Optic neuropathy as the first sign of central nervous system relapse in acute myeloid leukaemia: MRI findings and its diagnostic challenge

Abstract

We describe the case of a 22-year-old man who presented with right eye visual impairment and oral mucositis. MRI revealed findings compatible with right optic neuritis. Herpes simplex virus 1 was detected in oral swab. He has a previous history of acute myeloid leukaemia (AML) and was in clinical remission. Initial investigations for possible relapse of AML with central nervous system (CNS) involvement were negative. Treatment for HSV-related optic neuritis was initiated but the patient’s vision deteriorated. Repeat MRI revealed right optic nerve infarct, new left optic nerve abnormality and new leptomeningeal enhancement in the brain. Repeated cerebrospinal fluid analysis confirmed CNS relapse of AML. Despite prompt initiation of pulse steroid and high dose intrathecal cytarabine followed by cranial irradiation, the patient never regained his vision. We present a case of unexpected optic neuropathy as first and sole presentation of CNS relapse of AML.

Background

Acute myeloid leukaemia (AML) is cancer of the myeloid lineage of the blood cells where there is over production of abnormal myeloblasts.¹

Extramedullary involvement is rare, with skin, leptomeningeal, testicular and ocular involvement reported previously.^{2 3} Extramedullary involvement is associated with decreased rate of complete response, disease-free survival and overall survival.¹ Early recognition of central nervous system (CNS) involvement of AML is important.

There is a long list of differentials when we encounter optic neuropathy. This includes infiltration, infection, inflammation, compression and medication effects. Differentials are listed in the order that is considered most likely according to the clinical parameters with which our patients present. As different aetiology carries different prognostic implications necessitating different treatment modalities, confirming the underlying aetiology in a timely manner is crucial.⁴ Optic nerve infiltration as the sole presentation of AML relapse is extremely rare, and a high index of suspicion is required.¹

MRI is the imaging modality of choice for evaluation of optic neuropathy.⁵ When the optic nerve is involved by tumour infiltration, there are often associations with involvement in other sites of the CNS (eg, leptomeninges). It is rare to have infiltration of optic nerve without other parts of the CNS being involved. The isolated findings of T2-weighted hyperintensity, thickening and enhancement of the optic nerve on MRI cannot differentiate infiltration from optic neuritis.⁶

We present a case of clinical and radiological involvement of the optic nerve as the first and isolated sign of CNS infiltration in a patient who was considered in clinical remission of AML. This is a neuro-oncological emergency where prompt recognition and management are crucial in order to reduce the risk of acute ischaemic optic neuropathy and ultimate irreversible visual loss.

Case presentation

A 22-year-old-man of Chinese ethnicity, who was considered in his fourth year of clinical remission of AML presented with acute onset of right eye pain with visual blurring and mild oral mucositis. At the time of presentation, clinical examination found neither diplopia nor ophthalmoplegia. There was scotoma over the right eye in the superior field. There was also a reduction in visual acuity (20/40) and colour vision (red desaturation ~90%). On fundoscopy, the right eye disc was pink with cup disc ratio 0.3. The disc edges were mildly blurred and there was small amount of peripapillary haemorrhage. The left eye disc was pink with similar cup disc ratio 0.3 but edges were not blurred. No haemorrhage was seen in left eye.

Initial CT brain demonstrated no abnormality. MRI of the brain and orbits were obtained and demonstrated diffuse enhancement and swelling of the right optic nerve with no significant intracerebral abnormality (figure 1).

Figure 1.

MRI brain+orbits showing thickening of the right optic nerve with increased T2-Weighted signals, intraconal perineural fat strandings, and enhancement. (A) Axial T2-Weighted; (B) coronal T2-Weighted; (C) Axial T1-Weighted post-Gadolinium.

Initial laboratory investigations including complete blood count, liver and renal function tests and lactate dehydrogenase (LDH) were normal. Microbiological blood tests including aerobic, anaerobic and acid-fast bacilli culture, toxoplasmosis, cryptococcal antigen and venereal disease research laboratory were negative. Bartonella, Brucella and Lyme’s serology were negative. Blood test for antiaquaporin 4 was also negative. Lumbar puncture cell counts were unremarkable. Oral swabs taken were positive for herpes simplex virus 1 (HSV1).

Given the clinical signs and symptoms of optic neuropathy with supportive radiological findings of optic neuritis and positive oral swabs for HSV, intravenous foscarnet was promptly commenced as treatment for HSV-related optic neuritis.

Despite antiviral treatment, the patient’s vision continued to deteriorate and he developed new onset left eye discomfort and visual impairment. Visual acuity for both eyes dropped to 20/100. Examination revealed bilateral optic disc swelling, peripapillary haemorrhage as well as tortuous and congested retinal veins. Roth’s spots were found in the right eye (figure 2). There was no evidence of vasculitis, retinitis or vitritis. The macula was normal and there was no retinal break. Visual field by confrontation showed enlarged blind spot in both eyes and temporal visual field loss in left eye.

Figure 2.

Fundoscopy of both eyes showing bilateral optic discs swelling and bilateral discs haemorrhage, as well as tortuous and congested retinal veins (A) left, (B) right.

In view of symptom progression despite antiviral treatment, AML recurrence was reconsidered. Peripheral blood again showed no evidence supporting AML recurrence. A whole-body positron emission tomography-computed tomography (PET-CT) scan was obtained to detect the presence of any extramedullary disease. No hypermetabolic disease was identified and the activity in brain and orbits were within physiological limits (figure 3).

Figure 3.

PET-CT showing no hypermetabolic disease identified.

Patient developed bilateral total visual loss with acute loss of light perception suddenly on day 14 of presentation. A second MRI of the brain and orbits was obtained (figure 4), which showed non-enhancement and restricted diffusion of the right optic nerve, suggestive of probable infarct. The left optic nerve showed similar features with increased enhancement and swelling. In addition, there was also new leptomeningeal enhancement in the cerebellum which concomitantly supports a diagnosis of CNS infiltration and AML relapse.

Figure 4.

MRI Brain +orbits showing thickening of bilateral optic nerves (right >left) with non enhancement of the entire right optic nerve which is associated with restricted diffusion signals. Enhancement of left optic nerve is preserved. (A) Axial T2-Weighted; (B) coronal T2-Weighted; (C) Axial T1-Weighted post-Gadolinium; (D) Diffusion Weighted Imaging (B-value 1000 s/mm²); (E) Apparent diffusion coefficient; (F) Axial T1-Weighted post-Gadolinium enhancement of cerebellum (arrow).

A repeat CSF analysis revealed total cell count 148 x 10⁶/L with 97% blast cells, diagnostic for AML relapse.

Despite prompt treatment with pulse steroid therapy and intrathecal cytarabine and subsequent cranial irradiation, the patient’s vision did not recover.

Investigations

• Complete blood count, liver and renal function tests.

• LDH.

• CSF cytology.

• CT brain.

• MRI brain and orbits.

• PET-CT.

Differential diagnosis

Spectrum of aetiologies of optic neuropathy

• Compression.

• Infiltration.

• Paraneoplastic.

• Drugs/medication/toxic.

• Inflammation.

• Infection.

• Autoimmune.

• Vascular.

Treatment

The patient was initially given intravenous foscarnet as antiviral therapy for suspected HSV optic neuritis.

After the second MRI findings and repeat lumbar puncture with CSF analysis revealing 97% blast cells, patient was immediately started on pulse steroid therapy and subsequently intrathecal cytarabine treatment. Cranial irradiation was also given.

Outcome and follow-up

There was no improvement of patient’s vision on follow-up at 6 weeks since the commencement of therapy.

Discussion

Relapse of AML occurs in about 50% of patients who previously achieve clinical remission. Majority of relapses are found within the first 2–3 years after the initial treatment. CNS involvement in adult AML relapse is rare and may be as low as <1%–4% with current therapies.^7–9 Alakel et al found 0.6% of patients had CNS involvement at initial presentation of AML and 2.9% at relapse.⁹ It is associated with a lower rate of complete response as well as a poorer prognosis compared with acute lymphoblastic leukaemia (ALL). Reported risk factors for CNS disease in AML include high LDH, African-American ethnicity and young age. Young age was the only risk factor in our case.

Standard practice to diagnose CNS leukaemia is by CSF cytology. However, as adult AML is thought to be less common than adult ALL, lumbar puncture is not routinely performed unless there is clinical suspicion. It has limited sensitivity (50%–60%), but excellent specificity (>95%).¹⁰ Sensitivity and specificity can be improved by the additional use of CSF flow cytometry and PCR methods.⁷

Imaging plays an important role in the detection of CNS involvement, particularly when CSF cytology is negative. Our case illustrated how radiological findings had preceded cytological positivity.

Unlike childhood leukaemia, there is currently no consensus on the role of MRI in the evaluation of CNS involvement in adult leukaemia.⁷ Literature regarding the spectrum of imaging findings in adults is scarce.

Guenette et al described four types of positive findings on contrast-enhanced MRI (pachymeningeal enhancement, leptomeningeal enhancement, cranial nerve enhancement and mass-like enhancement) in adult patients with positive CSF cytology for leukaemia and new neurological symptoms.⁷ However each of these findings is relatively non-specific on its own and could be due to a long list of aetiologies. Other investigations should be sought to exclude other differential diagnoses (eg, infection, inflammation, medication, radiation, trauma) before drawing a conclusion. Patel reported a patient with AML relapse who similarly presented with visual loss. MRI of the brain and orbits showed enhancement in the optic nerve, trigeminal nerve and cerebellum.¹

Isolated involvement of the cranial nerves in the absence of other supportive radiological or cytological findings is extremely rare. There are limited reports available of such in the literature. An extensive literature review conducted by Myers et al on cases of isolated optic neuropathy in the context of haematological malignancy found 66 cases between 1966 and 2015, of which 36 were attributed to leukaemic infiltration.⁴ More than half of the cases were secondary to ALL while only five cases were associated with AML, in which none had optic neuropathy as the sole and initial presentation.

The presence of thickening and enhancement of the optic nerve in leukaemia patients should raise concern for leukaemic infiltration and necessitates a differentiation from optic neuritis.⁶ Leukaemic optic nerve involvement is a neuro-oncological emergency; delayed recognition can lead to irreversible visual loss. We postulate the progression into ischaemic optic neuropathy in our patient could be a result of hypercellularity. Emergent radiation and intrathecal chemotherapy have been shown to improve visual recovery and prolong survival.^{11 12}

Both leukaemic infiltration and inflammation of the optic nerve have comparable signs and symptoms that are highlighted in our case. Presence of other associating imaging findings of CNS involvement on MRI is helpful in distinguishing between the two. These include presence of leptomeningeal and pachymeningeal enhancement, or enhancement of other cranial nerves.⁶ In the event of severe visual loss or cases with equivocal diagnosis after preliminary investigations, optic nerve biopsy should be considered as soon as possible as the consequences of a missed or delayed diagnosis outweigh procedural risks.^{4 13}

A high index of suspicion is required to diagnose the condition. This alerts the clinician to intervene in a timely fashion to prevent irreversible neurological damage and visual loss. Optic nerve leukaemic infiltration should be placed higher on our list of differentials when we encounter an isolated finding of a thickened contrast-enhanced optic nerve. This rule should be applied even when clinical findings and initial investigations are not suspicious for CNS disease. In questionable situations, nerve biopsy may be the diagnostic test of choice.

Our case demonstrates the diagnostic challenges of AML relapse in patients with optic neuropathy and highlights the importance of obtaining a definitive diagnosis, as well as the devastating consequences of a delayed diagnosis.

Learning points.

• MRI plays an important role in the detection of central nervous system (CNS) involvement in acute myeloid leukaemia (AML).

• Isolated findings of optic nerve thickening and enhancement have a wide range of differentials.

• T2W hyperintensity, thickening and enhancement of the optic nerves are MRI features of optic nerve infiltration. This may progress to optic nerve infarction if left untreated.

• It is important to consider leukaemic infiltration of the optic nerves with CNS relapse in patients with a history of AML, even if initial investigation for relapse is negative.

• Optic nerve biopsy may be the diagnostic test of choice.

• Leukaemic optic nerve involvement is a neuro-oncological emergency. Early intervention may prevent irreversible visual loss.