Проблемы, связанные с диагностикой и лечением заболевания миелином Олигодендроцитом Гликпротеином противомоскитных заболеваний (МОГАД).

Introduction

Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is one of the latest in a line of well-characterized antibody-mediated autoimmune inflammatory disorders of the central nervous system (CNS).[ 1 ] There is significant clinical and radiological overlap [ Table 1 ] with multiple sclerosis (MS)[ 2 ] and aquaporin-4 (AQP4)-IgG–associated neuromyelitis optica spectrum disorders (NMOSDs).[ 3 ] Originally, myelin oligodendrocyte glycoprotein (MOG) was identified as a potent target for autoantibody generation in experimental models of autoimmune encephalitis.[ 4 ] In early years, MOG antibody was tested in clinical settings using enzyme-linked immunosorbent assay, but the results were not disease specific and often misidentified MS.[ 5 ] Refining of testing methods and the use of three-dimensional MOG protein as a substrate enabled the detection of MOG-IgG specifically in acute disseminated encephalomyelitis (ADEM) and optic neuritis (ON), but not MS.[ 6 ] Later, cell-based assays (CBAs) expressing full-length MOG on mammalian cells became the standard for diagnosis of MOGAD.[ 7 ]

Table 1 Differentiating MOGAD from AQP4-IgG + NMOSD and MS MOGAD AQP4-IgG + NMOSD MS Typical age of onset (age in years) 0–40 30–50 20–40 Gender (F: M) 1:1 9: 1 3:1 Preceding infection/vaccination Common Rare Rare Course Relapsing or monophasic Mostly relapsing Relapsing from onset mostly, progressive from onset (<10%) Optic neuritis Common, most often bilateral, optic disc edema common Common, may be bilateral, optic disc edema uncommon Less common (often detected subclinically), disc edema uncommon Myelitis Common Common Common Encephalopathy Common Rare Rare Area postrema syndrome Rare Common Not associated Seizures Common Rare Rare MRI of the optic nerve Uni/bilateral long lesions, anterior, pre-chiasmatic segments affected, perineural enhancement common Uni/bilateral, long segment, posterior segment and chiasmatic involvement common Short segment, anterior segment, mainly intraorbital involvement MRI of the spinal cord Longitudinally extensive lesions, may have short segment lesions also and >1 lesion, conus involved, H-sign axially, enhancement in 50% Longitudinally extensive, usually single lesion. Central/diffuse on axial images, ring or patchy enhancement Short segment peripheral lesions predominantly in the cervical cord, ring or nodular enhancement MRI of the brain ADEM-like lesions in cerebral hemispheres, thalamus, and deep nuclei; cerebellar peduncle lesions, uni/bilateral cortical hyperintensity Area postrema, peri-third/fourth ventricle, corticospinal tract involvement; often nonspecific white matter lesions Ovoid periventricular, infratentorial, juxtacortical, central vein sign. Ring enhancement CSF – oligoclonal bands -White cell count >50/μl Seen in <20% (transient) ~35% Seen in <20% (transient) 0–35% Seen in >85% (persistent) Rare ADEM: acute disseminated encephalomyelitis, AQP4-IgG + NMOSD: aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder, CSF: cerebrospinal fluid, MOGAD: myelin oligodendrocyte glycoprotein antibody-associated disease, MRI: magnetic resonance imaging, MS: multiple sclerosis

Differentiating MOGAD from AQP4-IgG + NMOSD and MS

ADEM: acute disseminated encephalomyelitis, AQP4-IgG + NMOSD: aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder, CSF: cerebrospinal fluid, MOGAD: myelin oligodendrocyte glycoprotein antibody-associated disease, MRI: magnetic resonance imaging, MS: multiple sclerosis

The search strategy for this paper involved searching PubMed database using the following search terms: “myelin oligodendrocyte glycoprotein antibody,” “MOG IgG,” “MOGAD,” “NMOSD,” “multiple sclerosis,” “demyelinating diseases,” “false positive MOG IgG,” “differential diagnosis of MOGAD,” and “treatment of MOGAD.”

Pathology and pathophysiology distinct to MOGAD

Characteristically, there is perivenous confluent white matter demyelination, MOG loss in myelin, and a prominent intracortical demyelination. Inflammatory response is marked by mainly CD4+ T-cell and granulocytic aggregation with complement deposition in areas of active demyelination.[ 8 9 ] These features are common to ADEM, and it is now known that 50% of the latter have MOG-IgG positivity.[ 10 ] There is also some pathological overlap with MS, especially “MS pattern type II,” due to the complement and IgG deposition seen histopathologically in both these conditions.[ 11 ] However, the predominance of CD4+ rather than CD8+ T cells, predominant intracortical demyelination, and absence of slowly expanding lesions distinguish MOGAD from MS.[ 12 13 ] It is worth noting that AQP4 expression is preserved, with no complement deposition in these regions and relative preservation of oligodendrocytes that distinguishes MOGAD from AQP4-IgG + NMOSD. The MOG protein is selectively expressed in the outermost layers of CNS myelin, where it becomes an easy target for circulating MOG-IgG. The exact role of MOG IgG in the pathophysiology of MOGAD is unclear. It is generally considered that binding of antibodies to the cell surface may cause damage through complement-mediated or antibody-dependent cellular cytotoxicity, though the specific pathophysiology is unclear.

Clinical features and radiological correlates typical of MOGAD

In general, there is a high frequency of disease onset in pediatric population and no gender predilection, when compared to other demyelinating disorders.[ 14 ] MOGAD lesions, on magnetic resonance imaging (MRI), often have ill-defined borders and may appear “fluffy.” Nearly 50% of lesions in the acute phase may show enhancement. Attacks may occur in isolation (e.g. ON or transverse myelitis [TM]) or in combination with multiple sites of involvement (e.g., ADEM with ON).

Acute disseminated encephalomyelitis

ADEM is a clinical phenotype found more frequently in pediatric population and is typically seen in children <10 years of age. Encephalopathy accompanied by a multifocal involvement is typically common. In 5% of patients, the disease may be severe enough to require ventilatory care. Brain MRI usually shows multiple large T2-weighted hyperintense lesions in bilateral supratentorial white matter, cortex, and bilateral or unilateral deep gray nuclei and also shows thalamic involvement [ Figure 1 k]. Occasionally, “ADEM-like” brain lesions may be seen without clinical encephalopathy in the background of ON or TM. Large supratentorial confluent lesions may occur bilaterally, which resembles leukodystrophy, usually in children.

(a) Unilateral long segment ON (marked by arrow). (b) Unilateral ON showing contrast enhancement of the optic nerve sheath. (c) Unilateral ON involving orbital segment of the optic nerve. (d) Bilateral ON. (e) LETM in the cervical cord. (f) Conus myelitis. (g) Bilateral middle cerebellar peduncle lesions. (h) Seventh and eighth cranial nerve hyperintensity unilaterally. (i and j) Examples of typical brainstem lesions. (k) ADEM lesions. (l and m) Nonspecific brain lesions in MOGAD. (n) Bilateral cortical encephalitis (FLAMES). ADEM: acute disseminated encephalomyelitis, FLAIR: fluid-attenuated inversion recovery, FLAMES: FLAIR-hyperintense lesion in anti-MOG–associated cortical encephalitis with seizures, LETM: longitudinally extensive transverse myelitis, MOG: myelin oligodendrocyte glycoprotein, MOGAD: MOG antibody-associated disease, ON: optic neuritis

Optic neuritis

It is the most common manifestation of MOGAD in adults and older children.[ 15 ] It occurs bilaterally in nearly 50% of patients and is accompanied by optic disc oedema in nearly 80% of patients. Occasionally, peripapillary hemorrhages and “macular star” may be seen in the fundus. Recurrent ON is a common phenotype and is occasionally associated with a steroid dependency state. Typically, visual deficit is severe at nadir with good visual recovery in the aftermath of steroid therapy. Orbital MRI shows long segment hyperintensity of the optic nerve with patchy contrast enhancement in ~ 85% of patients [ Figure 1 a–d]. Orbital sheath enhancement is a feature of MOGAD, with occasional orbital fat enhancement too. Optic chiasmal involvement is rare.

Myelitis

Spinal cord involvement is a common feature, occurring either as an isolated episode of TM or as part of an NMOSD phenotype. Recurrent TM may be rarely seen. On imaging, typically, longitudinally extensive TM (LETM) is seen, often coexisting with short segment myelitis [ Figure 1 e]. Occasionally, there are only multiple short segment myelitis, which should not be confused with eccentric short segment myelitis of MS.[ 16 ] The conus medullaris is more frequently involved in MOGAD compared to AQP4-IgG + NMOSD [ Figure 1 f]. Nonspecific enhancement of lesions and leptomeningeal enhancement may be seen, with the latter found particularly in children. Axially, the lesions may be more centrally placed and show an “H” sign in one-third of patients, which is not necessarily specific to MOGAD. In contrast, AQP4-IgG–associated LETM tends to be a single lesion, usually in the cervical cord with extension into the lower brainstem, and shows an elongated ring enhancement pattern.

Brainstem/cerebellar attacks

In MOGAD, brainstem or cerebellar symptoms usually occur in the context of polyfocal cerebral involvement or ADEM and are mainly represented by ataxia or diplopia. Area postrema syndrome has been rarely reported. Brainstem lesions are seen in nearly 20% of patients; they are often asymptomatic and are detected in the midbrain, pons, or medulla as T2-hyperintense lesions [ Figure 1 i and j]. “Fluffy” lesions may be typically seen in unilateral or bilateral middle cerebellar peduncles[ 17 ] [ Figure 1 g].

Cortical encephalitis

An uncommon but unique clinical presentation is cortical encephalitis manifesting with encephalopathy, seizures, and cortical hyperintensity on fluid-attenuated inversion recovery (FLAIR) images [ Figure 1 n]. It is often referred to by the acronym FLAMES (FLAIR-hyperintense lesion in anti-MOG–associated cortical encephalitis with seizures).[ 18 ] Other causes of encephalitis including infective and autoimmune causes must be excluded.

It is worth noting that nonspecific brain lesions may occur often asymptomatically in the background of ON and TM [ Figure 1 l and m].

The expanding spectrum of MOGAD

Raised intracranial pressure (ICP) associated with aseptic meningitis or specific phenotypes such as ADEM and ON has been reported with elevated MOG-IgG titers.[ 19 20 ] A high opening pressure on lumbar puncture was often recognized that occasionally required specific interventions including shunting. It is particularly important not to overlook the fact that optic disc edema is commonly associated with MOGAD ON, and that the two entities may coexist. Isolated seizure at the onset without MRI changes has been reported, with brain lesions developing months later.[ 21 ] An association with autoimmune encephalitis has been reported in several studies. In ~ 2% of patients diagnosed to have N -methyl d-aspartate receptor (NMDAR) encephalitis, MOG-IgG testing was positive. MOGAD was diagnosed before, simultaneously, or after the development of NMDAR encephalitis.[ 22 ] A few cases of biopsy-proven CNS vasculitis have been described with elevated MOG-IgG. These patients had varying clinical presentations that included encephalopathy with focal deficits and progressive cognitive decline accompanied by multifocal brain lesions involving both gray and white matter.[ 23 24 ] Cranial neuropathies other than ON have been described in MOGAD [ Figure 1 h]. The common cranial nerves involved include VII, VIII, and V nerve most often associated with brainstem encephalitis and occasionally in isolation.[ 25 26 ] Myeloradiculitis and inflammatory peripheral neuropathies have been described in a small number of patients.[ 27 ] Paraspinal muscle hyperintensity has been reported with LETM associated with MOGAD.[ 28 ]

Concomitant autoimmunity is less frequent in MOGAD compared to other demyelinating disorders. Reports of association with NMDAR encephalitis have been found. These patients may present with encephalopathy, seizures, and leptomeningeal enhancement.[ 29 ]

Diagnosis of MOGAD

Detection of MOG-IgG in the serum is critical to the diagnosis of MOGAD. The gold standard for MOG-IgG detection is CBA. Earlier, it was considered that live CBA (LCBA) was superior to fixed CBA (FCBA) for diagnostic sensitivity and specificity.[ 30 31 ] Recently, real-word studies that compared the performance of both assays suggested a high agreement between the results of FCBA in 1:10 dilutions EUROIMMUN (Lubeck, Germany) and LCBA in positive titers (as designated by individual labs).[ 32 33 ] It cannot be overemphasized that detection of a positive MOG-IgG test has to be interpreted carefully. The guidelines laid out in the international MOGAD panel proposed diagnostic criteria[ 1 ] [ Table 2 ], underscores the need for a matching clinical phenotype, provides guidelines for the interpretation of CBA results (both LCBA and FCBA) and highlights the need for a supportive criteria when assay results are inconclusive. False-negative results may be encountered, especially in patients receiving immunosuppressive treatments or when samples are tested after plasma exchange (PLEX). In addition, in the Indian scenario, where testing is mostly outsourced to commercial testing centers, suboptimal sample transporting conditions and technical expertise could likely influence test results. False-positive tests are equally important and low positive results may be seen in a variety of clinical settings including MS, migraine, hypoxic ischemic brain injury, and hypertrophic pachymeningitis.[ 34 ] Testing for MOG-IgG in the cerebrospinal fluid (CSF) is not routinely recommended. Infrequently, isolated CSF MOG-IgG positivity has been reported.[ 35 ] The interpretation of such results should be done cautiously since the same may be observed in MS and other diseases as well. MOG-IgG titers may wane over time, but may also persist for several years in some cases.

Table 2 International panel-proposed diagnostic criteria for MOGAD (Adapted from Banwell et al.)[ 1 ] Diagnosis of MOGAD (requires fulfillment of A, B, and C) (A) Core clinical demyelinating event a Optic neuritis Myelitis ADEM Cerebral monofocal or polyfocal deficits Brainstem or cerebellar deficits Cerebral cortical encephalitis often with seizures (B) Positive MOG-IgG test Cell-based assay: serum Clear positive b No additional supporting features required Low positive b • AQP4-IgG seronegative AND • ≥1 supporting clinical or MRI feature Positive without reported titer Negative but CSF positive Supporting clinical or MRI features Optic neuritis • Bilateral simultaneous clinical involvement • Longitudinal optic nerve involvement (>50% length of the optic nerve) • Perineural optic sheath enhancement • Optic disc edema Myelitis • Longitudinally extensive myelitis • Central cord lesion or H-sign • Conus lesion 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 the pons, middle cerebellar peduncle, or medulla • Cortical lesion with or without lesional and overlying meningeal enhancement (C) Exclusion of better diagnoses including multiple sclerosis a Clinical features should match typical presentations as described in text. b MOG-IgG titers required for diagnosis are outlined in text. ADEM: acute disseminated encephalomyelitis, AQP4: aquaporin-4, CSF: cerebrospinal fluid, MOG: myelin oligodendrocyte glycoprotein, MOGAD: MOG antibody-associated disease, MRI: magnetic resonance imaging

International panel-proposed diagnostic criteria for MOGAD (Adapted from Banwell et al.)[ 1 ]

a Clinical features should match typical presentations as described in text. b MOG-IgG titers required for diagnosis are outlined in text. ADEM: acute disseminated encephalomyelitis, AQP4: aquaporin-4, CSF: cerebrospinal fluid, MOG: myelin oligodendrocyte glycoprotein, MOGAD: MOG antibody-associated disease, MRI: magnetic resonance imaging

Interpretation of International MOGAD diagnostic criteria [ Table 2 ].[ 1 ] There are three components (A–C) to this classification. The most important step would be to identify clinical phenotypes (component A) that are suggestive of MOGAD. In a real-world setting, in the Indian setup, after a clinical evaluation, all patients would undergo MRI of the brain, optic nerve, and spinal cord. Imaging helps to clarify whether there are alternative conditions to be considered (component C) and, at the same time, identify the MRI characteristics which are supportive of the diagnosis (component B). The International MOGAD panel classification has categorized MOG-IgG titer (component B) as follows: clear positive/low positive when tested by LCBA, depending on the individual lab cut-off values (e.g., Mangalore MOGAD assay[ 33 ] recognizes a clear positive result if MOG-IgG is detected at >1:320 dilutions, low titer if detected at >1:160–320 dilutions, and negative if detected at <1:160 dilution). When tested by FCBA (Euroimmun) method, a titer ≥1:100 is considered as clear positive, while a titer >1:10 but <1:100 is deemed to be low positive. It is mandated that if there is a low positive titer in serum, isolated positivity in CSF alone, or the test results do not mention titers, there is a need for additional clinical and MRI criteria to be fulfilled.[ 1 ] In India, there is only one center which offers a live assay for MOG-IgG testing. Hence, for all practical purposes, the MOG-IgG testing (using commercially available EUROIMMUN testing) method in our region will be mostly a fixed assay at standard 1:10 dilution. Therefore, there is a real need for careful consideration of all components of the diagnostic criteria, with special attention given to the clinical phenotype and supportive features, before deciding on a final diagnosis.

Treatment of MOGAD

Acute therapy

Treatment in the acute phase would be similar to that for other demyelinating diseases such as MS and AQP4-IgG + NMOSD. It includes intravenous steroids and PLEX [ Table 3 ]. Intravenous immunoglobulin G (IVIg) may be substituted for PLEX and is cost effective in pediatric settings in our practice. Unlike in MS, the need to escalate primary therapy from steroids to PLEX/IVIg is more urgent for antibody-mediated demyelinating disorders such as MOGAD and NMOSD. Recent studies suggest that time to treat (<7 days from onset) is crucial for meaningful recovery from neurologic deficits in the latter.[ 36 ] There is also a need for careful and slow tapering of oral steroids over 1–2 months after the acute treatment to ensure that pseudo-relapses do not occur.[ 37 ]

Table 3 Treatment of MOGAD using accessible treatments available in India Acute therapy Dose (standard adult dose) Adverse effects/drawbacks Methylprednisolone IV 1 g daily ×5 days Hyperglycemia (especially in diabetics) and rarely steroid psychosis PLEX Five to seven exchanges on alternate days Vascular hypotension, cardiac arrythmias, PLEX-associated infections reported IVIg 0.4 g/kg/day×5 days Hyperviscosity, increased risk of thromboembolic events, rarely renal failure and aseptic meningitis. IgA levels to be obtained before therapy to avoid IgA deficiency-related anaphylaxis Maintenance therapy     Oral prednisolone 30–40 mg/day as a single dose×12 weeks and slow taper over remaining 6–12 weeks Hyperglycemia, cushingoid features, superinfection     Maintenance IVIg 0.4–2 g/kg monthly after initial acute therapy with IVIg High cost, frequent hospital visits for IV infusions (subcutaneous IVIg unavailable in India)     Azathioprine (oral) 2–3 mg/day in divided dose+oral steroids (30–40 mg/day tapered and stopped in 6 months) Leukopenia, GI dysfunction, hepatotoxicity, increased risk of infection     Mycophenolate mofetil (oral) 600 mg/m 2 or 2 g daily in divided doses+oral steroids (30–40 mg/day tapered and stopped in 3 months) GI side effects, hypercholesterolemia, elevation of transaminases, bone marrow suppression and infections, rarely PML     Rituximab (IV) 1 g IV (optional booster of 1 g after 2 weeks) every 6 months (frequency may be guided by CD19 counts) Infusion-associated allergic effects; in the long term, hypogammaglobulinemia and increased risk of infection     Tocilizumab (IV) 8 mg/kg monthly, for a maximum recommended dose of 800 mg/month in adults High cost, limited studies. Effective as a rescue therapy in raised ICT settings GI: gastrointestinal, ICT: intracranial tension, IV: intravenous, IVIg: intravenous immunoglobulin G, MOG: myelin oligodendrocyte glycoprotein, MOGAD: MOG antibody-associated disease, PLEX: plasma exchange, PML: progressive multifocal leucoencephalopathy

Treatment of MOGAD using accessible treatments available in India

GI: gastrointestinal, ICT: intracranial tension, IV: intravenous, IVIg: intravenous immunoglobulin G, MOG: myelin oligodendrocyte glycoprotein, MOGAD: MOG antibody-associated disease, PLEX: plasma exchange, PML: progressive multifocal leucoencephalopathy

Chronic therapy

More than 50% of MOGAD patients develop relapses.[ 38 ] Generally, it is recommended to start chronic therapy after the second attack, but in some exceptional circumstances such as incomplete recovery from a severe neurologic deficit, after the first attack, it may be justified. As yet there are no disease-specific US Food and Drug Administration–approved therapies for MOGAD. The current therapies that are being used for MOGAD, were introduced earlier for AQP4-IgG associated NMOSD. These include complement inhibitors such as eculizumab and ravulizumab, interleukin (IL)-6 receptor blockers such as satralizumab, and B-cell depletors such as inebilizumab, all of which are unavailable in India. The role of rituximab is not clear. Despite B-cell depletion, patients treated with rituximab may be unable to sustain remission, which suggests that there may be different immunological mechanisms underlying the disease.[ 39 ] Small observational studies suggest that mycophenolate mofetil (MMF) and azathioprine (AZA) may be useful.[ 40 ] When initiating AZA and MMF, it is recommended to bridge these patients with prednisolone for 3–6 months. Maintenance immunoglobulin therapy is effective, but the dosing strength and frequency required make it an expensive option in our settings. Tociluzimab, a humanized IL-6 receptor antagonist, has been found beneficial in a small number of patients studied.[ 41 ] Tociluzimab may be also used as an effective rescue therapy in intractable raised intracranial tension associated with MOGAD. Current treatments that are feasible in low–middle-income countries such as ours are listed in Table 3 and are based on currently available published data and the authors’ personal experience.

Conclusions and future challenges

Undoubtedly, MOGAD has overlapping clinical similarities with relapsing–remitting MS and NMOSD. Widening of the clinical spectrum of MOGAD that currently includes cranial and radicular neuropathies and raised ICP associated with aseptic meningitis, ADEM, or ON may present diagnostic dilemmas. Future revisions of the diagnostic criteria will hopefully include new phenotypes, MRI, and other supportive criteria that enable diagnosis in the convalescent and chronic phase of the disease. Interpretation of the results of MOG-IgG test requires a thorough understanding of the pitfalls and shortcomings related to the same. Relapse prediction is difficult and may be determined by the length of follow-up, pediatric versus adult populations, initial phenotype, assay titers at the onset and remission phase of attacks, and concomitant treatments.[ 10 14 40 41 42 ] Most importantly, as of now, there are no approved disease-specific treatments available for MOGAD. Currently, there are two ongoing clinical trials for rituximab and IL-6 receptor blocker sartralizumab, the results of which may impact future treatment practices for relapsing MOGAD.

Conflicts of interest

There are no conflicts of interest.