Clinical Reasoning: A 50-year-old woman with SLE and a tumefactive lesion

SECTION 1

A 50-year-old woman with a history of systemic lupus erythematosus (SLE) treated with methotrexate and hydroxychloroquine presented to the emergency department for evaluation of numbness and weakness of the left hand that began 12 hours earlier.

Twenty years ago, the patient had been diagnosed with SLE when she presented with Jaccoud arthropathy, nephritis, and bullous eruptions on the face, scalp, and trunk. Laboratory analysis at the time showed a positive antinuclear antibody with a speckled pattern and positive anti-dsDNA antibodies. Since her diagnosis of SLE, the patient had been hospitalized twice for suspected immune-mediated complications of the CNS.

On admission, the patient's initial examination revealed a left facial droop, left pronator drift, and decreased sensation to light touch in the distal left upper extremity. No lower extremity weakness or numbness was noted. Laboratory evaluation was remarkable for elevated erythrocyte sedimentation rate (40 mm/h), but normal levels of anti-dsDNA antibodies, C3, and C4. The brain MRI showed a new area of T2/fluid-attenuated inversion recovery (FLAIR) hyperintensity within the subcortical white matter of the right posterior central gyrus and associated heterogeneous faint enhancement (figure 1, A–C). The spine MRI was normal. CSF analyses were performed, demonstrating glucose 51 mg/dL, protein 21 mg/dL, erythrocytes 0/mm³, leukocytes 0/mm³, and immunoglobulin G (IgG) index 2110, and negative oligoclonal bands, Gram stain, culture, venereal disease research laboratory, herpes simplex virus, Borrelia burgdorferi, and JC virus.

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Figure 1 Neuromyelitis optica brain MRI

(A–C) Brain MRI on presentation including fluid-attenuated inversion recovery (FLAIR), T1 precontrast, and T1 postcontrast. (A) Axial FLAIR shows a large right hemispheric lesion in the precentral gyrus, with a smaller more anterior cortical hyperintensity. (B) Lesion appears heterogeneously hypointense on T1, with (C) faint contrast enhancement. (D–F) Repeat brain MRI acquired 3 days later. (D) Axial FLAIR, (E) T1 precontrast, and (F) postcontrast demonstrate progression of the same lesion 3 days later. (G–I) Brain MRI from patient's first presentation (5 years prior) of left hemiparesis and dysarthria, including FLAIR, diffusion-weighted imaging (DWI), and apparent diffusion coefficient (ADC), demonstrates (J) FLAIR-hyperintense R posterior internal capsule and thalamus, with (K) DWI restriction and (L) faint dropout on ADC. (J–L) Brain MRI from patient's second presentation (4 years prior) including FLAIR, DWI, and ADC are consistent with area postrema syndrome: (J) FLAIR hyperintense lesion adjacent to the 4th ventricle, with (K) DWI restriction without (L) ADC dropout.

Over the course of the following 4 days, the patient's condition rapidly deteriorated. She developed worsening left-sided weakness, now including the left lower extremity, a left homonymous hemianopia, and dysarthria. Multiple brain MRIs over this time course showed markedly worsening signal abnormality throughout the right cerebral hemisphere involving multiple lobes (figure 1, D–F).

SECTION 2

Tumefactive demyelinating lesions (TDL) are defined as demyelinating lesions greater than 2 centimeters. They often appear on MRI as large T2-hyperintense brain lesions with contrast enhancement and varying degrees of mass effect.¹ TDLs are most commonly seen as a rare manifestation of multiple sclerosis (MS) but may also result from other primary demyelinating diseases (other MS variants such as Schilder disease, Marburg variant, and Balo concentric sclerosis, acute disseminated encephalomyelitis, and neuromyelitis optica spectrum disorder [NMOSD]), which may coexist with SLE,^2,3 infection (particularly progressive multifocal leukoencephalopathy [PML]), genetic diseases¹ (leukodystrophies), and drug-induced conditions (methotrexate-induced leukoencephalopathy²). Other diagnoses that may radiologically mimic TDLs include nondemyelinating autoimmune diseases (IgG4-related disease⁴), malignancy (lymphoma, high-grade glioma, metastasis), and infarction.

Radiographically, tumefactive MS and tumefactive NMOSD look similar, and may have an incomplete ring of enhancement with the open side facing the cortex (which this case did not demonstrate) and involvement of the subcortical U fibers. PML also has a propensity for the subcortical U fibers, presenting as multifocal hyperintense FLAIR lesions, typically without significant mass effect or contrast enhancement, but there can be diffusion restriction. The imaging characteristics of methotrexate toxicity mirror that of PML. While lymphoma can heterogeneously enhance in immunocompromised patients, it more typically presents with a homogenously enhancing mass or masses and is more typically located in the basal ganglia or periventricular white matter.

SECTION 3

After the initial MRI evaluation, the lesion was thought to be neoplasm or severe demyelination such as MS, NMOSD, or PML. Methotrexate-induced leukoencephalopathy was considered less likely since the patient only received low oral doses and the complication is more common in patients who receive methotrexate for a cancer indication. Given the increased risk of PML in patients with SLE compared to the general population, potentially due to immunosuppressive therapy or other disease factors,⁵ methotrexate was temporarily held. However, as subsequent imaging studies over the course of days revealed rapid progression of the disease, PML and neoplasm were considered less likely diagnoses.

Extensive bloodwork was performed. Anti-dsDNA was negative, anti-SS-A and anti-SS-B titers were elevated but at the patient's baseline, and the C3 and C4 levels remained roughly within normal ranges. The antiphospholipid panel and anti-rib-P antibodies were also within normal ranges. HIV test was negative. Although other tests, including brain biopsy, were pending at this point, given that the patient's condition was rapidly deteriorating and infectious etiologies were determined to be less likely, the patient was treated with the following immunomodulatory therapies: high-dose IV methylprednisolone, IV immunoglobulin (IVIg), and 1 dose of cyclophosphamide.

The initial brain biopsy report demonstrated inflammation with prominent neutrophils and no evidence of malignancy or viral infection, but was inconclusive for any specific diagnosis. Several weeks later, the serum IgG neuromyelitis optica antibodies (anti-aquaporin-4) returned positive.

SECTION 4

With positive AQP4-Ab and symptomatic cerebral syndrome with a typical brain lesion, and exclusion of competing diagnoses, the patient was diagnosed with NMOSD.

The patient's biopsy sample was sent to Mayo Clinic for more specific analysis, which revealed AQP4 loss colocalized to regions with myelin-laden macrophages, pronounced glial fibrillary acid protein loss despite a fair amount of myelin preservation on proteolipid protein, scattered granulocytes (eosinophils and neutrophils) in non-necrotic regions, no evidence of Creutzfeldt cells, and vacuolated myelin consistent with myelin edema (figure 2). These pathologic findings are consistent with the pathologic diagnosis of NMOSD.⁶

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Figure 2 Pathologic evaluation of the right frontoparietal lesion

(A) Hematoxylin & eosin stain shows a perivascular eosinophil (indicated with arrowhead and enlarged view in the framed panel) and numerous foamy macrophages (arrows) in the white matter. (B) Glial fibrillary acid protein highlights the astrocyte loss with a few preserved reactive astrocytes (arrows). (C) Aquaporin-4 (AQP4) immunohistochemistry indicates extensive loss of AQP4 immunoreactivity. Scale bar in A = 20 μm. Scale bar in B = 50 μm. Scale bar in C = 100 μm.

The patient was treated acutely with 2 doses of rituximab, followed by maintenance dosing. Several weeks after receiving rituximab and weeks of inpatient rehabilitation, the patient regained strength but did not return to her baseline. At discharge, she had left inattention without neglect and residual left hemiplegia (persistent left facial droop, antigravity or better in all extremities).