Introduction

Myelin oligodendrocyte glycoprotein antibody disorder (MOGAD) is a demyelinating disease of the central nervous system (CNS) associated with antibodies against myelin oligodendrocyte glycoprotein (MOG). The clinical spectrum of MOGAD varies and sometimes meets the criteria for neuromyelitis optica spectrum disorder (NMOSD) [1]. Isolated brainstem involvement in MOGAD disease is rare. If brainstem disease does occur, it is often as one part of a multifaceted central nervous system attack [2]. In contrast, Bickerstaff brainstem encephalitis (BBE) commonly affects the brainstem and is defined by the triad of decreased consciousness, ataxia, and ophthalmoplegia. It is associated with the presence of GQ1b antibodies [3]. A recent retrospective observational study demonstrated frequent co-existence of neuronal antibodies and MOG-IgG in patients with MOGAD [4]. Additionally, a number of case reports have been published on the presence of two or more autoreactive antibodies in the same patient [5,6,7,8].

To our knowledge, the patient described herein is the first known case of MOGAD associated with GQ1b antibodies. This case is unique in that our patient was first diagnosed with GQ1b-antibody-mediated BBE, and later in the disease course was found to have positive high levels of anti-MOG antibodies.

Case presentation

A 66-year-old female presented in June 2013 with weakness of the right lower limb and numbness in the left lower limb. Other symptoms included diplopia, nausea, vomiting, and left-sided facial droop. Past medical history included hypothyroidism, well-controlled on supplementation.

On examination, she was noted to have a deficit in left eye adduction along with contralateral abducting nystagmus. Power in lower limbs overall was 3/5 (right) and 4/5 (left); reflexes were 3 + on bilateral ankles and knees. Plantar responses were up-going bilaterally.

Labs

Serum ganglioside anti-GQ1b antibodies were found to be positive. CSF analysis showed mild increase in protein with no WBCs, negative oligoclonal bands, and mildly increased myelin basic protein. MRI brain showed an enhancing lesion at the tegmental area (Fig. 1).

Fig. 1
figure 1

T2 FLAIR images on initial presentation with T2 hyperintensity within the posterior pons

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She was treated with five days of IVIG, repeated in monthly cycles for three months. She demonstrated clinical improvement on this regimen. However, three years later, the patient presented with new dizziness, ataxia, and dysarthria. Repeat MRI showed a new contrast-enhancing lesion extending from the posterior aspect of the pons to the midbrain suggestive of recurrent brainstem encephalitis (Fig. 2). MRI of the C spine showed some disk changes, but no signal abnormalities within the spinal cord. CSF showed increased protein and high MBP. Serum GQ1b antibodies were negative. She was treated with steroids and 5 courses of PLEX, followed by monthly IVIG and steroids. She demonstrated only partial improvement and was given a provisional diagnosis of NMOSD, aquaporin-4 negative. She demonstrated improvement in her symptoms on long-term rituximab q 6 months and monthly IVIG. However, seven years after initial presentation, MOG serum antibody (cell-based assay) was found to be positive at > 1:160 titer and remained high for 3 years so far. Despite this, the patient’s disease has remained clinically stable. During the last year, her rituximab dose was reduced (de-escalation) and the interval between IVIG cycles was increased.

Fig. 2
figure 2

MRI T2 FLAIR (left) and T1 post-contrast (right) at another event 3 years after initial presentation

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Discussion

In our case, the diagnosis of GQ1b-antibody-positive BBE was considered with a later diagnosis of AQP-4-negative NMOSD. Eventually, as anti-MOG antibodies testing became available, our patient was found to have elevated MOG antibodies. To our knowledge, this is the first case of MOGAD following an initial anti-GQ1b BBE.

Kunchok et al., found that NMDA-R-IgG was a frequently detected neuronal-IgG antibody co-existing with MOG-IgG in patients with MOGAD [4]. Additionally, several case reports of disease mediated by multiple autoimmune antibodies have been published. Liu et al. reported a patient with decreased vision in the right eye and neuropsychiatric disturbances. Detection of MOG-IgG in CSF and Caspr2-IgG in serum and CSF led to a diagnosis of co-existing MOGAD and anti-Caspr2 antibody-associated autoimmune encephalitis [8]. In another case, Guo et al. reported MOGAD and anti-NMDAR- encephalitis overlapping syndrome [5]. Reports of MOG-IgG-associated diseases co-existing with anti-NMDAR encephalitis and GFAP astrocytopathy have also been described [6, 7].

Our patient's diagnosis was based on the recently proposed criteria for MOGAD [9]. The patient demonstrated a clinical demyelinating event associated with brainstem deficits that was confirmed with MRI. The patient also had a high positive MOG serum antibody that remained elevated for 3 years.

However, due to lack of MOG testing early in this patient’s presentation, we cannot confirm if the MOG-associated and GQ1b-associated diseases were concurrent entities or developed several years apart from each other. Additionally, the patient’s initial presentation was uncommon due to a lack of decreased level of consciousness. Therefore, this could alternatively be interpreted as a case of recurrent brainstem attacks in the context of MOGAD with concomitant anti-GQ1b antibodies. The patient’s lack of response to steroids three years after her initial presentation was also atypical. The reason for this could be related to the patient’s history of immunosuppressive therapy or possibly due to a history of active brainstem lesions. Both of these etiologies are suggested by a recent retrospective analysis of steroid non-responders in NMOSD [10]. Regardless, this case demonstrates that multiple antibodies should be tested for at the onset of disease when BBE, or more broadly, anti-GQ1b encephalitis is suspected. Recognition of this phenomenon may improve management of disease course and prevent relapses due to early selection of more appropriate treatment modalities. We also posit that MOGAD may be amenable to de-escalation of therapy as we provided a decreased dose of rituximab with good disease control.

Conclusion

The discovery of autoreactive antibodies provided the groundwork for an improved understanding of autoimmune CNS inflammatory diseases. As more autoimmune antibody testing become available, it may be found that the variable presentations of MOGAD could be attributed to the co-existence of other autoimmune antibodies.