0
We're unable to sign you in at this time. Please try again in a few minutes.
Retry
We were able to sign you in, but your subscription(s) could not be found. Please try again in a few minutes.
Retry
There may be a problem with your account. Please contact the AMA Service Center to resolve this issue.
Contact the AMA Service Center:
Telephone: 1 (800) 262-2350 or 1 (312) 670-7827  *   Email: subscriptions@jamanetwork.com
Error Message ......
Access to paid content on this site is currently suspended due to excessive activity being detected from your IP address 54.211.190.232. Please contact the publisher to request reinstatement.
Clinical Sciences |

Clinical and Ocular Histopathological Findings in a Patient With Normal-Pressure Glaucoma FREE

Martin B. Wax, MD; Gülgün Tezel, MD; P. Deepak Edward, MD
[+] Author Affiliations

From the Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St Louis, Mo (Drs Wax and Tezel), and the University of Illinois, Chicago (Dr Edward). The authors have no proprietary interest in any of the materials used in this study.


Arch Ophthalmol. 1998;116(8):993-1001. doi:10.1001/archopht.116.8.993.
Text Size: A A A
Published online

Objective  To study the histopathological changes of eyes from a patient with normal-pressure glaucoma whose clinical and laboratory findings were well documented.

Methods  Postmortem histopathological findings in a patient with normal-pressure glaucoma who had monoclonal gammopathy and serum immunoreactivity to retinal proteins were examined in comparison with those of an age-matched control subject. Clinicopathological correlations to laboratory findings were examined.

Results  Clinical and histopathological findings of the patient, including cavernous degeneration of optic nerve and characteristic optic nerve cupping, were similar to those in patients with glaucoma who had high intraocular pressure. In addition, we found immunoglobulin G and immonuglobulin A deposition in the ganglion cells, inner and outer nuclear layers of the retina, and evidence of apoptotic retinal cell death using terminal deoxynucleotidyltransferase-mediated deoxyuridine triphosphate nick end labeling technique.

Conclusions  Serum antibodies to retinal proteins and retinal immunoglobulin deposition constitute novel findings in a patient with normal-pressure glaucoma and may contribute to better understanding of the mechanisms underlying glaucomatous optic neuropathy in this disorder.

Figures in this Article

GLAUCOMATOUS optic neuropathy is characterized by loss of retinal ganglion cells and their axons, excavated appearance of optic nerve head, and progressive loss of visual field sensitivity. Although clinical studies have shown the role of several risk factors in glaucomatous optic neuropathy, including high intraocular pressure (IOP),1,2 about 20% to 25% of glaucomatous optic neuropathy develops in patients with normal IOP.3 Despite several histopathological reports of postmortem human eyes from patients with primary open-angle glaucoma,47 and despite experimental studies using glaucoma models in which IOP is elevated,8,9 it is not clear whether the pathological findings of glaucomatous eyes with normal IOP are similar to those seen in glaucomatous eyes with high IOP. We herein present the clinical and postmortem histopathological findings in a patient with normal-pressure glaucoma, including evidence of immunoglobulin deposition in the retina and apoptotic retinal cell death using terminal deoxynucleotidyltransferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL) technique.10

CLINICAL FINDINGS

A 74-year-old, white woman received a diagnosis of normal-pressure glaucoma and was followed up for 5 years. The initial diagnosis was based on the presence of open iridocorneal angles, no evidence of IOP greater than 20 mm Hg without antiglaucoma treatment, progressive glaucomatous changes in visual fields and optic disc cupping, and absence of alternative causes of optic neuropathy. Alternative causes of optic neuropathy (ie, meningeal disease, infection, inflammation, ischemia, demyelinization, or compressive lesions) were excluded using neuro-ophthalmological examination with magnetic resonance imaging. She had coronary artery disease and family history of glaucoma. During the last 2 years of follow-up, she received topical β-blocker treatment in an effort to lower IOP from the middle to low teens and to retard progressive glaucomatous optic neuropathy.

During the initial diurnal IOP measurements (3 times between 6 AM and 5 PM and 3 times between 5 PM and 6 AM) and during regular visits every 3 to 6 months at which measurements were obtained using applanation tonometry, IOP readings never exceeded 20 mm Hg. A visual field analyzer, 30-2 program (Humphrey Instruments, San Leandro, Calif) was used for visual field examinations. Initial visual field defects were characterized by bilateral nasal steps and dense paracentral scotoma in the left eye close to fixation. These defects progressed compared with baseline values based on the glaucoma change probability analysis. In Figure 1, the last stereoscopic optic disc photographs of the patient taken 1 year before the date of death and first and last results of visual field testing (5-year interval) are shown. The patient had bilateral, large optic disc cups (larger in left than right eye) that further enlarged during follow-up. During regular optic disc examinations, recurrent optic disc hemorrhages were observed in both eyes. The patient had also bilateral advanced parapapillary chorioretinal atrophy consisting of the α and β zones.11 Results of indocyanin green angiography and early stages of fluorescein angiography showed nonperfusion areas of the choriocapillaris in the parapapillary region. Fundus fluorescein angiography demonstrated a window defect corresponding to zone α of parapapillary atrophy, in which there are pigmentary and structural changes of the retinal pigment epithelium. One of the nonperfusion areas that was located adjacent to the inferotemporal optic disc border corresponded to the more advanced zone of parapapillary atrophy (zone β). In the later stages of the fluorescein angiography, fluorescein diffusion was seen in the previously nonperfused area of the more advanced zone of parapapillary atrophy extending to optic disc (Figure 2).

Place holder to copy figure label and caption
Figure 1.

Clinical findings of glaucomatous optic neuropathy in a patient with normal-pressure glaucoma. Stereoscopic optic disc photographs of the right (A and B) and left (C and D) eyes; initial 30° visual field findings of the right (E) and left (G) eyes; and progression of visual field defects during 5-year follow-up of the right (F) and left (H) eyes are seen. Fixation losses, false positives, false negatives, pupil size, and fluctuations are as follows: E, 5/28, 0/17, 2/17, 5.5 mm, and 1.62 dB, respectively; F, 9/33, 0/20, 3/19, 5.0 mm, and 2.13 dB, respectively; G, 0/27, 0/18, 2/16, 5.0 mm, and 3.04 dB, respectively; and H, 8/24, 0/19, 1/14, 5.0 mm, and 1.68 dB, respectively.

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

Parapapillary atrophy in a patient with normal-pressure glaucoma. A and B, Indocyanin green angiography of the right eye showing the peripapapillary ischemic areas. Fundus fluorescein angiography of the same eye shows a window defect in zone α of parapapillary atrophy and a filling defect in zone β that is adjacent to inferotemporal optic disc border (C). D, Fluorescein diffused into zone β of parapapillary atrophy and optic disc in the late stages. E, Histopathological appearance of the parapapillary area with severe damage of retinal pigment epithelium and adjacent photoreceptors and choriocapillaris (arrow) (hematoxylin-eosin; original magnification ×100).

Graphic Jump Location

Laboratory studies revealed the presence of abnormal humoral autoimmunity, as demonstrated by an IgA-λ paraproteinemia in addition to anticardiolipin antibodies. To study the possible presence of antiretinal antibodies in serum, we performed immunoblotting using retinal substrates as previously described.12 Results of Western blot analysis and enzyme-linked immunosorbent assay showed the presence and high titers of circulating antibodies against several retinal proteins, including rhodopsin and heat shock proteins (hsp). Antibodies to retinal hsp included those directed to human and bacterial hsp60, hsp27, and αA-crystallin (Figure 3).

Place holder to copy figure label and caption
Figure 3.

Results of Western blot analysis of a patient with normal-pressure glaucoma. Each lane contains patient serum (dilution, 1:1000) against bovine retinal supernatant (BRS), bovine retinal membrane (BRM) (15 µg/lane), purified αA- and αB-crystallin, heat shock protein (hsp)27, bacterial (B) and human (H) hsp60, and rhodopsin (3 µg/lane), as labeled. Secondary antibody (goat anti–human IgG) dilution is 1:2000.

Graphic Jump Location
METHODS

Postmortem eyes of our patient with normal-pressure glaucoma and, for comparisons, of a 72-year-old, white female donor with no history of ocular or neurological disease were obtained. All eyes were enucleated within 4 hours of death and processed within 12 hours. All eyes were fixed in 10% formalin, processed, and embedded in paraffin. Eyes were sectioned in the coronal plane from the distal end of the optic nerve to the equator. Serial sections, 4 µm thick, were prepared. Some of the sections were stained with hematoxylin-eosin and examined under a light microscope. Some of the sections were used to identify the apoptotic cells or for immunohistochemical analysis.

Identification of the apoptotic cells was performed using TUNEL technique, an in situ end-labeling technique for apoptotic cells that couples 2 major approaches: morphological examination and DNA fragmentation.10 It is a sensitive and specific technique that allows precise and rapid identification and quantification of the cell population involved in apoptotic death. Using an in situ cell death detection kit (Boehringer Mannheim, Mannheim, Germany), deparaffinized sections were incubated with a mixture of fluorescein-labeled nucleotides and terminal deoxynucleotidyl transferase (TdT) from calf thymus for 1 hour. The TdT catalyzes the polymerization of labeled nucleotides to free 3‘-hydroxyl terminals of DNA fragments. A fluorescence microscope (Olympus, Tokyo, Japan) was used to visualize the apoptotic cells at the end of this period. Sections incubated with fluorescein-labeled nucleotide mixture without TdT served as a negative control. Sections previously treated with DNAse I (1 mg/mL) to induce breaks in the DNA strands served as a positive control.

The sections were also examined using Alcian blue to identify mucopolysaccharides, Masson trichrome to outline the areas of gliosis, Luxol fast blue to delineate the myelin sheaths of the optic nerve, phosphotungstic acid–hematoxylin to identify fibrin deposits in blood vessels, and Congo red to examine perivascular amyloid deposits.

We also performed immunohistochemical analysis to investigate the immunoglobulin deposition in the retina and optic nerve using antibodies against human IgG and IgA. For immunostaining, deparaffinized sections were incubated with proteinase K (20 µg/mL) for 20 minutes at room temperature. The samples were then treated with 3% bovine serum albumin at 37oC for 30 minutes to block nonspecific binding sites. After several washes, they were incubated at 37oC for 1 hour with fluorescein-conjugated monoclonal antibodies against human IgG or IgA (dilution, 1:16) (Sigma Chemical Company, St Louis, Mo). At the end of the incubation time, the sections were washed several times and examined using the fluorescence microscope. Age-matched healthy control eyes and antibodies against mouse immunoglobulins were used as negative controls.

The histopathological changes of the optic nerve head and retina were more severe in the left eye of the patient with normal-pressure glaucoma than those seen in the right eye that were correlated with the clinical appearance of the optic discs. Both optic nerve heads exhibited remarkable cupping characterized by disarrangement, compression, and backward bowing of lamina cribrosa. The number of axons passing through the nerve head were decreased, and there were compact bundles of extracellular matrix. However, in the normal eyes, the lamina cribrosa displayed a regular horizontal arrangement. In both eyes with normal-pressure glaucoma, there were empty spaces in the optic nerve suggestive of Schnabel cavernous degeneration that stained with Alcian blue (Figure 4). In the parapapillary area, the retinal pigment epithelium, choriocapillaris, and photoreceptors were atrophic (Figure 2).

Place holder to copy figure label and caption
Figure 4.

Optic nerve head in normal-pressure glaucoma. A, Optic disc cupping, posterior bowing of the lamina cribrosa (arrowheads), and Schnabel cavernous degeneration in the prelaminar (small arrows) and postlaminar (large arrows) areas of the right optic nerve head (Masson trichrome; original magnification ×25). B, Extensive Schnabel cavernous degeneration in the postlaminar area of the left optic nerve (S). Posterior bowing of the lamina cribrosa (arrowheads) is seen (hematoxylin-eosin; original magnification ×10). C, Cavernous areas in the left optic nerve (Alcian blue; original magnification ×25).

Graphic Jump Location

Examination of serial hematoxylin-eosin–stained sections of the retina from the patient with normal-pressure glaucoma revealed a significant loss of retinal ganglion cells and their axons compared with that of the control eyes. In addition, the thickness of the inner nuclear layer (3-4 cell layers) appeared to be diminished compared with that of control eyes (8-9 cell layers) (Figure 5, A). Examination of the retinal sections revealed occasional retinal cells with nuclear or cytoplasmic condensation, pyknotic nuclei, or apoptotic bodies. The TUNEL technique showed brightly fluorescein-stained nuclei representing fragmented DNA and nuclear chromatin condensation (Figure 5, B and C). The TUNEL-positive cells were found mostly in the ganglion cell layer of the retina; however, a few cells were found in the inner and outer nuclear layers. The TUNEL-positive ganglion cells were sparsely distributed, corresponding to 0.1% of the total number of ganglion cells in each section. The TUNEL-positive cells were virtually absent in the age-matched control eyes.

Place holder to copy figure label and caption
Figure 5.

Evidence of apoptosis in normal-pressure glaucoma. A, Loss of ganglion cells and their axons in the midperipheral retina of the patient with normal-pressure glaucoma. Arrowhead shows a ganglion cell with pyknotic nucleus and intact cytoplasm; arrows show a ganglion cell with condensed nucleus and shrunken cytoplasm (hematoxylin-eosin; original magnification ×100). B, Cells positively labeled using terminal deoxynucleotidyltransferase-mediated deoxyuridine triphosphate nick end labeling (TUNEL) technique (arrowheads) in the ganglion cells and inner nuclear layers of the retina sectioned from the eyes with normal-pressure glaucoma (original magnification ×40). C, Cells positively labeled using TUNEL technique (arrow) in the ganglion cells layer of the retina (original magnification ×100).

Graphic Jump Location

The inner retina and optic nerve head demonstrated a decrease in the number and volume of capillaries compared with the control eyes, especially in some areas that exhibited significant loss of ganglion cells and their axons. However, patent capillaries were still present, and normal red blood cells were seen in those vessels. On the right posterior laminar area of the optic nerve, scattered structures resembling the vascular lumen without endothelial cells (Figure 6) and adjacent areas of axonal swelling and microglial infiltration were noted. However, no amyloid or fibrin deposition was demonstrated along vessel walls, and the general loss of capillaries appeared proportionate to the loss of neural tissue in the retina and optic nerve head. The filling defects seen during angiography appeared to correlate with these findings.

Place holder to copy figure label and caption
Figure 6.

The appearance of vasculature in the patient with normal-pressure glaucoma. A, Diminished but intact retinal vasculature (hematoxylin-eosin; original magnification ×100). B, In the postlaminar area of the optic nerve, focal axonal swelling and adjacent, partly occluded vessel devoid of endothelial cells are seen (hematoxylin-eosin; original magnification ×100).

Graphic Jump Location

Immunostaining was observed with anti–human IgG and IgA antibodies in the retina and optic nerve head of the eyes with normal-pressure glaucoma, which demonstrates the presence of serum immunoglobulins in these tissues. Immunostaining was noticeable in ganglion cells and in the inner and outer nuclear layers of the retina. Control antibody did not stain these tissues, and the control eyes did not exhibit immunostaining with any of the antibodies used (Figure 7).

Place holder to copy figure label and caption
Figure 7.

Immunostaining of the retina from the patient with normal-pressure glaucoma with fluorescein-conjugated monoclonal antibodies to human immunoglobulins. Immunostaining with antibodies to human IgA (A) or IgG (C) is visible in the ganglion cells (g) and outer (on) and inner nuclear (in) layers of the retina sectioned from the patient. Fluorescein staining is not seen in the age-matched control eyes with antibodies to human IgA (B) or IgG (D) except normal autofluorescence.

Graphic Jump Location

We observed a disarrangement of the lamina cribrosa in our patient with normal IOP and glaucoma, similar to that described in patients with primary open-angle glaucoma.46 Similarly to our findings, Iwata13 has reported histopathological changes of the optic nerve head in normal-pressure glaucoma that were characterized by the disarrangement and backward bowing of the lamina cribrosa and loss of nerve fibers without evidence of vascular abnormality. Furthermore, histopathological optic nerve head changes correlated with the clinical appearance of the optic nerve head that is comparable in glaucoma with high and with normal IOP.14 It seems, then, that there are complex mechanisms related to individual anatomical, vascular, or other differences in the susceptibility to damage that result in similar changes of optic nerve head in glaucoma with high and normal IOP.

Several previous studies suggest the importance of the structural support of the lamina cribrosa and its role in optic nerve fiber damage resulting from distortion of the cribriform plates by elevated IOP. In postmortem glaucomatous eyes with high IOP and in experimental glaucoma models, there are dramatic changes in the lamina cribrosa, eg, disarrangement and remodeling.1518 However, it is not known whether these changes play a causal role in neural damage or whether they occur as a result of the rearrangement of optic nerve head tissues secondary to elevated IOP, glaucomatous neural tissue loss, and/or astroglial activation to rescue neural cells. The similar appearance of the lamina cribrosa in our patient to that in eyes with high IOP further suggests that, in many patients, the lamina cribrosa cannot sustain itself against elevated or normal IOP because of progressive weakness of the laminar beams, which may have a role in the increased vulnerability of remaining axons to mechanical forces.

Pathological studies of glaucomatous eyes from humans and experimental glaucoma models have demonstrated Schnabel cavernous degeneration in the optic nerve, which is characterized by the disappearance of axons, the accumulation of mucopolysaccharide within cavernous spaces, and the absence of macrophagic or glial proliferative reaction1922 similar to that observed in our patient with normal-pressure glaucoma. These features of cavernous degeneration are consistent with the apoptotic cell death and optic disc cupping that may develop secondary to the collapse of these cavernous spaces.

In experimental glaucoma models with elevated IOP, retinal ganglion cell death occurs mostly by apoptosis.8,9 Postmortem studies of human eyes with primary open-angle glaucoma also suggest apoptosis as a mechanism of retinal ganglion cell death.7 Our observation of the TUNEL-positive retinal cells in our patient suggests that apoptosis is also a mechanism of retinal cell death in glaucomatous eyes with normal IOP. These findings constitute, to the best of our knowledge, the first demonstration of apoptotic cell death in postmortem eyes with normal-pressure glaucoma. However, the mechanism(s) triggering the apoptotic retinal cell death in any form of glaucoma is unknown.

In glaucomatous eyes with high IOP, it has been hypothesized that the blockage of axoplasmic flow at the lamina cribrosa may block neurotrophic signaling from axon terminals in the lateral geniculate nucleus. Thus, retinal ganglion cells cannot obtain adequate amounts of neurotrophins to survive.7 Similarly, optic nerve transection may lead to apoptosis in retinal ganglion cells.8,9,23 Apoptotic retinal cell death may also be initiated with ischemia, as seen in anterior ischemic optic neuropathy24 or diabetes.25 The fact that apoptotic retinal ganglion cell death,24 cavernous degeneration of optic nerve,26,27 and excavation of the optic disc28,29 seen in glaucomatous optic neuropathy all may occur in anterior ischemic optic neuropathy suggests a shared common mechanism. However, there was no significant sign of vascular abnormality in our patient with normal-pressure glaucoma, except some scattered structures in one of the optic nerve heads resembling vascular lumen without endothelial cells.

We hypothesize that autoantibodies directed toward retinal antigens, as seen in our patient, may play a previously unrecognized role in facilitating apoptotic cell death in some patients with glaucomatous optic neuropathy, particularly those with normal IOP and evidence of serum abnormalities of humoral immunity.30 The serum from many patients with normal-pressure glaucoma contains higher titers of specific antibodies against several retinal proteins, including rhodopsin31 and hsp.12 Heat shock proteins are a family of cellular chaperone proteins of varying molecular weights that are considered neuroprotective, since their expression is induced in neurons to ameliorate damage in response to a variety of stress conditions, eg, ischemia and excitotoxicity.3234 Furthermore, they are highly antigenic, and the immune response to these proteins may have protective and pathogenic potential.35,36 The immune responses to hsp are implicated in the development of a number of human autoimmune diseases, including several types of inflammatory arthritis, type 1 diabetes mellitus, and multiple sclerosis.37,38

Mammalian retinal ganglion cells in culture express hsp72 in minutes to hours after exposure to hypothermic or hypoxic conditions, and this treatment renders the cells somewhat resistant to subsequent anoxia or glutamate treatment.39 Compelling evidence that retinal hsp are among the significant autoantigens in patients with glaucoma has recently been discovered.12 We propose that increased titers of circulating antibodies against retinal hsp, such as we have identified in our patient (Figure 3), may predispose toward retinal neuronal loss or damage of the vasculature of the retina or optic nerve due to antibody inactivation or attenuation of endogenously released retinal hsp. In this manner, high titers of autoantibodies to retinal hsp may contribute to glaucomatous optic neuropathy in these patients.

A previous report described an increased prevalence of monoclonal gammopathies in patients with normal-pressure glaucoma (12% in our current cohort) and hypothesized that the increased prevalence of paraproteinemias in patients with normal-pressure glaucoma suggests that autoimmunity may have a role in the glaucomatous disease process in these patients.30 Although the presence of a monoclonal protein in the serum of a patient with a peripheral neuropathy may be associated with systemic lymphoproliferative disorders (eg, multiple myeloma or lymphoma), the neuropathy is classified as a monoclonal gammopathy of undetermined significance40 if these disorders are excluded by appropriate studies, including bone marrow aspiration. Our patient's monoclonal gammopathy has been characterized as monoclonal gammopathy of undetermined significance.

Our finding of immunoglobulin deposition in the retina is the first such report in a patient with normal-pressure glaucoma and paraproteinemia. The potential pathogenic significance of paraproteinemias for glaucomatous optic neuropathy lies in the observation that a well-recognized spectrum of insidious, slowly progressive peripheral sensory and motor neuropathies has been demonstrated to be associated with benign monoclonal IgG, IgM, and IgA paraproteinemias.40,41 These paraproteins are considered to be likely causative agents of these peripheral neuropathies in which the neural antigenic targets of these proteins have been identified.42 In addition, there appears to be great similarity of the clinical course of patients with peripheral neuropathy and monoclonal gammopathy to that of patients with glaucoma. For example, the patients with peripheral neuropathy have reproducible features, with a symmetric sensory motor polyradiculopathy or neuropathy that is slowly progressive during months or years, and with a median age of 55 to 60 years.40,43

Approximately 20 years ago, a patient with peripheral neuropathy and IgM gammopathy was described, and IgM and IgM-producing lymphocytes were shown to have infiltrated the peripheral nerves.44 By 1982, 58 cases of monoclonal gammopathy were described in association with peripheral neuropathy.45 The demonstration of immunoglobulin deposition in peripheral nerves, combined with the recognition of a higher than usual prevalence of patients with paraproteinemia associated with peripheral neuropathy, was seminal in the recognition of the potential role of an autoantibody in the disease process. Unlike patients with peripheral neuropathies, patients with glaucoma cannot routinely be subjected to optic nerve biopsy to investigate the pathogenesis of their disease. We are therefore fortunate for the rare opportunity to study the ocular tissues in our patient with normal-pressure glaucoma and paraproteinemia promptly after her death. In our patient, immunoglobulin deposition in the ganglion cell layer and in the inner and outer nuclear layers may signify that proteins in these cell layers act as putative autoantigens in which an aberrant systemic humoral immune response has occurred.

Retinal immune deposits have been observed previously in cancer-associated retinopathy syndrome and have been suggested as a causative factor for retinal degeneration in these patients in whom there is no clinical evidence of a breakdown of the blood-retina barrier.46 However, we speculate that parapapillary chorioretinal atrophy commonly seen in patients with glaucoma,14 in which the outer blood-retina barrier is impaired, as supported by the clinical and pathological findings of our patient, may allow the circulating antibodies access to retinal antigens in these patients.

There is considerable evidence that autoantibodies can cause neuronal apoptotic cell death. It has been shown in many autoimmune diseases of the central nervous system that the specific interaction of an antibody with a target antigen or with voltage-gated channels (ie, Na+, Ca2+, and K+ channels) present on neural cells can result in selective neurological degeneration or dysfunction in these diseases.4749 In the eye, human serum antibodies specific to the retinal protein recoverin may enter retinal cells and cause apoptotic cell death.50 Thus, our observations of apoptotic retinal cell death and retinal immunoglobulin accumulation in a patient with normal-pressure glaucoma suggest that studies that further characterize the presence and role of retinal autoantibodies in similar patients will have important implications in elucidating the mechanism(s) of glaucomatous optic neuropathy.

Accepted for publication April 28, 1998.

This study was supported in part by grant EY06810 from the National Eye Institute, Bethesda, Md (Dr Wax); the Glaucoma Research Foundation, San Francisco, Calif; the American Health Assistance Foundation, Washington, DC; an unrestricted grant from Research to Prevent Blindness Inc, New York, NY (Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St Louis); the Otsuka Research Fellowship, Rockville, Md (Dr Edward); and a gift from the Binder Foundation, Chicago, Ill.

We thank Belinda McMahan for preparing the histopathological sections and the family of Mrs F. Koch.

Corresponding author: Martin B. Wax, MD, Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, Box 8096, 660 S Euclid Ave, St Louis, MO 63110 (e-mail: wax@am.seer.wustl.edu).

Drance  SMShulzer  MDouglas  GRSweeney  VP Use of discriminant analysis, II: identification of persons with glaucomatous visual field defects. Arch Ophthalmol. 1978;9657- 73
Hart  WMNYablonski  MKass  MABecker  B Multivariate analysis of the risk of glaucomatous visual field loss. Arch Ophthalmol. 1979;971455- 1458
Sommer  A Glaucoma: facts and fancies. Eye. 1996;10295- 301Doyne Lecture.
Quigley  HAGreen  WR The histology of human glaucoma cupping and optic nerve damage: clinicopathologic correlation in 21 eyes. Ophthalmology. 1979;861803- 1827
Quigley  HAHohmam  RMAddicks  EMMassof  RWGreen  WR Morphologic changes in the lamina cribrosa correlated with neural loss in open-angle glaucoma. Am J Ophthalmol. 1983;95673- 691
Quigley  HAAddicks  EMGreen  RManumenee  AE Optic nerve damage in human glaucoma, II: the site of injury and susceptibility to damage. Arch Ophthalmol. 1981;99635- 649
Kerrigan  LAZack  DJQuigley  HASmith  SCPease  ME TUNEL-positive ganglion cells in human primary open-angle glaucoma. Arch Ophthalmol. 1997;1151031- 1035
Quigley  HANickells  RWKerrigan  LAPease  METhibault  DJZack  DJ Retinal ganglion cell death in experimental glaucoma and after axotomy occurs by apoptosis. Invest Ophthalmol Vis Sci. 1995;36774- 786
Garcia-Valenzuela  EShareef  SWalsh  JSharma  SC Programmed cell death of retinal ganglion cells during experimental glaucoma. Exp Eye Res. 1995;6133- 44
Gavrieli  YSherman  YBen-Sasson  SA Identification of programmed cell death in situ via specific labeling of nuclear DNA fragmentation. J Cell Biol. 1992;119493- 501
Jonas  JBNguyen  XNGusek  GCNauman  GOH Parapapillary chorioretinal atrophy in normal and glaucoma eyes, I: morphometric data. Invest Ophthalmol Vis Sci. 1989;30908- 918
Wax  MBTezel  GSaito  I  et al.  Anti-Ro/SS-A positivity and heat shock protein antibodies in patients with normal pressure glaucoma. Am J Ophthalmol. 1998;125145- 157
Iwata  K Primary open angle glaucoma and low tension glaucoma: pathogenesis and mechanism of optic nerve damage. Nippon Ganka Gakkai Zasshi. 1992;961501- 1531
Tezel  GKass  MAKolker  AEWax  MB Comparative analysis of optic disc parameters in normal pressure glaucoma, primary open-angle glaucoma and ocular hypertension. Ophthalmology. 1996;1032105- 2113
Morrison  JCDorman-Pease  MEDunkelberger  GRQuigley  HA Optic nerve head extracellular matrix in primary optic atrophy and experimental glaucoma. Arch Ophthalmol. 1990;1081020- 1024
Hernandez  MRAndrzejewska  WMNeufeld  AH Changes in the extracellular matrix of the human optic nerve head in primary open-angle glaucoma. Am J Ophthalmol. 1990;109180- 188
Quigley  HABrown  ADorman-Pease  ME Alterations in elastin of the optic nerve head in human and experimental glaucoma. Br J Ophthalmol. 1991;75552- 557
Hernandez  MR Ultrastructural immunocytochemical analysis of elastin in the human lamina cribrosa: changes in elastic fibers in primary open-angle glaucoma. Invest Ophthalmol Vis Sci. 1992;332891- 2903
Schnabel  J Das Glaucomatose Sehnervenleiden. Arch Augenheilkd. 1892;24273- 292
Zimmerman  LE Pathology of glaucomatous cupping of optic nerve head. Armaly  MFBecker  BHaas  JS  et al. eds.Symposium on Glaucoma Transactions of the New Orleans Academy of Ophthalmology. St Louis, Mo Mosby–Year Book Inc1967;192- 207
Kalvin  NHHamasaki  DIGass  JDM Experimental glaucoma in monkeys. Arch Ophthalmol. 1966;7682- 103
Lampert  PWVogel  MHZimmerman  LE Pathology of the optic nerve in experimental acute glaucoma: electron microscopic studies. Invest Ophthalmol Vis Sci. 1968;7199- 213
Garcia-Valenzuela  EGorczyca  WDarzynkiewicz  ZSharma  SC Apoptosis in adult retinal ganglion cells after axotomy. J Neurobiol. 1994;25431- 438
Levin  LALouhab  A Apoptosis of retinal ganglion cells in anterior ischemic optic neuropathy. Arch Ophthalmol. 1996;114488- 491
Kohner  EMShilling  JSHamilton  AM The role of avascular retina in new vessel formation. Metab Ophthalmol. 1976;115- 23
Spencer  WHHoyt  WF A fatal case of giant-cell arteritis with ocular involvement. Arch Ophthalmol. 1960;64862- 867
Hinzpeter  ENNaumann  G Ischemic papilledema in giant-cell arteritis. Arch Ophthalmol. 1976;94624- 628
Hayreh  SS Pathogenesis of cupping of the optic disc. Br J Ophthalmol. 1974;58863- 876
Sebag  JThomas  JVEpstein  DLGrant  WM Optic disc cupping in arteritic anterior ischemic optic neuropathy resembles glaucomatous cupping. Ophthalmology. 1986;93357- 361
Wax  MBBarrett  DAPestronk  A Increased incidence of paraproteinemia and autoantibodies in patients with normal-pressure glaucoma. Am J Ophthalmol. 1994;117561- 568
Romano  CBarrett  DALi  ZPestronk  AWax  MB Anti-rhodopsin antibodies in sera from patients with normal pressure glaucoma. Invest Ophthalmol Vis Sci. 1995;361968- 1975
Birnbaum  G Stress proteins: their role in the normal central nervous system and in disease states, especially in multiple sclerosis. Springer Semin Immunopathol. 1995;17107- 118
Rordorf  GKoroshetz  WJBonventre  JV Heat shock protects cultured neurons from glutamate toxicity. Neuron. 1991;71043- 1051
Lowenstein  DHChan  PHMiles  MF The stress protein response in cultured neurons: characterization and evidence for a protective role in excitotoxicity. Neuron. 1991;71053- 1060
Young  RAElliott  TJ Stress proteins, infection, and immune surveillance. Cell. 1989;595- 8
Young  DB Chaperonins and the immune response. Cell Biol. 1990;127- 35
Lamb  JRBal  VMendez-Samperio  P  et al.  Stress proteins may provide a link between the immune response to infection and autoimmunity. Int Immunol. 1989;1191- 196
Young  DB Heat-shock proteins: immunity and autoimmunity. Curr Opin Immunol. 1992;4396- 400
Caprioli  JKitano  SMorgan  JE Hyperthermia and hypoxia increase tolerance of retinal ganglion cells to anoxia and excititoxicity. Invest Ophthalmol Vis Sci. 1996;372376- 2381
Kyle  RA Monoclonal proteins in neuropathy. Neurol Clin. 1992;10713- 734
Yeung  KBThomas  PKKing  RHM  et al.  The clinical spectrum of peripheral neuropathies associated with benign monoclonal IgM, IgG and IgA paraproteinaemia. J Neurol. 1991;238383- 391
Pestronk  A Motor neuropathies, motor neuron disorders, and antiglycolipid antibodies. Muscle Nerve. 1991;14927- 936
Kelly  JJKyle  RAO'Brien  PCDyck  PJ Prevalence of monoclonal protein in peripheral neuropathy. Neurology. 1981;311480- 1483
Forssman  OBjorkman  GHollender  AEnglund  N-I IgM-producing lymphocytes in peripheral nerve in a patient with benign monoclonal gammopathy. Scand J Haematol. 1973;11332- 335
Osby  ENoring  LHast  RKjellin  KGKnutsson  ESiden  A Benign monoclonal gammopathy and peripheral neuropathy. Br J Haematol. 1982;51531- 539
Grunwald  GBKornguth  SETowfighi  J  et al.  Autoimmune basis for visual paraneoplastic syndrome in patients with small cell lung carcinoma: retinal immune deposits and ablation of retinal ganglion cells. Cancer. 1987;60780- 786
Patrick  JLindstrom  J Autoimmune responses to acetylcholine receptor. Nature. 1973;180871- 872
Solimena  MDeCamilli  DP Autoimmunity to glutamic acid decarboxylase (GAD) in stiff-man syndrome and insulin-dependent diabetes mellitus. Trends Neurosci. 1991;14452- 454
Waxman  SG Sodium channel blockage by antibodies: a new mechanism of neurological disease. Ann Neurol. 1995;37421- 422
Adamus  GMachnicki  MSeigel  GM Apoptotic retinal cell death induced by antirecoverin autoantibodies of cancer-associated retinopathy. Invest Ophthalmol Vis Sci. 1997;38283- 291

Figures

Place holder to copy figure label and caption
Figure 1.

Clinical findings of glaucomatous optic neuropathy in a patient with normal-pressure glaucoma. Stereoscopic optic disc photographs of the right (A and B) and left (C and D) eyes; initial 30° visual field findings of the right (E) and left (G) eyes; and progression of visual field defects during 5-year follow-up of the right (F) and left (H) eyes are seen. Fixation losses, false positives, false negatives, pupil size, and fluctuations are as follows: E, 5/28, 0/17, 2/17, 5.5 mm, and 1.62 dB, respectively; F, 9/33, 0/20, 3/19, 5.0 mm, and 2.13 dB, respectively; G, 0/27, 0/18, 2/16, 5.0 mm, and 3.04 dB, respectively; and H, 8/24, 0/19, 1/14, 5.0 mm, and 1.68 dB, respectively.

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

Parapapillary atrophy in a patient with normal-pressure glaucoma. A and B, Indocyanin green angiography of the right eye showing the peripapapillary ischemic areas. Fundus fluorescein angiography of the same eye shows a window defect in zone α of parapapillary atrophy and a filling defect in zone β that is adjacent to inferotemporal optic disc border (C). D, Fluorescein diffused into zone β of parapapillary atrophy and optic disc in the late stages. E, Histopathological appearance of the parapapillary area with severe damage of retinal pigment epithelium and adjacent photoreceptors and choriocapillaris (arrow) (hematoxylin-eosin; original magnification ×100).

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

Results of Western blot analysis of a patient with normal-pressure glaucoma. Each lane contains patient serum (dilution, 1:1000) against bovine retinal supernatant (BRS), bovine retinal membrane (BRM) (15 µg/lane), purified αA- and αB-crystallin, heat shock protein (hsp)27, bacterial (B) and human (H) hsp60, and rhodopsin (3 µg/lane), as labeled. Secondary antibody (goat anti–human IgG) dilution is 1:2000.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 4.

Optic nerve head in normal-pressure glaucoma. A, Optic disc cupping, posterior bowing of the lamina cribrosa (arrowheads), and Schnabel cavernous degeneration in the prelaminar (small arrows) and postlaminar (large arrows) areas of the right optic nerve head (Masson trichrome; original magnification ×25). B, Extensive Schnabel cavernous degeneration in the postlaminar area of the left optic nerve (S). Posterior bowing of the lamina cribrosa (arrowheads) is seen (hematoxylin-eosin; original magnification ×10). C, Cavernous areas in the left optic nerve (Alcian blue; original magnification ×25).

Graphic Jump Location
Place holder to copy figure label and caption
Figure 5.

Evidence of apoptosis in normal-pressure glaucoma. A, Loss of ganglion cells and their axons in the midperipheral retina of the patient with normal-pressure glaucoma. Arrowhead shows a ganglion cell with pyknotic nucleus and intact cytoplasm; arrows show a ganglion cell with condensed nucleus and shrunken cytoplasm (hematoxylin-eosin; original magnification ×100). B, Cells positively labeled using terminal deoxynucleotidyltransferase-mediated deoxyuridine triphosphate nick end labeling (TUNEL) technique (arrowheads) in the ganglion cells and inner nuclear layers of the retina sectioned from the eyes with normal-pressure glaucoma (original magnification ×40). C, Cells positively labeled using TUNEL technique (arrow) in the ganglion cells layer of the retina (original magnification ×100).

Graphic Jump Location
Place holder to copy figure label and caption
Figure 6.

The appearance of vasculature in the patient with normal-pressure glaucoma. A, Diminished but intact retinal vasculature (hematoxylin-eosin; original magnification ×100). B, In the postlaminar area of the optic nerve, focal axonal swelling and adjacent, partly occluded vessel devoid of endothelial cells are seen (hematoxylin-eosin; original magnification ×100).

Graphic Jump Location
Place holder to copy figure label and caption
Figure 7.

Immunostaining of the retina from the patient with normal-pressure glaucoma with fluorescein-conjugated monoclonal antibodies to human immunoglobulins. Immunostaining with antibodies to human IgA (A) or IgG (C) is visible in the ganglion cells (g) and outer (on) and inner nuclear (in) layers of the retina sectioned from the patient. Fluorescein staining is not seen in the age-matched control eyes with antibodies to human IgA (B) or IgG (D) except normal autofluorescence.

Graphic Jump Location

Tables

References

Drance  SMShulzer  MDouglas  GRSweeney  VP Use of discriminant analysis, II: identification of persons with glaucomatous visual field defects. Arch Ophthalmol. 1978;9657- 73
Hart  WMNYablonski  MKass  MABecker  B Multivariate analysis of the risk of glaucomatous visual field loss. Arch Ophthalmol. 1979;971455- 1458
Sommer  A Glaucoma: facts and fancies. Eye. 1996;10295- 301Doyne Lecture.
Quigley  HAGreen  WR The histology of human glaucoma cupping and optic nerve damage: clinicopathologic correlation in 21 eyes. Ophthalmology. 1979;861803- 1827
Quigley  HAHohmam  RMAddicks  EMMassof  RWGreen  WR Morphologic changes in the lamina cribrosa correlated with neural loss in open-angle glaucoma. Am J Ophthalmol. 1983;95673- 691
Quigley  HAAddicks  EMGreen  RManumenee  AE Optic nerve damage in human glaucoma, II: the site of injury and susceptibility to damage. Arch Ophthalmol. 1981;99635- 649
Kerrigan  LAZack  DJQuigley  HASmith  SCPease  ME TUNEL-positive ganglion cells in human primary open-angle glaucoma. Arch Ophthalmol. 1997;1151031- 1035
Quigley  HANickells  RWKerrigan  LAPease  METhibault  DJZack  DJ Retinal ganglion cell death in experimental glaucoma and after axotomy occurs by apoptosis. Invest Ophthalmol Vis Sci. 1995;36774- 786
Garcia-Valenzuela  EShareef  SWalsh  JSharma  SC Programmed cell death of retinal ganglion cells during experimental glaucoma. Exp Eye Res. 1995;6133- 44
Gavrieli  YSherman  YBen-Sasson  SA Identification of programmed cell death in situ via specific labeling of nuclear DNA fragmentation. J Cell Biol. 1992;119493- 501
Jonas  JBNguyen  XNGusek  GCNauman  GOH Parapapillary chorioretinal atrophy in normal and glaucoma eyes, I: morphometric data. Invest Ophthalmol Vis Sci. 1989;30908- 918
Wax  MBTezel  GSaito  I  et al.  Anti-Ro/SS-A positivity and heat shock protein antibodies in patients with normal pressure glaucoma. Am J Ophthalmol. 1998;125145- 157
Iwata  K Primary open angle glaucoma and low tension glaucoma: pathogenesis and mechanism of optic nerve damage. Nippon Ganka Gakkai Zasshi. 1992;961501- 1531
Tezel  GKass  MAKolker  AEWax  MB Comparative analysis of optic disc parameters in normal pressure glaucoma, primary open-angle glaucoma and ocular hypertension. Ophthalmology. 1996;1032105- 2113
Morrison  JCDorman-Pease  MEDunkelberger  GRQuigley  HA Optic nerve head extracellular matrix in primary optic atrophy and experimental glaucoma. Arch Ophthalmol. 1990;1081020- 1024
Hernandez  MRAndrzejewska  WMNeufeld  AH Changes in the extracellular matrix of the human optic nerve head in primary open-angle glaucoma. Am J Ophthalmol. 1990;109180- 188
Quigley  HABrown  ADorman-Pease  ME Alterations in elastin of the optic nerve head in human and experimental glaucoma. Br J Ophthalmol. 1991;75552- 557
Hernandez  MR Ultrastructural immunocytochemical analysis of elastin in the human lamina cribrosa: changes in elastic fibers in primary open-angle glaucoma. Invest Ophthalmol Vis Sci. 1992;332891- 2903
Schnabel  J Das Glaucomatose Sehnervenleiden. Arch Augenheilkd. 1892;24273- 292
Zimmerman  LE Pathology of glaucomatous cupping of optic nerve head. Armaly  MFBecker  BHaas  JS  et al. eds.Symposium on Glaucoma Transactions of the New Orleans Academy of Ophthalmology. St Louis, Mo Mosby–Year Book Inc1967;192- 207
Kalvin  NHHamasaki  DIGass  JDM Experimental glaucoma in monkeys. Arch Ophthalmol. 1966;7682- 103
Lampert  PWVogel  MHZimmerman  LE Pathology of the optic nerve in experimental acute glaucoma: electron microscopic studies. Invest Ophthalmol Vis Sci. 1968;7199- 213
Garcia-Valenzuela  EGorczyca  WDarzynkiewicz  ZSharma  SC Apoptosis in adult retinal ganglion cells after axotomy. J Neurobiol. 1994;25431- 438
Levin  LALouhab  A Apoptosis of retinal ganglion cells in anterior ischemic optic neuropathy. Arch Ophthalmol. 1996;114488- 491
Kohner  EMShilling  JSHamilton  AM The role of avascular retina in new vessel formation. Metab Ophthalmol. 1976;115- 23
Spencer  WHHoyt  WF A fatal case of giant-cell arteritis with ocular involvement. Arch Ophthalmol. 1960;64862- 867
Hinzpeter  ENNaumann  G Ischemic papilledema in giant-cell arteritis. Arch Ophthalmol. 1976;94624- 628
Hayreh  SS Pathogenesis of cupping of the optic disc. Br J Ophthalmol. 1974;58863- 876
Sebag  JThomas  JVEpstein  DLGrant  WM Optic disc cupping in arteritic anterior ischemic optic neuropathy resembles glaucomatous cupping. Ophthalmology. 1986;93357- 361
Wax  MBBarrett  DAPestronk  A Increased incidence of paraproteinemia and autoantibodies in patients with normal-pressure glaucoma. Am J Ophthalmol. 1994;117561- 568
Romano  CBarrett  DALi  ZPestronk  AWax  MB Anti-rhodopsin antibodies in sera from patients with normal pressure glaucoma. Invest Ophthalmol Vis Sci. 1995;361968- 1975
Birnbaum  G Stress proteins: their role in the normal central nervous system and in disease states, especially in multiple sclerosis. Springer Semin Immunopathol. 1995;17107- 118
Rordorf  GKoroshetz  WJBonventre  JV Heat shock protects cultured neurons from glutamate toxicity. Neuron. 1991;71043- 1051
Lowenstein  DHChan  PHMiles  MF The stress protein response in cultured neurons: characterization and evidence for a protective role in excitotoxicity. Neuron. 1991;71053- 1060
Young  RAElliott  TJ Stress proteins, infection, and immune surveillance. Cell. 1989;595- 8
Young  DB Chaperonins and the immune response. Cell Biol. 1990;127- 35
Lamb  JRBal  VMendez-Samperio  P  et al.  Stress proteins may provide a link between the immune response to infection and autoimmunity. Int Immunol. 1989;1191- 196
Young  DB Heat-shock proteins: immunity and autoimmunity. Curr Opin Immunol. 1992;4396- 400
Caprioli  JKitano  SMorgan  JE Hyperthermia and hypoxia increase tolerance of retinal ganglion cells to anoxia and excititoxicity. Invest Ophthalmol Vis Sci. 1996;372376- 2381
Kyle  RA Monoclonal proteins in neuropathy. Neurol Clin. 1992;10713- 734
Yeung  KBThomas  PKKing  RHM  et al.  The clinical spectrum of peripheral neuropathies associated with benign monoclonal IgM, IgG and IgA paraproteinaemia. J Neurol. 1991;238383- 391
Pestronk  A Motor neuropathies, motor neuron disorders, and antiglycolipid antibodies. Muscle Nerve. 1991;14927- 936
Kelly  JJKyle  RAO'Brien  PCDyck  PJ Prevalence of monoclonal protein in peripheral neuropathy. Neurology. 1981;311480- 1483
Forssman  OBjorkman  GHollender  AEnglund  N-I IgM-producing lymphocytes in peripheral nerve in a patient with benign monoclonal gammopathy. Scand J Haematol. 1973;11332- 335
Osby  ENoring  LHast  RKjellin  KGKnutsson  ESiden  A Benign monoclonal gammopathy and peripheral neuropathy. Br J Haematol. 1982;51531- 539
Grunwald  GBKornguth  SETowfighi  J  et al.  Autoimmune basis for visual paraneoplastic syndrome in patients with small cell lung carcinoma: retinal immune deposits and ablation of retinal ganglion cells. Cancer. 1987;60780- 786
Patrick  JLindstrom  J Autoimmune responses to acetylcholine receptor. Nature. 1973;180871- 872
Solimena  MDeCamilli  DP Autoimmunity to glutamic acid decarboxylase (GAD) in stiff-man syndrome and insulin-dependent diabetes mellitus. Trends Neurosci. 1991;14452- 454
Waxman  SG Sodium channel blockage by antibodies: a new mechanism of neurological disease. Ann Neurol. 1995;37421- 422
Adamus  GMachnicki  MSeigel  GM Apoptotic retinal cell death induced by antirecoverin autoantibodies of cancer-associated retinopathy. Invest Ophthalmol Vis Sci. 1997;38283- 291

Correspondence

CME
Meets CME requirements for:
Browse CME for all U.S. States
Accreditation Information
The American Medical Association is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The AMA designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditTM per course. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Physicians who complete the CME course and score at least 80% correct on the quiz are eligible for AMA PRA Category 1 CreditTM.
Note: You must get at least of the answers correct to pass this quiz.
You have not filled in all the answers to complete this quiz
The following questions were not answered:
Sorry, you have unsuccessfully completed this CME quiz with a score of
The following questions were not answered correctly:
Commitment to Change (optional):
Indicate what change(s) you will implement in your practice, if any, based on this CME course.
Your quiz results:
The filled radio buttons indicate your responses. The preferred responses are highlighted
For CME Course: A Proposed Model for Initial Assessment and Management of Acute Heart Failure Syndromes
Indicate what changes(s) you will implement in your practice, if any, based on this CME course.
NOTE:
Citing articles are presented as examples only. In non-demo SCM6 implementation, integration with CrossRef’s "Cited By" API will populate this tab (http://www.crossref.org/citedby.html).
Submit a Comment

Multimedia

Some tools below are only available to our subscribers or users with an online account.

Related Content

Customize your page view by dragging & repositioning the boxes below.

See Also...
Articles Related By Topic
PubMed Articles