MOG antibody associated encephalomyelitis

Abstract

Background.

MOG antibody disease is a rare autoimmune disorder with antibodies against the myelin oligodendrocyte glycoprotein (MOG) predominantly involving the optic nerve and spinal cord leading to vision loss and paralysis. When MOG antibody disease involves the brain, the phenotype is similar to acute disseminated encephalomyelitis (ADEM). Unlike ADEM which is classically monophasic, seropositivity of the MOG antibody portends a high likelihood of relapse.

Objective.

In this review we discuss MOG positive cases presenting with encephalitis, encephalopathy or ADEM-like presentation based on recently published series.

Methods.

We reviewed the literature for all studies that addressed the topic of encephalitis in MOG antibody positive disease.

Results and conclusion.

MOG antibody disease has a characteristic pattern of brain involvement. It stands unique against MS and NMOSD. Acute disseminated encephalomyelitis is one of the most common presentations especially in patients with younger age at onset. Brain MRI show unique features that could warrant antibody testing as early as the first clinical attack.

Introduction.

MOG antibody disease refers to a relatively new spectrum of autoimmune disorder with antibodies against the myelin oligodendrocyte glycoprotein (MOG) predominantly involving the optic nerve and spinal cord leading to vision loss and paralysis [1, 2]. Clinically, MOG antibody disease bears resemblance to neuromyelitis optica spectrum disorder (NMOSD) in the localization of inflammatory attacks within the central nervous system. It accounts for up to 40% of NMOSD patients who are seronegative for the aquaporin-4 (AQP4) antibody [2, 3]. However, unlike AQP4 which is an astrocytic protein, MOG is expressed on the outer surface of CNS myelin [2, 4]. Thus, immune mediated attacks against MOG appear to be more demyelinating compared with AQP4 NMOSD, and therefore MOG is closer to multiple sclerosis (MS) in terms of its immunopathological features [2, 5]. When MOG antibody disease involves the brain, the phenotype is similar to acute disseminated encephalomyelitis (ADEM) with alterations in mental status and good outcomes after treatment with corticosteroids and intravenous immunoglobulins. Unlike ADEM which is classically monophasic, seropositivity of the MOG antibody portends a high likelihood of relapse [2, 6]. MOG has been ironically unique in that it shares features of NMOSD, MS and ADEM with only a serological antibody to distinguish itself.

In this review, we focus on encephalitis associated with the MOG antibody. Most of these cases were previously diagnosed as ADEM or recurrent ADEM but with widespread availability of MOG antibody testing since 2015, several case series and reports have been published on cases of encephalitis associated with MOG antibody [7–12]. These studies contribute to the emerging consensus that MOG antibody disease is likely to be a separate immunopathological entity with a distinctive clinical signature.

Methods.

We reviewed the literature for all studies that addressed the topic of encephalitis in MOG antibody positive disease. Two case series were published from Japan and China [8, 9]. A third case series from UK was focused primarily on seizures but included some data on encephalopathy [7]. A case series from Japan studied children who presented with inflammatory central nervous diseases and tested positive for MOG [11]. Two case reports were published from Japan and Italy [10, 12] were included as well as two studies describing overlap between MOG encephalitis and N-methyl-D- aspartate (NMDA) receptor antibodies [13, 14]. Finally, two studies from UK and France focused on MOG antibody disease in general also included some data on encephalitis [15, 16].

Epidemiology.

Recent data suggest that MOG antibody disease is generally a condition of younger Caucasians with less female predominance compared to other autoimmune diseases of the central nervous system (CNS) [2, 17, 18]. This is different from AQP4 NMOSD in which the average age of onset is in the late 30s/early 40s, race is overrepresented by non-Caucasians and females dominate up to 9:1 [19–23]. MS patients are slightly older than MOG patients on average and share the propensity for Caucasian descent but women with MS outnumber men by 3:1 [24]. ADEM tends to strike children much more than adults whereas MOG is found in both children and adults alike [25, 26].

In a Chinese study published in 2018, 20.7% of MOG positive patients had a typical presentation of encephalitis at some point in their disease course. Ten were males and 8 were females; the median age of onset was 22 years. In a related Chinese cohort of AQP4 seropositive NMOSD patients, only 3.6% of patients experienced an attack of encephalitis, all of whom were females in their late 30s [8].

In a small Japanese cohort of 4 cases with MOG antibody encephalitis, all were male with a median age of 37 years [9]. A second Japanese case series studied MOG seropositivity in 17 children presenting with inflammatory demyelinating disease [11]. Nine patients tested positive for MOG of whom 6 patients received an initial diagnosis of ADEM, encephalitis or meningitis. Five were males with only one female [11].

A UK study of 5 patients presenting with seizures as a manifestation of MOG seropositivity included 3 females and 2 males, with an average age of onset of 20 years (median: 10 years) [27]. In a second UK study, 18% of a larger cohort of MOG patients presented with an ADEM-like or encephalitis clinical picture [15]. Those patients with encephalitis were younger by an average of 19 years compared to MOG antibody disease patients who presented with optic neuritis or transverse myelitis, 46% of whom had a relapsing course. Whether the encephalitic phenotype in MOG disease is more likely in younger patients has been addressed in some other MOG studies. It was noted that MOG patients with younger age at onset were more likely to experience an ADEM-like encephalopathic picture[28–30].

In a French study published in 2018, 2.5 % (5 out of 197) of MOG patients presented with encephalopathy, and an additional 2% presented with brain stem syndrome along with encephalopathy [16].

A case report of a 46 year-old MOG antibody seropositive patient who presented with paraparesis secondary to bifrontal cortical encephalitis and relapsed later with optic neuritis is an example of a slightly older patient compared to the published series [10].

One interesting study described an overlap between NMDA receptor antibodies and CNS demyelinating diseases (including MOG). In that study, MOG antibodies were detected in 9/23 patients diagnosed with NMDA receptor encephalitis with prominent clinical and/or MRI findings compatible with MOG demyelination [13]. It is difficult to distinguish the contribution of NMDA receptor vs. MOG antibodies to the encephalitis presentations. In a different study published a year later, NMDA receptor antibody was detected in only one out of 336 patients with different demyelinating diseases. Of interest, 26 out of 51 ADEM patients tested positive for MOG antibodies. Their median age was 7 years (2–52), with 51 % being females [14].

Clinical Presentation.

Encephalitis of any etiology typically presents with focal neurological deficits depending on lesion localization, along with global change in mental status. Encephalitis is rare in NMOSD and MS, but pathognomonic in ADEM. When MOG attacks the brain, the presentation is more similar to ADEM, including changes in mental status as well as increased frequency of seizures.

In the UK series, seizures were observed more frequently in MOG positive patients: 14.3% as opposed to 1% in the AQP4 antibody seropositive group. All experienced generalized seizures with one having an additional focal seizure and one having only complex partial seizures. Four out of the five patients experienced altered sensorium/ encephalopathy along with seizures [7].

On the other hand, all 18 patients from the Chinese series had typical symptoms of encephalitis with decreased consciousness, headache, and behavioral changes; seizures were experienced in 9 of those patients [8]. Among the nine MOG Japanese patients reported by Hino-Fukuyo et al., two presented with ADEM, one with encephalitis and two with meningitis [11]. Among four Japanese MOG patients in a different series, two experienced disturbed sensorium and two had seizures [9]. The seizures were generalized convulsions with or without abnormal behavior or altered sensorium. [9]. In a single case report of an adult Japanese MOG patient, focal with secondary generalized motor fits followed by weakness of both lower limbs, fatigue and memory decline was the presentation [10]. In a case report of a 7 year-old Japanese boy, a cluster of partial seizure without a change in mental status occurred among 4 relapses of optic neuritis through his disease course [31].

Disease course.

MOG antibody seropositivity had been previously associated with a monophasic disease course, especially in children with ADEM [32–34]. More recently, MOG seropositivity has been reported to follow a relapsing disease course, not only among adults but also in pediatric patients [27, 28, 33, 35, 36]. The persistence or disappearance of MOG antibodies could be related to which disease course to be expected [16, 37, 38]. Although attacks can be severe at presentation, recovery is usually good and long-term outcomes appear to be much better compared to AQP4 antibody seropositive NMOSD [16, 32, 33, 39].

In the Chinese study, 72.2% of MOG encephalitis patients had a relapsing disease course. Two thirds presented with encephalitis relapse at disease onset while one third experienced optic neuritis attacks before presenting with encephalitis [8]. In a retrospective study including 8 MOG Japanese patients, two patients were monophasic while the third experienced a relapsing course [11]. Among four Japanese patients in another MOG cohort, two had a relapsing disease course with optic neuritis and the other two remained monophasic [9].

In the UK study, all MOG seropositive patients who experienced seizures and encephalopathy, experienced a relapsing disease course.

Cerebrospinal fluid examination.

Cerebrospinal fluid findings in MOG seropositive patients are similar to NMOSD with pleocytosis of predominantly lymphocytes, a normal or mildly elevated protein, and rare oligoclonal bands (OCBs) around the time of an attack. Whether that specifically applies to MOG encephalitis cases needs a dedicated study of such cases. The few studies found in literature confirm the same CSF findings [7–10].

In the Chinese case series, 41.2% of patients had increased intracranial pressure during the attack of encephalitis, and 64.7% showed CSF pleocytosis [8]. In the UK, the average white cell count in CSF was 251 cells/μl, while the average in the Japanese study was 126 cells/μl [7, 9]. Oligoclonal bands were detected in 20% and 25% of patients in UK and China, respectively [7, 8]. Interestingly, 2/5 and 5/15 patients in the same cohorts tested positive for NMDA receptor antibodies, which could suggest an overlap between the two clinical entities [7, 8].

MRI features.

MRI findings in MOG encephalitis usually report an ADEM-like pattern with diffuse signal changes noted in the cortical/subcortical white matter (WM), deep WM and deep grey matter as seen on both T2 weighted and FLAIR images. Scattered linear and nodular enhancement is seen in active lesions with these also demonstrating restricted diffusion in some cases [7–10, 12]. Resolution or significant decrease in conspicuity of lesions on follow up imaging is noted in the majority of cases but there are exceptions.

In the French study, despite the fact that 9 patients out of 197 presented with an ADEM-like clinical picture, no specific radiologic pattern could be identified to distinguish MOG antibody cases from non-MOG antibody cases except that leptomeningeal enhancement and thalamic lesions were unique to MOG positive cohort [16]. T2 hyperintense lesions in the deep white matter of the brain was the location most frequently involved on initial abnormal brain MRI. Tumefactive, poorly demarcated lesions and cortical lesions were more commonly observed in MOG patients compared to AQP4 antibody seropositive patients.

In the UK study, MOG antibody seropositive patients were more likely to present with an MRI classified as ADEM (44%) as opposed to (0%) in the AQP4 antibody seropositive group. The majority of patients showed complete resolution of their lesions on MRI follow up. In 2016, a Chinese study reported a different finding, where an ADEM like radiological picture was observed in both AQP4 and MOG antibody seropositive patients. The only remarkable feature in AQP4 patients was the lack of enhancement of their brain lesions which suggested an intact blood brain barrier and probably different pathophysiology [40].

In 2015, a study in Austria, reported that an ADEM like clinical picture was observed in one MOG antibody seropositive patient among 17 patients in its cohort and none of the 59 AQP4 antibody seropositive patients [33]. Despite the fact that most MOG seropositive patients showed abnormal MRIs, none of them fulfilled McDonald’s MS criteria.

In the Japanese case series, all 4 patients who presented with generalized epileptic seizures with or without altered sensorium, showed unilateral cortical brain lesions on FLAIR images. Moreover, the pattern correlated with hyperperfusion on SPECT. These lesions were differentiated from seizure-induced lesions by their presence on FLAIR rather than DWI, the presence of CSF pleocytosis and the favorable clinical response to high dose steroids. These clues suggested an inflammatory nature to these cortical lesions [9].

Treatment and outcome.

Acute treatment with corticosteroids and/ or plasma exchange or intravenous immunoglobulin (IVIG) is the current standard of care for MOG antibody encephalitis. In the published case series, the majority of cases were treated with intravenous methylprednisolone followed by slow oral prednisone taper with full recovery [9, 10], and some had extra treatment with IVIG [8, 12] or plasmapheresis [7]. Most patients showed excellent response to treatment with full recovery [7–9, 12], while other patients continued to have residual neurologic deficits as well as MRI changes [7, 10].

For patients having a relapsing course, long term immunosuppressive treatment is used. Rituximab and mycophenolate mofetil were the most commonly employed agents [7].

Due to uncertainty about the risk of recurrence in patients with MOG antibody disease, especially among those whose convert from seropositive to seronegative, long term treatment can be deferred. In the UK case series, 3 cases were started on mycophenolate mofetil, the first of whom was relapse-free for two years. Upon experiencing an optic neuritis attack, rituximab was initiated and 17 months later he remained in clinical remission. The second remained stable after 12 months of treatment, except for residual cognitive changes. And the third patient experienced no more events over 20 months of follow up [7].

Figure 1:

Axial FLAIR, T2-weighted and post-contrast images showing cortical, juxta-cortical and deep white matter signal changes with nodular avid enhancement in a patient with MOG during the first attack (upper row) and during the second attack (lower row).

Figure 2:

Axial FLAIR and post-contrast images showing cortical and juxta-cortical signal changes with associated avid enhancement [A, B] in a patient with MOG. Follow-up axial FLAIR image shows near complete resolution of signal changes [C].

Table 1:

Summary of the case series/reports that primarily targeted MOG associated encephalopathy and seizures:

Study	Number of patients	Female: Male	Mean (median) age at disease onset	Main clinical presentation	Disease course
Wang et al7	18	8:10	21.3 (22) years	Encephalopathy ± seizures	72.2% (13/18) had a relapsing disease
Ogawa et al8	4	0:4	34 (37) years	Seizures ± encephalopathy	2/4 had a relapsing disease
Hamid et al6	5	2:3	20 (10) years	Seizures± encephalopathy	5/5 had a relapsing disease
Mariotto et al11	1	0:1	31 years	encephalopathy	Relapsing disease.
Fujimori et al9	1	0:1	46 years	Dizziness, seizures and paraparesis.	Relapsing disease.
Hino-Fukuyo10	5	1:4	9 (11) years	Headache, seizures, vomiting.	NA