Breast cancer-associated paraneoplastic neuromyelitis optica with cervical cord compression and spondylosis requiring laminectomy: A case report

Introduction

Neuromyelitis optica (NMO) spectrum disorder (NMOSD), characterized by inflammatory lesions of the optic nerves and spinal cord, can present with a wide range of clinical manifestations and disease course, often leading to significant disability. Recent advances in immunology have led to the identification of a specific antibody, anti-aquaporin-4 immunoglobulin G (AQP4-IgG), confirming the diagnosis and differentiating NMO from NMOSD. The pathophysiology of the disease involves the binding of AQP4-IgG to AQP4 water channels, expressed primarily in astrocytes in the central nervous system, leading to a cascade of events culminating in neuroinflammation and neuronal damage. ¹

Paraneoplastic syndromes represent another complex facet of neuroimmunology. They are rare disorders triggered by an altered immune system response to a neoplastic process. These syndromes can affect various organ systems and are independent of tumor size or extent of the tumor. ² Paraneoplastic NMO, although rarely reported, has been associated with various malignancies. ³ Herein, we present a rare case of possible paraneoplastic NMO with respiratory failure in a patient with a history of triple-negative infiltrating ductal carcinoma. The intricacies of this case underscore the complexities of the diagnostic process and the nuances of NMO.

Case presentation

A 71-year-old woman, previously treated for triple-negative infiltrating ductal carcinoma with lumpectomy, chemotherapy, and radiation therapy, along with a history of type 2 diabetes mellitus, obesity (body mass index > 30 kg/m²), and hypertension, presented with a 10-day history of left breast pain, weakness of bilateral lower extremities, and neck pain. The patient was initially diagnosed with breast cancer 1 year before her current presentation based on positron emission tomography-computered tomography (PET/CT) imaging and histopathology (Figure 1). During the recent admission, the physical examination revealed a thickening of the skin in the upper outer left breast, and ultrasound suggested a seroma. Computerized tomography scan of the chest identified an intermediate rim-enhancing collection (2.6 × 4.5 × 2.8 cm) in the deep left breast tissue. Subsequently, her condition worsened with progressive shortness of breath and increased weakness, necessitating emergent intubation and admission to the intensive care unit (ICU). Neurological examination demonstrated significant weakness (2/5 muscle strength) in all four extremities, diffuse hyperreflexia, and loss of multimodal sensation below the shoulders.

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Figure 1.

(a) Anterior, (b) lateral, and (c) cross-sectional view of FDG-PET/CT showing FDG-avid left breast mass and axillary lymphadenopathy.

Magnetic resonance imaging (MRI) of the cervical and thoracic spine revealed an abnormal diffuse increase in T2 signal intensity extending from C1 to T7 consistent with longitudinally extended transverse myelitis (LETM), with multi-degenerative changes and moderate spinal canal stenosis at C3–C4 and C4–C5, causing cord compression. The brain MRI showed non-enhancing T2/FLAIR hyperintensities in the cerebral and cerebellar white matter and middle cerebellar peduncles (Figure 2). Serum studies produced a high AQP4-IgG cell-based assay (CBA) titer of >1:160 and AQP4 IgG fluorescence-activated cell sorting titer of >1:10000. Based on clinical, laboratory, and radiographic findings, the diagnosis of NMO was made. Cerebrospinal fluid (CSF) analysis was not completed due to body habitus and acuity. In addition, an abdominal and pelvic CT scan and an ovarian ultrasound were performed to rule out other malignancies or metastatic diseases.

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Figure 2.

(a) T2/FLAIR sagittal sequence of the cervical spinal cord, (b) T1 sagittal sequence, and (c) T2 sagittal sequence of the thoracic spinal cord with non-enhancing hyperintense lesion extending from C1 to T6. (e) T2/FLAIR axial view at C1 and (f) T6 depicting a predominantly hyperintense lesion within the central cord. (d) T2/FLAIR sagittal sequence of the brain and (g) axial view showing non-enhancing hyperintensities involving the cerebrum, cerebellum, and cerebellar peduncles.

Due to acute respiratory failure secondary to cervical cord compression and myelopathy, a C3–C6 bilateral laminectomy was performed. The family rejected a breast biopsy to assess for AQP4 antibodies. The patient’s ICU course was complicated by an acute kidney injury. Therefore intravenous immunoglobulin (IVIG) was not considered a suitable option due to worsening renal function. The patient received a 5-day course of intravenous methylprednisolone 1000 mg followed by a 5-day plasmapheresis course due to failure of ventilation weaning. Due to non-improvement, a tracheostomy and percutaneous endoscopic gastrostomy procedures were performed on the 20th day of hospitalization. A decision was made to start rituximab, and she received two infusions 2 weeks apart. Cytokine and antibody levels included CD 19 and CD 20 <1%, IgG 787 mg/dL (600–1540), IgA 60 mg/dL (82–453), and IgM 22 mg/dL (50–300).

During treatment, she was weaned off mechanical ventilation with a slight improvement in weakness and discharged to a rehabilitation facility. Repeat MRI did not show new lesions and stability of previously defined lesions. However, at 3 months of follow-up, the patient showed only minimal improvement in weakness and still experienced significant sensory difficulties with a modified Rankin score of 3. ⁴

Discussion

NMO is an inflammatory demyelinating disease that predominantly affects the optic nerves, brainstem, and spinal cord leading to optic neuritis and inflammatory myelopathy. The International Panel for NMO Diagnosis (IPND) has provided revised NMOSD diagnostic criteria. ⁵ They require the presence of at least one core clinical characteristic (optic neuritis, acute myelitis, area postrema syndrome, acute brainstem syndrome, symptomatic narcolepsy or acute diencephalic clinical syndrome with NMOSD-typical diencephalic MRI lesions, symptomatic cerebral syndrome with NMOSD-typical brain lesions), along with positive AQP4-IgG, and exclusion of alternative diagnoses. ⁵ Our patient presented with the clinical and imaging findings of LETM involving the cervical and thoracic spinal cord (C1–T6). Moreover, the patient demonstrated positive AQP4-IgG serology using the gold standard CBA, thus fulfilling the IPND criteria for NMOSD diagnosis. ⁵

Acute respiratory failure was likely due to superimposed cervical cord inflammation and edema on prior degenerative disk disease and spondylosis. Paraneoplastic NMOSD is exceptionally rare and only a handful of cases have been reported. ⁶ Carrillo et al. recently reported the case of a 32-year-old woman with triple-negative breast cancer diagnosed with NMOSD. ⁷ The patient was adequately treated with good effect with corticosteroids, plasma exchange, and rituximab. As in our patient, several malignancies, including breast cancer, have been associated with paraneoplastic NMOSD. ⁸ Although not universally accepted, the proposed mechanism suggests molecular mimicry or ectopic expression of neuronal antigens leading to the production of cross-reacting antibodies, leading to autoimmunity. ⁹ The temporal relationship between cancer treatment and the onset of myelopathy and AQP4 antibodies in serum suggests a possible paraneoplastic origin. NMOSD is typically present in adults in their late thirties to early sixties. However, in cases of paraneoplastic NMOSD, as demonstrated in our patient, the age at diagnosis is typically high, underscoring the possible role of malignancies in triggering this rare condition in older populations. ¹⁰

Management of NMOSD is with acute and preventive treatment strategies. Acute treatments aim to stop the ongoing attack and typically accelerate recovery, often achieved with high doses of intravenous steroids, plasma exchange, or IVIGs. ¹¹ Newer biologic therapies aim to prevent further attacks, as seen in our patient who received rituximab. Given the rarity and complexity of paraneoplastic NMOSD, future research must focus on the evaluation of targeted treatment strategies for this distinct subset of patients. ¹² Understanding the unique pathophysiological mechanisms and therapeutic responses in paraneoplastic NMOSD will enable clinicians to provide more effective personalized care.

Our case presents several limitations. A definitive link between NMO and malignancy in our patient is complex due to the lack of CSF studies, which makes it difficult to rule out other neuroimmunological processes that could mimic NMO. It is to be noted that serum testing for AQP4 antibodies has a greater sensitivity than CSF. ¹³ Therefore, the lack of CSF examination does not limit or hinder the diagnosis of NMO. The patient’s moderate response to rituximab treatment may be due to the advanced stage of the disease at the time of initiation. However, more recent therapeutic interventions with different targets as complements were not tested. The lack of direct tissue biopsy and staining to assess for AQP4 is also a limitation. Despite these limitations, this case highlights the importance of considering a paraneoplastic origin in patients with NMOSD and malignancy. Future research should focus on establishing diagnostic criteria for paraneoplastic NMOSD, screening protocols, and evaluating the optimal treatment approach. Longitudinal studies could provide valuable information on disease progression and the impact of early intervention on patient outcomes.

Conclusions

This case of a possible paraneoplastic NMOSD associated with infiltrating ductal carcinoma complicated by acute respiratory failure underlines the clinical complexities and management challenges in such rare presentations. The atypical onset of NMO symptoms correlating with the patient’s cancer journey suggests a possible paraneoplastic etiology. Furthermore, the moderate response to rituximab highlights the necessity of early recognition and intervention in paraneoplastic NMOSD cases. This case emphasizes the importance of heightened clinical vigilance for NMOSD symptoms in patients with malignancies and reinforces the need for future research to enhance our understanding of disease mechanisms, diagnostic criteria, and optimal treatment strategies for paraneoplastic NMOSD.