Inflammatory or immune-mediated demyelinating central nervous system (CNS) diseases are a heterogeneous group that includes mono- and multiphasic diseases with prognoses ranging from benign to fulminant and a variety of different treatment responses. The most common demyelinating CNS diseases have some chance of misdiagnosis that occurs in up to 10% of patients [1]. Diagnosis is based on a combination of clinical manifestation and radiological and laboratory findings. In 2004, the specific autoantibodies against aquaporin-4 (AQP4), a plentiful water channel on astrocytic endfeet in the CNS, in patients with neuromyelitis optica spectrum disorder (NMOSD) fortified the diagnosis of and research into demyelinating CNS diseases [2]. However, a subgroup of clinically definite NMOSD patients showed AQP4-seronegative results [3].

Myelin oligodendrocyte glycoprotein (MOG) is exclusively expressed in the CNS on the outer surface of the myelin sheath and oligodendrocyte plasma membrane [4]. MOG was comprehen sively studied as a potential target structure in CNS demyelinating diseases. The majority of MOG antibody (MOG-Ab)-seropositive patients have optic neuritis (ON), encephalitis with brain demyelinating lesions, and/or transverse myelitis (TM); the new term “MOG-Ab–associated ON, encephalitis, and myelitis” has been suggested to include these patients with CNS demyelinating syndromes and MOG-Ab positivity. Depending on the clinical assessment, patients can be clinically diagnosed with NMOSD, acute demyelinating encephalomyelitis (ADEM), multiple sclerosis (MS), or isolated ON or TM [5].

In the last few years, the MOG-Ab–associated disorder (MOGAD) spectrum has been rapidly broadening, and as more data regarding their clinical, radiological, and laboratory findings have become available, their immunopathogenesis has been elucidated. This review article discusses the evolving immunopathogenesis, clinical spectrum, diagnostic approach, prog nostic research data, and treatment principles for clinical practice.

MOG, a glycoprotein of the immunoglobulin superfamily, is a component of the CNS myelin sheath, as are myelin basic protein and proteolipid protein [6]. The precise functions of MOG remain to be clarified but likely include roles in the adhesion of myelin fibers, regulation of oligodendrocyte microtubule stability, and modulation of the interaction between myelin and the immune system by the complement pathway [7].

In humans, high-titer MOG-immunoglobulin G (MOG-IgG) levels in serum samples seem to efficiently activate the complement cascade in vitro [8]. Furthermore, purified IgG from MOG-IgG–positive patients, when incubated with oligodendrocytes in vitro, led to obvious cytoskeletal disorganization, further suggesting functional pathogenicity [9]. Initial studies revealed a pathogenic effect of the humoral immune response against MOG (human MOG-Ab); these antibodies were able to induce the death of MOG-expressing cells as well as natural killer cell-mediated cell death, with the extent of cell damage dependent on antibody levels [5]. In addition, MOG-Ab belongs to the complement binding IgG1 subtype and has been found to activate the complement cascade, leading to complement-dependent destruction of MOG-expressing cells [8]. The ac cumulation of MOG-Ab has been described in CNS antigen-presenting cells with subsequent activation of autoreactive T cells, followed by the induction of peripheral autoreactive T cells [10]. Significantly, MOG-Ab alone did not induce inflammation or tissue destruction; rather, their interdependence with T cells was required to develop their pathogenic potential [10].

Despite MOGAD’s ability to overlap with the clinical presentation of AQP4-IgG–associated NMOSD, the mechanisms of the two disease groups are likely different. While the pathological hallmark of AQP4-Ab–positive NMOSD is astrocytic damage with secondary oligodendrocyte loss and demyelination, no evidence of astrocytopathy has been reported in MOG-Ab positivity, which was related to the inflammation and myelin destruction affecting oligodendrocytes without astrocyte injury [11].

To our knowledge, several cases to date with obtainable neuropathology have been described in the literature [12-15]. Interestingly, most cases discovered MS pattern II lesions with obvious demyelination, marked infiltration of macrophages (containing myelin degradation products), and T cells, preoligodendrocytes, and relatively preserved axons and astrocytes. The inflammatory hallmark is an infiltrate consisting of T cells as well as a complement, B cell, and IgG [3] suggestive of a humoral pathogenesis. The clinical presentation of MOG-Ab–positive patients with MS pattern II pathology diverges and includes presentation with clinically isolated syndrome, MS, NMOSD, recurrent longitudinally extensive transverse myelitis (LETM), and atypical inflammatory demyelinating CNS syndromes [12-15].

Clinical MOG-Ab–positive patients can present with an NMOSD phenotype. Overall, in AQP4-negative patients, MOG-Ab had a prevalence of 25% in subsequent studies [3]. In contrast to AQP4-Ab–associated disorders with the well-defined phenotype of NMOSD, those with MOGAD have a less well-defined clinical presentation. The foremost findings that distinguish MOG-Ab from AQP4-Ab NMOSD are summarized in Table 1 [16].

Several clinical conditions compatible with MOGAD have been described in pediatric patients with MOG-Ab positivity, mainly multiphasic ADEM, ADEM followed by ON, relapsing ON, TM, and AQP4-Ab–negative NMOSD [34]. Particularly in relapsing diseases, the differentiation of rare conditions—such as NMOSD, multiphasic ADEM or relapsing ON—has important therapeutic counsel. The first evidence for the role of anti-MOG-IgG as biological markers in children was identified by O’Connor et al. in a subgroup of ADEM [35]. Some studies have found that MOG-Ab-positive patients different clinical features according to age [36]. They found a bimodal distribution in 13 pediatric MOG-Ab-positive patients, with encephalopathy being more common in younger patients (4–8 years) and ON in older patients (13–18 years) [36].

Overall, 39% of MOG-Ab–positive children have a recurrent disease course versus only 5% with a typical MS disease course. The serial analysis of MOG-Ab–positive patients was recommended at 6–12 months. As there is no gold standard for MOG antibody analysis, particularly for children, the clinical and laboratory findings suggestive of MOGAD retesting is reasonable. As the MOG-Ab titers found in pediatric MS are usually lower and MS diagnostic criteria differ [37], there is no clear association between MOG-Ab and MS, even in pediatric patients.

A preceding infectious episode was noticed in 47% (e.g., influenza, infectious mononucleosis, following vaccination), with median follow-up times of 12–24 months [38]. The proportion of patients with a single attack is likely reduced with long-term follow-up, in which the proportion of patients with a single attack was only 29% during a longer median follow-up time (43 months) [30]. The median time between the first and second attacks was longer in MOG-Ab–positive patients (11.3 years) than in AQP4-Ab-positive (3.2 years) or double seronegative (3.4 years) patients [29]. However, other study revealed the median time between the first and second attacks in MOGAD was 5 months, although the interval could be longer (more than 12 months in 8 patients and up to 492 months in one patient [24]).

In several studies, MOG-Ab was associated with a favorable outcome [17]. MOG-Ab-positive patients less frequently suffer motor disability and have a better extended disability status scale (EDSS) score, compared to AQP4-Ab-positive patients [23]. Although, MOG-Ab-associated ON is usually a recurrent disease, visual recovery was good [42]; the outcome was better in MOG-than in AQP4-Ab-positive patients correlating with a better preserved retinal fiber layer thickness [42]. In patients with TM, the presence of MOG-Ab has also been associated with a better recovery from acute attacks, and really similar frequency of severe attacks at the onset to AQP4-Ab-associated disorders [19]. However, not all individuals will recover fully [17]. In a large cohort of MOG-Ab-positive patients followed for a median 28 months, 28% were left with permanent bladder dysfunction; 21% (among males) with erectile dysfunction; 20% with bowel dysfunction; 16% with decreased visual acuity in at least one eye; and 5% with an EDSS score ≥6 [31].

Monophasic and recurrent diseases are associated with MOG-Ab [48]. Older age, female sex, and MRI findings of atypical MS were risk factors for a recurrent disease course in MOGAD. The informed relapse varied across different studies. Relapse was observed in 36%–80% of patients, with an annualized relapse rate of 0.2–0.9, the highest risk in those with ON or NMOSD phenotypes [24,49]. These relapse rates seem to be lower than those of AQP4-positive patients [17,23,27]. These highly variable data of relapse rates may be due to the different characteristics of the enrolled patients among studies.

No clear distinctive phenotype has been identified in patients with MOG-Ab. The red flag signs and symptoms for the diagnosis of MOGAD are summarized in Table 2. Antibodies against MOG and AQP4 should be tested for in patients with clinical symptoms suggestive of NMOSD, such as bilateral ON, severe brainstem involvement, or LETM; in special patient groups with a high risk of NMOSD; if there is evidence of large cerebral lesions; if MS criteria of dissemination in space are not fulfilled; or if brain MRI findings are normal (Table 2) [50,51]. As a lack of OCBs is a very rare finding in typical MS, MOG antibody testing should be considered in OCB negative MS patients. In pediatric-onset MS, antibody testing can support the diagnosis of AQP4-negative NMOSD or ADEM followed by relapsing ON or including chronic relapsing inflammatory optic neuropathy. Other red flags indicating MOG-Ab testing include lesions with poorly demarcated margins located in the cerebellar peduncle and a leukodystrophy-like MRI pattern [51]. In 2017, Hacohen et al. precisely described the routine diagnostic use of MOG-Ab testing for pediatric patients in clinical practice and proposed a diagnostic algorithm for any episode of CNS demyelination [51]. In contrast, preceding criteria should include the McDonald criteria with caution for children under 12 years, as the validation of the predictive value is lacking [52].

Di Pauli and Berger [50] generated a diagnostic algorithm and clini cal spectrum of MOGAD in patients with relapsing demyelinating syndromes (Fig. 1). As MS is the most common relapsing demyelinating disorder and reliably diagnosed with brain/spinal MRI and CSF study, brain/spinal MRI and CSF exams are recommended as a first step. In the case of typical MS findings, MS is diagnosed according to the revised McDonald criteria [53]. If, in clinically and/or radiologically suggested NMOSD, AQP4-Ab are negative, MOG-Ab should be tested. MOG-Ab testing is also recommended in patients with features of ADEM, particularly those with lesions with poorly demarcated margins located in the cerebellar peduncle or with a leukodystrophy-like MRI pattern. Physicians should be reminded that MOG-Ab-positive patients have distinct clinical features (young, less frequently affected by postrema area syndrome, typically presenting with ADEM initially, less disability during follow-up, and longer time to the first relapse [51]).

Predicting the prognosis of MOG-Ab-positive patients considering the possibility of a multiphasic disease course has important suggestions concerning additional initiation of disease-modifying treatment. The correlation between longitudinal changes in antibody level and clinical progress has been evaluated [29,43]. Studies have discovered an association of MOG-Ab titer decrease with a monophasic course compared to stable or increasing titers in patients with multiphasic attacks [27,33]. Persistent MOG-Ab has been predominantly found in multiphasic ADEM, NMOSD, and ADEM followed by ON [54]. One study of adult and pediatric MOG-Ab-positive ADEM patients reinforced the usefulness of serial MOG-Ab testing for predicting relapse, as 88% of patients with persistent MOG-Ab relapsed during long-term follow-up versus 12% with transient antibodies [55]. These findings indicate that the maintenance of MOG-Ab–positivity could predict its clinical progress. On the other hand, Cobo-Calvo et al. [27] confirmed the trend toward an association between a relapsing disease and persistent antibodies only in a subgroup; in some groups, no such association was noticed. Similarly, Duignan et al. [56] found persistent MOG-Ab in relapsing and monophasic diseases alike. Long-term studies are needed to evaluate the usefulness of MOG-Ab as a biomarker and follow up the outcomes of demyelinating episodes in the developing CNS.

The conversion to seronegativity of MOG-Ab during immune therapies was a predictive marker for disease-free activity during the subsequent disease course [57]. However, more prospective data are needed to confirm the predictive value of serial MOG-Ab testing because the results are in part inconsistent and severe relapsing disease courses have been described in patients with decreasing/disappearing antibody levels.

In an acute attack, similar strategies are used as in other CNS inflammatory or immune-mediated demyelinating diseases (intravenous methylprednisolone, plasma exchange, and intravenous immunoglobulin). A favorable recovery was demonstrated in 70%–90% of patients given pulsed intravenous methylprednisolone (dose 20–30 mg/kg/day for children, 500 mg to 1 g/day for adults over 3–5 days [17,58]). Patients were steroid responsive, but 70% of episodes treated with oral prednisone relapsed, particularly at doses <10 mg daily or within 2 months of cessation [58]. Long-term treatment with corticosteroids reduces the risk of relapse, and cessation has been associated with breakthrough disease [58]. Disease worsening or early relapse was observed after corticosteroid tapering or finishing [27,58]. Thus, some authors favored long-term oral prednisone treatment over 6 months (starting dose 1–2 mg/kg/day in children, 1 mg/kg in adults) given alongside other immune-modulating drugs. Use of plasma exchange seems to be associated with improved neurological deficits after corticosteroid failure [33].

A challenge in MOGAD is the choice of long-term immunotherapy since the pharmacological options for NMOSD have not been precisely evaluated in patients with MOGAD. Truly, it remains uncertain whether all MOGAD patients will require long-term treatment given the possibility of a mono phasic course, the commonly lower relapse rate, and the good recovery after attacks in response to acute treatment. A combination of corticosteroids and other immune-mediated therapies seems favorable. Some studies found a reduction in the annualized relapse rate with different immunotherapies such as azathioprine, rituximab, methotrexate, and mycophenolate, maintenance corticosteroids and rituximab being most effective at preventing disease activity, particularly if treatment is maintained for more than 3 months [27,58]. A recent study including children with relapsing MOGAD demonstrated a benefit of intravenous immunoglobulins on the annualized relapse rate [39]. It remains to be determined whether the disease course (i.e., single attack versus further relapses) or higher titers or persistence of MOG-Ab can predict the need for long-term therapy [16].

Typical MS drugs such as natalizumab, interferon, and glatiramer acetate revealed no treatment efficacy [24]. The failure of treatment efficacy in MS is well-known in NMOSD, suggesting a distinct pathomechanism in antibody-associated disorders.

Inflammatory demyelinating CNS diseases include a broad spectrum of diverse diseases, among which single diseases might show distinct clinical phenotypes and prognoses. Over the past few years, our knowledge of clinical, imaging, and laboratory data regarding MOGAD has developed. Despite some overlap, MOGAD exhibits different pathophysiological and phenotypic findings than both AQP4-Ab-associated NMOSD and typical MS. A different immunopathogenesis was found in MOG-Ab-associated NMOSD, with an oligodendrogliopathy rather than a classical astrocytopathy. This finding is clearly different from AQP4-associated disorders and suggests that other therapeutic strategies might be promising. MOG-Ab is of particular interest in pediatric patients with clinical or radiological non-MS typi cal findings and reliably predicts a non-MS demyelinating disease course. Indeed, early publications suggested that anti-MOG antibodies argue for a monophasic disease course, al though recent data have revealed an association with a risk for recurrence. Since persistent reactivity to MOG indicates a recurrent course, serial testing is recommended. Due to the increasing role of antibody testing, MOG-Ab was included in a diagnostic algorithm for children recommending for the first time a stand ardized use in clinical practice except in cases of typical MS. Further large prospective studies on the pathophysiology of MOGAD and the role of longitudinal analysis of antibodies are required to enable the development of evidence-based treatment strategies and assess the possible correlation of titers with disease activity.