Idiopathic myelofibrosis causing inflammatory central retinal vein occlusion mimicking frosted branch angiitis

Abstract

Primary idiopathic myelofibrosis is a clonal disorder arising from the neoplastic transformation of early haematopoietic stem cells leading to abnormal fibrous tissue within bone marrow. We present a 51-year-old man complaining of sudden loss of vision in the right eye along with multiple superficial retinal haemorrhages and perivascular infiltration. Fundus fluorescein angiography and optical coherence tomography confirmed the diagnosis of inflammatory central retinal vein occlusion with macular oedema which mimicked frosted branch angiitis. Laboratory tests and bone marrow biopsy confirmed underlying systemic disease to be Janus kinase 2 mutation positive primary idiopathic myelofibrosis. He received one intravitreal injection of antivascular endothelial growth factor along with dexamethasone for his ocular condition. In view of his systemic disease, he was started on systemic chemotherapy and oral corticosteroid which helped in stabilising the eye condition.

Background

Primary myelofibrosis is the least frequent among the chronic myeloproliferative diseases. Chronic idiopathic myelofibrosis is a clonal haematopoietic stem cell disorder characterised by increased bone marrow collagen fibrosis, leucoerythroblastic anaemia with teardrop-shaped red cells, splenomegaly and extramedullary haematopoiesis.¹ Primary myelofibrosis occurs in middle-aged and elderly people, with a median age of 67 years. Ophthalmic manifestations though rarely seen may present either as vascular occlusion, retinal neovascularisation or vitreous haemorrhage.² We report a case of inflammatory central retinal vein occlusion mimicking frosted branch angiitis in a setting of primary idiopathic myelofibrosis.

Case presentation

A 51-year-old man complained of sudden, diminution of vision in the right eye of 3 days duration. He also gave a recent history of sudden loss of weight and appetite with tiredness in the last 2 months. On general examination, he was cachexic with distinct pallor of fingernails. On ocular examination, his best-corrected visual acuity (BCVA) was hand motions in the right eye and 20/20 in the left eye. Intraocular pressure (IOP) measured 19 and 16 mm Hg in right and left eye, respectively. Both eyes bulbar conjunctiva showed multiple petechial haemorrhages (figure 1A). Anterior segment examination revealed grade 2 relative afferent pupillary defect in the right eye and normal acting pupil in the left eye. The right eye fundus examination showed multiple dilated tortuous veins and superficial retinal haemorrhages in all four quadrants. There was perivenous yellowish infiltrates from the optic disc towards the periphery resembling frosted branch angiitis (figure 1B). The optic disc was hyperaemic and oedematous. Left eye fundus showed few superficial and intraretinal haemorrhages with normal disc and macula.

Figure 1.

(A) Diffuse slit lamp examination showing multiple petechial haemorrhages in bulbar conjunctiva. (B) Montage colour fundus picture showing dilated and tortuous veins with superficial retinal haemorrhages with perivenous infiltrates mimicking frosted branch angiitis. (C) Fundus fluorescein angiography in late phase showing staining of the vessel wall without any leakage. (D) Optical coherence tomography showing an area of large neurosensory detachment with minimal cystoid oedema involving inner retinal layers.

Investigations

Considering his recent onset of loss of vision, he underwent fundus fluorescein angiography in the right eye which in the early phase showed delayed filling of the veins and late staining of the vessel wall without any leakage from vessel wall (figure 1C). Optical coherence tomography (OCT) in the right eye showed large neurosensory detachment along with minimal cystoid oedema (CME) involving the inner retinal layers and central macular thickness of 545 µm (figure 1D). A diagnosis of inflammatory central retinal vein occlusion resembling frosted branch angiitis with CME was made.

Initial laboratory work revealed leucocytosis (14.4×10⁹/L) with thrombocytopaenia (16.0 ×10⁹/L) and a raised reticulocyte count (7.06%). The peripheral blood smear showed normocytes, microcytes, polychromatophils, tear drop cells, a band form and thrombocytopaenia (figure 2A). Serum lactic acid dehydrogenase levels were raised (798 U/L). Serological tests to detect any autoimmune aetiology were rule out. Ultrasound of abdomen showed hepatosplenomegaly. A bone marrow biopsy demonstrated markedly hypocellular and severely fibrotic marrow with decreased trilineage haematopoiesis, lymphoplasmacytosis and occasional dysplastic megakaryocytes with reticulin stain condensation suggestive of idiopathic myelofibrosis (figure 2B). Flow cytometry study revealed paraoxysmal nocturnal haemoglobinuria clone positive for granulocytes. A positive Janus kinase2 mutation test confirmed the diagnosis of idiopathic myelofibrosis. This established a diagnosis of inflammatory central retinal vein occlusion secondary to idiopathic myelofibrosis which mimicked frosted branch angiitis.

Figure 2.

(A) Peripheral blood smear showing myelocytes, polychromatophils, tear drop cells and nucleated red blood cell (arrow) Giemsa ×100. (B) Bone marrow trephine biopsy showing hypocellular marrow with extensive fibrosis Giemsa ×40. (C) Colour fundus photos showing pallor of disc with resolved retinal haemorrhages. (D) Optical coherence tomography showing foveal atrophy.

Treatment

In view of gross macular oedema, we treated him with simultaneous intravitreal antivascular endothelial growth factor (VEGF; 1.25 mg/mL, 0.05 mL bevacizumab) and intravitreal dexamethasone (400 µgm/0.1 mL) injection. Following this treatment, BCVA improved to 20/80 with significant reduction in central macular thickness (204 µm). The treating haematologist advised multiple blood transfusions along with allogenic bone marrow transplantation in view of complete suppression of bone marrow; in absence of donor, however, he was put on systemic chemotherapy with thalidomide (50 mg once a day for 3 months) and oral corticosteroids (prednisolone acetate 0.5 mg/kg/day for 1 month and then taper for next 2 months) regimen and was later maintained on tablet danazol (600 mg/day for 6 months) to improve his bone marrow function.

Outcome and follow-up

At 2 years follow-up on maintenance dose of chemotherapy, his BCVA was 20/100, N24 and 20/20, N6 in the right and left eye. The right eye had grade 2 nuclear sclerosis, and the left lens was clear. The IOP was 14 and 16 mm Hg in right and left eye, respectively. Fundus examination in the right eye showed optic disc pallor with resolved retinal haemorrhages (figure 2C) and foveal atrophy as confirmed by OCT (figure 2D).

Discussion

Primary myelofibrosis is a myeloproliferative neoplasm characterised by stem cell derived clonal myeloproliferation that is accompanied by bone marrow fibrosis, anaemia, splenomegaly and extra medullary haematopoiesis.¹ Ocular manifestations of myelofibrosis reported in the literature as of this writing are intraretinal haemorrhages and exudative detachments, marked venous occlusion with neovascularisation, infiltration causing ciliochoroidal effusion and angle-closure glaucoma, bilateral papilloedema and impending central retinal vein occlusion (CRVO) due to jugular vein occlusion.^2–4

Frosted branch angiitis in typical form, unassociated with pre-existing intraocular inflammation, is likely to be a primary immunological process in response to a number of provoking antigens. Atypical frosted branch angiitis is secondary to concurrent inflammation, most commonly occurs in association with cytomegalovirus retinitis.⁵ Infiltrative form too is seen in association with intraocular lymphoma or leukaemia.⁶ Antibodies to tumour antigens may cross-react with endothelial cells and cause inflammation. Multiple case reports have been published wherein CRVO has been associated with frosted branch angiitis particularly in young individuals where intraocular inflammation along with blood hypercoagulability has been the main risk factor.⁷ In our case, inflammatory CRVO mimicked frosted branch angiitis. We hypothesise inflammatory component as the main aetiological factor for CRVO causing centrifugal spreading of perivascular infiltrates that resembled frosted branch angiitis. The cause could be either due to the hypercoagulable state or paraneoplastic inflammatory disease causing leucocyte infiltration in setting of myeloproliferative disorders.

In our case, initial treatment of anti-VEGF along with dexamethasone helped in reducing the macular oedema and inflammation. The systemic chemotherapy and oral corticosteroids started for idiopathic myelofibrosis helped to improve his bone marrow function and increase his life expectancy. To our knowledge, this is a first case of CRVO mimicking as frosted branch angiitis in a patient diagnosed to have primary idiopathic myelofibrosis (PubMed search). Timely recognition of the underlying aetiology and prompt referral to haemato-oncologist may help prevent ocular complications and improve life expectancy in this subset of patients.

Learning points.

• Frosted branch angiitis-like picture in a setting of retinal vascular occlusion should be investigated thoroughly to rule out any underlying blood dyscrasia or autoimmune diseases.

• Primary idiopathic myelofibrosis is a rare myeloproliferative condition which can present with associated ocular features like intraretinal haemorrhages, vascular occlusion, retinal neovascularisation and angle-closure glaucoma.

• Timely recognition of the underlying aetiology and prompt referral to haemato-oncologist may help prevent ocular complications and improve life expectancy in this subset of patients.