Tina Rutar,
Martin H. Reinke,
Donald J. D'amico,
Robert B. Bhisitkul
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Overview |
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Diffuse vitreal deposits can occur due to a variety of ocular and systemic diseases. Most common and familiar to ophthalmologists is asteroid hyalosis, the unilateral presence of globular refractile deposits in older patients. Though asteroid hyalosis is a common condition, its pathogenesis remains a mystery. Fortunately, it is of no clinical consequence in the vast majority of patients and does not require specific treatment. Rarely, vitrectomy is performed to adequately visualize the fundus in patients with asteroid hyalosis who have suspected retinal disease or vision loss of unknown etiology. In contrast, vitreous amyloidosis, characterized by the bilateral presence of cobweb-like opacities, is a rare condition for which we have an increasingly sophisticated molecular understanding. It is caused mutations in the transthyretin gene leading to deposition of beta-pleated sheet protein aggregates in the vitreous and other tissues. The systemic illness, called familial amyloid polyneuropathy, is characterized by polyneuropathy and cardiomyopathy in addition to vitreous deposits. The disease has a grave systemic prognosis. The ophthalmologist may be the one to diagnose this disease, and to offer patients vitrectomy surgery for improved visual function. The differential diagnosis of vitreous deposits includes cholesterolosis bulbi, vitreous hemorrhage, lymphoma, and inflammatory and infectious conditions. Usually, the clinical history and examination easily distinguish among these entities. Rarely, vitreous biopsy is needed to make the diagnosis. |
INTRODUCTION
The vitreous is a mostly acellular gel filling the posterior segment of the eye. It is a clear matrix composed of water, collagen, and hyaluronic acid. Typically, deposits that form in the vitreous accompany systemic diseases, especially those causing cells and macromolecules to escape the retinal vasculature. One exception is asteroid hyalosis, a condition leading to vitreous deposits in the absence of other ocular or systemic disease. In contrast, vitreous amyloidosis is a disease of vitreous deposits that is part of a rare systemic illness caused by amyloid deposition in multiple tissues.
Asteroid hyalosis and vitreous amyloidosis, as well as the differential diagnosis of diffuse vitreous deposits, are the basis of this chapter. Hereditary and degenerative diseases of the vitreous, including Jansen disease, Wagner disease, Stickler syndrome, Weill-Marchesani syndrome, familial exudative vitreoretinopathy, and posterior vitreous detachment are the subject of other chapters.
ASTEROID HYALOSIS
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Synonyms |
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* antiquated term which can lead to confusion with the snowballs opacities in uveitic conditions |
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Key Features: Asteroid Hyalosis |
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In 1894, Benson[1] described the unilateral presence of 'small, smooth, fixed spheres of a light cream colour' scattered throughout the vitreous. He chose the term asteroid hyalitis because the appearance resembled stars on a bright clear night. Although asteroid bodies had been identified previously, Benson is given credit for describing the condition and distinguishing it from another type of vitreous deposit, synchysis scintillans (cholesterolosis bulbi). It is unclear why Benson selected the term hyalitis rather than hyalosis, since even he acknowledged that there was no evidence of true vitreous inflammation. An alternate term used by Argyll Robertson in the 1800s and later by Holloway is 'snowball opacities',[2] which is no longer used to avoid confusion with the inflammatory opacities seen in posterior uveitis. 'Scintillatio albescens' or 'nivea' is a description forwarded by Wiegmann in 1918 and still used today in Europe.[3] In the United States, the preferred term is asteroid hyalosis, as suggested by Luxenberg and Sime in 1969.[4] Today, this condition still provides an interesting clinical picture and yet the precise cause remains a mystery.
CLINICAL CHARACTERISTICS
Epidemiology
The prevalence of asteroid hyalosis is ?0.8-2.0% of the adult population. Utilizing retrospective chart review, a large study found the prevalence of asteroid hyalosis in an elderly population to be 0.8%.[5]Utilizing fundus photography, a second large study found a similar prevalence of 1.2%.[6] Based on pathologic examination of the vitreous at autopsy, the overall prevalence rate was found to be 2.0%, and the prevalence increased with age.[7] For example, it was 3.2% among autopsy eyes from 61- to 70-year-old individuals and 6.6% among autopsy eyes from individuals 91 years and older. Asteroid hyalosis has been described in patients ranging in age from 9 to 98 years, with a mean age in the 60s.[4,7-12]
Asteroid hyalosis is unilateral in 75-90% of patients.[4,7-9] Two large studies have found a male to female predominance of ?2:1,[6,7] whereas one large study found males and females to be affected equally.[5]There is probably no racial predisposition.[4] Asteroid hyalosis is generally not heritable, though a few familial cases have been described.[13,14]
Symptoms
Asteroid hyalosis is usually asymptomatic and does not affect visual acuity.[11,15-19] Rarely, cases of visual symptoms of floaters and decreased acuity can be attributed to the asteroid bodies.
Signs
By slit-lamp examination and ophthalmoscopy, asteroid bodies are small round to oval opacities suspended in the vitreous (Fig. 188.1). These white, refractile bodies are often in strands associated with vitreous collagen, but they can also appear scattered in a disordered manner. The asteroid bodies move as the vitreous body moves and tend to settle back into their original positions. Gravity does not affect their location. Although asteroid hyalosis usually involves the entire vitreous cavity, occasionally only segments of the vitreous show asteroid collections.[8] The size of the granules varies from 3 to 100 ?m.[8,20,21]
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FIGURE 188.1 Slit-lamp view of asteroid hyalosis. |
The presence of asteroid in the vitreous has very little effect on a patient's vision. Only a small proportion of light rays are scattered by the discrete asteroid bodies; thus, enough unscattered light rays reach the macula to enable good vision. This situation is in contrast to the effect of irregular or diffuse vitreous opacities, such as vitreous inflammation or hemorrhage, which significantly degrade the retinal image. When an examiner performs ophthalmoscopy through asteroid, the reflected light returns to the examiner and confounds the view. Thus, asteroid hyalosis is an example in which the quality of the view does not predict the quality of vision.
Systemic Associations
The possible associations of asteroid hyalosis with systemic illness have led to controversy. Some researchers have noted an association with diabetes mellitus,[12,22-24] whereas others have found none.[7,25,26] In 1965, Smith showed that ?70% of patients with asteroid hyalosis had diabetes according to glucose tolerance test results; however, there was no control group.[27] Luxenberg and Sime published a clinic-based study in 1969 asserting that the prevalence of diabetes by either history or glucose tolerance testing in 98 patients with asteroid hyalosis was equal to the prevalence in control patients.[4] The first large study to address this issue was published by Bergren et al in 1991.[5] In an evaluation of 12 205 patients, these authors identified 101 patients with asteroid hyalosis. Among these patients, 29% had a history of diabetes as compared with 10% of 101 control patients. This increased prevalence of diabetes was statistically significant (P = 0.0007). In addition to diabetes, asteroid hyalosis was associated with systemic arterial hypertension and atherosclerotic vascular disease. Another large study of 10801 patients at autopsy, however, found no association with diabetes in either univariate or multivariate analyses.[7] Hypertension and atherosclerosis were associated with asteroid hyalosis in univariate analyses, but after adjusting for age in a multivariate analysis, these associations lost statistical significance. Thus, the possible association of asteroidhyalosis with diabetes, hypertension and atherosclerosis has not been reproduced in large population-based studies.
Many small studies have proposed other links between asteroid hyalosis and systemic conditions. There are conflicting reports about a possible correlation between asteroid hyalosis and hypercholesterolemia.[4,12,22,25] In a 1965 paper by Jervey and Anderson, patients with asteroid hyalosis were shown to have elevated serum calcium levels.[28] Safir and colleagues asserted that asteroid hyalosis is associated with gout.[29] Asteroid body formation has been suggested to be a component of a systemic lipid storage disorder associated with Whipple's disease.[30] These small studies do not provide convincing evidence that asteroid hyalosis is associated with systemic disease.
Ophthalmic Associations
Eyes with asteroid hyalosis tend to have attachment of the posterior hyaloid.[7,8,11,31] Two published series of patients with asteroid hyalosis have shown a vitreous liquefaction rate as low as 19%,[8,31] which is lower than expected compared to age-matched controls. The explanation for the negative association between posterior vitreous detachment (PVD) and asteroid hyalosis is not known. Asteroid bodies may interfere with vitreous liquefaction. Bergren and coworkers[5] postulated that an intact vitreoretinal interface could be important in asteroid formation. If this interface is absent (e.g., as in myopic patients), asteroid bodies tend not to form. In concordance with this idea, they have noted that asteroid is more common in patients with hyperopia. Weiter and Albert noted a decreased prevalence of not only myopia but also retinal detachment in their study group of 30 patients with asteroid hyalosis.[11]
Other ocular associations have been described. Reports have linked asteroid hyalosis to retinitis pigmentosa.[14,32-35] Asteroid hyalosis has been reported in a 14-year-old patient with pre-Descemet's dystrophy.[36] Meretoja described familial asteroid hyalitis in three brothers and speculated that a common metabolic genetic defect linked the three cases.[13]
HISTOPATHOLOGY
Voerhoeff and many ophthalmologists in the early and mid-1900s suggested that asteroid bodies were calcium soaps with lipid components.[20,37] Using thin-layer chromatography, Feldman noted that asteroid bodies from human vitreous were rich in sphingolipids with small amounts of cerebrosides, cholesterol, and cholesteryl esters.[38] Other research has shown these 3- to 100-?m bodies to be composed of calcium hydroxyapatite, other forms of calcium phosphate crystals, and various amounts of complex phospholipids.[8,21,39,40] Phospholipids, calcium, and phosphorus are present in high amounts in human asteroid bodies and in asteroid bodies from the galactose-fed beagle, an animal model for asteroid hyalosis.[41-43] Further evidence that asteroid bodies are composed of lipid and calcium comes from light microscopy studies showing asteroid bodies staining positively for fat with oil red O and for calcium with von Kossa stain.[37]
Asteroid bodies appear porous by scanning electron microscopy. The spicular appearance of asteroid bodies is best seen by transmission electron microscopy (Fig. 188.2). Usually, asteroid bodies are closely attached to histologically normal vitreous collagen fibrils. Macrophages or multinucleated giant cells can surround the asteroids (Fig. 188.3).[8,37,44] On high magnification, a characteristic lamellar pattern of lipids is noted (Fig. 188.4). The asteroid bodies consist of intertwined laminar ribbons (6 nmol periodicity) interspersed with opaque nodular material.[21] Miller and colleagues demonstrated a lamellar pattern with periodicity of 4.6 nmol.[16] They proposed that asteroid bodies are liquid crystals of phospholipid existing in an intermediate state between true crystals and true liquid.
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FIGURE 188.2 Transmission electron micrograph shows several asteroid bodies. Uranyl acetate and lead citrate, ×3713. |
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FIGURE 188.3 Transmission electron micrograph shows an asteroid body surrounded by a macrophage. Uranyl acetate and lead citrate, ×4950. |
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FIGURE 188.4 Transmission electron micrograph demonstrates the characteristic lamellar pattern of lipids found in asteroid bodies. Uranyl acetate and lead citrate, ×117 000. |
PATHOGENESIS
To date, the cause of asteroid hyalosis has not been clearly elucidated. Voerhoeff hypothesized that angiosclerosis of intraocular vessels in combination with a localized excess of fats and lipids leads to asteroid formation.[20] Rodman and associates described two types of asteroid hyalosis.[37] Type 1 referred to asteroid bodies found in normal vitreous, while type 2 was associated with a granulomatous reaction, implicating inflammation as a possible cause of asteroid formation. Rodman and associates believed that the asteroid bodies could arise due to degenerative changes in the vitreous collagen.[37]Streeten suggested that the asteroid bodies are derived from exogenous sources, since their components are not present in sufficient quantity in normal vitreous.[21] Degenerated retinal pigment epithelial cells may provide the components for asteroid formation.[16] Bergren and co-workers speculated that in cases of retinal degeneration, the release of cellular products such as phospholipids and calcium could predispose to asteroid hyalosis.[5] In the beagle model for asteroid hyalosis, Wang andcolleagues found palmitic acid to be the principal component of asteroid phospholipid.[43] Palmitic acid is found in rod outer segments and is associated with the apoptosis of retinal microvascular cells. Gass observed that asteroid bodies initially develop near retinal blood vessels.[45]
Experimentation has provided several more clues to possible causes. Asteroid formation has been achieved by altering serum cholesterol levels and blood flow. Zauberman and Livni demonstrated formation of asteroid bodies in the albino rabbit vitreous by inducing hypercholesterolemia in conjunction with vortex vein closure.[46] The altered endothelial cell permeability and high cholesterol levels were sufficient to allow asteroid formation. Lamba and Shukla, however, were not able to demonstrate asteroid formation in albino rabbits by inducing hypercholesterolemia or by combining hypercholesterolemia with focal scleral diathermy. On the other hand, they noted that intravitreal injection of hyaluronidase into the guinea pig eye led to formation of opacities similar in appearance to asteroids.[47]
The unilateral nature of asteroids is difficult to explain unless local factors play a role. A nidus could initiate the process of liquid crystal and therefore asteroid formation. Perhaps inflammation, retinal or retinal pigment epithelium (RPE) cell degeneration, or leakage from retinal vessels can alter vitreous calcium and lipid levels. Local changes in vitreous pH or localized collagen degeneration may be important in propagating asteroid formation. Increased vascular permeability could explain the possible correlation between asteroid hyalosis and diabetes.
MANAGEMENT
Because asteroid hyalosis is most commonly a disease with no visual symptoms or effect on visual acuity, it is managed by observation. At this time there is no recommended systemic disease screening for patients with asteroid. The ophthalmologist must be aware of asteroid hyalosis to anticipate possible difficulty visualizing funduscopic details and in interpreting ancillary studies, such as A- and B-scan ultrasonography.
In many patients with asteroid hyalosis, especially those with diabetes, good visualization of the retina is important. Fortunately, fluorescein angiography often provides an adequate means of assessing the fundus when ophthalmoscopy is limited by asteroid hyalosis (Fig. 188.5). Hampton and colleagues described the reason why fluorescein angiography provides an excellent view of the fundus and retinal vasculature in patients with asteroid hyalosis.[48] Blue light is used to excite the fluorescein dye flowing through the ocular vessels. The entering blue light is scattered by the asteroids in the same manner that an examiner's light is scattered. This reflected light, however, does not reach the fundus camera because it is screened out by the blue light barrier filter. The yellow-green light emitted from the excited fluorescein in the fundus, however, is able to reach the camera. Reflections of the yellow-green light by the asteroids will not travel toward the camera and thus will not degrade the image. In some situations, extremely dense asteroids near the retina may limit the amount of yellow-green light reaching the fundus camera.
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FIGURE 188.5 Asteroid hyalosis in a 78-year-old patient with decreased vision of unknown cause. (a) Fundus photograph. Asteroid bodies noted in the vitreous cavity preclude a view of the fundus. (b) Fluorescein angiogram of the same eye allows visualization of the fundus. |
Optical coherence tomography (OCT) can also been used to study the fundus in patients with asteroid hyalosis. One case report described a diabetic patient with asteroid hyalosis in whom vitreomacular traction causing macular edema was detected by OCT.[49]
Asteroid hyalosis can affect ultrasound results. These calcium bodies are highly reflective and occasionally confound B-scan evaluations by producing multiple tiny echoes. One case of choroidal melanoma was reported where the height of the tumor was not measured accurately due to the presence of overlying asteroids.[50] B-scan may give the false appearance of a PVD if asteroid bodies do not extend to the surface of the retina.[31]
A-scan ultrasonography is also affected in severe cases of asteroid hyalosis. Several authors have described problems making intraocular lens calculations based on A-scan data;axial length can be falsely short owing to confusing echoes associated with asteroid bodies.[51-54] Clinical examination and comparison with the axial length of the fellow eye should alert one to the possibility of a spurious measurement. Asteroid hyalosis can also create spuriously high hyperopic readings in autorefractors.[55]
Asteroid hyalosis can affect cataract surgery. Reflections off the asteroid can impair visualization of the posterior capsule. Three cases of unilateral silicone lens explantation due to posterior surface deposition of calcium and phosphorus have been reported in patients with unilateral asteroid hyalosis.[56] However, given the high prevalence of asteroid hyalosis in the elderly pseudophakic population, it is unlikely that this is a common occurrence.
INDICATIONS FOR VITRECTOMY
Pars plana vitrectomy may be indicated in select cases of asteroid hyalosis.[8,18,57-60] These indications are listed in Table 188.1. The view of the retina is occasionally markedly obscured by asteroid bodies. Although fluorescein angiography is useful, it does not help in all clinical scenarios. For example, contact lens examination and focal laser treatment for diabetic clinically significant macular edema may not be possible in the setting of dense asteroid hyalosis. If this is not possible owing to dense opacities, a vitrectomy may be needed (Fig. 188.6). Another situation is the patient with dense asteroid hyalosis and decreased vision of unknown cause. Feist and associates showed that pars plana vitrectomy in four of seven eyes with asteroid hyalosis allowed diagnosis of posterior segment pathology.[18] The authors concluded that vitrectomy is indicated for diagnostic reasons if fluorescein angiography and ultrasonography fail to reveal an etiology for diminished vision.
TABLE 188.1 -- Indications for Vitrectomy in Asteroid Hyalosis
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Poor visualization of fundus |
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Inability to perform laser photocoagulation |
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Inability to find retinal breaks in rhegmatogenous retinal detachment |
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Visual symptoms (rare) |
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FIGURE 188.6 Fundus photograph of a 70-year-old diabetic patient with asteroid hyalosis. The view was not sufficient to allow adequate monitoring of possible diabetic retinopathy. A vitrectomy was indicated to allow fundus visualization. |
Finally, although asteroid hyalosis is rarely symptomatic, complaints of floaters and decreased vision can lead one to consider vitrectomy. Visual acuity has been shown to improve after vitrectomy for asteroids,[57,61] and subjective complaints of glare have been documented to decrease postoperatively.[18] Nonetheless, attempts to explain visual symptoms by clinical examination, fluorescein angiography, and ultrasonography should be exhausted before considering vitrectomy.
As noted earlier, the PVD rate in eyes with asteroid hyalosis is low compared with expected age-matched rates. A stronger than normal vitreoretinal adhesion is usually found in patients with asteroids. Occasionally, this adhesion may make the vitrectomy a technically more difficult procedure. Several authors have noted that removing the vitreous in eyes with asteroid hyalosis can lead to retinal break formation.[59,62,63]
VITREOUS AMYLOIDOSIS
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Synonyms |
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Key Features: Vitreous Amyloidosis |
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Amyloidoses comprise a heterogeneous family of diseases characterized by the pathologic deposition of fibrillar hyaline material throughout the body. The unifying element of all amyloidoses is the formation of protein aggregates consisting primarily of beta-pleated sheets. These form insoluble, fibrillar aggregates that are resistant to proteolysis and progressively accumulate within a wide variety of tissues. These tissues include the eyelid and ocular adnexae, the orbit, and the globe.
Virchow first described amyloidosis in 1853, adopting the term amyloid because of the starch-like histologic appearance of this material. Amyloidosis affecting the vitreous was first reported in 1953 in siblings with familial amyloidotic polyneuropathy (FAP), a hereditary form of amyloidosis characterized by vitreopathy, cardiomyopathy and peripheral neuropathy.[64] First described by Andrade in a Portuguese pedigree,[65] FAP is the only form of amyloidosis that affects the vitreous. The protein responsible for vitreous amyloid formation is transthyretin (TTR). More than 50 TTR mutations have now been identified from FAP pedigrees throughout the world.
CLASSIFICATION OF AMYLOIDOSES
Historically, the myriad disorders constituting the amyloidoses have been classified according to a number of different parameters, which include systemic versus localized, hereditary versus nonhereditary (acquired), and primary versus secondary disease.[66-68] A single aberrant protein is responsible for the development of deposits in each of the amyloidoses. Increasingly, the identity of the specific amyloid protein has provided the defiitive basis for classification.
Familial Amyloidotic Polyneuropathy
FAP is a rare subtype of amyloidosis associated with mutations in the TTR gene.[69,70] This disease is of interest to the vitreoretinal specialist because it is the only amyloidosis with vitreal involvement. Amyloid deposition in the vitreous is in fact pathognomonic for the disease.[71] In some centers, vitreous biopsy is performed to rule out more common forms of systemic amyloidoses.
FAP belongs to the group of hereditary amyloidoses arising from specific mutant amyloid proteins that produce systemic disease. These rare disorders are typically transmitted in an autosomal dominant fashion (Table 188.2). Likewise, FAP is inherited in an autosomal dominant fashion with incomplete penetrance and variable expressivity.
TABLE 188.2 -- Heredofamilial Amyloidoses
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Amyloid Protein |
Disease Type |
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Transthyretin (TTR) |
Familial amyloidotic cardiomyopathy |
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Apolipoprotein AI (apo A-I) |
Familial amyloidotic polyneuropathy, type III (Iowa type) |
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Hereditary non-neuropathic amyloidosis (Ostertag's type) |
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Gelsolin |
Familial amyloidotic polyneuropathy, type IV (Meretoja's syndrome) |
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Serum amyloid A protein (AA) |
Familial Mediterranean fever[*] |
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Muckle-Wells syndrome |
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?-Amyloid protein |
Familial Alzheimer's syndrome |
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Hereditary cerebral hemorrhage with amyloidosis |
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Cystatin C |
Hereditary cerebral hemorrhage with amyloidosis |
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Lysozyme |
Hereditary nonneuropathic amyloidosis (Ostertag's type) |
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Fibrinogen a-chain |
Hereditary renal amyloidosis |
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Autosomal recessive inheritance (all others listed are autosomal dominant). |
There are four hereditary amyloidoses designated as FAP because they share peripheral neuropathy as a clinical feature. However, only two of the four types of FAP are associated with vitreous involvement. FAP type I, the form first reported in Andrade's Portuguese kindred,[65] causes a polyneuropathy affecting the lower extremities with attendant weakness and atrophy. FAP type II tends to involve the upper rather than the lower extremities.[72] Both FAP types I and II occur due to mutations in TTR and have vitreal involvement. FAP types III and IV have no vitreal involvement. FAP type III, also known as the Iowa type FAP, is due to mutations in apolipoprotein A-I and causes peripheral neuropathy, nephropathy and peptic ulcer disease. FAP type IV, also known as Meretoja's syndrome, is due to mutations in gelsolin and results in corneal lattice dystrophy, facial nerve and other cranial nerve palsies.[73,74]
Since the description of the original Portuguese kindred with FAP type I, FAP pedigrees have been found in families from Sweden, Japan, Italy, Costa Rica and many other locations worldwide.[75-78]
TTR, the protein causing FAP
TTR, the protein exclusively associated with vitreous amyloid deposits, has two normal physiologic functions. It is a transport protein for the hormone thyroxine; 25% of circulating thyroxine is bound to TTR. It also functions as a transport protein for the retinol-binding protein, which is a carrier for vitamin A. Virtually all circulating retinol-binding protein is bound to TTR.
Synthesis of TTR has been localized to a few sites in the body. Liver hepatocytes are the primary source of TTR, and this has provided the rationale for liver transplantation as a form of treatment for FAP.[79,80] Other sites of TTR production include the choroid plexus endothelium of the cerebral ventricles and the visceral yolk-sac endoderm. Importantly, TTR synthesis has been detected in the eye. In the rat, TTR is synthesized by the RPE,[81,82] where TTR messenger RNA (mRNA) is selectively localized.[83] Furthermore, wild-type TTR protein is a normal constituent of the vitreous.[81] Vitreous amyloid deposits may accumulate selectively in the eye both due to circulating mutant TTR delivered via the retinal vasculature and due to intrinsic ocular production of mutant TTR. Some authors have noted the progression of ocular manifestations of FAP even after liver transplantation, which should eliminate most circulating mutant TTR.[84,85]
The gene for TTR has been localized to chromosomal region 18 q11.2-q12.1 and has been sequenced. It contains four exons encoding four identical 127 amino acid subunits. These subunits in turn form a molecular complex that is a 55-kDa homotetramer.[86] When assembled in its normal tetrameric form, the native TTR protein is made up of over 50% beta-pleated sheet components. Senile systemic amyloidosis, which is associated with wild-type TTR,[87] is a subclinical form of amyloidosis found at autopsy in up to 25% of patients over the age of 80 years.[88]
FAP occurs due to mutant alleles of TTR that increase the likelihood of forming beta-pleated sheet protein aggregates. The most prevalent mutation found in FAP is the TTR Met 30 mutation, in which methionine is substituted for valine at amino acid position 30.[70,89] Over 50 other mutations in the TTR gene have been identified to date. Many of these TTR mutations, including TTR Met 30, Ile 3, Pro 36, Ala 49, His 58, His 69, Asn 70, Ala 71, Ser 84, Asn 90, and Cys 114, have been demonstrated to cause vitreopathy.[77,89-95]
An understanding of genotype-phenotype correlations is underway. For example, the TTR His 69 mutation causes oculoleptomeningeal amyloidosis, which has leptomeningeal enhancement and central nervous system manifestations in addition to vitreous amyloid deposition. The Cys 114 mutation is associated with a higher prevalence and earlier onset of vitreous opacities in FAP than the more common TTR Met 30 mutation.[96] Likewise, the TTR Cys 114 mutation may confer a higher risk of amyloid-induced glaucoma than the TTR Met 30 mutation.[85] As TTR gene sequencing becomes more available, understanding of genotype-phenotype associations will lead to improved prognostic counseling and patient management.
Other Amyloid Diseases
Although FAP is the only amyloidosis associated with vitreous deposits, other amyloid diseases are also reviewed here in brief. In primary AL amyloidosis, systemic amyloid deposits are composed of fragments of kappa or lambda immunoglobulin light chains. Primary AL amyloidosis develops in 6-15% of cases of multiple myeloma.[97,98] The light chain deposits can affect almost any organ system, including the heart, peripheral nervous system, kidneys, gastrointestinal system, skin, and respiratory systems. Cardiomyopathy and nephropathy carry a particularly grave prognosis. Rarely, amyloid deposits are formed by immunoglobulin heavy chains, which is called primary AH amyloidosis.
Reactive or AA amyloidosis develops in patients with chronic disease such as rheumatoid arthritis or other long-standing inflammatory or infectious processes. The causative protein is amyloid A protein, whose precursor is an acute-phase reactant. Increasing the confusion in classification, amyloid A protein is also responsible for two hereditary forms of amyloidosis: familial Mediterranean fever and Muckle-Wells syndrome, a nephropathy associated with urticaria and deafness.[99]
Neurodegenerative disorders, including Alzheimer's disease and Down's syndrome, are associated with the beta-amyloid protein. The amyloidogenic form of the beta-amyloid protein is a 40-42 amino acid cleavage fragment of the amyloid precursor protein, aggregates of which produce neurofibrillary plaques throughout the brain.
Amyloidosis is also implicated in the prion diseases, a group of transmissible encephalopathies that include Creutzfeldt-Jakob disease, Gerstmann-Straussler syndrome, bovine spongiform encephalopathy or 'mad cow disease', and scrapie in sheep. The prion diseases propagate in the absence of genetic material.[100,101] Exogenous amyloidogenic prions enter the host through ingestion or other means.[101,102]Exogenous prions then interact with native host proteins inducing a conformation change in the native proteins that makes them become amyloidogenic as well. This interaction begins a cascade leading to protein aggregation and amyloidogenesis.
Several other proteins have been identified in different forms of amyloidosis. Beta2-microglobulin is the causative protein in amyloidosis that occurs in patients undergoing chronic hemodialysis.[103]Precalcitonin has been shown to cause the localized form of amyloidosis sometimes seen in patients with medullary carcinoma of the thyroid.[104] For some types of amyloidoses, no specific protein has been isolated, but it is likely that more amyloid proteins will be identified in the future.
CLINICAL CHARACTERISTICS OF FAP
In FAP, the onset of symptoms usually begins after the third decade and is characterized by dysfunction of three major organ systems, either in isolation or in combination: the vitreous, the peripheral nervous system, and the heart.
Involvement of the vitreous is often a presenting feature.
Ophthalmic Features
Symptoms
Visual symptoms are common in FAP. Patients experience a progressive reduction in visual acuity accompanied by an increase in the density of the vitreal deposits. Vision loss is usually bilateral, but vitreous opacities can be markedly asymmetric or in some cases even unilateral.
Signs
Ophthalmic fidings are varied, as amyloid is deposited in various orbital and ocular tissues. Decreased tear production is common among individuals with type I FAP due to amyloid infiltration of the lacrimal gland. Within the conjunctiva, multiple perilimbal microaneurysms have been noted. A reduction of corneal sensitivity can lead to the development of neurotrophic corneal ulcers. The pupillary margin may have a scalloped or indented configuration,[96] possibly secondary to postganglionic parasympathetic denervation of the pupillary sphincter muscles.[85,105-107] This pupillary abnormality, when present, is thought to be pathognomonic for FAP. The pupils may also demonstrate anisocoria and are in some cases nonreactive to both light and near stimulation. Fleck deposits resembling pseudoexfoliation may be found on the anterior lens capsule and pupillary margin.[85] Pseudopodia lentis is a hallmark of vitreous amyloidosis, wherein multiple small dots or footplates are formed on the posterior lens surface (Fig. 188.7). Patients may also present with elevated intraocular pressure and glaucomatous optic nerve damage. Deposition of amyloid material within the trabecular meshwork and elevated episcleral venous pressure due to episcleral amyloid deposition are thought to be the causative factors.[44,85,108] Glaucoma occurs in approximately one-quarter of patients with FAP, most of whom require filtration surgery.[85]Scalloping of the pupillary margin, pupillary amyloid deposition and vitreous opacities are highly correlated with the occurrence of glaucoma.[85]
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FIGURE 188.7 Vitreous amyloid deposits in familial amyloidotic polyneuropathy (FAP). (a) Typical 'glass-wool' appearance of vitreous opacities. (b) Dense vitreous deposits produce a hazy view of the fundus. |
Within the posterior segment, the defiitive feature of this disease is the diffuse deposition of fibrillar opacities throughout the vitreous (Fig. 188.8). These whitish gray or yellow vitreous deposits have been described as having a 'cobweb', 'glass-wool', or 'cotton-wool' appearance. Rarely, the vitreous opacities may have a spheroidal configuration. In the early stages or after vitrectomy, there may be only beadlike opacities or tufts closely associated with retinal vessels (Fig. 188.9).[109,110] Retinal fidings may also include perivascular infiltrates or sheathing. The fiding of a perifoveal intraretinal gray ring has been reported,[107] possibly representing intraretinal amyloid deposition. Multiple superficial, grayish retinal lesions resembling cotton-wool spots are another manifestation of intraretinal amyloid infiltration.[111,112] In the equatorial regions of the retina, multiple intraretinal blot hemorrhages are occasionally seen. There has also been a report of peripheral retinal neovascularization in a patient with vitreous amyloidosis; in this case, neovascularization was present in an area of retina that was otherwise uninvolved with amyloidotic lesions.[113]
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FIGURE 188.8 Retinal involvement in vitreous amyloidosis. (a) In addition to opacities in the vitreous, amyloid can form focal, beadlike lesions associated with the retinal vasculature. Histopathologically, amyloid deposition occurs at both intraretinal (b) and preretinal (c) loci. |
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FIGURE 188.9 Homogeneous appearance of amyloid under hematoxylin and eosin stain. ×100. |
Fluorescein angiography
A number of abnormalities have been found with fluorescein angiography.[76,113] Arteriolar filling defects may be seen, and there may be pruning of the capillary margins of the foveal avascular zone. There may be leakage from the retinal vasculature resulting in macular edema. Multiple microaneurysmal abnormalities may be seen. There is staining of the cotton-wool-like retinal infiltrates. Of note, fluorescein angiography reveals normal filling of the choroidal vasculature in vitreous amyloidosis. However, abnormal choroidal vascular lesions may be detected with indocyanine green angiography.[114] A case report has described massive choroidal infarction in a patient with FAP who subsequently developed disseminated intravascular coagulation.[115]
Electrophysiology
Electrophysiologic investigations may reveal positive fidings even with minimal or absent ophthalmoscopic or angiographic abnormalities.[116] The electrooculogram may display reduced dark or light troughs, indicating retinal pigment epithelial dysfunction. The electroretinogram may be completely normal or there may be a reduced scotopic response. Visual-evoked potentials demonstrate a prolongation of the P100 latency in some cases, indicating optic nerve dysfunction.
Systemic Features
Involvement of the peripheral nervous system results in motor or sensory polyneuropathy. The initial manifestation is most commonly paresthesias and loss of pain and temperature sensation in the lower extremities. Subsequently, weakness of the extremities and atrophy of the distal musculature ensue. FAP patients also frequently present with single or multiple entrapment neuropathies such as carpal tunnel syndrome. Dysfunction of the autonomic nervous system is one of the more serious neurologic sequelae, with a variety of fidings including cardiac, gastrointestinal, and renal disturbances that can lead to significant morbidity. Although involvement of the peripheral nervous system is characteristic in FAP, the central nervous system is sometimes also affected. Patients may develop psychiatric features such as dementia or psychosis. Epileptic seizures occasionally develop. Patients may also suffer from intracerebral hemorrhage, presumably secondary to amyloidotic intracranial vascular lesions. Brain and spine magnetic resonance imaging show leptomeningeal enhancement on postgadolinium T1-weighted images due to amyloid infiltration of these tissues.[117-119]
Heart involvement features amyloid infiltration of the myocardial parenchyma, which produces fibrosis and hypertrophic cardiomyopathy. Congestive heart failure and hypertension are common and represent an ominous aspect of FAP. Conduction abnormalities such as atrial arrhythmias or heart block can also be detected by electrocardiography.
The prognosis in FAP is poor; the course is relentlessly progressive and leads to death 5-15 years after onset of symptoms. Mortality is generally due to cardiomyopathy or complications of autonomic dysfunction. Liver transplantation is an increasingly common treatment for FAP, with ?1000 transplants registered to date.[120,121] Posttransplantation survival in one clinical center was 93% at 1 year and 77% at 5 years.[121] Liver transplantation does not necessarily cure FAP because organ damage done by previously deposited amyloid is not reversible, and wild-type TTR can precipitate next to previously deposited amyloid.[122]
HISTOPATHOLOGY OF FAP
Amyloid is a homogeneous, acellular material that is strongly eosinophilic with H & E stain (Fig. 188.10). Positive staining with Congo red is a hallmark. Congo red-stained amyloid demonstrates a characteristic apple green birefringence when examined under polarized light (Fig. 188.11). In addition, amyloid displays dichromatism when examined with cross-polarized light. Amyloid also stains specifically with crystal violet and thioflavin T. Electron microscopy reveals that amyloid is composed of rigid nonbranching rods. These fibrils vary in diameter from ?70-130 Å, depending on the specific amyloid protein; the fiber formed by the TTR met 30 mutant form of TTR is ?130 Å in diameter (Fig. 188.12).[123]
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FIGURE 188.10 Apple-green birefringence of vitreous amyloid material stained with Congo red when viewed under polarized light. ×100. |
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FIGURE 188.11 Electron microscopy demonstrates amyloid fibrils in a vitrectomy specimen from a patient with the met30 transthyretin mutation. (a) Whole individual amyloid fibrils are seen with negative staining. (b) Fibril cross-sections are visible in this thin-section micrograph. Bar = 1000Å. |
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FIGURE 188.12 Amyloid deposition is seen at many ocular sites in a case of vitreous amyloidosis, including the trabecular meshwork (a) and ciliary nerves (b). |
Histologic confirmation that the vitreous opacities in FAP are indeed composed of amyloid was first reported by Kaufman using Congo red staining.[124] Vitreous opacities have since been demonstrated to be composed primarily of TTR.[125] In patients with vitreous amyloidosis, histopathology has revealed that the ocular loci of amyloid deposition are not limited to the vitreous but include multiple sites in the anterior and posterior segment.[126-128] Amyloid in the retina can be intraretinal or preretinal and tends to be associated with blood vessels in both intravascular and perivascular fashion (Fig. 188.9).[70,110,111]Amyloid can deposit in the choriocapillaris and the large choroidal vessels. In the anterior segment, amyloid can in some cases be found within the iris and ciliary body.[110] Deposition of amyloid within the trabecular meshwork has been associated with glaucoma (Fig. 188.12a).[129] The intertrabecular spaces have been found to be filled by amyloid, and there is an associated degeneration of the trabecular meshwork endothelial cells. Conjunctiva is also a frequent site of amyloid deposition and offers a convenient site for biopsy in suspected cases.[130] Other ocular sites demonstrating amyloid infiltration include the optic nerve, ciliary nerve (Fig. 188.13b), episclera, extraocular muscles, and ciliary ganglion.[109,127]
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FIGURE 188.13 Model of the transthyretin amyloid protofilament. (a) The protofilament, shown in longitudinal (above) and cross-sectional (below) views, consists of four helical ?-sheets associated parallel to the filament axis. (b) One of the four ?-sheets shown in isolation demonstrates the characteristic helical twist. Individual ?-strands, denoted by arrows in the diagrams, are arranged perpendicular to the long axis. (c) Space-filling model of the protofilament core, with each color representing two symmetrically paired ?-sheets. |
PATHOGENESIS OF AMYLOIDOSIS, INCLUDING FAP
The unifying element of the amyloid diseases is the pathologic formation of protein aggregates consisting almost entirely of beta-pleated sheets.[66,67] The amyloidoses are essentially diseases of protein misfolding. Whereas certain amyloid proteins can lead to highly specific disease phenotypes (as in the case of TTR and vitreous disease), it is their abnormal configuration, the beta-pleated sheet, which is the true basis of disease.
The beta-pleated sheet is not normally found in large amounts within human tissues. In this periodic structural motif, first formulated by Pauling and Corey in 1951,[131] polypeptide beta-strands are arranged in an antiparallel fashion, stabilized by hydrogen bonds to form pleated structures that can stack on each other like corrugated metal roofig sheets.[132] Beta-sheets in amyloid possess a 'cross-beta pattern', wherein the beta-strands are arranged perpendicular to the long axis of the fiber. Amyloid fibers are structurally homologous to the fibrous proteins of insect silk, and silk from the lacewing Chrysopa flava is the basis for some molecular models of amyloid.[133]
Mutant TTR fibrils recovered from opacified vitreous of FAP patients have been recovered, and their X-ray diffraction patterns were used to generate a structural model of the amyloid fiber.[123,134] It is composed of four identical and parallel subunits or 'protofilaments' arranged with a square cross-sectional symmetry. Each protofilament itself contains four beta-sheets twisted about each other to form a double helix with a hollow central core. The model is shown graphically in Figure 188.13. Each beta-sheet, composed of TTR monomers linked end-to-end, has its individual beta-strands (shown as arrows in Fig. 188.14a and b) oriented perpendicular to the filament axis. Cross-sectional views of the model demonstrate the hydrophobic central core that stabilizes the Beta-sheet components of the protofilament. A space-filling model shown in Figure 188.14c indicates the double-helical nature of the TTR protofilament. Hydrogen bonding extending along the length of the fibrils provides stability to the amyloid fibers. Amyloid fibers accumulate in tissues in part because they are insoluble and relatively resistant to proteolysis.
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FIGURE 188.14 A model of the structural mechanisms of amyloidogenesis. Mutations or other abnormalities in the amyloid protein allow stabilization of partially folded intermediate conformation. Rather than following the pathway to form functional globular proteins, the misfolded intermediates self-associate into polymeric fibrils, precipitating as amyloid aggregates in a kinetically irreversible manner. |
The protein core described in the previous model does not represent the entirety of the amyloid fibril. Associated elements including sulfated proteoglycans, serum amyloid P component, and possibly metals such as zinc or aluminum.[135,136] One model proposes that chondroitin sulfate stabilizes the helical protein core of the protofilament, which is then wrapped in an outer layer composed of basement membrane-type heparan sulfate.[137]
The histologic properties of amyloid are explained by the structural regularity imbued by their beta-pleated sheet composition. Congo red molecules, which have a planar structure, bind amyloid by slotting into axial folds on the beta-pleated sheet surface. The resulting parallel alignment of Congo red molecules gives amyloid its characteristic properties of birefringence and dichromatism after staining with Congo red.
The deposits found in the many different forms of amyloidoses are usually composed of a single aberrant protein. The underlying protein abnormality is often a mutation resulting in a single amino acid substitution. However, not all amyloid proteins are mutants. For example, wild-type proteins are capable of producing amyloid in some of the prion diseases. Similarly, in Alzheimer's disease, except in its rare inherited forms, amyloid plaques are produced by wild-type forms of the beta-protein. Besides mutations, abnormalities that could lead to beta-pleated sheet fibril formation include abnormal protein cleavage. In Alzheimer's disease, aberrant cleavage from amyloid precursor protein can produce a long form of the beta-amyloid protein that accelerates fibril formation and neurotoxicity.[138] Environmental conditions such as elevated serum protein concentration and abnormalities in pH and temperature stimulate amyloid aggregation in vivo.
How protein abnormalities lead to beta-pleated sheet formation and amyloidogenesis has been studied at the molecular structural level in several amyloid proteins, including TTR[139,140] and lysozyme.[141,142]In one proposed model,[143] mutations of these proteins destabilize but do not completely disrupt the normal protein conformation, thereby loosening the tertiary structure of the protein (Fig. 188.14). Intermediate conformational states that are partially unfolded result, allowing normally deeply buried internal residues to be exposed to and interact with other similarly configured proteins. Perhaps by contact of beta-strand segments between molecules, these aberrant molecules self-associate and polymerize into beta-pleated sheet fibrils. This cascade is self-generating and irreversible, producing amyloid precipitates that are relatively resistant to normal endogenous proteolytic mechanisms. Thus, amyloid accumulates in tissues and produces dysfunction via mass effect. It remains unclear how nonspecific structural destabilization brought about by mutations is able to produce the crystallization of highly ordered beta-sheet fibrils, rather than simply forming irregular, amorphous protein aggregates.
MANAGEMENT OF FAP
Diagnostic Workup
When vitreous amyloidosis is suspected on the basis of the ophthalmic fidings, the diagnostic workup should begin with a thorough family history, including determination of geographic origin. It should be noted that family history is commonly negative in vitreous amyloidosis secondary to incomplete penetrance. Pars plana vitrectomy can be performed for diagnostic biopsy as well as visual rehabilitation. The vitreous specimen is prepared for staining with Congo red as well as standard histologic stains. Cytology with flow cytometry may be indicated if large-cell lymphoma of the vitreous is in the differential diagnosis. Immunohistochemical techniques have been devised that can identify mutant TTR in serum.[144] Testing for genetic markers for TTR mutations provides defiitive evidence of FAP.[145,146]
Amyloid deposits can also be seen in extravitreal biopsy specimens. It is preferable to limit biopsy to the specific organs or tissues suspected of being involved with the amyloidotic process. However, in cases where this is not possible, some tissues may be biopsied in a nonspecific manner. Structures that are commonly chosen for biopsy owing to the ease of obtaining a specimen and the relatively high rate of involvement include the rectum, skin, gingiva and conjunctiva. Biopsy of the conjunctiva is frequently positive for amyloid in FAP.[130] Neural infiltration with amyloid can be tested by biopsies of peripheral nerves, most typically the sural nerve. It is important to test for other manifestations of FAP even in the absence of symptoms. Particularly, echocardiography may reveal signs of cardiomyopathy.
Vitrectomy
Vitrectomy has been used in the treatment of vitreous amyloidosis since the earliest development of the procedure. In fact, vitreous amyloidosis was the indication for the first reported successful complete vitrectomy, performed by Kasner and colleagues in 1968 using an open-sky approach with cellulose sponges and scissors.[147] In the inception of modern pars plana vitrectomy, Machemer and Norton[148]included in their first series a patient with vitreous amyloidosis. The efficacy of vitrectomy in the visual rehabilitation of these patients has been demonstrated in a number of subsequent reports.[149-151] Doft and associates,[152] in a series of 30 eyes, found that visual acuity after vitrectomy was better than 20/40 in almost 50% at 3-year follow-up. There is, however, a high rate of recurrence of vitreous amyloid opacities after vitrectomy.[152,153] In 20-25% of cases, repeat vitrectomy is necessitated by the reaccumulation of amyloid in the residual formed vitreous. It is important to perform as complete a vitrectomy as possible at the time of the initial surgery.
DIFFERENTIAL DIAGNOSIS OF VITREOUS DEPOSITS
Several conditions can lead to the presence of multiple and diffuse opacities in the vitreous cavity. First, we review the differences between asteroid hyalosis and vitreous amyloidosis,which can mimic one another (Table 188.3). Next, we describe cholesterolosis bulbi and other hemorrhagic, neoplastic, inflammatory, and infectious causes that can lead to diagnostic confusion (Table 188.4).
TABLE 188.3 -- Distinguishing between Asteroid Hyalosis and Vitreous Amyloidosis
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Asteroid Hyalosis |
Vitreous Amyloidosis |
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Laterality |
Unilateral |
Bilateral |
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Effect on vision |
None |
Decreased visual acuity |
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Progression |
Slow |
Rapid |
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Appearance of deposits |
Globular, refractile |
Cob-webs, steel wool |
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Systemic associations |
None |
Neuropathy, cardiomyopathy |
TABLE 188.4 -- Differential Diagnosis of Diffuse Vitreous Opacities
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Asteroid hyalosis |
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Cholesterolosis bulbi |
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Vitreous hemorrhage |
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Posterior uveitis |
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Pars planitis |
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Ocular lymphoma |
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Endophthalmitis |
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Vitreous amyloidosis |
DISTINGUISHING BETWEEN ASTEROID HYALOSIS AND VITREOUS AMYLOIDOSIS
In contrast to asteroid hyalosis, amyloidosis involving the vitreous is typically a bilateral process. Amyloid opacities have a typical 'glass-wool' or 'cobweb' appearance in the vitreous, whereas asteroid bodies have a globular appearance. Because amyloid originates from the retinal vasculature, it may be preferentially deposited in a perivascular location, and associated vascular sheathing and lesions resembling cotton-wool patches may be seen.[112] Asteroid, on the other hand, is more diffusely distributed in the vitreous. Unlike in asteroid hyalosis, these amyloid spots may collect at the posterior hyaloid face in eyes with PVD. Asteroid, in contrast, tends to occur in patients with an attached posterior hyaloid. Amyloidosis progresses relatively rapidly over several years leading to compromised visual acuity, whereas asteroid hyalosis progresses slowly and does not compromise vision. Distinguishing amyloidosis from asteroid hyalosis is easier when there are systemic fidings associated with the amyloidosis, such as cardiomyopathy or peripheral neuropathy. Also, familial amyloidosis is inherited as an autosomal dominant condition, whereas asteroid hyalosis is typically sporadic.
CHOLESTEROLOSIS BULBI
Benson in 1894 distinguished asteroid hyalitis (asteroid hyalosis) from cholesterolosis bulbi (synchysis scintillans).[1] The typical opacities of cholesterolosis bulbi are glistening, angular, and crystalline. The bodies are cholesterol crystals[154] that float freely in the usually liquid vitreous cavity and tend to settle inferiorly owing to gravity.[155] The particles probably come from leaking retinal vessels. Cholesterolosis bulbi results most commonly after vitreous hemorrhage or severe inflammation.
VITREOUS HEMORRHAGE
Old vitreous hemorrhage can create an appearance similar to asteroid hyalosis. The resolving hemorrhage and subsequent breakdown products create many appearances. Hemoglobin spherulosis is a variation of vitreous hemorrhage that presents with vitreous opacities.[156]
OCULAR LYMPHOMA
Neoplastic conditions such as large-cell lymphoma should be considered in the differential diagnosis of opacities in the vitreous. These conditions usually masquerade as uveitis with collections of fie cellular debris in the vitreous and are rarely confused with the larger particles characteristic of asteroid hyalosis. Nevertheless, in cases that cannot be distinguished with certainty on clinical examination alone, a vitreous biopsy specimen should be sent for cytologic analysis.
INFLAMMATION AND INFECTION
Inflammation from pars planitis or uveitis of unknown cause may present a confusing picture, particularly in the case of old quiescent vitritis with diffuse vitreous debris (Table 188.4). In pars planitis, the inflammation is usually bilateral, and anterior snowbanking with exudative changes is often found. In addition, granulomatous reactions within the vitreous secondary to processes such as sarcoidosis may be associated with large inflammatory vitreous deposits. History, associated ocular fidings, and a systemic workup will help in the diagnosis of sarcoidosis.
Propionibacterium acnes endophthalmitis is also in the differential diagnosis. P. acnes endophthalmitis typically follows intraocular surgery such as cataract extraction with intraocular lens implantation. Infectious white plaques are typically associated with lens remnants, the lens capsule, or the intraocular lens. Occasionally, these white opacities are seen on the anterior hyaloid surface and in the anterior vitreous.
CONCLUSION
The patient's medical and surgical history, family history, and time course of disease should be useful in distinguishing among the various etiologies of vitreous deposits. A careful inspection of the appearance of the vitreous opacities and the associated ocular or systemic signs will also be helpful. In rare cases, vitreous biopsy will be needed for diagnostic confirmation.
Though asteroid hyalosis is a common condition, its pathogenesis remains a mystery. Fortunately, it is of no clinical consequence to the vast majority of patients and usually requires little in the way of management. In contrast, vitreous amyloidosis is a rare disease for which we have an increasingly detailed molecular understanding. However, the disease continues to carry a grave systemic prognosis and there is no cure. Patients are managed by multidisciplinary teams of specialists. The ophthalmologist's role is important, as the ophthalmologist may be the one to diagnose this rare disease, and to offer patients vitrectomy surgery for improved visual function.
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