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Epidemiology and Biostatistics |

Clinical Course of Macular Holes:  The Eye Disease Case-Control Study FREE

Emily Y. Chew, MD; Robert D. Sperduto, MD; Rita Hiller, MS; Leila Nowroozi, MPH; Daniel Seigel, ScD; Lawrence A. Yanuzzi, MD; Thomas C. Burton, MD; Johanna M. Seddon, MD; Evangelos S. Gragoudas, MD; Julia A. Haller, MD; Norman P. Blair, MD; Marilyn Farber, PhD
[+] Author Affiliations

From the Division of Biometry and Epidemiology, National Eye Institute, National Institutes of Health, Bethesda, Md (Drs Chew, Sperduto, and Seigel and Mss Hiller and Nowroozi); Manhattan Eye, Ear, and Throat Hospital, New York, NY (Dr Yanuzzi); Department of Ophthalmology, Medical College of Wisconsin, Milwaukee (Dr Burton); Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston (Drs Seddon and Gragoudas); Wilmer Eye Institute, The Johns Hopkins University, Baltimore, Md (Dr Haller); and the University of Illinois Eye and Ear Infirmary, Chicago (Drs Blair and Farber). Dr Burton is now in private practice in Milwaukee, Wis.


Arch Ophthalmol. 1999;117(2):242-246. doi:10.1001/archopht.117.2.242.
Text Size: A A A
Published online

Objective  To describe the clinical course of affected and unaffected eyes in patients with idiopathic macular holes.

Patients  Prospective study of patients with macular holes enrolled in the Eye Disease Case-Control Study.

Main Outcome Measures  The best-corrected visual acuity at follow-up was compared with that at baseline. Changes in the macular holes, including increases in size or spontaneous regression, were assessed. The rates of development of new macular holes in fellow unaffected eyes were estimated.

Results  Of the 198 patients examined at baseline, 28 (14.1%) died before reevaluation. Of those who survived, 122 (71.8%) had a follow-up examination. Approximately 34% (34.4%) of all eyes with macular holes had an increase in the size of the macular hole. Forty-five percent of eyes had a decrease in visual acuity of 2 or more lines and 27.8%, of 3 or more lines; 40.9% remained stable, with a gain or loss of fewer than 2 lines. The rate of development of a new macular hole during follow-up in fellow eyes that were unaffected at baseline was 4.3% for 3 or fewer years of follow-up, 6.5% for 4 to 5 years of follow-up, and 7.1% for 6 or more years of follow-up. Spontaneous regression of the macular hole occurred in 3 (8.6%) of 35 patients with a follow-up interval of 6 or more years, whereas no regression occurred in patients with a shorter follow-up.

Conclusions  The visual acuity of 45.0% of eyes with macular holes deteriorated by 2 or more lines during follow-up. The rate of development of macular holes in unaffected fellow eyes was low.

Figures in this Article

IDIOPATHIC FULL-THICKNESS macular holes are a relatively common cause of unilateral central vision loss in older persons. The importance of the vitreous in the pathogenesis of macular holes was suggested as early as 1924 by Lister.1 Subsequently, other investigators have provided support for the theory that vitreous traction is the cause of the condition.28 Surgical treatment of the vitreous in eyes with macular holes was introduced in 1991, and various case series and randomized clinical trials evaluating the effect of surgical treatment on visual improvement have reported variable results.912

Retrospective studies and a few randomized clinical trials have provided some limited data on the clinical course of macular holes.3,1214 Identification of a large series of patients with idiopathic macular holes in the Eye Disease Case-Control Study (EDCCS) provided an opportunity to collect additional data on the natural history of the condition. Our major objectives in reexamining the series of patients with macular holes were to prospectively assess the visual outcome in the affected and unaffected eyes and to estimate the rates of progression and/or regression of the macular holes and of development of macular holes in unaffected fellow eyes.

This study was part of a larger project, the EDCCS, designed to identify potential risk factors associated with the following retinal diseases: branch retinal vein occlusion, central retinal vein occlusion, neovascular age-related macular degeneration, rhegmatogenous retinal detachment, and idiopathic macular hole. The study, supported by the National Eye Institute, Bethesda, Md, was conducted at the following 5 clinical centers: University of Illinois at Chicago; the Medical College of Wisconsin, Milwaukee; the Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston; the Manhattan Eye, Ear, and Throat Hospital, New York, NY; and the Johns Hopkins Wilmer Eye Institute, Baltimore, Md. The centers enrolled patients with (the cases) and without (controls) the various retinal diseases from May 1, 1986, to December 31, 1990. We invited the 198 patients with idiopathic macular hole for a follow-up examination that was conducted from November 17, 1992, to July 30, 1994, at each of the clinical centers. Approvals from the institutional review board for human subject research were obtained at each of the clinical centers for baseline and follow-up studies.

At baseline and follow-up examinations, trained and certified examiners used standardized questionnaires and procedures to obtain data. Best-corrected visual acuity was obtained using the LogMAR visual acuity chart. Eye examinations were conducted by a study ophthalmologist using a standardized protocol.

Fundus photographs and fluorescein angiograms of both eyes were obtained at baseline and follow-up visits. The photographs and angiograms from each visit were independently evaluated by a grader unaware of patient status using a classification system that had been developed earlier for use in a clinical trial of treatment for macular hole.15 Grading was performed by comparing characteristics on the photographs and the angiograms with those on a set of standards. The diameter of the macular hole was measured using standard circles with the following diameters for each grade: grade 0, 0; grade 1, no greater than 125 µm; grade 2, 126 to 250 µm; grade 3, 251 to 350 µm; grade 4, 351 to 640 µm; and grade 5, greater than 640 µm. Associated retinal findings including the presence of an operculum, epiretinal membrane, drusen, or retinal pigment epithelial abnormalities were also noted.

Commercially available software (SAS/STAT)16 was used to derive simple frequencies and to perform statistical analyses such as χ2 and t tests where appropriate. In patients with bilateral macular holes, the eye with the worse visual acuity was chosen as the study eye at baseline. If both eyes had the same visual acuity, the right eye was selected as the study eye at baseline. Because of the correlation of eyes, only the study eye data were analyzed in patients who had bilateral macular holes.

At baseline, there were 198 patients with macular holes.17 Twenty-eight patients (14.1%) died before reexamination. Of the 170 surviving patients, 143 (84.1%) were contacted, and 122 (71.8%) were examined. Most of the 21 patients contacted but not reexamined were too ill to return. The baseline systemic and ocular characteristics of the patients seen at follow-up were compared with those who did not return for the follow-up (Table 1). Patients who did not return for follow-up were more likely to be male, nonwhite, and older and to have missing baseline fundus photographs than the patients who returned.

Table Graphic Jump LocationTable 1. Baseline Characteristics of Study Patients

The following data are based on the 122 patients who returned for reexamination. Of these, 19.6% of patients were reexamined 3 or fewer years after the baseline examination; 49.2%, 4 to 5 years after the baseline examination; and 31.1%, 6 or more years after the baseline examination. Because of the variable follow-up intervals, the rates of progression and regression are presented separately for these 3 intervals of time.

VISUAL ACUITY

Best-corrected visual acuity at baseline correlated inversely with the diameter of the macular holes (Figure 1). Smaller holes were associated with better mean visual acuity (correlation test, P<.001).

Place holder to copy figure label and caption
Figure 1.

The best-corrected visual acuity at baseline by size of the macular hole.

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The distribution of visual acuity at follow-up shifted toward poorer visual acuity in eyes with macular holes (Figure 2). In contrast, little change in the distribution of visual acuity was seen in the fellow eyes (Figure 3). Of the 122 reexamined eyes with macular holes, 45.0% experienced visual acuity loss of 2 or more lines of visual acuity; 27.9%, loss of 3 or more lines of visual acuity (not shown). Gain or loss of less than 2 lines indicated unchanged visual acuity, as seen in 41.0%, whereas 13.1% had an increase of 2 or more lines of visual acuity. Similar rates of visual acuity loss were seen during each of the 3 follow-up intervals.

Place holder to copy figure label and caption
Figure 2.

Visual acuity at follow-up in eyes affected with macular holes at baseline.

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Place holder to copy figure label and caption
Figure 3.

Visual acuity at follow-up in unaffected fellow eyes at baseline.

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For patients who lost 2 or more lines of visual acuity during follow-up, the ophthalmologist indicated the main cause of vision deterioration was macular hole in (78.2%), cataract in (5.5%), age-related macular degeneration in (1.8%), glaucoma in (3.6%), and more than 1 cause in (11.9%).

SIZE OF MACULAR HOLES

Of the 122 patients who were reexamined, fundus photographs were ungradable in 5 (4.1%) and missing in 10 (8.2%) at baseline. Evaluation of the 107 gradable fundus photographs showed that the diameter of the macular holes at baseline was no greater than 250 µm in 16.8%, 251 to 640 µm in 75.7%, and greater than 640 µm in 7.5% (Table 2). At follow-up, macular holes in 33.6% of these patients had progressed to a larger size (Table 2). The rates of progression for each follow-up interval were 21.7% for 3 or fewer years of follow-up, 36.7% for 4 to 5 years, and 37.1% for 6 or more years (Table 2).

Table Graphic Jump LocationTable 2. Increase in the Size of the Macular Hole at Follow-up Examination*
OTHER OCULAR CHARACTERISTICS

Among the 107 patients with gradable fundus photographs at follow-up, 57.8% of the macular holes were round, 16.6% were oval, 9.1% were irregular in shape, and 15.9% could not be determined. Fluorescein angiographic findings at baseline showed no hyperfluorescence in 10.7%; a homogeneous, uniform hyperfluorescence in the affected area in 40.6%; and mottled, speckled hyperfluorescence in 28.9%. At follow-up, 22.5% had no hyperfluorescence; only 19.9% had homogeneous, uniform hyperfluorescence; and 41.1% had mottled or speckled hyperfluorescence. Associated retinal findings at baseline included epiretinal membranes (8.6%), retinal pigment epithelial abnormalities (14.4%), and drusen (41.7%).

The ophthalmologist clinically assessed the state of the posterior vitreous face to be partially detached over the macular hole in 71.3% of the 122 patients at baseline and in 18.0% at follow-up. In 28.6% of the eyes, complete detachment of the posterior vitreous face over the hole was seen at baseline, and in 59.0% at follow-up. In 23.0% of the eyes, the state of the vitreous could not be evaluated at follow-up.

Ocular surgical procedures performed before the baseline examination included cataract extraction (4.1%), vitrectomy (3.2%), and others (7.4%). At follow-up, these increased to 6.5% for vitrectomy and 9.3% for other intraocular surgical procedures and remained at 4% for cataract extraction. Although 9 patients underwent vitrectomy during follow-up, only 1 patient experienced an improvement of visual acuity greater than 2 lines of visual acuity, although 6 procedures resulted in the closure of the macular holes.

RATES OF DEVELOPMENT OF NEW MACULAR HOLE IN FELLOW NORMAL EYES

In fellow unaffected eyes, the rate of development of new macular holes during follow-up was 4.3% at 3 or fewer years, 6.5% at 4 to 5 years, and 7.1% at 6 or more years. All new macular holes were accompanied by a decrease in visual acuity.

RATES OF SPONTANEOUS REGRESSION IN EYES AFFECTED WITH MACULAR HOLE

None of the macular holes showed regression during the 2 shorter follow-up intervals. At 6 or more years, 3 (8.6%) of 35 eyes showed spontaneous regression or complete resolution of the macular hole. The visual acuity improved in only 1 of these eyes by 2 lines, whereas the other 2 eyes had a loss of visual acuity of 3 or more lines.

Our data showed an increase in the size of the macular hole in 36.7% of patients after 4 years of follow-up and a decrease in visual acuity of 2 or more lines in 44.8% of all patients for all 3 intervals of follow-up. Other investigators reported progressive enlargement of macular holes, but long-term visual acuity was noted to be generally stable in most patients, with only 18% of eyes losing visual acuity of 2 or more lines.14 Most earlier studies were retrospective or short-term prospective follow-up studies, making it difficult to compare their data with ours. The deterioration in visual acuity was especially evident in our study when the change in visual acuity in eyes with macular holes was compared with the lack of change in visual acuity in those eyes with no macular holes. Clinical assessment by the study investigators indicated that the major cause of visual deterioration during follow-up was the macular hole.

The rate of spontaneous regression was low in this study. In the randomized trial of vitrectomy for the treatment of macular holes, 2 (3.6%) of 56 eyes assigned to observation regressed spontaneously during 6 months of follow-up.13 None of the eyes observed for less than 6 years had regression in the EDCCS follow-up. It is not possible to know when the regression took place in the 3 eyes that had 6 or more years between examinations.

At baseline, approximately 89% of cases had an unaffected eye. The prospective design of our study allowed us to determine the rate of development of macular holes in these previously unaffected fellow eyes. The rates for the follow-up periods increased slightly from 4.3% to 7.1% for shorter and longer follow-ups, respectively. The recent analyses from a prospective study conducted at Moorfields Eye Hospital, London, England, showed higher short-term and similar long-term rates of development of macular holes in previously unaffected fellow eyes: 7.3% at 18 months and 7.4% at 5 years of follow-up.18 Previous retrospective studies reported variable rates of development of macular holes in the fellow eyes, ranging from 0% in a mean follow-up of 27 months to 12% in a mean follow-up of 57 months and 16% in a mean follow-up of 47 months.14,19,20 It is difficult to compare these data with those of our prospective study. Information about the risk of developing a macular hole in unaffected eyes from a prospective study such as the EDCCS may be of use in patients who present with unilateral macular holes.

The posterior vitreous face findings reported by the study ophthalmologists support theories about the importance of vitreous traction in the pathogenesis of macular holes. An earlier publication of the EDCCS reported an association between elevated serum fibrinogen levels and macular holes in men and women.17 This may be a chance finding, or higher levels of fibrinogen may increase susceptibility to the forces of vitreous traction, which are thought to play an important role in the pathogenesis of macular holes. The true clinical significance of this association with fibrinogen is not known. The EDCCS also confirmed previous findings that women are at increased risk for development of macular holes.

In summary, our study provides new, prospectively acquired information about the clinical course of affected and unaffected eyes in patients with idiopathic macular holes. These data may be helpful in counseling patients with macular holes and planning future studies of therapy for this important cause of central vision loss.

Accepted for publication September 29, 1998.

This study was supported by contracts N01-EY-5-2110, N01-EY-5-2109, N01-EY-5-2111, N01-EY-5-2105, N01-EY-5-2108, and N01-EY-5-2104 from the National Institutes of Health, Bethesda, Md.

Reprints: Emily Y. Chew, MD, Division of Biometry and Epidemiology, National Eye Institute, Bldg 31, Room 6A52, 31 Center Dr, MSC 2510, Bethesda, MD 20892-2510 (e-mail: echew@nei.nih.gov).

Lister  W Holes in the retina and their clinical significance. Br J Ophthalmol. 1924;81- 20
Link to Article
Schepens  CL Fundus changes caused by lacerations of the vitreous body. Am J Ophthalmol. 1955;39631- 633
Aaberg  TMBlair  CJGass  JDM Macular holes. Am J Ophthalmol. 1970;69555- 562
Avila  MPJalkh  AEMurakami  ITrempe  CLSchepens  CL Biomicroscopic study of the vitreous in macular breaks. Ophthalmology. 1983;901277- 1283
Link to Article
Trempe  CLWeiter  JJFurukawa  H Fellow eyes in cases of macular hole: biomicroscopic study of the vitreous. Arch Ophthalmol. 1986;10493- 95
Link to Article
Hikichi  TAkiba  JTrempe  CL Effect of the vitreous on the prognosis of full-thickness idiopathic macular hole. Am J Ophthalmol. 1993;111273- 278
Akiba  JYoshida  ATrempe  CL Risk of developing a macular hole. Arch Ophthalmol. 1990;1081088- 1090
Link to Article
Gass  JDM Idiopathic senile macular hole: its early stages and pathogenesis. Arch Ophthalmol. 1988;106629- 639
Link to Article
Kelly  NEWendel  RT Vitreous surgery for idiopathic macular holes. Arch Ophthalmol. 1991;109654- 659
Link to Article
Wendel  RTPatel  ACKelly  NESalzano  TCWells  JWNovack  GD Vitreous surgery for macular holes. Ophthalmology. 1992;1001671- 1676
Link to Article
Glaser  BMMichels  RGKuppermann  BDSjaarda  RNPena  RA Transforming growth factor-beta 2 for the treatment of full-thickness macular holes: a prospective randomized study. Ophthalmology. 1992;991162- 1173
Link to Article
Freeman  WRAzen  SPKim  JW  et al.  Vitrectomy for the treatment of full-thickness stage 3 or 4 macular holes: results of a multicentered randomized clinical trial. Arch Ophthalmol. 1997;11511- 21
Link to Article
Morgan  CSchatz  H Idiopathic macular holes. Am J Ophthalmol. 1985;99437- 444
McDonnell  PJFine  SLHillis  AI Clinical features of idiopathic macular cysts and holes. Am J Ophthalmol. 1982;93777- 786
Thompson  JTHiner  CJGlaser  BMGordon  AJMurphy  RPSjaarda  RN Fluorescein angiographic characteristics of macular holes before and after vitrectomy with transforming growth factor beta-2. Am J Ophthalmol. 1994;117291- 301
SAS Institute Inc, SAS/STAT User's Guide, Version 6. 4th ed. Cary, NC SAS Institute Inc1989;2
The Eye Disease Case-Control Study Group, Risk factors for idiopathic macular holes. Am J Ophthalmol. 1994;118754- 761
Ezra  EWells  JAGray  RH  et al.  Incidence of idiopathic full-thickness macular holes in fellow eyes: a 5-year prospective natural history study. Ophthalmology. 1998;105353- 359
Link to Article
Bronstein  MATrempe  CLFreeman  HM Fellow eyes of eyes with macular holes. Am J Ophthalmol. 1981;92757- 761
Lewis  MLCohen  SMSmiddy  WEGass  JD Bilaterality of idiopathic macular holes. Graefes Arch Clin Exp Ophthalmol. 1996;234241- 245
Link to Article

Figures

Place holder to copy figure label and caption
Figure 1.

The best-corrected visual acuity at baseline by size of the macular hole.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.

Visual acuity at follow-up in eyes affected with macular holes at baseline.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 3.

Visual acuity at follow-up in unaffected fellow eyes at baseline.

Graphic Jump Location

Tables

Table Graphic Jump LocationTable 1. Baseline Characteristics of Study Patients
Table Graphic Jump LocationTable 2. Increase in the Size of the Macular Hole at Follow-up Examination*

References

Lister  W Holes in the retina and their clinical significance. Br J Ophthalmol. 1924;81- 20
Link to Article
Schepens  CL Fundus changes caused by lacerations of the vitreous body. Am J Ophthalmol. 1955;39631- 633
Aaberg  TMBlair  CJGass  JDM Macular holes. Am J Ophthalmol. 1970;69555- 562
Avila  MPJalkh  AEMurakami  ITrempe  CLSchepens  CL Biomicroscopic study of the vitreous in macular breaks. Ophthalmology. 1983;901277- 1283
Link to Article
Trempe  CLWeiter  JJFurukawa  H Fellow eyes in cases of macular hole: biomicroscopic study of the vitreous. Arch Ophthalmol. 1986;10493- 95
Link to Article
Hikichi  TAkiba  JTrempe  CL Effect of the vitreous on the prognosis of full-thickness idiopathic macular hole. Am J Ophthalmol. 1993;111273- 278
Akiba  JYoshida  ATrempe  CL Risk of developing a macular hole. Arch Ophthalmol. 1990;1081088- 1090
Link to Article
Gass  JDM Idiopathic senile macular hole: its early stages and pathogenesis. Arch Ophthalmol. 1988;106629- 639
Link to Article
Kelly  NEWendel  RT Vitreous surgery for idiopathic macular holes. Arch Ophthalmol. 1991;109654- 659
Link to Article
Wendel  RTPatel  ACKelly  NESalzano  TCWells  JWNovack  GD Vitreous surgery for macular holes. Ophthalmology. 1992;1001671- 1676
Link to Article
Glaser  BMMichels  RGKuppermann  BDSjaarda  RNPena  RA Transforming growth factor-beta 2 for the treatment of full-thickness macular holes: a prospective randomized study. Ophthalmology. 1992;991162- 1173
Link to Article
Freeman  WRAzen  SPKim  JW  et al.  Vitrectomy for the treatment of full-thickness stage 3 or 4 macular holes: results of a multicentered randomized clinical trial. Arch Ophthalmol. 1997;11511- 21
Link to Article
Morgan  CSchatz  H Idiopathic macular holes. Am J Ophthalmol. 1985;99437- 444
McDonnell  PJFine  SLHillis  AI Clinical features of idiopathic macular cysts and holes. Am J Ophthalmol. 1982;93777- 786
Thompson  JTHiner  CJGlaser  BMGordon  AJMurphy  RPSjaarda  RN Fluorescein angiographic characteristics of macular holes before and after vitrectomy with transforming growth factor beta-2. Am J Ophthalmol. 1994;117291- 301
SAS Institute Inc, SAS/STAT User's Guide, Version 6. 4th ed. Cary, NC SAS Institute Inc1989;2
The Eye Disease Case-Control Study Group, Risk factors for idiopathic macular holes. Am J Ophthalmol. 1994;118754- 761
Ezra  EWells  JAGray  RH  et al.  Incidence of idiopathic full-thickness macular holes in fellow eyes: a 5-year prospective natural history study. Ophthalmology. 1998;105353- 359
Link to Article
Bronstein  MATrempe  CLFreeman  HM Fellow eyes of eyes with macular holes. Am J Ophthalmol. 1981;92757- 761
Lewis  MLCohen  SMSmiddy  WEGass  JD Bilaterality of idiopathic macular holes. Graefes Arch Clin Exp Ophthalmol. 1996;234241- 245
Link to Article

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