Exudative Retinitis (Coats Disease)

Abhishek Gupta; Vivek Paulbuddhe; Unnati Shukla; Koushik Tripathy

Exudative Retinitis (Coats Disease)

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Continuing Education Activity

Coats disease is an idiopathic ocular condition characterized by retinal telangiectasia and exudation. The incidence is relatively low, hence recognizing it will help in the early diagnosis and treatment. This activity reviews the evaluation and management of Coats disease and explains the role of the interprofessional team in improving care for patients with this condition.

Objectives:

Describe the etiology of Coats disease.
Explain the typical presentation of a patient with Coats disease.
Review the typical imaging findings associated with Coats disease.
Summarize the importance of collaboration and communication amongst the interprofessional team to improve outcomes for patients affected by Coats disease.

Introduction

Coats disease is an idiopathic ocular condition characterized by retinal telangiectasia, aneurysms, and exudation.[1][2][3] George Coats first described it in 1908 as a unilateral condition with retinal exudation and telangiectasia in male children.[4] Later, Theodor von Leber described a similar case with telangiectatic and aneurysmal vessels without subretinal exudation.[2] This condition was later known as Leber multiple miliary aneurysms.[2] It was identified as an earlier disease process of Coats disease. Subsequently, Shields et al. defined Coats disease as ‘idiopathic retinal telangiectasia associated with exudation and frequent exudative retinal detachment with no signs of retinal or vitreal traction.’[5]

Etiology

Coats disease is usually sporadic.[4] Considering the unilateral and sporadic nature of the disease, a somatic mutation is more likely.[6] Coats disease is characterized by peripheral retinal avascularity similar to other diseases like Norrie disease, familial exudative vitreoretinopathy (FEVR), facioscapulohumeral muscular dystrophy (FSHD), and osteoporosis pseudoglioma syndrome.[7][8][9][10][11][12][13] All of these conditions are related to abnormalities in the Wnt signaling pathway during retinal angiogenesis.[7][8]

Cremers and colleagues found a mutation in the CRB1 gene in 55% of eyes with retinitis pigmentosa and Coats-like secondary exudative vasculopathy.[14] They suggested that CRB1 could be involved in primary Coats disease as well as other retinal conditions.[14] Several reports have suggested a missense mutation within the Norrie disease pseudoglioma gene, NDP, on chromosome Xp11.2 in the pathogenesis of Coats disease.[15][16][17][18][19] Mutation in the PANK2 gene has also been implicated in Coats disease.[6][20][6]

Epidemiology

Morris et al. conducted a population bases study of Coats disease.[21] The incidence was 0.09 per 100,000 population. All cases were unilateral, and 85% were male.[21] The mean age at presentation was 146 months (median 96 months). Some authors have reported that the disease could be present at birth.[22] In a large series, only 5% of cases were bilateral.[2] The fellow eye was usually without symptoms and had subtle peripheral telangiectatic changes.[2] Adult-onset Coats disease (first diagnosed at a minimum age of 35 years) constituted 7% of the 646 patients with Coats disease in a tertiary eye care center.[23] The mean age at diagnosis of adult-onset Coats disease was 47 years in this series.[23]

Pathophysiology

In Coats disease, the blood-retinal barrier breaks down, which causes plasma leakage into the vessel wall.[24] The blood vessels become thickened and necrosed.[24] This leads to a ‘sausage-like’ shape of the vessel. The abnormal pericytes and endothelial cells in retinal blood vessels subsequently degenerate. These blood vessels form aneurysms and later occlude, leading to ischemia and rarely neovascularization.[25]

Histopathology

Coats studied the histologic features of enucleated eyes.[6] He described the subretinal fibrous tissue masses as tightly adherent to the outer retina. Most of the eyes had associated retinal thickening, degeneration, detachment, hemorrhages, cholesterol crystals, and vascular abnormalities.[6] One eye had evidence of bone formation. Other authors have also described the histopathologic features such as bullous retinal detachment and the presence of subretinal fluid. The outer retina is thickened due to exudation, and the inner retina contains telangiectatic vessels. The retinal vessels have perivascular sheathing and are degenerated. There is capillary dropout with areas of neovascularization.[26][27][28][29][30] Thick PAS (Periodic acid–Schiff)-positive deposits in the wall of retinal vessels and large aneurysms are typically seen in Coats disease.[24] Kase et al. have reported increased vascular endothelial growth factor (VEGF) levels in eyes with vascular abnormalities. They noted VEGF immunoreactivity in retinal macrophages and endothelium of blood vessels.[31]

History and Physical

The presenting symptoms are varied. The patients can present with decreased visual acuity (43%), strabismus (23%), leukocoria/xanthocoria (20%), pain (3%), heterochromia (1%), and nystagmus (1%).[2] Eight percent of patients may be asymptomatic and are detected coincidentally on routine examination.[2]

Visual acuity can range from 20/20 to 20/50 in 12% of cases, 20/60 to 20/100 in 11%, 20/200 to counting fingers in 18%, and hand motions to no light perception in 58%.[2] The main causes of poor vision include subfoveal fluid or lipids, subfoveal fibrosis, macular edema, epiretinal membrane, and optic atrophy.[5] The anterior segment is normal in 90% of cases. Those with findings include cataract, iris neovascularization, shallow anterior chamber, corneal edema due to high intraocular pressure, cholesterol in the anterior chamber, and megalocornea.[32][33]

Retinal findings include telangiectasia, fusiform aneurysms, and intraretinal exudation. There may be sheathing of the vasculature.[5] These findings are generally noted in the inferotemporal quadrant in the peripheral zones between the equator to ora serrata.[5] As the disease progresses, fluid exudation leads to exudative retinal detachment, retinal hemorrhage, vasoproliferative tumor, macular fibrosis, and optic disc neovascularization.[34] Advanced complications such as iridocyclitis, cataract, and secondary neovascular glaucoma can lead to phthisis bulbi.[35][36][37]

Adult-onset Coats disease is characterized by systemic associations (usually hypertension), incidental detection, involvement of less than six clock hours of the retina, a benign natural course of the disease, and usually better visual outcomes compared to childhood-onset Coats disease.[23] Seventy-three percent of patients with the adult-onset disease were male, and 93% of cases had unilateral involvement.[23]

Evaluation

The diagnosis of Coats disease is clinical. Ancillary investigations are done when the diagnosis is in doubt, particularly with bullous retinal detachment with exudation and dilated vessels.

Fundus Fluorescein Angiography (FFA)

The typical fluorescein angiographic features are telangiectasia, aneurysms, beading of vessel walls, and peripheral retinal nonperfusion.[38] The anomalous vessels show early leakage, which continues until the late phase.[39] The aneurysms are clearly visible as ‘light bulb’ dilations on the larger blood vessels. In the periphery, areas of capillary drop out and rarely neovascularization can be seen. FFA helps in treatment by identifying the telangiectatic leaking vessels, which can be selectively lasered. It also highlights the areas of nonperfusion which can be treated with photocoagulation in cases of neovascularization or even before the development of neovascularization.[5][40][41] With the development of wide-field angiography machines such as Retcam and Optos, peripheral vascular anomalies can be detected and selectively laser targeted.[42]

Optical Coherence Tomography (OCT)

OCT is helpful in monitoring for macular involvement. It helps in documenting cystoid macular edema, epiretinal membrane, subretinal/intraretinal fluid, subfoveal lipids, central macular thickness, and subfoveal choroidal thickness.[43] In a study, subretinal compact hyperreflectivity (fibrosis) and outer retinal atrophy were associated with worse final visual acuity.[44]

OCT Angiography (OCTA)

OCTA may be used to monitor the disease and response to therapy non-invasively.[45][46] Reported OCTA feature of Coats disease after therapy includes chorioretinal anastomoses, abnormal foveal vascular loops, and flow voids in the choroid.[45] Abnormal foveal avascular zone (FAZ) with retinal vessels traversing the FAZ may be noted in the affected and the fellow eye in cases with unilateral Coats disease.[47]

Ocular Ultrasonography (USG)

It depicts the extent of retinal detachment. It characterizes the subretinal space, which is usually acoustically clear, but sometimes hyperechogenicity can be seen due to the presence of cholesterol deposits. Calcification can occur in advanced Coats disease along the retinal pigmentary epithelium. It is seen as a curvilinear pattern in contrast to retinoblastoma, where it is randomly distributed.[4]

The analysis of subretinal fluid sometimes helps in diagnosis by demonstrating lipid-laden macrophages and cholesterol crystals.[2]

Computed Tomography (CT)

CT is useful to rule out retinoblastoma. The presence of a solid mass with calcification is present in retinoblastoma. This is better delineated in the CT scan. In Coats disease, the scan would be clear of these lesions.[48][49] CT also highlights the intraocular morphology and the subretinal exudation.

Magnetic Resonance Imaging (MRI)

MRI may be useful in diagnosing advanced Coats disease and ruling out retinoblastoma. The exudate in Coats disease is hyperintense on both T1-weighted and T2-weighted MRI images, whereas in retinoblastoma, the T1-weighted image will show a hyperintense mass, but the T2-weighted image shows a hypointense mass.[48][50] Retinoblastoma shows enhancement with gadolinium contrast, a feature not seen in Coats disease.[1]

Treatment / Management

The treatment for Coats disease depends on the stage of the disease. Mild cases with only retinal telangiectasia and no exudation can be observed and followed up at regular intervals. Treatment is needed when exudation develops. In less severe cases of exudation, laser photocoagulation to telangiectatic vessels is done.[51][52][53]

FFA helps in detecting the leaking vessels.[42] These are directly treated with moderate intensity burns. Laser therapy causes inflammation and leads to a transient increase in exudation. So, multiple sessions of laser are needed at intervals of 2 to 3 months. But the laser is ineffective in cases of extensive subretinal exudation and retinal detachment. Cryotherapy is useful in such cases. It is done by a double freeze-thaw technique over the affected retina. Cryotherapy is associated with more inflammation, pain, and sometimes exudative retinal detachment, so therapy should be limited per session and divided into multiple sessions.

Advanced cases with bullous exudative detachment abutting the lens might benefit from surgery. The subretinal fluid is drained either trans-sclerally or internally. The detached retina gets approximated. Pan retinal photocoagulation or cryotherapy is then done. In cases with the rhegmatogenous or tractional component, pars plana vitrectomy is done with or without tamponade. Surgery primarily aims to prevent a painful blind eye and avoid enucleation rather than vision restoration.

Enucleation is done in endstage disease with neovascularization or angle-closure glaucoma.[5][54] Alternatively, transscleral diode laser cyclophotocoagulation can be tried in eyes with neovascular glaucoma.[55]

Intravitreal corticosteroids and anti-VEGF agents may effectively reduce macular edema and subretinal fluid.[56][57][58][59][60][61][62][63][64] They are employed as adjunctive agents. They can also be given before laser and cryotherapy to reduce the reactive exudation associated with them.[65]

Differential Diagnosis

Diseases that produce leukocoria[66] and strabismus can simulate Coats disease.[66] The differential diagnosis includes retinoblastoma, FEVR, retinal detachment, Noorie disease, persistent hyperplastic primary vitreous (PHPV), retinopathy of prematurity (ROP), congenital cataract, retinal hemorrhage, hemangioblastoma, toxocariasis, choroidal hemangioma, coloboma, endophthalmitis, cytomegalovirus retinitis, and toxoplasmosis.[67][68][67] The most important differential is retinoblastoma. Retinoblastoma is the most common intraocular malignancy in children and is fatal if left untreated. Coats disease is the most common cause of erroneous enucleation reported.[2]

Retinoblastoma can present in a younger child below one year; Coats disease is not as common in this age group and generally presents after 2 or 3 years. The large vessels in retinoblastoma go subretinally within the tumor, whereas in Coats disease, the telangiectatic vessels are always noted in the retinal surface. Bilaterality is common in retinoblastoma but very rare in Coats disease. Retinoblastoma often has a family history, but family history is usually not present in Coats disease. Retinoblastoma presents with leukocoria, and Coats disease has xanthocoria. On USG, retinoblastoma presents as a solid mass and calcification with shadowing. This feature is absent in Coats. The calcification in retinoblastoma is randomly distributed. Calcification in Coats is rare but, if present, is curvilinearly distributed along the retinal pigment epithelium.

FEVR and Noorie disease can be differentiated based on bilaterality, a positive family history, and the presence of retinal dragging, all of which are rare in Coats disease. Retinopathy of prematurity (ROP) is seen in preterm low birth-weight babies. Proliferative retinopathy due to chronic rhegmatogenous retinal detachment and pars planitis is another differential.

The classical finding in Coats is dilated telangiectatic vessels, aneurysms, hard exudates, peripheral avascularity, and exudative retinal detachment.

Sometimes a mass forms which might simulate

Melanoma,
Papillary or retinal capillary hemangioblastoma,
Choroidal granuloma (sarcoidosis, tuberculosis), and
Vasoproliferative tumor.

Other differential diagnoses of diseases with extensive hard exudates include

Branch retinal venous occlusion,
Vasoproliferative tumor,
Capillary hemangioma,
Chronic retinal detachment,
Trauma, and
Inflammation.

A Coats-like response (retinal telangiectasia, aneurysm, and hard exudates) may also be noted in

Retinitis pigmentosa[69]
Healed choroiditis[70]
Tubercular subretinal abscess[71]
Retinal vasculitis,[72]
Pars planitis[73][74][75]
Leber Congenital amaurosis[76]
Facioscapulohumeral muscular dystrophy and deafness,
Progressive facial hemiatrophy or Parry-Romberg syndrome or progressive hemifacial atrophy or hemifacial atrophy[77]
Isolated hemihyperplasia
Tuberous sclerosis
Alport's syndrome
X-linked retinoschisis and regressed retinopathy of prematurity[78]
'Blood-filled senile retinoschisis'[79]
Linear Scleroderma[80]
En coup de sabre scleroderma[81]
Epidermal nevus syndrome

As described by Gass and Blodi, type I macular telangiectasia is characterized by nonfamilial and usually unilateral disease with retinal telangiectasia and hard exudates.[82] This disease is thought to lie in the spectrum of Coats disease.[83] The peripheral retinal yellow hard exudates in retinitis pigmentosa with a Coats-like response may be misdiagnosed as acute retinal necrosis.[84][85] Coats-like disease in FSHD is seen in around 75% of patients angiographically.[86] The retinal involvement is usually bilateral.[86] The posterior pole is usually not involved, and the disease usually has milder severity.[86] Visual loss is rarely (1%) noted.[86] Such bilateral Coats-like response in FSHD may affect females.[87]

Staging

Shields et al. introduced the staging of Coats disease in 2000, which is most widely used:

Stage 1 is characterized by retinal telangiectasia
Stage 2 has telangiectasia and intraretinal exudation
- Stage 2A: extrafoveal exudation
- Stage 2B: foveal involvement
Stage 3 denotes exudative retinal detachment
- 3A is a subtotal detachment
  - 3A1: extrafoveal
  - 3A2: foveal involvement
- 3B is a total retinal detachment
Stage 4 has a total retinal detachment plus increased intraocular pressure
Stage 5 is an endstage disease, occasionally with phthisis bulbi[5][88]

Prognosis

Shields et al. reported the visual outcome of 160 patients with Coats disease.[89] This study found that the advanced stage of the disease was associated with poor visual acuity after treatment. The advanced disease showed less frequent resolution of disease, subretinal fluid, and exudation. The enucleation rate was higher in Stages 4 and 5. Poor visual acuity in advanced stages was mainly due to persistent retinal detachment and macular fibrosis. For stages 1 and 2, telangiectatic vessels resolved completely (47%) or partially (53%) over a mean interval of 15 months following treatment.[5]

Overall most cases (76%) stabilized or improved anatomically following treatment. A minority (8%) of patients progressively worsened.[5] Approximately 20% required enucleation for neovascular glaucoma or painful phthisis bulbi. The risk of recurrence of disease persists even after the resolution of the disease. Patients should be followed lifelong for recurrence.[3][90][91] Lack of visual rehabilitation and subretinal fibrotic nodule indicate poor visual prognosis.[92] In a series of 67 patients, the identified poor prognostic factors for globe salvage included cataract, diffuse involvement, advanced presentation (stage 3B or worse), anterior hyaloid proliferation, vitreous hemorrhage, preretinal or subretinal fibrosis, and combined or tractional retinal detachment.[92]

Complications

The clinical course of Coats disease is progressive. Acute exacerbations of the disease infrequently occur, followed by a quiescent state. Spontaneous remissions are rare. In untreated eyes, secondary complications can develop, including:

Orbital cellulitis (which may simulate retinoblastoma)[93]
Neovascularization
Vitreous hemorrhage[92]
Cataract
Rubeosis iridis
Neovascular glaucoma
Phthisis bulbi

Deterrence and Patient Education

As Coats disease is idiopathic and sporadic, there are no preventative measures that can be taken by the patients' families. The patients' family members should be appropriately counseled regarding the prognosis of Coats disease and the importance of long-term follow-up.

Enhancing Healthcare Team Outcomes

Any patient presenting with Coats disease should not only receive treatment by an ophthalmologist as it requires an interprofessional team evaluation by pediatricians and oncologists. Interprofessional team communication can lead to better patient management. The patient will most often present to the primary clinician, and these professionals should be aware of the condition as it is treatable. Prompt referral to an ophthalmologist is necessary. These patients can then be followed by their primary clinicians and ensure compliance with treatment. The nursing staff will be the first to the department to come in contact with patients on follow-up and can assess treatment progress as well as evaluate compliance with therapy and report any issues to the primary care clinician. This collaborative, interprofessional approach to care can ensure optimal patient outcomes.

(Click Image to Enlarge)

Macular subretinal scar (nodule) and retinal hard exudates in a child with Coats disease
Contributed by Koushik Tripathy, MD

(Click Image to Enlarge)

The temporal retina in an eye with Coats disease shows the typical telangiectatic vessels, aneurysms, and hard exudates.
Contributed by Koushik Tripathy, MD

Details

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