Ординатура / Офтальмология / Английские материалы / Age-Related Changes of the Human Eye_Cavallotti, Cerulli_2008
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surgery, PVR is reported to occur in approximately 5-10 percent of rhegmatogenous retinal detachments.120,121 Because of its detrimental effect on visual function, PVR has been studied extensively over the last three decades.122,123
Preoperative risk factors for the development of PVR include size of retinal tear, multiple retinal tears, inflammation, vitreous hemorrhage, aphakia, and presence of preoperative choroidal effusion.124,125,126 Because PVR is rare in exudative retinal detachments, full-thickness retinal tears are considered to play a crucial role in the pathogenesis of membrane formation. The operative risk factors for postoperative PVR have been difficult to reproducibly quantify, but do include excessive amounts of cryotherapy, laser photocoagulation, and diathermy.127 When membrane contraction is sufficient to distort the retina, the lesion is described as a starfold. Epiretinal membranes in PVR tend to be more severe in the inferior quadrants and posterior to the equator. Proliferative membranes can form on either side of the retina. The more advanced stages of the disorder are characterized by the presence of fixed retinal folds in four quadrants. If left untreated, these detachments will progress to a closed funnel configuration.
The cellular composition of PVR has been studied extensively, and generally contains the same cells found in other vitreous membranes, although RPE cells are consistently present. Macrophages and lymphocytes are also commonly seen.128 As in other membranes, their contractile properties have been attributed to the presence of myofibroblasts. The extracellular matrix of PVR is made up of types I, II, IV and V collagen, laminin, and tenascin.129
A variety of clinical observations and experimental studies have emphasized the importance of inflammation in the pathogenesis of PVR.130 The identification of fibronectin (both cellular and plasma-derived), plasma-derived growth factors, macrophages, and help/suppressor lymphocytes reflect how similar PVR is to the prototypical inflammatory-repair process.131
In 1983, the Retina Society developed a classification system for PVR to improve communication among clinicians and to facilitate interpretation of clinical studies.132 Because of certain shortcomings in that system, the Silicone Study Group modified the classification algorithm. The classification system developed by the Silicone Group includes separate descriptions and grading of anterior and posterior forms of PVR.133 It also recognizes three different patterns of proliferation— focal, diffuse, and subretinal.
Treatment
Although the management of PVR is beyond the scope of this review, a basic overview is provided. While drugs and drug delivery systems that modulate the natural history of PVR are being developed and tested, the general approach to the treatment of retinal detachment with PVR is still surgical. The basic principles of surgical repair include closure of all retinal breaks, relief of anatomically important traction, and appropriate timing of corrective intervention. The overall approach to surgery is stratified according to the severity of clinical findings.
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The closure of retinal breaks with a chorioretinal adhesion is considered of primary importance because it allows for a more rapid return of homeostatic forces—particularly the function of the RPE pump. Although chorioretinal scar formation can be induced through freeze-thaw injury (cryopexy), diathermy, or laser photocoagulation, these processes also induce breakdown of the blood-ocular barrier, which can exacerbate PVR. The association of PVR with excessive cryotherapy has been used as a long-standing argument for its abandonment.134 Whichever method of scar induction is used, it is imperative to use no more thermal energy than necessary to insure closure of the retinal tear.
The relief of retinal traction can be accomplished through external buckling (scleral buckling), and/or removal of contracting bands and membranes through various vitrectomy techniques.135 Subretinal fibrosis, while not uncommon in PVR, does not commonly result in clinically significant traction. In those situations in which subretinal bands of fibrous tissue prevent reattachment of the retina, the tissue can be dissected through a retinotomy.136
After all elements of traction are relieved following vitrectomy, fluid-gas exchange can be performed to insure extended internal tamponade of retinal breaks. In cases of severe PVR, there has been considerable debate over the relative merits of the substances used for tamponade. The two major classes of agents used for intraocular tamponade are long-acting gases and silicone oil. The controversy over their use in PVR led to the Silicone Study, which began recruitment in 1985. Enrollment ended in 1990.137 The study provided a trove of information about the behavior of PVR and the nuances of its management. The main findings were that perfluoropropane gas was equally effective in terms of visual outcome and anatomic reattachment to silicone oil, placing greater weight on secondary outcome measures, like complications. Both perfluoropropane gas and silicone oil produced superior results to sulfur hexafluoride gas, even though both gases were not compared head-to-head in a randomized manner.138,139 Long-term follow-up of 36 months showed there was no significant difference between silicone oil and perfluoropropane gas in terms of achieving visual acuity of 5/200, or in terms of secondary keratopathy.140
In general, visual prognosis in patients with PVR is based on severity of preoperative findings, including initial visual acuity, duration of detachment, and extent of detachment.125,141 Because visual outcome is substantially better in cases requiring only a single surgery, careful planning of the primary procedure is vitally important.
Cells within the Vitreous
Under normal clinical conditions, the vitreous appears acellular, or pauci cellular, at most. Any increase in the number of cells in the vitreous beyond this baseline needs to be regarded as abnormal, and an appropriate diagnostic evaluation undertaken. The two major categories of disease that present with vitreous cells are
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inflammatory disease and lymphoma—with the great majority of all cases due to an underlying inflammatory process. While the number of inflammatory disorders that can cause secondary vitritis is large (e.g., differential diagnosis of posterior uveitis), there are relatively few conditions other than lymphoma that present as neoplastic vitritis. Metastatic vitritis from a systemic malignancy in the absence of uveal metastasis is rare.142
Primary Ocular Lymphoma
Primary ocular lymphoma (POL) describes a subset of B-cell lymphoma known as primary central nervous system lymphoma. Also know as reticular cell sarcoma in the older literature, POL often co-exists with primary central nervous system lymphoma. When POL presents as an isolated B-cell lymphoma of the retina, optic nerve head, or vitreous, the diagnostic evaluation can be challenging.143 This is particularly true when vitreous cells from POL occur without signs of retinal disease.
The incidence of primary central nervous system lymphoma is 1 per 100,000, or approximately 1/6 as common as uveal melanoma.144 POL is a disease of older persons with the majority of patients diagnosed between the late 50s and late 60s. Approximately three-quarters of the persons who present with ocular disease will ultimately have CNS involvement.145,146
The majority of patients with POL present with a picture of uveitis or vitritis that is not responsive to conventional therapy.147 Decreased vision, floaters, and photophobia are common complaints from patients with neoplastic vitritis. While the clinical appearance of the vitreous is nonspecific (similar to inflammatory vitritis), retinal lesions, if present, provide an important clue about the underlying diagnosis. The retinal tumors are cream-colored and covered by varying amounts of clumped RPE. When visualization of the fundus is not impeded by vitreous cells, the appearance of the retina is the most direct means of establishing a strong presumptive diagnosis of POL (see Fig. 8.13).
Clinical-pathological correllation studies have shown that the malignant B cells accumulate initially between Bruch’s membrane and the RPE, creating a characteristic detachment of the cellular monolayer (see Fig. 8.14). The transition from normal retina to RPE detachment is usually abrupt. Over days to weeks, the progressive destruction of the overlying RPE reveals the lesion’s cream color.
When the diagnosis of POL is considered, neurological examination and appropriate radiological studies should be undertaken to exclude primary central nervous system lymphoma because of the close relationship between the two entities. Both computed tomography and magnetic resonance imaging are useful in this regard. Nearly 70 percent of patients with primary central nervous system lymphoma have a solitary lesion on initial scan. Most patients with POL will develop multifocal disease of the brain as the lymphoma progresses.148
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Fig. 8.13 Retinal fundus in a patient with primary ocular lymphoma shows large cream color lesions. The edges of the lesions are discrete. Their surface reveals small residual clumps of pigment epithelium
Fig. 8.14 Retinal pigment epithelial (RPE) detachments due to primary ocular lymphoma. A larger RPE detachment is present to the left (arrows), and a smaller RPE detachment is noted on the right (arrowheads). Tumor cells are present beneath the RPE, resting on Bruch’s membrane (arrows and arrowheads). Tumor cells are two to four times larger than reactive lymphocytes in the choroids. Lymphoma cells are also in the subretinal space.(hematoxylin-eosin, 390x original magnification)
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When POL is suspected in both the eye and the central nervous system, tissue diagnosis can often be made by examination of the cerebral spinal fluid. In cases where the only manifestation of suspected POL is the eye, a diagnostic vitrectomy is necessary to harvest tissue. Most laboratories prefer to have fresh tissue brought immediately for processing.149 Cytologically, the cells of POL have large hyperchromatic nuclei and scant cytoplasm consistent with large cell lymphoma (see Fig. 8.15). Tumor cells may be associated with vitreous debris, necrosis, and reactive inflammatory cells. When the clinical suspicion of POL is high, and vitreous cytology benign, it is possible that malignant cells exist beneath the RPE but have not yet breached the neurosenory retina. A subretinal biopsy may be necessary to harvest an adequate specimen.150 Chorioretinal biopsy is another option, when vitreous cytology is nondiagnostic.151
Because the rate of false-negative biopsy is high,70 several other diagnostic modalities have been applied in this clinical setting. The immunoglobulin gene rearrangements that normally occur during lymphocyte maturation provide the basis for the molecular diagnosis of lymphoma.152 The demonstration of a predominant gene rearrangement allows for the identification of clonal expansions of malignant lymphocytes in an arrested phase of development. Because lymphoma represents the proliferation of unregulated lymphocytes, most neoplastic lymphocytes are conveniently tagged with a surface marker reflecting their aberrant ontology. The restricted expression of B-cell markers (CD19, CD20, CD22) are a phenotypic characteristic of POL and a useful clinical tool to distinguish these cells from other malignancies.153 The laboratory evaluation of lymphoma is
Fig. 8.15 Vitreous biopsy of primary ocular lymphoma shows large atypical cells, many of which have poorly discernable cytoplasm. The cell nuclei measure up to 40 microns.(Papanicolaou stain, 430x original magnification)
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directed towards identifying the expanded clone of neoplastic cells, either through phenotypic typing or genotypic analysis.
Flow cytometry has become a mainstay in the diagnosis of systemic lymphoma, usually enhancing the capabilities of histopathology to classify tumors. Flow cytometry of a vitreous biopsy can yield false negative results if tumor cells remain beneath the RPE and only inflammatory cells are present in the vitreous. Flow studies can test for several markers simultaneously, increasing the likelihood of a positive result and enhancing correlation with histological interpretation.154 Flow cytometry will not replace cytological examination of the vitreous, but does effectively compliment tissue diagnosis.155,156 The role of flow cytometry to diagnosis lymphoma in situations where the cytological diagnosis of POL is negative, or inconclusive, is not established.
Genotypic analysis for the germline mutation can also be used to establish the diagnosis of POL. For most B-cell lymphomas, the heavy chain immunoglobulin (IgH) gene sequence is selected. When the Southern blot technique was the standard method of identifying DNA gene rearrangements, the amount of material obtained from a vitreous biopsy was often inadequate for analysis. Problems with small sample size have been overcome with the introduction of polymerase chain reaction (PCR), which requires less than one-tenth the amount of DNA for analysis compared to Southern blot. PCR can be run on fresh or paraffin-embedded tissue, which makes the study of archival cases possible. Several different primers can be used for PCR in this setting.157,158 In one study of 57 samples of POL, all demonstrated the IgH germline mutation at the CDR3 site.159
The use of cytokine concentration in the vitreous to diagnosis POL is more controversial. The theory behind their use is based on the fact that interleukin-6 is produced in high levels by inflammatory cells, while interleukin-10 is released by neoplastic B cells. The ratio of interleukin-10 to interleukin-6 in the vitreous has been promoted as a diagnostic test of POL. Several studies recommend a ratio of greater than 1.0 be used as the cutoff for POL.160,161,162 Not everyone agrees on the sensitivity or specificity of the test. Reports of POL with interleukin ratios less than 1.0 have cast doubt on the predictive value of the test.163,164 Because vitreous interleukin assays are not yet standardized, the reliability of laboratory results must always be considered when weighing clinical evidence.
Treatment
The management of patients with POL and primary central nervous system lymphoma is undergoing constant modification. In general, treatment differs from that of systemic lymphoma, whose drug regimens tend to have limited efficacy in penetrating the blood-retinal and blood-brain barriers. Optimal treatments for POL have not been determined. Intravenous methotrexate has been the standard drug used in most regiments because of its ability to penetrate the globe.165 More recently, other trials using Ara-C alone or in combination with methotrexate have been reported.166,167,168 While the management of POL and primary central nervous
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system lymphoma is beyond the scope of this chapter, other options include combinations of whole-brain and ocular radiation in concert with systemic and intrathecal chemotherapy.169
Isolated POL presents several management dilemmas in which there is little evidence-based data to fall back on. How frequently patients with POL need to be monitored for central nervous system disease is one example. Initially, treatment consisted of ocular radiation, but it soon became evident that the rate of local complication was so high that radiation was generally abandoned. An alternative means of delivering localized treatment is through intravitreous injection of methotrexate. Results of several small series have been published and appear encouraging. Initially used as an adjunct to systemic chemotherapy and radiation therapy, intravitreous methotexate was able to induce a local remission in seven of seven patients with follow-up between nine and 19 months.170 Another series used an induction phase of twice weekly intravitreous injections followed by weekly injections (consolidation phase).171 The majority of eyes were free of tumors, but required up to 12 injections. Three patients had recurrences, but all responded to a repeat course of injections. Intravitreous methotrexate seems well-suited for persons with POL isolated to the eye because it minimizes systemic toxicity while delivering a high concentration of the drug to the tumor. Long-term monitoring for central nervous system involvement, however, is mandatory. While a variety of local complications can occur, including cataracts, corneal decompensation, and maculopathy, their overall impact is less severe than the complications of ocular radiation.97,98 Delivering methotrexate by intravitreous injection prolongs the drug’s half-life from several hours to approximately five days, which may explain its effectiveness at local tumor control.172
Stem-cell transplantation is an option for patients with primary central nervous system lymphoma and recurrent disease, or who are refractory to standard therapy.173 The roles of blood-brain barrier disruption and whole-brain radiation are being defined.174,175
Vitreous Hemorrhage
Vitreous hemorrhage is a relatively common cause of severe vision loss, having an annual incidence of approximately seven cases per 100,000 in the population.176 Depending on the location of the hemorrhage and its volume, symptoms can range from mild peripheral floaters to profound vision loss. The presence of blood in the vitreous often gives rise to other entopic symptoms. Small hemorrhages can be asymptomatic. A wide variety of underlying disorders can lead to vitreous hemorrhage, but the causes can be condensed into three major categories—bleeding from abnormal or pathological vessels, bleeding from normal vessels, or extension of bleeding into the vitreous from an external tissue.177 The frequency of specific causes of vitreous hemorrhage varies depending on study design and the time it was conducted. More recent studies have found proliferative diabetic retinopathy and retinal tears as the most common primary causes. 175,178
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The risk of spontaneous vitreous hemorrhage from pathologic or normal vessels is difficult to quantify, although massive intraocular bleeding appears to occur more frequently in persons on anticoagulants, including aspirin.179,180 The pathophysiological events following vitreous hemorrhage have been studied in experimental animals and humans. The fate of blood in the vitreous is one of progressive catabolism. The breakdown of blood cells in the vitreous gel parallels that in other tissues, with a few notable exceptions. Clot formation in the vitreous gel develops rapidly with diffusion of red blood cells limited by the latticework of collagen fibers.181 Unlike hemorrhage into soft tissues, fibrin persists in the vitreous, in part due to the lack of neutrophil response. The lack of an early neutrophil response contributes to the delay in red blood cell lysis. Macrophages, which typically enter a fibrin clot within several days of bleeding, may not be able to clear degenerating red blood cells and other debris as efficiently in the vitreous as other tissues.182 The natural history of vitreous hemorrhage has been studied in experimental animals using chromium labeled isotopes. These studies show that blood disappears from the vitreous gel in stages with very little clearing during the first three days.183,184
The degradation of red blood cells proceeds on a cellular level while hemoglobin undergoes metabolic oxidation and conversion to a variety of breakdown products, including hematin, biliverdin, hematoidin, and hemosiderin. Red blood cells in the vitreous lose their normal shape, become fragmented and often lyse (see Fig. 8.16). As hemoglobin degrades, the denatured molecule can adhere to the cell membrane forming a Heinz body. Loss of the cytoplasmic constituents of the red blood cell results in so-called ghost cell formation. As red blood cells are broken down and their carcasses carried off by macrophages, cholesterol from
Fig. 8.16 Enucleated eye with relatively fresh vitreous hemorrhages estimated to be about one week old. The cortical vitreous shows myriad fragment red blood cells and no inflammatory cells. A few nucleated cells are present on the surface of the retinal to the left (hematoxylin-eosin, 290x original magnification)
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the plasmalemma remains within the vitreous where it can incite a moderate inflammatory reaction. This form of localized cholesterolosis within the vitreous is referred to as synchysis scintillans (see section on synchysis scintillans).
Free hemogloblin may also coalesce within the vitreous gel forming spherical aggregates. This condition is referred to as hemoglobin spherulosis and consists of spheres ranging in size from 10 to 20 microns. When suspended in the vitreous, they are visible via slit lamp biomicroscopy, appearing as golden brown droplets.185
The iron liberated during the breakdown of red blood cells in the vitreous occurs intracellularly within macrophages (where it is stored as hemosiderin or ferritin), or extracellularly (where it is bound to lactoferrin or transferrin).186 Unbound vitreous iron (Fe+2 and Fe+3) likely exerts toxic effects on a variety of local tissues and contributes to vitreous syneresis.187 Iron from intraocular hemorrhage does not have the toxic effects of iron-containing foreign bodies, which cause severe damage to the neurosensory retina. Part of this discrepancy may be due to the higher amount of free bivalent iron released from iron-containing foreign bodies, which is more likely to interfere with the glycolytic activity of the retina.188
Based on clinical observations and experimental studies, blood within the vitreous may play a role in the development of fibrovascular proliferation.189 It is often difficult, however, to separate the role of red blood cells from other confounding factors, like trauma (accidental or surgical), or the underlying disease process causing the hemorrhage. In experimental studies, preretinal membranes follow the accumulation of red blood cells and macrophages on the retina surface.190 Vitreous hemorrhage appears to have a deleterious effect on pre-existent fibrovascular membranes, mediated through cellular-molecular mechanisms, mechanical disruption of the vitreous gel, or both.
Treatment
Treatment of vitreous hemorrhage falls into two general categories—treatment of the underlying condition and treatment of the media opacity. The indications and guidelines for the treatment of the multitude of disorders that give rise to vitreous hemorrhage will vary with each disorder, and their review is beyond the intent of this chapter. Many of the algorithms for the management of vitreous hemorrhage have a common final pathway despite variations in the treatment of the underlying condition. Once the reason for vitreous bleeding has been dealt with, visual rehabilitation often requires removal of the media opacity.
Nonclearing vitreous hemorrhage is one of the most common clinical indications for pars plana vitrectomy. Its role in diabetic retinopathy has been studied in the Diabetic Retinopathy Vitrectomy Study and in smaller studies.191,192,193,194 While the measured benefits of vitrectomy may vary in different studies, certain trends in surgical outcome have become apparent. Improved instrumentation and possibly better training have resulted in steady improvement in most measures of clinical outcome, including declining rates of complications. As a result, the indications of pars plana vitrectomy have been changing with lower thresholds for surgery.
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Although surgery remains the standard of care for nonclearing vitreous hemorrhages, the concept of pharmacological vitrectomy has been a long-time dream of researchers. Still far from a reality, chemically induced clearing of vitreous hemorrhages has rarely advanced beyond the stage of a pilot study.176,195 Although the primary target of drug therapy has been the red blood cell, an alternative approach to accelerating the removal of blood is to liquefy the vitreous. One potentially promising therapy includes intravitreous injection of highly purified hyaluronidase, which has facilitated visualization of the fundus by liquefying the vitreous gel.196,197
Summary
A variety of unrelated disorders affect the vitreous throughout life. Common degenerative conditions due to aging (e.g., vitreous syneresis) place everyone at some risk for PVD, retinal tear, and retinal detachment. While the environmental factors that predispose to vitreous syneresis are not completely understood, posterior segment inflammation of any type readily promotes vitreous liquefaction. The vitreous is often the site of overflow, or secondary, inflammation from primary uveitic disorders. Additionally, primary ocular lymphoma must always be considered in the differential diagnosis of chronic vitreitis.
The aging vitreous can loose it transparency from the accumulation of amyloid, phospholipids (asteroid hyalosis), or cholesterol (synchesis scintillans). Among the three disorders, only amyloid causes significant ocular morbidity or carries any implication for general health.
Vitreous membranes are the final common pathway for a number of different types of ocular injury. While their pathogenesis likely differs according to underlying cause, they share many features with the nonspecific inflammatory-reparative processes that promote wound healing.
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