Downloaded from http://bjo.bmj.com/ on August 21, 2017 - Published by group.bmj.com Clinical science Natural history and effect of therapeutic interventions on subretinal fluid causing foveal detachment in macular telangiectasia type 2 Hemal Mehta,1,2 Simone Müller,3 Catherine A Egan,2 Simona Degli Esposti,2 Adnan Tufail,2 Dawn A Sim,2 Frank G Holz,3 Andrew C Browning,4 Winfried M Amoaku,4 Peter Charbel Issa,3 Mark C Gillies1

►► Additional material is ABSTRACT intervention on this unusual MacTel phenotype are published online only. To view Aim To report the natural history of subretinal fluid described in this larger case series. please visit the journal online (http://​dx.​doi.​org/​10.​1136/​ (SRF) causing foveal detachment in macular bjophthalmol-​2016-​309237). telangiectasia type 2 (MacTel) and our experience of METHODS therapeutic intervention with intravitreal steroids or Three of the MacTel study’s largest registries 1Macular Research Group, Save antivascular endothelial growth factor inhibitor (anti- (n=427 participants), at the Save Sight Institute in Sight Institute, University of VEGF) agents in some cases. Sydney, Sydney, Australia Sydney, Moorfields Eye Hospital in London and 2Medical Department, Methods Retrospective case series. Three of the University of Bonn in Germany, were searched to ’ Moorfields Eye Hospital NHS MacTel study s largest registries were searched to identify identify study eyes with foveal detachment. Trust, London, UK eyes with foveal detachment. 3 This was a retrospective case series but the inclu- Department of , Results We identified 7 eyes from 6 exclusively female University of Bonn, Bonn, sion and exclusion criteria and outcome measures Germany patients. The prevalence of foveal detachment was low, were prospectively defined. The MacTel study eligi- 4Division of Ophthalmology and present in 1.4% of the assessed MacTel population. Age bility criteria required the participants to be at least Visual Sciences, University of at presentation ranged from 50 to 66 years. Follow-up 18 years of age with a diagnosis of MacTel type 2 Nottingham, Queen’s Medical ranged from 2 to 8 years. There was late-phase leakage made by a retinal specialist at each clinical centre.8 Centre, UK fl on uorescein angiography from what was presumed to After enrolment, the diagnosis was confirmed by be ectatic capillaries. The SRF fluctuated without a rapid Correspondence to the MacTel Reading Centre, which assessed compli- Dr Hemal Mehta, Macular decline in visual acuity in cases that were not treated. ance with the eligibility criteria from colour fundus Research Group, Save Sight When they were, intravitreal anti-VEGF and steroid photographs, fluorescein angiograms, OCT and/or Institute, 8 Macquarie Street, in general reduced SRF, at least temporarily, but autofluorescence imaging.8 Indocyanine green and Sydney, 2000, New South Wales, did not halt the gradual long-term decrease in visual Australia; ​HM@​cantab.​net OCT angiography imaging were included when acuity. In one case, optical coherence tomography performed. Eyes with MacTel were searched to fi Received 22 June 2016 angiography showed signi cant reduction in the extent identify those with a foveal detachment that led to Revised 17 September 2016 of the predominantly deep intraretinal vascular complex alteration of the vitreoretinal interface. The inner Accepted 9 October 2016 1 month after anti-VEGF therapy. retinal change was stipulated to ensure that eyes Published Online First Discussion and conclusions As the natural history 28 October 2016 only with outer retinal degenerative cavitation were of this unusual MacTel phenotype is not characterised by not included. Eyes with obvious vitelliform lesions rapid visual decline, intervention with intravitreal anti- were excluded. We aimed to identify common VEGF or steroid therapy may not be necessary. demographic and imaging features that would better characterise this phenomenon, estimate its prevalence and record best-corrected visual acuity INTRODUCTION (BCVA) outcomes in cases that were either observed Macular telangiectasia type 2 (MacTel) is an or received treatment. acquired bilateral neurodegenerative disease.1 Its Data collection and analysis adhered to the prevalence was reported at 0.1% in persons aged tenets set forth in the Declaration of Helsinki. 43–86 years in the Beaver Dam Eye Study based on Local Institutional Review Board approval was grading from stereoscopic fundus photographs, granted from the human research ethics committees although the true incidence using more sensitive of South Eastern Sydney Local Health District, fi diagnostic methods may be higher.2 Characteristic Moor elds Eye Hospital and the Medical Faculty signs include reduced retinal transparency, crystal- of the Rheinische Friedrich-Wilhelms at the line deposits, ectatic capillaries, blunted venules, University of Bonn. abnormal macular pigment distribution, foveal and, sometimes, neovascular complexes.134 RESULTS Gaudric et al5 identified subretinal fluid (SRF) Prevalence and demographics causing a foveal detachment in their early report on From 427 individuals in three international MacTel the optical coherence tomography (OCT) features registries, we identified 7 eyes from 6 patients who of MacTel. There are also case reports with short- had SRF causing a foveal detachment. The preva- To cite: Mehta H, Müller S, term follow-up of foveal detachments associated lence of this phenomenon was low, present in 1.4% Egan CA, et al. with MacTel, which resolved after intravitreal of the assessed MacTel population. All identified Br J Ophthalmol triamcinolone or .67The natural patients were female. Age at presentation ranged 2017;101:955–959. history and long-term effects of therapeutic from 50 to 66 years. The follow-up period ranged

Mehta H, et al. Br J Ophthalmol 2017;101:955–959. doi:10.1136/bjophthalmol-2016-309237 955 Downloaded from http://bjo.bmj.com/ on August 21, 2017 - Published by group.bmj.com Clinical science

from 2 to 8 years. Foveal detachment tended to develop in detachment. Her BCVA at presentation was 6/60 right eye and more advanced cases of MacTel, with all cases stage 3 and 6/24 left eye. Although she admitted to bilateral blurred vision, beyond using the Gass and Blodi classification.3 All patients her main complaint was long-standing right . were Caucasian, although this may represent ascertainment bias. On clinical examination, there was typical bilateral loss of Participants’ demographic features are summarised in table 1. macular transparency, temporal macular right angled vessels and telangiectasia. There were no macular haemorrhages or exu- Natural history dates. An OCT scan of the right eye demonstrated a foveal In case 1 (figure 1), a Caucasian woman in her 50s was diagnosed detachment while the left eye revealed typical intraretinal cavita- with MacTel in 2007. At that point, her BCVAwas 6/15 right eye tion. revealed intense late parafoveolar and 6/12 left eye. Six years later, although she did not report new leak in the right eye, but indocyanine green angiography at the visual symptoms, OCT showed presence of a new foveal detach- same time point did no show choroidal leakage. After discussing ment in the left eye. The patient was observed closely and the the risks and benefits of treatment, the patient received 4 mg of foveal detachment gradually resolved over the next 3 months intravitreal triamcinolone acetonide (IVTA) (Kenalog, without treatment. The BCVAwas 6/15 left eye 2 years later. Bristol-Myers Squibb) to the right eye. The patient reported a In case 2 (figure 2), at initial presentation, the patient resolution of metamorphopsia within 7 days and there was reso- reported a central in both eyes and reading difficulties lution of the foveal detachment on OCT and an improvement in for a period of 6 months. Metamorphopsia was denied. OCT BCVA to 6/36 by week 4. Although the foveal detachment showed SRF with a foveal detachment in both eyes as well as started to recur by week 39, the patient did not report a return temporal paracentral disruption of the outer retinal layers. A of metamorphopsia until week 52 (BCVA 6/36). The foveal single hyporeflective cavity located in the inner retinal layers detachment was still present 15 months after the IVTA treat- was visible in the right eye. Fluorescein angiography showed tel- ment and the BCVA had dropped to 6/48 due to cataract. There angiectatic vessels with late leakage. Findings were symmetric was no significant intraocular pressure rise. Subsequent cataract on both eyes. Prompt intravitreal antivascular endothelial improved the BCVA back to 6/36. At 21 months growth factor inhibitor (VEGF) therapy was planned for both post-IVTA injection, the foveal detachment had spontaneously eyes. However, 7 weeks passed without intervention due to dif- resolved with associated atrophy of the macular outer retinal ficulties accessing funding. After this period of observation, layers on OCT imaging, with the BCVA having declined to OCT revealed a complete regression of SRF in both eyes 6/60. The patient was followed-up for a further 6 years without any therapeutic intervention. BCVA was stable in the without recurrence of the foveal detachment. right eye (6/12) and had even improved in the left eye (6/9.5) with no subjective change in their visual function. In case 3 (figure 3), BCVA was 6/18 left eye at presentation. Intervention with intravitreal anti-VEGF She denied metamorphopsia throughout. Macular OCT imaging In case 5 (see online supplementary figure S2), an incidental showed foveal detachment in the left eye in February 2013, finding of a new intraretinal haemorrhage in the left macula which persisted for 1 year and after 2 years had largely resolved was noted but fluorescein angiography was unchanged com- without treatment. The SRF recurred the following year with pared with a study performed 2 years earlier so the asymptom- BCVA recorded at 6/24. The subsequent effect of treatment atic patient was observed closely. BCVA was 6/15 right eye and with intravitreal anti-VEGF in case 3 is described below. 6/9 left eye. By April 2012, after the intraretinal haemorrhage The foveal detachments were associated with a gradual had resolved, the patient remained asymptomatic and vision decline in visual acuity in these untreated eyes. The SRF fluctu- was stable but a left foveal detachment developed. After ated in some cases without leading to a rapid decline in visual 3 months, there was a substantial increase in SRF on OCT and acuity. There was temporal parafoveolar intense late-phase BCVA was reduced to 6/12 left eye, although the patient did leakage on fluorescein angiography, which usually obscured the not report decreased vision. After discussing risks and benefits view of the subretinal space. There was no evidence of active of intravitreal bevacizumab therapy, the patient agreed to a choroidal leakage on indocyanine green angiography in case 3 course of treatment. One month after left eye intravitreal beva- or 4 (described below). cizumab, there was no improvement in BCVA or reduction in SRF. After the second intravitreal bevacizumab, the amount of Intervention with intravitreal triamcinolone SRF in her left eye decreased significantly, with subjective and Case 4 (see online supplementary figure S1) had received right objective (6/7.5) improvement in BCVA. After the third intravi- macular argon laser with no benefit 2 years prior to diagnosis treal bevacizumab, the treatment was given on a pro ra nata with MacTel in 2006 for an idiopathic serous macular basis when there was evidence of recurrent SRF. The interval

Table 1 Summary of demographic features of identified cases Presenting age Presenting Gass and VA at VA at last Follow-up Case (decade) Sex Race Blodi disease stage presentation follow-up (years)

1 OS 50s Female Caucasian 3 6/12 6/15 8 2OD 50s Female Caucasian 3 6/12 6/12 2 OS 4 6/12 6/9.5 3 OS 50s Female Caucasian 3 6/18 6/24 7 4 OD 50s Female Caucasian 3 6/60 6/60 8 5 OS 60s Female Caucasian 3 6/9 6/15 6 6 OS 50s Female Caucasian 3 6/6 6/15 4 OD, right eye; OS, left eye.

956 Mehta H, et al. Br J Ophthalmol 2017;101:955–959. doi:10.1136/bjophthalmol-2016-309237 Downloaded from http://bjo.bmj.com/ on August 21, 2017 - Published by group.bmj.com Clinical science

Figure 1 Colour (A) of the left eye of case 1 showed loss of retinal transparency and blunted, right-angled vessels (white arrows). Early (B), mid-phase (C) and late-phase (D) fluorescein angiograms showed predominantly temporal parafoveolar late intense leakage. The macular optical coherence tomography (OCT) images showed presence of temporal outer retinal disruption (E) and then subsequent development of subretinal fluid (SRF) disturbing the inner retinal contour (F). The patient was observed closely and the SRF gradually resolved over the next 3 months without treatment (G).

Figure 2 Colour fundus photography (A) of the right eye of case 2 identified a pronounced loss of retinal transparency, mildly ectatic capillaries and right-angled venules. Early (B), mid-phase (C) and late-phase (D) fluorescein angiography revealed temporal parafoveolar intense late leakage that was symmetrical to the patient’s left eye. Optical coherence tomography (OCT) images showed subfoveal subretinal fluid (SRF) and disruption of the outer retinal layers (E). Without any therapeutic intervention, 7 weeks later, the SRF had completely resolved and the neurosensory retina had reattached. (F) The disruption of the outer retinal layers persisted only in the temporal paracentral fovea (F, arrows), but spared the foveola itself. Colour fundus photography of the left eye of case 2 (G) revealed retinal greying and small retinal pigment plaques located temporal to the foveola (G, arrow). Fluorescein angiography in early phase (H), mid-phase and late phase (I, J) showed intense late leakage that was symmetric to the patient’s right eye. On OCT, a foveal detachment with SRF and paracentral disruption of the outer retinal layers was observed (K). Without any treatment, 7 weeks later the SRF had resolved completely and the neurosensory retina reattached. Upon resolution, best-corrected visual acuity (BCVA) improved and no resulting atrophy could be observed in the area where the neurosensory retina was previously detached (L).

between intravitreal injections was between 8 and 16 weeks. In case 6 (figure 4), the left BCVA had deteriorated from 6/6 BCVA was 6/30 right eye and 6/15 left eye after 2 years of to 6/12, while the right remained at 6/6. A left eye foveal treatment. detachment was present on OCT. No intraretinal haemorrhage

Mehta H, et al. Br J Ophthalmol 2017;101:955–959. doi:10.1136/bjophthalmol-2016-309237 957 Downloaded from http://bjo.bmj.com/ on August 21, 2017 - Published by group.bmj.com Clinical science

Figure 3 The left eye late-phase (A) fundus fluorescein angiogram of case 3 showed telangiectasis of the temporal parafoveolar vessels with intense late hyperfluorescence obscuring the view to the subretinal space. Contemporaneous indocyanine green angiograms at 1 min (B) and 20 min (C) did not show evidence of choroidal leakage. Macular optical coherence tomography (OCT) imaging showed foveal detachment in February 2013 (D), which persisted for 1 year (E) and had largely resolved without treatment after 2 years (F). The subretinal fluid (SRF) recurred the following year (G). With intravitreal bevacizumab therapy, the SRF cleared and OCT angiography showed a significant reduction in the extent of the predominantly deep retinal vascular complex 1 month after therapy (H) without improvement in visual acuity.

Figure 4 There was no evidence of intraretinal haemorrhage in case 6 (A). Again there was intense late temporal parafoveolar hyperfluorescence on fluorescein angiography obscuring the view to the subretinal space (B–D). The subretinal fluid (SRF) responded to four intravitreal (IVR) injections given every month (E and F). In August 2012, the left macula was dry with best-corrected visual acuity (BCVA) stable at 6/12. No further treatment was given until October 2013, when the left eye BCVA deteriorated to 6/15 with recurrence of SRF on optical coherence tomography (OCT). Macular OCT imaging showed that the SRF responded to resumption of IVR therapy (G and H).

was seen. Again there was temporal parafoveolar late hyperfluor- bevacizumab therapy and OCT angiography showed a significant escence on fluorescein angiography obscuring the view to the reduction in the predominantly deep retinal vascular complex subretinal space. The SRF responded to four intravitreal ranibi- 1 month after therapy. The left eye BCVA remained unchanged zumab injections given every month. In August 2012, the left at 6/24 following intravitreal bevacizumab therapy. macula was dry with BCVA stable at 6/12. No further treatment was given until 14 months later, when the left eye BCVA dete- DISCUSSION riorated to 6/15 with accumulation of SRF on OCT again. This case series expands upon the early report on the OCT fea- Macular OCT imaging showed that the SRF responded to tures of MacTel by Gaudric et al,5 where they identified a foveal resumption of intravitreal ranibizumab therapy. After 6 months, detachment in two study eyes. As the surface contour of the BCVA was 6/15 left eye with no SRF but disruption of the sub- fovea was altered in all included cases, degenerative outer foveal ellipsoid layer and external limiting membrane consistent retinal cavitation does not explain the foveal detachments with foveal atrophy. described here.5 Similar to central serous chorioretinopathy, the Treatment was offered in case 3 after recurrence of the foveal subfoveal pooling of SRF in these cases did not lead to a rapid detachment in the left eye. The SRF cleared with intravitreal decline in visual acuity.9 There was a gradual visual decline in all

958 Mehta H, et al. Br J Ophthalmol 2017;101:955–959. doi:10.1136/bjophthalmol-2016-309237 Downloaded from http://bjo.bmj.com/ on August 21, 2017 - Published by group.bmj.com Clinical science cases over the course of several years with intermittent or no Intravitreal anti-VEGF or steroid therapy may not be required as intravitreal pharmacotherapy, probably due to the progressive the natural history without treatment is good. neuronal loss and foveal atrophy usually associated with MacTel.1 Correction notice This article has been corrected since it was published Online First. The bottom of Figure 2 was missing from the original article and is now There are case reports of foveal detachments associated with present. MacTel, which resolved after intravitreal triamcinolone or beva- 67 fi Contributors Study concept and design: MCG. Acquisition, analysis or cizumab. In our cases with signi cantly longer follow-up, the interpretation of data: all authors. Drafting of the manuscript: HM. Critical revision SRF appeared to respond to intravitreal steroid or anti-VEGF of the manuscript for important intellectual content: all authors. Obtained funding: treatment, suggesting that the origin of the SRF is vasogenic. MCG, CAE and FGH. Study supervision: MCG, CAE and PCI. The reduction in SRF was not always associated with a signifi- Funding Supported by the Lowy Medical Research Institute (The Macular cant improvement in visual acuity. Intravitreal steroid therapy Telangiectasia Project, www.mactelresearch.com). 6 has risks of cataract and glaucoma. Poor long-term outcomes Competing interests None declared. with anti-VEGF therapy in non-proliferative MacTel have been Ethics approval Local Institutional Review Board approval was granted from the 10 reported. Therefore, intravitreal pharmacotherapy may not human research ethics committees of South Eastern Sydney Local Health District, always be required as the natural history without treatment is Moorfields Eye Hospital and the Medical Faculty of Rheinische Friedrich-Wilhelms at good. This study is limited by its retrospective nature and by the University of Bonn. treatment not being applied in a standardised manner. Provenance and peer review Not commissioned; externally peer reviewed. The source of the vascular complex in the MacTel phenotype described here that is presumably contributing to subfoveal fluid accumulation is likely from ectatic capillaries of the deep retina REFERENCES 1 Charbel Issa P, Gillies MC, Chew EY, et al. Macular telangiectasia type 2. that characterises MacTel rather than choroidal neovascularisa- Prog Retin Eye Res 2013;34:49–77. tion. OCT angiography identified a reduction in the extent of 2 Klein R, Blodi BA, Meuer SM, et al. The prevalence of macular telangiectasia type 2 the predominantly deep retinal vascular complex 1 month after in the Beaver Dam eye study. Am J Ophthalmol 2010;150:55–62.e2. intravitreal bevacizumab therapy in case 3. Spectral-domain 3 Gass JD, Blodi BA. Idiopathic juxtafoveolar retinal telangiectasis. Update of ’ classification and follow-up study. Ophthalmology 1993;100:1536–46. OCT imaging did not identify breaks in Bruch s membrane and 4 Gillies MC, Mehta H, Bird AC. Macular telangiectasia type 2 without clinically indocyanine green angiography did not show evidence of active detectable vasculopathy. JAMA Ophthalmol 2015;133:951–4. choroidal leakage in case 3 or 4. Also, there is a previous report 5 Gaudric A, Ducos de Lahitte G, Cohen SY, et al. Optical coherence tomography in of non-response of SRF in MacTel to photodynamic therapy.11 group 2A idiopathic juxtafoveolar retinal telangiectasis. Arch Ophthalmol – The above findings do not support leakage from the choroid as 2006;124:1410 19. 6 Maguluri S, Recchia CC, Recchia FM. Neurosensory macular detachment in group seen in central serous chorioretinopathy. However, the current 2a juxtafoveolar telangiectasis and resolution following intravitreal triamcinolone. generation of en face OCT angiography devices have limited Retin Cases Brief Rep 2007;1:20–1. depth resolution and are susceptible to projection artefacts; 7 Lira RP, Silva VB, Cavalcanti TM, et al. Intravitreous ranibizumab as treatment for therefore, the possibility of chorioretinal anastomoses as has macular telangiectasia type 2. Arch Ophthalmol 2010;128:1075–8. 8 Clemons TE, Gillies MC, Chew EY, et al. Baseline characteristics of participants in been described in other MacTel phenotypes cannot be 12 13 the natural history study of macular telangiectasia (MacTel) MacTel Project Report excluded. High-resolution three-dimensional reconstructions No. 2. Ophthalmic Epidemiol 2010;17:66–73. of OCT angiography images could provide further insights into 9QuinG,LiewG,HoIV,et al. Diagnosis and interventions for central serous the pathogenesis of MacTel.14 15 chorioretinopathy: review and update. Clin Experiment Ophthalmol 2013;41:187–200. A pathogenic basis for the observations in this case series can 10 Kupitz EH, Heeren TF, Holz FG, et al. Poor long-term outcome of anti-vascular endothelial growth factor therapy in nonproliferative macular telangiectasia type 2. be postulated. Gass and Blodi suggested a temporal sequence of Retina 2015;35:2619–26. 3 disease stages in idiopathic juxtafoveolar retinal telangiectasis. 11 De Lahitte GD, Cohen SY, Gaudric A. Lack of apparent short-term benefitof Stage 3 is characterised by dilated right-angled vessels diving photodynamic therapy in bilateral, acquired, parafoveal telangiectasis without down from the plane of the retina and stage 4 by intraretinal subretinal . Am J Ophthalmol 2004;138:892–4. 12 Roisman L, Rosenfeld PJ. Optical coherence tomography angiography of macular proliferation of pigment epithelial cells typically along these – 3 telangiectasia type 2. Dev Ophthalmol 2016;56:146 58. vessels that form a right-angle with the retinal surface. 13 Spaide RF, Fujimoto JG, Waheed NK. Image artifacts in optical coherence Histology from a postmortem specimen in a patient with con- tomography angiography. Retina 2015;35:2163–80. firmed MacTel revealed abnormally dilated vessels in the deeper 14 Zhang Q, Wang RK, Chen CL, et al. Swept source optical coherence tomography angiography of neovascular macular telangiectasia type 2. Retina plexus of the retinal paracentral vasculature and Müller cell dys- – 16 2015;35:2285 99. function. Müller cells play a role in maintaining blood retinal 15 Spaide RF, Klancnik JM Jr, Cooney MJ, et al. Volume-rendering optical coherence 17 barrier integrity. During vascular remodelling in these MacTel tomography angiography of macular telangiectasia type 2. Ophthalmology cases, the equilibrium in Müller cell fluid transport may be tem- 2015;122:2261–9 porarily disturbed, providing a possible explanation for the tran- 16 Powner MB, Gillies MC, Zhu M, et al. Loss of Muller’s cells and photoreceptors in fl macular telangiectasia type 2. Ophthalmology 2013;120:2344–52 sient accumulation of uid in the subretinal potential space. 17 Shen W, Fruttiger M, Zhu L, et al. Conditional Müller cell ablation causes In conclusion, we characterise an unusual phenotype of independent neuronal and vascular in a novel transgenic model. MacTel where accumulation of SRF leads to foveal detachment. J Neurosci 2012;32:15715–27

Mehta H, et al. Br J Ophthalmol 2017;101:955–959. doi:10.1136/bjophthalmol-2016-309237 959 Downloaded from http://bjo.bmj.com/ on August 21, 2017 - Published by group.bmj.com

Natural history and effect of therapeutic interventions on subretinal fluid causing foveal detachment in macular telangiectasia type 2 Hemal Mehta, Simone Müller, Catherine A Egan, Simona Degli Esposti, Adnan Tufail, Dawn A Sim, Frank G Holz, Andrew C Browning, Winfried M Amoaku, Peter Charbel Issa and Mark C Gillies

Br J Ophthalmol 2017 101: 955-959 originally published online October 28, 2016 doi: 10.1136/bjophthalmol-2016-309237

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