htnsive retinopathy

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HTNsive retinopathy:

MildRetinal arteriolar narrowing related to vasospasm, arteriolar wall

thickening or opacification, and arteriovenous nicking, referred to as nipping

ModerateHemorrhages, either flame or dot-shaped, cotton-wool spots, hard

exudates, and microaneurysms

SevereSome or all of the above, plus optic disc edema. The presence of

papilledema mandates rapid lowering of the blood pressure.

Anemic RetinopathyThe anemias occur when the level of healthy red blood cells (RBCs) or hemoglobin (an ironbinding, oxygen-carrying protein within the red blood cells) is too low. Anemia can be due tonutritional problems such as an iron deficiency, vitamin deficiency or folate deficiency. Irondeficiency is the most common type of anemia. A deficiency of vitamin B12 is known aspernicious anemia. Other causes of anemia include blood loss, inadequate production of redblood cells (aplasic anemia) or increased destruction of red blood cells (hemolytic anemia) that

may present lifelong health problems.

Retinopathy in patients with anemia is well documented.Common findings include hemorrhages that can presentat all levels of the retina and choroid, Roths spots,exudates, cotton wool spots, retinal edema and venoustortuosity (Figure 1). Roths spots or white centeredhemorrhages are typically associated with bacterialendocarditis, however the association is not exclusive,since they occur in diverse conditions including anemia.The white center could represent focal ischemia,inflammatory infiltrates, infectious organisms, fibrin andplatelets, or an accumulation of neoplastic cells.2The

exact pathophysiology of anemic retinopathy is notcompletely understood. However, it seems to be related

to retinal hypoxia, venous stasis, angiospasm and increased capillary permeability.3Anemicretinopathy is most likely to occur in patients with severe anemia or when thrombocytopenia, adisorder of low platelets, is coexistant.4 The ocular changes found in anemic retinopathy arenonspecific and may closely resemble diabetic or hypertensive retinopathy. 5
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Anemic retinopathy may also be a secondary manifestation of other systemic diseases such ascancer, infection or autoimmune disorders. Therefore, in addition to ordering a complete bloodcount (CBC w/differential), other appropriate medical testing may be necessary. In regards tothe management, anemic retinopathy is reversible with correction of the anemia.

Leukemic RetinopathyLeukemia is defined as a neoplastic blood disorder characterized by the overproduction ofabnormal white blood cells. Leukemia can be divided into two types; myelogenous andlymphocytic. Leukemia is further divided into acute myelogenous leukemia (AML), acutelymphocytic leukemia (ALL), chronic myelogenous leukemia (CML) or chronic lymphocyticleukemia (CLL). Approximately 50% or more of all leukemias manifest some form of ocularinvolvement.15,16

The ocular complications of leukemia may be due to a direct involvement by leukemic infiltratesor secondary to concomitant anemia or thrombocytopaenia. 17Leukemic retinopathy is acommon manifestation of leukemia and is found in both the acute and chronic forms. Featuresof leukemic retinopathy include multiple preretinal and intraretinal hemorrhages that are most

commonly found in the posterior pole. Other features include Roths spots, cotton wool spots,exudates, retinal venous tortuosity, perivascular sheathing, and neovascularization. Roths spothemorrhages may represent small areas of retinal leukemic infiltration or plateletfibrin deposits.Retinal lesions such as peripheral neovasularization or sea fans neovascularization (reminiscentof sickle cell retinopathy) may develop in patients with chronic leukemia and are thought tooccur as a result of peripheral nonperfusion and ischemia from the hyperviscosity. 15Serousretinal detachments and various other retinal anomalies have been reported, as well as pallorand swelling of the optic nerve, which indicate optic nerve infiltration.15

In pathological studies, the choroid is the most commonly affected ocular structure. Choroidalmasses lead to a disruption of the retinal pigment epithelium which result from decreased bloodflow to the choriocapillaris.16 In some cases a serous or exudative retinal detachment mayensue.

Leukemic retinopathy usually is not treated directly. Systemic treatment involves the use ofchemotherapy, immunotherapy, and radiotherapy. Intraocular leukemic infiltrate is best treatedwith chemotherapy that is appropriate for the type and stage of leukemia. External-beamradiation may be applied to lesions of the optic nerve or orbit. The presence of leukemicinfiltration is usually a poor prognostic indicator.18

Retinitis Pigmentosa
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Retinitis pigmentosa (RP) is a rare, inherited disease in which the light-sensitive

retina of the eye slowly and progressively degenerates. Eventually, blindness

results.

Retinitis Pigmentosa Symptoms and Signs

The first signs of retinitis pigmentosa usually occur in early childhood, when botheyes typically are affected. Night vision can be poor, and the field of vision may

begin to narrow.

During later stages of retinitis pigmentosa, only a small area of central vision

remains, along with slight peripheral vision.

What Causes RP?

Not much is known about what causes retinitis pigmentosa, except that the

disease is inherited. Even if your mother and father don't have retinitis

pigmentosa, you can still have the eye disease when at least one parent carries

an altered gene associated with the trait.

A shrinking field of vision is one of the early warning signs of retinitis pigmentosa.

In fact, about 1 percent of the population can be considered carriers of recessive

genetic tendencies for retinitis pigmentosa that, in certain circumstances, can be

passed on to a child who then develops the disease (Ophthalmology 2004).

Rather than being considered a single disease, retinitis pigmentosa instead is

viewed as a group of diseases affecting how light-sensitive cells in the back of

the eye (retina) function.

Rods

the light-sensing retinal cells that are responsible for vision in dim light gradually deteriorate until seeing at night becomes more difficult.

Retinitis Pigmentosa Tests and Treatment

Visual field testing likely will be done to determine the extent of peripheral vision

loss. Other eye exams may be conducted to determine whether you have lost

night or color vision.

No treatments are available currently for retinitis pigmentosa, although some

practitioners believe that vitamin A may slightly delay vision loss.

Occupational therapy may be helpful, because it's easier to adjust to decliningvision in earlier stages of vision loss.

People with retinitis pigmentosa also might consider using low vision devices that

can help magnify and illuminate objects in home and work spaces.

Researchers are looking into ways to treat RP in the future, such as retinal

implants and drug treatments.


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RETINAL HEMORRHAGES

Retinal hemorrhages may take various configurations based on their

location within the retina. Flame-shaped and dot-blot hemorrhages arethe most commonly encountered intraretinal hemorrhages in blooddyscrasias (Fig. 1). Flame-shaped hemorrhages are located in the nerve

fiber layer of the retina, and dot-blot hemorrhages are typically locatedin the inner nuclear and outer plexiform layers (Fig. 2). Large blot orboat-shaped hemorrhages may be observed and are present beneath theinternal limiting membrane (ILM) of the retina (i.e., sub-ILM

hemorrhage) (Fig. 3). These large superficial retinal hemorrhages maybreak through the ILM and extend into the vitreous cavity (Fig. 4).White-centered hemorrhages (seeFig. 1)and, much less commonly, red-

centered infiltrates (Fig. 5)are seen in the retinae of patients with ablood dyscrasia. The white center may be associated with a leukemicembolus (Fig. 6)or more commonly a platelet-fibrin thrombus.1The red

center is blood, which may be associated with a cotton wool spot (CWS)or a leukemic retinal infiltrate.

Fig. 1. Intraretinal hemorrhages in acute myelocyticleukemia (AML) and anemia. Note the flame-shaped (arrow), blot (arrowhead), and white-

centered (open arrows)hemorrhages.

Fig. 2. Histopathology of intraretinal hemorrhages.Flame-shaped hemorrhages are located in the nervefiber layer (arrows)and dot-blot hemorrhages are

typically located in the inner and outer plexiform andinner nuclear layers (arrowheads).

Fig. 3. Histopathology of sub-internal limitingmembrane (sub-ILM) hemorrhage. Note the denseblood beneath the ILM (arrows)of the retina.

Fig. 4. Extensive intraretinal hemorrhages in acute

myelocytic leukemia (AML). Note the flame-shaped,blot, and white-centered hemorrhages. A premacularsubhyaloid hemorrhage (arrows)with a hyphema-like

or boat-shaped configuration is present. (Courtesy Dr.

Helmut Buettner.)

Fig. 5. Red-centered retinal infiltrate in acute lymphocytic

leukemia (ALL). This retinal leukemic infiltrate with acentral blot hemorrhage is localized to a branch retinal

vein. (Courtesy Dr. Helmut Buettner.)
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Fig. 6. Histopathology of a leukemic infiltrateassociated with hemorrhage in chronic myelocyticleukemia (CML). Note the leukemic infiltrate (betweenarrows)beneath the internal limiting membrane

(ILM) (arrowhead)in the nerve fiber layer and the

associated intraretinal hemorrhage(asterisk). (Courtesy Dr. W. RichardGreen.)

Factors that contribute to the development of retinal hemorrhages in the

setting of blood dyscrasias include anemia, thrombocytopenia, elevated

white blood cell count, and blood or serum hyperviscosity. In a study of67 patients with anemia and/or thrombocytopenia, Rubenstein and

coworkers2found that retinal hemorrhage is much more likely to occur

when anemia is accompanied by thrombocytopenia than when either ispresent alone. The same authors postulated that thrombocytopenia is an

important causative factor in ocular bleeding in an anemic patient. In astudy of 152 patients with blood diseases, Holt and Gordon-

Smith3reported that retinal hemorrhages occurred most often inleukemic patients with significantly more severe anemia and

thrombocytopenia and a high percentage of circulating blast cells. In a

prospective study of 117 patients with acute leukemia, Guyer andcolleagues4reported that thrombocytopenia is the most important factor

in the pathogenesis of intraretinal hemorrhages. On the contrary,Jackson and coworkers found no association between intraretinal

hemorrhages and the hemoglobin level or platelet count in 63 newlydiagnosed acute leukemia patients.5The same authors reported a higher

median white blood cell count in patients with intraretinal hemorrhagesthan in those without intraretinal hemorrhages and concluded that a high

white blood cell count may be at least as important as anemia andthrombocytopenia in the pathogenesis of retinopathy in acute leukemia.

In a 4-year prospective study of 82 patients with acute leukemia,

Jackson and coworkers6found that patients with a macular hemorrhage

were at significantly greater risk for developing intracranial hemorrhage[particularly in the promyelocytic (M3) subtype of acute myeloid

leukemia (AML)] within the first 30 days following diagnosis comparedwith patients without a macular hemorrhage. Based on these findings,

the authors recommended that patients with a macular hemorrhage bemonitored intensively for the development of intracranial hemorrhage

and receive priority in the allocation of platelets when platelets are inshort supply. Richards and colleagues7also reported a high incidence of

intraocular hemorrhage in patients with acute promyelocytic leukemia

(M3 subtype of AML) and found no consistent detectable abnormalities inthe hematologic parameters or coagulation studies predictive of ocularhemorrhage.

In a pathologic study of the eyes of 76 patients who died of leukemia andallied disorders, Allen and Straatsma8found that retinal hemorrhage was

the most frequent and serious ocular complication and that the mostsignificant hemorrhages occurred in the acute forms of leukemia.
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MICROANEURYSMS

Microaneurysms are small outpouchings in the retinal capillary wall that

appear as tiny red dots in the retina on ophthalmoscopic examination.They are classically seen in the posterior fundus in diabetic retinopathy.Microaneurysms have also been reported in leukemia and plasma cell

dyscrasias.912Interestingly, the microaneurysms in blood dyscrasiastend to be located in the peripheral retina, in contrast to the location inthe posterior retina in diabetic retinopathy. In a pathologic studyemploying trypsin digestion of flat mounts of the retina, Duke and

coworkers10emphasized the relative preservation of pericytes in patientswith chronic leukemia as compared with the marked loss of pericytes indiabetic retinopathy.Figure 7shows the typical microaneurysms in the

retinal periphery in a flat mount preparation with trypsin digestion in apatient with a blood dyscrasia [multiple myeloma (MM)]. Commonpathologic features between the microaneurysms of diabetes and blood

dyscrasias include the globular shape of the lesion, the location

predominantly on the venous side of the capillary, and the presence of

intramural and intraluminal periodic acid-Schiff (PAS)-positivedeposits.10Factors that may play a role in the formation of

microaneurysms in the setting of blood dyscrasias include increasedvenous pressure [i.e., central retinal vein occlusion (CRVO)], increasedblood viscosity with a secondary increase in venous pressure (i.e.,

hyperviscosity syndrome associated with plasma cell dyscrasias), andanoxia (i.e., severe anemia).

Fig. 7. Retinal trypsin digest preparation showing aperipheral microaneurysm (arrow)in multiple

myeloma. (Courtesy Dr. W. Richard Green.)

HARD EXUDATES

Hard exudates are refractile, yellowish deposits of proteins and lipids that

are derived from incompetent or leaky retinal capillaries.Hyperpermeability of the retinal capillaries may be seen in hyperviscosity

syndromes, retinal venous congestion, and CRVO secondary to plasma

cell dyscrasias.1315The hard exudates that result from this capillaryhyperpermeability are localized predominantly to the outer plexiformlayer of the retina (Fig. 8).

Fig. 8. Histopathology of hard exudates. Note the thickretinal ganglion cell layer (more than 2 to 3 cells

thick) (between brackets)identifying the macular regionand the periodic acid-Schiff (PAS)-positive dense

proteinaceous material (arrows)in the outer plexiformlayer (nerve fiber layer of Henle).

RETINAL EDEMA
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In addition to the formation of hard exudates, hyperpermeable or leakyretinal capillaries can lead to focal or generalized retinal edema. Mildopacification or graying of the normally transparent retina is noted in

areas of retinal edema on ophthalmoscopic examination. Cystic

degeneration of the retina may result from long-standing retinal edema.Retinal edema localized to the macular region may manifest as cystoidmacular edema (CME). Histologically in CME, the cysts often contain

eosinophilic proteinaceous material and are located in the outer plexiformand, to a lesser extent, in the inner nuclear layers of the retina (Fig. 9).Occasionally, aggregates of lipid-laden macrophages are observed in the

regions of the cystic degeneration (seeFig. 9). As with hard exudates,

retinal edema may be seen in hyperviscosity syndromes induced by theblood dyscrasias. The CME observed in blood dyscrasias may respond tospecific treatment for CME (i.e., acetazolamide) and may resolve

completely with treatment of the underlying disease process [i.e., afterbone marrow transplantation in chronic myeloid leukemia (CML)].16

Fig. 9. Histopathology of cystoid macular edema. Note

the intraretinal cysts (asterisk)partially filled withproteinaceous material and the focal aggregates of lipid-

laden macrophages (arrow)in the inner nuclear andouter plexiform layers.

COTTON WOOL SPOTS

CWSs, also known as soft exudates, are microinfarctions in the nervefiber layer. The normal flow of axoplasm is blocked in response to focal

retinal ischemia caused by occlusion of a precapillary

arteriole.17Clinically, CWSs are superficial whitish retinal lesions withirregular feathery borders that may be associated with small retinal

hemorrhages. With resolution, the CWSs will fade and an area of retinaldepression may develop secondary to inner retinal ischemic atrophy.

Histologically, CWSs are characterized by fusiform thickening of thenerve fiber layer with globular cytoid bodies (Fig. 10)swollen ganglion

cell axons with degenerated cellular organelles (i.e., mitochondria,neurofilaments, endoplasmic reticulum). CWSs are often encountered in

the retinopathy associated with blood dyscrasias. In one report,18thepresence of a single CWS in each eye of a patient in the absence of

diabetes and systemic hypertension led to the diagnosis of MM. In a

prospective study of 54 newly diagnosed patients with acute leukemia,Abu El-Asrar and coworkers19reported that patients with CWSs had

significantly lower mean and median survival times than those patients

without CWSs. Thus in this study, the presence of CWSs was a poorprognostic sign for survival in acute leukemia.

Fig. 10. Histopathology of cotton wool spot. Note thethickening of the nerve fiber layer (between arrows),

the characteristic eosinophilic cytoidbodies (arrowheads), and the associated retinal

hemorrhage (asterisk).
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The presence of severe anemia may be a risk factor for the development

of CWSs in blood dyscrasias. Holt and Gordon-Smith3observed CWSs in

14 patients with severe anemia with a mean hemoglobin concentration of5.6 g/100 ml. In contrast, Guyer and coworkers4found no statisticallysignificant association between the presence of CWSs and hematologic

parameters (including the hematocrit) in their prospective series. CWSsmay result from occlusion of the precapillary arterioles by leukemic cellsor by platelet-fibrin thrombi.

RETINAL VASCULAR CHANGES

Retinal venous dilatation and tortuosity similar to, and in some casesindistinguishable from, the ophthalmoscopic findings in CRVO may be

observed in blood dyscrasias, particularly the plasma cell dyscrasias [i.e.,

Waldenstrm's macroglobulinemia (WM), monoclonal gammopathies, andless commonly MM].9,1315With venous distention, arteriovenous nickingmay become more apparent and give rise to the sausage link

appearance of the retinal veins. The classical picture of venous stasisretinopathy associated with hyperviscosity is seen in WM (Fig. 11). In aprospective study of 120 patients with newly diagnosed leukemia of all

cell types, Schachat and coworkers20diagnosed a CRVO in 5 patientsall

of whom had myeloid leukemia with extremely high white blood cellcounts or platelet countsand attributed the venous occlusion to bloodhyperviscosity. The pathologic findings in venous stasis retinopathy

associated with blood dyscrasias may be indistinguishable from thosefound in CRVO (Fig. 12).

Fig. 11. Venous stasis retinopathy in Waldenstrm'smacroglobulinemia. Note the dilatation and tortuosity

of the retinal veins, scattered intraretinalhemorrhages, and serous maculardetachment(between arrows). (Courtesy Dr. HelmutBuettner.)

Fig. 12. Histopathology of central retinal vein occlusion(CRVO). Note the intraretinal hemorrhages in variouslayers of the retina (arrows)and the eosinophilic

proteinaceous exudates in the outer plexiform

layer (asterisk)and subretinal space (S).

Perivascular sheathing may be observed in the ocular fundus in patients

with blood dyscrasias. The apparent opacification or loss of transparency

of the retinal blood vessel wall may be due to infiltration by benigninflammatory cells in response to immune complex or other protein (e.g.,

amyloid, immunoglobulin heavy or light chains) deposition, direct

infiltration by leukemic cells, or fibrosis secondary to hypertensive retinalvascular disease. Perivascular sheathing and a clinical picture of retinal

vasculitis (with leakage from retinal vessels on fluorescein angiography)have been prominent ocular findings in patients presenting with certain

blood dyscrasias, including human T-lymphotropic virus 1 (HTLV-1)-
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associated adult T-cell leukemia/lymphoma,21,22cryoglobulinemia,23hairycell leukemia,24and, rarely, MM.25Kim and coworkers26described apatient with relapsing acute lymphoblastic leukemia who presented with

a retinal vasculopathy resembling frosted branch angiitis and an

infiltrative optic neuropathy, which resolved with local radiation andintrathecal chemotherapy.

PALLOR OF THE OCULAR FUNDUS

The normal color of the ocular fundus is derived from the retinal pigmentepithelium (RPE), the choroidal melanocytes, and the blood in the retinaland choroidal vasculature. The retina is normally transparent. In patients

with severe anemia, the fundus may appear pale and the retinal vesselsmay be less red than normal.

OPTIC DISC EDEMA

In optic disc edema, nerve fiber swelling in the optic disc andperipapillary retina is present and often associated with flame-shapedhemorrhages, whitish punctate lesions (secondary to obstructed

axoplasmic flow), and peripapillary CWSs. On ophthalmoscopy, the optic

disc and peripapillary retina appear elevated and the normally well-defined margins of the optic disc are blurred. Optic disc edema is usually

bilateral and may be due to elevated intracranial pressure (i.e.,

papilledema) (Fig. 13)secondary to hemorrhage or a mass effectassociated with the blood dyscrasia (i.e., meningeal infiltration,granulocytic sarcoma). The disc edema may also be secondary to serum

(blood) hyperviscosity and may resemble that seen in CRVO. Lesscommonly, direct infiltration of the optic nerve or optic disc may causemarked optic disc edema.

Fig. 13. Histopathology of papilledema. Note themarked swelling and elevation of the nerve fiber

bundles in the optic disc (asterisks), lateraldisplacement of the peripapillary retina from the discmargin (bracket),nerve fiber layer

hemorrhage (arrowhead),and subhyaloid hemorrhage (arrow).

Rosenthal27emphasized that optic nerve infiltration occurs predominantly

in children with acute lymphocytic leukemia (ALL) and must bedifferentiated clinically from papilledema. Patients with leukemicinfiltration of the prelaminar optic nerve typically have marked swelling

of the optic disc with a fluffy superficial infiltrate and variablehemorrhage (Fig. 14). The visual acuity may be minimally or severelyaffected. With retrolaminar optic nerve infiltration, moderate to marked

disc elevation and edema with variable hemorrhage may be present and

marked vision loss is usually observed. Optic nerve infiltration may occurdespite prophylactic brain irradiation in leukemia because of the shieldsemployed to protect the eyes.28In general, optic nerve infiltration by

leukemia responds well to radiotherapy (with or without intrathecal
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chemotherapy). Brown and coworkers29reported the case of a patientwith acute promyelocytic leukemia and optic disc infiltration who showedcomplete resolution with oral all trans-retinoic acid alone.

Fig. 14. Optic disc infiltration in a child with acute

lymphocytic leukemia (ALL). (Courtesy Dr. LawrenceFrankel.)

Bilateral optic disc swelling is a common early sign (in up to 73% of

cases) of the peripheral neuropathy, organomegaly, endocrinopathy,monoclonal gammopathy, and skin changes (POEMS) syndrome, which

typically occurs in middle-aged men in association with a plasma cell

dyscrasia.30,31The optic disc edema may occur in the absence of elevatedintracranial pressure and may be mediated by autoantibodies or

cytokines.31Cases of POEMS syndromealso known as Crow-Fukasesyndromehave been reported worldwide, with the greatest

concentration of cases in Japan. Other major features of the syndromeinclude widespread edema with ascites and pleural effusions,lymphadenopathy, lethargy, weakness, and shortness of breath.30

RETINAL AND OPTIC DISC NEOVASCULARIZATION

Retinal neovascularization with a sea fan configuration, as seen in sickle

cell retinopathy, has been reported in four patients with chronic

myelogenous leukemia.27In most of these reports, the affected patientshad extremely high white blood cell counts. Prolonged leukocytosis with

or without an increased number of circulating platelets increases the

blood viscosity, which may reduce blood flow and cause vascular

stagnation.27The hyperviscosity may lead to microaneurysm formationand retinal capillary nonperfusion or dropout. Retinal ischemia may

ensue with the subsequent development of proliferative retinopathy (i.e.,

neovascularization of the retina and optic disc) (Figs. 15and16). Morerecently, Anderton and coworkers32reported the case of a patient with

chronic myelogenous leukemia who initially presented with a vitreoushemorrhage associated with bilateral retinal and optic disc

neovascularization. Wiznia and colleagues33reported the case of apatient with ALL who developed severe bilateral ischemic retinopathy

during chemotherapy with cytosine arabinoside, which progressed to

bilateral optic disc and retinal neovascularization despite panretinalphotocoagulation. The patient had received low-dose irradiation to the

brain within 2 months before presenting with bilateral severe vision loss.The toxic effects of the combination of irradiation and chemotherapy, as

well as a hyperviscosity syndrome induced by the leukemia, may havecontributed to the acute presentation with proliferative retinopathy.
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Fig. 15. Histopathology of neovascularization of the retina.Note the blood vessels on the surface of the retinaextending into the vitreous cavity (arrows)and the cystoid

degeneration of the retina(asterisks)predominantly in the

inner nuclear and outer plexiform layers.

Fig. 16. Histopathology of neovascularization of the optic

disc. Note the condensed vitreous (asterisks)with smallblood vessels (arrowheads)on the surface of the optic disc

and associated vitreous hemorrhage (arrow).

In diabetic patients, the concomitant development of a blood dyscrasia

may cause rapid progression from mild background diabetic retinopathy

to severe proliferative retinopathy in an unusually short period.

34,35

Thehyperviscosity syndrome and anemia associated with blood dyscrasias

may exacerbate and accelerate diabetic retinopathy. The combination ofanemia and diabetes results in both reduced blood oxygen-carrying

capacity and a reduced dissociation of oxygen from the blood causinggreater tissue hypoxia (i.e., retinal ischemia).34

VITREOUS HEMORRHAGE AND INFLAMMATION

Vitreous hemorrhage may be an ophthalmic manifestation of blood

dyscrasias, particularly in patients with the combination of anemia andthrombocytopenia. Vitreous hemorrhage may occur in 10% to 15% of

patients with aplastic anemia.36Schachat and coworkers20reported 3

patients with vitreous hemorrhage in a prospective series of 120 patientswith newly diagnosed leukemia of all cell types. Vitreous hemorrhagemay occur more often in acute promyelocytic leukemia (M3 subtype of

AML), which is characterized by severe hemorrhagic manifestations

either at presentation or following commencement of cytotoxictherapy.7In addition, patients with acute promyelocytic leukemia may

develop Terson's syndrome (vitreous hemorrhage associated withintracranial bleeding) during induction therapy with all trans-retinoic

acid.37The vitreous hemorrhage may also occur as a complication ofproliferative retinopathy32from neovascularization of the retina (seeFig.15) or disc (seeFig. 16).

Apparent vitreous inflammation may be caused by the presence ofleukemic cells within the vitreous.21,38,39Swartz and Schumann38reported

the case of a patient with acute lymphoblastic leukemia in apparent

remission who presented with vitreous infiltration diagnosed bycytopathologic evaluation of a vitreous aspirate. The apparent vitreous

inflammation was the first clinical sign of central nervous systeminvolvement. Prompt institution of radiotherapy and chemotherapy

produced a rapid reduction of cells in the vitreous and clearing of cellsfrom the cerebrospinal fluid.
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Vitreous deposits of amyloid are rarely observed in primary systemicnonfamilial amyloidosis.40This systemic disorder is characterized by anaberrant deposition in various organ systems of insoluble polypeptidesderived from a portion of the light chain of immunoglobulins.

RETINAL AND RETINAL PIGMENT EPITHELIUM DETACHMENT

Retinal and retinal pigment epithelium (RPE) detachments are not

infrequently observed in blood dyscrasias. A clinical picture with

fluorescein angiography resembling central serous retinopathy (i.e.,serous retinal and RPE detachments) has been described in patients withplasma cell dyscrasias, including monoclonal gammopathies and

cryoglobulinemia.41,42Rarely, apparent serous macular detachments can

occur, and fluorescein angiography shows macular hypofluorescence andno evidence of retinal vascular or RPE leakage associated with the

macular elevation. Ho and coworkers43reported three such cases inpatients with MM, WM, and benign polyclonal gammopathy. The sameauthors hypothesized that the macular detachments were transudative

rather than exudative with subretinal precipitates of immunoglobulin orother serum proteins. Ogata and colleagues44described a patient withWM who presented with an apparent serous macular detachment with noabnormal hyperfluorescence on fluorescein angiography; however, with

optical coherence tomography (OCT), a large occult RPE detachment was

noted beneath the serous retinal detachment. In plasma cell dyscrasias,the choriocapillaris may be partly obstructed by light chain or otherimmunoglobulin deposits, and this may play an important role in the

pathogenesis of the serous retinal and RPE detachments observed inthese disorders.12,45

Rarely, visual impairment secondary to a retinal or RPE detachment may

be the first clinical sign of a blood dyscrasia or a leukemic relapse duringapparent remission.4649In leukemia, the serous retinal and RPE

detachments may occur secondary to leukemic infiltration of thechoroid.11,27,50Solid detachments of the retina by leukemic cell infiltratesin the subretinal space have also been reported.11,51In one such case, a

hypopyon-like configuration of the leukemic cells was observed in thesubretinal space.51

Serous retinal and RPE detachments may also be seen in plateletdisorders and coagulopathies such as thrombotic thrombocytopenicpurpura (TTP) and disseminated intravascular coagulation (DIC).5255The

mechanism of retinal and RPE detachment in these disorders isassociated with choriocapillary occlusion by platelet-fibrin thrombi (Fig.

17).

Fig. 17. Histopathology of disseminated intravascular

coagulation (DIC). Note the platelet-fibrin thrombi in

the choriocapillaris and inner choroidalvessels (arrows), the vacuolar changes in the overlyingretinal pigment epithelium (RPE), the proteinaceous

subretinal exudate (asterisk),the cysts in the outer plexiform layer
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14/18

Fig. 19. Choroidal infiltrates resemblingacute posterior multifocal placoid pigmentepitheliopathy (APMPPE) in acute

myelocytic leukemia (AML). A.Note the

deep yellowish-white lesions (arrows)in

the posterior fundus.B.

Laminar venousphase (24.8 seconds) of fluorescein

angiogram showing earlyblockage (arrows)corresponding to thefundus lesions noted in A.C.Late phase

(676 seconds) of fluorescein angiogram

showing late leakage corresponding to the earlyhypofluorescence (arrows)in Band the yellow-white lesions in A.D.Four months after local irradiation. Note the resolution of the yellow-

white lesions and few small punched-out atrophic chorioretinal

scars (arrows)in areas corresponding to previous lesions as noted in A.

McManaway and Neely60reported the case of a patient with acute

lymphoblastic leukemia who presented with leukocoria and proptosis

resulting from an extensive intraocular and orbital tumor mimicking

advanced retinoblastoma. An elevated leukocyte blood count, blast formson the peripheral blood smear, rubbery suboccipital nodules, and

subcutaneous scalp masses all suggested leukemia, although the funduspicture was atypical and caused diagnostic confusion. No intratumoral

calcification was observed on a computed tomography (CT) scan. Theocular and orbital infiltrates responded rapidly to chemotherapy and low-dose orbital irradiation.

The frequency of these infiltrates, particularly choroidal infiltrates, ismuch higher in pathologic studies (compared with clinical studies) of

eyes from patients with acute and chronic leukemia and ranges between28% and 80%.8,11,61In a prospective study of 120 patients with newly

diagnosed leukemia (all cell types), Schachat and coworkers20found 4

patients (3%) with leukemic retinal infiltrates and none with choroidalinfiltrates. Leukemic choroidal infiltrates may be difficult to diagnose

clinically without special ancillary tests (i.e., fluorescein angiography, A-and B-scan ultrasonography). In a pathologic study of 135 autopsy eyes

in patients with leukemia, Leonardy and coworkers61reported choroidalinvolvement in 93% of eyes with leukemic infiltrates. Allen and

Straatsma8found a much higher incidence of ocular involvement,including choroidal infiltration, in eyes of patients with acute leukemia

(80%) compared with chronic leukemia (29%). The same authors

emphasized the diffuse pattern of leukemic infiltration of the posteriorchoroid (Fig. 20)and infrequent association with hemorrhage as opposed

to the focal leukemic infiltration observed in the retina with associatedhemorrhage in nearly every case.
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Fig. 20. Histopathology of leukemic choroidal infiltrate.Note the diffuse thickening of the choroid by leukemiccell infiltration (between arrows)in acute myelocytic

leukemia (AML). Leukemic cells are also present in the

episclera (asterisk)and in scleral emissary canals. The

inset shows retinal pigment epithelium (RPE) changes, including focalhyperplasia (open arrow)and depigmentation(arrowhead)overlying the

leukemic choroidal infiltrate. (Courtesy Dr. W. Richard Green.)

Diffuse bilateral chorioretinal abnormalities including deep hemorrhages

and pigment mottling in the posterior pole, diffuse areas ofhypofluorescence on fluorescein and indocyanine green angiography in

the posterior pole, and hypofluorescent lines or streaks in the

midperipheral fundus were observed by Pece and coworkers62in apatient with primary systemic nonfamilial amyloidosis. These authors

postulated that the areas of hypofluorescence may represent eitherchoroidal vascular occlusion or intravascular and/or perivascular amyloid

deposits.

Back to TopTHE BLOOD DYSCRASIAS

ANEMIA

The term anemiarefers to a reduction in the concentration of hemoglobin

or red blood cells in the blood. Three concentrationshemoglobin,

hematocrit, and number of red blood cellsmay be measured toestablish the presence of anemia. Blood hemoglobin concentration is thepreferred measure because of its accuracy, reproducibility, and

pathophysiologic correlation. The morphologic classification of anemia

divides the anemias into three broad groups on the basis of average cellsize and hemoglobin content: the macrocytic anemias; the microcytic

and hypochromic anemias; and the normocytic, normochromic anemias.

The number of red blood cells in the circulation at any given time is aresult of the production and delivery of cells into the circulation and theirdestruction or loss from the circulation. Iron-deficiency anemia and

anemia of chronic disease are the most common causes of anemia andare characteristically of the microcytic, hypochromic type. In the blooddyscrasias, the bone marrow may be infiltrated and replaced byneoplastic white cells, resulting in pancytopenia. Retinal hemorrhages are

common findings in anemic patients, particularly when the anemia isaccompanied by thrombocytopenia.2,4In profound anemia, CWSs3and

white-centered hemorrhages4may be observed with greater frequency in

addition to retinal hemorrhages.

Pernicious anemiathe prototype of megaloblastic (macrocytic)

anemiais a chronic illness resulting from the lack of Castle's intrinsicfactor in gastric secretions. In the absence of intrinsicfactor, a bindingprotein, the absorption of vitamin B12is impaired, resulting in a vitamin

deficiency. Pernicious anemia occurs in two forms. In the relativelycommon adult type, the lack of intrinsic factor is associated with gastric
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atrophy and a deficiency of many other gastric secretions. In the

congenital form, only intrinsic factor is lacking, and levels of other gastric

secretions are normal. Holt and Gordon-Smith3reported the retinalabnormalities in 13 patients with pernicious anemia: 54% of the patients

had intraretinal hemorrhages (flame-shaped, dot-blot, and white-

centered) and 31% had CWSs. Only one patient was thrombocytopenic.

The retinal abnormalities invariably cleared after the administration ofvitamin B12.

Aplastic anemia is a life-threatening disorder characterized by

pancytopenia and a hypoplastic bone marrow. Two deaths per million

occur annually in patients with aplastic anemia secondary to cerebralhemorrhage, septicemia, or gastrointestinal bleeding. This type ofanemia is especially prevalent in the first three decades of life. Exposure

to insecticides and certain drugs have been implicated in the bone

marrow suppression. Ocular fundus findings are often observed (up to75%) in patients with aplastic anemia and include, in order of decreasing

frequency, retinal hemorrhages, CWSs, vitreous hemorrhage, a CRVO-

like picture, and papilledema.36

Preretinal and vitreous hemorrhagesoccur almost exclusively in patients with combined anemia andthrombocytopenia.

POLYCYTHEMIA

Polycythemia vera (PV) is a chronic, clonal, myeloproliferative disordercharacterized by a striking absolute increase in the number of red blood

cells and in the total blood volume and is usually accompanied byleukocytosis, thrombocytosis, and splenomegaly. The bone marrow ishypercellular and exhibits hyperplasia of myeloid, erythroid, and

megakaryocyte lineages. PV occurs most commonly in older men (60 to

80 years of age). The signs and symptoms of PV can be attributed to theexpanded total blood volume and to the slowing of blood flow as a resultof increased blood viscosity.

Secondary causes of polycythemia include disorders that involve

decreased tissue oxygen delivery, usually as a result of decreased

arterial oxygen saturation. Such disorders include cyanotic congenitalheart disease, right-sided heart failure, and chronic obstructivepulmonary disease. In these disorders, tissue hypoxia causes an increase

in renal erythropoietin production, which stimulates the erythroidprecursors in the bone marrow and increases the number of circulating

red blood cells to increase tissue oxygen delivery. In PV and secondarypolycythemia, the consequences of marked hyperviscosity that

accompany a hematocrit greater than 60% include decreased cerebralblood flow, decreased cardiac output, and a tendency to thrombosis.

The ocular findings in polycythemia are actually manifestations of theassociated hyperviscosity syndrome and similar to those observed in

plasma cell dyscrasias. Ocular fundus findings include retinal venousdilatation and tortuosity and intraretinal hemorrhages.
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LEUKEMIA

The acute leukemias are a heterogeneous group of neoplasms affecting

hematopoietic stem cells. Some differentiation in these white blood cell

precursors allows for phenotypic classification. Acute leukemias aredivided into nonlymphocytic (commonly referred to as myeloid) andlymphoid categories depending on the cell of origin and are further

subclassified by the French-American-British (FAB) system based onmorphologic characteristics.

Myeloid and lymphoid leukemias differ in regard to their clinicalpresentation, course, and response to therapy. Current managementwith specific therapeutic regimens is based on phenotypic

characterization of the leukemic cells at diagnosis [i.e., ALL vs. acutenonlymphocytic leukemia (ANLL) or AML]. In addition to morphologicassessment, cytochemical, immunologic, cytogenetic, and occasionally

ultrastructural and molecular genetic analyses are performed to furthercharacterize the specific subtype of acute leukemia.

Clinical features are useful but not pathognomonic in the differentiationof ALL and AML. ALL has a peak incidence in childhood, and AML has apeak incidence in adult age; however, some overlap exists between the

two types of acute leukemia. Massive lymph node enlargement is much

more common in ALL than in AML. Solid masses of leukemic cells(chloromas or granulocytic sarcomas) usually involving facial orintracranial structures are observed in AML. Extensive involvement of the

gums is characteristically seen in acute monocytic leukemia.

Chronic lymphocytic leukemia (CLL) is characterized by the accumulation

of nonproliferating, mature-appearing lymphocytes in the blood, marrow,

lymph nodes, and spleen. In most cases, the cells are monoclonal Blymphocytes. CLL is the most common form of leukemia in North

America and Europe, accounting for one third of all cases. CLL typicallyoccurs in older patients, with a peak incidence at 50 to 55 years, and itaffects men twice as often as women. The cause of CLL is unknown;

however, there is an increased incidence in farmers, rubber

manufacturing workers, asbestos workers, and tire repair workers.Genetic factors may play a role. Clinical manifestations include slowlyenlarging lymph nodes and gradual enlargement of the liver and spleen

resulting from the accumulation of neoplastic lymphocytes. As patientsbecome symptomatic from these clinical manifestations or if progressive

anemia and/or thrombocytopenia occur, alkylating agents (i.e.,chlorambucil) and prednisone are beneficial. Radiotherapy to the spleen

or to areas of bulky adenopathy may also be employed.

CML is a clonal stem cell disorder characterized by increased proliferationof myeloid elements at all stages of differentiation. The incidence of CMLsteadily increases with age (1 in 100,000 in Western countries), with a

peak incidence at 53 years. Men are affected more often than women.

The etiology of CML is unknown, although it may develop after radiationexposure. All marrow cell lines in CML express a marker chromosome


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the Philadelphia chromosomea reciprocal translocation of part of the

long arm of chromosome 22 to chromosome 9. CML generally occurs in

two distinct clinical phases. The first or chronic phase (usually lasting 3to 5 years) is marked by a proliferation of myeloid cells showing a full

range of maturation. Eventually, a decrease in myeloid differentiation

typically occurs, and the disease enters an accelerated phase or blast

crisis with a very poor prognosis. Clinically, leukocytosis with earlymyeloid precursors in the peripheral blood, thrombocytosis, and

splenomegaly are commonly present at the time of diagnosis. Initially,

patients are managed with periodic oral chemotherapy (alkylating agentsor hydroxyurea) to normalize the blood count and reduce splenomegaly.

Eventually, anemia and thrombocytopenia develop, and fever andincreasing weakness may occur with transformation to the acceleratedphase or blast crisis (usually lasting 3 to 6 months).

The ocular fundus manifestations of leukemia include intraretinalhemorrhages (flame-shaped, dot-blot, white-centered, and boat-

shaped), microaneurysms, hard exudates, retinal edema, CWSs, venous

stasis retinopathy, perivascular sheathing, papilledema, optic discinfiltration, retinal and optic disc neovascularization, vitreous

inflammation and/or hemorrhage, retinal and RPE detachment, andretinal and choroidal infiltrates.11,27The presence of intraretinal

hemorrhages63or other ophthalmic manifestations64in acute leukemia,particularly in childhood leukemias, may be a poor prognostic sign for

long-term survival. Reddy and Menon65recommended routineophthalmologic examination as part of a complete evaluation at the time

of diagnosis in childhood acute leukemias because of the high prevalence

(17%) of asymptomatic ocular lesions in their prospective series of 82children. Treatment of the underlying cause of the ocular fundus

manifestations (i.e., anemia, thrombocytopenia, retinal or choroidal

leukemic infiltrate, hyperviscosity syndrome, circulating neoplastic white

blood cells, and/or bone marrow infiltration) will often result inimprovement or complete resolution of the ocular fundus findings.66
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