myeloid lines usually with increased bone marrow cellularity and normal or increased blasts up to 20%. The incidence in the USA is approximately 10,000 new cases per year; risk increases with age and slightly with male gender [87]. The prevalence of myelodysplastic syndrome (MDS) is estimated to be 4.1/100,000 and the median age is 71 [88, 89]. Although predominantly a primary process, treatment-induced MDS accounts for 10% of cases [89]. Childhood MDS is much more unusual and is most commonly associated with monosomy 7 [90]. Transformation to acute leukemia is variable largely because of different clinical and biological features, with MDS more a disorder of increased apoptosis versus uncontrolled proliferation in leukemia with some overlap between the two [91].

Most, if not all, of the retinal and choroidal changes due to MDS are secondary effects caused by anemia, thrombocytopenia, or neutropenia. A study of ocular complications in those with MDS was found in 19/41 patients, with one case each of vitreous hemorrhage, central retinal vein occlusion (CRVO), and cot- ton-wool spots, ten subjects with retinal hemorrhages (red and white centered), and two with optic neuritis, with some patients having more than one complication [92]. Retinal hemorrhages were associated with low platelet counts of 27,000 ± 29,000 (p < 0.006), while hemoglobin concentration was not found to be significant. As expected, higher rates of retinal hemorrhage were associated with refractory anemia with excess blasts due to the higher degree of neoplastic change. Unlike in acute leukemia, where evidence has been equivocal regarding platelet counts and retinal hemorrhages, MDS has morphologic and maturational platelet defects that predispose to bleeding independent of platelet count [93]. One reported case of birdshot retinochoroidopathy in an HLA-A29-negative individual with trisomy 8 MDS was thought to be an autoimmune response, possibly related to S-antigen [94, 95]. Very rare cellular infiltration has been reported, including increased optic nerve thickness, ciliochoroidal effusion, and non-arteritic anterior ischemic optic neuropathy (AION) [96–98].

Myeloproliferative Disorders

The myeloproliferative neoplasms (MPN) are a proliferation of one or more myeloid lineages with proliferation of bone marrow progenitor cells. In contrast to MDS, MPN usually have effective hematopoiesis with more terminally differentiated cell line or lines. These manifestations can be classified as classic, including chronic myelogenous leukemia (CML), essential thrombocythemia (ET), polycythemia vera (PCV), and primary myelofibrosis (PMF); as atypical, including systemic mastocytosis, hypereosinophilic syndrome, chronic neutrophilic and basophilic leukemia; as well as many others including unclassifiable types and MPN/MDS overlaps. These diseases often share mutations resulting in overexpression of tyrosine kinase activity such as BCR-ABL in CML and Janus kinase 2 (JAK2) or thrombopoietin receptor (MPL) in the other classic MPN, resulting in growth factor–independent proliferation [99].

Chronic Myelogenous Leukemia

This MPN is associated with the Philadelphia chromosome, a by-product of a t(9;22) resulting in a fusion protein of BCR and c-ABL (nonreceptor tyrosine kinase), which results in uncontrolled production of mature granulocytes. The incidence is 0.6–2 per 100,000 persons and accounts for 15–20% of adult leukemias, with a slight male predominance [100]. Median age at presentation is 50 years with no familial predisposition, and there is an increased risk with ionizing radiation.

The intraocular sequelae of CML may be subtle until blast crises where it takes the appearance of acute leukemia. During the chronic phase, with repeated vascular injury and nonperfusion, there appears to be a higher prevalence of peripheral microaneurysms and neovascularization in contrast to other leukemias [101, 102]. A rare occurrence of bilateral peripheral retinal nonperfusion with arteriovenous anastomosis and sea-fan neovascularizations in the setting of a CBC within

normal limits and no other retinal findings has been reported [103]. Thrombotic microangiopathy or papilledema can be manifestations of this disease, in addition to optic disk edema possibly secondary to imatinib therapy or ocular infections after bone marrow transplant (BMT) [104–107].

ophthalmic migraine, scintillating scotomata, and thrombotic or embolic phenomena [118, 119]. There are also more uncommon reports of PCV presenting as isolated monocular visual loss secondary to profound retinal ischemia; bilateral CRVO, isolated papilledema, or AION; an orbital mass from extramedullary hematopoiesis; and/or impaired dark adaptation [120–125].

Polycythemia Vera

Polycythemia vera involves a clonal proliferation of myeloid cells with a primary increase in red cell mass and has been defined as a hemoglobin concentration greater than 16.5 g/dl in females, 18.5 g/dl in males, and a low serum erythropoietin level [108, 109]. The age of onset typically ranges from 20 to 85, with a median of 60 years, and the incidence is 1.9/100,000 per year with a female predominance except in men over 70 years [110, 111]. It has been postulated that erythroid progenitors develop signaling defects downstream of cytokine receptors that are unrelated to erythropoietin or its receptor. There is increased tyrosine kinase activity via the insulin-like growth factor 1 system or decreased tyrosine phosphatase activity resulting in overexuberant red cell production [112–114].

Systemic manifestations characteristically involve pruritus especially after a warm bath, erythromelalgia, dyspepsia, and thrombotic events. The pathogenesis of thrombosis appears to be related to platelet hyperfunction and thromboxane overexpression, while the increased risk of hemorrhage may be related to membrane receptor abnormalities, acquired von Willebrand syndrome, or other defects of function/structure [115, 116]. In general, the ocular effects of PCV are mostly secondary to hyperviscosity and thrombosis resulting in amaurosis fugax, migraine, arteriospasm or arteriosclerosis, and sometimes a cyanotic hue in the eyelids and conjunctiva [117]. The retinal arteries attenuate and veins can become engorged and tortuous, with a variable amount of flame-shaped hemorrhages and/or CWS. This can progress to vein or artery obstruction. Vasomotor symptoms include headache, amaurosis fugax, transient ischemic attack,

Essential Thrombocythemia

This is a clonal stem cell disorder resulting in chronic primary thrombocytosis with platelet count >450,000/uL that by definition is not reactive, not a result of the other myeloproliferative disorders, and occurs in the setting of normal iron stores [126]. In fact, neither thrombopoietin nor its receptor, c-Mpl, appears to be involved in the pathogenesis of this disorder, unlike other familial thrombopoietin/c-Mpl-related thrombocytoses, and appears to be more often related to JAK2 mutations [127]. The incidence has been reported to be 2.5 per 100,000 individuals per year, with a prevalence of approximately 24/100,000, a male to female ratio of 0.69, and median age at diagnosis of 60 years and occurring rarely in children [128–130]. Retinal artery and vein occlusions, peripheral ischemia, and neovascular complications have all been reported [119, 131–133].

Primary Myelofibrosis

Primary myelofibrosis is characterized by chronic clonal proliferation derived from multipotent myeloid stem cells with atypical megakaryocytic hyperplasia with secondary fibrosis, osteosclerosis, and angiogenesis of the bone marrow causing eventual failure with extramedullary hematopoiesis as anemia progresses along with constitutional symptoms [134, 135]. Platelet and leukocyte counts can be variable, although thrombocytopenia tends to develop as the disease progresses with platelet hypofunction [136]. Bone marrow biopsy ultimately shows fibrosis and the absence of granulomatous disease or foci