Recalcitrant Optic Nerve and Retinal Infiltration in a Relapse of Acute Lymphoblastic Leukaemia

ABSTRACT

Isolated ocular relapse of leukaemia is rare. We present the case of a 20-year-old male with T-cell acute lymphoblastic leukaemia (ALL) who reported sudden blurring of vision in both eyes 6 months after documentation of ALL remission. Ocular examination showed bilateral infiltrative optic neuropathies and serous retinal detachments. Cerebrospinal fluid and bone marrow samples were negative for blast cells. Systemic work-up did not reveal any other sites of involvement. The ocular infiltration partially responded to reinduction chemotherapy, intraconal steroids, and radiotherapy. This report demonstrates a challenging case of isolated ocular ALL relapse presenting as bilateral optic nerve and retinal infiltration.

Introduction

The eye is a rare site of relapse in acute lymphoblastic leukaemia (ALL). Somervaille et al. reported that ocular involvement occurred in only 2.2% of children with ALL relapses.¹ Ophthalmic involvement is classified as direct or indirect, depending on whether the effects result from direct leukaemic infiltration of ocular structures or as secondary effects from blood dyscrasia. Direct leukaemic infiltration may present in three patterns: 1) anterior segment, vitreous, and uveal infiltration, mimicking ocular inflammatory conditions; 2) optic nerve infiltration with or without cranial nerve involvement, mimicking neuro-ophthalmological conditions; and 3) orbital infiltration, mimicking orbital inflammatory diseases. Indirect ophthalmological manifestations are secondary to systemic conditions such as anaemia, thrombocytopaenia, or hyperviscosity syndromes.² While optic nerve infiltration is not an uncommon manifestation of ocular relapses, serous retinal detachment is unusual.³ In this paper, we report the challenging case of a young male with ALL in remission, who developed bilateral ocular relapse in the absence of concomitant central nervous system involvement. This report also illustrates partial response of the patient to retrobulbar steroid injection, reinduction chemotherapy, and radiotherapy.

Case report

A 20-year-old male, diagnosed with T-cell ALL, presented at our institution with blurred vision. He had been undergoing treatment with the hyperCVAD regimen (cycle A – intravenous cyclophosphamide, dexamethasone, doxorubicin, and vincristine + intrathecal methotrexate and cytarabine; cycle B – intravenous and intrathecal methotrexate and cytarabine) and achieved remission 4 months into therapy. 6 months after documentation of remission he reported sudden blurring of vision in both eyes.

Ocular examination revealed a best-corrected visual acuity (BCVA) of 3/200 with the right eye and no light perception with the left eye. The left eye had a grade 4 relative afferent pupillary defect. The anterior segments were unremarkable. Right eye funduscopy showed a poorly defined optic nerve with creamy-yellow infiltrates extending to the adjacent retina. Multiple intraretinal haemorrhages and exudates were seen over the disc. Subretinal fluid was seen surrounding the nerve extending up to the retinal mid-periphery. The left fundus showed a greater degree of creamy-yellow optic disc infiltration with haemorrhages, exudates, subretinal infiltrates, and total serous retinal detachment. Large dot and blot haemorrhages and occasional Roth spots were spread all over the retina (Figure 1). No pertinent findings were found on physical and neurological examination.

Figure 1.

Bilateral optic disc infiltration and peripapillary serous retinal detachments.

Ocular ultrasonography (US) of the right eye showed a plateau-shaped, immobile, moderate-amplitude, homogeneous, hyperechoic mass lesion abutting the optic nerve and the adjacent areas. US of the left eye showed a thick, poorly mobile, irregular mid- to high-amplitude band from the disc to the mid-periphery and a serous retinal detachment. Both choroids appeared normal (Figure 2). Blood work-up revealed anaemia (116 g/L) and leukopaenia (2.70 x 10⁹/L). The differential cell counts were within normal limits. No blasts were appreciated in the peripheral blood smear. The cerebrospinal fluid (CSF) and bone marrow aspirate were also clear of leukaemic blasts.

Figure 2.

Ocular ultrasonography of both eyes showing bilateral mass lesions abutting the optic nerve head, with a serous retinal detachment in the left eye.

He was managed as a case of isolated bilateral ocular relapse and was treated with the chemotherapy protocol R11 (intravenous dexamethasone, cytarabine, vincristine, L-asparaginase, etoposide + intrathecal methotrexate and cytarabine). Four milligrams of triamcinolone were also injected in the bilateral intraconal spaces. Funduscopy performed after a few days showed decreased optic nerve infiltration and reattachment of the superior retina of the left eye; however, the bilateral peripapillary serous retinal detachments persisted. After four weeks on protocol R11, the BCVA of the right eye improved to 20/200, although the left eye vision was still no light perception. Magnetic resonance imaging revealed enhancing mass lesions at the optic discs on a T1-weighted fat-saturated sequence with gadolinium contrast. The left retrobulbar optic nerve also showed enhancement. The brain was unremarkable (Figure 3).

Figure 3.

Contrast-enhancing bilateral optic nerve head masses on T1-weighted fat saturated sequence magnetic resonance imaging with gadolinium contrast.

While on maintenance chemotherapy, the vision of the right eye diminished to light perception only. Total retinal detachment was seen in the right eye, while the left eye showed increased optic disc infiltration. A total of 30 Gy was delivered to the whole brain and both globes via external beam radiotherapy. His subjective vision improved halfway during radiotherapy. Fundus photographs showed reattachment of the retina of the right eye and regression of tumour infiltrates in both eyes (Figure 4).

Figure 4.

Fundus photographs after 5 weeks of radiotherapy showing bilateral decreased optic nerve infiltration and persistence of retinal leukaemic infiltrates that was more severe in the left eye.

Three months after radiotherapy, he developed multiple skin papules and was diagnosed with leukaemia cutis. The fundus findings were unchanged. The final BCVA was 10/200 with the right eye and no light perception with the left eye. He died 8 months after the initial diagnosis of isolated bilateral ocular relapse.

Discussion

The optic nerve in leukaemia is considered as a “pharmacological sanctuary.”^4,5 As chemotherapeutic agents do not readily penetrate ocular barriers, the eye has been identified as a potential site for leukaemic relapse.⁵ Gillete et al. suggested that even a combination of systemic and intrathecal chemotherapy may be ineffective in preventing subretinal infiltration.⁶ This supports the importance of a thorough ophthalmological evaluation upon diagnosis, during, and after therapy, especially in patients presenting with visual symptoms.

Vishnevskia-Dai et al. recommended eye screening upon presentation and then every six months thereafter, unless there are ocular complaints that warrant earlier examination.² In the evaluation of a patient with leukaemia, it is crucial to correctly establish whether intraocular findings are due to direct or indirect leukaemic involvement. While retinal findings such as haemorrhages and small infarcts may be corrected with proper management of the blood parameters, direct infiltration of ocular structures by leukaemic cells warrants a more aggressive and targeted approach.

Leukaemic optic neuropathy is considered a neuro-oncological emergency, warranting urgent intervention in the form of chemotherapy, radiation, and corticosteroids. Ocular manifestations are often accompanied by neurological and systemic signs and symptoms. In the absence of related findings, the diagnosis and management of leukaemic optic nerve infiltration becomes more challenging.⁷ Our patient had isolated bilateral ocular relapse; hence, response to therapy was monitored by serial funduscopy. The creation of a multidisciplinary team involving the ophthalmologist, haematologist, and radiation oncologist was necessary to ensure proper monitoring and formulation of an appropriate treatment plan.

Leukaemic retinal infiltration may be observed as perivascular sheathing, white-centred retinal haemorrhages, greyish white nodules, and as pallid optic disc oedema.^7,8 Infiltration of the choroid may present as serous retinal detachment with yellowish infiltrates at the level of the choroid or the retinal pigment epithelium.⁹ There are only a few reports that have described bilateral leukaemic retinal involvement with no blast cells in the CSF, as seen in our case.^4,7,10

Treatment of leukaemia involves systemic chemotherapy and biological agents; although the ocular penetration of these drugs may be limited.² The primary goal in the management of ocular involvement is the remission of the leukaemic infiltrates. Radiation therapy has been traditionally employed for lesions that fail to respond to chemotherapy.¹⁰ Myers et al. suggested early orbital radiation with or without induction chemotherapy to preserve vision in patients with obvious optic nerve infiltration.⁵ Newer studies have begun to investigate intravitreal injection of drugs, such as methotrexate, dexamethasone, and anti-vascular endothelial growth factor.² To date, there are no large retrospective and prospective studies that can support the effectiveness of intravitreal therapy for ocular leukaemia.

The prognosis of patients with optic nerve infiltration in leukaemia is poor. Myers et al. reported a mean lifespan of 11 months after diagnosis of optic neuropathy among patients with ALL.⁵ Despite our therapeutic efforts, our patient succumbed to his condition 8 months after discovery of the optic nerve and retinal infiltration. Progressive ocular infiltration in leukaemia is difficult to manage and the need for better treatment protocols and newer treatment modalities is apparent.

Conclusion

Isolated ocular relapse of ALL is rare. In this report, we describe an uncommon case of isolated ocular ALL relapse presenting as bilateral optic nerve and retinal infiltration. The response to systemic and intrathecal chemotherapy, retrobulbar steroids, and radiotherapy was only partial. We believe that there is a need to develop new drugs and treatment protocols that can address ocular infiltration in leukaemia.

Declaration of interest statement

The authors report no conflict of interest.