Ординатура / Офтальмология / Учебные материалы / Retinal Vascular Disease Joussen Springer

Core Messages

Disseminated intravascular coagulopathy (DIC) is a pathologic condition associated with a severe underlying systemic illness characterized by simultaneous bleeding tendency and thrombosis

The most common ocular manifestation of DIC is bilateral serous retinal detachment, submacular choroidal hemorrhage, or both

The characteristic histopathologic feature in the eyes of patients with DIC is thrombotic occlusion of the choriocapillaris and adjacent choroidal vessels by fibrin-platelet clots

Treatment is usually supportive and directed at the underlying systemic illness

While the systemic prognosis of DIC is poor, the visual prognosis may be good in patients who survive the condition

Disseminated intravascular coagulopathy (DIC) is not a primary disease, but rather a pathologic condition associated with a severe underlying systemic illness. It is characterized by simultaneous bleeding tendency and thrombosis. The mechanism of DIC is complex, but involves the simultaneous activation of fibrinolytic and coagulation systems. The process is thought to begin with the entrance of pro-coagulative substances such as thrombin, thromboplastin, or thromboplastic-like substances into the circulation, which leads to destruction of platelets, activation of plasma clotting factors, and activation of the plasminogen system. The secondary consumptive coagulopathy results in generalized hemorrhage. DIC may accompany many systemic illnesses, but is most commonly seen in association with sepsis, neoplasm, severe trauma, cardiopulmonary arrest, and obstetrical complications such as retained fetus, abruptio placentae, placenta previa, and septic abortion. The diagnosis of DIC can generally be made with laboratory studies that demonstrate severe thrombocytopenia, fragmented circulating red blood cells, hypofibrinogenemia, prolonged aPTT, and elevated levels of fibrin split products [2]. Treatment of DIC is directed at the underlying disease process. In addition, success of treatment is dependent on prompt recognition of its systemic manifestations, including characteristic findings in the eye.

Azar and colleagues first described ocular features of a neonate who developed DIC in 1974 [1]. This patient had bilateral hyphemas, retinal hemorrhages, and optic disk edema. The authors attributed these ocular findings to the patient’s heparin therapy. The first comprehensive description of adult ocular manifestations of DIC was provided by Cogan in 1975 in seven autopsied eyes from patients who died of DIC [3]. Characteristic findings in the posterior segment of the eye including serous retinal detachment, disruption of the retinal pigment epithelium, and thrombotic occlusions of choroidal vessels were present in these cases. Similar ocular findings had been previously described by Yoshioka and Percival in patients with thrombotic thrombocytopenic purpura (TTP), a disease closely related to DIC [9, 10, 13]. Several subsequent studies provided additional clinical and histopathological descriptions of ocular involvement in DIC in a wide range of patients and clinical settings, including neonates, obstetrical complications, and patients with acquired immunodeficiency syndrome [5 – 8, 12].

24.3.3 Pathologic Features

Essentials

Thrombotic occlusions of the choriocapillaris and choroidal vessels

Thrombi consist of fibrin and platelets

Submacular and peripapillary regions most commonly affected

Choroidal hemorrhage Serous retinal detachment

The characteristic histopathologic finding in eyes of patients with DIC is thrombotic occlusion of the choriocapillaris and adjacent choroidal vessels by

Fig. 24.3.1. Histopathological appearance of choroid and outer retina from a patient who died of DIC. Fibrinous thrombi (stained by phosphotungstic acid hematoxylin) in varying stages of organization and recanalization are seen in the choriocapillaris and large choroidal vessels. The photoreceptor inner and outer segments show marked degeneration and the retinal pigment epithelium exhibits patchy thinning and focal proliferation. (Courtesy of Helmut Buettner [3]). Original magnification × 320

Essentials

Bilateral, usually symmetric process

Serous retinal detachment

Choroidal hemorrhage, usually submacular

Cystoid macular edema

Retinal pigment epithelium mottling

Fluorescein angiography: dark central choroid, multifocal leakage from choroidal vessels

Anterior segment findings in neonates

As is the case in most ocular findings of systemic conditions, ocular features of DIC are bilateral and usually symmetric. The characteristic fundus manifestations consist of serous retinal detachment, hemorrhage in the submacular choroid, or both (Fig. 24.3.3a). However, a wide range of clinical findings may exist. In mild cases, retinal hemorrhages may be the only fundus finding on exam. In more severe cases, a dark fundus consisting of an elevated retina against a dark background of choroidal hemorrhage may be present. The latter appearance has rarely been described in conditions other than DIC and TTP [4]. Other fundus features reported in the literature include cystoid macular edema, optic nerve swelling, and mottling of the retinal pigment epithelium.

Clinical symptoms can vary from no visual disturbance to profound loss of vision. In some patients, blurred vision was posture-dependent secondary to the dependent nature of serous retinal detachment. In most clinical settings, patients with DIC may be too ill to report visual symptoms.

Fluorescein angiography typically reveals areas of non-perfusion in the posterior choriocapillaris in early phases of the study (Fig. 24.3.3b). Multifocal leakage from adjacent choroidal vessels with accumulation of dye in the subretinal space is seen in later phases of the study (Fig. 24.3.3c) [4, 5]. Choroidal hemorrhage, when present, causes blocked fluorescence. Retinal pigment epithelium mottling may cause patchy areas of increased fluorescence secondary to window defects [5].

Ophthalmic findings of DIC are usually confined to the posterior segment of the eye. However, anterior segment findings have been reported in a few cases of DIC in infants and neonates. Azar et al. reported an infant with DIC who developed bilateral hyphemas in addition to retinal hemorrhages and optic disk edema, although the authors attributed these ocular findings to the patient’s heparin therapy [1]. Ortiz and colleagues reported two cases of neo-

natal DIC with intravascular fibrin clots in the ciliary body and iris vessels [8].

24.3.5 Differential Diagnosis

The diagnosis of DIC is usually not in doubt by the time an ophthalmic examination has been requested. In the appropriate clinical setting, the diagnosis of systemic DIC is confirmed by laboratory tests that show severe thrombocytopenia, fragmented circulating red blood cells, hypofibrinogenemia, prolonged aPTT, and elevated levels of fibrin split products. A closely related hematologic condition, thrombotic thrombocytopenic purpura (TTP), may present with similar systemic and ocular manifestations.

The differential diagnosis for ocular complications of DIC includes other systemic conditions that produce serous retinal detachment (Table 24.3.1) [12].

Table 24.3.1. Systemic conditions associated with serous retinal detachment [12]

Systemic condition Disease

Essentials

Treat underlying condition

Poor systemic prognosis

Good visual recovery in patients who survive DIC

Treatment of DIC consists of supportive care and is directed at the underlying cause. Historically, the prognosis for DIC has been poor with a high mortality rate. This is supported by the fact that most published reports of ocular manifestations of DIC consist of autopsy studies.

Long-term follow-up data of eyes affected with DIC are not available in the literature, most likely due to the poor prognosis of this condition. In the few cases of surviving patients, visual acuity usually returns to the 20/20 to 20/30 range as serous retinal detachment resolves [5, 7]. However, this may be secondary to selection bias as patients who survive DIC may be more likely to have milder forms of the condition.

1.Azar P, Smith RS, Greenberg MH (1974) Ocular findings in disseminated intravascular coagulation. Am J Ophthalmol 78:493 – 496

2.Bell WR (1998). Bleeding disorders. In: Stobo JD, Hellmann DB, Ladenson PW, Petty BG, Traill TA (eds) The principle

3.Buettner H (1983) Department of Ophthalmology, Mayo Clinic. Ophthalmology 90:914 – 916

4.Cogan DG (1975) Ocular involvement in disseminated intravascular coagulopathy. Arch Ophthalmol 93:1 – 8

5.Hoines J, Buettner H (1989) Ocular complications of Disseminated intravascular coagulation (DIC) in abruption placentae. Retina 9:105 – 109

6.Lertsumitkul S, Whitcup SM, Chan C-C (1997) Ocular manifestations of disseminated intravascular coagulation in a patient with the acquired immunodeficiency syndrome. Arch Ophthalmol 115:676 – 677

7.Martin VAF (1978) Disseminated intravascular coagulopathy. Trans Ophthal Soc UK 98:506 – 507

8.Ortiz JM, Yanoff M, Cameron JD, Schaffer D (1982) Disseminated intravascular coagulation in infancy and in the neonate: ocular findings. Arch Ophthalmol 100:1413 – 1415

9.Percival SPB (1970) Ocular findings in thrombotic thrombocytopenic purpura (Moschcowitz’s disease). Br J Ophthalmol 54:73 – 78

10.Percival SPB (1970) The eye in Moschcowitz’s disease (Thrombotic thrombocytopenic purpura); a review of 182 cases. Trans Ophthalmol Soc UK 90:375 – 382

11.Samples JR, Buettner H (1983) Ocular involvement in disseminated intravascular coagulation (DIC). Ophthalmology 90:914 – 916

12.Wolfensberger TJ, Tufail A (2000) Systemic disorders associated with detachment of the neurosensory retina and retinal pigment epithelium. Curr Opin Ophthalmol 11:455 – 461

13.Yoshioka H, Yamanouchi U (1962) Case of retina and vitreous body hemorrhage due to thrombocytopenic purpura with special reference to pathohistological findings of the eye. Nagasaki Med J 37:234 – 237

Core Messages

Retinopathy occurs in 4.3 – 10 % of patients with bone marrow transplants

Bone marrow transplant associated retinopathy includes occlusive retinal microangiopathy, choroidopathy, and optic neuropathy

Predisposing factors include capillary endothelial damage by drugs or irradiation, microemboli, hematological abnormalities and secondary diseases such as hypertension and septicemia Treatment is not required unless proliferative retinopathy develops

24.4.1 Introduction

Essentials

Allogeneic BMT involves:

–Conditioning by chemotherapy, total body irradiation, prophylactic cranial irradiation

–Transfusion of human leukocyte antigen (HLA) matched donor hematopoietic progenitor cells

–Immunosuppression

–Supportive treatment until leukocyte, erythrocyte, and platelet population stabilize

Advances in immunosuppressive and antibacterial therapies during recent decades have significantly improved the success of bone marrow transplantation (BMT). BMT has become an important treatment modality for hematological and other forms of malignancies, and hereditary and acquired disorders such as sickle cell and aplastic anemias [1]. The international bone marrow transplant registry estimated that about 50,000 bone marrow transplants were performed during 1999. BMT involves intravenous infusion of hematopoietic progenitor cells in order to repopulate the dysfunctional host bone marrow, reestablishing the function.

Bone marrow transplant can be classified into allogeneic, autologous, and syngeneic transplant depending on the source of the donor tissue. Allogeneic transplant utilizes bone marrow obtained from

an HLA-matched donor. Autologous transplant involves harvesting of the patient’s own bone marrow that is subsequently transplanted back to the patient. Synergic bone marrow transplant is the least commonly performed type of BMT and involves the transplantation of bone marrow from one monozygotic twin to the other.

In most allogeneic BMTs a conditioning regimen is required before the transplantation can take place [7, 30, 38, 40]. Conditioning ablates the recipient’s bone marrow in order to allow subsequent repopulation with donor cells. In the case of malignant disorders such as leukemia, conditioning also helps treat malignant cells that have spread throughout the body. By suppressing the immune system, conditioning reduces and may prevent the ability of the host to mount an immune reaction to the infused allogeneic bone marrow cells, therefore reducing the possibility of transplant rejection. Conditioning regimens include chemotherapeutic agents with or without total body irradiation (TBI) and prophylactic cranial irradiation. The most commonly used chemotherapeutic and immunosuppressive agents include cyclophosphamide, busulfan, and cytosine arabinoside. Following conditioning, the donor bone marrow is infused intravenously, allowing the cells to reach the host bone marrow. Prolonged immunosuppression is required in order to prevent the rejection of the transplanted tissue by the host, as well as avoid reaction of transplanted immunocompetent donor cells against the host, resulting in graft versus host disease (GVHD). Immunosuppressive drug therapies include corticosteroid, cyclosporine, and methotrexate in various combinations.

Essentials

Bone marrow transplant associated retinopathy includes:

–Occlusive retinal microvasculopathy

–Choroidopathy

–Optic neuropathy

–Retinal manifestations of hematological abnormalities

–Chorioretinal infections

–Others – e.g., serous retinal detachment

The major systemic complications of BMT include vaso-occlusive disease, infection, graft failure, GVHD, and hematologic abnormalities. GVHD mostly affects the skin, liver, gastrointestinal tract, and the eyes. In GVHD the transplanted bone marrow perceives the host as a foreign tissue and mounts a T-lymphocyte-mediated immunologic attack on the host [1, 7, 30, 41].

Ophthalmic complications of BMT may result from the underlying disease process, the conditioning regimen, immunosuppressive therapy, or secondary disorders such as infections, GVHD, hypertension, and hematologic abnormalities. Anterior segment complications of BMT are more common than those affecting the posterior segment and include keratoconjunctivitis sicca, pseudomembranous conjunctivitis, conjunctival graft-versus-host disease, bacterial and viral conjunctivitis, superficial punctate keratitis, sterile and infectious corneal ulceration, and cataracts [2, 6, 11, 14, 21 – 25]. Posterior segment manifestations of BMT include vitritis, retinopathy, choroidopathy, and optic neuropathy [3, 4, 11, 13, 15, 17, 18, 21, 27, 34].

Retinopathy associated with BMT was initially reported in 1983, consisting of multiple, bilateral cot- ton-wool spots, retinal hemorrhages, optic disk edema and ocular infections [18, 21, 22]. The term “BMT retinopathy” has been used to describe a number of retinal and posterior segment abnormalities that are encountered in patients who undergo BMT. The condition includes an occlusive retinal microvasculopathy, choroidopathy, optic neuropathy, retinal manifestations of hematological abnormalities, and infections. The retina findings are not specific to BMT and occur in other disorders that can predispose to occlusive retinopathy. The term “BMT associated retinopathy” will be used throughout the current chapter in an attempt to represent the condition more accurately.

24.4.2 Pathophysiology

A number of factors contribute to the development of BMT associated retinopathy (Table 24.4.1). Capillary endothelial damage results from composite

insults related to drug toxicity, irradiation, or immune system abnormalities. Injury to retinal capillary endothelium leads to microvascular occlusion and incompetence causing ischemia, hemorrhage, vascular leakage, edema, hard exudates, microaneurysms, and telangiectasia. Webster and coworkers suggested that normal T-cell function may be neces-

sary for the protection of retinal endothelial cells III 24 from insults such as radiation, which lower the

threshold for subsequent endothelial loss and retinal ischemia [44]. Microvascular occlusion can also result from microembolization of small cellular aggregates during the administration of donor bone marrow as well as transfusion of platelet, red blood cells and other blood products in the period following transplantation. Septicemia complicating BMT may be associated with clinically significant septic embolization to the retina. Hematological abnormalities such as hypercoagulable states, hyperviscosity, thrombocytopenia, and anemia are often present in patients who undergo BMT and predispose to occlusive or hemorrhagic vasculopathy. Similarly, development of secondary conditions such as hypertension, or the presence of preexisting conditions such as diabetes, may promote microvasculopathy.

Reversible visual loss due to cyclosporine-in- duced retina toxicity has been reported in BMT patients [33]. Electrophysiological studies confirmed retinal dysfunction, with the improvement of visual function after withdrawal of cyclosporine.

Table 24.4.1. Factors predisposing to BMT associated retinopathy

Capillary endothelial damage

Drugs

Irradiation

Immune system abnormalities

Microemboli

Leukocyte microaggregates

Platelet transfusion

Blood transfusion

Septic emboli

Hematological abnormalities

Hypocoagulable state

Hyperviscosity

Anemia

Thrombocytopenia

Secondary diseases

Hypertension

Septicemia

Coexisting predisposing diseases

Diabetes mellitus Sickle cell disease

Other disorder associated with microvascular retinopathy

Neurotoxicity

Drugs

24.4.3Bone Marrow Transplant Associated Retinopathy

Essentials

Fig. 24.4.3. Histopathologic section showing cellular infiltration of choroid in a patient with graft versus host disease. (Courtesy of W. Richard Green, MD)

BMT associated retinopathy comprises a number of retinal and posterior segment abnormalities that occur in patients who undergo BMT. The condition includes an occlusive retinal microvasculopathy, choroidopathy, optic neuropathy, retinal manifestations of hematological abnormalities, and infections.

In one report, 51 (12.8 %) of 397 patients developed posterior segment complications after BMT [11]. The cause of these findings is likely to be multifactorial, resulting from the combined effects of high dose chemotherapy, TBI, infections, GVHD, immunosuppressive therapy, and recurrent malignancies.

24.4.3.1 Microvascular Retinopathy

Fig. 24.4.1. Bone marrow transplant associated retinopathy in a 26-year-old patient with lymphoma. Retrohyaloid hemorrhage covering the central macular area reduced the vision to 20/400. Flame-shaped hemorrhages and white centered hemorrhages (pseudo-Roth hemorrhage), and cotton-wool spots were present. Visual acuity improved to 20/25 within 2 months

Fig. 24.4.2. Histopathologic section showing superficial retinal hemorrhage in a 19-year-old male following bone marrow transplantation for acute lymphocytic leukemia. (Courtesy of W. Richard Green, MD)

BMT microvascular retinopathy is characterized by the presence of multiple superficial and intraretinal hemorrhages, microaneurysms, cotton-wool spots, telangiectasia, macular edema, and hard exudates. Rarely, severe capillary non-perfusion may result in retinal fibrovascular proliferation and neovascularization of the iris. BMT associated retinopathy is usually bilateral and symmetrical. Patients may be visually asymptomatic or present with decreased vision and scotoma. The reported occurrence of retinopathy ranges from 4.3 % to 10 % of patients with BMT. The variable rate likely represents variability in the diagnostic criteria, as well as differences in conditioning regimens and irradiation protocols.

BMT associated retinopathy usually occurs within 6 months of the transplantation [5, 21, 34] although there are reported cases of microvascular retinopathy occurring as late as 62 months after BMT [9]. Coexisting diseases such as diabetes mellitus and hypertension facilitate the development of BMT retinopathy by contributing to the microvasculopathy [19]. In patients that undergo BMT, hypertension may develop secondary to nephropathy or as a side

effect of cyclosporine. Although mild to moderate ischemic retinopathy represented by retinal hemorrhages and cotton-wool spots is frequently seen in BMT retinopathy, severe ischemia resulting in retinal neovascularization is rare. Lopez et al. reported an occlusive microvascular retinopathy in five of eight (62 %) long-term survivors of autologous and allogeneic transplant for acute leukemia [34]. Of this group, only one patient developed retinal neovascularization. Fluorescein angiography findings in patients with BMT associated retinopathy include microaneurysms, telangiectasia, intraretinal microvascular abnormalities, leakage consistent with macular edema, and a variable degree of capillary nonperfusion [5, 27].

Risk factors for development of BMT associated retinopathy include allogeneic BMT, TBI, prophylactic irradiation, shortened interval between TBI and BMT, acute lymphoblastic leukemia as the underlying disease, cyclosporine, prolonged immunosuppression, and the presence of other primary or secondary disorders that predispose to retinopathy.

The differential diagnosis for BMT associated retinopathy includes radiation retinopathy and other causes of microvascular retinopathy (Table 24.4.2). There are similarities and often an overlap between radiation and BMT associated retinopathies. Both conditions result in retinal hemorrhages, cottonwool spots, telangiectasia, and other manifestations of an occlusive microvasculopathy. The retinopathy associated with BMT usually occurs within 6 months of transplantation and is typically reversible with a relatively benign course. The mean time for the development of radiation retinopathy is 18 months. Once it develops, radiation retinopathy often has a progressive course, often resulting in permanently decreased visual function [8].

Table 24.4.2. Differential diagnosis of BMT associated retinopathy

Radiation retinopathy

Hypertensive retinopathy

Leukemia retinopathy

Diabetic retinopathy

Retinal vein occlusion

Purtscher-like retinopathy

HIV retinopathy

Collagen vascular disorders

Ocular ischemic syndrome

Retinitis

Other forms of microvascular retinopathy

24.4.3.2Retinal Pigment Epitheliopathy and Choroidopathy

Central serous chorioretinopathy (CSCR) has been reported to occur in association with bone marrow and solid organ transplantation. Friberg and Eller reported occurrence of CSCR in cardiac and renal

transplant recipients [16]. Others have reported III 24 cases of CSCR after BMT [15, 26]. In a study of 270

patients with BMT, Karishma et al. described two patients with CSCR, who responded well to photocoagulation [26]. BMT associated CSCR has also been reported in the setting of GVHD [10, 15]. The combined effects of high doses of corticosteroid, emotional stress, systemic hypertension, cyclosporine, and other chemotherapeutic agents contribute to the pathogenesis of CSCR after bone marrow transplantation [10, 16, 21, 26]. Stewart et al. suggested that leukemic infiltration causes choriocapillary ischemia and reversible disruption of retinal pigment epithelium function, predisposing to serous retinal detachment [39]. The visual prognosis for CSCR in transplanted patients is generally good, and photocoagulation may be required only in persistent cases.

24.4.3.3 Hematologic Complications

Hematologic complications occur in the early postoperative period and are presumably related to the iatrogenic bone marrow aplasia, resulting in anemia, leukopenia, and thrombocytopenia. These changes lead to the development of intraretinal hemorrhages, microaneurysms, cotton-wool spots, and vitreous hemorrhage. In addition, during the early posttransplantation period, most patients receive frequent blood and platelet transfusions as well as other blood products. Blood and platelet transfusions are associated with formation of leukocyte, red blood cell, and platelet microaggregates. Embolization of these microaggregates to the retina vasculature results in an occlusive microvasculopathy with characteristic features of retinal hemorrhages, microaneurysms, and cotton-wool spots [31]. Cellular microaggregate embolization may also occur with the initial transfusion of the donor bone marrow. The leukopenic state and presence of multiple indwelling catheters predispose to the development of septicemia and subsequent septic microembolization that can potentially cause an occlusive microvascular retinopathy.

In a retrospective study of 397 patients, Coskuncan and coworkers reported 14 (3.5 %) patients developed vitreous or intraretinal hemorrhages at a median of 51 days after BMT [11]. Over 90 % of hemorrhagic complications were observed within 6 months after the transplantation. Visual loss due to

vitreous and/or preretinal hemorrhages occurred in 1 % of patients, and usually resolved spontaneously. In an autopsy study, 11 (28.9 %) of 39 patients who were recipients of BMT had intraretinal hemorrhages [22].

Thrombocytopenia is an important factor in the development of retinal hemorrhages in patients who 24 III undergo BMT [42]. Hirst et al. reported two patients out of 45 patients that had transient visual loss as a result of subhyaloidal hemorrhages. The hemorrhages cleared with resolution of the underlying

thrombocytopenia [21].

24.4.3.4 Optic Neuropathy

Bilateral optic disk edema has been described after BMT. One study observed optic disk edema in 11 of 397 patients after BMT [11]. In 8 patients, the disk edema resolved after discontinuation of cyclosporine, suggesting cyclosporine toxicity as the cause. Khawly and associates noted optic neuropathy in six of nine patients with advanced breast cancer who underwent autologous BMT without cyclosporine therapy [27]. All patients subsequently developed optic disk pallor.

24.4.3.5 Infectious Complications

Systemic infections account for most of the morbidity and mortality associated with bone marrow transplantation. Ocular infections are relatively uncommon and occur in approximately 2 % of the patients [11]. Ocular infections are part of the spectrum of chorioretinopathies associated with BMT and are related to the recipient’s iatrogenic immunodeficient state. The advent of effective antibacterial therapy has markedly decreased the occurrence and severity of both systemic and ocular bacterial infections in BMT patients. In the series of 397 patients reported by Coskuncan and associates, no cases of bacterial retinitis or endophthalmitis were encountered after BMT. Fungal infections, including Candida endophthalmitis and Aspergillus retinitis, were the most common intraocular infections, occurring in 1.5 % of the patients [11]. Fungal infections generally occur within the first 4 months of BMT, with a median time to diagnosis of 2 months. The immunodeficient status and the increased frequency of invasive procedures such as intravenous lines during the first few months after BMT account for the higher incidence of infections. Although rare cases of Aspergillus endophthalmitis have been described, ocular aspergillosis is often limited to the subretinal or subretinal pigment epithelium space and is frequently associated with a negative yield for vitreous biopsy. Fusarium endophthalmitis, resulting in enucleation

of the affected eye, has been reported following autologous BMT for leukemia [37].

Viral retinitis caused by cytomegalovirus (CMV), herpes zoster (HZV) and herpes simplex (HSV) viruses is among the late ocular complications of BMT [11]. In a series of 785 patients who underwent BMT, 1 % developed CMV retinitis [45]. In another study, only one patient out of 379 patients had CMV retinitis [11]. The incidence of CMV retinitis appears to be higher in HLA-matched unrelated donor transplants than in HLA-matched sibling transplants [29]. Repeated treatment with antithymocyte globulin and the use of certain immunosuppressive agents such as mycophenolate mofetil may increase the likelihood of CMV retinitis [20, 28]. CMV retinitis in the setting of BMT often responds to treatment with systemic and intravitreal administration of foscarnet and ganciclovir [35]. Severe, progressive CMV retinitis may result in poor visual outcome [29]. Prophylactic use of valacyclovir for prevention of CMV infection in BMT patients has been advocated by some authors.

Although cutaneous involvement by herpes zoster virus is a frequent complication following BMT and solid organ transplants, herpes zoster retinitis is an infrequent occurrence [43]. In a series of 397 patients, Coskuncan and coworkers reported one case of herpes zoster retinitis that occurred following disseminated herpes zoster infection 370 days after the BMT [11]. The clinical features of herpes zoster retinitis are similar to those of the acute retinal necrosis, and the progressive outer retinal necrosis. Management includes intravenous acyclovir therapy, as well as systemic or intravitreal ganciclovir or foscarnet for the refractory cases [32].

Toxoplasma retinochoroiditis may occur as an early or late complication of BMT, particularly in patients with GVHD who are chronically immunosuppressed [11]. It can be either unilateral or bilateral and is often due to reactivation of preexisting ocular toxoplasmosis [36], although acquired primary ocular disease may also occur. Many patients with old Toxoplasma chorioretinal scars do not experience reactivation of their disease after BMT. Ocular toxoplasmosis responds well to appropriate antibiotic therapy including pyrimethamine, sulfadiazine, and clindamycin. Toxoplasma retinochoroiditis in BMT patients can be associated with cerebral dissemination, resulting in significant morbidity and mortality. It is imperative to follow up these patients with serial CT scans of the brain [12].

24.4.3.6 Other Complications

Other posterior segment complications of BMT include posterior scleritis and serous retinal detachment.

24.4.4 Pathologic Features

In a light and electron microscopic study of a patient with BMT, Webster and coworkers noted infarction of the innermost layers of the retina with shrinkage of the inner plexiform layer, foci of cystoid bodies within the nerve fiber layer consistent with cotton-wool spots, and no gross abnormality of the outer layers of the neurosensory retina, retinal pigment epithelium, or choroid [44]. Electron microscopy confirmed the cystoid bodies as axonal swellings filled with degenerate organelles. Surrounding capillaries revealed loss of endothelial cells with relatively preserved pericytes. The authors suggested that normal T-cell function may be necessary for the protection of retinal endothelial cells from insults such as radiation, which may lower the threshold for subsequent endothelial loss and retinal ischemia. In an autopsy study of 39 patients with BMT, Jabs and coworkers noted infiltration of choroid by histiocyte-like cells, occasionally accompanied by chronic inflammatory cells in 80 % of cases and retinal hemorrhages in 29 % [22].

24.4.5 Management

BMT associated retinopathy generally has a good visual prognosis. The retinopathy typically resolves within 2 – 4 months after the cessation or lowering of the dosage of cyclosporine with or without use of systemic prednisone [5, 11]. Bernauer and coworkers noted complete resolution of the retinal findings in 69 % of patients, and full recovery of the baseline visual acuity in 46 % of patients [5]. In another study, the median visual acuity after BMT retinopathy was 20/50 [34]. Because of the relatively favorable prognosis and non-progressive nature of most cases of BMT associated retinopathy, aggressive treatment is usually not necessary. In severe cases resulting in proliferative retinopathy, panretinal laser photocoagulation may be indicated.

Ophthalmologic examination of patients after BMT with regular follow-up of those with retinopathy is recommended. In cases where drug toxicity is assumed to be a predisposing factor, discontinuation of the suspected medication should be considered. Ocular infections are treated in conjunction with the medical oncology team.

References

1.Armitage JO (1994) Bone marrow transplantation. N Engl J Med 330:827 – 838

2.Arocker-Mettinger E, Skorpik F, Grabner G, Hinterberger W, Gadner H (1991) Manifestations of graft-versus-host disease following allogenic bone marrow transplantation. Eur J Ophthalmol 1:28 – 32