**3. Cryotherapy**

Much of the robust data regarding prophylactic treatment of patients with Stickler syndrome comes from two studies that first popularized the Cambridge prophylactic cryotherapy treatment protocol. The prophylaxis approach consisted of 360-degree cryotherapy, transconjunctivally in a contiguous fashion to the postoral retina while the patient was under general anesthesia. The cryotherapy lesions were applied "shoulder to shoulder" to ensure continuity of treatment without gaps.

The first retrospective review was published in 2008 and examined a cohort of 204 patients with type 1 Stickler syndrome (confirmed with genetic testing). The cohort was divided into three groups: group 1 consisted of patients who received no prophylaxis, group 2 consisted of patients with bilateral 360 prophylactic cryotherapy, and group 3 included patients who had unilateral surgical repair for a retinal detachment and subsequently underwent prophylaxis in the fellow eye [21]. The study found 73% of patients without treatment developed a retinal detachment, 48% of which were bilateral. In patients with bilateral prophylactic treatment, only 8% developed retinal detachments. Finally in patients who underwent unilateral prophylaxis, only 10% developed an RD.

The results of this trial demonstrated a clear benefit from prophylactic cryotherapy treatment. The study was followed up 6 years later with a larger retrospective comparative case series looking at 487 patients with type 1 Stickler syndrome. The study examined patients who received bilateral prophylactic treatment compared to those who received no prophylactic treatment. 53.6% of patients in the bilateral control group (i.e., no treatment) developed retinal detachment, 10.3% of which were unilateral and 43.3% of which were bilateral. In patients with bilateral prophylaxis, 8.3% developed a retinal detachment, of which 7.9% were unilateral and 0.4% were bilateral [11].

Despite their retrospective nature, together these two studies laid a robust foundation indicating the benefits of prophylactic treatment for retinal detachment in patients with Type 1 Stickler syndrome. Unfortunately, the use of cryotherapy as prophylaxis is limited worldwide.

*Approaches to Retinal Detachment Prophylaxis among Patients with Stickler Syndrome DOI: http://dx.doi.org/10.5772/intechopen.107289*

#### **4. Laser retinopexy**

One of the first retrospective case series that looked at the use of laser retinopexy as prophylaxis for Stickler syndrome was reported in 1996. The series looked at a small family cohort of patients with Stickler syndrome and compared the incidence of retinal detachments in 10 laser treated eyes to 34 non-treated eyes. The study found a 10% detachment rate in the argon laser retinopexy treated cohort [22].

Since then, several studies have looked at use of laser retinopexy. In 2016, a retrospective case series of 70 eyes from 62 patients found a 36.3% rate of retinal detachment among eyes that received prophylactic retinopexy in Saudi Arabia. However, the study lacked a control group and excluded all Stickler syndrome patients who did not develop RDs [18]. In 2018, a case series of 30 eyes from 15 patients with genetically confirmed Type 1 Stickler syndrome demonstrated a 5% detachment rate in patients with laser prophylaxis compared to 50% of patients who did not receive laser treatment [23]. Neither of these case series reported on their laser retinopexy approach, making it difficult to replicate a similar laser protocol.

In 2021, a small case series of 5 eyes from 4 family members with confirmed Type 2 Stickler Syndrome using a two-step laser retinopexy approach, "ora secunda cerclage" (OSC). OSC involves first a laser burn of moderately high intensity placed in a tight grid pattern (one spot width separation) 2 mm onto the pars plana to the ora serrata and 4 mm posteriorly halfway to the vortex vein ampullae. This is followed by an optional step 2 where the laser grid is posteriorly extended to and between the vortex vein ampullae [24]. Although the case series was limited in size, with 8.7 years of follow up, none of the eyes developed a retinal tear or RRD.

In 2022, two additional studies evaluating laser retinopexy were published. The first retrospective case series examined a cohort of 95 eyes from 48 patients and found that the retinal detachment rate was 26.7% among eyes without previous prophylactic laser retinopexy and only 4.6% among eyes with previous prophylactic laser retinopexy [25]. Laser burns of approximately 500 microns applied with a power titrated to a gray-white color in a nearly confluent pattern of 7–10 rows from the ora serrata for 360 degrees was performed in one session (**Figure 1**). The other retrospective case series evaluated patients receiving either extended vitreous base laser (EVBL), non-protocol laser (NPL) or no laser prophylaxis in a group of 230

**Figure 1.** *Example of prophylactic laser Retinopexy used in patient with Stickler syndrome.*

eyes. There was a 3% retinal detachment rate in the EVBL treatment group compared to a 73% detachment rate in patients who had received no laser retinopexy [26]. EVBL protocol was to treat from the ora serrata to the equator 360 degrees with laser burn spacing between one half to 1 spot size.

Over the past several years there has been a large increase in the number of series reporting positive outcomes using laser retinopexy as prophylaxis for retinal detachments in patients with Stickler syndrome. Laser retinopexy is often preferred to cryotherapy because of its ease of use and more widely spread familiarity. While the evidence supporting laser retinopexy continues to mount, as with the cryotherapy studies, this data is retrospective in nature. In addition, unlike the studies from the cryotherapy group, many of the large studies presented here are based on a clinical diagnosis of Stickler syndrome making it difficult to determine which patients were inherently at a higher risk because of their Stickler syndrome mutation. Additionally, as previously alluded to, each of the studies presented here have a unique approach to the laser retinopexy performed, making even head-to-head comparisons in the laser group alone difficult.

### **5. Scleral buckle**

The last commonly used prophylactic approach is use of a scleral buckle. Use of scleral buckle to prevent detachments in patients with stickler syndrome has been reported in the literature as far back as 30 years ago. Retrospective case series in 1994 of 22 patients with "Wagner-Stickler" syndrome looked at rates of detachment in patients with various prophylactic treatment approaches. Eight patients were treated with an encircling scleral buckle but none of these patients developed a retinal detachment [27].

Unlike cryotherapy and laser retinopexy which target retinal adhesions, scleral buckle targets the issue of vitreous traction. However, by addressing the risk of vitreous traction, patients undergoing scleral buckle must also consider the increased risks of a more invasive procedure.

A recent retrospective case series published in 2022 assessed the impact of prophylactic scleral buckle in patients with genetically confirmed type 1 Stickler syndrome whose fellow eyes had a retinal detachment. All scleral buckles were performed by the same surgeon and used a 6 mm wide encircling band [20]. Thirty-nine patients underwent a scleral buckle with cryotherapy while 13 patients underwent a scleral buckle alone. In total, with an average of 15 years of follow up, only five patients developed a retinal detachment, all of whom had only received a scleral buckle alone. 0% of patients receiving both a scleral buckle and cryotherapy had a retinal detachment. Although the results of one retrospective case series must be interpreted with caution, these results suggest that the combination of scleral buckle and cryotherapy may significantly reduce the risk of retinal detachment in patients with Stickler syndrome.

#### **6. Management approach**

The first step is often determining when to offer prophylactic treatment for RRD prevention in Stickler syndrome patients. Among an International group of pediatric retinal surgeons, the most important factors influencing the decision to

#### *Approaches to Retinal Detachment Prophylaxis among Patients with Stickler Syndrome DOI: http://dx.doi.org/10.5772/intechopen.107289*

offer prophylactic treatment were a history of retinal detachment in the fellow eye, a family history of retinal detachment, and whether the patient had a high-risk genotype (i.e., COL2A). At the same time, almost half of respondents (41%) offered prophylactic treatment to all patients with Stickler syndrome [28].

Once the decision to provide prophylactic treatment is decided, the type of treatment must then be determined. In this international cohort of pediatric retinal surgeons, 76% reporting using laser retinopexy, 12% used scleral buckle, and 12% used cryotherapy [28].

Similar to what has been reported in the literature, the surveyed group of pediatric retinal surgeons reported using a wide variety in laser technique used. For example, 71% applied laser 360 degrees, 23% applied to visible lattice only, and 6% applied to both visible lattice and 360-degree laser to the vitreous base. The number of rows of laser also varied. 58% applied 3–5 rows of laser, 19% applied 5–7 rows of laser, and 32% applied 7–10 rows of laser. Respondents on average used a spot size of 350 microns (range 200–1500 microns, mode: 200 microns) [28].

Use of scleral buckle was less common in the surveyed cohort. Respondents reported use of scleral buckle ranged from in combination with laser retinopexy in all patients with Stickler syndrome to only those with high-risk genotypes. Other respondents reported use of a scleral buckle only if there was a family history of RD or a history of RD in the fellow eye. Finally, some respondents indicated use of SB for patients with high-risk genotypes, if there was a family history of RD or if there was a history of RD in the fellow eye. Of the respondents using both laser retinopexy and scleral buckle, 50% performed laser retinopexy at the same time as buckle placement while the other 50% performed the two procedures in a staged manner [28].

Cryotherapy was also similarly less common. Similar to the results presented above in Section 4.0, 100% of respondents applied cryotherapy confluently for 360 degrees but 50% reported application of 1 row of cryotherapy while the other half reported two rows. This suggests that while cryotherapy is a viable treatment modality that has robust evidence supporting its efficacy in preventing retinal detachments in patients with Stickler syndrome, its use is limited [28].

Another important step in management is determining what age to offer treatment. Patients with Stickler syndrome often start to develop retinal detachments in young adulthood. One study reported an average age of presentation with retinal detachment at 11 years (3–45 years), however others have reported detachments as early as 18 months [18, 21]. This can pose challenges as patients that young are nonverbal and often may present with detachments much later. In the study group that was surveyed, the recommended age of prophylactic treatment was 4.6 years but ranged from 3 months to 12 years old.

After the decision of when and who to treat have been determined, the follow up interval must also be decided. The majority of pediatric retinal surgeons reevaluated patients between 1 to 6 months after prophylactic treatment was performed. However, the decision as to when patients were to follow up was often heavily dependent on individual patient factors. The same factors that influenced pediatric retinal surgeons' decision to offer prophylactic treatment in the first place (i.e., high risk genotype, family history of RD, and history of RD in fellow eye). In addition, the respondents also mentioned the patients age, monocular status, rural location, activities the child was involved in all also impacted their follow up interval.

If prophylactic treatment was not offered, pediatric retinal surgeons, on average, followed patients every 6 months but this ranged from 3 months to 12 months.
