FIRST SYMPTOMS AND THEIR AGE OF ONSET IN MACULAR TELANGIECTASIA TYPE 2 TJEBO F. C. HEEREN, MD, FRANK G. HOLZ, MD, PETER CHARBEL ISSA, MD Purpose: To investigate the first symptoms and their age of onset in a large cohort of patients with macular telangiectasia type 2. Methods: Patients with the characteristic findings of macular telangiectasia type 2 were interviewed. Data collection also included a chart review to determine the delay of the correct diagnosis and visual function 10 years after the onset of first symptoms. Results: Of 91 patients, 72 (79%) reported impaired reading ability as their first symptom, followed by metamorphopsia in 12%. The age of onset was most frequent (76%) in the sixth or seventh decade of life (50–69 years), and 58% of the patients were symptomatic before the age of 60 years. The median delay between first symptoms and the diagnosis of macular telangiectasia type 2 before the year 2005 was 7 years and has decreased to 1 year thereafter. Ten years after the onset of first symptoms, distance visual acuity of the better eye was $20/25 in 35% and #20/50 in 17%. Conclusion: Impaired reading ability was the most common initial visual disturbance of patients with macular telangiectasia type 2, starting generally between the age of 50 and 70 years. Knowledge of the presenting symptoms of macular telangiectasia type 2 together with recently identified characteristic morphologic alterations on retinal imaging will likely lead to earlier accurate diagnosis of this disease entity. RETINA 34:916–919, 2014

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acular telangiectasia (MacTel) type 2 is a bilateral macular disease with degeneration of the neurosensory retina in association with characteristic vascular alterations.1 The disease is assumed to have a genetic component and is more common than previously assumed.1–3 In recent years, several characteristic phenotypic findings have been identified that allow a clear differentiation of MacTel type 2 from other similar macular diseases.1 However, such phenotyping requires advanced imaging technologies such as optical coherence tomography or fundus autofluorescence. This especially applies to early disease stages, when funduscopic or angiographic changes may be very subtle.4 Functionally, impaired reading ability associated with deep paracentral scotomata has been reported in patients with MacTel type 2.5,6 Another frequent

symptom when specifically asked or tested for is the perception of metamorphopsia.7 Best-corrected visual acuity may remain normal or is only slightly reduced in many patients until late-disease stages have evolved. The earliest symptoms indicating MacTel type 2 have not yet been investigated systematically. However, such knowledge may be essential for identifying patients early based on their history which would then prompt further diagnostic imaging examinations to confirm or to rule out the diagnosis. Therefore, we conducted a survey in a large cohort of patients with MacTel type 2 to describe the earliest symptoms and their age of onset. In addition, a chart review was performed to determine the delay of diagnosis and the visual acuity 10 years after the occurrence of first symptoms.

From the Department of Ophthalmology, University of Bonn, Bonn, Germany. Supported by ProRetina, Lowy Medical Research Institute. None of the authors have any financial/conflicting interests to disclose. Reprint requests: Peter Charbel Issa, MD, Department of Ophthalmology, University of Bonn, Ernst-Abbe Street 2, 53127 Bonn, Germany; e-mail: [email protected]

Methods The survey included 94 patients (44% male, 56% female) from a single center, the Department of Ophthalmology at the University of Bonn, Germany. 916

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Patients were interviewed between August 2012 and August 2013 either during their visit in the hospital or through telephone. The diagnosis was based on characteristic findings on funduscopy, spectral domain optical coherence tomography, and fluorescein angiography (Spectralis HRA-OCT; Heidelberg Engineering, Heidelberg, Germany).1 Macular pigment distribution (assessed with a modified 2-wavelength HRA classic, Heidelberg Engineering) showed the typical (para-) central depletion of macular pigment.1,8 None of the patients had any other relevant retinal disease except for MacTel type 2. The study was conducted in adherence to the tenets of the Declaration of Helsinki. The Department of Ophthalmology, University of Bonn, has approval of the local institutional review board for all study-related data acquisition. All patients were interviewed by the same physician (T.F.C.H.). They were asked about the nature of their first visual difficulties that could not be corrected with glasses (to distinguish between presbyopic and MacTel type 2-related reading difficulties). If patients could not recall a specific symptom, they were asked more specifically during which activity they had noted first visual difficulties. A choice of visual disturbances including perception of metamorphopsia and difficulties in reading, driving, or watching television was given to the subgroup of patients (n = 10) who still had no clear response. Eventually, three patients were excluded from the analysis because they could not recall their first symptoms at all and because of a lack of adequate information in the patient chart. Moreover, patients were asked to provide information on the age of onset of their first symptoms. The exact year was sometimes difficult to recall, either because of the long time interval since their first symptoms or the slow onset. In this case, patients were asked to choose a predefined 5-year interval as the period during which they noted initial symptoms.

Results Of 91 analyzed patients, 72 (79%) reported reading difficulties as their first symptom (Figure 1A). The most frequent specifically mentioned reading deficit was missing letters (n = 18), followed by blurred or distorted (single) letters (n = 12). Twelve percent (n = 11) of patients reported that the perception of distortion was the first sign of their disease. A proportion of 9% (n = 8) of all patients noted various other symptoms including blurry vision (n = 4) or difficulties recognizing faces (n = 1). A total of 81 patients, that is, 90% of the entire cohort, could recall their first visual symptoms that could not be corrected by glasses without providing them with a choice of symptoms. Patient charts in most cases confirmed notes derived from the interview, adding additional certainty to the data. In two patients, the patient chart was used to help deciding on the nature of the first symptoms. The age of onset of first symptoms ranged between 35 years and 79 years and followed an approximate Gaussian distribution (Figure 1B). First symptoms occurred before the age of 50, 60, or 70 years in 16 (18%), 53 (58%), or 85 (93%) patients, respectively. Sixty-nine patients (76%) became symptomatic in their sixth or seventh decade (50–69 years). Information on visual function 10 years after first symptoms had occurred, was available from 52 patients (mean follow-up ± standard deviation, 10.0 ± 1.72 years; range, 8–14 years). Distance visual acuity of the better eye was $20/25 in 35% and #20/50 in 17% of those patients. There was no significant correlation between the age of onset of first symptoms and visual acuity 10 years later. Ten patients (11%) had developed a neovascular complex, one of them in both eyes. The median delay between the first symptoms and the diagnosis of MacTel type 2 in all patients was 2.0 years (n = 91, range, 0–36 years; interquartile range,

Fig. 1. First symptoms (A) and their age of onset (B) in patients with MacTel type 2.

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1–7 years). There was a significantly shorter delay of the correct diagnosis in patients who became symptomatic after the MacTel study was initiated in 2005, indicating increased awareness for the disease (P , 0.0001; 2-tailed Mann-Whitney test. Before 2005: n = 46, median = 7 years; range, 0–36 years; interquartile range, 2–12 years; 2005 and later: n = 45, median = 1 year; range, 0–7 years; interquartile range, 0–3.5 years; Figure 2). Discussion This study identified impaired reading ability as the most frequent initial symptom in patients with MacTel type 2. This finding is in line with studies on the vision-related quality of life that identified reading as one of the most challenging visual tasks for patients with MacTel type 2 later in the disease course.9,10 Distance visual acuity measured using single optotype testing charts may remain well preserved over many years. This is reflected by data from the MacTel study showing that 42% of all analyzed patients (n = 290) had a visual acuity of $20/25 in the better eye.11 Notably, this cohort included all disease stages, suggesting that visual acuity $20/25 might be even more frequent in patients presenting with their first symptoms. Early disease stages may be virtually inconspicuous on fundus examination which may misdirect clinicians and delay the correct diagnosis. Thus, reading difficulties to a higher degree than expected by morphologic findings (despite optimal refractive correction for reading), together with a good visual acuity in a middle-aged or older patient may prompt ophthalmologists to perform advanced retinal imaging examinations to confirm or to rule out MacTel type 2. This certainly applies with the limitation that although

Fig. 2. Time delay (years) between the occurrence of first symptoms and the diagnosis of MacTel type 2 before and after the initiation of the MacTel study in 2005.

reduced reading ability may be sensitive as the first symptom of MacTel type 2, it may be the presenting symptom of a large variety of ocular diseases and thus is not disease specific. Considering MacTel type 2 in patients with reading difficulties and/or metamorphopsia also seems sensible because of its much higher prevalence than previously assumed.3 Early definite diagnosis would decrease patient burden from uncertainty about the cause of visual disturbance and might decrease the rate of potentially harmful treatment efforts. Currently, there is no therapy with proven benefit for MacTel type 2 patients in the absence of a secondary neovascular complex or a full-thickness macular hole.1,12 First symptoms show a peak age of onset in the second half of the sixth decade of life (55–59 years) and overall occur most frequently between 50 years and 69 years. However, the disease may become symptomatic as early as in the fourth decade. Decline of visual acuity may occur at any time point after the onset of first symptoms. Nevertheless, most patients still have well preserved visual acuity in the better eye 10 years after the onset of first symptoms. This may reflect either a slow functional decline early in the disease course and/or the inability of standard distance visual acuity testing to detect disease progression in patients with MacTel type 2. The long median delay of 2 years from the first symptoms to identification of the correct diagnosis might reflect the difficulties of recognizing MacTel type 2. The delay has recently been reduced (Figure 2), possibly because of an increased awareness for the disease by clinicians through promotion by activities of the MacTel study group (www.mactelresearch. com). The wider availability of spectral domain optical coherence tomography technology may also contribute to the earlier diagnosis because it allows the detection of characteristic alterations in the majority of MacTel type 2 patients early on by noninvasive means. Limitations of the presented data include the lack of a standardized questionnaire. However, to our knowledge, there is no standard questionnaire similar to the National Eye Institute Visual Function Questionnaire 25 (NEI-VFQ25) for the history of visual functioning. Moreover, open questions together with the possibility to respond directly to the patients’ responses allowed helping patients to focus on the first symptoms that could not be corrected with glasses. Causes for reading difficulties such as the loss of accommodation because of age or diabetes, and incident cataract might even better be excluded by specific questioning by an experienced ophthalmologist, compared with fixed questions of a standard questionnaire. A further limitation of the

FIRST SYMPTOMS IN MACTEL TYPE 2  HEEREN ET AL

study is the retrospective nature of the survey and the chart review. Patients sometimes had difficulties remembering their first symptoms, especially if these occurred decades ago. However, a prospective study on such a relatively rare disease would take several years and would not insure that patients recall their first symptoms better. Moreover, although reduced reading ability may be sensitive as first symptom of MacTel type 2, it may be the presenting symptom of a large variety of ocular diseases and thus is not disease specific. In summary, reading difficulties and metamorphopsia are the most frequent presenting symptoms in patients with MacTel type 2. Together with the recently well-characterized morphologic alterations, early detection of the disease will become more likely. Key words: macular telangiectasia type 2, symptoms, age of onset, reading, visual acuity. References 1. Charbel Issa P, Gillies MC, Chew EY, et al. Macular telangiectasia type 2. Prog Retin Eye Res 2013;34:49–77. 2. Parmalee NL, Schubert C, Figueroa M, et al. Identification of a potential susceptibility locus for macular telangiectasia type 2. PLoS One 2012;7:e24268. 3. Klein R, Blodi BA, Meuer SM, et al. The prevalence of macular telangiectasia type 2 in the Beaver Dam eye study. Am J Ophthalmol 2010;150:55–62.

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4. Gillies MC, Zhu M, Chew EY, et al. Familial asymptomatic macular telangiectasia type 2. Ophthalmology 2009;116:2422– 2429. 5. Finger RP, Charbel Issa P, Fimmers R, et al. Reading performance is reduced due to parafoveal scotomas in patients with macular telangiectasia type 2. Invest Ophthalmol Vis Sci 2009; 50:1366–1370. 6. Charbel Issa P, Helb HM, Rohrschneider K, et al. Microperimetric assessment of patients with type II macular telangiectasia. Invest Ophthalmol Vis Sci 2007;48:3788–3795. 7. Charbel Issa P, Holz FG, Scholl HPN. Metamorphopsia in patients with macular telangiectasia type 2. Doc Ophthalmol 2009;119:133–140. 8. Charbel Issa P, van der Veen RLP, Stifjs A, et al. Quantification of reduced macular pigment optical density in the central retina in macular telangiectasia type 2. Exp Eye Res 2009;89: 25–31. 9. Clemons TE, Gillies MC, Chew EY, et al. The National Eye Institute Visual Function Questionnaire in the Macular Telangiectasia (MacTel) Project. Invest Ophthalmol Vis Sci 2008; 49:4340–4346. 10. Lamoureux EL, Maxwell RM, Marella M, et al. The longitudinal impact of macular telangiectasia (MacTel) type 2 on vision-related quality of life. Invest Ophthalmol Vis Sci 2011;52:2520–2524. 11. Clemons TE, Gillies MC, Chew EY, et al. Baseline characteristics of participants in the natural history study of macular telangiectasia (MacTel) MacTel Project Report No. 2. Ophthalmic Epidemiol 2010;17:66–73. 12. Charbel Issa P, Scholl HP, Gaudric A, et al. Macular fullthickness and lamellar holes in association with type 2 idiopathic macular telangiectasia. Eye (Lond) 2009;23:435–441.

First symptoms and their age of onset in macular telangiectasia type 2.

To investigate the first symptoms and their age of onset in a large cohort of patients with macular telangiectasia type 2...
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