Central nervous system relapse with optic nerve infiltration and meningeal involvement in B-cell acute lymphoblastic leukemia

INTRODUCTION

Acute lymphoblastic leukemia (ALL) is a common hematologic malignancy, particularly in younger individuals, although adult presentations are well recognized and often associated with a poorer prognosis. Central nervous system (CNS) involvement occurs in approximately 5–10% of patients with ALL at diagnosis or during the disease course^[1-3] and represents a major cause of morbidity and relapse.

Ocular involvement is considerably rarer, with isolated optic nerve infiltration reported in approximately 2–3% of cases of CNS leukemia.^[4-7] Despite its low incidence, optic nerve involvement is clinically important as it may represent the first or only manifestation of CNS relapse.

The optic nerve is considered a pharmacologic sanctuary site because of the blood–brain and blood–nerve barriers, which limit penetration of systemic chemotherapeutic agents and allow leukemic cells to persist despite apparent systemic disease control.^[2,4,8] Early recognition of visual symptoms and prompt neuroimaging are therefore critical to prevent irreversible visual loss.

CASE REPORT

Six months before the current presentation, an adult male with no known comorbidities presented with a sudden-onset severe headache and recurrent vomiting. This was his first point of contact with medical services. Magnetic resonance imaging of the brain performed at that time revealed superior sagittal sinus thrombosis with associated hemorrhagic changes in the right frontal region [Figure 1a and b]. Subsequent hematological evaluation established a diagnosis of B-cell ALL, and the patient was started on induction chemotherapy.

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Figure 1:

(a) Magnetic resonance (MR) venography from initial MR imaging (an year ago) showing thrombosis of the anterior superior sagittal sinus (white arrows). (b) Susceptibility-weighted imaging sequence showing hemorrhagic areas (white arrows) in the right frontal lobe in the territory of the right superficial cerebral veins and sagittal sinus.

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Following initial clinical improvement, the patient discontinued therapy and was lost to follow-up due to socioeconomic constraints.

He now presented 6 months later with progressively worsening bilateral visual blurring accompanied by pain on eye movements. There was no history of fever, seizures, or recent trauma. Ophthalmologic examination revealed bilateral optic disc edema with blurred margins [Figure 2a and b], and visual acuity was reduced in both eyes.

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Figure 2:

(a) Fundus photograph of the right eye showing optic disc edema with blurred margins. (b) Complementary fundus photograph of the left eye showing elevation and swelling of the optic disc.

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Magnetic resonance imaging of the brain and orbits was performed on a 3.0-T system. Imaging demonstrated bilateral enlargement and post-contrast enhancement of the optic nerves and their sheaths [Figure 3a-c]. Flattening of the posterior sclera was noted [Figure 3b], suggestive of raised pressure within the optic nerve sheaths. Post-contrast brain imaging also revealed leptomeningeal enhancement [Figure 3d] over the cerebral hemispheres, consistent with meningeal involvement.

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Figure 3:

(a) Post-contrast axial T1-weighted magnetic resonance imaging (MRI) showing enhancement, blurring, and thickening of optic nerves (white arrows). (b) Axial post-contrast T1-Fast spin echo MRI showing flattening of the posterior globes consequent to raised pressure within the optic nerve sheaths corresponding to fundoscopic findings [Figure 2]. Also is shown (arrows) enhancement and blurring of both the optic nerves. (c). Coronal post-contrast T1-weighted MRI showing bilateral enhancing optic nerves and their sheaths (white arrows). (d) Post-contrast axial T1-weighted MRI showing leptomeningeal enhancement over cerebral hemispheres, suggestive of meningitis.

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Cerebrospinal fluid analysis showed lymphocytic pleocytosis with the presence of malignant lymphoid cells, confirming CNS relapse with optic nerve infiltration.

The patient was restarted on CNS-directed chemotherapy including cytarabine, cyclophosphamide, and methotrexate. On follow-up, mild improvement in visual acuity was observed. He continues to remain under close multi-disciplinary surveillance.

DIFFERENTIAL DIAGNOSIS

The imaging differential diagnosis for optic nerve thickening and enhancement includes optic neuritis (demyelinating or autoimmune), infectious optic perineuritis, inflammatory disorders affecting the optic nerve, infiltrative neoplasms such as lymphoma or metastasis, and papilledema secondary to raised intracranial pressure. In this case, the presence of malignant lymphoid cells in cerebrospinal fluid and characteristic imaging findings strongly supported leukemic optic nerve infiltration.

DISCUSSION

Optic nerve infiltration is a rare yet vision-threatening manifestation of CNS relapse in ALL and has been documented in both pediatric and adult populations.^[4-7] In some patients, ocular involvement may precede systemic or other neurological manifestations, making early recognition critical.^[5,6]

The optic nerve functions as a pharmacologic sanctuary site because of the blood–brain and blood–nerve barriers, which restrict penetration of systemic chemotherapeutic agents and allow leukemic cells to persist despite apparent systemic remission.^[4,8] This explains isolated optic nerve relapse in patients otherwise believed to be in disease control.

Visual symptoms such as progressive visual loss, eye pain, or optic disc edema may represent the earliest clinical indicators of CNS leukemia. Although cerebrospinal fluid cytology is confirmatory, it may be falsely negative in early disease because of low tumor burden or intermittent shedding of malignant cells.^[9] In such scenarios, contrast-enhanced magnetic resonance imaging (MRI) plays a pivotal complementary role.^[2,10]

Neuroimaging protocol considerations: In patients with known or suspected CNS leukemia presenting with visual symptoms, MRI protocols should routinely include dedicated orbital imaging. Post-contrast T1-weighted fat-suppressed axial and coronal images of the orbits are essential for detecting optic nerve and sheath infiltration and for differentiating leukemic infiltration from inflammatory optic neuritis.^[10] In addition, post-contrast fluid attenuation and inversion recovery (FLAIR) imaging of the brain improves sensitivity for leptomeningeal disease, which may be inconspicuous on conventional post-contrast T1-weighted sequences alone.^[2]

Early identification of optic nerve infiltration allows timely initiation of CNS-directed therapy, which may preserve vision and improve neurological outcomes. Studies have demonstrated that prompt CNS-directed chemotherapy, with or without radiotherapy in selected cases, improves visual and survival outcomes in CNS relapse of ALL.^[3,6,7] Radiologists therefore play a crucial role in early detection and communication of relapse suspicion to the treating team.

CONCLUSION

Optic nerve infiltration, although rare, may be the first or only manifestation of CNS relapse in ALL. Any patient with leukemia presenting with new-onset visual symptoms warrants urgent MRI evaluation with dedicated orbital and post-contrast brain imaging, in conjunction with cerebrospinal fluid analysis. Strict adherence to therapy and long-term surveillance are essential to prevent relapse and irreversible neurological morbidity.

TEACHING POINTS

1. Optic nerve infiltration is a rare but vision-threatening manifestation of CNS relapse in ALL and may be the initial presenting feature, even in the absence of overt systemic disease.

2. Dedicated orbital MRI, including post-contrast fat-suppressed T1-weighted sequences and post-contrast FLAIR imaging of the brain, is essential for detecting optic nerve and leptomeningeal involvement in patients with suspected CNS leukemia.

MCQs

1. Which of the following MRI findings is most suggestive of leukemic optic nerve infiltration?

   1. T2 hyperintensity of the optic nerve without enhancement

   2. Restricted diffusion confined to the optic chiasm

   3. Post-contrast enlargement and enhancement of the optic nerve and sheath

   4. Isolated optic disc protrusion without optic nerve abnormality Correct

   Answer Key: c

2. Why is the optic nerve considered a pharmacologic sanctuary site in leukemia?

   1. High metabolic activity of optic nerve axons

   2. Limited penetration of systemic chemotherapy due to blood–brain and blood–nerve barriers

   3. Increased vascular permeability of the optic nerve

   4. Absence of lymphatic drainage from the orbit Correct

   Answer Key: b

3. Which MRI sequence improves the detection of subtle leptomeningeal involvement in CNS leukemia?

   1. Non-contrast T1-weighted imaging

   2. Diffusion-weighted imaging

   3. Susceptibility-weighted imaging

   4. Post-contrast FLAIR imaging Correct

   Answer Key: d