FP1139 : Pseudoexfoliation Study: 5 year post-operative results

RANGACHARI SESSION VIDEO

Dr. Haripriya Aravind, Dr. Shivkumar Chandrashekharan, Dr. Madhu Shekhar, Dr. Manas Nath 

Introduction

Pseudoexfoliation (PEX) has a strong association with zonular weakness, lens instability and insufficient pupil dilation, all of which increases the risk of complications during and after cataract surgery.^1,2 Surgeons who are aware of the presence of PEX in a subject undergoing cataract surgery must often use maneuvers or devices that manage poor pupil dilation (e.g. iris hooks) and prevent complications due to zonular instability (e.g. capsular tension rings) during surgery.²

The risk of intraoperative and postoperative complications of cataract surgery in eyes with pseudoexfoliation has been studied by various investigators with conflicting results. Some studies reported that eyes with PEX were at an increased risk for complications during and after cataract surgery as compared to eyes without PEX,^3,4  while others found no such association.^5,6 Limitations of prior studies on this topic include retrospective design, lack of formal criteria for judging the presence of PEX, small sample sizes, and/or review of surgeries done over several years, during which time surgical techniques may have changed. There is also a lack of conclusive evidence whether use of a specific IOL design or the use of a capsular tension ring might reduce the chance of late IOL dislocation in eyes with apparently good zonular integrity.^7,8

The Aravind Pseudoexfoliation (APEX) study is a large, prospective, longitudinal study designed to compare both the intraoperative and long-term postoperative outcomes in eyes with and without PEX undergoing cataract surgery. The PEX and control eyes were randomized to receive a single or 3-piece acrylic IOL. Herein, we compare postoperative complication rates at five years, and visual acuities at five years in PEX and control eyes. Additionally, we compare results for control and PEX eyes randomized to one-piece vs. 3-piece IOLs.

METHODS

The Aravind Pseudoexfoliation study (APEX) is a prospective, multicenter study. The primary goal was of the study was to compare outcomes in PEX and control eyes undergoing cataract surgery; a randomized controlled clinical trial randomizing subjects to various lens/capsular tension ring (CTR) implants was embedded within the study. All subjects were recruited from four Aravind eye hospitals between January 2011 and March 2012.

Both PEX and control eyes were randomized to receive either a single or three-piece acrylic IOL and PEX eyes were further randomized to either receive a capsule tension ring (CTR) (Aurolab, Madurai, India) or not. The study was designed for 10 year follow up to determine the association between PEX, lens type and CTR use with the rate of IOL dislocation and incident glaucoma, and the association of PEX with ocular comorbidity, systemic disease, and mortality.

The study was approved by the Aravind Eye Hospital’s institutional review board and ethics committee and written informed consent was obtained from all participants. All study procedures adhered to the principles outlined in the Declaration of Helsinki for research involving human subjects. The study was registered with clinicaltrials.gov (ClinicalTrials.gov identifier:  NCT01255995 ).

Subject Recruitment

Subjects with cataract and PEX were screened and information regarding anterior segment findings were documented. Those who were eligible and willing to participate based on the inclusion criteria presented below were recruited as cases. Eyes with PEX were randomized into four groups using computer generated randomization table: Single piece acrylic IOL (SA60AT, Alcon Labs, USA) with and without use of a capsule tension ring (CTR) (Aurolab, Madurai, India) and 3 piece acrylic IOL (MA60AC, Alcon labs, USA) with and without use of a CTR. Control eyes were randomized to receive either a single or 3 piece acrylic IOL but with no CTR.

Inclusion criteria:

Patients aged 40 to 75 years with at least one eye demonstrating a nuclear opalescence grade of 3 or greater on the Lens Opacities Classification System (LOCS) III, a pupil size > 4 mm after dilation, an axial length between 20.5 mm to 25 mm and a willingness to undergo phacoemulsification with IOL were eligible for the study. Patients in the PEX group were also required to demonstrate clinically apparent PEX (diagnosed by the presence of typical white deposits on the anterior lens surface with or without such deposits on the cornea, iris, and anterior chamber angle) with or without open angle glaucoma in at least one eye also meeting the above criteria.

Exclusion criteria:

Eyes were ineligible for inclusion if they had an IOP more than 21mm Hg with IOP lowering medications, angle closure glaucoma, any preexisting clinical zonular dialysis or phacodonesis, suspected traumatic etiology for cataract, posterior polar cataract, shallow anterior chamber depth (<2.5 mm), concomitant corneal/retinal pathology which could impact visual outcomes, severe visual field defects (defined as a Mean Deviation >12.0 dB on Humphrey automated testing) or requirement of a combined glaucoma-cataract surgical procedure. We also excluded monocular subjects (fellow eye visual potential felt to be 3/60 or less) as well as subjects with advanced cardiac pathology, uncontrolled diabetes, hypertension, severe asthma or other disability likely to interfere with long-term follow up. Persons with evidence of PEX, glaucomatous optic disc changes in either eye, or other intraocular abnormalities were not eligible for the control group.

Preoperative examination

Preoperative systemic evaluation and patient history were performed to determine diabetes, hypertension, ischemic heart disease and dyslipidemia. PEX status, slit lamp examination, and a complete ocular exam, including dilated fundus exam, was performed to rule out other ocular disease. Visual acuity was measured using projected Snellen charts, with lines graded as read if subjects read half or more of the letters correctly. Refraction was done pre operative and at each visit postoperative except post op day 1. Intraocular pressure was measured by applanation tonometry and specular microscopy with KSS version 417 machine (Konan Medical USA Inc., Irvine, CA). Cataracts were graded after dilation at the slit lamp with respect to nuclear opalescence (NO: range 0.1-6.9), nuclear color (NC: range 0.1-6.9), cortical opacities (C: range 0.1-5.9) and posterior subcapsular changes (P: range 0.1-5.9) using LOCS the III system (Chylack Incorporated, Duxbury, MA). Eyes with NO scores of >3 were eligible for inclusion. Glaucoma was defined by the presence of corresponding optic disc and visual field changes, independent of intraocular pressure (IOP), and we assessed angle status prior to dilation using the Shaffer system of gonioscopic classification. Visual fields were obtained, when necessary, using the Humphrey automated perimeter, Model No 750i, (Carl Zeiss Meditec AG Jena, Germany) Central 24-2 full testing strategy for all subjects.

Surgical approach

At each recruiting center, 4-5 experienced surgeons who have performed a minimum of 10,000 phacoemulsification procedures performed the phacoemulsification surgeries. The basic surgical technique for phacoemulsification and intraocular lens (IOL) implantation was similar among all surgeons and in both study groups. Subjects received either topical anesthesia or a retrobulbar block based on surgeon’s preference. A temporal 2.8 mm clear corneal incision was made along with a limbal paracentesis 60 to 90 degrees away from the main wound. Pupil size after maximum dilation, before injection of viscoelastic, was measured with calipers. A continuous curvilinear capsulorhexis of approximately 5 – 5.5 mm diameter was created. Cortical hydrodissection was performed followed by nucleus phacoemulsification using either the “stop and chop” or “phaco chop” technique or automated irrigation/aspiration of cortical material. The uses of iris retractors, or iris expansion device if used were recorded. Capsule tension rings were inserted in the PEX CTR group and as needed in other study groups if zonulopathy was noted during surgery. The specified IOL based on randomization was implanted in the capsular bag. Viscoelastic was evacuated from the eye and wounds hydrated. Major intraoperative complications were defined as posterior capsule rupture, zonular dialysis, vitreous loss, and capsulorhexis extension. Any reoperation done within 90 days of surgery was documented.

Postoperative protocol

Subjects were examined per protocol post operatively on day 1, month 1, 3 months, 1 year, 2 years, 3 years, 4 years and 5 years after surgery, and continue to be followed-up annually. Any unscheduled visits requiring a new medication, laser treatment or reoperation from the primary surgery were also documented.

The following were classified as late postoperative complications: IOL decentration (>0.8 mm) and posterior capsule opacification. Subjects who developed posterior capsule opacification which caused reduction in vision of one line or more, underwent neodymium-doped yttrium aluminium garnet (Nd:YAG) laser posterior capsulotomy.

Sample size and power calculation

We required a sample of 876 PEX eyes and 438 control eyes to find the estimated difference between the two groups. The sample size was calculated based on an assumed intraoperative complication rate in two groups to be 7.7% and 5.2%, 85% power, and a type I error rate of 5%. ⁹ We recruited 1000 PEX subjects and 500 control subjects in the trial. Further randomization of subjects within the PEX and control groups was performed using a computer-generated randomization list. We used chi-square test and Fisher’s exact test to assess the differences between categorical variables. P-values less than 0.05 were considered statistically significant. Analysis was performed using Stata software (version 11.0, Stata Corp LP, Texas, USA).

Primary Outcome Variables

• IOL decentration
• Nd:YAG capsulotomy rates for posterior capsule opacification

Secondary Outcome Variables

• New glaucomas, diagnosed between 1year and 5 years post op
• Endothelial cell loss at 5 years post op

RESULTS

Follow up at 5 years was 74.8% (748/1000) in PEX and 79.8% (399/500) in control group.

 

Table-1: Comparison of IOL decentration in PEX and control groups

	PEX					CONTROL
Sub Group	1 piece Acrylic with CTR	1 piece Acrylic without CTR	3 piece Acrylic with CTR	3 piece Acrylic without CTR	TOTAL	1 piece Acrylic without CTR	3 piece Acrylic without CTR	TOTAL
n	179	190	197	182	748	196	203	399
Decentration (%)	3(1.7%)	15(7.9%)	13(6.6%)	4(2.2%)	35(4.7%)	3(1.5%)	13(6.4%)	16(4%)

p=0.58

PEX- pseudoexfoliation

IOL- intraocular lens

CTR- capsule tension ring

 

 

 

 

Table-1A: Comparison of IOL decentration in PEX eyes which received three piece and single piece IOLs

1 piece Acrylic		3 piece Acrylic
369		379
18(4.9%)		17(4.5%)
	p value	0.799

 

PEX- pseudoexfoliation

IOL- intraocular lens

Table-1B: Comparison of IOL decentration in PEX eyes which received and did not receive a CTR

With CTR		Without CTR	TOTAL
376		372	748
16(4.25%)		19(5.1%)	35(4.7%)
	p value	0.581

 

PEX- pseudoexfoliation, IOL- intraocular lens

CTR- capsule tension ring

 

Table-2: Nd:YAG posterior capsulotomy rates in PEX and control groups

	PEX					CONTROL
Sub Group	1 piece Acrylic with CTR	1 piece Acrylic without CTR	3 piece Acrylic with CTR	3 piece Acrylic without CTR	TOTAL	1 piece Acrylic without CTR	3 piece Acrylic without CTR	TOTAL
n	179	190	197	182	748	196	203	399
YAG (%)	16(8.9%)	16(8.4%)	16(8.1%)	11(6%)	59(7.9%)	13(6.6%)	5(2.5%)	18(4.5%)

p=0.029

PEX- pseudoexfoliation, CTR- capsule tension ring

Nd: YAG- neodymium-doped yttrium aluminium garnet

 

Table-2A: Nd:YAG posterior capsulotomy rates in PEX and control groups comparing single piece and three piece acrylic IOLs

	PEX			Control
Sub Group	1 piece Acrylic	3 piece Acrylic	TOTAL	1 piece Acrylic	3 piece Acrylic	TOTAL
n	369	379	748	196	203	399
YAG (%)	32(8.7%)	16(4.2%)	59(7.9%)	13(6.6%)	5(2.5%)	18(4.5%)
p value 0.013				p value 0.045

 

Table-3: Newly diagnosed glaucoma in PEX and control groups

	PEX					CONTROL
Sub Group	1 piece Acrylic with CTR	1 piece Acrylic without CTR	3 piece Acrylic with CTR	3 piece Acrylic without CTR	TOTAL	1 piece Acrylic without CTR	3 piece Acrylic without CTR	TOTAL
n	179	190	197	182	748	196	203	399
New glaucoma(%)	14(7.8%)	14(7.4%)	10(5%)	17(9.3%)	55(7.4%)	0	7(3.4%)	7(1.8%)

p<0.0001

PEX- pseudoexfoliation, CTR- capsule tension ring

Table 4: Endothelial cell density at first and fifth year post op in PEX and control groups

Visit	PEX (mean, SD)	Control (mean, SD)	p-value
Pre-op ECD	2144.43 (349.38)	2241.86 (330.66)	<0.001*
1 year ECD	1827.59 (399.65)	1955.78 (402.21)	<0.001*
% reduced from pre op	14.67	12.52	0.018#
5 year ECD	1973.50 (462.80)	2085.80 (442.30)	0.0004*
% reduced  from pre op	6.9	6.34	0.427#
p value pre-op to 5th year	<0.001	<0.001

 

PEX- pseudoexfoliation

ECD- endothelial cell density

Pre-op- preoperative

*t-test

#Mann-Whitney U test

DISCUSSION

The prevalence of PXF was reported to be 3% and 3.8% among those above the age of 40 in two studies from south India, while in the 2003 study in the southern state of Tamilnadu the prevalence in the same age group was reported to be 6%. ^9,10,11 The association  Pseudoexfoliation with an increased risk of  intraoperative and postoperative complications has been studied by various investigators, and the results have been conflicting.^12,13,14 This is the first long term large prospective study evaluation surgical outcomes of subjects with and without pseudoexfoliation requiring cataract surgery. Prior studies had far smaller sample sizes.^15,16

We recruited relatively younger subjects and only those subjects with mild to moderate disease, as we wanted to study the clinical course of the disease over 10 years and better understand the role of IOL design and CTR in early and mid-stage disease. At 5 years post op IOL decentration was similar in PEX (4.7%) and control (4%) eyes. Inclusion of cases of PEX with phacodonesis would most likely have increased the risk of IOL decentration. Also IOL design and use of a capsule tension ring had no role in reducing decentration. There are numerous reports of IOL decentration in PEX eyes in the literature with or without CTR and capsular bag complex. These eyes had weak zonules noted preoperatively or during surgery.^17-20

ND YAG posterior capsulotomy rates for posterior capsule opacification was significantly higher in the PEX group (8.1%) compared to controls (4.5%) although both groups received the IOLs with the same material and design. One study reported PCO rates of 31% in PEX eyes at 1 year post op.²¹ The authors believe that incomplete cortical removal and absence of capsule polish in these eyes could have contributed to higher PCO in these eyes. Another study however reported ND-YAG posterior capsulotomy rates of 16% with both PEX and age matched control eyes, 6 to 7 years after cataract surgery.²²

At the time of recruitment only 23 (2.3%) eyes were diagnosed with glaucoma in the PEX group however 5 years after cataract surgery an additional 7.4% (55 eyes) were newly diagnosed with glaucoma. 1.8% (7 eyes) of controls were diagnosed with glaucoma. Kristianslund et al reported a low incidence of PEX glaucoma compared to age and gender matched controls 6 years after surgery.²³ Both groups had a similar incidence and the authors propose that indicates that PEX eyes benefit particularly from cataract surgery in terms of IOP and glaucoma development. Results from the Chennai glaucoma study shows that baseline ocular hypertension is a significant factor for conversion to glaucoma.²⁴ Endothelial cell density was significantly lower at 5 years post op compared to pre op in both the PEX and control groups. However it had increased compared to the first year follow up.

Long-term follow-up data from the Blue Mountains eye study suggest that the presence of PEX is associated with an increased risk of nuclear cataract and cataract surgery.²⁵ Our study is unique because we were able to recruit a large number of subjects for the study and track them 5 years post-operatively. Based on our results we conclude that in PEX eyes without preoperative zonular weakness, capsule tension ring is not required as risk of IOL decentration is comparable to the control group. Likewise immaterial of whether a 3 piece or single piece IOL is used, the rate of IOL decentration is low. However, IOL design does have a significant role in reducing posterior capsule opacaificaiton in both PEX and control eyes. Longer term follow up will give us further information regarding how the disease progresses in relation to the use of CTR and IOL design.

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