Schwartz-Matsuo syndrome consists of three major clinical signs: rhegmatogenous retinal detachment (RRD), usually with oral dialyses or tears of the nonpigmented epithelium of the pars plana or pars plicata of the ciliary body; high intraocular pressure (IOP) with marked fluctuation; and the presence of aqueous cells, which also fluctuate in number. Human angiogenesis and growth factor biomarkers underlie many pathologic retinal angiogenesis, so it is likely that the expression of such cytokines in the Schwartz-Matsuo syndrome patient's aqueous humor is increased or decreased. Until now, there has been no report on such aqueous humor cytokines assay. In this article, a case report is presented with regular clinical signs, electron microscopic observation, and immunoassay results. Informed consent was signed by the patient for publication of this report and its related images.
A 36-year-old man presented with blurred vision and swelling pain in the left eye (OS) since 2 months prior to the medical examination. He had been struck with a fist in both eyes 10 years ago. Eye examination revealed visual acuity (VA) of 20/20 in the right eye (OD) and 20/125 OS. IOP was 15.4 mm Hg OD and 51.6 mm Hg OS. Physical examination OS showed conjunctival hyperemia, corneal edema, mild keratic precipitates, Tindall's phenomenon, and mild cell and flare in the anterior chamber. Gonioscopy revealed an open angle with no obvious abnormalities. Ultrasound biomicroscopy (UBM) demonstrated multiple ciliary body cysts (Figure 1). In the left eye, the anterior retina was detached near ora serrata from 8- to 12-o'clock meridian. The left eye of the patient was treated with the eye drops of 2% carteolol hydrochloride, 0.2% brimonidine tartrate, and 1% brinzolamide (Azopt; Alcon, Fort Worth, TX), twice a day respectively. He was also systemically administrated with 500 mg methazolamide (Neptazane; Perrigo, Allegan, MI) twice a day, and 250 mL 20% mannitol for 3 days. One week after treatment, the IOP OS decreased to 31.7 mm Hg, but still fluctuated from 31.7 mm Hg to 40.4 mm Hg in the following 2 weeks. The patient then received a scleral buckle surgery. Intraoperatively, paracentesis of anterior chamber was performed at 3-o'clock meridian corneoscleral limbus and 0.5 mL aqueous humor sample was obtained. Next day after the operation, the VA improved to 20/20 and IOP decreased to 15 mm Hg, which remained normal in follow-up.
Ultrasound biomicroscopic images of ciliary body cysts (arrows) between ciliary processes (radial section). (A) One cyst in the left eye. (B) Three cysts in the left eye. (C) Two cysts in the right eye.
Cytological examination under electron microscope (EM) for aqueous cells and demonstration of photoreceptor outer segments has been considered as the gold criteria for diagnosis and provided the experimental basis for the speculation of the mechanism of Schwartz-Matsuo syndrome.1–4 The electron microscopic examination result is shown in Figure 2. Consistent with past reports,3,5–7 numerous degenerated outer segments were detected in aqueous humor. The well-preserved outer segments had regularly arranged lamellar structures: two membranes composed a lamella, with edge loops at both ends and not continuous to the plasma membrane. These finding indicated that they were from rods.2 Our results support the speculation on the mechanism of Schwartz-Matsuo syndrome: outer segments flow from the subretinal space into the anterior chamber and covered the trabecular meshwork, which are similar to those ghost cells in hemolytic glaucoma.1–3
Electron micrograph of photoreceptor outer segments in the aqueous humor. (A) (×20,000) (bar gauge = 1 μm). (B, C, D) (×25,000) (bar gauge =1 μm). nOS = non-destroyed segments; pOS = partially destroyed outer segments; dOS = destroyed outer segments; gOS = ghost cell-like outer segments.
Until now, there was no report of human angiogenesis and growth factor biomarker cytokines immunoassay performed on the aqueous humor of Schwartz-Matsuo Syndrome patient. In this case, MILLIPLEX MAP Human Angiogenesis/Growth Factor Magnetic Bead Panel 1 (EMD Millipore, Burlington, MA), a 16-plex magnetic bead-based assay, was chosen to make simultaneous quantification of the following 17 human angiogenesis and growth factor biomarkers: angiopoietin-2, bone morphogenetic protein-9, epidermal growth factor (EGF), Endoglin, Endothelin-1, fibroblast growth factor (FGF)-1 (acidic FGF), FGF-2 (basic FGF), Follistatin, granulocyte colony-stimulating factor, heparin-binding EGF-like growth factor, hepatocyte growth factor, interleukin-8, Leptin, placental growth factor, vascular endothelial growth factor-A (VEGF-A), VEGF-C, and VEGF-D. Two patients with RRD without Schwartz-Matsuo syndrome (control RRD) and 10 patients with cataracts without RRD (non-RRD) were chosen to be the control. None of the patients had any other ocular disease.
The aqueous humor was centrifuged to remove debris. The plate was run on Luminex 200, HTS, FLEXMAP 3D or MAGPIX with xPONENT software (Thermo Fisher Scientific, Waltham, MA). The median fluorescent intensity (MFI) data were saved and analyzed. The levels of each cytokine in different samples are shown in Table 1. Several cytokines increased in Schwartz sample compared with non-RRD samples (Table 2). Only Angiopoietin-2 level increased significantly in Schwartz sample compared with the control RRD samples: 168.16 pg/mL and 18.33 pg/mL ± 4.26 pg/mL, respectively.
Cytokine Levels In Different Samples
Cytokines That Showed Increased Expression Comparing Schwartz to Non-RRD
The patient was found to have bilateral multiple ciliary body cysts. Ciliary body cysts, one type of anterior-segment cysts (ASCs), are uncommon and usually non-pigmented, small sacs arising from the posterior iris and ciliary body that may be detected incidentally. Most ASCs are stable and asymptomatic, but they can occasionally cause the elevation of IOP due to an increase in size and iris angulation.8 Trauma is also one of the causes of ciliary body cysts. Therefore, the differential diagnosis of this case includes not only glaucoma and iritis, but also ciliary body cysts. This patient had ciliary body cysts in both eyes, and the IOP of the fellow eye was normal. Besides, there was no sign of angle closure or narrowed pupillary aperture, which was the mechanism of ASC-induced high IOP, possibility of cysts as the cause of elevated IOP in this case was ruled out.
RRD, usually with oral dialyses or tears of the nonpigmented epithelium of the pars plana or pars plicata of the ciliary body, with secondary occurrence of high IOP with marked fluctuation, and aqueous cells is a clinical entity designated Schwartz-Matsuo syndrome (which is often referred to as Schwartz Syndrome, or sometimes Photoreceptor Outer Segment Glaucoma). The aqueous cells of these patients consist of photoreceptor outer segments, which clog the trabecular meshwork, and result in high IOP.1 Clinical diagnosis of this syndrome depends on the three main signs mentioned above, whereas cytological examination under EM is necessary for definite diagnosis to be made.1 However, the EM is not feasible in clinical routine practice. Thus, in this study, in addition to the EM, we attempted to identify cytokine in aqueous humor with significant change to assist the diagnosis of Schwartz Syndrome.
Besides VEGF, angiopoietin-2 is one of the key factors in hypoxia-mediated neovascularization, and both increase in response to hypoxia. VEGF is effective during the formation of the initial vascular plexus, and angiopoietins act later in the later phase of vascular development, such as remodeling, maturation and stabilization.9 VEGF's effect is reinforced by angionpoietin-2, and their combined effect facilitates the angiogenic response.9,10 In some ocular diseases such as RRD, hypoxia induces high level of VEGF and angiopoietin-2, and together they play a fundamental role in the stimulation of pathologic retinal angiogenesis.10–12 Although according to patients' description of present medical history, for reference, the period of impaired vision might partially represent the length of history of RRD, which of the study case was 2 months, that of the control RRD-1 was 1.5 months, and that of the control RRD-2 was 2 months. Additionally, there was no significant difference of the length of history of RRD between the study case and the control RRD. In this case, the detachment was located at anterior retina near ora serrata, where the blood supply is not as abundant as posterior retina, so the hypoxia was more severe and angiopoietin-2 was remarkably high compared with that of control RRD samples. VEGF expression was also elevated compared to that of non-RRD sample. There is also the possibility that the high IOP might lead to revascularization, subsequently resulting in elevated VEGF and angiopoietin-2 expression. According to the function of angiopoietin-2 and VEGF described above, more active retinal angiogenesis occurred. We speculate the newly formed vessels to some extend alleviated retinal hypoxia and provide more metabolic support to the retina. Owing to this, retinal degeneration (including photoreceptor cell death) was slowed down and outer segments were released into subretinal space continuously for a relatively longer time.9 Continuous supply of photoreceptor outer segments shedding from the detached retina into subretinal space is one of the two key factors to cause Schwartz-Matsuo syndrome.1 The mechanism described above may explain why the angiopoietin-2 and VEGF levels are increased and its correlation to Schwartz-Matsuo syndrome.
In this case, we demonstrated the remarkable high expression of angiopoietin-2 in aqueous humor from a patient with Schwartz-Matsuo Syndrome. Whether the over-expression of angiopoietin-2 is general in Schwartz-Matsuo Syndrome needs to be further investigated on more cases. Anyway, our result in this case may help us to illuminate the pathogenic mechanisms underlying Schwartz-Matsuo Syndrome. Perhaps cytokines could be able to assist the diagnosis of disease in the future.
- Matsuo T. Photoreceptor outer segments in aqueous humor: Key to understanding a new syndrome. Surv Ophthalmol. 1994;39(3):211–233. doi:10.1016/0039-6257(94)90195-3 [CrossRef]
- Matsuo N, Takabatake M, Ueno H, Nakayama T, Matsuo T. Photoreceptor outer segments in the aqueous humor in rhegmatogenous retinal detachment. Am J Ophthalmol. 1986;101(6):673–679. doi:10.1016/0002-9394(86)90767-1 [CrossRef]
- Netland PA, Mukai S, Covington HI. Elevated intraocular pressure secondary to rhegmatogenous retinal detachment. Surv Ophthalmol. 1994;39(3):234–240. doi:10.1016/0039-6257(94)90196-1 [CrossRef]
- Lambrou FH, Vela MA, Woods W. Obstruction of the trabecular meshwork by retinal rod outer segments. Arch Ophthalmol. 1989;107(5):742–745. doi:10.1001/archopht.1989.01070010760041 [CrossRef]
- Callender D, Jay JL, Barrie T. Schwartz-Matsuo syndrome: Atypical presentation as acute open angle glaucoma. Br J Ophthalmol. 1997;81(7):609–610. doi:10.1136/bjo.81.7.608b [CrossRef]
- Matsuo T, Muraoka N, Shiraga F, Matsuo N. Schwartz-Matsuo syndrome in retinal detachment with tears of the nonpigmented epithelium of the ciliary body. Acta Ophthalmol Scand. 1998;76(4):481–485. doi:10.1034/j.1600-0420.1998.760417.x [CrossRef]
- Mitry D, Constable I, Singh J. Photoreceptor outer segment glaucoma in rhegmatogenous retinal detachment. Arch Ophthalmol. 2009;127(8):1053–1054. doi:10.1001/archophthalmol.2009.147 [CrossRef]
- Dusak A, Baykara M, Ozkaya G, Erdogan C, Ozcetin H, Tuncel E. Ultrasound biomicroscopic evaluation of anterior segment cysts as a risk factor for ocular hypertension and closure angle glaucoma. Int J Ophthalmol. 2013;6(4):515–520.
- Joussen AM. Vascular plasticity – the role of the angiopoietins in modulating ocular angiogenesis. Graefes Arch Clin Exp Ophthalmol. 2001;239(12):972–975. doi:10.1007/s004170100365 [CrossRef]
- Campochiaro PA. Ocular neovascularization. J Mol Med (Berl). 2013;91(3):311–321. doi:10.1007/s00109-013-0993-5 [CrossRef]
- Hackett SF, Ozaki H, Strauss RW, et al. Angiopoietin 2 expression in the retina: Upregulation during physiologic and pathologic neovascularization. J Cell Physiol. 2000;184(3):275–284. doi:10.1002/1097-4652(200009)184:3<275::AID-JCP1>3.0.CO;2-7 [CrossRef]
- Loukovaara S, Lehti K, Robciuc A, et al. Increased intravitreal angiopoietin-2 levels associated with rhegmatogenous retinal detachment. Graefes Arch Clin Exp Ophthalmol. 2014;252(6):881–888. doi:10.1007/s00417-013-2508-z [CrossRef]
Cytokine Levels In Different Samples
Cytokines That Showed Increased Expression Comparing Schwartz to Non-RRD
|Cytokine||Schwartz (pg/mL)||Non-RRD (pg/mL)|
|Angiopoietin-2||168.16||44.48 ± 17.49|
|VEGF-C||24.86||10.13 ± 5.46|
|HB-EGF||2.99||1.21 ± 0.38|
|PLGF||6.11||2.55 ± 1.06|
|EGF||0.99||0.74 ± 0.08|
|IL-8||16.25||5.85 ± 3.62|