Idiopathic Retinitis, Vasculitis, Aneurysms, and Neuroretinitis (IRVAN)

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This article presents a comprehensive review of a rare syndrome with distinctive retinal findings. Idiopathic retinal vasculitis, aneurysms, and neuroretinitis or IRVAN syndrome was first described in 1995 although case reports have been published since the 70s. This article is dedicated to all readers, especially our patients, who do not have easily access to scientific literature. The latest technique to study this disease, optical coherence tomography angiography of the retina, will be available for very first time to Eye Wiki users.

Disease Entity

Idiopathic Retinal Vasculitis, Aneurysms and Neuro-retinitis ( Chang et al )[1] and Idiopathic Retinitis, Vasculitis, Aneurysms, and Neuroretinitis ( Samuel et al )[2] are synonyms for IRVAN syndrome.

IRVAN is a subtype of retinal vasculitis. As such, it is recognized by the following codes as per the International Classification of Diseases (ICD) nomenclature[3]:

ICD-9 ICD 9 Data

362.18 Retinal Vasculitis

ICD-10 ICD 10 Data

H35.061 Retinal Vasculitis, right eye

H35.062 Retinal Vasculitis, left eye

H35.063 Retinal Vasculitis, bilateral

H35.069 Retinal Vasculitis, unspecified eye

External Links

Disease

Figure 1 : J. Donald M. Gass, MD

Idiopathic retinal vasculitis, aneurysms, and neuroretinitis (IRVAN) syndrome is a rare clinical entity of unknown etiology. IRVAN syndrome is one of the contributions to Ophthalmology of J. Donald M. Gass, MD [4]( Figure 1 )

Etiology

Unknown.[5] Some authors[6] have speculated an association with positive P-ANCA s (Perinuclear AntiNeutrophil Cytoplasmic Antibodies) systemic vasculitis[7] and antiphospholipid syndrome[8].

Risk Factors

Slight female preponderance[1]. There is no race predilection[9]. Young or middle-aged people mainly affected[10].

Stages

Samuel et al proposed a new staging system in 2006 [2]:

  • Stage 1 : Macroaneurysms, exudation, neuroretinitis, retinal vasculitis.
  • Stage 2 : Capillary nonperfusion (angiographic evidence)
  • Stage 3 : Posterior segment neovascularization of disc or elsewhere and/or vitreous hemorrhage.
  • Stage 4 : Anterior segment neovascularization (rubeosis iridis)
  • Stage 5 : Neovascular glaucoma..

Pathophysiology

Inflammation appears to be integral to IRVAN. It is possible that the inflammation damages the retinal arteries in a way that promotes aneurysmal dilations. Interestingly, the aneurysms in IRVAN appear to occur primarily in the first several orders of the retinal arteries, and aneurysms are not seen anterior to the equator. Although no histopathology of IRVAN is available, it is interesting to note that the muscular wall of the retinal arterioles continues to the equator as well. Perhaps inflammatory-driven damage to the retinal arteriolar wall induces the abnormal dilations seen in IRVAN. At present, there is no apparent cause for IRVAN, but an immunopathogenic cause may be the inciting event.[11]

Diagnosis

The diagnosis of idiopathic retinitis, vasculitis, aneurysms,and neuroretinitis (IRVAN) is based on a constellation of clinical features. Three major criteria (retinal vasculitis, aneurysmal dilations at arterial bifurcations, and neuroretinitis) and 3 minor criteria (peripheral capillary nonperfusion,retinal neovascularization, and macular exudation) are used to diagnose IRVAN.[1][5]

Patients with IRVAN usually present with decreased visual acuity in one or both eyes[12]. They may have a variable number of cells in the anterior chamber and the vitreous.

Macroaneurysms are a sine qua non condition to diagnosis of IRVAN syndrome[9]. The retinal arterioles have multiple aneurysmal dilatations extending through the first several orders of arterial branching until mid-periphery. The aneurysms are commonly found on the optic nerve, a site where typical senile retinal macroaneurysms are not. The aneurysms are typically found at branching points of the arteries, and may be fusiform, Y-shaped, or spheroid in shape. In segments between the aneurysms the retinal arteries frequently show marked caliber variations. Arterial aneurysms clinically resemble multiple and consecutive "knots of a cord" ( Figure 2 )

Disc neovascularization may be observed in severe and advanced cases of IRVAN, especially with peripheral capillary dropout. A thick posterior hyaloid may exert vitreoretinal traction causing vitreous hemorhhage. Non-complicated cases may have a slight swelling of the optic nerve head, highlighted in late phases of fluorescein angiography. Some authors think there is no a true neuroretinitis, but leaking aneurysms on the optic nerve head and periarterial lipid exudation.

Figure 2. Fluorescein angiography : Arterial macroaneurysms . Courtesy of Juan Verdaguer T. MD

Retinal vascular sheathing may occur, but it is not a prominent feature of the disorder in most patients. ( Figure 3 )

Figure 3. Color fundus photography : Retinal vascular sheathing , hemorrhages and peripapillary exudation. Macroaneurysm on optic nerve . Courtesy of Lawrence A. Yannuzzi MD.

In the retinal periphery, there is a variable amount of retinal nonperfusion, with obliteration of the arteries, veins, and retinal capillaries. In the perfused area bordering the peripheral areas of nonperfusion, the retinal veins may show abnormal caliber alterations. If the ischemic load of the nonperfused retina reaches a critical level, retinal and iris neovascularization may develop. Interestingly , neo-vessels may sometimes reproduce arterial macroaneurysms seen in the retinal vasculature ( Richard F Spaide MD, personal communication ). In severely affected individuals, vitreous hemorrhage and neovascular glaucoma have developed.[13]

Although lipid deposition is not common in most patients with uveitis, patients with IRVAN frequently have marked intraretinal lipid deposition. This lipid is usually found in the peripapillary region and may extend into the macula leaving a macular star or massive lipid accumulation . The lipid is generally found near the greatest concentration of aneurysms ( peripapillary location and along the arcades ) . The retina in these areas is commonly edematous and may be detached by exudative fluid. As time goes by, a fibrous grayish macular scar may develop as a legacy of long-standing exudation in the macula.[10]

History

Figure 4 . Fluorescein angiography : Hyperfluorescence from retinal vessels, macroaneurysms, and optic nerve,1978. Courtesy of Juan Verdaguer T. MD
Figure 5 : Color fundus photography. 15 year-old female patient, 1978. Courtesy of Juan Verdaguer T. MD

In 1973, Karel I. et al. published one case correspondent to a 15 year-old girl, in a series of pediatric uveitis, who matched the typical findings showed much later in IRVAN’s syndrome.[14] In 1978, Verdaguer T. presented, at a national conference, two otherwise healthy subjects who presented multiple arterial aneurysms from optic nerve up to mid-periphery ( Figure 4 ). He described a 20 year-old female with numerous aneurysmal dilatations within the arterial tree and marked lipid accumulation in both maculas and a 32 year-old man who had a gliotic macular scar secondary to a long-standing exudation in his macula. This author certified the leakage from retinal aneurysms by fluorescein angiography and stated that “ this disease as an independent entity” [15]( Figure 5 )

In 1983, Kincaid and Schatz described a bilateral inflammatory eye disease associated with multiple retinal aneurysms[16]. Since then, only few reports [17][18]were added to the scientific literature with no evidence of any concomitant systemic disease [19]and, relatively, a good visual prognosis.

In 1995 , Chang et al [1]first described the largest series of ten patients, ranging from 7 through 44 years of age, who met the criteria for a new retinal syndrome ( presence of retinal vasculitis, multiple aneurysms, and neuroretinitis not associated with any systemic abnormalities ) So, the authors proposed the acronym IRVAN to highlight the most prominent clinical features of this syndrome ( Idiopathic Retinal Vasculitis, Aneurysms and Neuro-retinitis ) . This report was presented at the ARVO Annual Meeting and published by the Retinal Vasculitis Study Group led by J. Donald M.Gass.

In 2007, Samuel et al[2] made new observations on the follow up of these originally described patients and adding twelve more subjects. Although IRVAN syndrome was believed to be a benign condition, they found and clarified that it can lead to a severe visual loss.

They also proposed a staging classification based on retinal ischemia status and established that an early panretinal laser photocoagulation should be considered when angiographic evidence of retinal nonperfusion is present. The latter is considered the first line of treatment until nowadays. IRVAN word stood for Idiopathic Retinitis, Vasculitis, Aneurysms, and Neuroretinitis, a small variation from the original acronym.

Finally, between 2009 through 2011 , Soheilian [6]and Nourinia[7] have found some patients affected by IRVAN syndrome, an association with positive perinuclear antineutrophil cytoplasmic antibody levels ( P-ANCA ) on systemic workup as a only notable finding. Thus, IRVAN syndrome would be a retinal manifestation of a P-ANCA associated systemic vasculitis.

Signs

  • Multiple postequatorial arterial aneurysms in the retina and optic disc head.
  • Peripapillary lipid exudation associated with macroaneurysms and retinal vasculitis.
  • Retinal hemorrhages in posterior pole.
  • Peripheral capillary nonperfusion
  • Retinal vascular sheathing
  • Swelling of the optic nerve
  • Retinal neovascularization
  • Optic disc neovascularization

Symptoms

Asymptomatic

Figure 6 : Color fundus photography. Patient with IRVAN syndrome and 20/20 vision in his asymptomatic right eye
Sometimes a patient will not complaint about a loss of vision in spite of having a severe disease because it is not affected during initial presentation ( Figure 6 )

Unspecific symptoms

For instance , multiple visits for a change of glasses due to blurred vision.

Symptoms of Retinal Vasculitis

Clinical diagnosis

Patients with IRVAN are , sometimes, overinvestigated for systemic causes of retinal disease. However, IRVAN seems to produce only ophthalmic manifestations, with general workup being mostly unremarkable. Retinal imaging is a key element for a rapid diagnosis of IRVAN[20], and a multimodal imaging approach is recommended when this syndrome is suspected, to collect all possible diagnostic criteria. Dye-mediated angiographies ( fluorescein and indocyanine green[21] ) remain the standard imaging modalities for confirming clinical diagnosis of IRVAN.[22]

Diagnostic procedures

Fluorescein angiography

Fluorescein angiography highlights the arteriolar abnormalities. The aneurysms are more evident and the alterations in arteriolar caliber are more obvious. Leakage of fluorescein from the aneurysms is apparent. Patients with IRVAN usually have optic nerve head staining. Of course, disc and/or retinal neovascularization show marked fluorescein leakage. The areas of peripheral non- perfusion are easier to appreciate with fluorescein angiography, especially wide-field fluorescein angiography.[23] ( Figure 7 )
Figure 7 : Wide-field fluorescein angiography shows extensive capillary nonperfusion
Figure 8 . Wide-field indocyanine-green angiography highlights round-shaped hyperfluorescences on the optic disc and peripapillary corresponding to arterial macroaneurysms in IRVAN

Indocyanine green angiography

The aneurysmal dilatations showed uniform staining. No abnormalities were seen in the choroidal vessels; in particular, no aneurysms of the choroidal vessels have been observed. For example, the retinal abnormalities and macroaneurysms in IRVAN are more clearly imaged with ICG angiography, especially at the very late stages, but the leakage, ischemia, and retinal neovascularization are still best delineated with FA.[24] ( Figure 8 )

Figure 9 : Structural OCT B scan : Macular edema and epiretinal membrane in a patient with IRVAN syndrome.

OCT or Optical coherence tomography

It is useful to assess macular edema , vitreoretinal traction over both the macula and optic nerve head , neovascular tufts in posterior pole and epiretinal membrane , as an example[25] [26]( Figure 9 ).

Optical coherence tomography angiography ( OCT-A )

OCT-A is a dye-free, noncontact modality to image the eye. It is a noninvasive imaging modality that provides three-dimensional images of the retina and choroidal microvasculature in vivo. It utilizes movement disparities on the OCT to identify vascular structures that exhibit sufficient blood flow characteristics. Images are high resolution and depth resolved. A variety of devices are commercially available, with others pending approval. One common principle for OCT-A devices is the Fourier domain OCT. There are two types: Spectral domain OCT ( SD-OCT ) and Swept source OCT ( SS-OCT )

Some clinical advantages of SS-OCT are:

  • Faster acquisition speed ( 100,000 A-scans per second or greater )
  • Wider scanning range : 12-mm to 16-mm scan length
  • Less sensitivity roll-off than SD-OCT: Possibly to image vitreous and choroid well simultaneously.
  • Longer wavelength : Better ability to penetrate choroid,lens opacity and vitreous debris.


However, OCT-A has its clinical shortcomings and is less useful for identification of retinal vasculitis

  • It doesn’t show leakage
  • Patients with poor fixation are difficult to image effectively.
  • Opaque media such as vitreous hemorrhage blocks OCT signal and decrease the quality of the angiography.
  • Although widefield OCT-A will allow for imaging of the vascular layers, likely out to the mid-periphery and vortex veins, ultra-wide field FA will still provide information about retinal capillary perfusion out to the ora serrata.


Some videos will be shown using a SS-OCT-A device available for research purposes only and FDA approved in United States for this reason.

Laboratory test

There are no specific tests for diagnosing IRVAN.

Differential diagnosis

At presentation, the physician must distinguish clinical elements of this interesting disease : arterial macroaneurysms , lipid exudation , retinal periphery capillary dropouts and neovascularization. [5]The syndrome’s striking ophthalmoscopic picture is not shared by any other disease.[9] However, four principal conditions may be diagnosed initially. The first is idiopathic retinal vasculitis[27], if the aneurysmal dilations are not noticed. Careful ophthalmoscopic and fluorescein angiographic examination should reveal any aneurysmal dilations, if present. The second is senile retinal arterial macroaneurysm. This acquired macroaneurysm is usually found in older patients with a history of high blood pressure and/or cardiovascular diseases[9][5]. It usually is single, mostly unilateral, located temporal to the optic nerve along the midsegment of an artery, and associated with hemorrhage. Although there may be capillary telangiectasis surrounding the macroaneurysm, there is no peripheral nonperfusion or signs of inflammation. Patients with IRVAN are otherwise healthy young people and arterial macroaneurysms are bilateral and multiple.The third element in the differential diagnosis is Coats´ disease[5]. Patients with Coats’ disease have a unilateral presentation with no signs of intraocular inflammation. The aneurysms of Coats’ disease usually involve more than one element of the vascular circuit and may involve the arteries, capillaries, and veins. The aneurysms in Coats’ disease do not involve arterial bifurcations and they are observed in the mid and far periphery usually surrounded by abundant circinate lipid exudation. Finally , peripheral telangiectasias are irregular in shape compared to aneurysms. The fourth condition is Eales´ disease.[9] Peripheral retina non-perfusion is almost always present with retinal neovascularization and sometimes arising from the optic disc. Nevertheless, it is not possible to observe typical fusiform or " tied-knot " arterial aneurysms from IRVAN syndrome.

Management

Currently , retinal laser photocoagulation and the use of intravitreal injections of anti-vascular endothelial grow factor antibodies ( anti-VEGF ) are considered within the first line of treatment. Interestingly, arterial macroaneurysms may regress or vanish after treatment or during follow-up.[28][29][30][31]

General treatment

  • Observation : Basha et al [32]have published a pediatric case with IRVAN , one eye treated and the fellow eye untreated. A long-term follow-up demonstrated that observation is a consideration in IRVAN syndrome if the vision remains good with hard exudation.[33][34]

Medical therapy

Corticosteroids

Patients affected with IRVAN have been treated with corticosteroids in an attempt to reduce any inflammatory worsening of their ophthalmoscopic appearance. Unfortunately, corticosteroids have not been particularly useful. Although corticosteroids undoubtedly decrease inflammation, much of the morbidity of IRVAN results from chronic secondary changes such as persistent leakage from the aneurysms and vitreous hemorrhage from the neovascularization.

  • Systemic use: Prednisone 1mg/Kg daily or intravenous[35]
  • Intravitreal injections: Triamcinolone Acetate and Dexamethasone implant to treat chronic macular edema[36]

Anti - VEGF intravitreal injections

Pegaptanib ( MACUGEN )[37] , Bevacizumab ( AVASTIN ) [38], Ranibizumab ( LUCENTIS )[39] and Aflibercept ( EYLEA ) have been used for treating IRVAN syndrome in patients with macular edema , retinal ischemia and neovascularization of the eye.

Immunosuppressive drugs

Cheema et al [40]showed improvement in two patients treated with infliximab, an anti-TNF. TNFα might be a causative factor in mediating inflammation and causing tissue destruction in IRVAN patients. Saatci et al used oral azathioprine as an adjuvant in a patient with IRVAN.[41]

Medical follow up

It is recommended to follow an IRVAN patient up no more than 12 weeks apart.[42]

Surgery

Thermal Focal Laser and Peripheral Retinal Photocoagulation

Focal laser treatment to the macroaneurysms may decrease the amount of lipid exudation, but carries the risk of causing focal occlusion of the retinal arteriole, thus its use is controversial[43]. Laser spots may be applied surrounding macroaneurysms areas but never directly. Laser-induced arteriolar occlusion has caused in some patients to lose substantial visual acuity[44].Panretinal photocoagulation to the peripheral areas of nonperfusion is performed in patients even before retinal / optic disc neovascularization appear. Several laser sessions may be required for each eye. The aim of this treatment is causing a regression of the new vessels. Some patients with substantial amounts of vitreous hemorrhage have required vitrectomy and laser endophotocoagulation to treat bleeding areas of retinal neovascularization. Although retinal and vitreous hemorrhages occur from typical senile retinal arterial macroaneurysms, bleeding from the aneurysmal dilations of IRVAN is not common.

Peripheral cryotherapy

Some authors have used this procedure, especially when opaque media is present so it is not possible to perform a scatter laser treatment.

Figure 10 : Color fundus photography. Vitreous hemorrhage and proliferative fibrovascular tissue . Chorioretinal scars due to peripheral laser treatment.

Pars plana Vitrectomy

Indications:

  • Vitreous Hemorrhage that persists more than 1-2 months.
  • Dense vitreous hemorrhage (intravitreal blood/clots do not allow to see optic nerve head and/or retina details.
  • Severe loss of vision secondary to vitreous hemorrhage which does not allow to treat a patient. (Figure 10)
  • Tractional retinal detachment, due to proliferative retinopathy, especially if center of retina ( macula ) is off. Severe cases may need lensectomy , core vitrectomy, separation of posterior hyaloid, peeling of epiretinal membranes and vitreous base for eliminating vitreoretinal traction and silicone oil for a long-term vitreous tamponade.

Surgical follow up

Figure 11 : Color fundus photography : Patient shown in Figures 4 and 5 , 34 years after treatment.

A regular follow up is needed for these patients and a long-term follow up is possible.[45] ( Figure 11 )

Complications

Anterior segment

Iris neovascularization , Neovascular Glaucoma[46] , blind eye , painful blind eye.

Figure 12 : Fluorescein angiography demonstrates capillary nonperfusion and retinal neovascularization

Posterior segment

Disc neovascularization , retinal neovascularization ( Figure 12 ) , vitreous hemorrhage, tractional retinal detachment , retinal artery occlusion.[47][48][49]

Prognosis

Variable. Visual prognosis of IRVAN may vary depending on the development of related complications[50].

Additional Resources

Organizations Supporting this Disease

  • American Foundation for the Blind : 2 Penn Plaza, Suite 1102 , New York, NY 10121. Toll-free: 800-232-5463 .Telephone: 212-502-7600 , Fax: 888-545-8331 E-mail: afbinfo@afb.net , Website: http://www.afb.org/

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