Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD): Clinical features and diagnosis

INTRODUCTION — Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is an inflammatory disorder of the central nervous system characterized by attacks of immune-mediated demyelination predominantly targeting the optic nerves, brain, and spinal cord. The disease has a predilection for children.

The epidemiology, pathogenesis, clinical manifestations, and diagnosis of MOGAD are reviewed here. Treatment and prognosis are reviewed separately. (See "Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD): Treatment and prognosis".)

BACKGROUND — Myelin oligodendrocyte glycoprotein (MOG), a protein on the surface of oligodendrocytes, was once considered as a potential antibody target in multiple sclerosis (MS), but early studies were inconclusive. In 2007, a breakthrough occurred, associating MOG-immunoglobulin G (IgG) as a separate demyelinating disease. In a study using MOG self-antigen tetramers detected by a radioimmunoassay technique, MOG antibodies were detected in a subset of patients with acute disseminated encephalomyelitis (ADEM) but rarely in adult patients with MS [1].

Subsequently, newer generation cell-based assays were developed, and the MOGAD phenotype became clearer, with patients now recognized to have episodes of optic neuritis, ADEM, transverse myelitis, or other central nervous system (CNS) manifestations, either alone or in combination. There were overlapping features and important differences clinically, radiologically, and on cerebrospinal fluid analysis distinguishing MOGAD from MS and aquaporin-4-IgG seropositive neuromyelitis optica spectrum disorder (AQP4-IgG NMOSD). Thus, MOGAD has now been confirmed as a distinct CNS demyelinating disease.

PATHOGENESIS — The discovery of a disease-specific serum immunoglobulin G (IgG) antibody that selectively binds myelin oligodendrocyte glycoprotein (MOG) has led to increased understanding of a diverse spectrum of disorders, which are now termed MOGAD. Overall, the pathologic features support an antibody-mediated central nervous system (CNS) demyelinating disease distinct from multiple sclerosis (MS).

●MOG and MOG antibodies – MOG is a minor component of myelin and is expressed on the surface of oligodendrocytes [2]. As a member of the immunoglobulin superfamily, MOG is highly immunogenic [2]. The function of MOG has not been fully elucidated, but it may act as a cell adhesion molecule, regulate microtubule stability, and modulate myelin immune interactions [2]. Its location on the outermost part of the myelin sheath in the CNS makes it a potential target for MOG antibodies. These induce demyelination in experimental autoimmune encephalomyelitis animal models immunized with MOG [3]. However, most human MOG antibodies do not recognize rodent MOG, which has hampered the application of many rodent studies to human MOGAD [4]. It is notable that when human MOG antibodies that do recognize rodent MOG were injected intrathecally in rodents with myelin-reactive T cells, the MOG antibody was noted to be directly pathogenic, inducing demyelination and leading to complement deposition [5].

●Pathology – Human pathology studies of MOGAD have provided some insight into its pathogenesis and mostly have focused on the brain lesions during biopsy or at autopsy [6,7]. An example is shown in the figure (image 1). These studies have revealed coexisting perivenous and confluent demyelination [6,7]. Cortical demyelination is frequent, and intracortical demyelinating lesions predominate [6]. Selective MOG loss was reported in one case series [7] but was not present in another [6]. A CD4-positive T cell inflammatory reaction with granulocytic inflammation is typical, which differs from MS, in which a CD8-positive predominant infiltrate is observed [6,7]. Complement deposition is also noted, and an overlap with pattern II MS pathology has been reported [6-8]. In contrast to aquaporin-4-IgG seropositive neuromyelitis optica spectrum disorder, the expression of aquaporin-4 is preserved in MOGAD, and astrocyte damage is much less prominent [6].

EPIDEMIOLOGY — Epidemiology data for MOGAD are limited mainly because myelin oligodendrocyte glycoprotein immunoglobulin G (MOG-IgG) was discovered only in 2007, and widespread testing was not available until years to a decade later. Thus, initial epidemiology reports may have underestimated the frequency of MOGAD. The incidence and prevalence are largely unknown, although studies in Europe suggest the incidence of MOGAD is between 1.6 and 3.4 per 1,000,000 person-years [9,10]. Children account for up to half of reported cases. In one report, the incidence of MOGAD was higher in children compared with adults (3.0 versus 1.3 per million person-years, respectively) [10]. No major sex differences have been found, and females and males appear to be much more equally affected compared with aquaporin-4-IgG seropositive neuromyelitis optica spectrum disorder (AQP4-IgG NMOSD), in which females predominate by a ratio of up to 10:1 [9-12]. (See "Neuromyelitis optica spectrum disorder (NMOSD): Clinical features and diagnosis", section on 'Epidemiology'.)

The median age of MOGAD onset is 20 to 30 years [13-15]. Comparatively, multiple sclerosis (MS) has a median age of onset of 24 years and an estimated female to male incidence of 2.3:1. (See "Pathogenesis and epidemiology of multiple sclerosis", section on 'Epidemiology and risk factors'.)

Although regional differences in frequency have been reported, particularly high-risk ethnicities have not been identified. There are also geographic differences in the proportion of MOGAD in comparison with AQP4-IgG NMOSD. For example, in the United Kingdom and Sri Lanka, MOGAD was more frequent than AQP4-IgG NMOSD [9,10,16], whereas in Korea, AQP4-IgG NMOSD predominated over MOGAD [11].

A comparison of differences in epidemiology and demographics of MOGAD versus AQP4-IgG NMOSD and MS is outlined in the table (table 1).

CLINICAL FEATURES

Characteristic attacks — While none of the clinical features of MOGAD are disease-specific, some are highly characteristic. These include acute attacks of [13-15,17-21]:

●Unilateral or bilateral optic neuritis resulting in severe visual loss

●Acute disseminated encephalomyelitis (ADEM), resulting in altered mental status, focal neurologic features, and features of transverse myelitis

●Transverse myelitis, often causing limb weakness, sensory loss, and bowel, bladder, or sexual dysfunction

MOGAD may have a monophasic or relapsing course.

Attacks usually develop over days and may plateau with variable recovery over weeks to months. Attacks may be preceded by an infectious illness or vaccination [17,22].

Other central nervous system (CNS) involvement may occur, including the clinical syndrome of neuromyelitis optica spectrum disorder (NMOSD) without aquaporin-4-immunoglobulin G (AQP4-IgG) detected. The latter is characterized by any combination of transverse myelitis and optic neuritis, sometimes with other CNS regions involved. Patients with MOGAD may also present with unilateral cerebral cortical encephalitis resulting in seizures, headache, and other focal neurologic signs. The brainstem can also be involved, but that often occurs in the setting of more widespread ADEM rather than in isolation.

Optic neuritis — Optic neuritis is the most common clinical manifestation of MOGAD at onset and is even more predominant during relapses [13,19]. Optic neuritis occurring with MOGAD is outlined here briefly but discussed in detail separately. (See "Optic neuritis: Pathophysiology, clinical features, and diagnosis" and "Optic neuritis: Prognosis and treatment".)

Optic neuritis presents with varying degrees of vision loss and is almost always associated with eye pain that worsens with movement of the eye. In children, eye pain can be mistaken for nonspecific headache [23].

Optic neuritis (inflammation of the optic nerve) can be caused by any inflammatory condition or may be idiopathic. The features of optic neuritis in MOGAD overlap with optic neuritis occurring in multiple sclerosis and AQP4-IgG NMOSD, although there are certain clinical clues that can suggest MOGAD. Pain with eye movement is common with all causes of optic neuritis, and in the majority of MOGAD cases this precedes the vision loss. Again, in pediatric patients this can be reported as headache and careful distinction can be challenging in young children. Visual loss is typically central and severe (more severe in MOGAD than in multiple sclerosis [MS] but similar in severity to AQP4-IgG NMOSD) with a median visual acuity at nadir of counting fingers [19,24]. Particularly in younger children, vision loss can be underreported or less recognized [25].

On examination, optic disc edema is found in up to 86 percent of MOGAD acute optic neuritis attacks (figure 1); disc edema is more common than with MS or AQP4-IgG NMOSD and may be severe enough to result in peripapillary hemorrhages. When bilateral it can be mistaken for papilledema [19]. In MOGAD, some data suggest that optic neuritis is bilateral in up to 50 percent of cases, with simultaneous vision loss in both eyes [26].

The recovery from MOGAD is typically good, with just 6 to 14 percent of MOGAD patients having a residual visual acuity 20/200 or worse in comparison with a third in AQP4-IgG NMOSD, although residual optic disc pallor is common in MOGAD (figure 2) [24,26]. However, at least half of cases will go on to develop a relapse, and some patients exhibit a glucocorticoid-dependent course, fulfilling criteria for chronic relapsing inflammatory optic neuropathy (CRION) [27]. (See "Optic neuropathies", section on 'Chronic relapsing inflammatory optic neuropathy'.)

Transverse myelitis — Transverse myelitis is defined as inflammation across the spinal cord parenchyma leading to neurologic dysfunction that develops over hours or days and reaches its nadir (maximal deficit) within 21 days [28]. Transverse myelitis is reviewed here briefly and discussed in greater detail separately. (See "Transverse myelitis: Etiology, clinical features, and diagnosis".)

Spinal cord involvement in MOGAD may occur as an isolated attack or in conjunction with involvement in other regions of the CNS (eg, ADEM, optic neuritis) [17,29,30]. The symptoms include the subacute onset of paraparesis or quadriparesis with loss of sensation below the lesion and a sensory level across the trunk [31]. Neurogenic bowel and bladder are frequent, and erectile dysfunction in males is also common, possibly from the frequent involvement of the conus [17,29,30]. Residual bowel, bladder, and erectile dysfunction are common and often more prominent than residual motor deficits [17,29]. Additional features include Lhermitte (electrical sensation radiating into the extremities with neck flexion) or Uhthoff (heat-induced worsening) phenomena. The severity of the myelitis is more than that seen with MS, and up to one-third will be nonambulatory at nadir [17].

In approximately three-quarters of patients, the lesions accompanying a myelitis on sagittal T2-weighted magnetic resonance imaging (MRI) are three or more vertebral segments in length, which is termed longitudinally extensive transverse myelitis (LETM); these are usually located centrally in the spinal cord [17,29,30]. This is helpful to discriminate MOGAD from MS, in which lesions are almost always less than three vertebral segments and often located posteriorly [32]. However, multiple spinal cord lesions are common with MOGAD, and some patients will have a longitudinally extensive lesion combined with a short lesion, while a minority may have only short lesions [17,29,30].

AQP4 seronegative NMOSD — As MOGAD can be associated with optic neuritis and LETM, it is not surprising that MOGAD accounts for one-third to one-half of patients with the clinical syndrome of NMOSD but without aquaporin-4-IgG detected (ie, AQP4-IgG-seronegative NMOSD). However, only 20 to 30 percent of MOGAD patients will fulfill diagnostic criteria for AQP4-IgG seronegative NMOSD, highlighting that MOGAD needs its own separate diagnostic criteria [33]. (See "Neuromyelitis optica spectrum disorder (NMOSD): Clinical features and diagnosis", section on 'MOG autoantibody'.)

ADEM — ADEM is a clinical syndrome characterized by a first polyfocal CNS episode from presumed demyelination that includes encephalopathy not explained by fever, systemic illness, or postictal features [34]. It requires MRI abnormalities that include large poorly demarcated lesions in the white matter with or without gray matter lesions [34]. (See "Acute disseminated encephalomyelitis (ADEM) in children: Pathogenesis, clinical features, and diagnosis" and "Acute disseminated encephalomyelitis (ADEM) in adults".)

ADEM is the most common initial presentation of MOGAD in children, noted in 68 percent of all MOG-positive pediatric cases [35]. Some patients with MOGAD may not have encephalopathy but otherwise have clinical and MRI features of ADEM; these patients are considered along the same spectrum and have sometimes been termed ADEM-like.

While ADEM is usually monophasic, a subset of patients develop relapsing disease with multiple separate ADEM attacks known as multiphasic ADEM; historically, many of these patients may have had MOGAD. Myelin oligodendrocyte glycoprotein (MOG)-IgG is found in 30 to 50 percent of ADEM patients, and its presence may predict a higher likelihood of recurrence [36]. However, patients with MOGAD who have an initial manifestation of ADEM can also have monophasic disease and never relapse.

Cerebral monofocal or polyfocal deficits — Neurologic deficits with MOGAD may be monofocal or polyfocal and develop over hours to days [37]. They are caused by demyelinating brain lesions typically located in the middle cerebellar peduncle, periventricular (fourth ventricle region), supratentorial white matter, juxtacortical, cortical, and/or deep gray nuclei. These lesions are hyperintense on T2-weighted MRI sequences and may or may not enhance with gadolinium. Note that periventricular lesions are less common than they are for multiple sclerosis.

Brainstem and cerebellar features — Isolated brainstem attacks with MOGAD are uncommon when compared with MS. Most often, involvement of these regions occurs as a component of a multifocal CNS demyelinating attack involving other regions of the brain, optic nerve, and/or spinal cord [22,38]. Ataxia and diplopia are the most common clinical accompaniments [22]. While nausea and vomiting may occur as a component of ADEM or its preceding viral prodrome, a distinct area postrema syndrome typical of AQP4-IgG NMOSD with isolated intractable nausea, vomiting, and hiccups is not typically encountered [39-41].

Cerebral cortical encephalitis — A novel clinical syndrome termed cerebral cortical encephalitis is now recognized as a characteristic feature of MOGAD [42]. Clinical manifestations include seizures, aphasia, stroke-like episodes, headache, and fever [43,44]. The majority (up to 80 percent) are unilateral with symptoms referable to one hemisphere and are accompanied radiologically by cortical swelling, T2 hyperintensity, and leptomeningeal enhancement (see 'MRI brain' below). T2 hypointensity in the adjacent white matter has also been reported [45]. Some have used the term "unilateral cortical fluid-attenuated inversion recovery (FLAIR)-hyperintense lesions in anti-MOG-associated encephalitis with seizures" with an acronym FLAMES to describe these episodes [43]. Pathology reveals extensive subpial cortical demyelination with microglial activation and an inflammatory infiltrate [44]. In pediatric patients with encephalitis not meeting ADEM criteria, MOG antibody positive status was found in half of the cases [35].

Cases of bilateral cerebral cortical encephalitis are also described but are less common [46,47]. Limited data suggest that bilateral cerebral cortical encephalitis in children is associated with more fulminant presentations, including critical illness, severe encephalopathy, seizures, and worse outcomes [47].

Seizures — In some patients with MOGAD, seizures may be the presenting feature; this occurs most often in children with cerebral cortical encephalitis or ADEM [48]. The most common seizure types are focal motor seizures and focal to bilateral tonic-clonic seizures. Infrequently, seizures may lead to status epilepticus and the need for temporary mechanical ventilation [48,49].

In a report of 23 patients (19 children and 4 adults) with MOGAD-associated seizures, seizures occurred at disease onset in 16 (70 percent) and resolved within two weeks of the initial presentation in 16 (70 percent) [48]. For the seven patients (30 percent) with ongoing seizures, the time from seizure onset to seizure freedom ranged from 0.5 to 9 years (median 3 years) [48].

Seizures occur more frequently with MOGAD than AQP4-IgG NMOSD [49,50].

Additional syndromes — Caution is advised in attributing novel clinical features to MOGAD, given the potential for false positive MOG-IgG results to occur, particularly at low titer. Thus, for new symptoms or phenotypes to be attributable to MOGAD, patients should have either other characteristic clinical features associated with this disease as outlined above, a very high titer, or both. The spectrum of MOGAD is distinguished by clinical, imaging, and antibody findings. This spectrum includes the following:

●MOGAD is recognized to occasionally coexist with anti-N-methyl-D-aspartate (NMDA) receptor encephalitis, and clinical manifestations can precede or postdate that disorder [51,52].

●Cranial nerve involvement has rarely been reported [53].

●Peripheral nervous system involvement has been reported, and extension of myelitis to the cauda equina nerve roots in a myeloradiculitis phenotype is recognized [54]. Reports of peripheral nerve involvement beyond myeloradiculitis require further study [54], and caution is advised prior to attributing any peripheral nervous system involvement to MOGAD given the propensity for false positive MOG-IgG, particularly at low titers.

●Prolonged fever, presenting as fever of unknown origin, aseptic meningitis, or accompanying an acute demyelination syndrome [55].

Children — Children appear to be predisposed to MOGAD and account for approximately 50 percent of all incident cases of MOGAD [14,15]. The incidence of positive MOG antibodies has been recognized as a common finding in initial presentations, and MOG-IgG is present in approximately one-third of pediatric acute acquired demyelinating syndromes [35,56,57].

In the majority of children presenting with MOGAD, the clinical phenotype is that of ADEM, optic neuritis, or a combination of both, followed by transverse myelitis. In a large study, ADEM composed as high as 68 percent of cases at initial presentation with MOGAD [35]. The optico-spinal phenotype increases in frequency as children get older [58]. In some children, a progressive worsening accompanied by a leukodystrophy-like MRI pattern has been described after one or more ADEM episodes [35,59].

Clinical course: monophasic versus relapsing — MOGAD differs from MS and AQP4-IgG NMOSD in that a large proportion of patients (40 to 50 percent) have a single attack without recurrence, what is termed a monophasic course. Identifying patients destined to have a monophasic course is crucial to avoid using attack-prevention immunosuppressant medications in those destined never to relapse.

The exact frequency of a monophasic course is not yet known with this newly identified disease, as longer follow-up is needed to better determine the relapse risk. Long intervals between attacks have been described, though, and follow-up studies will give more information on these patterns. In a study of 366 patients, 56 percent of adults and 53 percent of children had relapsed after a median follow-up of 2.5 to 3 years [15].

Coexisting autoimmunity — It is recognized that NMDA receptor autoantibodies can have a concomitant demyelinating syndrome at presentation [51]. NMDA antibodies have been shown to coexist on occasion with MOG antibodies, and patients can manifest with combinations of features from both disorders, either concurrently or sequentially. Thus, in patients with features suggestive of and anti-NMDA receptor encephalitis (orofacial dyskinesias, psychosis, seizures), testing cerebrospinal fluid for NMDA receptor antibodies should be considered [51,52]. It is rare for AQP4 antibodies to coexist with MOG autoantibodies (0.06 to 1.1 percent) [60-62]. In such reported cases, the MOG-IgG titer was often low, and the clinical and radiologic syndrome in those cases was more suspicious for AQP4-IgG NMOSD; treatment should be targeted towards the latter [60-62].

In contrast to AQP4-IgG NMOSD, coexisting systemic autoimmunity with clinical features or serologic evidence of connective tissue disorders such as systemic lupus erythematosus or Sjögren's disease are not commonly found with MOGAD [63].

EVALUATION

When to suspect MOGAD — Clinical presentations that should raise suspicion for MOGAD include the following:

●Optic neuritis that is simultaneously bilateral, involves the anterior optic pathway, and is associated with optic disc edema.

●Acute disseminated encephalomyelitis (ADEM) or ADEM-like presentations accompanied by large, poorly demarcated T2 hyperintense lesions in the brain and with T2 lesions within the spinal cord.

●Unilateral cortical encephalitis with headache, fever, seizures, encephalopathy, or other focal neurologic findings with cortical T2 hyperintensity and swelling.

●A complete (rather than partial) spinal cord syndrome, especially with prominent bowel, bladder, or erectile dysfunction symptoms.

Anti-myelin oligodendrocyte glycoprotein immunoglobulin G (MOG-IgG) is required for the diagnosis of MOGAD. While a broader spectrum of clinical features may be seen, caution is needed in cases without any of these core manifestations, given the potential for false positives to occur, particularly at lower titers.

Other clinical, laboratory, and MRI features are considered "red flags" that raise the likelihood of alternative diagnoses (table 2) [64]. In adult patients, it is most important to distinguish MOGAD from multiple sclerosis (MS). Absence of a progressive phase, lower frequency of oligoclonal bands (5 to 20 percent with MOGAD, versus 88 percent with MS), and more frequent MRI T2 lesion resolution in follow-up favors MOGAD over MS (table 1).

In pediatric patients, a similar approach can help with distinguishing MS from ADEM. (See "Differential diagnosis of acute central nervous system demyelination in children", section on 'Distinguishing ADEM and multiple sclerosis'.)

Investigations — The evaluation of suspected MOGAD on initial presentation entails the following imaging and laboratory studies:

●MRI with and without contrast of any symptomatic region of the neuraxis, and all of the following if there is any diagnostic uncertainty or when encephalopathy confounds the neurologic examination:

•Orbits and with fat saturation images

•Brain

•Spinal cord

●Serum for MOG-IgG, tested using a cell-based assay (see 'MOG autoantibody' below)

●Cerebrospinal fluid (CSF) analysis for routine studies (eg, cell count, differential) and oligoclonal bands; in select patients, polymerase chain reaction (PCR) testing for viral infections, and in select patients with features suggestive of anti-N-methyl-D-aspartate (NMDA) receptor encephalitis (orofacial dyskinesias, psychosis, seizures), testing CSF for NMDA receptor antibodies (see 'Cerebrospinal fluid' below and 'Coexisting autoimmunity' above)

In the appropriate clinical setting, the detection of serum MOG-IgG antibodies confirms the diagnosis. However, as with any test, indiscriminate ordering of MOG-IgG in a clinical situation with low prevalence will result in potential false positive diagnoses [64,65].

MRI orbits — An MRI of the orbits, with and without gadolinium contrast and with fat suppression (sometimes also termed fat saturation) images, is often informative in MOGAD. Optic neuritis is the most common manifestation in adults, and dedicated MRI of the orbits is more sensitive than brain MRI for detecting optic neuritis.

●Enhancement of the optic nerve is typical and usually extends >50 percent the length of the nerve (image 2), which differs from MS in which <50 percent of the nerve is more common, despite some overlap [66]. In MOGAD, enhancement of the optic nerve most often involves the anterior optic nerve pathway extending up to the fundus (image 2), which may explain the frequent optic disc edema accompanying it [19]; isolated involvement of the chiasm is more suggestive of aquaporin-4-IgG seropositive neuromyelitis optica spectrum disorder (AQP4-IgG NMOSD) [67].

●Bilateral optic nerve enhancement is noted in approximately 50 percent of cases of MOGAD optic neuritis (image 2). In some cases, the enhancement involves the optic nerve sheath in isolation (image 2) (termed optic perineuritis) [68] or can extend into the orbital fatty tissues (image 2) [19].

MRI brain

●Multiple large poorly demarcated (fluffy) T2 hyperintensities of the white matter are typical with ADEM or ADEM-like like presentations of MOGAD (image 3) [36]. Involvement of the deep gray matter with unilateral or bilateral thalamic or basal ganglia T2 hyperintensities is well recognized (image 3) and helps distinguish MOGAD from MS, although these imaging features do have overlap with AQP4-IgG NMOSD [36,69].

●Tumefactive brain lesions, defined as ≥2 cm diameter T2 hyperintense MRI lesions (image 4), are common in MOGAD. In a retrospective study of 43 patients with MOGAD, at least one tumefactive brain lesion was seen in 22 percent [70].

●Gadolinium enhancement accompanying parenchymal lesions is less well demarcated compared with MS lesions and tends to be patchy, although the pattern has not yet been fully elucidated [36]. Leptomeningeal enhancement occurs in less than 10 percent of adults [71] but may occur in up to 33 percent of children [72].

●Large T2 hyperintense lesions in the middle cerebellar peduncles are a common infratentorial brain lesion (image 3 and image 5), and the large size and indistinct borders can help distinguish MOGAD from MS T2 lesions, which can also involve this region but tend to be smaller and well demarcated [22,38].

●Diffuse brainstem lesions involving the medulla, pons, or midbrain (image 5) account for approximately 20 percent of infratentorial lesions and differ from the focal small, well-demarcated infratentorial T2 lesions of MS (image 6) [22].

●The cerebral cortical encephalitis clinical phenotype may be accompanied by subtle or more dramatic cortical swelling that is often unilateral and may or may not be associated with enhancement (image 7) and has been reported to be accompanied by hyperperfusion on single photon emission computerized tomography (SPECT) scans [42-44].

●A leukodystrophy-like MRI pattern of more diffuse white matter signal abnormality has been noted after one or more attacks of MOGAD [35,59].

MRI spinal cord

●Longitudinally extensive spinal cord lesions on T2-weighted sagittal spine MRI extending ≥3 vertebral segments are common with MOGAD and found in the majority (60 to 100 percent) of cases (image 8). These can occur in isolation or with additional longitudinally-extensive or short lesions [17,29,30]; isolated short lesions may occur but are less common, and consideration for the possibility of MS should be made, particularly if peripherally located or accompanied by a ring of enhancement (image 9).

●On axial images, the lesions are usually central in up to 75 percent [29], and in approximately one-third may be restricted to the gray matter and form a sagittal line and axial H-sign (image 8 and image 9) [17].

●Myelitis with MOGAD has a predilection for the conus (image 8 and image 9), which may explain the high frequency of bowel, bladder, and sexual dysfunction [29]. The lesions are accompanied by mild to moderate swelling, and accompanying gadolinium enhancement occurs in approximately 50 percent but tends to be faint, patchy, and less avid than with AQP4-IgG NMOSD or MS, which can both have ring enhancement (image 9) [17,29]. Leptomeningeal enhancement may occur and extend to cauda equina nerve roots and be accompanied by lower motor neuron signs clinically [54]. Differentiation from acute flaccid myelitis is particularly important in these cases. (See "Acute flaccid myelitis".)

MRI lesion evolution

●Most lesions resolve over time – Most T2 lesions in MOGAD resolve completely (image 6) over the course of months to a few years, which makes it a very useful discriminator from MS and AQP4-IgG NMOSD, in which the majority will have residual T2 hyperintensities [17,22,73]. Gadolinium enhancement tends to resolve within a few months, although this does not distinguish it from MS and AQP4-IgG NMOSD, in which resolution of enhancement is also typical.

●New silent lesions are rare – Outside of clinical attacks, new silent lesions on MRI rarely develop in MOGAD compared with MS, suggesting that the utility of surveillance MRI (which is standard of care in MS) may be less useful in MOGAD [74-76].

MOG autoantibody — We test for serum MOG-IgG antibody using a cell-based assay. Testing is indicated for patients with characteristic clinical, MRI, and laboratory features of MOGAD and in those with a CNS demyelinating syndrome that is atypical for MS. Clinical judgement is required when selecting patients for MOG-IgG testing and when interpreting a positive result, since false positives results do occur.

Uniform testing of MOG-IgG for patients who present with clinical features and have MRI findings typical for MS is not recommended.

Since MOGAD is defined by the presence of MOG-IgG, it is important for clinicians to have at least a cursory knowledge of the MOG-IgG assay, especially the potential for false positives at low titer. Some principles and pitfalls of MOG-IgG testing are summarized in the table (table 3).

●Specimens – Testing serum MOG-IgG is the gold standard. Reports of MOG-IgG detected in CSF but not in serum suggest CSF testing may have a role [77-80]. As an example, a study that included 133 patients with MOGAD found that most patients had MOG-IgG antibodies in both CSF and serum (70 percent), while a minority had antibodies restricted to serum (13 percent) or restricted to CSF (17 percent) [80]. CSF-restricted MOG-IgG was associated with ADEM and cortical encephalitis phenotypes. However, the utility of CSF testing for MOG-IgG antibodies requires further study.

●Assays – Cell-based assays are optimal and recommended [81]. The live cell-based assay performed slightly better than inactivated cell-based assays in assay comparison studies [82,83]. Testing for the IgG isotype is recommended, while testing for other MOG antibody isotypes (IgA, IgM) does not appear to have clinical utility [3]. Protein-based enzyme-linked immunosorbent assay (ELISA) MOG-IgG tests have no clinical utility and tend to give unreliable results [81].

•Clear positive assay – A clear positive MOG-IgG is defined by a live cell-based assay according to the individual assay cutoffs or by fixed cell-based assay result with a titer ≥1:100.

•Low positive assay – A low positive MOG-IgG is defined by a live cell-based assay according to the individual assay cutoffs or by fixed cell-based assay result with a titer ≥1:10 and <1:100.

●Accuracy – MOG-IgG when assessed using a cell-based assay with MOG in its full-length conformational form is a highly specific biomarker of MOGAD [81,82]. The specificity ranges from 97.8 to 100 percent [65,82]. The positive predictive value (true positives/total positives) is more variable, ranging from 72 to 94 percent. This positive predictive value is dependent on the test-ordering practices and disease prevalence. Testing for this rare disease in low-probability settings increases the risk of false positivity [65].

●False positives – There is an important background rate of low-titer MOG-IgG (eg, 1:20 to 1:40) positivity in the general population. Consequently, false positive titers are a significant problem in the evaluation for MOGAD.

As an example, in one study of 1260 clinical samples tested with 92 positive MOG-IgG results, approximately 50 percent of low titers (1:20 to 1:40) were false positives, while at moderate titers (1:100), 18 percent were false positive, and at higher titers (≥1:1000), 0 percent were false positives [65]. Another study tested 2107 consecutive adult inpatients evaluated at a German hospital for a broad range of neurologic diseases and found MOG antibody positivity in 1.2 percent, usually at low titer; only 0.2 percent had true MOGAD [84]. In this study, many of the patients with low positive titers became negative in follow-up assays. Multicenter assay comparison studies have shown excellent agreement for high positives but poor agreement for low positives [81]. Thus, endpoint titers (defined as the reciprocal of the highest dilution giving a signal above a formula-derived cutoff value) are useful when available, with higher titers more predictive of MOGAD. This differs from AQP4-IgG, in which, when using cell-based assays, false positives are extremely rare [85].

●Serial testing – Serial antibody testing may have a role in prognosis, as patients with transient seropositivity are more likely to have a monophasic course, while patients with persistent seropositivity are more likely to relapse [36,57]. Nonetheless, at this stage, treatment decisions are generally made on clinical grounds rather than based on follow-up serology or titer.

Cerebrospinal fluid — The most useful finding on lumbar puncture in MOGAD is that CSF unique oligoclonal bands are typically absent and only found in 5 to 20 percent of patients with MOGAD [86-88] versus up to approximately 88 percent of adult patients with MS [89]. Moreover, CSF oligoclonal bands are less common with MOGAD optic neuritis (<6 percent) than with other MOGAD phenotypes [86-88]. (See "Evaluation and diagnosis of multiple sclerosis in adults", section on 'CSF analysis and oligoclonal bands'.)

In MOGAD, approximately 50 percent of patients have a CSF pleocytosis that, when present, is usually lymphocyte predominant. The frequency of pleocytosis is higher at the time of an attack (55 to 60 percent) versus between attacks, where it is noted in 25 to 30 percent [87,88]. In one study, 29 percent of MOGAD patients had a white cell count that was >50/microL [86], which is higher than MS, in which white cell count elevation >50/microL is rare [22].

The frequency of CSF pleocytosis also differs by attack location and phenotype. With MOGAD myelitis or ADEM phenotypes, a CSF pleocytosis occurs in approximately 75 percent of patients, while with optic neuritis the corresponding value is approximately 25 percent.

An elevated CSF protein is found in up to 50 percent but is nonspecific [86]. Viral PCR testing, in particular for (seasonal) viral infections, is important to assess for alternative diagnoses to MOGAD.

Optical coherence tomography — Optical coherence tomography (OCT) is an imaging tool that can provide quantitative information of the size of the various layers of the retina using near infrared light. OCT is useful test in adult patients with MOGAD given that optic neuritis is the most common manifestation. OCT can assess the features of optic neuritis acutely, identify prior episodes of optic neuritis, and quantify the severity of prior optic nerve damage.

With MOGAD acute optic neuritis attacks, OCT shows peripapillary retinal nerve fiber layer (pRNFL) thickening at the time of presentation consistent with the high frequency of optic disc edema identified clinically in up to 86 percent (figure 1) [90].

Over the course of three to six months after optic neuritis from MOGAD, thinning of the pRNFL and macular ganglion cell and inner plexiform layer (mGCIPL) ensues in almost all cases and may be accompanied by clinically apparent optic atrophy (figure 2); mGCIPL thinning emerges within a few weeks, while pRNFL takes longer to develop, possibly due to the optic nerve head edema, which masks initial thinning in the pRNFL [90]. The thinning of the pRNFL and mGCIPL is more severe with MOGAD than MS, although visual outcomes are similar; the severity of thinning with MOGAD is similar to AQP4-IgG NMOSD, but the visual outcomes in MOGAD are better. The exact reasons for these discrepancies are not yet clear. (See "Optic neuritis: Pathophysiology, clinical features, and diagnosis", section on 'Optical coherence tomography'.)

DIAGNOSIS

Diagnostic criteria — Proposed diagnostic criteria for MOGAD require the following [37]:

●The presence of a core clinical demyelinating event:

•Optic neuritis (see 'Optic neuritis' above)

•Transverse myelitis (see 'Transverse myelitis' above)

•Acute disseminated encephalomyelitis (ADEM) (see 'ADEM' above)

•Cerebral monofocal or polyfocal deficits (see 'Cerebral monofocal or polyfocal deficits' above)

•Brainstem or cerebellar deficits (see 'Brainstem and cerebellar features' above)

•Cerebral cortical encephalitis, often with seizures (see 'Cerebral cortical encephalitis' above and 'Seizures' above)

●A positive myelin oligodendrocyte glycoprotein immunoglobulin G (MOG-IgG) antibody test, fulfilled when the MOG-IgG is clearly positive as defined above. (See 'MOG autoantibody' above.)

In cases where the serum MOG-IgG titer is low positive, positive without a reported titer, or seronegative but with a clear positive cerebrospinal fluid (CSF) MOG-IgG, at least one additional supportive clinical or MRI feature is required along with a seronegative aquaporin 4 (AQP4)-IgG test to fulfill this criterion. (See 'Supportive features' below.)

●The exclusion of a better diagnosis, including multiple sclerosis. (See 'Differential diagnosis' below.)

Supportive features — One or more of the following clinical and MRI features are required for the diagnosis in the absence of a clear positive cell-based serum MOG-IgG assay [37]:

●For optic neuritis:

•Bilateral simultaneous clinical involvement

•Longitudinal optic nerve involvement (>50 percent length of the optic nerve)

•Perineural optic nerve sheath enhancement

•Optic disc edema

●For myelitis:

•Longitudinally extensive myelitis

•Central cord lesion or axial H-sign on imaging

•Conus lesion

●For brain, brainstem, or cerebral syndrome:

•Multiple ill-defined T2-hyperintense lesions in supratentorial and often infratentorial white matter

•Deep gray matter involvement

•Ill-defined T2-hyperintensity involving pons, middle cerebellar peduncle, or medulla

•Cortical lesion with or without lesional and overlying meningeal enhancement

Red flags — Key features suggesting against a diagnosis of MOGAD include the following [37]:

●Progressive neurologic impairment in the absence of attacks

●Rapid worsening of clinical deficits from onset to nadir within minutes to hours

●No improvement following treatment with high-dose glucocorticoids for an acute attack

●MRI findings of well-circumscribed T2-hyperintense lesions in a pattern meeting dissemination in space criteria for multiple sclerosis (MS), especially when accompanied by CSF oligoclonal bands and by the accrual over time of new silent T2-hyperintense focal lesions and retention of most previous T2-hyperintense lesions

●Lesion contrast enhancement that persists for six months or longer

DIFFERENTIAL DIAGNOSIS — The most common considerations in the differential diagnoses of MOGAD are multiple sclerosis (MS) and aquaporin-4-immunoglobulin G positive neuromyelitis optica spectrum disorders (AQP4-IgG NMOSD). A comparison of these three disorders is summarized in the table (table 1). MRI discriminating features are illustrated in the figures for orbital and brain MRI (image 6) and for spine MRI (image 9).

It is crucial to distinguish MOGAD from other disorders, particularly as low-titer false-positive myelin oligodendrocyte glycoprotein (MOG)-IgG antibody results may occur. Recognizing atypical features and red flags that might suggest an alternative diagnosis is essential (table 2).

It is relatively easy to distinguish MOGAD from AQP4-IgG NMOSD, as both have reliable serum biomarkers, and dual positivity of MOG-IgG and AQP4-IgG is rare. However, distinguishing MOGAD from MS, which lacks an antibody biomarker, is more difficult. Given that MS is more common worldwide than MOGAD, distinguishing MOGAD is important, particularly for patients with relapsing disease, as some disease-modifying therapies for MS appear to be ineffective for MOGAD [91].

The best discriminators of MOGAD and MS are:

●MOG-IgG antibody status; the presence of MOG-IgG supports the diagnosis of MOGAD, particularly at higher titers. However, the presence of the antibody alone is insufficient, given that MOG-IgG at low titer can be found in up to 2.5 percent of MS patients [65].

●Cerebrospinal fluid oligoclonal bands; these are absent in most patients with MOGAD and are present in most patients with MS.

●Clinical and magnetic resonance imaging features, particularly the evolution of T2 lesions; most MS lesions leave a residual signal abnormality, while most MOGAD T2 lesions resolve over time (image 5).

CNS demyelinating disorders such as AQP4-IgG seronegative NMOSD and acute disseminated encephalomyelitis (ADEM) are characteristic clinical syndromes associated with MOGAD and should prompt testing for MOG-IgG. When seropositive, the diagnosis should be switched from these syndromic terms to MOGAD. However, the syndromic descriptions are appropriate if MOG-IgG and AQP4-IgG are negative. The same is true for those who have single/recurrent myelitis or optic neuritis not fulfilling diagnostic criteria for another disease (eg, MS); if they are noted to be MOG-IgG positive, it would be more appropriate to use the term MOGAD than the syndromic term.

Aside from MS and AQP4-IgG NMOSD, the differential diagnosis of MOGAD is broad and encompasses disorders that involve the optic nerve, brain, and spinal cord either alone or in combination. The most common differential diagnoses can be stratified by the following categories: genetic, infectious, inflammatory/autoimmune, neoplastic, structural/other, toxic/metabolic, and vascular (table 4).

In children presenting with a rapidly worsening myelitis, another important disorder in the differential diagnosis is acute flaccid myelitis (AFM), which can have significant overlapping features with MOGAD, including a longitudinally extensive spinal cord lesion. With AFM, acute motor weakness is caused by dysfunction or death of anterior horn cells within the gray matter of the spinal cord; MRI of the spinal cord typically identifies T2 hyperintense lesions restricted to or predominantly involving the gray matter. (See "Acute flaccid myelitis".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Multiple sclerosis and related disorders".)

SUMMARY AND RECOMMENDATIONS

●Description – Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is an inflammatory disease of the central nervous system (CNS) characterized by attacks of immune-mediated demyelination. (See 'Background' above and 'Pathogenesis' above.)

●Epidemiology – MOGAD is rare and has a predilection for children but can affect any age, with males and females affected equally. (See 'Epidemiology' above.)

●Clinical features – Characteristic clinical features include attacks of (see 'Clinical features' above):

•Optic neuritis, unilateral or bilateral, causing visual loss, often with optic disc edema

•Acute disseminated encephalomyelitis (ADEM), leading to altered mental status in conjunction with features of transverse myelitis

•Transverse myelitis, often causing limb weakness or numbness with bowel, bladder, and sexual dysfunction

•Cerebral cortical encephalitis, with headache, seizures, and focal neurologic deficits

●Evaluation – The evaluation for MOGAD entails MRI, with and without contrast, of the orbits, brain, and spinal cord; serum testing for myelin oligodendrocyte glycoprotein immunoglobulin G (MOG-IgG) antibody by cell-based assay; and cerebrospinal fluid (CSF) analysis with testing for oligoclonal bands. (See 'Investigations' above.)

•MRI – With optic neuritis, orbital MRI typically shows unilateral or bilateral gadolinium enhancement involving >50 percent of the nerve, with predilection for the anterior optic pathway (image 2). (See 'MRI orbits' above.)

With an ADEM phenotype, brain MRI usually reveals multiple large, poorly demarcated T2 hyperintense lesions in white matter, deep gray matter, the brainstem, or middle cerebellar peduncles (image 3 and image 5). (See 'MRI brain' above.)

With transverse myelitis, spinal cord MRI typically shows longitudinally extensive T2 hyperintense lesions on sagittal images that are located centrally on axial images sometimes restricted to the gray matter forming an H sign; these often involve the conus (image 6 and image 8 and image 9). (See 'MRI spinal cord' above.)

Most T2 hyperintense MRI lesions in the brain and spinal cord of patients with MOGAD resolve completely during follow-up (image 6). (See 'MRI lesion evolution' above.)

•MOG-IgG antibody – Serum MOG-IgG antibody has a high specificity for MOGAD, but false positives (often low titer) can occur, particularly when ordered in low-probability situations. (See 'MOG autoantibody' above.)

•Oligoclonal bands – CSF oligoclonal bands are positive in only 5 to 20 percent of patients with MOGAD versus 88 percent of patients with MS. (See 'Cerebrospinal fluid' above.)

●Diagnosis – Diagnostic criteria for MOGAD require the presence of a core clinical demyelinating event (ie, optic neuritis, transverse myelitis, ADEM, cerebral monofocal or polyfocal deficits, brainstem or cerebellar deficits, or cerebral cortical encephalitis), a positive MOG-IgG antibody test, and the exclusion of a better diagnosis, including multiple sclerosis. Full criteria, along with supportive features and red flags, are listed above. (See 'Diagnostic criteria' above.)

●Differential diagnoses – The most common considerations in the differential diagnoses of MOGAD are multiple sclerosis and aquaporin-4-IgG positive neuromyelitis optica spectrum disorders (AQP4-IgG NMOSD) (table 1). (See 'Differential diagnosis' above.)

●Treatment and prognosis – The treatment and prognosis of MOGAD are discussed in detail separately. (See "Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD): Treatment and prognosis".)