INTRODUCTION:

Coats disease is an attenuate, unilateral and progressive ocular vasculopathy illustrated by intra-retinal along with sub-retinal secretion in the absence of vitreo-ocular traction^1-3. Despite momentous advances in understanding the disease, its exact underlying cause remains unknown. George Coats, a Scottish ophthalmologist, spotted the illness for the first time in 1908². However, it is imperative to remember that his initial case collection included eyes with opthalmic capillary hemangiomas, also known as Von-Hippel Lindau disease⁴.

The name "Coats' disease," which has since been widely embraced by the medical community, was coined by Reese in 1956 after he amended the disease's nomenclature as well as description⁵.

HISTOPATHOLOGY:

A critical mediator of Coats disease’s aetiology is vascular endothelial growth factor (VEGF). The complete system being caused by the results of VEGF on the retinal vasculature is angiogenesis and retinal hypoxia, which ultimately lead to exudative retinal detachment. Mutations in retinal proteins expressed by the Crumbs cell polarity complex component have been linked to blindness, a serious consequence of Coats disease⁶. The pathophysiology of Coats illness is believed to be linked to these mutations, which disrupt the polarity of retinal pigment epithelium (RPE) cells. This, in turn, causes abnormal capillary growth and development in the retina. The resulting blood capillaries are fragile and leaky, leading to the fluid buildup and lipids in the subretinal cavity and ultimately causing retinal edema⁷. Previous research has demonstrated that there are two different pathogenic pathways that contribute to Coats disease that affect the vasculature. The first pathway involves a breach blood-retinal barrier at the vascular level, leading to the thickening of the vessel membrane and necrotic changes in specific regions. This leads to sausage-like shapes and disorder within the vessel wall^8,9.

The second pathway in Coats disease is associated with anomalous pericytes and endothelium, resulting in aneurysms and arterial closure, which ultimately leads to ischemic changes. The resulting ischemic modifications cause the retina to generate a lipid-rich secretion that increases thickness, cyst formation, and retinal detachment¹⁰. NDP genes, located on chromosome Xp11.4.11, have been shown to be associated with Coats disease. NDP plays a crucial role in the Wnt signaling system, which modifies retinal vascular development patterns and retinal vascular endothelial growth factor (VEGF) transmission, as previously described in studies¹¹.

Signs and Symptoms:

The most common symptoms are diminished visual acuity (VA), leukocoria, and xanthocoria¹². During the initial stages, there may not be any apparent symptoms¹. Unilateral exudative retinal detachment, and gradual loss of visual function are the most common clinical features of Coats disease¹¹. Other indications that may be present include pain, nystagmus, and iris heterochromia, although these symptoms are less frequent¹⁰. Edema and macular exudation are common presenting signs in as many as 75% and 37% of cases, respectively³, while macular telangiectasia is only observed in 1% of patients¹. It also includes symptoms like aneurysms, capillary non-perfusion, sectoral retinal dissociation, yellowish exudates, telangiectasia, and hemorrhages^1,13,14. The signs include progressive loss of vision, yellowish masses with blood oozing over and neovascularization in the temporal periphery retina, considerable exudation in the lower temporal region of the eye, posterior pole inclusion, intraretinal lipid accumulation, poor VA, an afferent pupillary defect, esotropia, sub-exudative retinal detachment, massive lipid secretion, and inferior temporal retinal hemorrhage^15,16.

COMPLICATIONS:

Macular fibrosis¹, Retinal detachment¹, Uveitis, cataract¹², Refractory glaucoma¹⁷, Vitreoretinal fibrosis^18,19.

Table 1: Stages of Coats disease

Stages	Description
Stage-1	Retinal telangiectasia
Stage-2 Stage-2a and 2b	Telangiectasia and exudation Retinal telangiectasia plus extra-foveal and foveal exudation
Stage-3 Stage-3A-subtotal; 3B-total	Exudative retinal detachment Retinal telangiectasia plus extra-foveal and foveal exudation
Stage-4	Total retinal detachment and secondary glaucoma
Stage-5	Endstage

Source: Shields, 2001¹

Affected Population:

Coats disorder is a inherent retinal vasculature that may manifest in early infancy, as early as three to four months, despite not being explicitly documented at birth^20-22. Clinical presentation and statistical data suggest that Coats disease disproportionately affects males over females at a ratio of at least 3:1. Additionally, the condition is unilateral in more than 75% of cases, and there is no association with any specific ethnicity or geographic location^1,13,21.

CAUSES:

Transmutations in the Norrie deficiency protein (NDP) gene positioned on chromosome Xp 11.2 lead to Norrin deficiency, which is related to Coats disorder. The NDP gene encodes norrin, a peptide crucial for efficient retinal revascularization. The high male-to-female ratio is attributed to the incomplete persistence of X-inactivation in females. This incomplete X-inactivation is most likely the cause of the sporadic NDP mutation that triggers Coats disorder during a phase of retinal development in neuroectodermal-derived cells^12,23

DIAGNOSIS:

The timely detection of Coats disease in adolescence can be challenging, and this often results in late detection. However, the availability of portable devices such as optical coherence tomography angiography and spectral-domain optical coherence tomography (OCT) can assist in the alternative prognosis for Coats syndrome from further similar conditions, such as diffuse retinoblastoma²⁴and glaucoma^25,26. OCT is a vital intraoperative approach that can identify subretinal fluid, exudate, and haemorrhage and assess the integrity of specific retinal layers in patients with Coats disease making it an efficient way for monitoring the response of the illness to treatment^27-29.

Ultrasonography:

Ultrasonography can be an effective alternative for posterior segment examination when patients present with medial opacity or other factors that limit standard examination techniques. In the case of Coats disease, ultrasonography can be particularly useful in determining the degree and absence of a choroidal mass lesion. Ocular B-scan ultrasonography can provide a valuable alternative when standard examination techniques are limited. Ultrasonography can also provide valuable information about other aspects of the disease, including the presence of calcification, which can help detect the presence of malignancy. Overall, ultrasonography is a valuable tool in the diagnosis and management of Coats disease and other ocular conditions that may limit traditional examination techniques^1,24.

Angiography:

Fluorescein angiography is a useful tool for detecting arterial abnormalities in stage 1 patients. Massive exudation may complicate detection of arterial lesions, but may facilitate identification of distinct findings on angiograms³⁰. Areas of nonperfusion, "light bulb" aneurysms, and telangiectatic capillaries, which are particularly noticeable in the temporal macula, are among the angiographic markers of Coats disease. Tortuosity, Vascular leakage and blockage from protruding exudate are frequent angiographic findings. Wide-field angiography and RetCam imaging can aid in the early recognition of disease severity and improve the detection of isolated peripheral Coats disease. Indocyanine green angiography has hardly been linked to Coats disorder, but it may be useful for detecting choroidal illnesses such as tumours or neovascularization^1,31-34.

Fundus Examination:

Possible differential diagnoses for condition include FEVR and IRVAN. Retinal exudation, fibrovascular growth, and distal retinal involvement, particularly in the temporal region, are characteristics of FEVR. Clinical and subclinical FEVR features may be detected through family members fundus examinations. IRVAN is characterised by peripheral capillary nonperfusion zones, neuroretinitis, and peripapillary retinal arteriolar aneurysms. Invasive diagnostic procedures like FNAC are not recommended for these conditions but may be employed if noninvasive procedures prove insufficient¹.

Others:

In order to diagnose and treat Coats disease, radiologic imaging is crucial. Common imaging methods include computed tomography (CT) and magnetic resonance imaging (MRI). These imaging techniques have been widely used to distinguish people with Coats disease from those who have additional cancerous tumours that display comparable clinical symptoms. CT scans, with and without contrast, are useful in identifying tumours of the subretina, vascularity, brain tumours or extraocular orbital lesions, and calcifications typical of retinoblastoma but not Coats disease. In MRI, a T1- and T2-weighted transmission with high intensity is evident, which is related to exudative retinal detachment converging on nucleus of the optic nerve. T2-weighted imaging can be helpful in distinguishing retinal melanoma from other diseases, as it appears relatively dim in this type of imaging^24,35-39.

RELATED DISORDERS:

Norrie syndrome¹², familial exudative vitreoretinopathy (FEVR)²are the two related disorders of Coats disease, which were observed by Leber and Reese in 1912.

Investigational Therapies:

1. Assessing Ocular and the Vascular Characteristics of Coats Disease After Intravitreal Ranibizumab Injections:

Effectiveness of ranibizumab in treating Coats disease, was evaluated using OCT and OCT angiography parameters. Three monthly injections of ranibizumab at a dosage of 0.5mg/0.05 ml were administered to patients. However, no results have been made available from this investigation. Previous studies have shown promising results with ranibizumab, but further research is needed to determine long-term effectiveness and safety. Overall, ranibizumab is a promising treatment approach for Coats disease⁴⁰.

2. Anecortave acetate (15 mg) in Congenital Telangiectasia (Coat's Disease): A Study with Open Label:

Anecortave acetate is used to control abnormal blood vessel increase in retinal diseases like diabetic retinopathy and age-related macular degeneration (AMD). The drug is administered via a specialized juxtascleral injection of 15mg and follow-up visits are scheduled to assess efficacy. If anecortave acetate is not effective, photodynamic therapy or thermal lasers may be recommended. However, no results are currently available from the clinical trial. Additional research is required to assess the medication's effectiveness and safety as well as to identify the best way to use it to treat ocular conditions characterised by abnormal blood vessel formation⁴¹.

3. Treatment for Choroidal Neovascularization (CNV)-Related Maculopathy and Related Exudative and Vasogenic Chorioretinal illnesses, Including AMD Variants:

A potential therapy for neovascular non-AMD illnesses, that are characterised by anomalous blood vessel growth, is lucentis (ranibizumab). The FDA has already given the medication approval for age-related moist (neovascular) macular degeneration. The intravitreal dosing and half-life characteristics of ranibizumab make it a suitable candidate for treating angiogenesis, and monthly doses with a one-month interval between doses are recommended for maximum therapeutic benefit. Previous studies have shown promising results; however, more study is required to assess the approach's long-term effectiveness and safety.

Table 2: Dose of Ranibizumab

(Ranibizumab) Lucentis 0.5%

Drug: ranibizumab injection (0.5 mg)

ranibizumab 10 m mg/ml., 0.3ml/vial, 0.05 ml./injection intravitreally for 3 months then prn for the next 21 months (Lucentis)

Source: Lawrence, 2012⁴¹

Unfortunately, the results of this completed clinical trial are not yet available available⁴¹.

STANDARD THERAPIES:

Recent research and advancements in medication development have led to new therapeutic options for Coats' disease, including vitrectomy, cryotherapy, laser photocoagulation, intravitreal steroids, and/or VEGF injections. Several studies have shown that dexamethasone intravitreal steroid implants are effective in treating Coats' disease^8,42-46. The treatment for Coats disease depends on disease progression stage. Patients with retinal telangiectasia in stage 1 or stage 2 with secretion that has no impact on eyesight should undergo frequent evaluation. Cryotherapy is beneficial for victims of Coats with stages 2 to 3A. Surgical intervention is recommended for retinal detachment (stage 3A or above) and has shown favorable outcomes. Enucleation may be necessary for stage 4 Coats' syndrome with significant eye discomfort. Asymptomatic, blind, and depressed stage 5 Coats' patients may be monitored but do not require treatment⁴⁷.

Cryotherapy:

Cryotherapy is a therapeutic intervention that has shown efficacy in treating various retinal ailments, including peripheral telangiectasia, considerable exudation, and retinal detachment. However, its implementation is predominantly reserved for severe stages of these conditions due to the potential occlusion of the retina, even when detached^48,49. To administer cryotherapy, indirect ophthalmoscopy is employed, and the technique of double or triple freeze-thaw can be used. This involves applying the cryoprobe to the area of treatment for a specific duration, followed by thawing and refreezing the same area. The process can be repeated two or three times to achieve the desired therapeutic effect. It should be noted that the use of cryotherapy can result in a significant breach in the blood-retinal barrier, leading to an elevation in the levels of retinal fluid. This should be closely monitored, and caution should be exercised in the administration of cryotherapy to avoid exacerbating the condition^50,51.

Photocoagulation:

Laser photocoagulation is an effective treatment for various retinal conditions by addressing exudation, enlarged aneurysms, and aberrant vessels. Using green or else yellow lasers with pulse durations of 0.1 to 0.5 seconds achieves vessel closure. Early laser photocoagulation is crucial in maintaining macular vision, and it stabilizes exudates. In individuals with macular follicular telangiectasia, laser photocoagulation can avoid granulomatous retinal detachment and lessen exudation in phases 2 or 3 of Coats disease⁴⁶. However, for advanced Coats disease with aqueous retinal detachment, endolaser photocoagulation by two-port pars plana non-vitrectomy has emerged as a secure and successful treatment option. This approach has achieved a retina reattachment rate of 96% and an improvement in vision of 29.41%^52,53.

Surgery

Vitrectomy:

Bevacizumab is a medication that can be utilised to treat severe Coats disease⁵⁴. In a research by Imaizumi et al., a person suffering from severe Coats syndrome was given 0.5 mg of bevacizumab intravenously during an lens-preserving vitrectomy and external SRF. After the operation, epiretinal membrane ablation was performed to improve vision⁵⁵. Cryotherapy, laser photocoagulation, intraocular tamponade, and 23-gauge PPV have all been shown by Karacorlu to be beneficial therapies for severe Coats disease. This therapy resulted in stable or better eye acuity, good anatomic effectiveness, and a reduced need for retreatment⁵⁶. Additionally, a research by Chen et al. found that adult-onset Coats' condition with a proliferative membrane can be successfully treated with 25-gauge PPV in conjunction with epiretinal barrier stripping, laser photocoagulation, and cryotherapy¹⁴. By eliminating cytokines from the vitreous, a vitrectomy may be successful in slowing the development of the illness.

Anti-VEGF therapy:

Coats disease is caused by abnormal VEGF-mediated vascular regeneration, resulting in increased VEGF levels and subsequent lipoprotein exudation, edema, and capillary wall permeability. Anti-VEGF drugs such as bevacizumab and ranibizumab have shown assurance in treating disease by reducing exudation and edema and improving visual acuity. Aqueous VEGF concentrations increase significantly as Coats disease progresses, providing a potential diagnostic and treatment avenue. In recent years, anti-VEGF drugs have emerged as a promising treatment option for Coats disease. Specifically, intravitreal bevacizumab has been recommended as a treatment option for advanced 2B-stage illness since 2008. Studies have demonstrated that anti-VEGF drugs can improve laser treatment by reducing the permeability of capillary endothelial cells. These findings were reported in research conducted by^57,58, which evaluated the efficacy of anti-VEGF drugs in treating Coats disorder.

Intravitreal corticosteroids:

Clinical trials have shown that intravitreal dexamethasone implants have significant promise as a first-line therapy for Coats disease. In a study conducted by⁴⁴, intravitreal dexamethasone was shown to be effective in reducing disease symptoms such as retinal edema and exudation, improving visual acuity, and reducing the need for additional interventions. These findings suggest that intravitreal dexamethasone may offer a viable alternative to current treatment options for Coats disease.

CONCLUSION:

In conclusion, Coats disease is an attenuate retinal vasculopathy that chiefly affects young males and can lead to vision loss if left untreated. Although significant advances have been made in understanding the disease's prevalence, morphological characteristics, patient variables, and history, the exact cause remains unknown. However, current treatment options, including laser photocoagulation, cryotherapy, and anti-VEGF therapy, have been shown to be efficient in slowing disease progression and preserving vision in patients. Ongoing research is necessary to improve patient outcomes and develop more effective treatments. Early detection and diagnosis through imaging techniques such as OCT, OCT angiography, and fluorescein angiography are crucial for optimal management. Ultimately, timely and appropriate treatment can significantly improve the prognosis for patients with Coats disease.

CONFLICT OF INTEREST:

The authors have no conflict of interest regarding this review.

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Received on 08.06.2023 Modified on 11.09.2023

Res. J. Pharmacology and Pharmacodynamics.2023;15(4):217-222.

DOI: 10.52711/2321-5836.2023.00038