Prevention of Blindness in Stickler Syndrome

Abstract

Stickler syndromes are inherited conditions caused by abnormalities of structural proteins in the eye, inner ear and cartilage. The risk of retinal detachment, particularly due to the development of giant retinal tears, is high. Stickler syndrome is the most common cause of childhood retinal detachment. Although retinal detachment surgery in the general population has a high success rate, outcomes from surgical repair in Stickler syndrome patients are notoriously poor, providing a strong argument for prophylactic intervention. Variable case selection, absence of molecular genetic sub-typing and inconsistent treatment strategies have all contributed to the historic uncertainty regarding the safety and efficacy of prophylactic treatment. This paper reviews the major published clinical studies that have evaluated different methods and strategies for prophylaxis. Based on the current body of literature, there is extremely strong evidence from cohort comparison studies demonstrating the efficacy and safety of prophylactic retinopexy to reduce, but not eliminate, the risk of retinal detachment in Stickler syndrome patients. It is vital that this body of evidence is provided to Stickler syndrome patients, to enable them to make their own fully informed choice about whether to receive prophylaxis for themselves and particularly on behalf of their affected children, to reduce the risk of retinal detachment.

Full text

Citation: Alexander, P.; Snead, M.P.
Prevention of Blindness in Stickler
Syndrome. Genes 2022,13, 1150.
https://doi.org/10.3390/
genes13071150
Academic Editor: Rui Chen
Received: 3 May 2022
Accepted: 17 June 2022
Published: 26 June 2022
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genes
G C A T
T A C G
G C A T
Article
Prevention of Blindness in Stickler Syndrome
Philip Alexander 1, 2, * and Martin P. Snead 1,2,3
1NHS England Stickler Syndrome Highly Specialised Service, Cambridge University Hospitals NHS
Foundation Trust, Cambridge CB2 0QQ, UK; mps34@cam.ac.uk
2
Vitreoretinal Service, Addenbrooke’s Hospital, Hills Road, Cambridge University Hospitals NHS Foundation
Trust, Cambridge CB2 0QQ, UK
3Vitreoretinal Research Group, John van Geest Centre for Brain Repair, University of Cambridge, Forvie Site,
Cambridge CB2 0PY, UK
*Correspondence: philip.alexander@addenbrookes.nhs.uk; Tel.: +44-(0)-1223-216106
Abstract:
Stickler syndromes are inherited conditions caused by abnormalities of structural proteins
in the eye, inner ear and cartilage. The risk of retinal detachment, particularly due to the development
of giant retinal tears, is high. Stickler syndrome is the most common cause of childhood retinal
detachment. Although retinal detachment surgery in the general population has a high success rate,
outcomes from surgical repair in Stickler syndrome patients are notoriously poor, providing a strong
argument for prophylactic intervention. Variable case selection, absence of molecular genetic sub-
typing and inconsistent treatment strategies have all contributed to the historic uncertainty regarding
the safety and efficacy of prophylactic treatment. This paper reviews the major published clinical
studies that have evaluated different methods and strategies for prophylaxis. Based on the current
body of literature, there is extremely strong evidence from cohort comparison studies demonstrating
the efficacy and safety of prophylactic retinopexy to reduce, but not eliminate, the risk of retinal
detachment in Stickler syndrome patients. It is vital that this body of evidence is provided to Stickler
syndrome patients, to enable them to make their own fully informed choice about whether to receive
prophylaxis for themselves and particularly on behalf of their affected children, to reduce the risk of
retinal detachment.
Keywords:
retinal detachment prophylaxis; cryotherapy; laser retinopexy; giant retinal tear; stickler
syndrome; COL2A1; COL11A1
1. Introduction
Stickler syndromes are hereditary vitreoretinopathies caused by abnormalities in
structural proteins that are essential for the normal development of the eye, inner ear, and
cartilage. Although originally thought to be a single disorder, at least 10 different subtypes
of Stickler syndrome have now been defined, with Type 1 Stickler syndrome accounting
for 80% of patients. The most common threat to vision in patients with Stickler syndrome
is the risk of rhegmatogenous retinal detachment, which frequently affects both eyes and
can occur in childhood. This article explores the rationale and evidence for preventative
strategies against retinal detachment in patients with Stickler syndrome.
2. Methods
The PubMed database was searched for cohort studies and reports of novel techniques,
investigating retinal detachment prophylaxis for patients with Stickler syndrome. Rele-
vant articles were retrieved, and the authors then manually reviewed the reference lists
of primary studies and review articles to retrieve additional articles. The last search was
performed in February 2022. The literature search strategy was based on the patient, inter-
vention, comparison and outcome principle. The search included, but was not limited to,
Genes 2022,13, 1150. https://doi.org/10.3390/genes13071150 https://www.mdpi.com/journal/genes

Genes 2022,13, 1150 2 of 9
combinations of the following terms: ‘Stickler Syndrome’, ‘COL2A1
0
, ‘COL11A1
0
, ‘cryother-
apy’, ‘cryopexy’, ‘laser retinopexy’, ‘retinal detachment’, ‘prophylaxis’, ‘prevention’, ‘giant
retinal tear’.
3. Is Prevention of Retinal Detachment Required?
The adage that “prevention is better than cure”, attributed to the Dutch philosopher
Desiderius Erasmus, is now a fundamental principle of modern healthcare policy [
1
]. In
contrast, Karl Popper argued that “In the realm of errors, cure is better than prevention”,
the corollary being that prevention of disease can only be applied in well-understood,
homogenous conditions [
2
]. In his book, which tackles the dilemma of prevention versus
cure, Christopher Dye argues that the most acceptable preventative strategies are those
that are low-cost, high-efficacy methods for preventing a large, probable and imminent
threat to health [3].
If retinal detachments could be consistently repaired with a high degree of anatomical
and visual success, there would be a valid argument that prophylaxis is unnecessary.
Surgical repair of rhegmatogenous retinal detachment is highly effective in the general
population. Anatomical success rates after one operation are 80–90% [
4
,
5
], with success
rates well over 90% in some centres [
6
]. However, retinal detachment in Stickler syndrome
is more complex and difficult to manage, and success rates for retinal detachment repair in
patients with Stickler syndrome are much lower. Stickler syndrome is the commonest cause
of retinal detachment in children, and paediatric retinal detachments characteristically
present late, resulting in higher rates of macula-off detachment, proliferative vitreoretinopa-
thy and poor visual acuity at presentation [
7
]. In the series described by Abeysiri et al. of
Stickler syndrome patients with retinal detachment presenting to a large centre, more than
20% of the patients had inoperable retinal detachment at presentation, and of the patients
that underwent surgery, one-third had bilateral retinal detachment, and primary success
was achieved in just 50% (14/28) of patients [8].
Similar outcomes were achieved by Lee et al., who reported a 55% primary reattach-
ment rate in patients with Stickler syndrome [
9
]. Read et al. studied children with Stickler
syndrome presenting with retinal detachment and found that final anatomical success was
achieved in 60% of them, with 20% of the patients resulting in either enucleation or phthi-
sis [
10
]. Visual outcomes were correspondingly poor, with just 30% of the patients achieving
20/200 or better.10 In the series by Wubben et al., five of six eyes became phthisical despite
surgical intervention [11].
Given that the lifetime risk of retinal detachment in Stickler syndrome is so high [
12
]
and that the success of retinal detachment repair in these patients is poor, there is a strong
argument for the use of prophylactic intervention.
4. Which Stickler Syndrome Patients Should Receive Prophylaxis?
Stickler syndrome, first described by Gunnar Stickler as a hereditary arthro-ophthalmolopathy,
was originally thought to be a single-gene disorder. However, it is now known to en-
compass at least 10 different subtypes, with likely further genetic heterogeneity still to
be resolved. Some of the early papers that discuss prophylaxis in Stickler syndrome re-
fer to the Wagner–Stickler syndrome [
13
,
14
], because Wagner syndrome was at one time
considered synonymous with the ocular-only variety of Stickler syndrome [
15
]. It is now
known that Wagner syndrome is caused by mutations in the VCAN (5q13-q14) gene, has
no systemic features, and is a completely separate disorder (OMIM #143200) from Stickler
syndrome [16].
Early studies of prophylactic treatment for Stickler syndrome do not provide any
details of genetic testing [
13
,
14
]. In all reports where genetic confirmation of Stickler syn-
drome was conducted prior to performing surgical prophylaxis [
11
,
12
,
17
–
19
], the patients
had Type 1 Stickler syndrome, caused by mutations in COL2A1. Type 1 disease accounts
for around 80% of all cases of Stickler syndrome and represents the majority of cases seen
by ophthalmologists [
16
]. Type 2 Stickler syndrome patients also have a high risk of retinal

Genes 2022,13, 1150 3 of 9
detachment, but it is unclear whether the risk is as high as in the Type 1 Stickler syndrome
patients [20], and prophylaxis in Type 2 patients has been much less studied [21].
5. How Should Prophylactic Treatment Be Performed in Stickler Syndrome?
A summary of the literature for prophylactic strategies in Stickler syndrome is shown
in Table 1. All of the published studies are retrospective, and there is considerable variability
in prophylaxis strategies and methods.
Table 1.
Summary of studies evaluating strategies to prevent retinal detachment (RD) in patients
with Stickler syndrome.
Author Stickler Type (n) Laser/Cryotherapy/Buckle Type of Study Follow Up Results
Monin et al., 1994, Paris,
France [14]
22 patients with
Wagner–Stickler
syndrome
Laser photocoagulation,
or encircling scleral
buckle in fellow eyes of
patients with RD in the
first eye
Retrospective case
series (no control group) Up to 5.5 years
50% of patients
receiving laser
treatment developed
RD. None of the scleral
buckle patients
developed RD.
Leiba et al., 1996,
Rehovat, Israel [17]
10 patients from a single
family with genetically
confirmed Type 1
Stickler syndrome.
Untreated family
members were used as
controls during the
study follow-up
Primary prophylactic
laser photocoagulation,
either (a)
circumferentially, at the
posterior border of
retinal lesions, or (b)
around areas of
abnormal retina
Retrospective study 1–15 years
10% of lasered eyes
developed retinal
detachment, compared
to 44% of non-lasered
eyes
Ang et al., 2008,
Cambridge, UK [18]
93 patients (155 eyes)
with genetically
confirmed Type 1
Stickler syndrome and
111 control patients (222
eyes) who did not
receive any intervention
360-degree cryotherapy
of the juxtaoral retina,
for prevention of giant
retinal tear
Retrospective
comparative case series Up to 33 years
With no retinopexy, 73%
of the patients suffered
RD, and 48% were
bilateral. Of those
receiving retinopexy, 8%
developed RD, but none
were bilateral.
Fincham et al., 2014,
Cambridge, UK [12]
293 patients with
genetically confirmed
Type 1 Stickler
syndrome and 194
control patients who
did not receive any
intervention
Cambridge Prophylactic
Cryotherapy Protocol:
360-degree cryotherapy
of the juxtaoral retina,
for prevention of giant
retinal tear
Retrospective
comparative case series,
matched for age and
follow-up duration
1–36 years
The bilateral and
unilateral control group
had a 5.0-fold and
8.4-fold, respectively,
increased risk compared
to eyes receiving
prophylaxis
Al-Shahrani et al., 2015,
Riyadh, Saudi Arabia,
[22]
70 eyes of patients with
Stickler syndrome.
Genetic testing not
specified. No control
group.
Details of prophylactic
laser retinopexy not
specified
Retrospective case
series 1 week to 10 years
No genetic
confirmation, no control
group and no details of
type of laser
prophylaxis, so
impossible to assess
prophylaxis efficacy
from this study.
Wubben et al., 2018,
Ann Arbor, Michigan,
USA [11]
15 patients with
genetically confirmed
Type 1 Stickler
syndrome; of these, 20
eyes had prophylactic
laser retinopexy
Laser (details not
reported)
Retrospective
comparative case series 4 months -16 years
5% risk of RD with
prophylaxis; 50% risk of
RD without prophylaxis
Morris et al., 2021,
Birmingham, Alabama,
USA [21]
5 eyes of 4 patients from
a single family with
confirmed Type 2
Stickler syndrome
Encircling grid laser
(Modified Ora Secunda
Cerclage)
Retrospective case
series 3–12 years
0/5 eyes developed
retinal tear or retinal
detachment.
Ripandelli et al. (2022),
Rome, Italy [19]
Fellow eyes of patients
with genetically
confirmed Type 1
Stickler syndrome who
had had unilateral
retinal detachment.
All eyes received a 6
mm-wide encircling
band. Cryoretinopexy
was performed on any
retinal tears, holes or
lattice degeneration
Retrospective case
series
Mean 15.6 years,
all >12 years
Scleral buckle without
cryo: 5/13 developed
RDScleral buckle with
cryo: 0/39 developed
RD
In 1994, Monin et al. described 22 patients with “Wagner–Stickler” syndrome who had
developed a retinal detachment [
14
]. Of these, 10 patients received “peripheral confluent
laser photocoagulation” in the fellow eye, but 5 developed retinal detachment. Four
patients, receiving cryotherapy, vitrectomy, or “focal or circular” laser photocoagulation

Genes 2022,13, 1150 4 of 9
posterior to the equator, also developed retinal detachment. A further eight patients were
treated with an encircling scleral buckle, but none of these patients developed detachment.
Alshahrani et al. described their experience of retinal detachment repair in 70 patients
with Stickler syndrome and observed that 44 patients (62.8%) had had previous prophylactic
laser therapy. The authors’ conclusion is that prophylaxis is not helpful in these patients,
but none of these patients had had genetic testing to confirm the diagnosis, and only 22.6%
of the patients had a family history, which is lower than would be expected. There was
no control group, and there no details were provided about where or how the laser was
applied. Due to these study limitations, it is impossible to make any assessment on the
efficacy of prophylactic laser treatment from this study.
Leiba et al. described 10 patients from a family of 42 members with genetically
confirmed Type 1 Stickler syndrome, who received one of two types of prophylactic laser
treatment. Patients with extensive peripheral retinal degeneration with lattice degeneration
in three or more retinal quadrants received 4–8 rows of encircling laser burns at the junction
between the posterior border of the lesions and the unaffected retina, with extension of the
laser barrier (2–3 rows) to include isolated areas of lattice degeneration at or posterior to the
equator. In eyes with only small, localised lesions of lattice degeneration or isolated breaks,
only focal treatment was applied, with visibly abnormal areas encircled with
3–6 rows
of
laser burns. This group found that there was a significantly higher incidence of retinal
detachment in non-lasered eyes compared to lasered eyes.
Ang et al., based in Cambridge UK, were the first to describe a standard protocol for
applying retinopexy in “high-risk” genetically confirmed type 1 Stickler syndrome patients,
using monitored transconjunctival cryotherapy applied in a contiguous fashion to the
post-oral retina, with the specific objective of preventing elevation and progression of the
posterior flap of a giant retinal tear, should it occur at the time of posterior vitreous detach-
ment (Figure 1). This treatment, now known as the Cambridge Prophylactic Cryotherapy
Protocol”, was offered to all Type 1 Stickler syndrome patients with eyes unaffected by reti-
nal detachment, irrespective of the presence or absence of lattice degeneration. Eyes treated
prophylactically exhibited a much lower prevalence of retinal detachment, and importantly,
no patients receiving bilateral prophylaxis developed bilateral retinal detachment. The
authors acknowledged the difference in mean ages and follow-up durations between the
study and the control groups. In a subsequent paper by the Cambridge group [
12
], the
limitations of their first study were addressed by matching study and control patients not
only by age but also by follow-up duration. This study was intentionally biasing against the
benefit of treatment, to ensure that any true treatment effect of the Cambridge Prophylactic
Cryotherapy Protocol would be underestimated. The study, which included 487 patients
with Type 1 Stickler syndrome, found that patients with no prophylaxis in either eye had a
5.0-fold increased risk of retinal detachment compared to the matched bilateral prophylaxis
group. For patients who had already had retinal detachment in one eye, the risk of retinal
detachment in the fellow eye was 8.4-fold compared to fellow eyes receiving prophylaxis.
This study remains the largest case series of prophylactic treatment for Stickler syndrome in
the literature (and indeed is larger than the rest of the world literature combined), has the
longest follow-up and presents powerful evidence in favour of prophylactic cryotherapy in
patients with Stickler syndrome.

Genes 2022,13, 1150 5 of 9
Genes 2022, 13, x FOR PEER REVIEW 5 of 9
of the Cambridge Prophylactic Cryotherapy Protocol would be underestimated. The
study, which included 487 patients with Type 1 Stickler syndrome, found that patients
with no prophylaxis in either eye had a 5.0-fold increased risk of retinal detachment com-
pared to the matched bilateral prophylaxis group. For patients who had already had reti-
nal detachment in one eye, the risk of retinal detachment in the fellow eye was 8.4-fold
compared to fellow eyes receiving prophylaxis. This study remains the largest case series
of prophylactic treatment for Stickler syndrome in the literature (and indeed is larger than
the rest of the world literature combined), has the longest follow-up and presents power-
ful evidence in favour of prophylactic cryotherapy in patients with Stickler syndrome.
Figure 1. Prophylactic 360-degree cryoretinopexy in Type 1 Stickler syndrome according to Cam-
bridge Prophylactic Cryotherapy Protocol. White circles show locations of individual cryotherapy
applications, which are contiguous with one another and include the ora serrata (red line).
Wubben et al. described 15 patients with genetically confirmed Type 1 Stickler syn-
drome. The mean follow-up time was 6.4 years (range, 4 months–16 years). The authors
did not describe their laser prophylaxis technique but found that the risk of developing
retinal detachment was only 5% in eyes receiving laser prophylaxis (1/20) compared to
50% in eyes not receiving laser prophylaxis (5/10). Of interest was the very poor outcome
in patients developing retinal detachment—five of the six eyes became phthisical despite
surgical intervention.
Ripandelli et al. reported a single-surgeon series of 52 patients with genetically con-
firmed Type 1 Stickler syndrome, who had developed retinal detachment in one eye and
therefore received prophylaxis with a 6 mm scleral encircling band in the fellow eye. The
rationale for this technique was to reduce vitreoretinal traction, and mean follow-up was
15.6 years, with a minimum of 12 years in all cases. In 39/52 eyes, cryotherapy retinopexy
was also performed due to the presence of retinal tears, retinal holes and/or lattice degen-
eration. The authors found that none of the patients receiving adjuvant cryotherapy de-
veloped retinal detachment, yet 5/13 eyes receiving scleral buckling, without associated
cryotherapy, developed retinal detachment. This not only supports the argument for
Figure 1.
Prophylactic 360-degree cryoretinopexy in Type 1 Stickler syndrome according to Cam-
bridge Prophylactic Cryotherapy Protocol. White circles show locations of individual cryotherapy
applications, which are contiguous with one another and include the ora serrata (red line).
Wubben et al. described 15 patients with genetically confirmed Type 1 Stickler syn-
drome. The mean follow-up time was 6.4 years (range, 4 months–16 years). The authors
did not describe their laser prophylaxis technique but found that the risk of developing
retinal detachment was only 5% in eyes receiving laser prophylaxis (1/20) compared to
50% in eyes not receiving laser prophylaxis (5/10). Of interest was the very poor outcome
in patients developing retinal detachment—five of the six eyes became phthisical despite
surgical intervention.
Ripandelli et al. reported a single-surgeon series of 52 patients with genetically
confirmed Type 1 Stickler syndrome, who had developed retinal detachment in one eye
and therefore received prophylaxis with a 6 mm scleral encircling band in the fellow eye.
The rationale for this technique was to reduce vitreoretinal traction, and mean follow-
up was 15.6 years, with a minimum of 12 years in all cases. In 39/52 eyes, cryotherapy
retinopexy was also performed due to the presence of retinal tears, retinal holes and/or
lattice degeneration. The authors found that none of the patients receiving adjuvant
cryotherapy developed retinal detachment, yet 5/13 eyes receiving scleral buckling, without
associated cryotherapy, developed retinal detachment. This not only supports the argument
for retinopexy but also indicates that relief of vitreoretinal traction is less important than
preventing the development and/or progression of retinal breaks.
Morris et al. (2021) described a two-step prophylactic retinopexy in five eyes of
four patients with type 2 Stickler syndrome [
21
]. Step 1 of the prophylaxis emulated the
successful Cambridge strategy by applying moderately high-intensity burns in a tight
grid pattern from the juxtaoral serrata and extending to 4 mm posteriorly, halfway to the
vortex vein ampullae, to produce a “second ora”. Step 2 of the prophylaxis extended the
laser grid posteriorly to beyond the line of the vortex vein ampullae to try to prevent the
development of posterior tears [
22
]. In their series, none of the five treated eyes developed

Genes 2022,13, 1150 6 of 9
retinal detachment or retinal tear over the mean follow-up period of 8.7 years. There was
an asymptomatic visual field constriction to an average of 50 degrees in each meridian.
One eye developed pupillary mydriasis which persisted for 6 months before resolution.
There was no epimacular proliferation in any of the treated eyes [22].
6. Laser vs. Cryotherapy Retinopexy
There has been no head-to-head comparative study to evaluate the efficacy of laser
retinopexy versus cryotherapy retinopexy to prevent retinal detachment. The location
of retinopexy within the retina is likely to be much more important than the modality of
treatment (see Figures 2and 3). Some groups express a preference for barrage laser over
cryotherapy because of the perceived increased inflammatory reaction associated with
the latter. Cryotherapy of retinal breaks can cause dispersion of retinal pigment epithelial
(RPE) cells within the vitreous [
23
] but avoids the tissue vaporisation that can occur with
laser and can be used in the presence of compromised ocular media [
24
]. Both laser and
cryotherapy cause a significant breakdown of the blood–retinal barrier [
25
]. A clinical trial
comparing the two modalities for retinal detachment repair showed no difference in visual
outcome [26].
Genes 2022, 13, x FOR PEER REVIEW 6 of 9
retinopexy but also indicates that relief of vitreoretinal traction is less important than pre-
venting the development and/or progression of retinal breaks.
Morris et al. (2021) described a two-step prophylactic retinopexy in five eyes of four
patients with type 2 Stickler syndrome [21]. Step 1 of the prophylaxis emulated the suc-
cessful Cambridge strategy by applying moderately high-intensity burns in a tight grid
pattern from the juxtaoral serrata and extending to 4 mm posteriorly, halfway to the vor-
tex vein ampullae, to produce a “second ora”. Step 2 of the prophylaxis extended the laser
grid posteriorly to beyond the line of the vortex vein ampullae to try to prevent the devel-
opment of posterior tears [22]. In their series, none of the five treated eyes developed ret-
inal detachment or retinal tear over the mean follow-up period of 8.7 years. There was an
asymptomatic visual field constriction to an average of 50 degrees in each meridian. One
eye developed pupillary mydriasis which persisted for 6 months before resolution. There
was no epimacular proliferation in any of the treated eyes [22].
6. Laser vs. Cryotherapy Retinopexy
There has been no head-to-head comparative study to evaluate the efficacy of laser
retinopexy versus cryotherapy retinopexy to prevent retinal detachment. The location of
retinopexy within the retina is likely to be much more important than the modality of
treatment (see Figures 2 and 3). Some groups express a preference for barrage laser over
cryotherapy because of the perceived increased inflammatory reaction associated with the
latter. Cryotherapy of retinal breaks can cause dispersion of retinal pigment epithelial
(RPE) cells within the vitreous [23] but avoids the tissue vaporisation that can occur with
laser and can be used in the presence of compromised ocular media [24]. Both laser and
cryotherapy cause a significant breakdown of the blood–retinal barrier [25]. A clinical trial
comparing the two modalities for retinal detachment repair showed no difference in vis-
ual outcome [26].
Figure 2. Retinal detachment due to a giant retinal tear in a patient type 1 Stickler syndrome. Note
previous laser prophylaxis is too posterior to prevent detachment. Arrow = Giant retinal tear, arrow
head = equatorial laser prophylaxis. Reproduced with permission from Snead, MP (2022): Retinal
detachment in childhood. Chapter in: Paediatric Ophthalmology and Strabismus 6th Edition. Edi-
tors Lyons C & Hoyt C. Elsevier Saunders. In press.
Figure 2.
Retinal detachment due to a giant retinal tear in a patient type 1 Stickler syndrome. Note
previous laser prophylaxis is too posterior to prevent detachment. Arrow = Giant retinal tear, arrow
head = equatorial laser prophylaxis. Reproduced with permission from Snead, MP (2022): Retinal
detachment in childhood. Chapter in: Paediatric Ophthalmology and Strabismus 6th Edition. Editors
Lyons C & Hoyt C. Elsevier Saunders. In press.

Genes 2022,13, 1150 7 of 9
Genes 2022, 13, x FOR PEER REVIEW 7 of 9
Figure 3. Laser retinopexy to arrest the progression of a giant retinal tear in type 1 Stickler syndrome
(no previous prophylaxis). Reproduced with permission from Snead, MP (2022): Retinal detachment
in childhood. Chapter in: Paediatric Ophthalmology and Strabismus 6th Edition. Editors Lyons C
& Hoyt C. Elsevier Saunders. In press.
Our group’s experience with cryotherapy prophylaxis has been overwhelmingly
positive, with high efficacy, retention of good visual acuity, and no associated epiretinal
membrane (ERM) formation. Cryotherapy is performed contiguously at the juxtaoral ret-
ina even in the absence of retinal breaks. Despite the experimental evidence that cryother-
apy may enhance RPE cell dispersion into the vitreous cavity using giant or other retinal
tears as a conduit, it is interesting to note that of the 964 eyes that have received cryother-
apy prophylaxis under our care, none of the patients with successful prophylaxis devel-
oped a visually significant epiretinal membrane. One patient, whose prophylaxis failed,
developed an epiretinal membrane requiring treatment (unpublished data). We also ob-
served significant epiretinal membrane formation after retinal detachment in patients that
did not receive prophylactic therapy. The association between retinal tears prior to treat-
ment and ERM is well established.
Shapiro et al. astutely noted that prophylactic strategies are learned during training
and therefore the choice of cryotherapy vs. laser is highly influenced by each surgeon’s
particular educational lineage [24]. There may be a reluctance to perform 360-degree cry-
otherapy as per the Cambridge prophylactic cryotherapy protocol, because of a lack of
exposure to training in performing this procedure [21,24].
7. Conclusions
This paper has reviewed the rationale and evidence for the prevention of retinal de-
tachment in patients with Stickler syndrome. All of the studies on this topic were retro-
spective. However, the studies shown in Table 1 demonstrate an overwhelming support
for the use of prophylactic retinopexy in these patients [11,12,17–19,21]. The two case se-
ries that reported no benefit after prophylaxis are less persuasive because of the poorly
defined patient selection, unspecified treatment protocol and lack of a control group
[14,22]. Despite this, some still question the effectiveness of prophylaxis in the absence of
a randomised controlled trial. While randomised controlled trials would provide the best
level of evidence, there is already proof of safety and efficacy from non-randomised, co-
hort comparison studies, and it is essential that Stickler syndrome patients (i) receive
Figure 3.
Laser retinopexy to arrest the progression of a giant retinal tear in type 1 Stickler syndrome
(no previous prophylaxis). Reproduced with permission from Snead, MP (2022): Retinal detachment
in childhood. Chapter in: Paediatric Ophthalmology and Strabismus 6th Edition. Editors Lyons C &
Hoyt C. Elsevier Saunders. In press.
Our group’s experience with cryotherapy prophylaxis has been overwhelmingly
positive, with high efficacy, retention of good visual acuity, and no associated epiretinal
membrane (ERM) formation. Cryotherapy is performed contiguously at the juxtaoral retina
even in the absence of retinal breaks. Despite the experimental evidence that cryotherapy
may enhance RPE cell dispersion into the vitreous cavity using giant or other retinal tears
as a conduit, it is interesting to note that of the 964 eyes that have received cryotherapy
prophylaxis under our care, none of the patients with successful prophylaxis developed
a visually significant epiretinal membrane. One patient, whose prophylaxis failed, devel-
oped an epiretinal membrane requiring treatment (unpublished data). We also observed
significant epiretinal membrane formation after retinal detachment in patients that did not
receive prophylactic therapy. The association between retinal tears prior to treatment and
ERM is well established.
Shapiro et al. astutely noted that prophylactic strategies are learned during training
and therefore the choice of cryotherapy vs. laser is highly influenced by each surgeon’s
particular educational lineage [
24
]. There may be a reluctance to perform 360-degree
cryotherapy as per the Cambridge prophylactic cryotherapy protocol, because of a lack of
exposure to training in performing this procedure [21,24].
7. Conclusions
This paper has reviewed the rationale and evidence for the prevention of retinal detach-
ment in patients with Stickler syndrome. All of the studies on this topic were retrospective.
However, the studies shown in Table 1demonstrate an overwhelming support for the
use of prophylactic retinopexy in these patients [
11
,
12
,
17
–
19
,
21
]. The two case series that
reported no benefit after prophylaxis are less persuasive because of the poorly defined
patient selection, unspecified treatment protocol and lack of a control group [
14
,
22
]. Despite
this, some still question the effectiveness of prophylaxis in the absence of a randomised con-
trolled trial. While randomised controlled trials would provide the best level of evidence,
there is already proof of safety and efficacy from non-randomised, cohort comparison
studies, and it is essential that Stickler syndrome patients (i) receive accurate genotyping

Genes 2022,13, 1150 8 of 9
to stratify their risk of RD and (ii) are provided with all of the information available, to
enable them to make their own fully informed choice about whether to receive prophylaxis
for themselves and particularly on behalf of their affected children. Late presentations of
bilateral inoperable retinal detachment, especially in the context of hearing impairment
and speech and mobility issues, have a devastating and life-long impact on the future
development of these children.
Author Contributions:
Conceptualization, P.A. and M.P.S.; methodology, P.A. and M.P.S.; validation,
P.A. and M.P.S.; formal analysis, P.A. and M.P.S.; writing—original draft preparation, P.A.; writing—
review and editing, P.A. and M.P.S. All authors have read and agreed to the published version of
the manuscript.
Funding: This research received no external funding.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Conflicts of Interest: The authors declare no conflict of interest.
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