Seizures and myelin oligodendrocyte glycoprotein (MOG) antibodies: Two paradigmatic cases and a review of the literature

HIGHLIGHTS

• MOG Abs are associated with seizures in heterogeneous clinical settings.

• Isolated seizures in MOG Ab-positive patients can precede demyelinating events.

• Testing for MOG Abs might be considered in children with unexplained seizures.

• Evidence of MOG Ab-associated autoimmune epilepsy is circumstantial at present.

Abstract

Background

Myelin oligodendrocyte glycoprotein (MOG) antibodies (Abs) have been associated with a heterogeneous range of acquired CNS demyelinating disorders. More recently, increasing evidence correlates the presence of such Abs with seizures, occurring in concomitance with CNS demyelinating events, or even as isolated phenomena. In this scenario, the full clinical spectrum of MOG Ab-associated seizures and the contribution of such Abs to epileptogenesis are unclear.

Methods

We report on two paradigmatic cases of MOG Ab-associated seizures, one showing isolated seizures, without evidence of encephalopathy or MRI changes, followed by a demyelinating event one month later, and the other presenting with seizures as the main manifestation of an acute disseminated encephalomyelitis (ADEM) event. To better frame this topic, we performed a literature review, identifying 49 patients with MOG Ab-associated disorders presenting seizures at any stage of their disease, and analysed the clinico-therapeutic, brain MRI, cerebrospinal fluid, and EEG features.

Results

MOG Ab-associated seizures occurred mostly during encephalitis, including: a) “cortical encephalitis”, a clinically poorly defined syndrome characterised by gray matter lesions on brain MRI, with or without subcortical white matter involvement; b) ADEM; c) NMDAR encephalitis with demyelinating features. Seizures can also occur in isolation, often in clusters of focal motor seizures, in patients with normal brain MRI, heralding the more typical MOG Ab-associated demyelinating syndrome by days to months.

Conclusion

Testing for MOG Abs should be considered in children with isolated and unexplained seizures, and in adults with suspected encephalitis and/or seizures. In these cases, MOG Abs detection is highly relevant for patients’ clinical management.

Introduction

Myelin oligodendrocyte glycoprotein (MOG) is a highly conserved protein uniquely expressed in oligodendrocytes in the central nervous system (CNS) of humans and other mammals (Allamargot and Gardinier M, 2007). Despite the limited knowledge about the biological role of MOG, its encephalitogenic potential has been exploited for the development of animal models of demyelination (experimental autoimmune encephalomyelitis, EAE) (Iglesias et al., 2001). For this reason, MOG antibodies (Abs) have been thoroughly investigated and, for over 20 years, associated with multiple sclerosis (MS), the most frequent and disabling acquired demyelinating disease that typically affects young adults (Reindl and Waters, 2019; Lindert et al., 1999; Reindl et al., 1999; Berger et al., 2003). However, the denaturing techniques used for MOG Ab detection (i.e., ELISA and Western blot) led to poorly reproducible results without clinical relevance (Reindl and Waters, 2019; Kuhle et al., 2007; O'Connor et al., 2007). With the recognition of the conformational B cell epitopes of MOG (Menge et al., 2007; Mayer et al., 2013; Waters et al., 2015) and the introduction of conformational immunoassays (i.e. cell-based assay [CBA]), MOG Abs were detected in various demyelinating diseases, such as acute disseminated encephalomyelitis (ADEM), optic neuritis (ON), transverse myelitis, clinically isolated syndrome (CIS), and neuromyelitis optica spectrum disorders (NMOSD), but only rarely in patients with MS (Waters et al., 2015; Hacohen et al., 2017; Jarius et al., 2016; López-Chiriboga et al., 2018; Hennes et al., 2017; Mariotto et al., 2017). In the attempt of unifying this heterogeneous spectrum of inflammatory demyelinating disorders, the term MOG encephalomyelitis (MOG-EM) has been recently proposed (Jarius et al., 2018). The diagnosis of MOG-EM or MS entails different prognosis and therapies.

There is growing recognition of seizures as a clinical manifestation of MOG-EM, especially in adult patients with large unilateral cortical lesions (the so-called “focal cortical encephalitis”) (Ogawa et al., 2017; Ikeda et al., 2018), in children with multiphasic ADEM and ON (Gutman et al., 2018), and in both children and adults with NMOSD (Hamid et al., 2018), with a higher frequency in comparison with that reported in AQP4 Ab-associated NMOSD (Hamid et al., 2018). In addition, and quite surprisingly, clusters of focal seizures in children have been recently described as an isolated presentation of MOG-EM, preceding the typical clinical and radiological manifestations of the CNS demyelination by months to years (Ramanathan et al., 2019). In this complex scenario, the epidemiology and clinical spectrum of MOG Ab-associated seizures is still unclear, as well as the MOG Ab contribution to epileptogenesis.

We herein report on two paradigmatic cases of children, one of them with isolated seizures and MOG Abs detected on retrospective serum samples. To contextualize the cases, we also briefly summarize the current knowledge on the coexistence between MOG Abs, demyelinating lesions and seizures, describing clinical presentations, brain and spinal MRI patterns, electroencephalographic (EEG) characteristics, treatment options, and outcomes.