Detection of Anti-Aquaporin-4 Antibodies in a Patient With Glioma: A Case Report

Introduction

Aquaporin-4 (AQP4) is a water channel expressed on the end-foot of astrocytes in the central nervous system (CNS). Autoantibodies against AQP4 (AQP4-Ab) are known to cause neuromyelitis optica spectrum disorder (NMOSD). ¹ Cell-based assays (CBA) for AQP4-Ab are now considered to have the highest sensitivity and specificity among assay techniques. ¹ In the serostatus of AQP4-Ab measured using CBA during routine clinical care among patients with various neurological disorders, the specificity for the diagnosis of NMOSD was 100%. ² However, it is not clear whether patients with malignant tumors, such as gliomas, were included in this study. The frequency of AQP4-Ab positivity in patients with non-inflammatory diseases, including malignant tumors, remains unknown. In this report, we present a patient with a high-grade glioma who presented with spinal cord and brain lesions suggestive of NMOSD, including an area-postrema lesion, and a ring-enhancing cervical spinal cord lesion on magnetic resonance imaging (MRI) with positive AQP4-Ab in serum measured using CBA.

Case Presentation

A 54-year-old man developed progressive weakness and dysesthesia of the right upper limb over 2 months. His initial cervical MRI revealed diffuse swelling of the cervical spinal cord with T2 hyperintense signal in the area postrema, and at the C7 and Th1 levels of the spinal cord (Figure 1A). The spinal lesions showed ring enhancement after gadolinium dimeglumine was administered (Figure 1B). There was no abnormal signal in the cerebrum or the optic nerves. Blood tests were positive for AQP4-Ab, as measured by CBA. Cerebrospinal fluid tests revealed 113 cells/μL (88% polymorphonuclear cells) and a normal protein level (38.2 mg/dL). The cytological examination did not reveal any malignant cells (Class I). The patient was diagnosed with NMOSD, and four cycles of intravenous methylprednisolone (1000 mg/day for 3 days each), one course of plasmapheresis, and 5 days of intravenous immunoglobulin (0.4 g/kg/day) were administered. However, his weakness gradually progressed, extending to both upper limbs and the right lower limb, and intractable neck pain and bladder and bowel disturbance developed. A cervical spine MRI performed 4 months after the initial MRI demonstrated more diffuse enlargement of the cervical spinal cord, longitudinal extension of the T2 hyperintense lesion, and an increased number of ring-enhancing lesions (Figure 1C and D).OPEN IN VIEWER

Given the atypical clinical course of the presumed diagnosis of NMOSD, a spinal cord biopsy was performed. Hematoxylin and eosin staining revealed tumor cells with microvascular proliferation (Figure 1E). Immunohistochemistry staining was positive for glial fibrillary acidic protein (GFAP) and H3K27 M (Figure 1F and G), and negative for isocitrate dehydrogenase 1 (IDH1) and H3K27me3 loss (Figure 1H), consistent with high-grade glioma with H3K27 M mutation. Interestingly, staining against AQP4 was positive on the tumor cells (Figure 1I). The patient received radiation treatment and chemotherapy with bevacizumab and temozolomide against high-grade glioma. Subsequently, an MRI revealed improvement in the spinal cord swelling and diminished lesion enhancement. Serum AQP4-Ab levels measured using CBA turned negative.

Discussion

Herein, we present a case of high-grade glioma initially diagnosed as NMOSD based on AQP4-Ab positivity. To the best of our knowledge, there have been two previous reports of cases with positive AQP4-Ab measured using CBA, in which the patients were initially misdiagnosed with NMOSD (Table 1).^3,4 Notably, all cases, including ours, were finally diagnosed as glioma. Although all patients received immunotherapy, the treatment was either ineffective or less effective. Compared with previous cases, our case shares several imaging abnormalities which are considered characteristic of NMOSD, such as lesions in the area postrema and ring-enhancing spinal cord lesions (Table 1). Lesions in the area postrema are considered the hallmark of NMOSD imaging. ¹ Additionally, ring enhancement is reportedly found in 32% of myelitis episodes in NMOSD, ⁵ although contrast enhancement of glioma with H3K27 M mutation was a ringlike pattern in 8 of 9 cases. ⁶ In contrast to previous cases of glioma with positive AQP4-Ab, which involved either the spinal cord or brain alone, our case showed lesions in both the spinal cord and the area postrema. This distribution more closely parallels the typical lesion pattern seen in NMOSD. Our case emphasizes that NMOSD should not be diagnosed solely based on antibody positivity and imaging findings, but also on the clinical course.

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Table 1.

Clinical Features of Cases With Non-Demyelinating Disorders, Presenting Positive Anti-Aquaporin-4 Antibodies Measured Using CBA

Reference		(3)	(4)	Our case
Age/Sex		Young/Female	56/Female	54/Male
Symptom		Progressive spastic paraparesis for 2 months	Transient loss of consciousness	Upper limb weakness, dysesthesia and neck pain for 1 month
Lesion distribution	Cerebrum	−	+	−
	Optic nerve	N. D.	−	−
	Brainstem	−	−	Area postrema +
	Spinal cord	+	−	+
Ring-enhancement		−	−	+
Anti-AQP4 antibodies	Sample	Serum	Cerebrospinal fluid	Serum
	Assay	CBA	CBA	CBA
	Targeting isoform	M23 isoform	N. D.	M23 isoform
	Positivity	+	+	+
Pathology		High-grade glioma	Anaplastic astrocytoma	High-grade glioma
Response to immunotherapies		No	Yes, only initially	No

In the pathogenesis of glioma, AQP4 is reportedly overexpressed in the tumor cells, contributing to tumor cell invasion and cerebral edema. ⁷ This overexpression could potentially promote the production of AQP4-Ab. We hypothesize that the disruption of the blood-brain barrier, indicated by microvascular proliferation in tumor tissue, ⁸ might expose AQP4 to the peripheral blood, contributing to the production of AQP4-Ab. Further studies are needed to investigate the frequency of AQP4-Ab positivity and the mechanisms of autoantibody production in patients with glioma.

Of note, although immunohistochemistry was positive for H3K27 M in our case, H3K27me3 expression was retained. Therefore, the diagnosis did not strictly fulfill the criteria for diffuse midline glioma, H3K27-altered, defined in the 2021 WHO classification. ⁹ One possible explanation is that the expression level of mutant H3K27 M protein may have been insufficient to fully inhibit the Polycomb Repressive Complex 2 (PRC2), resulting in preserved H3K27me3.

In conclusion, we present a case of spinal cord glioma with AQP4-Ab positivity, suggesting tumor-triggered antibody production. Physicians should be aware that glioma patients may present with AQP4-Ab positivity.