Stickler syndrome - lessons from a national cohort.

In 2011 NHS England commissioned a new national specialist MDT service for patients and families affected by Stickler syndrome. The Stickler syndromes form part of the spectrum of inherited vitreoretinopathies and are the most common cause of retinal detachment in childhood and the most common cause of familial retinal detachment. Now in its 10th year, the Stickler Highly Specialised Service (HSS) has assessed 1673 patients from 785 families. Using a combination of accurate phenotyping and molecular genetic analysis it is possible to identify the underlying genetic mutation in over 95% of cases including those with deep intronic mutations likely to be missed by conventional exome panel analysis and which require whole gene sequencing and supplementary functional analysis to confirm pathogenicity. The vast majority that presents to ophthalmologists will be from one of three autosomal dominant sub-groups with a high associated risk of retinal detachment but the diagnosis is often overlooked, especially in adults. In contrast to many other blinding retinal conditions, blindness through giant retinal tear detachment particularly in children is largely preventable provided these high-risk groups are identified and appropriate evidence-based prophylaxis offered. This article summarises ten selected briefcase histories from the national dataset with key learning points from each.

Montgomery and informed consent during Covid-19: Pneumatic retinopexy versus pars plana vitrectomy or scleral buckling for retinal detachment repair.

Recent reports suggest that the use of an outpatient-based procedure (pneumatic retinopexy, PR) for retinal detachment repair should be encouraged within the UK, especially in light of Covid-19 and possible restrictions/competing demands on access to operating theatres. It is therefore essential that patients receive comprehensive information about the risks and benefits of this approach compared with a formal surgical repair either by pars plana vitrectomy (PPV) and/or scleral buckling (SB). We report a retrospective case series of retinal detachments (RD) satisfying the strict selection criteria for PR but who were managed with formal surgery. Single-operation success rate for PPV/SB at six months follow-up was 93.8% in our study, higher than published primary success rates for PR (60-80%). When counselling patients for possible PR, the ease, speed and potentially reduced co-morbidity of an outpatient-based procedure needs to be balanced against its significantly higher failure rate in comparison with primary PPV/SB.

Stickler syndrome in children: a radiological review.

AIM: To review the radiological findings of the largest cohort to date of paediatric patients with Stickler syndrome, all with confirmed molecular genetic analysis and sub-typing. PATIENTS AND METHODS: It is understood that the National Health Service (NHS) commissioned service at Addenbrookes Hospital, Cambridge, UK has the largest cohort of Stickler syndrome patients in the paediatric age group worldwide with 240 registered children. Fifty-nine were assessed radiologically and for their genotypes. These radiographs were reviewed and 74 knee, 45 pelvic, and 47 spinal examinations were evaluated. RESULTS: Radiological features were noted in 45.9% of knee radiographs, 11.1% of pelvic radiographs, and 42.6% of spinal radiographs. The findings were reviewed in the light of each patient's specific genetic Stickler syndrome subtype. CONCLUSION: The prevalence of orthopaedic abnormalities overall in the present series is substantially below those published in previous smaller case series. This would support the more recent findings of an array of ocular only phenotypes of Stickler syndrome described in the literature.

Ophthalmic and molecular genetic findings in Kniest dysplasia.

PURPOSE: To study the variability of the ophthalmic phenotype in Kniest dysplasia. Kniest dysplasia is an inherited disorder associated with defects in type II collagen and characterised by short-trunked dwarfism, kyphoscoliosis, and enlarged joints with restricted mobility. Other features include marked hand arthropathy, cleft palate, hearing loss, and ocular abnormalities (myopia, abnormal vitreous, and high risk of developing retinal detachment). METHODS: Data from eight unrelated individuals with a clinical and molecular diagnosis of Kniest dysplasia are reported. Clinical assessment included an audiogram and ophthalmological examination in all but one patient who died in the immediate postnatal period. Sanger sequencing of the COL2A1 gene was performed. RESULTS: Six of the seven patients tested were high myopes with one patient being an emmetrope. Bilateral quandratic cataracts and subluxed lenses were noted in one subject. Variable but abnormal vitreous architecture was observed in all seven individuals tested. Six of the seven patients had significant hearing impairment and five of the seven patients exhibited clefting abnormalities. One patient had bilateral retinal detachments in his twenties. Six dominant disease-causing COL2A1 variants were detected. In three cases, testing of parental samples revealed that the disease-causing variant was not present in either parent. CONCLUSION: The ophthalmic features in Kniest dysplasia are very similar to those in other disorders of type II collagen such as Stickler syndrome. It is likely that different type II collagenopathies have a similar level of ocular morbidity and regular ophthalmologic examination is recommended. Kniest dysplasia is associated with heterozygous COL2A1 mutations that are frequently de novo.

Stickler syndrome, ocular-only variants and a key diagnostic role for the ophthalmologist.

The entity described by Gunnar Stickler, which included hereditary arthro-ophthalmopathy associated with retinal detachment, has recently been recognised to consist of a number of subgroups, which might now more correctly be referred to as the Stickler syndromes. They are the most common clinical manifestation of the type II/XI collagenopathies and are the most common cause of inherited rhegmatogenous retinal detachment. This review article is intended to provide the ophthalmologist with an update on current research, subgroups, and their diagnosis together with a brief overview of allied conditions to be considered in the clinical differential diagnosis. We highlight the recently identified subgroups with a high risk of retinal detachment but with minimal or absent systemic involvement--a particularly important group for the ophthalmologist to identify.

Clinicopathological changes at the vitreoretinal junction: posterior vitreous detachment.

Separation of the vitreous and posterior hyaloid membrane (PHM) or posterior vitreous detachment (PVD) typically occurs between the ages of 45 and 65 years in the general population, but may occur earlier in myopic or otherwise predisposed individuals. Age-related synergetic changes occurring within the cortical and central gel must be distinguished from the PHM, which envelopes it. This study reports on the correlation between 'true' PVD seen clinically by the physician using dynamic examination, high-power slit-lamp biomicroscopy, and oblique illumination with some of its histological, immunohistochemical, and ultrastructural features post-mortem. The presence of the Weiss ring does not necessarily indicate total clean separation of PHM, nor does its absence confirm that the PHM remains attached, since it may be destroyed during the process of separation. Immediately prior to PVD with the vitreous gel attached, the PHM must, by definition, form part of the inner limiting membrane. The detached PHM frequently exhibits basement membrane (BM) and its indigenous laminocytes stain focally for GFAP and type IV collagen. The PHM is distinct from and much thicker than the BM of Müller cells alone and the factors that initiate or limit separation of the PHM require greater study, particularly the role of laminocyte proliferation and migration.

The influence of pre-mRNA splicing on phenotypic modification in Stickler's syndrome and other type II collagenopathies.

PURPOSE: This paper will illustrate how variation in the processing of mutant pre-mRNA can affect the phenotypic outcome of inherited disorders of type II collagen. METHODS: Type 1 Stickler's syndrome is one of the different phenotypes resulting from mutations in COL2A1 (the type II collagenopathies). It is also the commonest, but often goes undiagnosed due to the variability of phenotypic features, which in some cases may consist of only abnormal vitreous development. Most cases of type 1 Stickler's syndrome are due to premature termination codons in the mRNA, resulting in haploinsufficiency. This leaves a conundrum as to why the disease is so variable. Using RT-PCR of illegitimate transcript and also minigenes, we have investigated how certain mutations can variably affect mRNA processing. RESULTS: Here, we demonstrate and discuss how apparently similar mutations can have a dramatically different effect on splicing of the pre-mRNA, switching transcripts from ones which would be degraded by nonsense-mediated decay into messages that will be translated into mutant proteins that can exert a dominant-negative effect and ultimately modify the resulting phenotype. CONCLUSION: Variability of Stickler's syndrome can, in part, be due to the variable effect that mutations have on the processing of the COL2A1 transcript.

Pathological changes in the vitreoretinal junction 1: epiretinal membrane formation.

PURPOSE/BACKGROUND: Epiretinal membrane (ERM) formation is a common change resulting in disturbance of macular vision and predisposing to rhegmatogenous retinal detachment. Current treatment strategies rely chiefly on surgical removal of the membranes from the surface of the retina, allowing the retina to remodel and reattach. Improved knowledge of the pathological process behind the formation of these membranes, particularly knowledge of the cell types involved in their formation, is likely to increase our understanding of the way this group of diseases behave and to improve treatment. METHODS: We reviewed the histological findings of 109 surgically removed specimens and correlated these to age-related changes seen in a 32 cadaver eyes studied after corneal harvesting. The samples were studied using light microscopy and immunocytochemistry. RESULTS: In all cases of idiopathic ERMs, including cellophane maculopathy, macular hole, and vitreomacular traction syndrome, laminocytes were the exclusive cell type present. In cases of macular pucker associated with retinal tears, the membranes contain variable cohesive groups of retinal pigment epithelial (RPE) cells in addition to laminocytes. In cases of proliferative diabetic retinopathy, membranes consist almost entirely of capillaries and hyaline stromal tissue, with or without haemosiderin pigment and RPE cells and in which laminocytes and ILM were not identified. In cadaver eyes PVD was seen in 17/32 (53%) of cases, and the vitreous was attached in 14/32 (43.7%) and in one case no vitreous was present. Isolated laminocytes were present on the retinal surface in 12/18 cases with detached vitreous and in 1/14 cases with attached vitreous. In all cases laminocytes were scanty and confined to the optic nerve head, macular or subjacent macular retina. Immunohistochemistry findings indicate that laminocytes are positive for glial fibrillary acidic protein (GFAP), cytokeratin marker AE1/AE3, type II collagen, and type IV collagen. In some cases novel basement membrane formation was seen. There was a tendency for increased positivity of GFAP and AE1/AE3 with increased cellularity, and where novel basement membrane formation was present. CONCLUSION: Laminocytes are the fundamental cell type in idiopathic ERMs. These cells are frequently found in small and dispersed numbers in eyes containing a PVD. The presence of retinal pigment cells invariable indicates proliferative retinopathy and is only seen in association with a retinal detachment or tear. Diabetic membranes are composed of neovascular stromal tissue, which is most likely to be a response to retinal hypoxia.

Scleral buckling combined with vitrectomy for the management of rhegmatogenous retinal detachment associated with inferior retinal breaks.

AIM: The use of adjunctive scleral buckling during vitrectomy for retinal detachment associated with inferior breaks has been the recent focus of some debate. It has been suggested that any benefit might be outweighed by potential complications associated with buckling surgery. The purpose of this study was to compare the success rate of vitrectomy, gas, and supplementary scleral buckling with the results of two recently published case series suggesting that acceptable results in inferior break detachments can be achieved with vitrectomy and gas alone. METHODS: A retrospective analysis of 60 consecutive patients with inferior break retinal detachments was conducted. All patients underwent vitrectomy, gas, and scleral buckling. In all cases, fellow eyes were examined under anaesthesia for retinal breaks if posterior vitreous detachment (PVD) had occurred at the time of presentation. Demographics, preoperative, and postoperative complications and outcome were recorded. RESULTS: Primary retinal attachment at 3 months was achieved in 95% of patients. This exceeds success rates of published data of patients who underwent vitrectomy and gas without buckling (81-89%). In patients with PVD in the fellow eye, 53% had horseshoe tears and all were treated with cryopexy. No sight-threatening complications occurred, but five patients developed minor buckle-related complications postoperatively. CONCLUSION: Supplementary scleral buckling is a safe procedure that improves and enhances primary success rates in inferior break detachments over vitrectomy and gas without buckling. There is a high rate of PVD-related breaks requiring treatment in the fellow eyes.

Prevention and control of proliferative vitreoretinopathy: primary retinal detachment surgery using silicone oil as a planned two-stage procedure in high-risk cases.

AIMS: For rhegmatogenous retinal detachment, reattachment with a single procedure is associated with better visual outcomes. In the past, silicone oil has been used mostly as a last resort following failed primary surgery. This study evaluates a novel approach to patients at high risk of primary failure, using silicone tamponade as the primary stage of a planned two-stage procedure. METHODS: We report a series of 140 eyes that underwent primary surgery for rhegmatogenous retinal detachment. Patients at higher risk of surgical failure (eg giant retinal tear, inability to posture, poor view, uncertainty of location of primary break, primary proliferative vitreoretinopathy (PVR), multiple tears with rolled posterior edges, retinoschisis/detachment, staphyloma with macular hole) were managed by a planned staged procedure using primary silicone oil tamponade. This was followed by silicone removal at a later date. RESULTS: Fifty-four eyes underwent scleral buckling alone, with primary success in 52/54 (96%). Fifty-three eyes underwent vitrectomy and gas, achieving primary success in 50/53 (94%). Thirty-three eyes were classified high risk and managed with primary silicone. Silicone was safely removed in 22/25. In eight eyes, silicone was retained without attempt at removal. In total, primary retinal reattachment was achieved in 128 of 140 eyes (91.4%). Of these, 124 (97%) did not require long-term tamponade. Only four eyes (2.9%) developed PVR. DISCUSSION: A planned two-stage approach to highrisk cases of retinal detachment using primary silicone oil tamponade followed by silicone removal can achieve a high primary reattachment rate with less than 3% incidence of PVR.

A rationale for membrane peeling in the repair of stage 4 macular holes.

AIM: To examine the histological and immunocytochemical characteristics of epiretinal membranes (ERM) associated with stage 4 macular holes (MH) so as to establish a vitreoretinal rationale for surgery in stage 4 MH. METHOD: Consecutive patients with stage 4 MH undergoing vitrectomy and membrane peeling were recruited. Preoperatively, the eyes were examined for ERM formation over the macula and completeness of posterior hyaloid membrane (PHM) separation from the retina. ERM peel specimens obtained during surgery were sent for histological and immunocytochemical studies and were compared with the PHM specimens taken from a previous post-mortem study of eyes with physiological posterior vitreous detachment but without macular holes. RESULT: A total of 13 patients with stage 4 MH fulfilled the inclusion criteria and were recruited. Preoperatively, all eyes had an ERM over the macula and incomplete separation of the PHM seen as a defect in the PHM on specular biomicroscopy. Histologically, the ERM specimens had very similar morphological characteristics to PHM, consisting of an eosinophilic membrane of varying thickness with scattered spindle-shaped cells. The membranes stained positively for type IV collagen while the cells were glial fibrillary acidic protein positive. Postoperatively, successful closure of MH was achieved in all cases. CONCLUSION: Stage 4 MH is characterised by incomplete separation of the PHM from the retina with remnants overlying the macula manifesting as ERM. Removal of the ERM is required during vitrectomy in order to relieve the tangential forces involved in the development of MH.

Type 1 Stickler syndrome: a histological and ultrastructural study of an untreated globe.

AIMS: To present a histological and ultrastructural study of an untreated globe in a patient with genetically confirmed type 1 Stickler syndrome. METHODS: Histological and electron microscopic examinations were performed on the enucleated globe from the proband of a pedigree with type 1 Stickler syndrome. Linkage analysis was carried out using polymorphic markers flanking the COL2A1 gene and the mutation was identified by direct sequencing. RESULTS: The significant retinal abnormality was incarceration of vitreous collagen within glial strands on the inner surface of an atrophic and gliotic detached retina. The incarcerated collagenous layers contained glial cells and extended from the retina to form strands, some of which contributed to a retrolental membrane. Mutation screening detected a C to T mutation in exon 47 that inserted a premature termination codon into the reading frame of the mRNA. Sequence analysis of three of the four affected children confirmed that they were also heterozygous for the base change. The youngest child's DNA was not analysed. CONCLUSIONS: The study represents the first evidence of abnormal interactions between pathological vitreous collagen and the inner retina in a patient with type 1 Stickler syndrome with a confirmed mutation in the COL2A1 gene.

Clinical features and surgical management of retinal detachment secondary to round retinal holes.

AIMS: The majority of rhegmatogenous retinal detachments result from pathological posterior vitreous detachment (PVD) and secondary horseshoe or giant retinal tears. Retinal detachment without PVD is usually associated with either retinal dialysis or round retinal holes. This study characterises the features, surgical outcome, and incidence of bilateral involvement of detachment associated with round retinal holes. METHODS: In all, 110 retinal detachments from 96 consecutive patients with retinal detachment secondary to round retinal holes were studied. Analysis of patient age, sex, refraction, preoperative visual acuity, presented symptoms, position and extent of detachment, number and distribution of holes present, posterior hyaloid membrane status, surgical management, outcome of surgery, and postoperative visual acuity were studied. RESULTS: The mean age for patients was 34 years with a marked female preponderance (64%) and myopia (83%). The posterior hyaloid membrane remained attached in 95 eyes (86%). In all, 45% patients had bilateral pathology, of which 33% had 'mirror image' distribution. Detachments were predominantly shallow (93%) and slow in progression (17%). A total of 100 detachments were repaired with cryotherapy and scleral buckling, eight with cryotherapy alone, and one with laser retinopexy. In all, 99% detachments were successfully reattached with a single procedure. The mean follow-up period was 2 years. There were no instances of redetachment. CONCLUSIONS: Round hole detachments are slowly evolving detachments with attached vitreous gel in young, predominantly female myopes. Examination of the fellow eye should be mandatory as there is a high incidence of bilateral pathology. Scleral buckling procedures remained highly effective in this selected group of patients.

Intraocular surgery for optic nerve disorders.

This article discusses two current indications for intraocular surgery for optic nerve conditions. The first topic is macular detachment in association with congenital optic disc pit, and includes a review of the theories of pathogenesis and management options including our own experience of treatment with vitrectomy and gas tamponade. In addition, the histopathological findings of a new case of optic disc pit with serous macular detachment are presented, adding to the rare examples previously reported. The second subject is a radial optic neurotomy, a recently advocated treatment for central retinal vein occlusion, which, despite its controversial nature, is gaining in popularity.

Hyperconvolution of the inner limiting membrane in vitreomaculopathies.

BACKGROUND: This study investigates the similarities and differences between epiretinal membranes in four clinically distinct types of vitreomaculopathy. We propose a hypothesis on the origin of the predominant cell type and its potential role in causing these conditions. METHODS: Epiretinal membranes (ERMs) surgically removed from a prospective, consecutive series of vitrectomies for macular pucker associated with an untreated peripheral horseshoe tear (MP), cellophane maculopathy (CM), stage 4 macular hole (MH) and vitreomacular traction syndrome (VMT) were examined by light microscopy and by immunocytochemistry (ICC) using antibodies marking type IV collagen, type II collagen, glial fibrillary acidic protein (GFAP), and low- and high-molecular-weight cytokeratin (MNF116). These specimens were compared with post-mortem control eyes with and without physiological posterior vitreous detachment (PVD). Light microscopy was carried out on 5-microm-thick sections cut from formalin-fixed, paraffin-embedded tissue blocks. Appropriate autoclave or enzyme pre-digestion steps were deployed to retrieve antigens for ICC. No patient had undergone previous vitreoretinal surgery or peripheral retinopexy. RESULTS: From a series of 38 patients, (13 CM, 8 MP, 16 MH and 1 VMT) a total of 20 specimens contained sufficient tissue for histology and immunocytochemistry. All specimens contained portions of inner limiting membrane (ILM) coated by GFAP-positive cells. Specimens from patients with MP and CM exhibited hyperconvolution of the ILM, which was not found in the specimens from patients with MH or VMT or in the control eyes. Hyperconvolution was associated with increased glial cell density, GFAP staining intensity and duplication of ILM basement membrane. Three cases of ERMs from the MP group contained, in addition, cytokeratin-positive cells. In the control group; post-mortem eyes with PVDs showed patchy staining of the posterior hyaloid membrane for GFAP and type 4 collagen. Post-mortem eyes with attached gel showed weak positivity of the ILM for type 4 collagen, and a monolayer of GFAP-positive cells lined the vitreous aspect of the ILM. CONCLUSIONS: These results indicate that glial cells are fundamentally important in the formation of ERMs found in this group of vitreomaculopathies. The hyperconvolution and duplication of the ILM in CM and MP were striking and distinctive features and suggest a mechanism by which these membranes exert tractional forces on the retina. Post-mortem control eyes contained a similar (but more dispersed) population of GFAP-positive cells in the region of the ILM, suggesting the primary aetiology for CM and MP may originate within the ILM. ERMs from MP cases may, in addition, contain cytokeratin-positive cells, of probable RPE origin.