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Figure 1.
Vitreous with a monolayer of spindle-shaped cells on one surface (Millipore filter, modified Papanicolaou, original magnification × 100).

Vitreous with a monolayer of spindle-shaped cells on one surface (Millipore filter, modified Papanicolaou, original magnification × 100).

Figure 2.
Layer of cortical vitreous (asterisk) with a monolayer of retinal pigment epithelium (arrow) with numerous mitochondria and spotty basal lamina on one surface (original magnification × 12 000).

Layer of cortical vitreous (asterisk) with a monolayer of retinal pigment epithelium (arrow) with numerous mitochondria and spotty basal lamina on one surface (original magnification × 12 000).

Figure 3.
Internal limiting lamina of the retina (asterisk) with a layer of collagen with a fiber diameter of 16 nm (cortical vitreous) (arrow) on its smooth internal surface (original magnification × 20 000).

Internal limiting lamina of the retina (asterisk) with a layer of collagen with a fiber diameter of 16 nm (cortical vitreous) (arrow) on its smooth internal surface (original magnification × 20 000).

Figure 4.
A thin layer of native collagen (cortical vitreous) (asterisk) is sandwiched between the internal limiting lamina of the retina (arrowhead) and a layer of cells with bundles of 10-mm cytoplasmic filaments (probable fibrous astrocytes) (arrow) (original magnification × 20 000).

A thin layer of native collagen (cortical vitreous) (asterisk) is sandwiched between the internal limiting lamina of the retina (arrowhead) and a layer of cells with bundles of 10-mm cytoplasmic filaments (probable fibrous astrocytes) (arrow) (original magnification × 20 000).

Figure 5.
A 2-μm-thick layer of cortical vitreous (asterisk) is interposed between the internal limiting lamina of the retina (arrowhead) and a monolayer of probable retinal pigment epithelium (arrow) (original magnification × 8100).

A 2-μm-thick layer of cortical vitreous (asterisk) is interposed between the internal limiting lamina of the retina (arrowhead) and a monolayer of probable retinal pigment epithelium (arrow) (original magnification × 8100).

Figure 6.
A tapered layer of vitreous cortex (asterisk) is interposed between the internal limiting lamina of the retina (arrowhead) and a layer of cells (arrow) with bundles of 10-nm cytoplasmic filaments and basal lamina (fibrous astrocytes) (original magnification × 20 000).

A tapered layer of vitreous cortex (asterisk) is interposed between the internal limiting lamina of the retina (arrowhead) and a layer of cells (arrow) with bundles of 10-nm cytoplasmic filaments and basal lamina (fibrous astrocytes) (original magnification × 20 000).

Figure 7.
Eye with extensive central liquefaction of vitreous. A rim of intact cortical vitreous (arrow) remains attached to the retina (periodic acid–Schiff, original magnification × 40).

Eye with extensive central liquefaction of vitreous. A rim of intact cortical vitreous (arrow) remains attached to the retina (periodic acid–Schiff, original magnification × 40).

Figure 8.
Postmortem eye with macular hole (A). The macular hole has rounded margins (B) and a layer of cortical vitreous (asterisk) is present (C). Debris along the inner surface of cortical vitreous is present (B and C) (A, gross ×1.25; B, hematoxylin, original magnification ×40; C, hematoxylin, original magnification ×160).

Postmortem eye with macular hole (A). The macular hole has rounded margins (B) and a layer of cortical vitreous (asterisk) is present (C). Debris along the inner surface of cortical vitreous is present (B and C) (A, gross ×1.25; B, hematoxylin, original magnification ×40; C, hematoxylin, original magnification ×160).

Figure 9.
Postmortem eye. Nasal (A) and temporal (B) margins of an idiopathic macular hole with a cellular proliferation (arrows) along the inner surface of cortical vitreous (asterisks) (periodic acid–Schiff, original magnification ×100).

Postmortem eye. Nasal (A) and temporal (B) margins of an idiopathic macular hole with a cellular proliferation (arrows) along the inner surface of cortical vitreous (asterisks) (periodic acid–Schiff, original magnification ×100).

1.
Kelly  NEWendel  RT Vitreous surgery for idiopathic macular holes. Arch Ophthalmol 1991;109654- 659
PubMedArticle
2.
Sadda  SRCampochiaro  PAde Juan  EHaller  JAGreen  WR Histopathological features of vitreous removed at macular hole surgery. Arch Ophthalmol 1999;117478- 484
PubMedArticle
3.
Kampik  AKenyon  KRMichels  RGGreen  WRde la Cruz  ZC Epiretinal and vitreous membranes: comparative study of 56 cases. Arch Ophthalmol 1981;991445- 1454
PubMedArticle
4.
Johnson  MWVan Newkirk  MRMeyer  KA Perifoveal vitreous detachment is the primary pathogenic event in idiopathic macular hole formation. Arch Ophthalmol 2001;119215- 222
PubMed
5.
Gaudric  AHaouchine  BMassin  PPaques  MBlain  PErginay  A Macular hole formation: new data provided by optical coherence tomography. Arch Ophthalmol 1999;117744- 751
PubMedArticle
6.
Chauhan  DSAntcliff  RJRai  PAWilliamson  THMarshall  J Papillofoveal traction in macular hole formation: the role of optical coherence tomography. Arch Ophthalmol 2000;11832- 38
PubMedArticle
7.
Fujii  GYde Juan  EBressler  NM Vitrectomy surgery for impending macular hole based on optical coherence tomography. Retina 2001;21389- 392
PubMedArticle
8.
Guyer  DRGreen  WRde Bustros  SFine  SL Histopathologic features of idiopathic macular holes and cysts. Ophthalmology 1990;971045- 1051
PubMedArticle
9.
Guyer  DRGreen  WR Idiopathic macular holes and precursor lesions. In:Franklin  RM Proceeding of the Symposium on Retina and Vitreous, New Orleans Academy of Ophthalmology. New Orleans, LA  New York, NY Kugler Publications1993;135- 162
10.
Lewis  HCowan  GMStraatsma  BR Apparent disappearance of a macular hole associated with development of an epiretinal membrane. Am J Ophthalmol 1986;102172- 175
PubMedArticle
11.
Bidwell  AEJampol  LMGoldberg  MF Macular holes and excellent visual acuity. Arch Ophthalmol 1988;1061350- 1351
PubMedArticle
12.
Guyer  DRde Bustros  SDiener-West  MFine  SL Observations on patients with idiopathic macular holes and cysts. Arch Ophthalmol 1992;1101264- 1268
PubMedArticle
13.
Tadayoni  RMassin  PHaouchine  BCohen  DErginay  AGaudric  A Spontaneous resolution of small stage 3 and 4 full-thickness macular holes viewed by optical coherence tomography. Retina 2001;21186- 189
PubMedArticle
14.
Gass  JDM Idiopathic senile macular hole: its early stages and pathogenesis. Arch Ophthalmol 1988;106629- 639
PubMedArticle
15.
Johnson  RNGass  JDM Idiopathic macular holes: observations, stages of formation, and implications for surgical intervention. Ophthalmology 1988;95917- 924
PubMedArticle
16.
Funata  MWendel  RTde la Cruz  ZGreen  WR Clinicopathologic study of bilateral macular holes treated with pars plana vitrectomy and gas tamponade. Retina 1992;12289- 298
PubMedArticle
17.
Madreperla  SAGeiger  GLFunata  Mde la Cruz  ZGreen  WR Clinicopathologic correlation of a macular hole treated by cortical vitreous peeling and gas tamponade. Ophthalmology 1994;101682- 686
PubMedArticle
18.
Rosa  RHGlaser  BMde la Cruz  ZCGreen  WR Clinicopathologic correlation of an untreated macular hole and a macular hole treated by vitrectomy, transforming growth factor-β2, and gas tamponade. Am J Ophthalmol 1996;122853- 863
PubMed
19.
Frangieh  GTGreen  WREngel  HM A histopathologic study of macular cysts and holes. Retina 1981;1311- 336
PubMedArticle
20.
Madreperla  SAMcCuen  BW  IIHickingbotham  DGreen  WR Clinicopathologic correlation of surgically removed macular hole opercula. Am J Ophthalmol 1995;120197- 207
PubMed
21.
Fekrat  SWendel  RTde le Cruz  ZGreen  WR Clinicopathologic correlation of an epiretinal membrane associated with a recurrent macular hole. Retina 1995;1553- 57
PubMedArticle
Clinical Sciences
March 2006

The Macular HoleHistopathologic Studies

Author Affiliations

Author Affiliations: The Eye Pathology Laboratory, Wilmer Institute and Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, Md.

Arch Ophthalmol. 2006;124(3):317-321. doi:10.1001/archopht.124.3.317
Abstract

Objective  To delineate the light and electron microscopic features of tissue removed at the time of macular hole surgery.

Methods  The ocular fluid specimens were concentrated using Millipore filters and stained with a modified Papanicolaou and the periodic acid–Schiff stains in 697 cases. In 92 cases, surgically isolated tissue was processed and examined by electron microscopy.

Results  The findings in the specimens studied by the Millipore filter technique included vitreous strands; cellular fragments in 108 cases (13.3%); fibrocellular fragments in 75 (9.2%); and fragments of internal limiting lamina (ILL) of the retina in 104 (12.8%). Findings in the 92 specimens with tissue studied by electron microscopy included native vitreous collagen in 48 cases (52.2%); new collagen in 6 (6.5%); native and new collagen in 1 (1.2%); ILL of the retina in 54 (58.7%); and a variety of cells in 22.5% of cases, including fibrocytes, myofibrocytes, fibrous astrocytes with and without myoblastic features, Mueller cells, retinal pigment epithelium with and without myoblastic features, and inflammatory cells. The organization of the tissue elements included a cellular layer along one surface of a layer of cortical vitreous in 18 cases, cortical vitreous along the inner surface of the ILL of the retina in 10, and cortical vitreous sandwiched between the ILL of the retina and a layer of cells in 9.

Conclusions  Tangential traction induced by fluid movements affecting the cortical vitreous is a major factor in the pathogenesis of idiopathic macular holes. Cellular proliferation is a secondary change seen in 22.2% of cases.

Until recently there was little enthusiasm for the treatments of macular holes. The emergence of a classification that incorporated new ideas on pathogenesis and the recognition that vitreous surgery may be beneficial for some patients have generated a renewed interest in idiopathic macular holes and their precursor features. Kelly and Wendel1 found that the surrounding area of macular detachment could be eliminated by vitrectomy, gas tamponade, and meticulous face-down positioning. Since then, vitrectomy has become the standard treatment for macular holes. The histopathologic study of ocular fluid specimens obtained at vitrectomy for macular holes is the subject of this report.

METHODS

Eight hundred fifteen ocular fluid specimens were obtained at macular hole surgery over a 30-year period in the Wilmer Eye Pathology Laboratory, Baltimore, Md. This is an extension of a previous study of 200 consecutive cases.2 The specimens were concentrated using a Millipore filter (Millipore Filter Corp, Billerica, Mass) and were stained with a modified Papanicolaou and the periodic acid–Schiff techniques.

In 118 cases, tissue clinically considered to be opercula or “epiretinal membranes” were isolated by the surgeon and placed in a buffered solution of 2% glutaraldehyde and 4% formaldehyde for transmission electron microscopy. Identification of cell types and native collagen was based on previously reported criteria.3

RESULTS
MILLIPORE FILTER

Of the 815 cases, almost all had vitreous strands. Cellular fragments (Figure 1) and fibrocellular fragments were observed in 108 cases (13.3%) and 75 cases (9.2%), respectively. Fragments of internal limiting lamina of the retina were present in 104 cases (12.8%). Possible retinal fragments were present in 55 cases (6.7%) and chronic inflammatory cells, in 39 (4.8%). Blood vessels were present in 4 cases (0.5%) and posterior lens capsule fragments, in 110 (13.5%). Forty-three cases (5.3%) were reoperations, 9 (1.1%) had an associated retinal detachment, and 4 (0.5%) followed ocular trauma.

ELECTRON MICROSCOPY

Of the 118 cases, no tissue was identified in 26 (22.0%). The 92 specimens with tissue contained native vitreous collagen in 48 cases (52.2%), new collagen in 6 (6.5%), and native and new collagen in 1 (1.2%). Fragments of internal limiting lamina of the retina were present 54 cases (58.7%). A variety of cell types present included fibrocytes, 20 cases (21.9%); myofibrocytes, 12 (13.0%); fibrous astrocytes, 39 (42.4%); fibrous astrocytes with myoblastic features, 4 (4.3%); Mueller cells, 14 (15.2%); retinal pigment epithelium, 14 (15.2%) and retinal pigment epithelium with myoblastic features, 9 (9.8%); lymphocytes, 3 (3.2%); macrophages, 13 (14.1%); degenerated cells, 4 (4.3%); and an unidentified type of cell in 15 cases (16.3%). Retinal neurons were present in 3 cases (3.3%) and retinal nerve fibers, in 12 (13.0%). Fibrin and blood vessels were present in 2 cases (2.2%) each.

The organization of the tissue elements supports the role of vitreous in the pathogenesis of macular holes. In 18 instances, a layer of native collagen was present with a cellular proliferation along one surface (presumably the inner surface) (Figure 2). A layer of native collagen was present along the inner surface of the internal limiting lamina of the retina in 10 cases (Figure 3). In 11 instances, a layer of native collagen was sandwiched between the internal limiting lamina of the retina and a layer of cells (Figures 4, 5, and 6). A layer of cells was present along the inner surface of the internal limiting lamina of the retina in 9 cases.

COMMENT

In recent years, several authors, using ultrasonography4 and optical coherence tomography,57 have reported posterior vitreous detachment in eyes with macular holes. Johnson and colleagues4 stated that perifoveal vitreous detachment is the primary pathogenesis event in idiopathic macular hole formation. I take exception with this and offer an alternative interpretation. I believe that these authors are likely imaging a cellular proliferation along the inner surface of the tapered cortical vitreous.

There are 2 main scenarios regarding age-related vitreous degeneration. One is extensive central vitreous liquefaction and posterior vitreous detachment, which may lead to retinal tears and detachment. The other is extensive central liquefaction where a rim of cortical vitreous remains attached to the retina (Figure 7). Unfortunately, we cannot consistently see this layer even with a slitlamp, contact lens biomicroscopy, optical coherence tomography, or ultrasonography.

In a study of 22 eyes with idiopathic macular holes obtained post mortem, Guyer et al8 observed epiretinal cortical vitreous in 16 (73%) (Figure 8 and Figure 9). The findings of a cellular proliferation along the inner surface of a layer of cortical vitreous and cortical vitreous sandwiched between the internal limiting membrane of the retina and a layer of cells by electron microscopic studies of tissue removed at macular hole surgery support this concept.

Important developments in the history of macular holes were the observation of spontaneous resolution,913 the evolution of the tangential traction theory,14,15 and that vitrectomy could result in resolution of the macular hole.1 That macular holes can undergo spontaneous resolution suggested that whatever caused the hole was no longer in play. Sealing of macular holes with glial cell proliferation after vitrectomy supports the tangential traction theory.1618

Studies of eyes with macular holes obtained postmortem and tissues recovered at the time of vitrectomy for macular hole support the tangential vitreous traction theory. The posterior cortical vitreous tapers to a thin layer over the foveal area where it is somewhat more firmly attached. With movement of the eyes, there are countermovements of the fluid vitreous. The countermovements create tension against the remaining cortical vitreous and the tension is transmitted where the cortical vitreous is thinnest—at the fovea. Deformation of the eye, as with rubbing, also contributes to tension on the cortical vitreous. These forces lead to chronic, low-grade traction with localized foveal detachment and hole formation. This low-grade traction also stimulates proliferation of cells (fibrous astrocytes, Mueller cells, and retinal pigment epithelium) to extend onto the inner surface of the cortical vitreous in some cases.

In some cases, the cellular proliferation may be pulled away from the macular area, giving rise to a pseudooperculum,19,20 and, in some cases, contributing to persistence or recurrence of the macular hole.21

CONCLUSIONS

The presence of cystoid macular edema, a surrounding area of retinal detachment, and tangential vitreous traction establishes rationale for the surgical treatment of macular holes and the associated secondary reparative cellular proliferation. Fluid movement and countercurrents of the central liquefied vitreous affecting the rim of the cortical vitreous is likely the pathogenesis of most idiopathic macular holes. With the removal of the tapered cortical vitreous, the edges of the hole come together, and healing with glial cell proliferation occurs in most instances.

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Article Information

Correspondence: W. Richard Green, MD, Eye Pathology Laboratory, Maumenee 427, Johns Hopkins Hospital, 600 N Wolfe St, Baltimore, MD 21287-9248 (wrgreen@jhmi.edu).

Submitted for Publication: January 28, 2005; final revision received June 13, 2005; accepted June 21, 2005.

Financial Disclosure: None.

Funding/Support: This study was supported in part by the Independent Order of Odd Fellows, Winston-Salem, NC, and the Macula Foundation, New York, NY.

Previous Presentation: This study was presented at the 67th Annual George E. de Schweinitz Lecture, The College of Physicians of Philadelphia, Section on Ophthalmology; November 18, 2004; Philadelphia, Pa.

References
1.
Kelly  NEWendel  RT Vitreous surgery for idiopathic macular holes. Arch Ophthalmol 1991;109654- 659
PubMedArticle
2.
Sadda  SRCampochiaro  PAde Juan  EHaller  JAGreen  WR Histopathological features of vitreous removed at macular hole surgery. Arch Ophthalmol 1999;117478- 484
PubMedArticle
3.
Kampik  AKenyon  KRMichels  RGGreen  WRde la Cruz  ZC Epiretinal and vitreous membranes: comparative study of 56 cases. Arch Ophthalmol 1981;991445- 1454
PubMedArticle
4.
Johnson  MWVan Newkirk  MRMeyer  KA Perifoveal vitreous detachment is the primary pathogenic event in idiopathic macular hole formation. Arch Ophthalmol 2001;119215- 222
PubMed
5.
Gaudric  AHaouchine  BMassin  PPaques  MBlain  PErginay  A Macular hole formation: new data provided by optical coherence tomography. Arch Ophthalmol 1999;117744- 751
PubMedArticle
6.
Chauhan  DSAntcliff  RJRai  PAWilliamson  THMarshall  J Papillofoveal traction in macular hole formation: the role of optical coherence tomography. Arch Ophthalmol 2000;11832- 38
PubMedArticle
7.
Fujii  GYde Juan  EBressler  NM Vitrectomy surgery for impending macular hole based on optical coherence tomography. Retina 2001;21389- 392
PubMedArticle
8.
Guyer  DRGreen  WRde Bustros  SFine  SL Histopathologic features of idiopathic macular holes and cysts. Ophthalmology 1990;971045- 1051
PubMedArticle
9.
Guyer  DRGreen  WR Idiopathic macular holes and precursor lesions. In:Franklin  RM Proceeding of the Symposium on Retina and Vitreous, New Orleans Academy of Ophthalmology. New Orleans, LA  New York, NY Kugler Publications1993;135- 162
10.
Lewis  HCowan  GMStraatsma  BR Apparent disappearance of a macular hole associated with development of an epiretinal membrane. Am J Ophthalmol 1986;102172- 175
PubMedArticle
11.
Bidwell  AEJampol  LMGoldberg  MF Macular holes and excellent visual acuity. Arch Ophthalmol 1988;1061350- 1351
PubMedArticle
12.
Guyer  DRde Bustros  SDiener-West  MFine  SL Observations on patients with idiopathic macular holes and cysts. Arch Ophthalmol 1992;1101264- 1268
PubMedArticle
13.
Tadayoni  RMassin  PHaouchine  BCohen  DErginay  AGaudric  A Spontaneous resolution of small stage 3 and 4 full-thickness macular holes viewed by optical coherence tomography. Retina 2001;21186- 189
PubMedArticle
14.
Gass  JDM Idiopathic senile macular hole: its early stages and pathogenesis. Arch Ophthalmol 1988;106629- 639
PubMedArticle
15.
Johnson  RNGass  JDM Idiopathic macular holes: observations, stages of formation, and implications for surgical intervention. Ophthalmology 1988;95917- 924
PubMedArticle
16.
Funata  MWendel  RTde la Cruz  ZGreen  WR Clinicopathologic study of bilateral macular holes treated with pars plana vitrectomy and gas tamponade. Retina 1992;12289- 298
PubMedArticle
17.
Madreperla  SAGeiger  GLFunata  Mde la Cruz  ZGreen  WR Clinicopathologic correlation of a macular hole treated by cortical vitreous peeling and gas tamponade. Ophthalmology 1994;101682- 686
PubMedArticle
18.
Rosa  RHGlaser  BMde la Cruz  ZCGreen  WR Clinicopathologic correlation of an untreated macular hole and a macular hole treated by vitrectomy, transforming growth factor-β2, and gas tamponade. Am J Ophthalmol 1996;122853- 863
PubMed
19.
Frangieh  GTGreen  WREngel  HM A histopathologic study of macular cysts and holes. Retina 1981;1311- 336
PubMedArticle
20.
Madreperla  SAMcCuen  BW  IIHickingbotham  DGreen  WR Clinicopathologic correlation of surgically removed macular hole opercula. Am J Ophthalmol 1995;120197- 207
PubMed
21.
Fekrat  SWendel  RTde le Cruz  ZGreen  WR Clinicopathologic correlation of an epiretinal membrane associated with a recurrent macular hole. Retina 1995;1553- 57
PubMedArticle
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