An AQP-4-IgG-Positive Patient with Neuroimaging Findings Suggestive of Multiple Sclerosis

Background

Multiple sclerosis (MS) and neuromyelitis optica spectrum disorders (NMOSDs) are 2 diseases with similar clinical manifestations but distinct pathogeneses. Aquaporin-4-IgG (AQP-4-IgG) plays a pivotal role in the diagnosis of NMOSD [1], and its serum titers show no significant differences between the relapse and remission phases [2]. Previously, researchers have discussed the issue of overlap between MS and NMOSD, but relevant cases are rare [3, 4]. We recently encountered a patient who exhibited some typical magnetic resonance imaging (MRI) features of MS but was positive for serum AQP-4-IgG. The patient’s general condition and MRI results are reported below.

Case Report

A 54-year-old woman developed weakness in her right lower extremity that gradually returned to normal 4 years prior. According to her self-report, there was no noticeable decline in her vision, and she did not receive any specific treatment at that time. Fortunately, over the course of the following months, her weak lower limb gradually regained strength. Recently, she was admitted to the hospital for numbness and weakness of both lower limbs and the right upper limb for more than 10 days. Routine blood tests, rheumatoid immunology screenings, and tumor screenings did not reveal any significant abnormalities. Her cerebrospinal fluid (CSF) pressure was 90 cm-H2O, her CSF white blood cell count was 0, and her CSF protein level was 21.54 mg/dL. The patient had a positive CSF oligoclonal band, a CSF IgG index of 0.95, and a negative serum oligoclonal band. No obvious abnormalities were observed in the visual evoked potentials (VEPs). The patient’s MRI results are shown in Figure 1. The patient’s history of relapse-remission, multiple spatially distributed MRI lesions, and positive CSF oligoclonal bands were considered in the diagnosis. The findings from these examinations indicated a potential diagnosis of MS in this patient [5]. However, during treatment, we found that she was positive for serum AQP-4 IgG, with a titer of 1: 100 (cell-based assay, Kindstar Globalgene Technology, Inc., China). This discovery indicated the potential presence of another disorder, NMOSD [1]. In this situation, it is possible that prioritizing NMOSD immunosuppressive therapy over MS disease-modifying therapy (DMT) approaches should be considered [3,6].

Discussion

Clinically, it is easy to misdiagnose MS and NMOSD, which can have serious consequences, as incorrect treatment approaches can exacerbate these diseases [3,6]. This patient presented a challenge in the differential diagnosis, as she exhibited characteristics of both diseases. AQP-4-IgG seropositivity is a key biomarker to distinguish NMOSD from MS [1]. Analyzing the features of this case improves our understanding and ability to differentiate between these 2 diseases, which is clinically significant. Furthermore, this case has referential value for future research. Therefore, further discussion about NMOSD with MRI findings suggestive of MS is warranted.

MRI plays an important role in differentiating between NMOSD and MS. In NMOSD, white-matter lesions in the hemispheres, which can be large and tumefactive cloud-like or spindle-like lesions following white matter tracts (particularly the cortico-spinal tract), are usually associated with variable vasogenic edema from inflammatory dysfunction in water channels [7,8]. In the common presentation of MS, intracranial lesions are usually ovoid or round, with a minimum size of 3 mm, and are asymmetrically distributed along the main axis. The distribution of these lesions is often observed in the juxtacortical, periventricular, and infratentorial regions [9,10]. Lesions in the corpus callosum region are observed in approximately 12–40% of NMOSD patients [11]. These lesions typically affect the ependymal surface and involve a substantial portion of the corpus callosum length [11]. However, in this particular patient, the observed lesion was characterized by a “callosalseptal interface lesion,” which is a typical lesion pattern observed in MS [7,8]. Lesions in the spinal cord in NMOSD are typically characterized by longitudinally extensive transverse myelitis involving extensive spinal cord involvement with T2-weighted hyperintensity spanning at least 3 vertebral body segments in length [11]. These lesions predominantly occur in the central cord, with more than 70% of lesions typically located within the central gray matter [11]. Additionally, more than half of spinal cord lesions typically involve more than 50% of the cross-sectional area of the spinal cord [11,12]. In contrast, spinal cord lesions in MS are typically short segments with a longitudinal extension of 2 or fewer vertebral bodies [11]. They commonly appear in the dorsal and lateral regions of the spinal cord, extending toward the peripheral areas where white matter predominates [11,13].

Serum AQP-4-IgG is an important inflammatory marker for NMOSD [14]. The serum AQP-4-IgG titer was not associated with disease activity but did indicate disease severity in the attack phase in patients with NMOSD [2]. The serum AQP-4-IgG test utilizes a cell-based assay (CBA), a testing method recommended by the 2015 international consensus diagnostic criteria for NMOSD [6]. A pooled analysis showed a specificity of 99.8% (1 false positive of 531 samples in 9 CBA studies), which was much higher than that of the enzyme-linked immunosorbent assay (ELISA) (96.6%) [15]. In addition, the authors of the article found that the one false-positive patient by the CBA method could be due to a misclassification [15]. Therefore, the AQP-4-IgG-seropositive CBA results should be reliable.

The appearance of right lower-limb weakness in this patient 4 years prior could be the primary symptom of MS. The disease’s tendency for spontaneous alleviation without proper medical treatment is a distinguishing feature that aligns more with MS than with NMOSD. This onset pattern aligns with the course characteristics of relapsing-remitting MS [5]. The recurrence of the patient’s illness and subsequent hospital admission, coupled with the MRI characteristics and the presence of CSF oligoclonal bands, indicated a probable diagnosis of MS (Figure 1A–1G’). However, considering the presence of “red flags” on the patient’s MR images (Figure 1D, 1F, 1G) [10], lesions resembling NMOSD were found in areas associated with aquaporin-4 distribution, such as the periventricular and central canal regions [6,10]. Consequently, we proceeded to perform additional testing for AQP-4-IgG, myelin oligodendrocyte glycoprotein-IgG (MOGIgG), and other autoantibodies commonly associated with autoimmune diseases. As expected, we detected the presence of AQP-4-IgG in the patient’s serum (CBA was repeated twice). Despite the nonactive nature of the AQP-4 lesions observed on the MR images, these findings suggest the gradual impact of AQP-4-IgG on the patient’s neurological system.

The overlap of NMOSD with other systemic inflammatory diseases has gradually garnered attention. According to the 2015 International Panel for NMO Diagnosis (IPND) criteria, the presence of systemic lupus erythematosus, Sjögren syndrome, or myasthenia gravis in AQP-4-IgG-seropositive NMOSD patients supports an NMOSD diagnosis [6]. NMOSD can be complicated by a variety of autoimmune diseases, which may be related to autoimmune dysfunction in those patients. The present case exhibits similarities to this immune overlap condition.

Therefore, on the basis of the available findings, we speculate that the patient’s final diagnosis was NMOSD with MS-like manifestations. Due to the inherent difficulty in distinguishing between these 2 diseases, it was not until the discovery of AQP-4-IgG that they could be differentiated [1]. Jurynczyk et al studied NMOSD/MS overlap syndrome in people who were seronegative for the relevant antibodies. Over the course of the study, many experts on the diagnosis of the 2 types of diseases expressed differing opinions [4]. This indicates that distinguishing between these 2 diseases is not always a simple task. Pittock et al reported that the incidence of NMOSD with MS-like brain lesions was approximately 10% [16], and Flanagan et al reported that the incidence of NMOSD spinal short lesions was 14% [17]. Their study provides an epidemiological perspective on the prevalence of this specific type of NMOSD. We demonstrated the clinical manifestations and MRI conditions of these patients through this specific case, which echoed previous studies and provided a more complete understanding of this unique type of NMOSD.

This case can assist in further discerning the differences between MS and NMOSD. Regrettably, this case report does have some shortcomings. Some of the medical history is based on the patient’s recollection; thus, objective examination results are lacking, which may result in deviations in the details of the medical history. Our hospital is in an economically disadvantaged area, and outdated examination equipment resulted in suboptimal clarity of the MR images. Due to the patient’s poor financial situation, some MRI sequences were omitted, and contrast-enhanced scans were not performed to save on examination costs. We will closely follow up with this patient and dynamically observe the prognosis of her illness.

Conclusions

Our aim was not to demonstrate a causal relationship between AQP-4-IgG and MS. Our objective was to strongly recommend, regardless of the possibility mentioned above, that when the patient’s MRI results reveal the presence of the “red flag” signs associated with MS [10], it is advisable to conduct additional examinations of AQP-4-IgG, MOG-IgG, and other relevant markers to screen for associated diseases because the MS DMT approach may lead to a deterioration in the state of NMOSD patients [6]. This finding fully illustrates the importance of meticulously differentiating the diseases before commencing treatment.