13.1.7  Incidence

The incidence of STK is estimated at 1 in 10,000 [15].

[4]. Combined scleral buckle and pars plana vitrectomy with advanced vitreoretinal surgical techniques such as perfluorocarbon and silicone oil may be necessary.

13.1.8  Natural History and Prognosis of STK (Signs, Symptoms, Timing, etc.)

The natural history and course of disease for patients with STK vary, even within families. Early vitreous liquefaction usually results in an “optically empty vitreous” evident on clinical examination at an early age. Perivascular radial lattice degeneration is a predominant feature, which leads to a high risk of rhegmatogenous retinal detachment. It fact, it is not uncommon for patients to present in adolescence or childhood with retinal detachments. Other ocular associations include premature cataracts and strabismus.

13.1.9  Diagnosis and Diagnostic Aids

The differential diagnosis includes Wagner disease (WGN) and Goldmann-Favre Disease. The diagnosis is based on clinical history and examination. If the diagnosis is uncertain, genetic diagnostic tests based on the identification of specific mutations in a certain family may lead to the diagnosis. Examination of family members is useful.

13.1.10  Treatment

Treatment of retinal tears and vitreoretinal pathology, such as lattice degeneration, should be considered in patients with STK. The treatment may consist of either laser or cryopexy. Some retina specialists may actually advocate prophylactic scleral buckles for fellow eyes of patients with rhegmatogenous retinal detachment caused by giant retinal tears [16]. Patients with STK have an abnormal vitreoretinal interface that can lead to complex retinal detachment. Since the retinal detachments in STK usually involve multiple retinal tears and posterior retinal tears, the surgical repair of these rhegmatogenous retinal detachments may require aggressive complex treatment

13.1.11  Complications and Associations

Patients with STK experience complications, which result from the vitreoretinal pathology. Retinal detachments complicated by multiple retinal tears, posterior or radially located retinal tears, are not uncommon; patients may require scleral buckling and pars plana vitrectomy for repair [4]. An association with cataract is common with the reported incidence varying from 30 to 80% [17, 18]. A distinctive “wedge” or “fleck” cataract has been described in patients with STK [18].

13.1.12  Social and Family Impact

STK has major ramifications for a family. Given the autosomal dominant genetic inheritance, a family usually has multiple affected members who can present at an early age with complex retinal detachments. This should lead to early screening of other family members prior to visual symptoms. The decision to closely follow vs. prophylactic laser treatment is controversial. Given the known abnormal vitreoretinal interface in patients with STK as well as a family history of complex retinal detachments, the retinal surgeon may consider an aggressive surgical intervention such as combined vitrectomy and buckling or longterm tamponade with silicone oil. However, no controlled clinical trials are available to aid in the surgical decision forcing decisions to be made on a case-by- case basis.

13.2  Wagner Disease

13.2.1  Introduction

WGN is an autosomal dominant ocular condition with abnormal vitreous and no associated systemic conditions. It has a progressive course that can be evident in early childhood.

WGN was first described in 1938 by Hans Wagner in a three-generation Swiss pedigree with thirteen affected patients [19]. It was described as an autosomal dominant disorder in low myopic (3.0 diopters or less) patients with fluid (optically empty) vitreous, cortical cataracts, and variably affected dark adaptation. Retinal detachment was not characteristic in the original description although it has been well established by modern reports [20, 21]. The detachments may be peripheral, tractional, or rhegmatogenous.

13.2.3  Overview with Clinical Significance

The findings in WGN are low myopia, usually less than three diopters, an optically empty vitreous with vitreous liquefaction and band formation, radial perivascular pigmentary changes, peripheral retinal pigmentation (Fig. 13.2), peripapillary chorioretinal atrophy, narrowed retinal arterioles, and optic atrophy. No systemic associations are found with WGN.

The original description as well as other reports describes no increased risk of retinal detachment in patients with WGN [19, 22]. However, retinal detachment has been shown in patients with WGN with a reported incidence between 47 and 67% of cases [20, 21, 23].

Fig. 13.2  Peripheral retinal pigmentation found in patient with Wagner disease

None available

13.2.5  Genetics

WGN has an autosomal dominant inheritance with variable clinical expressivity [21]. The genetic basis of the disease has been established in at least one large French-Canadian kindred as a frame shift mutation in exon 2 of the Type II procollagen gene (COL2A1) on chromosome 12. This is one of the genes implicated in Type 1 STK (Gupta et al. 2002). This mutation arises in an exon that is only present in vitreous collagen and absent in joint cartilage, which supports the clinical difference between the two diseases: WGN manifests with isolated ocular findings, and STK is associated with skeletal joint changes. However, because of the nature of tissue specific splicing of COL2A1, the occurrence of this mutation in an exon that is not naturally expressed in cartilage could have silenced the expression of the STK skeletal phenotype, giving the appearance of a WGN-type vitreoretinopathy (Richards et al. 2000; Meredith et al. 2007). That is, COL2A1 is an STK disease gene and not a WGN disease gene.

Patients with WGN show linkage to a 20-cM region of chromosome 5q14.3, which defines the location of the gene responsible for the disease [10, 14, 24, 25]. The WGN disease gene identified at 5q14.3 is the chondroitin sulfate proteoglycan two gene (CSPG2) (Brown et al. 1995). That CSPG2 is at least one disease gene is strongly supported by the findings of causally associated mutations in the original Wagner family (Kloeckener-Gruissem et al. 2006). The protein encoded by this gene is known as versican, which is abundantly expressed in the vitreous. For both WGN and erosive vitreoretinopathy (ERVR), a number of studies have identified splicing mutations in the CSPG2 gene of affected patients but not normal controls that impact the functional integrity of the seventh and eighth exons. These diseases share similar clinical features and likely represent a spectrum of disease. Exons seven and eight of the CSPG2 gene encode regions of the protein that contain the CS covalent modification sites.

13.2.6  Pathophysiology

Versican is an abundant extracellular matrix protein that is expressed into the secondary vitreous and contributes approximately 15% to its total protein content (Bishop 2000; Le Goff and Bishop 2008). Versican is believed to play a major role in the gel state of the secondary vitreous by binding to the collagen fibrils and preventing aggregation. It is a large protein (3,396 amino acids) with a molecular weight of around 370 kD (Zimmermann and Ruoslahti 1989). The N-terminal region of versican has a hyaluronan binding site, which allows interaction with a bulk glycosaminoglycan of the secondary vitreous. The center of the versican protein is extensively modified with CS residues, which are both large and densely negatively charged. The C-terminal domain has capacity for binding­ potential regulatory factors. There are four different CSPG2 splicing variants (V0, V1, V2, and V3) that are naturally generated by alternative splicing within the large central region of the CSPG2 premRNA that encodes the seventh and eighth exons. All splicing variants appear to be expressed in the mammalian eye. The different splicing variants encode variant information from exons seven and eight (V0 contains both exons seven and eight; V1 contains exon eight; V2 contains exon seven; V3 lacks both exons). As the seventh and eighth exons encode the sites for covalent modification of versican by CS, the different splicing variants contain different numbers of CS glycosaminoglycan residues and hence have variant size and charge as CS is a negatively charged molecule. The number of CS residues that are attached to versican splice variants is established (V0: 17–23; V1: 12–15; V2: 5–8; V3: 0) (Miyomoto et al. 2005). The current hypothesis is that the CS residues exert antiadhesive properties through the electrostatic repulsion of like-charged macromolecules. This would be expected to exert an antiaggregation force in the vitreous to keep the fibrillar collagen molecules separate and in the native gel state. The relative distribution of versican splice variants in the normal eye is biased to V1 and V0 with much less V2 and V3. With splice variant mutations, the relative compositions change from the largest species with the greatest negative charge to species that have lower molecular weight and are either considerable less electronegative or have lost all CS binding capacity (V3) (Mukhopadhyay et al. 2006).

The impact of CSPG2 mutations in WGN becomes understandable as a perturbation in the distribution of variant versican molecules that are expressed and secreted into the secondary vitreous. If the role of versican is to maintain the solubility of fibrillar collagens through electrostatic repulsion, then a shift toward V2 and V3 molecules through splice variant mutations would promote deficiency of highly charged versican species and decrease in the biophysical forces that act to keep molecules separate as needed for maintenance of gel state of the normal secondary vitreous. Syneresis and an optically empty vitreous could result as is found in WGN and ERVR syndromes.

13.2.7  Incidence

Unknown

13.2.8  Natural History and Prognosis

(Signs, Symptoms, Timing, etc.)

WGN is a progressive autosomal dominant disorder. All affected patients exhibit an optically empty vitreous with vitreous strands and veils, the hallmark of the disease. Myopia is not as severe as STK, and cataract formation is common.

Graemiger reported a follow-up on the original Swiss pedigree and stressed the importance of clinical progression of the disease with evidence of electrophysiologic abnormalities paralleling the progression of chorioretinal abnormality [21]. The chorioretinal atrophy may become severe in the fourth and fifth decades of life mimicking choroideremia. Although rhegmatogenous retinal detachment is not closely associated with WGN in the original pedigree, peripheral tractional retinal detachment is described in the most recent follow-up [21].

13.2.9  Diagnosis and Diagnostic Aids

Differential diagnosis of WGN includes STK and Goldmann-Favre Disease. Examination of all available family members with close attention to systemic problems and retinal exam may help elucidate the diagnosis. The progressive nature of the disorder necessitates