Idiopathic Macular Telangiectasia Type 2 and its Relationship with Macular Pigment Optical Density

Idiopathic Macular Telangiectasia Type 2 and its Relationship with Macular Pigment Optical Density Christopher Putnam* University of Missouri-St Louis College of Optometry, St Louis, Missouri, USA *Address for Correspondence: Christopher Putnam, University of Missouri-St Louis College of Optometry, St Louis, Missouri, One University Blvd, 417 Marillac Hall St Louis, MO 63121, USA, Tel: +210-360-0334; E-mail:


INTRODUCTION
Idiopathic Macular Telangiectasia type 2 (IMT2) is an acquired, bilateral maculopathy associated with a spectrum of clinical presentations related to inner retinal telangiectatic vascular anomalies [1]. As a result of this wide-ranging clinical presentation, cases of IMT2 oft en are underdiagnosed or misdiagnosed. Current retinal imaging modalities such as Spectral-Domain Optical Coherence Tomography (SD-OCT), multi-spectral fundus photography and Fluorescein Angiography (FA) are increasingly valuable to the understanding of the clinical pathology [2,3]. More recently, the emerging noninvasive technology known as Optical Coherence Tomography Angiography (OCTA) was shown to be particularly useful in the assessment and management of IMT2.
In 1982, Gass and Owakawa re-examined the classifi cation of idiopathic macular telangiectasia and coining an alternate description termed idiopathic juxtafoveal retinal telangiectasis [4]. In 1993, Gass and Blodi performed a meta-analysis examining 140 such cases over a 28-year period and refi ned the clinical spectrum of these entities with subgroups and stages. Th e resulting classifi cation structure resulted in 3 distinctive groups each with a presumed, independent etiology on the basis of fundoscopic fi ndings, fl uorescein angiographic features and clinical severity [5]. Furthermore, the advent of improved resolution, high-speed retinal angiography integrated with Optical Coherence Tomography (OCT) have provided an enhanced clinical understanding of the nature of the vascular abnormalities and the associated macular sequella. To some degree, these improved imaging techniques have led to fi ndings paralleling histopathological observations described in the ophthalmic literature. Below is a review of the 3 subgroups.

Type 1: Aneurysmal telangiectasia
Clinical appearances of aneurysmal telangiectasia reported in the literature vary. However, the consistent retinal feature included microangiopathy with multiple capillary aneurysms both arterial and venous. Th ese vascular abnormalities were evident in the superfi cial and deep retinal capillary circulations although larger aneuritic changes were confi ned to the superfi cial circulation. In addition, some patients had isolated non-perfusion or capillary ischemia with lipid deposition. Th e lipid deposition was more commonly recorded in association with numerous minor capillary abnormalities or focal, large aneurysms. Pathological fi ndings also varied in location with areas of involvement not only in the juxtafoveolar and paramacular regions but also in the peripheral fundus. Some larger macroaneurysms were associated with hemorrhage. Th e central macular vascular abnormalities were associated with edema or cystic change in the retina identifi ed with angiography and confi rmed with OCT imaging. Preretinal neovascularization or sub-retinal neovacularization is uncommon. Related systemic diseases are not commonly associated with aneurysmal telangiectasia. More commonly, aneurysmal telangiectasia is a unilateral, exudative condition associated with micro and macroaneurysms in the absence of pigmentary changes, crystalline deposits or neovascularization. Vascular macular leakage is generally associated with intra-retinal cystic changes that are welldocumented on OCT imaging.

Type 2: Perifoveal telangiectasia
Perifoveal telangiectasia tend to follow a bilateral presentation although there is a degree of asymmetry with regard to severity. Literature reports of concurrent diabetes mellitus and hypertension show an incidence rate of approximately 18.5% reported in the general population of the same age [6]. In contrast to the aneurysmal telangiectasia cases, the perifoveal telangiectasia cases are typically well-defi ned by their clinical and imaging manifestations. Early clinical changes consisted of a mild loss of transparency of the retina, usually in the temporal juxtafoveolar area but surrounding the fovea in more advanced cases. In these cases, the telangiectatic vessels were absent or barely evident clinically while retinal thickening was readily evident with OCT imaging. In patients with early clinical manifestations of perifoveal telangiectasia, fl uorescein angiography shows mild, diff use intraretinal leakage or staining while patients with more advanced stages of the disease had a prominent dilation of capillaries. In patients with more prominent telangiectasis, fl uorescein leakage in the superfi cial circulation can also cascade over the deep

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ISSN: 2640-5660 capillary leakage. Additionally, superfi cial retinal circulations may reveal segmental or sectoral dilation overlying the dilated deep retinal telangiectatic vessels revealing capillary aneurysmal changes without lipid ischemia or preretinal neovascularization. Cystic spaces in the perifoveal area are uncommon. OCT imaging can show preservation of the inner limiting membrane that constituted the anterior aspect of the cystic changes. More advanced cases reveal deeper inner lamellar cysts with further loss of the outer retina and a correlating visual decline in the absence of prominent aneurysms, hemorrhage or lipid accumulation. Vitreoretinal interface crystalline deposits appeared at various stages of the disease as an inconsistent but characteristic fi nding which also included subretinal plaques of pigmentation and dilated right-angle retinal vessels. In some cases, the dilated vessels show retinal-retinal anastomosis within the retina or extending to communicate with new vessels beneath the retina or SRN. Th e development of SRN from deep retinal circulation may lead to neurosensory detachment, subretinal hemorrhage, fi brosis, and visual decline in advanced stages of the disease due to cystic changes in the retina. Perifoveal telangiectasia is a bilateral perifoveal disease that is not commonly associated with aneurysms or cystoid leakage. A non-proliferative stage is identifi ed by exudative telangiectasia and foveal atrophy and the proliferative stage is characterized by SRM and fi brosis.

Type 3: Occlusive telangiectasia
Occlusive telangiectasia is highly uncommon classifi cation of IMT2 characterized by ischemic foveal disease with fl anking capillary dilation in response to retinal non-perfusion. In previous reviews, occlusive telangiectasia has been classifi ed as perifoveal capillary non-perfusion disease manifesting as a result of systemic or cerebral familial syndrome.
A recent published study of perifoveal Müller cell depletion in IMT2 revealed an absence of macular pigment within the macula along with abnormally dilated macular capillaries were spatially correlated with regions of fl uorescein leakage [7]. Th ese telangiectatic vessels displayed additional pathologic features and no reactive Müller cells, a key factor in MP deposition, were identifi ed. Th e areas defi cient in Muller cells corresponded with regions of negligible macular pigment supporting the hypothesis that Muller glial cells are a critical component of IMT2. Retinal capillary telangiectasia is commonly the result of antecedent retinal vascular infl ammatory or occlusive disease. In the macular region, diabetic retinopathy, hypertension, venous occlusion, infl ammatory diseases and blood dyscrasias are the typical causative factors [8]. However, alternative forms of telangiectasia can develop in the macula and perifoveolar areas without a defi nitive etiology.
In a peer-reviewed comparison of IMT imaging techniques, en face SD-OCT C-scans and conventional B-scans both provided repeatable identifi cation capabilities for a number of retinal fi ndings. Th ese retinal fi ndings included inner crystalline deposits (15% of subjects), retinal capillary anomalies (100% of subjects), intra-retinal cysts (80% of subjects), hyper-refl ective spots in the outer nuclear layer (100% of subjects) and external limiting membrane (80% of subjects), hyperplastic pigment plaques (30% of subjects), intraretinal neovascularization (20% of subjects), photoreceptor loss (100% of subjects), and choroidal cavitations (30% of subjects). However, en face OCT C-scans provided more information than B-scans on intra-retinal neovascularization, photoreceptor loss and choroidal cavitations in addition to better visualization of the retinal vessels and telangiectasia than fl uorescein angiography [9]. En face OCT showed promise as a noninvasive, reproducible technique that may lead to enhanced assessment and follow up for IMT2 associated retinal and choroidal changes. Recently, SD-OCTA has emerged in the literature as a reliable, reproducible, non-invasive method to accurately image early retinal changes associated with IMT2 [10]. Specifi cally, the OCTA capabilities to precisely record vascular abnormalities through the use of coherent motion imaging has provided a useful toll in detection of the choroidal neovascular changes associated profound vision loss second to IMT2 [11,12].
In a separate study, patients with retinal fi ndings characteristic of IMT2 were interviewed regarding visual symptoms and corresponding age of onset in a large cross-sectional patient demographic. Th e most commonly reported clinical symptom was impaired reading ability (79%) followed by metamorphopsia (12%). Th e most frequently reported age of diagnosis was the seventh decade (76%) and 58% of the patients were symptomatic before the age of 60 years. Th e median delay between fi rst reported symptoms and IMT2 diagnosis was ~7 years. Ten years aft er the fi rst reported clinical symptoms, distance visual acuity of the better eye was better than 20/25 in 35% and ≤ 20/50 in only 17%. Increased awareness of IMT2 symptoms in conjunction with improved imaging retinal imaging of characteristic morphologic changes will likely lead to more timely, accurate diagnosis.
Macular Pigment (MP) is consists of of two principal elements: Lutein (L) and Zeaxanthin (Z) [13,14]. Within the human retina, MP is a membrane-bound compound predominantly found within the photoreceptor axons (outer plexiform layer and Henle layer within macular region) and the inner plexiform layer [15]. MP has also been documented at the level of the Retinal Pigmented Epithelium (RPE) [5] and photoreceptor outer segments [16]. MP is measured highest in the central retina peaking at the foveola and decreasing to optically undetectable levels at 8° of eccentricity [17]. Lutein is found at higher values within the peripheral retinal tissue as the ratio of L: Z inverts from 1:2.4 at the foveola to 1.8:1 in the parafovea to 2.7:1 in the peripheral retina [18,19]. Th e inversion of the L: Z ratio with eccentricity matches the corresponding rod:cone ratio demonstrated by Osterberg [20] and Curcio et al. [21]. Suggestive of structure-specifi c MP accumulation. Bone et al. posited that MP spatial distribution suggests a specifi c role in photoreceptor function [22]. Published work has posited three primary roles for MP: protection, neural effi ciency and optical enhancement. In support of the protection role, MP has well-established potent antioxidant properties and acts as an effi cient optical fi lter of short wavelength, high energy visible light. A protective association with age-related macular degeneration was postulated in the Eye disease case-control study [23] and explored further in the AREDS II study [24]. Current macular degeneration models implicate a combination of cumulative damage from Reactive Oxygen Intermediates (ROIs) created through metabolic processes catalyzed by high energy, short wavelength light and chronic infl ammation [25]. Existing case reports involving IMT2 demonstrate a reduction in MP within the central 4° of eccentricity relative to demographic-matched controls [26] and preservation of MP at 5-7° of eccentricity [27]. Th e focal, centralized reduction of MP in patients with IMT2 represents a novel phenotypic retinal characteristic and lends evidence of compromised traffi cking or deposition of MP as a feature of the disease process. Patients also showed a disproportionately greater reduction in zeaxanthin relative to lutein supporting the hypothesis that IMT2 may serve as an exemplar for MP deposition mechanisms within the

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retina. Zeimer et al. identifi ed associations between changes in stages of macular telangiectasia and restrictions in visual function support the use of MP distribution classifi cation as a severity scale for IMT2 [28]. Recent confocal refl ectance studies have confi rmed the earlier identifi ed abnormalities in MP deposition and Müller cells pathology contributing to the underlying pathophysiology of IMT2 [29].

CASE REPORT
A 56 year old Hispanic female presented to the public health optometric service reporting bilateral blurred vision that began approximately four years ago and has been progressively worsening over time. She denied history of trauma, surgery, pain, diplopia or loss of visual fi eld in either eye. Her family medical and ocular history was unremarkable and she reported no current medical or ocular conditions. Her last medical and ophthalmic exam were unknown and she reported no known allergies or drug sensitivities. Entering distance uncorrected visual acuities were 20/150 in the right eye and 20/200 in the left eye with no improvement in pinhole acuities. Entrance testing showed equal, symmetric pupils with 3+ reaction to light in both eyes and full range of motion without restriction of both eyes during extraocular muscle motility testing. Confrontational visual fi eld testing was full to fi nger counting with no evidence of peripheral fi eld loss in either eye. Manifest refraction yielded a +1.50DS in the right eye and +2.50DS in the left eye with a best corrected visual acuity of 20/100 OD and 20/150 OS. Goldmann applanation tonometry was performed resulting in readings of 20mmHg in both the right and left eyes. Anterior segment slit exam fi ndings showed unremarkable adnexa, lids and lashes with normal tearfi lm fi ndings in both eyes. Th e conjunctiva was recorded as 1+ symmetrical pinguecula nasal and temporal with unremarkable corneal fi ndings in both eyes. Th e anterior chamber was deep and quiet with Van Herrick measurements of 3+ nasally and temporally in both eyes and the iris was fl at with no signs of atrophy or neovascularization in either eye. Th e lens showed early nuclear sclerotic changes recorded as 2+ nuclear sclerosis.
One drop of tropicamide 1% and phenylephrine 2.5% were instilled to each eye to allow a dilated retinal examination. Th e vitreous of each eye was grossly unremarkable with 1+ syneresis and no evidence of retinal traction in either eye. Th e optic nerve appeared well-perfused with distinct margins, 1+ peripapillary atrophy of the temporal disc margin and unremarkable neuroretinal rim with unremarkable nerve fi ber fi ndings in each eye. Th e cup-to-disc ratio was recorded as 0.50/0.50 right eye and 0.35/0.35 OS. Macular evaluation revealed a scattered drusen appearance with prominent pigmentary changes and atrophy in both eyes with subtle fi brotic changes in the left eye. Vessels appeared unremarkable in both eyes and peripheral retinal fi ndings were unremarkable and recorded as fl at, attached with negative holes, tears in both eyes. A baseline retinal photo of both eyes was taken (Figure 1). Due to the suspicious appearance of the fundus evaluation, the patient was also imaged using high-resolution Optical Coherence Tomography (SD-OCT) and SD-OCT angiography (SD-OCTA) in both eyes. Th e SD-OCT of the right eye indicated substantial choroidal and RPE disruption with sensory-retinal thinning and intra-retinal cystic formation ( Figure  2) while the SD-OCT of the left eye indicated substantial choroidal disruption and sensory-retinal thinning similar to the right eye. However, foveal disruption nasal at the level of Bruch's membrane was highly suggestive of neovascular changes in the left eye ( Figure  3). SD-OCTA analysis of the right eye confi rmed the IMT2 features showing an increased foveal avascular zone with distinct sensory retinal thinning ( Figure 4) and SD-OCTA analysis of the left eye confi rms the macular telangiectasia features showing sensory retinal thinning with the well-demarcated disruption of Bruch's membrane consistent with neovascular changes ( Figure 5). Th e OCTA Custom analysis of the left eye clearly indicates neovascular changes at the level of Bruch's membrane ( Figure 6).
Th e patient was diagnosed with chorioretinal macular scarring in both eyes secondary to macular telangiectasia type II with suspicion of choroidal neovascularization OS. Th e patient was started on a high bioavailability 20 milligram lutein / 5 milligram zeaxanthin oral supplement to provide potential mitigation of retinal infl ammation and lipid membrane peroxidation. Additionally, the patient was referred to a retinal specialist for confi rmation of the macular fi ndings

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and initiation of anti-VEGF treatment for the neovascular changes OS.
IMTII is a highly complex conditions with a diverse of accompanying clinical presentations ranging from Coat's disease [30] to diabetic retinopathy [31] to age-related macular degeneration [32] to presumed unilateral cases [33]. Common to this diverse set of clinical conditions is the relationship with neovascular membrane development and an anomalous retinal vascular complex [34,35]. An emerging need for a non-invasive mitigation to progressive infl ammatory damage with concurrent stabilization to retinal cytoarchitecture is crucial. MP has demonstrated the ability to reduce singlet oxygen [36], moderate ROIs [37], inhibit cell membrane perioxidation [38] and reduce lipofuscin formation [39]. Th e presence of MP within the photoreceptor outer segments and retinal pigmented epithelium off ers further support of the ROI and singlet oxygen reducing properties of MP [40,41]. Work by Beatty et al. confi rmed the inhibition of light-induced oxidative damage within retinal tissue [42]. Th eir study showed that metabolic oxidative products including singlet oxygen, free peroxyl radicals, and ROIs are attenuated in the presence of MP. Th e free radical scavenging abilities of MP attenuates the progression of damage to lipophilic structures including cellular membranes and axonal structures [43]. MP shows a high affi nity to lipid containing structures and, along with their effi ciency in peroxyl radical mitigation, may serve a critical role in cell membrane protection and oxidative damage [44]. Central to the benefi ts of increased MPOD is the de novo nature of MP and the welldocumented response to oral supplementation [45,46]. However, study of MP distribution response to oral supplementation of L and Z in patients with IMT2, have shown MP increases only in locations were MP was present at baseline [47]. According to Eposti et al. a majority of IMT2 patients demonstrate a normal total MP value across the central 21° with highly abnormal paracentral distribution within the central 16° of foveal eccentricity [48]. Th is fi nding further highlights the hypothesis that impaired L and Z transport and deposition underlies the pathogenesis of IMT2. Further research into MP deposition mechanisms in IMT2 patients is warranted.