is an asymptomatic disease until the very late stages. It has been estimated that more than 50% of all prevalent glaucoma cases are undiagnosed (Hennis 2007; Quigley 1996; Topouzis 2008; Weih 2001); diagnosis is commonly a result of screening during routine eye examinations. Glaucoma diagnosis is based on structural assessment of the optic nerve head and retinal nerve fiber layer (RNFL) clinically, and with the use of optical coherence tomography and the functional evaluation of the mid‐peripheral visual field. Other relevant clinical examinations include IOP evaluation, central corneal thickness measurement, and gonioscopy.
Description of the intervention
The goal of glaucoma treatment is to preserve visual function and the related quality of life of the patient. Lowering IOP is the only approach known to reduce the risk of disease progression (EGS 2014). IOP can be lowered with medication, laser procedures or surgery (Burr 2012). Laser procedures such as cyclophotocoagulation (CPC) target the ciliary body to decrease the production of aqueous humor. In 1972, Beckman and colleagues introduced a laser method for CPC that uses a Hruby laser (Beckman 1972). Over the years, laser CPC has become the main form of cyclodestructive treatment; other methods have been used to coagulate the ciliary body, such as diathermy, cryotherapy and ultrasound (Coleman 1985; Meyer 1948).
CPC procedures include transpupillary CPC, transvitreal CPC, endoscopic CPC and transscleral CPC, based on the different paths used to approach the ciliary body. For example, transscleral CPC coagulates the ciliary body through the sclera and can be performed using a neodymium:yttrium‐alluminum‐garnet (ND:YAG) laser with a sapphire‐tipped contact probe, or a semi‐conductor diode laser equipped with disposable probes (G‐probe). Traditionally, CPC is indicated for people with refractory glaucoma who have failed filtration procedures, such as trabeculectomy and aqueous tube shunt procedures, for people with limited useful vision and elevated IOP on maximum tolerated medical therapy, and for people with no visual potential in need of pain relief (Ansari 2007; Beckman 1972; Bloom 1997; Hauber 2002; Lin 2008; Murphy 2003; Pastor 2001). More recently, the use of this procedure has been extended to those with non‐refractory glaucoma and good vision (Ansari 2007; Sinchai 2008). Most evidence supporting the use of lasers for ciliary body destruction comprises non‐comparative case studies (Lin 2008; Pastor 2001). Fewer studies have evaluated the most effective laser parameters for accepted lasers or the different modes of delivery (Murphy 2003).
Although cyclodestructive procedures are described as safe in many of the observational case series, serious postoperative complications have been reported, including prolonged inflammation, intraocular hemorrhage, hypotony (pathologically‐low IOP), loss of vision and, in some cases intractable ocular pain or phthisis bulbi (an end‐stage process characterized by atrophy, shrinkage, and disorganization of the eye and intraocular contents; Pastor 2001). Conjunctival burns have been observed with the transscleral approach (Pastor 2001), and sympathetic ophthalmia (severe inflammation in the untreated fellow eye) has been observed with Nd:YAG cyclophotocoagulation (Bechrakis 1994; Edward 1989; Lam 1992; Pastor 1993). Reports of these serious complications have limited the use of Nd:YAG lasers regardless of the mode of delivery, and studies on diode CPC have focused on its use in refractory glaucoma, not considering it as a primary surgical option. However, in recent publications, diode laser use in non‐refractory glaucoma has been reported, with the main methods of delivery being transscleral and endoscopic.
How the intervention might work
The non‐pigmented layer of the ciliary body epithelium is the site of production of aqueous humor for the eye. Aqueous humor is an ultrafiltrate of blood serum and is produced by one or more of the following processes: ultrafiltration, simple diffusion, and active transport across the ciliary body epithelium. Laser energy targeting the epithelium and ciliary processes destroys these tissues and causes a reduction in the production of aqueous humor. Thus, the goal of cyclodestructive procedures is to reduce IOP by destroying the ciliary body epithelium, the site of aqueous humor production. The thermal effect of the laser has been demonstrated to induce coagulative necrosis of the pars plicata (the area of the ciliary body that produces most aqueous humor), thereby lowering IOP, as well as undesired necrosis of surrounding structures, such as sclera, iris and pars plana. There is also evidence that transscleral cyclophotocoagulation may enhance uveal scleral outflow of aqueous humor (Liu 1994).
Why it is important to do this review
Cyclodestructive procedures have been used most commonly in people with poor vision and refractory glaucoma in which medication or other surgeries or both have failed, due to the risk of additional vision loss occurring after the destruction of the ciliary body. However, their use has more recently been expanded to include individuals with good visual acuity and non‐refractory glaucoma, which represent clinical scenarios traditionally treated by other medical and surgical options. Cyclodestructive procedures may be especially important in low‐income regions (such as parts of Africa and Asia) where access to medical treatment is difficult, making surgery – particularly non‐invasive procedures like transscleral CPC ‐ simpler and less expensive than continual medical therapy with eye drops.
Keeping this in mind, it is important to demonstrate a consistent effect across studies and to analyze effects on visual acuity as an important outcome measure in addition to IOP control when CPC is used in people with good visual acuity. An evaluation of cyclodestructive procedures for people with refractory glaucoma is covered in a separate Cochrane review (Chen 2016).
Objectives
To assess the effectiveness and safety of cyclodestructive procedures for the management of non‐refractory glaucoma (i.e., glaucoma in an eye that has not undergone incisional glaucoma surgery). We also aimed to compare the effect of different routes of administration, laser delivery instruments, and parameters of cyclophotocoagulation with respect to IOP control, visual acuity, pain control, and adverse events.
Methods
Criteria for considering studies for this review
Types of studies
We included only randomized clinical trials.
Types of participants
We included trials of participants who had undergone laser cyclodestruction as a primary surgical treatment for glaucoma (i.e. had not received any prior incisional surgery for glaucoma). We imposed no restriction regarding the underlying cause or mechanism of glaucoma or age of the participant. We excluded trials limited to those who had undergone palliative treatment for end‐stage glaucoma, as these trials are covered in another Cochrane Review (Chen 2016).
Types of interventions
We included only head‐to‐head trials that evaluated CPC using different types of lasers, delivery methods, parameters, or a combination of these factors. We included all types of lasers (e.g. Nd:YAG, diode), routes of administration (transpupillary, transvitreal, non‐contact and contact transscleral, and endoscopic), and laser settings (including power, number of applications, extent of treatment). We included trials in which CPC was performed alone or in combination with another procedure. We excluded trials in which endoscopic cyclophotocoagulation was compared with non‐cyclodestructive glaucoma treatments, as these trials are covered in another Cochrane Review (Tóth 2017).
Types of outcome measures
We selected outcomes for this review based on those reported by Tseng 2017.
Primary outcomes
The primary outcome of this review was control of IOP at one year, defined as a decrease in IOP by 15% from baseline value (or by another percentage of IOP reduction, as reported by included trials). We also assessed mean change in IOP measurements by any recording device; contact or non‐contact tonometry, collected prior to intervention and at one year.
Secondary outcomes
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Preservation of visual acuity at one year postintervention. We considered the proportion of participants with a loss of no more than 1 line of visual acuity at one year to have had stable vision and the proportion of participants with greater than 1 line of vision loss to have had decreased vision.
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Stability of visual field measured by automated perimetry (mean deviation and pattern standard deviation, measured as continuous variables), as available, throughout follow‐up and at study end.
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Total number of glaucoma medications, both topical and systemic, prescribed as adjuncts to surgery throughout the study period.
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The proportion of participants who required additional glaucoma surgery throughout the study period.
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Pain control as reported by the participant or amount of pain medication prescribed from baseline throughout the study period.
Adverse outcomes
We documented adverse outcomes as reported by included trials. Adverse outcomes of particular interest included: intractable ocular pain, prolonged inflammation, intraocular hemorrhage, hypotony, loss of vision, phthisis bulbi, and loss of an eye.
Economic data
We reviewed cost effectiveness data whenever reported.
Quality of life data
We compared quality‐of‐life outcomes when available.
Search methods for identification of studies
Electronic searches
The Cochrane Eyes and Vision Information Specialist conducted systematic searches in the following databases for randomised controlled trials and controlled clinical trials. There were no language or publication year restrictions. The date of the search was 7 August 2017, with the exception of mRCT which is no longer in service.
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Cochrane Central Register of Controlled Trials (CENTRAL; 2017, Issue 9) (which contains the Cochrane Eyes and Vision Trials Register) in the Cochrane Library (searched 7 August 2017) (Appendix 1);
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MEDLINE Ovid (1946 to 7 August 2017) (Appendix 2);
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Embase.com (1980 to 7 August 2017) (Appendix 3);
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LILACS (1982 to 7 August 2017) (Appendix 4);
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metaRegister of Controlled Trials (mRCT) (last searched 28 June 2013) (Appendix 5);
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US National Institutes of Health Ongoing Trials Register ClinicalTrials.gov (www.clinicaltrials.gov; searched 7 August 2017) (Appendix 6).
Searching other resources
We searched the references of reports from included trials for additional relevant trials, without restriction by language or date of publication.
Data collection and analysis
Selection of studies
Two review authors independently assessed all records identified by the electronic and manual searches as in the Criteria for considering studies for this review. Each review author classified the titles and abstracts as 'definitely relevant', 'possibly relevant' or 'definitely not relevant'. We resolved discrepancies through discussion. We retrieved the full‐text report for those records classified as 'definitely relevant' or 'possibly relevant'. We grouped the reports by study and each review author assessed each study as 'include, 'exclude' or 'unsure', resolving discrepancies through discussion. We did not need to contact study authors for further information, as described in the protocol for this review, because we classified no study as 'unsure' after review of the full‐text. For studies excluded after review of the full‐text, we documented the reasons for exclusion. We were unmasked to the report authors, institutions and trial results during these assessments.
Data extraction and management
Two review authors independently extracted data for included studies onto paper data collection forms developed in collaboration with Cochrane Eyes and Vision, and resolved discrepancies by discussion and consensus. We collected data related to trial methods, characteristics of participants and interventions, and outcomes. One review author entered data into Review Manager 5 (RevMan 5) (Review Manager 2014) and a second review author verified the values.
Assessment of risk of bias in included studies
Two review authors independently assessed the risks of bias of the included studies as outlined in Chapter 8 of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We examined six main criteria: sequence generation, allocation concealment before randomization, masking, incomplete outcome data, selective reporting, and other potential sources of bias (such as funding source). Each review author assessed each included trial as having a low risk of bias, an unclear risk of bias (lack of information or uncertainty over the potential for bias), or a high risk of bias. We resolved discrepancies through discussion.
Measures of treatment effect
Dichotomous outcomes
We analyzed dichotomous outcomes as summary risk ratios (RRs) with 95% confidence intervals (CIs). Dichotomous outcomes included the proportions of participants with IOP control, stable visual acuity, decreased visual acuity, those needing additional glaucoma surgery, and those with adverse events.
Continuous outcomes
We analyzed continuous outcomes as summary mean differences (MDs) with 95% CIs. Continuous outcomes included mean change in IOP, mean visual acuity, mean and pattern standard deviations from visual field tests, mean numbers of glaucoma medications prescribed, degree of pain control reported by participants and amount of pain medication prescribed, cost effectiveness, and quality‐of‐life scores.
Unit of analysis issues
The unit of analysis was the individual (one study eye per person).
Dealing with missing data
We planned to contact trial investigators for missing details including study methods, effect estimates, standard deviations, and intention‐to‐treat (ITT) data when information was not reported or unclear. If there was no response within six weeks, we planned to use the available information reported in the study.
Assessment of heterogeneity
We did not assess heterogeneity as we included only one trial in the review. If more trials are included in updates of the review, we will assess clinical and methodological heterogeneity by examining potential variations in participant characteristics, inclusion/exclusion criteria and assessments of primary and secondary outcomes. When meta‐analysis is appropriate, we will use the I2 statistic (%) to determine the proportion of variation due to heterogeneity, with a value above 50% suggesting substantial statistical heterogeneity. We will also examine the result of the Chi2 test for heterogeneity and the degree of overlap in confidence intervals of included studies; poor overlap of confidence intervals suggests heterogeneity.
Assessment of reporting biases
We planned to examine funnel plots of the intervention effect estimates for signs of asymmetry, to evaluate small study effects, if 10 or more studies were to be included in our meta‐analysis. We assessed selective outcome reporting as part of the 'Risk of bias' assessment.
Data synthesis
We did not perform meta‐analysis, as we included only one trial in this review. If more trials are included in updates of the review and neither the I2 statistic nor an inspection of the forest plot suggest substantial heterogeneity, we will combine the results of included trials in a meta‐analysis using a random‐effects model. We will use a fixed‐effect model if there are fewer than three trials and there is no evidence of statistical, clinical or methodological heterogeneity. In this instance, the fixed‐effect model will provide a more robust estimate of the treatment effect.
Subgroup analysis and investigation of heterogeneity
We did not conduct planned subgroup analysis due to insufficient data. When sufficient data become available, we will perform subgroup analysis comparing different types of cyclophotocoagulation: transpupillary, transvitreal endocyclophotocoagulation, transscleral (non‐contact and contact Nd:YAG), semiconductor diode laser, and endoscopic. We will also conduct subgroup analysis for underlying causes of glaucoma (primary open‐angle, angle‐closure glaucoma, neovascular glaucoma, other secondary glaucoma), laser parameter settings (total power delivered per treatment) and number of treatments performed.
Sensitivity analysis
Due to lack of data, we did not conduct sensitivity analyses as specified in the protocol. When sufficient data become available, we will undertake sensitivity analyses to determine the impact of excluding studies at high risk of bias, industry‐funded studies, and those studies providing only unpublished data.
Summary of findings
For each outcome, we assessed the certainty of evidence using the GRADE approach (GRADEpro GDT). The GRADE approach considers the following five criteria: risk of bias in individual trials, indirectness, heterogeneity, imprecision of estimate (wide confidence intervals), and publication bias. Two review authors independently judged the certainty of each outcome estimate according to the criteria as very low, low, moderate, or high. We resolved any discrepancy by discussion.
We summarized the main outcomes evaluated in this review in summary of findings Table for the main comparison, which presents the comparative effects between treatments. Because a 'Summary of findings' table was not part of the original Cochrane protocol, we chose the outcomes presented in the table post hoc. We based our selection on core outcomes for glaucoma research that have been proposed in the literature (Ismail 2016). The main outcomes for this review include:
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Control of IOP at one year, defined as a decrease in IOP by 15% from baseline value (or by another percentage of IOP reduction, as reported by included trials)
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Mean change in IOP measurements (by any recording device; contact or non‐contact tonometry) collected prior to intervention and at one year
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Proportion of participants with a loss of visual acuity at one year, defined as greater than 1 line of vision loss (or by more lines, as reported by included trials)
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Mean visual field measured by automated perimetry (mean deviation and pattern standard deviation) at one year
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Total number of glaucoma medications, both topical and systemic, prescribed as adjuncts to surgery throughout the study period to one year
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Proportion of participants who required additional glaucoma surgery throughout the study period to one year
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Proportion of participants with an adverse event to one year.
Results
Description of studies
Results of the search
The electronic searches yielded 7379 unique records (Figure 1). We removed 7350 records by screening titles and abstracts, and excluded 27 records after reviewing the full‐text report. We included two reports from one trial in this review (Egbert 2001). We identified no potentially relevant completed or ongoing trials from searching other sources.
Study flow diagram.
Included studies
We include one trial (92 eyes of 92 participants) in this review. The trial was conducted in Ghana and enrolled adults with primary open‐angle glaucoma. Although eyes with previous glaucoma surgery or no light perception were not eligible for the trial, most of the included eyes had very advanced glaucoma, as assessed using clinical examination of the optic nerve and measurement of IOP. Participants were treated with diode transscleral CPC and randomized to one of two energy settings with different power‐to‐exposure time ratios: low energy of 45.0 joules (1.5 watts for 1.5 seconds x 20 spots over 360 °) or high energy of 62.5 joules (1.25 watts for 2.5 seconds x 20 spots over 360 °). Retreatment was performed at the discretion of the treating ophthalmologist whenever the first treatment failed to lower IOP. Mean follow‐up was 13.2 months after the first treatment. The trial investigators excluded participants with less than three months of follow‐up from the analyses. The primary outcomes of the trial were change in IOP and reduction of medications; secondary outcomes included change in visual acuity, additional glaucoma surgery, and complications. No data for visual field, pain control, cost effectiveness, or quality‐of‐life outcomes were reported by the trial investigators. The primary analyses include 40 (85%) of 47 participants in the low‐energy group and 39 (87%) of 45 participants in the high‐energy group.
Excluded studies
We excluded 27 studies after review of the full‐text report. The studies, with reasons for exclusion, are documented in the Characteristics of excluded studies table. We excluded 16 studies that were not randomized (case series, cohort studies) and 11 RCTs of cyclodestructive procedures in refractory glaucoma (covered in a separate Cochrane Review; Chen 2016).
Risk of bias in included studies
Allocation
We assessed risk of selection bias to be low, as randomization was performed adequately by coin toss and allocation was done after participants received retrobulbar anesthesia; the treatment assignment would therefore not have been known prior to an individual's enrollment in the trial.
Masking (performance bias and detection bias)
Because no information was provided on masking of participants or trial personnel, we assessed the trial to have unclear risk of performance bias. We judged the trial to be at high risk of detection bias, due to outcome assessors being unmasked to the treatment assignments.
Incomplete outcome data
We assessed the risk of attrition bias to be high, because trial investigators excluded 13 (14%) of 92 participants from analysis for all outcomes, except complications. When participants who were excluded for missing three months of follow‐up were compared with those who were not excluded, the excluded participants were more often male and older than 50 years; however, preoperative IOP was similar in the excluded and non‐excluded groups.
Selective reporting
Results were reported for all outcomes specified in the Methods section of the published report. We therefore judged the trial to be at low risk of selective outcome reporting bias.
Other potential sources of bias
The laser used in the trial was provided by the manufacturer, and the trial had not been registered prospectively. For these reasons, we judged the trial to be at unclear risk of other potential sources of bias.
Effects of interventions
The one trial included in this review (Egbert 2001) reported control of IOP and burden of glaucoma medications after diode transscleral cyclophotocoagulation (TSCPC), and compared two energy settings for diode TSCPC. Because neither energy setting is considered the standard, we report the comparison of the two settings as documented in the trial: the low‐energy group versus the high‐energy group. All outcomes are reported for participants with at least three months of follow‐up (mean 13.2 months; 12.9 months in the low‐energy group and 13.5 months in the high‐energy group).
Control of IOP
Data for control of IOP, defined as a decrease in IOP of 15% from baseline value (our planned threshold), was not reported. However, data were reported for a decrease in IOP of 20% from baseline value; this level of control was seen in 37 of 79 eyes, 47%. Although the proportions of participants with a decrease in IOP by 20% were similar between the low‐energy group (19 of 40 participants, 48%) and the high‐energy group (18 of 39 participants, 46%), the small study size creates uncertainty in the effect estimate between energy settings (RR 1.03, 95% CI 0.64 to 1.65). We graded the certainty of evidence for this outcome as low, downgrading for risk of bias (‐1) and imprecision (‐1).
Egbert 2001 also reported a mean decrease in IOP of 3.3 mmHg (95% CI 0.70 to 5.90). The highest percentages of IOP reduction (57%) were observed in the subgroup of eyes having higher pretreatment IOP (> 22 mmHg). The mean difference (MD) in the mean decrease in IOP between energy settings was small, ‐0.50 mmHg (95% CI ‐5.79 to 4.79). Again, we graded the certainty of evidence for this outcome as low, downgrading for risk of bias (‐1) and imprecision (‐1).
Visual acuity
Egbert 2001 defined decreased vision as the proportion of participants with a decrease of 2 or more lines on the Snellen chart or one or more categories of visual acuity if unable to read the eye chart. Eighteen of 79 eyes demonstrated decreased vision. Considering eyes with good pretreatment visual acuity (20/60 or better), only one eye out of 19 (5%) experienced decreased vision after laser treatment. The proportions of participants with decreased vision were similar between the low‐energy group (10 of 40 participants, 25%) and the high‐energy group (eight of 39 participants, 21%); however, the effect estimate between energy settings was imprecise (RR 1.22; 95% CI 0.54 to 2.76). We graded the certainty of evidence for this outcome as low, downgrading for risk of bias (‐1) and imprecision (‐1).
Data were not available for mean visual acuity, proportion of participants with stable vision, or proportion of participants with decreased vision defined as greater than 1 line of vision loss.
Visual field
Egbert 2001 reported no visual field outcomes.
Number of glaucoma medications
The mean number of glaucoma medications used in the studied eyes fell from 1.8 ± 0.82 to 1.3 ± 1.18 after TSCPC treatment. The mean difference in the number of glaucoma medications used after TSCPC in the low‐energy group (1.4; standard deviation (SD) 1.3) compared with the high‐energy group (1.3; SD 1.1) was less than one (MD 0.10, 95% CI ‐0.43 to 0.63). We graded the certainty of evidence for this outcome as moderate, downgrading for risk of bias (‐1).
Pain control
Egbert 2001 reported no outcomes related to pain control.
Additional glaucoma surgery
The numbers and proportions of participants undergoing retreatment were reported by Egbert 2001. Overall, 16 eyes (20%) were retreated. Seven (17%) of 40 participants in the low‐energy group compared with nine (23%) of 39 participants in the high‐energy group required retreatment (RR 0.76, 95% CI 0.31 to 1.84). We graded the certainty of evidence for this outcome as low, downgrading for risk of bias (‐1) and imprecision (‐1).
Adverse events
Most adverse events were reported for the total study population, rather than by treatment group. The authors of Egbert 2001 reported that "most patients experienced mild to moderate pain for a few days, but none complained of severe pain." Many participants also had transient conjunctival burns (percentages not reported). Severe iritis occurred in two eyes and hyphema occurred in three eyes. No instances of hypotony or phthisis bulbi were reported. The only adverse event that was reported by treatment group was atonic pupil, which was observed in 13 (28%) of 47 eyes in the low‐energy group and 14 (31%) of 45 eyes in the high‐energy group (RR 0.89, 95% CI 0.47 to 1.68). We graded the certainty of evidence for this outcome as low, downgrading for risk of bias (‐1) and imprecision (‐1).
Economic data
Egbert 2001 reported no cost‐effectiveness outcomes.
Quality of life data
Egbert 2001 reported no outcomes related to quality of life.
Discussion
Summary of main results
Our review to evaluate the effectiveness and safety of cyclodestructive procedures for the management of non‐refractory glaucoma identified one eligible randomized clinical trial (Egbert 2001). Results from this trial did not compare cyclophotocoagulation to other procedural interventions, so we are unable to comment on the benefit of cyclodestructive procedures relative to other procedural therapies; this represents a knowledge gap in the glaucoma literature. The included trial compared two settings for diode transscleral CPC: low energy (45.0 joules) and high energy (62.5 joules). Mean follow‐up was 13.2 months after the first treatment. The primary analyses included 40 (85%) of 47 participants in the low‐energy group and 39 (87%) of 45 participants in the high‐energy group. Due to the small number of participants analyzed, we can draw no conclusions about between‐group differences for control of IOP, mean change in IOP, decrease in visual acuity, need for additional glaucoma surgery, and adverse events. The overall efficacy was modest, with IOP reduction by 20% or more in 47% of eyes. IOP control was highly variable and affected by pre‐operative IOP, with the highest percentages of IOP reduction observed in the subgroup of eyes having higher pretreatment IOP (> 22 mmHg). Vision loss occurred in 23% of eyes, but in only 5% (one out of 19) of eyes having a pretreatment visual acuity of 20/60 or better. In both groups, the amount of laser energy applied was quite conservative and lower than the energy usually used in other studies investigating CPC procedures.
The number of glaucoma medications used was reduced after diode transscleral CPC treatment in both groups; however, the difference was less than one medication when comparing treatment groups. No data for visual field, pain control, cost effectiveness, or quality‐of‐life outcomes were reported in this trial.
Overall completeness and applicability of evidence
The included trial reported on IOP control as well as visual outcomes and glaucoma medication use following diode transscleral CPC. It compared low‐energy versus high‐energy diode transscleral CPC. We found no evidence comparing one type of laser with another (e.g. Nd:YAG versus diode) or different routes of administration (e.g. non‐contact versus contact).
Most participants included in the trial were reported to have advanced glaucoma, although the proportion of 92 included eyes with this diagnosis was not given. Also, the definition of advanced glaucoma used in this trial did not include visual field findings. It is unclear whether similar effects would be observed in populations with less advanced glaucoma. Furthermore, the criteria used to decide to repeat diode CPC treatment of study participants were not reported, limiting the reproducibility of the trial.
Quality of the evidence
We graded the certainty of evidence for most outcomes as low, due to high risk of detection bias and attrition bias in the trial and imprecision in the effect estimates. Another limitation of the trial is that follow‐up was not standardized among participants. Only mean follow‐up time was reported for participants with at least three months of follow‐up.
Potential biases in the review process
To minimize potential biases in the review process we designed a comprehensive, sensitive search strategy to identify relevant studies, and followed standard Cochrane methodology. We adhered closely to methods as specified in the protocol and noted any deviation from the protocol in the Differences between protocol and review section.
Agreements and disagreements with other studies or reviews
We identified no other systematic review on this topic. From the search results for this review we found few studies, randomized or non‐randomized, that had evaluated cyclodestructive procedures in eyes with non‐refractory glaucoma. Most of the research for cyclodestructive procedures has been conducted in eyes with refractory glaucoma (see Characteristics of excluded studies). More recently, non‐randomized studies have been reported which evaluate cyclodestructive procedures in combination with phacoemulsification in eyes with glaucoma and cataract (Berke 2006; Janknecht 2005). Furthermore, individual studies have often reported findings for small samples of treated individuals and many are non‐comparative case series that were not designed to assess the benefits and harms of one method over another.
Study flow diagram.
| Low‐ versus high‐energy diode transscleralcyclophotocoagulation for non‐refractory glaucoma | ||||||
| Population: people with primary open‐angle glaucoma and no previous glaucoma surgery Settings: ophthalmology clinics Intervention: low energy; 1.5 watts for 1.5 seconds x 20 spots over 360 ° (45.0 J) Comparison: high energy; 1.25 watts for 2.5 seconds x 20 spots over 360 ° (62.5 J) | ||||||
| Outcomes* | Illustrative comparative risks** (95% CI) | Relative effect | No of participants | Quality of the evidence | Comments | |
| Assumed risk | Corresponding risk | |||||
| High‐energy diode transscleralcyclophotocoagulation | Low‐energy diode transscleralcyclophotocoagulation | |||||
| Control of intraocular pressure | 462 per 1000 | 475 per 1000 | RR 1.03 (0.64 to 1.65) | 79 | ⊕⊕⊝⊝ | Control of intraocular pressure defined as a decrease in IOP by 20% from baseline value |
| Mean change in intraocular pressure | On average intraocular pressure in the high energy group dropped by 3 mmHg | On average intraocular pressure in the low‐energy group was 0.5 mmHg lower than the IOP in the high‐energy group (5.79 mmHg lower to 4.79 mmHg higher) | ‐ | 79 | ⊕⊕⊝⊝ | ‐ |
| Decrease in visual acuity | 205 per 1000 | 250 per 1000 | RR 1.22 (0.54 to 2.76) | 79 | ⊕⊕⊝⊝ | Decrease in visual acuity defined as a decrease of 2 or more lines on the Snellen chart or one or more categories of visual acuity if unable to read the eye chart |
| Mean visual field | No visual field outcomes reported | ‐ | ‐ | ‐ | ‐ | ‐ |
| Number of glaucoma medications after treatment | The mean number of glaucoma medications in the high energy group was 1.3 | The mean number of glaucoma medications in the low energy group was 0.10 more (0.43 fewer to 0.63 more) | ‐ | 79 | ⊕⊕⊕⊝ | ‐ |
| Additional glaucoma surgery | 231 per 1000 | 175 per 1000 | RR 0.76 (0.31 to 1.84) | 79 | ⊕⊕⊝⊝ | Additional glaucoma surgery defined as retreatment with cyclophotocoagulation according to randomized assignment |
| Adverse events: atonic pupil | 311 per 1000 | 277 per 1000 | RR 0.89 (0.47 to 1.68) | 92 | ⊕⊕⊝⊝ | Atonic pupil was the only adverse event reported by treatment group. Trial authors noted that most participants had mild to moderate pain for a few days following the procedure and many also had transient conjunctival burns (number not reported). Severe iritis occurred in 2 eyes and hyphema occurred in 3 eyes. No instances of hypotony or phthisis bulbi were reported |
| *All outcomes are reported for participants with at least 3 months follow‐up; mean follow‐up was 13.2 months. | ||||||
| GRADE Working Group grades of evidence | ||||||
| 1Downgraded for risk of bias in the trial (unmasked outcome assessors and 14% attrition). | ||||||
