Bilateral Amyloidosis of the Vitreous Body Report of Andrew P.

a

Case Without

Ferry, MD,

Systemic or

Familial Involvement

Theodore W. Lieberman, MD

\s=b\ Amyloidosis of the vitreous body is and often misdiagnosed

an uncommon

condition that causes progressive visual loss. It is usually associated with primary familial systemic amyloidosis. The patient described in this report has amyloidosis of both vitreous bodies; her case is unusual because no other family members are affected and because there has been no evidence of systemic involvement over a seven-year observation period. After part of the vitreous body of her right eye was removed surgically, visual acuity improved from light perception to 20/60. New concepts regarding the nature, classification, and histochemical identification of amyloid are discussed.

(Arch Ophthalmol 94:982-991, 1976)

A myloidosis of the vitreous body is *t\. an uncommon and often misdiagnosed condition that causes pro¬ gressive visual loss. The process is usually associated with primary famil¬ ial systemic amyloidosis' - and only rarely has been described in the Submitted for publication Aug 22, 1975. From the departments of ophthalmology (Drs Ferry and Lieberman) and pathology (Dr Ferry), Mount Sinai School of Medicine, New York. Read before the 110th annual meeting of the American Ophthalmological Society, May 22, 1974. Reprint requests to Mount Sinai School of Medicine, Fifth Ave and 100th St, New York, NY 10029 (Dr Ferry).

form of the disease.'1,4 In both types, vitreous body involvement represents only one site of amyloid deposition in a widespread

primary nonhereditary

process. Our paper describes a patient with amyloidosis of both vitreous bodies. Her case is unusual because no other

members are affected and be¬ there has been no evidence of systemic involvement over a sevenyear observation period.

family cause

REPORT OF A CASE A 59-year-old white woman first noted black spots in the field of vision of her right eye in October 1967. As the floaters increased, veil-like scotomas developed and the vision of her right eye gradually dimin¬ ished. She noticed similar symptoms in her left eye in April 1969. Her ophthalmologist referred her to two retinal specialists, each of whom diagnosed membranes in the vitreous bodies resulting from previous hemorrhages, although at no time had fresh retinal bleeding been seen by any

observer. In August 1969, she was hospitalized for evaluation of her bilateral visual loss and her complaints of severe, progressive head¬ aches of one year's duration. The visual acuity of her right eye was limited to light perception. The acuity of her left eye was 20/30 after moving the eye about to minimize the number of opacities in the visual axis. The vitreous body of each eye

described as being filled with "debris." An extensive diagnostic survey revealed only diverticulosis on barium enema. Neu¬ rologic examination and bilateral carotid angiography were normal. A three-week course of systemic corticosteroid treatment did not change her ocular status. We first saw the patient in ophthalmic consultation at the Mount Sinai Hospital in November 1969. She was then 61 years old. The visual acuities were perception of hand movements at one foot with the right eye and 20/70 with the left eye. On visual field testing with the Goldmann perimeter, only an island of vision remained inferiorly in the right eye to a IV/4 white target. The visual field of her left eye was constricted and had a central scotoma. There was no ptosis, proptosis, or abnormality of the lids and conjunctivas. The ocular movements were normal. The pupils were round, equal, and reacted briskly to light and to near fixation. The Gunn pupillary phenomenon was not present. A Schirmer test disclosed no evidence of diminished lacrimal secre¬ tion. The corneas had bilateral arcus, Hudson-Stähli lines, and fine pigment dusting of their endothelial surfaces. The intraocular pressure was equivalent to 13 mm Hg in both eyes (Goldmann applana¬ tion tonometer). On examination with the slit-lamp biomicroscope, the anterior cham¬ bers were deep and the aqueous humor and lenses were clear. The vitreous body of each eye was filled with wavy sheets of material with the appearance of glass wool that were composed of dull, yellowishwas

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particles and similarly colored, stringy fihrils (Fig 1). This material totally precluded viewing the posterior pole of the right eye with the ophthalmoscope, but the peripheral part of the retina could be seen white

well and showed no abnormalities. The retina of the left eye (Fig 2) could also be seen more clearly in the periphery than posteriorly. The only retinal abnormality was sheathing of the macular branch of the superior temporal artery for a distance of about three disc diameters as it coursed above the left macula. A fluorescein angio¬ gram of the left retina was too indistinct for interpretation. We suspected amyloidosis of the vitreous bodies and admitted the patient to the hospital for further evaluation. Her medi¬ cal history included recurrent bouts of diverticulitis, labile hypertension, and las¬ situde. She had undergone eight operative procedures and was taking 13 different medications, prescribed for her vascular hypertension and her gastrointestinal and emotional problems. Review of systems was extensively positive and defied sum¬ mation. Her family history did not suggest familial amyloidosis in any relative. No history of peripheral neuropathy or pro¬ gressive visual deterioration was elicited. Both parents died at age 51 years, her father after an accident and her mother from carcinoma. An older brother died at age 64 years from a pulmonary carcinoma and was said to have seen well. The pa¬ tient's older sister, age 69 years, had inter¬ mittently blurred vision, but there was no evidence of vitreous body amyloidosis when we examined her in 1973. Her physi¬ cian advised us that she was in good health. The third sibling is a younger sister who is in good health and good sight. We found no ocular abnormality when we examined the

patient's two daughters. On physical examination, the vital signs, including blood pressure, were normal. was no enlargement of the tongue, heart, spleen, or liver. She had no neurolog¬ There

ical deficits. A complete blood count and urinalysis were normal, as were the erythrocyte sedi¬ mentation rate, serum protein-bound io¬ dine level, serum electrolytes, hepatic func¬ tion tests, serum protein electrophoresis, and serum quantitative immunoglobulins. A serologie test for syphilis (VDRL test), febrile agglutinins, lupus erythematosus preparations, antinuclear antibodies, latex fixation, Coombs direct antiglobulin tests, urine culture, and examination of urine for Bence Jones proteins gave negative find¬ ings. A toxoplasmosis serum fluorescent antibody titer was 1:16. Skin tests for tuberculosis, histoplasmosis, coccidioido-

mycosis, and blastomycosis were negative. electrocardiogram was normal. Skull roentgenograms showed hyperostosis frontalis interna. An intravenous pyelogram was interpreted as normal. Biopsy speci¬ mens of skin, gastrocnemius muscle, gingi¬ The

va, and rectum

normal and did not stains. By March 1970, the visual acuity of the patient's left eye had diminished to 20/400, and we readmitted her to the hospital for a lens extraction and subtotal vitrectomy of the more involved right eye. The operation was performed with the patient under general anesthesia. After opening the eye with a 300° limbal incision, a large superior sector iridectomy and an inferior sphincterotomy were performed, and the lens was delivered intracapsularly with a cryophake. We did not use a-chymotrypsin. The oper¬ ating microscope was used for the subtotal vitrectomy. Suction with an eye dropper and with a syringe fitted with a large bore needle afforded little success in bringing the vitreous body anteriorly, nor were Week sponges of help. A hand-over-hand technique of removing the vitreous body, reveal

amyloid

were

on

special

using Arruga forceps, proved most success¬ ful. As the vitreous body strands were brought anteriorly, they were cut with

Vannas scissors. Material was removed until we saw a good red reflex at the posterior pole. The limbal incision was closed with interrupted 6-0 silk sutures and saline solution was injected into the eye. The excised portion of the vitreous body was passed through a millipore filter to separate out the opacified material. One portion, sent for immunoglobulin studies, had 12 mg/100 ml of IgG but no detectable IgA or IgM. A second part was fixed in glutaraldehyde for electron microscopy but was lost. The third part was fixed in A% neutral buffered formaldehyde solution (101 formalin) and was sent to the Ophthalmic Pathology Laboratory for

processing. The patient's postoperative course was complicated by a suspected pulmonary embolism. Moderate postoperative intra¬ ocular inflammation diminished with the use of topically administered dexametha¬ sone. The visual acuity of the right eye improved to 20/60 and remained at the 20/60 to 20/70 level until April 1972. Glau¬ coma developed several months after the operation because of almost total peri¬

pheral anterior synechia formation. Pro¬ gressive visual field loss, glaucomatous cupping of the optic nerve head, and recur¬ rent corneal edema supervened, despite the fact that the intraocular pressure was being medically controlled between 15 mm Hg to 25 mm Hg (Goldmann applanation tonometer). After April 1972, the visual

acuity

of the right eye gradually deterio¬ rated to 20/400 and the intraocular pres¬ sure became more difficult to control. We readmitted the patient to the Mount Sinai Hospital in August 1973 for cyclocryotherapy. This improved the situation for about five months, but vision now appears to be irretrievably failing in the right eye. It is our impression that during the five years since subtotal vitrectomy, there has been little or no reaccumulation of amyloid in the right eye. During her hospitalization for cyclocryotherapy, we again found no evidence of systemic amyloidosis. No amyloid was present in a repeat rectal biopsy specimen. Serum protein electrophoresis and quanti¬ tative immunoglobulins were normal. In 940 ml of urine collected over 24 hours, 0.06 gm of protein were present, none of it of Bence Jones type. The vision of the left eye had deterio¬ rated to light perception with good projec¬ tion when the patient was last examined in January 1975. The progressive reduction in vision in her left eye resulted from increased accumulation of amyloid in the vitreous body. The intraocular pressure of the left eye rose above normal in 1974, reaching a level equivalent to 32 mm Hg (Goldmann applanation tonometer), de¬ spite the fact that the patient was receiving acetazolamide for her glaucoma¬ tous right eye. Its anterior chamber angle is open with minimal pigmentation. The elevated intraocular pressure in the left eye has been reduced to normal levels by using 2% epinephrine bitartrate drops topi¬

cally.

An electroretinogram of the left eye performed in March 1971 demonstrated "... lower than average /?-wave voltage, but within the normal range. Oscillatory potentials: almost absent." The left eye was studied ultrasonographically by D. Jackson Coleman, MD, in June 1971. His interpretation of the /J-ultrasonogram (Fig 3) was reported as follows.

Definite fibrillar vitreous changes noted with sheet-like mem¬ branes extending from the posterior pole, in the region of the optic disc, anteriorly to the lens. The mem¬ branes are of low reflectance and are, therefore, not consistent with a retinal detachment. The acoustical reflectance is similar to that seen with a fibrinous deposit along the posterior limiting membrane of a retracted vitreous. The midvitreous pattern is not typical of that seen in vitreous hemorrhage, but in terms of the acoustic characteristics, per se, they cannot be differentiated are

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Fig

2—Retina inferonasal to left optic head is partially obscured by grayish-white, veil-like, opaque accumula¬ tion of amyloid in vitreous body (April 21, nerve

1971).

Fig 3.—jS-Ultrasonogram (courtesy Coleman, MD). June 8, 1971

Fig 1.—Vitreous body in left one third of field is filled with wavy sheets of material with glass wool appearance, composed of dull, yellowish-white particles and stringy, fibrillar material. Vitreous body at right is located more posteriorly; it is in different plane of focus but on slit-lamp examina¬ tion exhibited changes identical with those present in portion of vitreous body at left. Posterior surface of lens appears as area of high reflectance at far left side of field

of left eye, of D. Jackson

(March 9, 1970).

Fig

4.—In

midportion

of far

right

side of

field, structure of vitreous body is normal. Elsewhere, there are prominent, globular excrescences

that stain metachromatical-

ly (crystal violet, original magnification

Fig 5.—Same field photographed in polarized light. Amyloid deposits exhibit prominent yellowish-green birefringence. Left, Portion of amyloid accumulation that is stained orange-red (arrow). Much of rest of collection of amyloid in this part of field exhibits yellowish-green birefringence. Right, Polarizer has been rotated several degrees. Portion of amyloid deposit designated by arrow at left is now markedly biréfringent, while those areas that had been biréfringent in figure at left have now assumed red color. Same features are observed in fibrillar collection of amyloid just below and to left of center of field. At right, amyloid appears red, but in left figure, red appearance has given way to prominent yellowish-green birefringence (Congo red, original magnification X480).

X120).

Fig 6.—Accumulations of amyloid exhibit intense yellowish-green fluo¬ rescence when viewed in ultraviolet light (Thioflavine T, original magnifi¬ cation x480).

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from old vitreous hemorrhage. The anatomic configuration, however, is typical of that seen in vitreous degenerative diseases.

perform

subtotal vitrec¬ tomy of the left eye in the future. We

plan

to

a

PATHOLOGICAL FINDINGS Gross Examination.—The specimen consisted of a crystalline lens and a fragment of vitreous body, the latter measuring about 9x6x3 mm. Both the lens and the vitreous body had been fixed in formaldehyde solution. Microscopic Examination.—Sections prepared from the vitreous body showed the latter to be normal in some areas, but throughout most of its extent the vitreous body was distinct¬ ly abnormal. Interspersed with its normal fibrillar material were promi¬ nent globular excrescences that, in sections stained with hematoxylineosin, were rather amorphous and strongly eosinophilic. These abnormal areas were metachromatic (purplishred) after staining with crystal violet (Fig 4). They stained intensely with Congo red and, in Congo red-stained sections, exhibited yellowish-green bi¬ refringence. When viewed with polar¬ ized light, the Congo red-stained material appeared orange-red in some areas of a given field and yellowishgreen in others (Fig 5). By rotating the polarizer several degrees, the optical picture was reversed, so that those areas that were originally

yellowish-green yellowishgreen were now orange-red (Fig 5). In some areas of the vitreous body, rotating the polarizer resulted not in a yellowish-green color but in a pale violet-blue. In addition to the forego¬ ing, dichroism was another feature orange-red

were now

and those that had been

demonstrable in the areas of abnor¬ mality in sections stained with Congo red. The abnormal areas exhibited an intense yellowish-green fluorescence after staining with Thioflavine when viewed in ultraviolet light (Fig 6). A special stain for acid mucopolysaccharides (Alcian blue) demon¬ strated the presence of abundant amounts of these substances in the normal-appearing portion of the vitre¬ ous body, but the abnormal areas did

not stain

positively for acid mucopolysaccharides. They accepted the Nu¬ clear Fast Red counterstain. After pretreatment with hyaluronidase, no blue staining persisted in the normal areas of the vitreous body, but the acceptance of Nuclear Fast Red by the areas of abnormality was undiminished. A special stain for iron gave negative findings.

The lens was unremarkable in sections stained with hematoxylineosin. The lenticular substance stained orange with Congo red but on examination with polarized light did not exhibit birefringence of the type characteristic of amyloid. CLASSIFICATION OF AMYLOIDOSIS

Amyloid deposition produces dys¬

function in any organ, for the most part, by replacing its functioning mesenchymal or parenchymal cells. Amyloidosis of the vitreous body is an exception in that the amyloid is produced in the retina (which is not totally replaced) and seems to be secreted into the vitreous body. The latter eventually becomes sufficiently opacified to interfere with light trans¬ mission. Amyloid is quite inert and usually does not incite an inflamma¬ tory response by its presence, al¬ though a foreign body giant cell reac¬ tion may be occasionally observed about deposits in the ocular adnexa.

Attempts at classifying amyloidosis (Table 1) by either the coexistence or absence of associated diseases, distri¬ bution of the organs involved, tissue localization, or, most recently, by the chemical composition of amyloid have been only partially successful because of overlapping of the various catego¬ ries and an incomplete knowledge of this process. The primary amyloidoses, by definition, were consid¬

ered unrelated to antecedent or coex¬ isting diseases. But at least in the primary nonfamilial type, recent evi¬ dence demonstrates a high incidence of serum and/or urine immunoglobulin abnormalities.' Some authors consider primary nonfamilial amyloi¬ dosis to be an expression of, and secondary to, an occult plasma cell dyscrasia.' Sera from some patients with primary hereditary amyloidosis have shown abnormal protein electro-

phoretic patterns and lipoprotein ab¬ normalities,1' although investigation of this type of amyloidosis has not

been as intensive as in the nonfamilial form. The amyloidoses have also been classified according to predominant organ distribution (Table 1). Critics of this classification insist that the over¬ lapping in organ distribution is exten¬ sive, especially as found at autopsy.7 For instance, the nephrotic syndrome commonly occurs in primary, in mye¬ loma-related, and in secondary types of amyloidosis, although classically it is considered characteristic of second¬ ary amyloidosis." Histologie examination of amyloid deposition has demonstrated a pericollagenous distribution associated with the primary and myeloma-related types (mesenchymal tissue distribu¬ tion pattern I) of amyloidosis." In this pattern, amyloid is laid down where collagen fibers prevail (adventitia of arteries and veins, submucosal con¬ nective tissue, stroma, sarcolemma of muscle, and neurilemma of nerves). In the secondary form of amyloidosis associated with parenchymatous or¬ gan invasion (pattern II), amyloid is initially deposited in locations rich in reticulin (intima of arteries, basement membranes, and sinusoids of liver, spleen, and adrenals)-the so-called

perireticulin pattern."

The clearest classification of amy¬ loidosis may result from the rapidly advancing chemical characterization of the amyloid proteins. Glenner and associates have shown that the amino acid sequencing of the major amyloid constituents associated with primary nonfamilial amyloidosis and plasma cell dyscrasia is homologous with the light chain of immunoglobulins.'" Immunoamyloid is now considered a polymer of either whole light chains alone or in combination with the vari¬ able portion of the light chain. In one patient, these investigators found the tissue amyloid protein to be identical with the monoclonal Bence Jones protein of the patient."1 In other ex¬ periments they showed that proteolytic digestion of Bence Jones protein resulted in an insoluble protein precip¬ itate having the electron microscopic features and histochemical staining properties characteristic of amyloid.

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Table 1.—Classification of

Type Primary systemic amyloidosis

Heredity Nonfamilial

(?)

Associated Diseases Occult plasma cell

dyscrasia

Systemic

(?) None (?) Serum protein lipoprotein

Amyloidoses

Organ Distribution Pattern I: tongue; heart;

skin; gastrointestinal tract; skeletal, cardi¬ ac

Familial

and Localized

and

abnormalities

Histologie Amyloid Distribution Composition Light chain immunoglobulins, Pericollagenous especially the variable region of the light chain

and smooth mus¬

cle; nerves; carpal ligaments; and (?) rarely vitreous body Pattern I, with frequent involvement of periph¬ eral nerves; deposi¬ tion in vitreous body, retina, choroid, orbit, ciliary ganglion, extraocular muscles, and cornea (some cases

Pericollagenous

of lattice

dystrophy) Secondary systemic amyloidosis

Nonfamilial

Multiple myeloma

Pattern I

Infectious diseases

Pattern II:

liver; spleen; kidneys; adrenal glands

(tuberculosis, leprosy, syphilis) Inflammatory diseases (rheumatoid arthri¬

Light chain immunoglobulins, Pericollagenous especially the variable region of the light chain Nonimmunoglobulin protein Perireticulin (protein A)

tis and other connective tissue

disorders) Hodgkin disease Familial

Primary localized amyloidosis

Nonfamilial

Familial

Familial Mediterranean fever None

Pattern II

Orbit; lacrimal glands; skin; conjunctiva; trachea; lung; bladder; gasserian

Perireticulin

Nonimmunoglobulin protein (protein A) Immunoglobulin light chain found in isolated

one case

of

pulmonary amyloidosis

ganglion Skin; most cases of

None

lattice corneal

Secondary

Nonfamilial

localized

amyloidosis

Trachoma Psoriasis Endocrine tumors: pheo-

Skin

Adrenal; thyroid;

Apudamyloid

Tumors: pheochromo-

Adrenal; thyroid

Apudamyloid

chromocytoma; medullary carci¬ noma of thyroid; insulinoma; gastrinoma

Familial

dystrophy Conjunctiva pancreas; stomach

cytoma; medullary

carcinoma of

thyroid

It is

postulated that in primary or myeloma-related amyloidosis, plasma cells produce light chains that are both

excreted in the urine as Bence Jones and subjected to proteolytic breakdown and polymerization with the formation of amyloid. Whether or not amyloid is produced may depend on the characteristics of the light chain.'" It has also been suggested that amyloid formation may result from a defect in intralysosomal proteolysis of the precursor immunoglobulin. Why amyloid is regularly depos-

protein

ited in some organs but rarely in others is not clear. The initial tissue binding may be an immunologie inter¬ action (autoantibody formation) or a less specific physiochemical attrac¬ tion. In contrast to immunoamyloid, the amino acid sequence of amyloid pro¬ tein of the secondary type does not resemble any known sequenced immunoglobulin. This protein has been designated "protein A." A protein antigenically related to protein A has been found in the sera of normal

subjects and in increased amounts in patients with secondary amyloido¬ sis."'- The origin of the major protein constituent of secondary amyloid is not

known, but it

may be the

proteo-

lytic product of a larger molecule, perhaps the antigenically related cir¬ culating protein. Light chain compo¬ nents have been isolated from second¬

amyloid, a finding consistent with the presence of increased serum and urinary monoclonal immunoglobulins in some patients with pattern II ary

amyloid deposition.

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'

In

one

case

of localized nodular

amyloidosis of the lung, the major amyloid protein was a lambda light polypeptide chain.'" A dense plasmacytic infiltrate was present at the borders of the lesion and "histiocytes" were found centrally. Bone marrow plasmacytosis was absent, it was hypothesized that the localized plasma cells produced monoclonal immunoglo¬ bulins that loid by the

histiocytes.

modified into amy¬ proteolytic action of the

were

Still another form of amyloid exists in isolated tumors of endocrine ori¬ gin." These tumors include pheochromocytomas, medullary carcinomas of the thyroid gland, and insulinomas. The cells of origin of these tumors all arise from the neural crest and have been termed the amine precursor uptake and decarboxylation (APUD) series of polypeptide secreting cells. Some of these tumors (apudomas) have been associated with the produc¬ tion of amyloid (apudamyloid). This amyloid differs from immunoamyloid in that it does not demonstrate yellow autofluorescence, and it also lacks the aromatic amino acids tryptophane and tyrosine that are present in immuno¬ amyloid. The origin of apudamyloid may be the nonhormone residue of

prohormone or a polypeptide produced concomitantly with the hormone it¬ self.

Although three different types of amyloid have been described, the elec¬ tron microscopic appearance and his¬ tochemical staining reactions of all three types are practically identical. This appearance is, in part, dependent on similar structural configurations of the various amyloid molecules (antiparallel B-pleated configuration). PATHOLOGICAL IDENTIFICATION OF AMYLOID In sections stained with hematoxy¬ lin-eosin, amyloid appears as an amor¬ phous, eosinophilic material. Pearse notes that the deposition of a hyaline homogeneous substance in the walls of blood vessels and in the connec¬

tive tissues had been observed by many workers before it was described by Rokitansky in 1842 under the comprehensive term lardaceous dis¬ ease.'41™' " Virchow subsequently

named the carbohydrate component of the substance amyloid because of its starch-like behavior (ie, as¬ sumption of a blue coloration) when stained with iodine. Demonstration of metachromasia with crystal violet (amyloid stains purplish-red) is helpful in differen¬ tiating amyloid from other hyaline proteins that may resemble it superfi¬ cially in sections stained with hema¬

toxylin-eosin. Congo red staining is simpler than the crystal violet technique. It is more permanent and has provided consid¬ erable information about the struc¬ ture of amyloid. In properly stained

sections, amyloid appears rose to orange-red against a faint pink to light orange background. Differentia¬ tion between the amyloid deposits and the adjacent collagenous and elastic

tissue may be difficult in sections stained with Congo red. Unstained amyloid exhibits a faint greenish positive birefringence that is markedly increased after staining with Congo red." Examination with

polarized light is, therefore, important in the histological identification of amyloid and should always be carried

out if there is any doubt as to the identity of any Congo red-stained

tissue component,"""1

" The yellow¬ color of Congo ish-green anisotropie red-stained amyloid is regarded as highly specific and results from the orientation of the dye particles bound to the bundles of parallel fibrils of which amyloid is composed."""1 " Dichroism is another feature impor¬ tant in identifying amyloid. Unfortu¬ nately the terms dichroism and bire¬ fringence have sometimes been used interchangeably.1' Birefringence is the possession of different refractive indices with respect to light polarized in different directions."""1 -' Dich¬ roism is the property of preferentially absorbing light polarized in a certain

direction, light polarized at right angles to this direction being trans¬

mitted to a greater extent."""' Amyloid stained with Congo red ex¬ hibits dichroism. In contrast to bire¬ fringence, dichroism can be specific for a particular substance."""1-' Dichroism can be observed in a micro¬ scope, similar to a conventional polar-

-'

izing microscope, but using only either a polarizer or an analyzer, not both (the dichroic substance itself serves as

analyzer or polarizer, depending on the optical arrangement). Either the polarizer or the object should be rotated through at least 90° while watching for changes in intensity of light transmitted through the region of the specimen thought to be dichro¬ ic."""1 Amyloid is dichroic only to The parallel bun¬ green light."""1 dles of amyloid fibrils stained with Congo red absorb green light very strongly if the plane of vibration of the light is parallel to the fiber axis but not if the plane of vibration is perpendicular to the axis. Stated another way, parallel-oriented dye molecules will show different absorp¬ tion coefficients toward plane polar¬ ized light, according to whether the plane of polarization is parallel to or at right angles to the axis of the mole¬ -'

-'

cules. In the

case

of dichroism of

amyloid dyed with Congo red, the inference is that the long dye mole¬ cules are lying along the fiber

axis.""'"1 Detection of fluorescence is of great assistance in identifying amyloid. This substance is naturally fluores¬ cent (autofluorescent). But in recent years, the secondary fluorescence im¬ parted by using an alternative fluorochrome, Thioflavine T, has achieved great popularity as a method for identifying amyloid."". After be¬ ing stained with Thioflavine T, amy¬ loid fluoresces greenish-yellow when viewed in ultraviolet light. This meth¬ od is extremely sensitive and at first was thought to be specific for amyloid. -'

Recently, false-positive

or

nonspecific

fluorescence with Thioflavine has been reported by some investigators, but few of these false-positive reac¬ tions were of practical importance." Electron microscopy is also of great value in establishing the presence of amyloid in cases where the histochem¬ ical reactions are equivocal. Pearse has observed that the fibrillar ultrastructural pattern of amyloid has been found in all types of amyloid tested, "... and thus the electron microscope must be considered the absolute arbi¬ ter of the presence or absence of

amyloid.""""1

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"

OCULAR AND ADNEXAL INVOLVEMENT IN AMYLOIDOSIS

Systemic secondary amyloidosis is the form of amyloidosis most fre¬ quently observed in general clinical medicine. In this disorder, however,

small, clinically unimportant deposits

of ocular amyloid have only rarely been described, and ophthalmologic signs attributable to the presence of amyloid are virtually unknown.'" Primary amyloidosis (both the sys¬ temic and nonsystemic types) is the form associated with clinically impor¬ tant depositions of amyloid in the eyes or ocular adnexa. Rukavina and asso¬ ciates observed that signs of ocular involvement were present in 8% of cases of primary familial systemic amyloidosis." Their report was based on a retrospective survey of cases previously reported in the literature. Many of those patients may not have had a thorough ocular examination. The incidence of ocular involvement in primary familial systemic amyloidosis is probably higher than the 8% figure arrived at by Rukavina and asso¬ ciates. Ocular and adnexal involvement in the various types of primary amyloi¬ dosis may be outlined as follows.

follow-up examinations may ulti¬ mately reveal the presence of sys¬ temic amyloidosis. Nonfamilial Type.—Accumulations of that

amyloid in the cornea without appar¬ ent systemic involvement or a heredi¬ tary pattern have been described by a

number of authors, most often as a result of pre-existing ocular disease. Ramsey and associates have recently summarized this disorder.-'

Conjunctiva

Clinically detectable conjunctival involvement has not been a feature of systemic familial amyloidosis. There have been many reports of nonfam¬ ilial amyloidosis confined to the con¬ junctiva. These are regarded as exam¬ ples of primary amyloidosis, although some authors have incriminated ante¬ cedent local diseases for the amyloid deposition.'"

Eyelid The skin of the eyelids is the site of predilection for the characteristic cu¬ taneous eruption of primary systemic amyloidosis.'" The lesions typically are

bilateral, symmetrical, small, smooth, discrete or confluent papules. They may be yellowish and waxy or purple

nation of the trabecular meshwork of those patients with normal intra¬ ocular pressure."-'-' The patient of Legrand et al had previously under¬ gone filtering surgery for glaucoma, but the authors did not comment on the presence or absence of amyloid in his trabecular meshwork.-" Paton and Duke's patient had amyloid deposition in the trabecular meshwork of his glaucomatous right eye but not in his normotensive left eye.2T It appears, therefore, that the presence of amy¬ loid in the trabecular meshwork may bear some relationship to the presence of elevated intraocular pressure. Uveal Tract

The uveal blood vessels, particularly those of the choroid, have been shown to contain large amounts of amyloid in patients with primary systemic amy¬ loidosis.----''-"--s In the case reported by Tso and Bettman, the choriocapil¬ laris was extensively involved and appeared as an amorphous mass of amyloid without residual cells or vascular lumens.-4 Despite this, there was no evidence for secondary mor¬ phological or functional derangement of the overlying retina. Retina and Vitreous

and

Cornea

Systemic Seitelberger and

Familial

Type.—In 1961,

Nemetz reported that the stromal lesions of corneal lattice dystrophy, a hereditary disor¬ der, contained amyloid.17 These obser¬ vations were confirmed by Klint¬ worth.'" Investigators at several insti¬ tutions subsequently examined their patients with corneal lattice dystro¬ phy for evidence of systemic amyloi¬ dosis but were unable to demonstrate the presence of this disorder. More recently, Meretoja has reported sev¬ eral instances of corneal lattice dys¬ trophy occurring in patients with familial systemic amyloidosis.'"

Nonsystemic

Familial

Type.—Kirk

and associates recently reported three siblings with bilateral primary amy¬ loidosis of the cornea.2" The lesions

appeared as centrally located, raised, gelatinous masses with a mulberry¬

like surface. The condition is rare, course, it is entirely possible

and, of

hemorrhagic. A positive familial history is present in many cases. Primary localized (nonsystemic) amyloidosis is said to not affect the skin of the eyelids.'" Trabecular Meshwork

reading clinical reports in the literature, one gains the impression that there is an increased incidence of open angle glaucoma in patients with primary amyloidosis. Our patient is of interest in this regard. Although the glaucoma in her right eye can be ascribed to postoperative peripheral anterior synechias, the recently devel¬ oped glaucoma in her left eye cannot be explained on this basis. The chamber angle of the left eye is open, and we wonder whether the trabe¬ cular meshwork has developed ac¬ cumulations of amyloid that interfere with its normal functioning. In patients with primary systemic amyloidosis, amyloid deposition has not been noted on pathological examiFrom

Body

Involvement of the retina and vitreous body is discussed elsewhere in this paper. Orbit

Orbital involvement in

primary nonsystemic amyloidosis has been reported on several occasions. A recent paper describes a patient first seen by one of us (A.P.F.) in 1958 and

summarizes other cases with orbital involvement.-" Proptosis has been a prominent feature in these patients. Amyloid has also been found in the orbits of some patients with primary familial systemic amyloidosis. Al¬ though proptosis was not a feature in these patients, involvement of impor¬ tant orbital structures has caused ocular symptoms and signs. For exam¬ ple, Wong and McFarlin attributed their young patient's keratitis sicca to amyloid deposition in the lacrimal gland."1 This patient had also exhib¬ ited internal ophthalmoplegia. The

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demonstrated prominent amyloid deposition in the ciliary ganglion and ascribed to this the internal ophthalmoplegia that had been observed clinically. Similarly, the patient of Paton and Duke had slug¬ gish pupillary reactions, but no amy¬ loid was found in the sphincter muscle of the iris of either eye on subsequent pathological examination.27 The au¬ thors attributed the abnormal pupil¬ lary reactions to deposition of amyloid in ciliary nerves; they were able to demonstrate these deposits patholog¬ authors

ically.

Neuro-ophthalmic Manifestations

Pupillary

abnormalities

are

the

neuro-ophthalmic sign found in primary familial systemic amyloidosis. The pupils have been described as dilated and unequal with absent or sluggish reactions to light, at times accompanied by poor ac¬ most

common

commodative responses.' The relation¬ ship of amyloid deposition in ciliary nerves and the ciliary ganglion to pupillary abnormalities has been com¬ mented on in the preceding para¬ graph. Most patients with pupillary abnormalities have had prominent, or overtly exophthalmic, eyes. External ophthalmoplegia, diplopia, and optic neuropathy have been reported in isolated cases of familial amyloidosis. PREVIOUS PATHOLOGICAL EXAMINATIONS OF THE EYE IN PRIMARY AMYLOIDOSIS

Listed in Table 2

13 other cases primary amyloidosis in which the eyes or vitreous bodies of the patients are

of

have been examined pathologically. We have included all cases of systemic primary familial amyloidosis in which ocular pathological examination has been done.23-25-28-30-31 We have also listed the cases of Koletsky and Stech¬ er,32 Götze and Krücke,33 Crawford,22 Kasner et al,4 and Tso and Bettman,-'4 in which the family history seemed to be negative for amyloidosis. The vitreous body was involved in 9 of the 13 patients (Table 2). In five of these nine patients, the eyes were obtained at autopsy, and in each of these five cases the retinal vessels also contained prominent accumulations of amyloid (cases 3, 7, 8, 11, and 12).

Several authors illustrated the appar¬ ent passage of

amyloid from the walls of the retinal blood vessels into the vitreous body (cases 7, 8, and 12). In many retinal vessels the entire wall contained amyloid, but in less affected vessels the amyloid was found almost exclusively in the outer layers of the vessels—a distribution in keeping with the "pericollagenous" concept ad¬ vanced by Heller et al.9 These observations provide addi¬ tional presumptive evidence for the role of the retinal blood vessels in elaborating the amyloid present in the vitreous body. Of further interest in this regard is the observation that in the well-studied cases of Crawford2'-' and Tso and Bettman,24 despite the presence of extensive amyloid deposi¬ tion in the eyes, there was no amyloid in either the vitreous body or in the retinal blood vessels. It appears, therefore, that in the absence of amyloid deposition in the walls of retinal blood vessels, amyloidosis of the vitreous body does not occur. CLINICAL RECOGNITION OF AMYLOIDOSIS OF THE VITREOUS BODY Involvement of the vitreous body in primary familial amyloidosis was first reported only 22 years ago by Kantarjian and de Jong.34 The patients mentioned in their report were described subsequently in greater detail by Falls and associates.1 In the early stages of the process,

prominent perivascular

sheathing

may be observed in the retina.1-23 It is presently believed that the amyloid in the vitreous body arises from the walls of the retinal blood vessels. Amyloid in the vitreous body is dull white or yellow-white and has been variously described as "veil-like, opaque, gray strands," "heavy, whit¬ ish-yellow, cotton wool-like opacities," "sheet-like opacities," "filmy glass

wool," and "cobweb appearing opaci¬ ties." The amyloid in our patient had a prominent particulate, as well as a fibrillar, quality. The particles were dull yellowish-white and were larger than those seen with an inflammatory

cellular exúdate. In

our

patient

vitreous bodies

the was

periphery of the generally less

involved than was the case more posteriorly. This permitted easy vi¬ sualization of the peripheral portions of her retinas when the pupils were widely dilated. If the ophthalmologist is unaware of amyloidosis of the vitreous body as a clinical entity, he will not, of course, make the correct diagnosis. In many patients with this disorder, the vitreous body opacities have been regarded as an inflammatory exúdate resulting from "iridocyclitis" or as the aftermath of a hemorrhage into the vitreous body. Our patient is a good example of this. She had consulted several ophthalmologists, two of whom were specialists in retinal diseases. Both of these consultants believed the vitreous body opacities had resulted from previous hem¬ orrhage, but, on our further inquiry in this regard, none of her ophthalmolo¬ gists had ever seen fresh retinal

bleeding.

In some patients with amyloidosis of the vitreous body, the nature of the opacities was not recognized until systemic symptoms had called atten¬ tion to the presence of amyloidosis. In still other patients, despite prominent systemic manifestations of amyloido¬ sis, the possibility of this disorder being present had been completely overlooked by the patients' internists. In these patients (for example, the cases reported by Hamburg25) the presence of systemic amyloidosis was first recognized at postmortem exam¬ ination. In some patients the vitreous body opacities are the presenting manifes¬ tation of the disease. In others, they develop later in the course of the disorder in a patient already known to have systemic amyloidosis. In some cases the interval from appearance of vitreous body opacities to demon¬ strable evidence of systemic disease has been remarkably long (eg, 13 years in case 2 of Kaufman and Thomas, although the evidence for systemic disease here is not complete¬ ly convincing31). Our patient has now been followed for seven years since developing symptoms of vitreous body involvement, and there is still no demonstrable evidence of systemic amyloidosis. Whether she will remain

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Table

Surgical

2.—Pathological Examination or

Material

Author Koletsky & Stecher32

Postmortem Postmortem

Studied

2

Götze & Krücke33

3

Case 1

of the

Eye in Primary Amyloidosis

Family History

Vitreous Body Involved

Both eyes

of Amyloidosis None mentioned

No

Postmortem

Both eyes

Not established

No

Kaufman30 later, Paton & Duke27

Surgical

Positive

Postmortem

Vitreous body Both eyes

Yes (both eyes)

Kaufman & Thomas3'

Surgical

Vitreous body

Positive

Yes

Surgical

Vitreous body

Positive (suspected)

Crawford22

Postmortem

Both eyes

Negative

7

Wong & McFarlin23

Postmortem

Both eyes

Positive

8

Leg rand

Postmortem

Both eyes

Positive

9

Kasner et al4

Surgical

Vitreous

body

Negative

Yes (both

10

Kasner et aK

Surgical

Vitreous

body

Negative

Yes

Franceschetti and Rabinowicz28

Postmortem

Posterior segment of both eyes

Positive

Yes

12

Hamburg« (second case)

Postmortem

Botheyes

Positive

13

Tso & Bettman2*

Postmortem

Both eyes

Negative

Sites of Amyloid Deposition in Eye

Central retinal artery of left eye but not elsewhere in retina; posterior ciliary vessels No amyloid in retina, choroid, or

4

(first case) 5

Kaufman & Thomas3'

(second case)

et al26

optic

nerve

Vitreous body; retinal blood vessels; choroid and choroidal blood vessels; trabecular

meshwork; ciliary nerves (both eyes) Vitreous body (remainder of

eye not available for exam¬

ination) (both eyes) Vitreous body (remainder of eye not available for examination) Blood vessels; beneath Bruch No membrane; ciliary nerve sheaths; sarcolemma of extraocular muscles; no amyloid in retina, retinal blood vessels, or vitreous body Yes (both eyes) Vitreous body; all vascular layers of eye; retina; optic nerves and chiasm; third cranial nerve; right ciliary ganglion and ciliary nerves Yes (both eyes) Vitreous body; retina; retinal vessels; choroidal vessels; Yes

iris vessels

(first case) (second case) 11

eyes) Vitreous body (remainder of eye not available for examination) (both eyes) Vitreous body (remainder of eye not available for examination) (both eyes) Vitreous body; retina; retinal blood vessels; choroidal vessels; scierai vessels

(both eyes) Vitreous body; retina; retinal blood vessels; optic nerve No Diffusely in choroid, with oblitera¬ tion of choriocapillaris In

Yes

in vitreous retinal blood vessels

some areas; none

body

free of, or eventually develop, sys¬ temic involvement remains to be seen. We know of only one other report of a patient with amyloidosis of the vitreous body in whom there was no demonstrable amyloid deposition else¬ where in the body.4 Except for that one patient and ours, all reported patients with amyloidosis of the vitreous body had ocular involvement merely as one component of a

systemic amyloidosis. Amyloidosis of the vitreous body has generally been thought to occur in patients with the hereditary form of primary systemic amyloidosis rather than those with the primary nonfam¬ ilial form of the disease. Our patient is also atypical in this regard. There is no evidence of amyloidosis in the other members of her family. Lack of

a positive family history in patients with amyloidosis of the vitreous body has been observed in only three previously reported patients.3-' It is, of course, entirely possible that one or more of our patient's relatives may eventually develop evidence of the disease. When, on the basis of observing the rather characteristic lesions of the vitreous body, the ophthalmologist has reason to believe that a patient has amyloidosis, referral to an internist is indicated for appropriate diagnostic evaluation.

THERAPY

Medical treatment of this condition is unsatisfactory. A variety of surgical techniques, therefore, has been used in attempting to improve the vision of

or

with amyloidosis of the vitreous body. The surgical objective in these patients is removal of part of the opacified vitreous body. Subtotal vit¬ rectomy can be carried out either by the "open-sky" technique or through a trans-scleral, pars plana incision. In the former method, the vitreous body is removed through the pupil after a 300° limbal incision, sector iridec¬ tomy, and lens extraction have been performed. This is the technique we used in our patient. It was introduced by Kasner and associates, who achieved improved vision in both of their patients despite corneal edema and glaucoma as postoperative com¬

patients

plications.4

In both of the above-mentioned use of the oper-

surgical techniques,

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ating microscope is essential. The "open-sky" procedure is preferable

when a cataract is present or when the vitreous body is so densely opacified as to either obscure the instruments introduced through the pars plana or preclude adequate visualization of the retina. One of the major complications of the anterior approach has been persistent corneal edema with even¬ tual opacification of the cornea. Ashrafzadeh et al have developed a

chamber-like corneal protector that envelops the reflected cornea.3" Con¬ tinuous infusion through this corneal protector with tissue culture medium 199 prevented corneal edema in sim¬ ian eyes subjected to the "open-sky"

technique.35

New instruments for cutting the vitreous body, designed primarily for the pars plana approach, have simpli¬ fied the removal of the vitreous body and the cutting of bands.3"-3" These

instruments can also be used via the anterior approach. As in subtotal vitrectomy for any cause, removing the vitreous body for amyloidosis may result in severe retinal and vitreous body hemorrhages, as well as in retinal detachment. This study was supported in part by Public Health Service grants 5 TOI EY00041-08 and EY00340. Drs Shaul Kochwa and Morton Seelenfreund assisted with the care of the patient whose case is described in this paper.

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