Goldberg was the first to devise a classification system for proliferative sickle cell retinopathy (PSR) based on clinical findings. The following is a brief description of each stage of PSR [68, 69].

Untreated sickle cell retinopathy has been reported to cause vision loss (20/60 or worse) in 10 % of patients. Half of these were legally blind at 20/200 or worse. Almost all vision loss was attributable to proliferative disease. This was almost always caused by epiretinal membrane, traction retinal detachments (although one patient developed a rhegmatogenous detachment) or vitreous hemorrhage. Angioid streaks [leading to choroidal neovascular membrane (CNV)], sickling maculopathy and branch retinal artery occlusion (BRAO) were less frequent causes of vision loss in non-proliferative disease [71]. Proliferative retinopathy (and retinopathy in general) is more common in SC disease and HbSβthal than SS disease [72].

Clarkson found the prevalence of proliferative retinopathy to be 18 % when all three groups (SS, SC, HbSβthal) were combined. If each group was examined independently, SS patients had a prevalence of 11 % and HbSβthal patients had a prevalence of 17 % [35]. He found a prevalence of vitreous hemorrhage of 21 % in patients with SC disease and 1.8 % in patients with SS disease. Retinal detachment was seen in 10 % of patient with SC disease. The incidence of PSR increased in patients over 40 years. While PSR is less common in children than in adults, it can occur and be vision threatening. Clarkson also reports an 11 year old that had Stage III disease in one eye and non-proliferative retinopathy in the other on initial exam. He eventually lost all vision in the more severely affected eye due to unsuccessful surgery to repair a retinal detachment.

Friberg found in patients with SS disease from 8 to 20 years old (34 patients) that the incidence of peripheral vascular occlusions was 9 %, arteriovenous anastomoses was 2 % and vitreous hemorrhage was 3 % [36]. However, Hayes did not find any proliferative retinopathy in patients with SS disease who were under 19 years old [73].

Penman looked at peripheral retinal changes angiographically in children with sickle cell disease in the hopes of stratifying risk for development of PSR. He classified type I as “fairly” normal peripheral retinal vasculature, with continuous arteriovenous loops. Type II did not have continuous loops and gave the appearance of “moth-eaten” vasculature. While few patients in his study developed PSR, all that did had Stage II disease prior to its development. He therefore concluded that this method of assessing angiography could be used for screening for the development of PSR [74]. Interestingly, all but one of the patients that developed PSR had SC disease [74].

Eruchalu looked at 37 patients under 13 years old who had severe systemic SS disease. “Severe” was defined as three or more vaso-occlusive events in 1 year. Thirty-two percent had retinopathy and three eyes of two patients had proliferative disease. All of these patients were 8 years old or older. After one year, one had received laser treatment and the other was stable. They recommend yearly screenings after age 8 in this high-risk group [75].

Goldberg found a tendency toward progression of PSR in 25 eyes of 16 patients with SC disease, although only one lost vision [76]. In Clarkson’s study, only three patients had 20/30 or less vision on presentation and only five developed vision loss over the 6 years of follow-up [35]. Condon found that 61 % of PSR lesions autoinfarcted in his study of sickle cell patients followed over 8 years. He noted that the fastest progression of PSR lesions occurred in patients 15–29. Only, 12 % of eyes lost vision due to PSR. While many lesions autoinfarct, others go on to cause vitreous hemorrhage, retinal detachments, and vision loss [77].

Since a significant percentage of cases of PSR autoinfarct (20 % according to Nagpal) [77, 78], the treatment of PSR is somewhat controversial. Usually treatment is not indicated until active neovascular proliferation (Stage III) has occurred in both eyes, or rapid progression of PSR, or proliferative disease in patients with only one remaining eye [79]. Historically, laser occlusion of the feeder vessel to the proliferation was employed. However, this was fraught with complications, including breaks in Bruch’s membrane, choroidal neovascular membrane development, choroidal ischemia, retinal detachments and vitreous hemorrhage [80, 81]. More recently panretinal photocoagulation, either sector or 360° treatments, has been utilized (see Fig. 11.6). Farber reported on 174 eyes in 116 patients randomized to either scatter photocoagulation (99 eyes) or observation (75 eyes). In the treatment group, 30 % achieved total resolution and 51 % partial resolution. In the observation group 22 % and 24 % achieved total and partial resolution, respectively. The treated eyes had slightly less visual loss (3 %) than did the control group (8 %) [82]. Fox reported a series of 88 patients with SC disease that were randomized to observation or sector laser photocoagulation. There was a higher rate of regression of neovascularization (NV) in the treatment group, although only a few in both groups had complete resolution of NV. If the patient was younger than 25 years old and NV was flat and small, there was a better chance that the lesion would infarct [81]. Sayag noted that Stage III was more common in SC disease and in the 20–31 year olds. Lesions in patients in their 40s tended to remain stable [83]. Condon reports that progression of PSR is more common in younger patients (15–29 years) and autoinfarction more common in older ones (29 and older) [77]. Fox also found progressive disease only in patients under 40. He also noted higher rates of autoinfarction in patients over 40 and in patients with SS disease. This would suggest the need for more aggressive management of younger patients and a tendency to observe in patients 40 and over, especially in the setting of SS disease [84].

Sayag classified sea fans (Stage III PSR) in order to attempt to stratify risk of progression. He defined the following: Grade A: “sea fan with leakage less than 1 Macular Photocoagulation Study (MPS) disc area” on fluroscein angiography; Grade B: “elevated sea fan with hemorrhage”; Grade C: “elevated sea fan with partial fibrosis”; Grade D: “complete sea fan fibrosis without well demarcated vessels”; Grade E: “Complete sea fan fibrosis with well demarcated vessels”. He identified 73 eyes of 101 patients with PSR and randomized them to scatter laser photocoagulations with argon green laser (38 eyes) or observation (35 eyes). He found that Grades A and C did not do statistically better with treatment while Grade B did. He further found that the only complications that occurred were in patients that were untreated and belonged to Grades B and E. Four developed vitreous hemorrhage and three developed rhegmatogenous retinal detachment [83].

While laser photocoagulation is the usual modality for the treatment of Stage III PSR, Seiberth reported a case of successful trans-scleral diode laser photocoagulation for the treatment of PSR. In this particular case, there was a vitreous hemorrhage, obscuring the view of the retina, so traditional laser treatment was not an option [85].

Vitreous hemorrhages usually remain localized over the site of neovascularization. They can, at times, spread over the macula and interfere with vision [69]. If vision is affected, the patient is usually followed for 6 months to see if the vitreous hemorrhage will clear. If it does not or a retinal detachment occurs, surgery is performed. However, both systemic and ocular complication rates are higher in patients with sickle cell disease . Therefore, careful consideration of the risks and benefits as well as proper pre-operative care of the patient are required [86].

The need for surgical treatment of Stage V sickle cell retinopathy (retinal detachment) is rare in children, however it is indicated at times. The techniques have improved over the years. Anterior segment ischemia was a dreaded complication of retinal buckling procedures. Ryan and Goldberg [87] reported six of ten eyes in patients with SC disease that developed anterior segment ischemia after scleral buckling for retinal detachments. Four eyes became phthisical or prephthiscial, while the other two regained 20/20 or 20/25 vision [87]. Some advocated transfusion prior to such surgeries and even then had significant post-operative complications. Newer vitrectomy and buckling techniques have been employed successfully , without anterior segment ischemia. Pre-operative transfusion is no longer recommended routinely. Intraoperative attention to adequate hydration and oxygenation by the anesthesiologist and good control of intraocular pressure by the surgeon seem to limit the rates of this complication [88]. Chen looked at 15 eyes of 14 patients that underwent retinal surgery for sickle cell eye disease: six for vitreous hemorrhage, one for ERM, and eight for retinal detachment. All had local anesthesia. All had vitrectomy, and two additionally had retinal bands placed. While four patients in the retinal detachment group developed another detachment and required further surgery, none developed anterior segment ischemia. Visual results were good in the vitreous hemorrhage and ERM group (20/60 or better), and as expected in the retinal detachment group (20/400 or better) [88].

Williamson reported the results of 27 patients with PSR, ERM, or vitreous hemorrhage. For reasons not fully explained, 10 of them were observed. One had an inoperable retinal detachment. Some (no number given) were vitreous hemorrhages that cleared and some had traction retinal detachments that did not progress. Two resolved, one with a rhegmatogenous retinal detachment that spontaneously flattened and one with an ERM that resolved with posterior vitreous detachment development. None of the patients had pre-op laser surgery because the author believed it would increase the risk of anterior segment ischemia. There were no reports of this in any of the patients studied. Of the 18 eyes of 17 patients who had surgery, iatrogenic retinal tears developed in seven, vitreous hemorrhages in two (one requiring more surgery), and cataracts in three. Eighty-three percent had improved vision after surgery or surgeries [89].

Leen reported a case of anterior segment ischemia after vitrectomy. The patient had hypotension during surgery and intraoperative laser was employed, possibly contributing to the complication [90].

The role of bevacizumab in the treatment is still being elucidated. Several case reports have noted regression of neovascularization in patients with PSR [91, 92], but one noted a hyphema after injection [93].

Central retinal artery occlusion is a rare complication of sickle cell disease . Liem reports three cases in patients with SS disease. In his review of the literature, no other types of hemoglobinopathy have been reported to have CRAO. His patients, as well as most in his review, were treated with exchange transfusion resulting in 71 % recovering some or all of their vision [94]. Fine reported a case of spontaneous CRAO in a patient with sickle cell disease . This case was also remarkable because vision improved, without treatment, to 20/60 [95]. Brown reports one case of a 14-year-old patient with SS disease who developed a central retinal artery occlusion during an acute pain crisis. No further details are given [96].

Ocular involvement by leukemia has long been recognized [118]. Leukemia is a neoplasm of the leukocytes (white blood cells). The prognosis for childhood leukemia has improved enormously since the 1970s [119] due to improved chemotherapy, new understanding of the natural history of the disease, bone marrow transplantation and better supportive care of the patient [120].

The leukemias are classified into acute and chronic forms as well as lymphoid and myeloid cell types. The classification is based on the cell type and maturation. In general, acute leukemias have more primitive appearing cells. The clinical course of the acute and chronic leukemias is also quite different, with acute leukemia having a relatively rapid and relentless deterioration unless treated aggressively.

The cells of acute lymphoblastic leukemia (ALL) are derived from the lymphocyte cell line. Acute and chronic myleoblastic leukemias (AML and CML, respectively) are derived from primitive myeloid cells [119]. There is increasing use of genetic evaluations to determine prognosis and subtypes of ALL and AML [121].

Leukemia was initially thought to be a suppurative disease of the blood [122]. With the advent of formal histopathology in the nineteenth century, leukemia was recognized to be a malignancy of leukocytes. Prior to the advent of bone marrow biopsy, Liebreich in the 1860s [123] recognized that the fundus examination was helpful in making the diagnosis of leukemia [118]. The study of Ridgway and coworkers was the first to review leukemic ophthalmopathy in children [124].

The leukemias are the most common malignancies of childhood. It is estimated that approximately 3250 new cases are diagnosed each year in the United States in children less than 20 years old [119]. Of childhood leukemias, ALL makes up 75 %, AML accounts for 15–20 %, chronic myeloid leukemia makes up less than 5 %, and chronic lymphocytic leukemia is virtually never seen in children [120]. ALL occurs at a rate of 29.2/1 million while AML occurs at a rate of 7.6/1 million in children less than 20 years old [119].

Common presenting signs of ALL are fever, hemorrhage, bone pain, lymphadenopathy, hepatosplenomegaly, splenomegaly, mediastinal mass, and central nervous system (CNS) disease [120, 125]. Clinical features of childhood ALL at the time of presentation depend on the extent of disease. An elevated white blood cell count may cause cerebrovascular accident, renal failure, retinal cotton wool spots, or mild respiratory distress. Central nervous system involvement, while occurring in both AML and ALL is more common in ALL. Distinctive presentations of AML are granulocytic sarcomas or chloroma (tissue infiltration of leukemic cells) seen principally in the orbit, spinal cord or skin, which may precede the development of frank leukemia . Gum hyperplasia and disseminated intravascular coagulation may also be seen in AML [126]. Loss of weight is a common non-specific feature at the time of presentation [127].

Many of the systemic features of established leukemia are the consequences of therapy [121]. Infections (viral, bacterial, and fungal) are common and reflect the compromised state of the body’s immune mechanisms. Doxorubicin (Adriamycin ) is known to cause cardiac toxicity. High doses of intrathecal chemotherapy in association with cranial irradiation (as used for early CNS prophylaxis) may cause a late leukoencephalopathy. Graft-versus-host disease is a serious complication of bone marrow transplantation and has significant ocular, dermatological and gastrointestinal effects.

The prognosis for both ALL and AML has improved dramatically since the 1970s [119]. Five-year disease-free survival is reported to be approximately 80 % for ALL and 41 % for AML [119], although this is affected by age and other risk factors. Infection and the complications of hemorrhage are the usual cause of death.

While blood counts are often abnormal, bone marrow aspiration is necessary for diagnosis of any leukemia . Blast cells must make up more than 20 % of the bone marrow for the diagnosis to be made. Cytogenetics and other diagnostic testing such as FISH, PCR, microarray, and spectral karyotyping are often used to further define the disease and tailor treatment [120].

A detailed discussion of the treatment of leukemia is beyond the scope of this book. For such a discussion, the reader should consult a standard text such as the chapter by Margolin and coworkers in Cancer: Principles and Practices of Oncology [120].

The principles of treatment are the induction of disease remission and the maintenance of this disease free state. This involves multi-agent (combination) chemotherapy and CNS prophylaxis (both intrathecal chemotherapy and craniospinal irradiation) [121]. Supportive care involves the use of blood products to treat anemia and clotting disorders, the detection and treatment of infection, metabolic and nutritional support and psychosocial care of the patient and family [121]. Bone marrow transplantation (BMT ) is an important treatment modality especially in the management of AML and high risk or refractory ALL [128].

With increasing overall cure rates for most children with ALL and AML, considerable research efforts have been expended to devise the most effective therapies with the least associated morbidity. Attention has been directed towards identifying high-risk subgroups and designing more aggressive treatment protocols for these groups in an attempt to improve overall survival.

The effects of leukemia on any tissue may be primary or secondary. Leukemic infiltration is an example of a primary effect while hemorrhage secondary to thrombocytopenia is a secondary effect. This distinction becomes readily apparent when considering the ophthalmic manifestations of leukemia .

The incidence of various sites of leukemic ocular involvement depends upon the method of ascertainment and the stage of the disease in which the examination is made. Pathological studies consistently show higher incidence of eye involvement than clinical series. This is almost certainly because these are autopsies with a large number of patients dying of disseminated disease. Pathological examination often detects leukemic involvement that is clinically silent. Choroidal leukemic involvement, which is generally cited as the most common site of ocular involvement in autopsy series, is a good example of this phenomenon [145, 146].

Ocular involvement is detected in approximately 30–80 % of autopsy eyes [145–148]. In a prospective study of 120 patients examined at the time of initial diagnosis, only 3 % were found to have primary ocular involvement (retinal infiltrates). Thirty-nine percent had secondary manifestations (hemorrhage, cotton wool spots and central retinal vein occulsions secondary to hyperviscosity). The authors of this study acknowledge that choroidal infiltration may easily have been missed [149]. Reddy and Menon examined 82 children with acute leukemia within two days of diagnosis and found that three had ocular symptoms, while 14 (17 %) had ocular signs related to leukemia [150].

There have been several excellent reviews of the ocular manifestations of leukemia [124, 145, 146, 148, 151]. The most recent series of ophthalmic manifestations of leukemia have focused on ocular involvement of leukemia within two days of diagnosis. Reddy and co-workers found that 17 % of newly diagnosed children with acute leukemia had ocular changes related to their disease [150]. Ohkoshi reported that of 28 patients found to have ophthalmic manifestations of acute childhood leukemia , 27 died within 28 months of the diagnosis of eye abnormalities [152]. All 28 patients had either CNS or bone marrow relapse at the time of diagnosis of ocular involvement. They further reported that the 5-year survival was reduced by half (from 45.7 to 21.4 %) if there was ocular pathology [152]. However, Somervaille and colleagues reported 17 cases of ocular relapse (as a first relapse) in ALL. Eight of them had a relapse in the CNS or bone marrow at the time or ocular relapse. All were treated with chemotherapy and radiation. Eleven of those were still alive and in remission over 4 years after diagnosis of relapse. These authors note that more aggressive treatment at the time or relapse seems to improve survival. All of the 11 survivors were treated with intense relapse protocol chemotherapy with radiation to the involved eye(s). If treated less intensely, all but one expired and the one survivor was in chronic relapse at the time of publication of the study. This suggests that aggressive treatment is warranted in the setting of ocular involvement at the time of relapse [153].