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CLINICAL SCIENCE
AlphaCor
Clinical Outcomes
Celia R. Hicks, FRCOphth,* Geoffrey J. Crawford, FRANZCO,* John K. G. Dart, FRCOphth,†
Günther Grabner, MD,‡ Edward J. Holland, MD,§ R. Doyle Stulting, MD, PhD,k
Donald T. Tan, FRCOphth,¶ and Max Bulsara, PhD#
Purpose: To study the outcomes of AlphaCor implantation.
evolving with experience. Continued data collection is important for
a fuller understanding of AlphaCor’s role.
Methods: The AlphaCor artificial cornea is indicated for corneal
blindness not treatable by donor grafting. Prospective preoperative
and follow-up data were collected. Data were evaluated using SPSS
for statistical analysis of outcomes, trends, and associations.
Key Words: AlphaCor, corneal graft, keratoprosthesis
Results: This report includes data returned through February 28,
2006, for all 322 devices implanted, with mean follow-up in situ of
15.5 months and a maximum of 7.4 years. The probability of
AlphaCor retention at 6 months and 1 and 2 years for protocol cases
was 92%, 80%, and 62%, respectively, and off-label cases were at
higher risk (P = 0.010), as were cases not prescribed medroxyprogesterone (MPG; P = 0.001). Currently, the most common
complications were stromal melting, fibrous reclosure of the posterior
lamellar opening, and white intraoptic deposits, with incidences in
2005 of 11.4%, 5.1%, and 2.6%, respectively. MPG seems to protect
against melts, and eyes with a history of herpetic keratitis were not at
increased risk. A history of glaucoma or the presence of tubes did not
affect device retention. Complications culminated in loss of an eye in
1.3%. Mean preoperative visual acuity (VA) was hand movements.
The VA achieved postoperatively (light perception to 20/20) was
affected by previous pathology and postoperative course, with a mean
improvement of 2 lines.
T
Conclusion: AlphaCor provides a treatment option where a donor
tissue graft would not succeed in severe corneal conditions, while
being reversible to a donor graft in the event of complications for
anatomic integrity. Surgical technique and adjunctive therapies are
Received for publication September 27, 2005; accepted April 7, 2006.
From the *Biomaterials Research Centre, Lions Eye Institute and Centre for
Ophthalmology and Visual Science, University of Western Australia,
Perth, Australia; †Moorfields Eye Hospital and Institute of Ophthalmology, London, United Kingdom; ‡Landesaugenklinik, Salzburg, Austria;
§Cincinnati Eye Institute, Cincinnati, OH; kEmory Laser Vision, Emory
University, Atlanta, GA; {Singapore National Eye Center, Singapore; and
#School of Population Health, Faculty Medicine and Dentistry, University
of Western Australia, Perth, Australia.
Presented in part at the meeting of the American Academy of Ophthalmology,
October 15–18, 2005, Chicago, IL, and the World Ophthalmology
Congress, February 19–24, 2006, Sao Paulo, Brazil.
Disclosure: Hicks and Crawford have a financial interest with the
manufacturer of AlphaCor, CooperVision Surgical, through support of
departmental funding, travel and research.
Reprints: C. R. Hicks, Lions Eye Institute, 2 Verdun Street, Nedlands, WA
6009, Australia (e-mail: [email protected]).
Copyright Ó 2006 by Lippincott Williams & Wilkins
1034
(Cornea 2006;25:1034–1042)
he Lions Eye Institute in Western Australia developed
a novel biointegratable artificial cornea from poly(2hydroxyethyl methacrylate) (PHEMA), exploiting the difference in the physical properties engendered by altering water
content, so that a 1-piece device comprising a transparent optic
unified with an opaque sponge skirt could be produced. The 2
regions are joined by an interpenetration of the polymers.1
The research group believed that biointegration, lack of
rigidity, and reversibility are important features for a fullthickness corneal replacement and conducted extensive preclinical studies.2–14 The device had a low complication rate in
both healthy and inflamed animal eyes.10 However, in view of
the long history of complications related to keratoprostheses
(KPros) of all designs,8,15,16 it was recognized that implantation in pathologic human eyes would introduce new challenges
necessitating long-term data collection to evaluate the efficacy
of the device in comparison with other devices and grafting
strategies.8,17
Human studies started in 1998, and after a change from
sutured penetrating keratoplasty (PK)–style implantation to
a lamellar procedure,17 the final device, known as AlphaCor
(Fig. 1), received market clearance (Australia, Europe, United
States).
Several complications, associations, and risk factors have
been identified through data review, including stromal
melting,18,19 optic deposition,20,21 and retroprosthetic membranes.22 The indications and surgical technique have been
described,23–25 and histologic findings from early trial devices
that were explanted have been presented.26 This study aims to
review current AlphaCor data to reassess clinical performance
and indications.
MATERIALS AND METHODS
Approvals
Informed consent was obtained in all cases. Institutional
Review Board/Ethics Committee approval was obtained
where required for return of anonymous data postapproval
Cornea Volume 25, Number 9, October 2006
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Cornea Volume 25, Number 9, October 2006
AlphaCor
Data Collection and Management
Participating in voluntary post-trial data compilation and
review, surgeons document the deidentified patient’s preoperative ocular status, medications, and ophthalmic history. Surgical
and follow-up data were collected by faxed hard copy or through
a secure Web site and include IOP estimates, medications, visual
acuity, and complications, and statistical analysis was performed
using SPSS (SPSS, Chicago, IL). Since device approval, data
entries were voluntary and unmonitored, but the data system
provides prompts, notes data amendments, and complies with
U.S. Food and Drug Administration standards and security
requirements. Surgeons are urged to report complications
without waiting for a routine reporting interval. The database
is saved monthly so that trend analysis can be conducted.
RESULTS
Data
FIGURE 1. AlphaCor: postoperative appearance (this image
shows a case after the ‘‘small incision’’ implantation technique).
of the AlphaCor device and for all cases before market
clearances.
Surgical Technique
There are 2 stages to device implantation, separated by
about 3 months.23,24,27 In the first, a corneal lamellar pocket is
created with a central 3.5-mm opening in the posterior lamella,
and the device is positioned with its optic centered over the
posterior trephination. The access wound is closed, and
optionally, although now rarely, a Gunderson flap is placed
over the surface. In stage 2 surgery, tissues anterior to the optic
are removed over the central 3.0 mm to expose the device as
a full-thickness corneal replacement centrally, while its skirt
remains integrated within the stromal pocket. Stage 1
traditionally involved a 180° entry wound 1.5 mm posterior
to the superior limbus to provide access for a standard trephine
for the posterior opening. A ‘‘small incision’’ technique, using
a 90° access wound, has been evaluated, with various lowprofile trephines being used for the posterior trephination25 but
not found to be ideal. There has been a trend over the last 12
months toward operating within an existing PK wound rather
than dissecting from the limbus.28
Postoperative Care
Topical medroxyprogesterone 1% (MPG; compounded)
is recommended indefinitely, along with a long-term topical
antibiotic of choice and optional medications such as topical
cyclosporine 0.05% emulsion (Restasis; Allergan, Irvine, CA)
or artificial tears to optimize the ocular surface. Postoperative
intraocular pressure (IOP) was monitored by several methods
including digital, TonoPen (Medtronic Ophthalmics, Jacksonville, FL) over the limbus, air tonometers, the ProView
phosphene tonometer (Bausch & Lomb, Rochester, MN), or
the TGDc-01 (Ryazan State Instrument Making Enterprise,
Ryazan, Russia), which is also applied over the eyelid but gives
an objective electronic reading.29 After stage 2, visualization of
the optic disc is generally possible, and visual field tests may be
performed.
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As reported to March 16, 2006, 322 AlphaCor devices
had been implanted to February 28, 2006, including 46 (14.3%)
during regulatory trials and 276 (85.7%) since market
clearances. Preoperative data were collected in all cases. Of
the 84 participating surgeons, 89.3% are current with follow-up
data. Five recipients have died of unrelated causes since
receiving AlphaCor. Cases correspond to devices implanted
rather than individual patients, so that repeat implants and
second eyes can be separately evaluated, in the same manner as
graft registries analyze each tissue graft implanted. The 322
devices were implanted into 304 eyes of 302 individuals with
only 2 bilateral implantations. Eighteen devices were explanted
and replaced with a second device.
Centers of Surgery
AlphaCor has been implanted by 84 surgeons who have
implanted 1 to 24 devices each (mean, 3.8). AlphaCor has
been implanted in 11 countries, and during the last 12 months,
most implantations have occurred within the United States,
which now accounts for 69.6% of all cases.
Follow-Up
Follow-up ranged from 0.5 months to 7.4 years in situ
(mean, 15.5 months; median, 12.6 months). Only 68 (21.1%)
have more than a 2-year follow-up in situ (Fig. 2).
Patient Demographics and
Preoperative Status
The device is approved for implantation into adults with
an absence of current inflammation, a satisfactory tear film,
and no history of ocular herpes simplex viral (HSV) infection
by a surgical technique outlined in the device labeling. Thirtysix (11.2%) cases are ‘‘off-label’’ in 1 or more respects.
Patients typically had complex ocular histories with multiple
pathologies including bullous disease, trauma, dystrophies,
HSV, other infections and aniridia (Tables 1 and 2), and up to
13 prior failed PKs (mean, 2.4). One hundred thirty-eight
cases (42.9%) exhibited 4 quadrants of deep vessels. A
descriptive risk score30 shows the degree of risk of failure that
these patients with preoperative risk scores of 7 to 23 (mean,
14) would have faced with further PK; in comparison,
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Hicks et al
origin receiving the device for the first time (now 12.1%
cases), Asians/Inuit representing 14.3% of cases, and whites
representing 73.6% of cases. Age at surgery ranged from 1 to
95 years (mean, 57.9 years).
Surgical Data
FIGURE 2. Percentage of AlphaCor cases to have achieved
follow-up in situ of less than 6 months, more than 6 months,
and more than 1, 2, 3, 4, 5, or 6 years (through February 28,
2006).
a series of PK recipients judged to require systemic
immunosuppression had risk scores of 8 to 13 (mean,
10.5).30 The racial profile changed after the device became
available in the United States, with those of Afro-Caribbean
TABLE 1. Preoperative Ocular History/Conditions
(Nonexclusive)
Condition
No. AlphaCor Cases
Bullous keratopathy
Aphakic
Pseudophakic
Phakic
Trauma
Mechanical only
Alkali
Acid
Heat
Unknown
Dystrophy
Fuchs dystrophy
Irido-corneo-endothelial syndrome (ICE)
Other dystrophy
Descemetocoele
Keratoconus and keratoglobus
Keratoconus
Keratoglobus
HSV
Bacterial/fungal keratitis/ulcer
Bacterial
Fungal
Unknown
Limbal stem cell failure
Aniridia
123
38
83
2
77
34
32
7
3
1
66
19
5
42
5
25
24
1
Confirmed 23, suspected 7
36
30
4
2
29
28
Original pathology (reason for first graft) was not always reported.
1036
A full Gunderson flap was originally regarded as routine
and was formed in 106 (32.9%) cases, a partial flap in 2 (0.6%)
cases, a flap was formed secondarily in 3 (0.9%) cases after the
ocular surface deteriorated, buccal mucosa was used in 3
(1.6%) cases, and a lamellar graft was used in 6 cases (1.9%).
Since 2004, only 3 cases have received a Gunderson flap.
The ‘‘standard’’ 180° incision technique was used in 262
(81.4%) cases, and the small-incision technique with the lowprofile trephine was used in 30 cases (9.3%). The ‘‘within the
existing PK’’ technique was used in 25 (7.8%) cases overall
but in 60% of cases to date in 2006. Other variants were used
in remaining cases. Perioperative complications were reported
to have occurred in 64 cases (19.9%; Table 3). To date, stage 2
has been done in 195 cases (60.6%). Cataract surgery was
performed concurrently with AlphaCor implantation in 14
cases (22% of phakic eyes). Of the 49 cases that were phakic
after AlphaCor implantation, 4 (8.2%) showed some subsequent progression of lenticular opacity, and in 1 case, the
crystalline lens was removed after severe blunt trauma to the
eye that occurred 12 months after AlphaCor implantation.
Outcome Data
Complications
Stromal Melting
Postoperative stromal melting was defined as any
episode of stromal thinning or loss, whether or not the
TABLE 2. Status Before AlphaCor Implantation
Status Before AlphaCor
No. AlphaCor Cases (% Series)
Ocular
Phakic
Aphakic
Pseudophakic—PCIOL
Pseudophakic—ACIOL
Pseudophakic—iris IOL
Sutured IOL
Glaucoma
Trabeculectomy
Shunt
Laser only
Existing retrocorneal membrane
Silicone oil in eye
General
Male
Female
Tobacco smoker
Insulin-dependent diabetic
Non–insulin-dependent diabetic
Systemic hypertension
63
61
176
16
3
3
189
32
84
3
10
7
(19.6)
(18.9)
(54.7)
(5.0)
(0.9)
(0.9)
(58.7)
(9.9)
(26.1)
(0.9)
(3.1)
(2.2)
193
129
30
31
19
51
(59.9)
(40.1)
(9.3)
(9.6)
(5.9)
(15.8)
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Cornea Volume 25, Number 9, October 2006
AlphaCor
TABLE 3. Perioperative Complications Reported After Stage 1
AlphaCor Surgery
Complication
No. Cases
% Series
Opening old graft wound
Perforation posterior lamella
Perforation anterior lamella
AlphaCor damaged
Vitreous loss
Perforation scleral incision
28
15
15
1
3
2
8.7
4.7
4.7
0.3
0.9
0.6
process subsequently stabilized. Melts occurred in 26.4% of
all cases and contributed to the need for device explantation in
64.5% of cases where a device was removed. The following
factors were analyzed for a possible effect on melt occurrence
(log-rank analysis): world region, racial origin, sex, preoperative corneal vascularization, dry eye, blepharitis, HSV,
smoking, aniridia, keratoconus, dystrophies, silicone oil,
bullous keratopathy, trauma and chemical burns, preoperative
glaucoma, preoperative lens status, diabetes, systemic hypertension, cataract surgery with or after AlphaCor surgery,
small- or large-incision surgery, surgical complications,
Gunderson flap, and use of systemic tetracycline or of MPG
(Table 4).
In contrast to earlier findings,19,31 neither HSV nor
concurrent cataract surgery were risk factors for melts. The
tear film and ocular surface seem to influence risk, unsurprisingly, and a possible influence of a keratoconus history
may be an artifact of the small dataset or possibly reflect
differences in metalloproteinase activity.32 MPG seems to
protect against melts, although other ocular surface–protecting
measures such as bandage contact lens wear postoperatively
may be complimenting its role. Conjunctival flaps were not
found to be protective, perhaps partly because of selection of
worse eyes to have a flap, but possibly because of limbal and
ocular surface trauma during flap formation. The incidence of
stromal melting has fallen considerably (Table 5).
Optic Deposition and Damage
Intraoptic deposits have been reported in 27 cases
(8.4%). Deposits have never been noted at stage 2, implying
exogenous factors. Three types of intragel deposition have
been identified: brown (10 cases), diffuse white (16 cases), and
focal fungal (1 case). Surface spoliation of a contact lens type
(protein, calcium, or mucoid) has been reported in 16 cases
and iatrogenic optic damage in 1 case. The incidence of all
types of deposits seems to be falling (Table 5).
Brown Deposits. The following putative causative factors were
evaluated (log-rank): sex, glaucoma history (associated with
likelihood of multiple medications), and smoking. Analysis
was performed on post–stage 2 eyes, because deposits can be
diagnosed (and probably only occur) only after exposure to the
external environment. Only smoking was found to be
a statistically significant risk factor (P = 0.015), as shown in
Figure 3A. Iodine-containing fluids contacting the optic when
a device was explanted after stromal melting caused visible
staining in 2 cases, suggesting that these skin preparation
fluids should be used with care when AlphaCor is in situ.
White Deposits. Diffuse white intraoptic deposition has
previously been identified as calcium and associated with
coprescription of topical b-blockers and steroids after stage
2;20 it is not seen when these medications are given separately.
Of the 16 affected cases, 10 (62.5%) had a history of glaucoma
before AlphaCor and 1 had elevated IOP postoperatively,
requiring topical medication. The following were evaluated
TABLE 4. Factors Found to Influence Risk of Stromal Melting
Factor
Region of world
(Australasia, Europe,
United States)
Racial origin (father)
Dry eye
History ocular HSV
Off-label
Original history
keratoconus or
keratoglobus
Surgical
complications
MPG
Significance (Log-Rank)
for All Cases
Significance (Log-Rank)
for Cases Treated With MPG
P = 0.004; lower melt rate
in the United States
No longer significant
(P = 0.096)
P = 0.024; higher rate
in Asian patients
Not statistically significant
(P = 0.497)
Not statistically significant
(P = 0.105)
P = 0.015; off-label cases at
higher risk
P = 0.018; keratoconus
history seems to increase
melt risk
P , 0.001; recorded
perioperative complications
associated with higher
subsequent melt risk
P = 0.001; MPG seem
protective against melting
No longer significant
(P = 0.613)
P = 0.002; higher risk
in dry eyes
Not statistically significant
(P = 0.805)
No longer significant
(P = 0.069)
P = 0.045; higher risk in
keratoconus cases
No longer significant
(P = 0.091)
NA
NA, not applicable.
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Hicks et al
TABLE 5. Changes in Annual Incidences of Complications
Complication
Melts
White deposits
Brown deposits
Surface spoliation
RPM
PPB
Trial Data in
Labeling
(N = 26)
Annual Incidence (%)
2003 On-Label
Cases (N = 105)
Annual Incidence (%)
2004 On-Label
Cases (N = 192)
Annual Incidence (%)
2005 On-Label
Cases (N = 266)
32%
11%
23%
23%
19%
Complication
not recognized
24.7
5.7
6.6
7.6
8.6
0
10.6
4.6
2.1
2.6
11.9
3.1
11.4
2.6
0.4
1.6
5.1
1.2
RPM, RetroProsthetic membranes; PPB, poor primary biointegration.
(log-rank) as possible risk factors for white intraoptic
deposition post–stage 2: sex; preoperative glaucoma (associated with likelihood of multiple medications); silicone oil;
simultaneous prescription of topical steroids and topical bblockers after stage 2; and MPG, a white, sedimentary
formulation. Only the concurrent topical steroids and bblocker prescription was significant (P , 0.001; Fig. 3B). The
prevalence of this type of deposition in posttrial subjects was
4.3% compared with 8.7% in trial subjects. A similar posttrial
fall in reported prescription of this combination of medications
was seen, from 8.7% of trial subjects (who all became
affected), to 2.2% post-trial, suggesting that awareness of the
risk factor is helping to reduce incidence.
Focal Fungal Deposits. Fungal invasion of the AlphaCor
occurred in an elderly man wearing a rigid gas-permeable
(RGP) contact lens with suspected poor lens hygiene.27
Surface Spoliation. Log-rank analysis of post–stage 2 cases for
onset of surface spoliation examined the following factors:
sex, dry eye, meibomianitis/blepharitis, smoking, MPG, and
conjunctival flap (perhaps by causing poor wetting of the
recessed optic). Of these, dry eye was significant (P , 0.001).
Severe surface spoliation in 3 cases required excimer laser
ablation; these were eyes with particularly poor tear films. In
others, contact lens cleaners, such as Opti-Free Supra Clens
(Alcon Laboratories, Ft. Worth, TX), were effective. A bandage
lens seemed to prevent recurrence in some cases.
Iatrogenic Damage. In 1 case (0.3%), the device was removed
after a circular 3.0-mm-diameter cut was noted in the optic
several months after stage 2; presumably, partial thickness
trephine marks subsequently became full thickness after eye
rubbing.
Retroprosthetic Membranes: Fibrous Closure of
Posterior Stromal Opening
A fibrous reclosure of the posterior lamellar opening was
seen in 42 cases (13.0%). Possible associations were evaluated
by x2 because exact timing of onset was hard to define.
Membranes were significantly associated with systemic
hypertension (P = 0.015) and Afro-Caribbean parentage
(P = 0.001). Diabetes mellitus was not a significant risk factor
(P = 0.258), differing from earlier data,22 perhaps because of
specific precautions in patients with diabetes since that report.
Neither a large number of previous failed grafts (P = 0.210)
nor a history of retrocorneal membrane (P = 0.106) reached
statistical significance.
FIGURE 3. A, Influence of smoking on onset brown optic
deposition (data through February 28, 2006). B, Influence of
concurrent prescription of topical steroids with topical bblockers on subsequent onset of diffuse white intraoptic
deposition (data through February 28, 2006).
1038
Poor Primary Biointegration
‘‘Poor primary biointegration’’ (PPB) denotes cases where
a device is found, or suspected, to be suboptimally integrated,
so that aqueous leakage could occur at stage 2. It occurred in 8
(2.5%) cases and was diagnosed during stage 2 (aqueous
leakage) in 6 and by prior ultrasound biomicroscopy (UBM) in
2. Most cases had involved a prototype small-incision technique trephine and an oversized (8.0 mm) sizing device (to
ensure trephine access), but in all but one, the incision was
extended to 180°. Surgical reports detailed 6 cases with
perioperative complications including lamellar perforations,
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Cornea Volume 25, Number 9, October 2006
graft wound breakdown, and in 1 case, extremely poor
apposition of the posterior lamella to the device was
recognized at completion of surgery. On x2 analysis, the only
factor statistically significantly associated with PPB relates not
to preoperative status but to perioperative complications (P ,
0.001). Disruption of PK wounds and overdissection of the
pocket, perhaps related to bulky small-incision instrumentation, may underlie the problem. Racial origin was not
statistically significant, but PPB has not been reported in an
Afro-Caribbean individual. Fluid pockets surrounding the
AlphaCor in these cases seen by UBM seem generally to
resolve slowly. Imaging before stage 2 is recommended so that
stage 2 can be deferred when good biointegration has not
occurred.
Other Complications
Diabetic retinal detachments (RDs) thought to have been
present preoperatively were seen after a clear view was
achieved after stage 2 in 3 cases (0.9%). A rhegmatogenous
RD occurred in 2 cases (0.6%) during surgery for recurrent
RPM. Two cases (0.6%) of endophthalmitis, resulting in loss
of light perception, were reported, both in patients noncompliant with antibiotics: 1 after a recurrent stromal melt and
1 after PPB with aqueous leakage where the anterior lamella
was not repaired. There were 2 cases (0.6%) of presumed
vitreitis without apparent cause.
Complications: Overall Prevalence
Overall, 148 cases (46.0%) had 1 or more mild or severe
complications during follow-up, whereas 174 cases (54.0%)
have not. The mean time to onset of the first complication is
12.3 months (range, 0.2–60.5 months). Complication rates
were highest in the preapproval cohort and annual incidences
are falling (Table 5).
AlphaCor
FIGURE 4. Kaplan–Meier curve: device retention.
may predict the best corrected VA (BCVA) achievable. Many
AlphaCor cases had preexisting pathologic conditions expected
to limit VA postoperatively including macular disease (25.3%)
and glaucomatous cupping (58.7%), whereas there was no view
of the posterior pole in another 18.1%. The best VA recorded
before failure of the last graft ranged from light perception (LP)
to 20/20 (mean, 20/200). Mean preoperative VA was hand
movements (HMs). Postoperative BCVA ranges from LP to
20/20 (mean, 20/200; Table 6). The mean BCVA after AlphaCor
was better but not significantly different from the mean BCVA
before the most recent graft failed (paired t test, P = 0.575).
There was a decrease in mean postoperative BCVA from best
recorded to current of 0.5 lines, and on comparing data for
complicated cases (melt, deposit, or RPM) versus uncomplicated
cases, the decrease in postoperative VA occurred only in the
complication group. There was no trend of decreasing BCVA
after AlphaCor in other cases, suggesting an absence of attrition caused by undiagnosed glaucoma or macular disease. The
AlphaCor data (41.4% of all post–stage 2 cases achieve
$ 20/200) are similar to those for pooled regraft VA.33
Device Retention In Situ
Of 322 AlphaCors implanted to date, 65.8% are in situ,
6.2% were replaced with a second device, 26.7% were reversed
to PK, and 1.2% resulted in loss of an eye. Of 276 implanted
after the regulatory trial, 198 (71.7%) are currently in situ, 10
(3.6%) were replaced with a second AlphaCor, 3 (1.1%) were
replaced with another device, 61 (22.1%) were reversed to PK,
and in 4 cases (1.4%), enucleation or evisceration followed
recurrent complications. The leading cause of device removal
was stromal melting, associated with 64.5% of explantations.
The probability of retention in situ is strongly affected by
patient selection and management, particularly by factors that
affect the incidence of melts. Off-label implantation significantly reduces the probability of 1-year retention (log-rank, P =
0.010) and controlling for the use of MPG in posttrial cases (the
protective effect of MPG is also significant; P = 0.001). For onlabel cases receiving MPG, the probability of retention to 6
months, 1 year, and 2 years was 92%, 80%, and 62%, respectively (Fig. 4).
Glaucoma
Visual Acuity
Aniridic Patients
Twenty-eight patients (8.7%) had aniridia. The probability of device retention (log-rank), controlling for on-label
The presence of ocular pathology and the best visual
acuity (VA) recorded after the most recent graft before AlphaCor
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Almost 60% of cases had glaucoma before AlphaCor
surgery, and more than one quarter had drainage tubes in situ
(Table 2), most commonly Baerveldt or Molteno, single- or
double-plated. In 2 cases, tubes were implanted during
AlphaCor surgery; in 1, this procedure was complicated by
dislocation of the AlphaCor. Postoperatively, 2.2% with no
glaucoma history needed topical glaucoma therapy after
AlphaCor implantation; 9.9% with a history of previous
glaucoma medications were taken off those medications after
AlphaCor. Continuation of pre-AlphaCor glaucoma medications was unconfirmed in 20.2%. One case (0.3%) underwent
tube placement after AlphaCor implantation. Controlling for
on-label status and MPG treatment, preoperative glaucoma did
not affect device retention (log-rank, P = 0.483; Fig. 5) and
neither did the presence of drainage tubes (P = 0.558).
Subset Analysis
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Hicks et al
TABLE 6. VAs Before and After AlphaCor
BCVA
Minimum
Maximum
Mean
Best VA obtained with previous graft before it failed (N = 240)
VA immediately before AlphaCor (N = 322)
6/12 after AlphaCor (N = 108)
12/12 after AlphaCor (N = 64)
18/12 after AlphaCor (N = 36)
24/12 after AlphaCor (N = 22)
30–42/12 after AlphaCor (N = 14)
Best BCVA at any time postoperative (N = 192)
Current VA (or censored at time of death if died) (N = 161)
LP
LP
LP
NLP
NLP
NLP
NLP
LP
NLP
20/20
20/200
20/20
20/20
20/20
20/20
20/20
20/20
20/20
20/200
HM
20/400
20/200
20/400
20/400
CF
20/200
20/300
Inclusive of data for all cases to February 28, 2006.
status and MPG therapy, was not significantly different from
the balance of the dataset (P = 0.169), although visual
potential is more limited.
Number of Prior Failed Grafts
The number of previous failed grafts ($4 or ,4) did not
affect the probability of AlphaCor retention (log-rank,
P = 0.482), in contrast to corneal graft outcome data in
which an inverse relationship was seen.33
Chemical Injury
A prior chemical injury did not significantly affect the
probability of AlphaCor survival (log-rank, P = 0.478), but
data are currently insufficient to allow separate analysis of
different types of chemical injury.
Silicone Oil
Seven eyes had silicone oil before AlphaCor and devices
remained in situ with no recurrent RD and no optic depositions.
Follow-up in this group ranged from 4 to 31.5 months (mean,
18.3 months), and postoperative BCVA ranged from HM to
20/80.
Children
The trial excluded children younger than 18 years, but
11 posttrial recipients were between 1 and 17 years (mean,
10.5 years). In these patients, 82% of devices were retained
in situ, with a follow-up of 2.1 to 23.5 months (mean, 9.8
months). Two devices were removed, both in children younger
FIGURE 5. Kaplan–Meier survival curve to examine effects of
preoperative glaucoma on AlphaCor retention.
1040
than 4 years, associated with difficulties in postoperative care
and medications.
Safety Analysis
Where a device required removal, 18.2% were exchanged for a new one, 78.2% reversed to PK (ie, preAlphaCor state regained), and 3.6% were removed with the
globe. A total of 4 eyes (1.3%) were enucleated or eviscerated,
3 of which were the result of device-related complications. A
further 2 eyes became no perception light (NPL) because of
dense recurrent RPMs. Thus, 6 eyes permanently lost vision
over a summed 416 years of follow-up. This finding equates to
an annual risk per eye of 0.014.
DISCUSSION
AlphaCor was designed to address the classic triad of
sight-threatening KPro complications—progressive glaucoma,
endophthalmitis, and retinal detachment. It was intended to
avoid reliance on donor tissue for its implantation while providing for reversibility to PK in the event of complications to
minimize long-term risk to the eye. Have these aims been met?
AlphaCor does not seem to exacerbate glaucoma. In
contrast, glaucoma is associated with a three-fold increase in
the risk of graft failure without immune reaction,34 and any
history of raised IOP before graft, whether surgically managed
or not, reduces graft survival.33 A glaucoma drainage device in
situ is an independent risk factor for graft failure. In
a retrospective study of 1974 PK cases, Alvarenga et al35
found that, of 40 cases with a drainage device in situ, only
58.5% had a clear graft at 12 months and only 25.8% at 24
months; the hazard ratio for a glaucoma drainage device with
respect to graft survival was found to be 6.8. Glaucoma has
been reported a common complication of rigid keratoprostheses,36 commonly requiring drainage devices and frequently
resulting in loss of vision. AlphaCor retention is not affected
by glaucoma or the presence of drainage devices, and
AlphaCor implantation does not seem to worsen glaucoma
control; explanations could include the lack of chronic steroid
treatment and perhaps an evaporative outflow route through
the optic. Topical medications are restricted to those that do
not cause optic deposits20; those requiring multiple medications might benefit from a tube to simplify post-AlphaCor
management.
q 2006 Lippincott Williams & Wilkins
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Cornea Volume 25, Number 9, October 2006
The risk of the other feared KPro complications seems low
in present data, comprising 416 patient-years of experience, with
the risk to an eye of endophthalmitis or rhegmatogenous RD
each being less than 0.005 per year, comparing well with
complication rates reported for other devices.37,38 AlphaCor’s
design and lamellar position may minimize risk of RD and
biointegration may minimize risk of intraocular infection,
without reliance on the lifelong vancomycin preparations
recommended for nonintegrating devices.37 Whether maintenance of topical antibiotics is essential after AlphaCor is debated,
but the majority view is that a broad-spectrum, preserved drop
applied at least twice daily is useful for decontaminating the
optic surface, where a biofilm harboring organisms could be
expected to exist; anecdotally, both cases of endophthalmitis
occurred in patients noncompliant with medication, and several
cases of stromal melting also occurred after cessation of
medications and development of an inflamed ocular surface. In
Australia, cases have been managed with chronic use of
chloramphenicol 1% for up to 7 years without any evidence of
unwanted effects or need to rotate antibiotics. It also seems
advisable to optimize the ocular surface after AlphaCor implantation by supporting the tear film, with supplementary tears,
Restasis, oral omega-3 oils and oral tetracycline, bandage lenses
regularly changed, and with partial tarsorrhaphy in some cases,
although formal studies have not been conducted to evaluate the
individual contributions of these measures on device outcome.
The lamellar surgical procedure has been refined such
that stage 1 generally takes less than 1 hour and does not
routinely require adjunctive tissue or devices. Replacement or
reversal to PK is readily achieved, meeting the intention for
a device that does not result in an end-stage condition. Allinclusive complication rates are still significant, but falling
markedly with growing experience.
Data suggest that AlphaCor does elicit, in general, the
best visual acuities of which these typically compromised eyes
are capable, but refraction and optimization of visual acuity
outcomes is an area still being developed. Early cases with
thick Gunderson flaps were particularly hard to refract and
some gave disappointing acuities. AlphaCor has limitations in
performance and cosmesis that presently restrict its use to
cases where PK would not succeed and where there is no
urgency to restore best possible VA. Refractive correction
after stage 2 can represent a frustrating delay and can be
more difficult than with a rigid device. The optic material,
with its susceptibility to certain depositions, also represents a
limitation.
Despite use of MPG, stromal melting anterior to the
device skirt can occur, particularly when the ocular surface is
relatively dry and unprotected, and reduced tear production
postoperatively may contribute. Melts are probably not caused
by nutritional deprivation over the porous device skirt, but
inflammation related to its molecular structure13 may contribute.
To date, these limitations have been accepted as unavoidable
attributes of the only material, PHEMA, which lends itself to
AlphaCor’s design. Research into an optimized device continues.
As with all KPros, ongoing vigilance in follow-up is
essential, and care of these patients can be time-consuming for
the physician. The degree of participation in data collection
and review by user surgeons indicates support for the concept
q 2006 Lippincott Williams & Wilkins
AlphaCor
that pooling current knowledge facilitates clinical decision
making and informed consent. This collaborative effort also
seems to be improving outcomes and provides a stimulus for
design improvements. Long-term data collection and reporting
are required.
ACKNOWLEDGMENTS
The Scientific Advisory Board thanks all users for
participation in data collection and analysis. Data for analysis
were returned by K. Aasly, R. Abel, N. Afshari, E. Akpek, A.
Aldave, J. Aquavella, S. Awwad, H. Bleckmann, J. Bobrow, J.
Bokosky, A. Caparossi, J. Caudill, P. Channa, P. Chen, K.
Chern, J. Chodosh, I. Cohen, S. Cohen, M. Conners, J.
Cowden, G. Crawford, J. Dart, S. Daya, D. Dhaliwal, N.
Downie, S. Dunn, H. Eguchi, R. Eiferman, S. Fulcher, R.
Gaster, G. Geerling, T. Gillette, K. Goins, T. Gondhowiardjo,
L. Goodwin, M. Gorovoy, G. Grabner, D. Gritz, R.
Grutzmacher, A. Gulani, S. Hamilton, D. Hardten, L. Hirst,
E. Holland, T. John, M. Karbassi, D. Katsev, H. Kaufman,
J. Kim, W. Lahner, D. Lam, A. Leahey, M. Lundergan, M.
Macsai, F. Mah, M. Malecha, E. Manche, M. Mayers, C.
McCaa, M. Moshifir, R. Pangalinan, J. Parker, S. Pflugfelder, F.
Price, G. Prosdocimo, I. Raber, B. Randleman, A. Rapisarda,
C. Rapuano, L. Remejier, L. Rodriguez, G. Rosenwasser, W.
Rotkis, P. Rozsival, S. Silverstein, G. Snibson, J. Song, R. D.
Stulting, J. Sutphin, G. Sutton, T. Taravella, J. Tauber, S.
Tauber, D. Tan, U. Tran, and M. Wang. The authors thank
Joanna Gregg for assistance with data collection and
maintenance.
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