Ординатура / Офтальмология / Английские материалы / Age-Related Changes of the Human Eye_Cavallotti, Cerulli_2008
.pdf164 |
C. E. Margo |
conditions must be inferred indirectly. While there is little evidence to support the prophylactic treatment of operculated tears or atrophic holes, the treatment of lattice degeneration is more controversial.68 Symptomatic operculated tears have a low risk, if any, of progression to retinal detachment. Those that do may be caused by vitreous adherent to retina in the area of the break.69,70 Although lattice degeneration generally increases the chance of retinal detachment, there is insufficient evidence-based data to support prophylactic treatment of asymptomatic lattice degeneration.71 Given that the annual incidence of rhegmatogenous retinal detachment is between 10 to 15 cases per 100,000, and the prevalence of lattice degeneration in the general population is 6 to 8 percent, an individual with lattice degeneration has a relatively low lifetime risk of retinal detachment.72,73,74,75
Amyloidosis
The majority of patients with vitreous amyloid deposits present after the age of 40, although the disease is generally considered a genetic disorder—either inherited as an autosomal dominant trait or through a spontaneous mutation of the transthyretin gene.76 Amyloidosis refers to a heterogeneous group of disorders characterized by the deposition of various abnormal proteins (i.e., amyloid).77 The amyloids are biologically insoluble and poorly digestible aggregates of low-molecular weight proteins with beta-pleated sheet configurations. The three-dimensional orientation of these aggregates imparts certain highly specific physical features to amyloids. The most clinically useful properties are its affinity for Congo red and birefringence under polarized light.78 Amyloid is dichroic to green light when stained with Congo red,
due to the preferential transition of light along certain planes of the molecule. The classification of amyloidosis has changed as new insight into its pathogenesis
has been made. Vitreous amyloidosis is essentially a manifestation of a hereditary form of the disease known as familial amyloidotic polyneuropathy (FAP).79 Vitreous amyloid is not a feature of other systemic forms of amyloidosis. Although FAP has been divided into four types, only two of the four types (types I and II) develop vitreous deposits. The disease is caused by the accumulation of mutant transthyretin protein. It is transmitted in an autosomal dominant fashion, with similar patterns of phenotypic expression among both homozygous and heterozygous affected individuals. The genetic mutation that gives rise to FAP is within the chromosome region 18q11.2-q12.1.80 Because of the variable clinical expression of FAP, the few reports of isolated or nonfamilial amyloid deposits of the vitreous may represent sporadic mutation of the transthyretin gene.81,82,83
Transthyretin is a transport protein for both thyroxin and retinal-binding protein. It carries almost all of the circulating retinal-binding protein, but complexes with less than 1 percent of thyroxin.84 Also referred to as prealbumin, transthyretin carries nearly 40 percent of circulating retinal-binding protein. The most frequently reported mutation of transthyretin giving rise to amyloidosis involves the substitution of a methionine for valine at position 30.85
8 Age-Related Diseases of the Vitreous |
165 |
Vitreous amyloid deposits accumulate at a relatively slow rate, with the onset of symptoms beginning over the age of 40 or 50.86 Floaters and decreased vision are invariably present, usually bilaterally, although substantial asymmetry might be noted. The rate of progression to significant visual loss in 18 patients with vitreous amyloid ranged from several months to several years.87 Clinically, the vitreous opacities have a glass wool appearance (see Fig. 8.2). As the density of vitreous deposits increase, visualization of the retina becomes more difficult. There are few other, if any, ocular manifestations of FAP, with the exception of sheathing of retinal vessels that are noted occasionally.88
Vitrectomy can be used to diagnose the disease when suspected clinically, or for treatment of visual symptoms. Confirmation of the diagnosis is based on the typical staining properties of amyloid with Congo red and behavior under polarized light. Ultrastructural examination of the vitreous biopsy is another diagnostic option, looking for characteristic 7-10 nm amyloid fibrils. These fibrils, however, may be difficult to distinguish from vitreous fibrils with diameters ranging from 10 to 15 nm.89 Clinical symptoms following vitrectomy may signal the reaccumulation of amyloid deposits (see Fig. 8.3).90 Nearly a quarter of patients treated surgically require a second vitrectomy for recurrent amyloid.91 Progressively worsening opacity of residual vitreous has led surgeons to remove as much cortical vitreous as safely possible.92 Systemic therapies for amyloidosis have been generally ineffective, but novel treatments are being developed.93
Fig. 8.2 Vitreous amyloid visualized at the slit lamp just posterior to the lens. The mass of amyloid fibrils appears like glass wool (Photograph courtesy of Scott Pautler, MD)
166 |
C. E. Margo |
Fig. 8.3 The eye from a man with familial amyloidosis obtained at autopsy. Arteriole in the inner retina is surrounded by amyloid (arrow). Extracellular deposits of amyloid are also present in the inner retina adjacent to the internal limiting membrane (arrowheads) and in the cortical vitreous.(hematoxylin-eosin, 290x original magnification) (Glass slide courtesy of Ted Dryja, MD)
Asteroid Hyalosis
First described as asteroid hyalitis by Benson in 1894,94 this noninflammatory condition is characterized by variable numbers of buff-colored deposits suspended in the vitreous. The average age of diagnosis in 217 patients with this condition was 64 years.95 Approximately three-quarters of cases occur unilaterally. In a consecutive clinical evaluation of over 12,000 patients, the prevalence of asteroid hyalosis was 0.83 percent.96 Among the patients in this series, there was a positive association between the vitreous deposits and diabetes, atherosclerosis, hyperopia, and hypertension. The biological basis for these associations, however, is far from clear. Several earlier studies failed to find an association between asteroid hyalosis and systemic disease.48,97
In routine hematoxylin and eosin-stained sections, asteroid bodies are round- to-oval amphophilic masses that are visible under polarized light (see Fig. 8.4). They stain positive with alcian blue. Histochemical analysis reveals neutral fats and phospholipids.98 Chemical analysis for inorganic substances has disclosed calcium, phosphorus, and trace amounts of sulfur.99,100,101 Electron microscopic studies have shown twisted and intertwined electron-dense multilaminar membranes. Smaller asteroid bodies were more amorphous and contained fewer multilaminar membranes.53,102,103
8 Age-Related Diseases of the Vitreous |
167 |
Fig. 8.4 Asteroid bodies of the vitreous appear as gray amorphous deposits when stained with hematoxylin-eosin (left). They literally sparkle like diamonds when viewed under polarized light (right) (hematoxylin-eosin, 390x original magnification)
Given the striking clinical appearance of asteroid hyalosis, there are relatively few clinical symptoms. Most patients are unaware of floaters and few have any measurable decline in visual function due to asteroid hyalosis. Vitrectomy has been used to remove the vitreous deposits in persons who are symptomatic, but the clinical indications for elective surgery are not clearly established. Occasionally, asteroid bodies are found in epiretinal membranes where the mild foreign body reaction they incite may aggravate the severity of the epiretinal membrane (see Fig. 8.5).
Synchysis Scintillans
First described in the late nineteenth century, synchysis scintillans refers to the glistening crystals present in the liquefied vitreous. Clinically, the highly reflective crystals are dispersed with movement of the eye. Over time, the crystals will settle to the gravity-dependent portion of the vitreous cavity. Unlike asteroid hyalosis in vitreous gel, synergetic fluid cannot support the crystals of synchysis scintillans. Histologically, the crystals cannot be seen directly because the solvents used in processing the tissue dissolve them. They leave, however, slit-like spaces where
168 |
C. E. Margo |
Fig. 8.5 An asteroid body is inciting a foreign-body giant cell reaction. This focal inflammatory cell reaction is present within an idiopathic epiretinal membrane that was removed in surgery (hematoxylin-eosin, 390x original magnification)
cholesterol once existed. Also known as cholesterolosis bulbi, the presence of synchysis scintillans is a secondary manifestation of intraocular hemorrhage or inflammation.104
Though synchysis scintillans is not strictly a disorder of aging, the underlying causes of intraocular hemorrhage and inflammation steadily increase with age, as does the prevalence of cholesterolosis bulbi. The cholesterol liberated from degenerating red blood cells frequently incites an inflammatory reaction, which includes a foreign body reaction. On histological inspection of globes with synchysis scintillans, there is usually evidence of localized hemosiderosis from remote hemorrhage (also see vitreous hemorrhage).
Vitreous Membranes
Vitreous membranes describe the final common pathway of a number of primary ocular diseases—including surgical and accidental trauma. Though arising from diverse causes, these membranes have in common the ability to interfere with the optical transparency of the vitreous and disrupt retinal function through a variety of mechanisms. While there is no standard nomenclature of vitreous membranes, classification is usually based on underlying etiology (diabetic, traumatic, etc.), anatomic location (anterior, epriretinal, cyclitic, etc.), or morphology (acellular, cellular, pigmented, etc.).
8 Age-Related Diseases of the Vitreous |
169 |
The pathophysiological mechanisms involved in vitreous membrane formation overlap those of wound healing. The vitreous normally inhibits cellular proliferation and growth of blood vessels.105,106,107,108,109,110 Loss of inhibitor function and/or the overriding influence of growth promoters are likely involved in membrane formation.111,112 Diabetic vitreoretinopathy—the prototypical vitreous-membrane disorder—up-regulates a number of growth factors. The majority of putative growth factors, both for stromal and vascular cells, likely originate from the serum.
Most membranes are composed of several cell types and, unlike reactive membranes in other tissues, are often composed of both glial cells and fibroblasts. Depending on location and primary injury, the proportion of glial cells (including Muller), fibroblasts, macrophages, lens epithelial cells, pigment epithelial cells, and ciliary non-pigmented epithelial cells will vary.
Cyclitic membranes are often the sequela to endophthalmitis, uveitis, or anterior segment trauma. They are notoriously difficult membranes to manage clinically because much of their bulk is hidden from view behind the iris leaflets at their site of origin in the posterior chamber (see Fig.8.6). When mature, the membrane extends from the ciliary body centrally to occlude the visual axis like a diaphragm. Typically well-endowed with fibroblasts and thick bundles of collagen, cyclitic membranes have powerful contractile properties. Myofibroblasts within the membrane contribute to its contractile strength that may secondarily detach peripheral retina, displace the crystalline lens or pseudophakic implant, and promote uveal effusion and hypotony.
Fig. 8.6 A relatively young cyclitic membrane is present in the anterior vitreous, forming between the peripheral retina (arrows) and lens capsule (arrowheads). Delicate spindle cells, small caliber vessels and modest amounts of collagen make up the membrane (hematoxylin-eosin, 160x original magnification)
170 |
C. E. Margo |
Vitreous membranes following trauma, retinal detachment, and complicated diabetic retinopathy usually grow on surfaces and do not invade the vitreous gel directly. Membranes that occupy the vitreous cavity likely use the pre-existing posterior vitreous surface as a scaffolding to grow on as the vitreous body collapses (see Fig. 8.7). They tend to grow parallel to the surface of the posterior hyaloid or tangential to the interface created by transvitreal trauma (see Fig. 8.8). Ultrastructural studies have shown that more than 90 percent of these membranes contain myofibroblasts.113 The contractile properties of the myofibroblast can exert a deleterious affect on the neurosensory retina, including tractional retinal detachment (see Fig. 8.9). Nearly half of epiretinal membranes developing after retinal detachment contain retinal pigment epithelium (RPE). The contraction mediated by myofibroblasts may secondarily induce fibrocytes within the membrane to produce more collagen. Old or so-called burned out membranes may consist of nothing more than mature collagen (see Fig. 8.10).
The presence of blood within the vitreous further complicates the healing process by inciting an even greater inflammatory reaction (see Fig. 8.11). The breakdown products from red blood cells not only provoke a foreign body reaction on a macroscopic level, they trigger a multitude of inflammatory cascades on a biochemical level. Hemosiderin-laden macrophages and so-called cholesterol granulomas are frequent findings in end-stage membranes.
Fig. 8.7 Advanced proliferative membranes in the eye of a diabetic patient with extensive tractional retinal detachment. The thick fibrovascular bundles of tissue are adhered to the retina and have used the posterior hyaloid as a scaffold on which to grow
8 Age-Related Diseases of the Vitreous |
171 |
Fig. 8.8 A thin epiretinal membrane grows on the inner surface of the retina. A few spindleshaped nuclei (arrows) can be seen (hematoxylin-eosin, 290x original magnification)
Fig. 8.9 A diabetic tractional retinal detachment of the macula shows the relationship of internal limiting membrane (arrows) and posterior hyaloid (arrowheads) (hematoxylin-eosin, 290x original magnification)
Idiopathic epiretinal membrane (ERM) is considered a distinct clinicopathologic entity, but it has shared features with other forms of periretinal membranes (see Fig. 8.12). Usually regarded as an age-related degenerative process of the retinal basal lamina, ERM is characterized by small dehiscences in the basement membrane
172 |
C. E. Margo |
Fig. 8.10 A thick collagenous epiretinal membrane in the eye of a diabetic patient. This so-called burnt-out diabetic membrane followed panretinal photocoagulation. The membrane rests on the internal limiting membrane (arrows) and contains only larger caliber vessels (hemotoxylin-eosin, 290x original magnification)
Fig. 8.11 A complex epiretinal membrane containing red blood cells, fibrin, inflammatory cells, and spindle-shaped cells rests on the surface of the retina (arrows). There is evidence that the addition of red blood cells and fibrin into a pre-existent epiretinal membrane enhances its growth (hematoxylin-eosin, 290x original magnification)
of the neurosensory retina that allow glial cells access to the inner surface. The transmigration of RPE through the retina has been documented on optical coherence tomographic studies.114 Once on the epiretinal side of the basement membrane, glial cells can proliferate unimpeded. This rather simple view, however, has been
8 Age-Related Diseases of the Vitreous |
173 |
Fig. 8.12 Idiopathic epiretinal membrane in an enucleated eye without evidence of a full-thickness retinal tear shows surface wrinkling throughout the posterior pole
challenged after finding remnants of cortical vitreous within ERMs.115 This observation raised the possibility that detachment of the cortical vitreous from its retinal attachments may incite or promote the formation of ERMs. Others contend that hyalocytes in the cortical vitreous are the source of epiretinal membranes.116 When Gass proposed that the tangential forces exerted by cortical vitreous are involved in the formation of idiopathic macular holes, investigators took a more serious look at this obscure anatomic territory.117 Epiretinal membranes tend to occur in areas where the basal lamina of the retina is the thinnest (over the fovea and disc) and, presumably, the easiest to breach.
The majority of ERMs contain fibrous astrocytes that grow in a centripetal pattern on the inner retina. The membrane is loosely attached to the underlying basal lamina. They may demonstrate an occasional hemidesmosome-type of structure, but, for the most part, ERMs are not anchored to underlying tissue.118 This situation explains the ease with which most epiretinal membranes can be peeled from the retina, and also their occasional spontaneous detachment. The fact that nearly 50 percent of membranes studied by electron microscopy contain RPE suggests that a full-thickness retinal hole may be present in many of these cases.119
Proliferative Vitreoretinopathy
It is unclear if proliferative vitreoretinopathy (PVR)—massive periretinal proliferation or massive preretinal retraction—is a distinct nosologic entity or an exaggerated manifestation of wound healing associated with retinal detachment. The term PVR is used to clinically describe the exuberant membranes associated with rhegmatogenous retinal detachment. As the most common cause of failed retinal reattachment