MOGAD: Key Neurological Insights and Relapse Patterns

Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is an autoimmune condition affecting the central nervous system, leading to episodes of inflammation in the optic nerves, spinal cord, and brain. While it shares similarities with other demyelinating disorders, its distinct immune mechanisms and clinical features set it apart. Understanding MOGAD’s relapse patterns and neurological impact is critical for early diagnosis and effective management.

Pathophysiology And Immune Mechanisms

MOGAD results from an autoimmune attack on myelin oligodendrocyte glycoprotein (MOG), a surface protein expressed on oligodendrocytes and myelin sheaths in the central nervous system. Unlike multiple sclerosis (MS) or neuromyelitis optica spectrum disorder (NMOSD), MOGAD is driven by antibodies targeting MOG rather than a T-cell-driven process. This antibody-mediated mechanism leads to inflammatory demyelination, disrupting neural conduction and triggering neurological dysfunction.

Studies using passive transfer experiments in rodents show that human-derived MOG antibodies induce demyelination and inflammatory lesions similar to those seen in MOGAD patients. Unlike aquaporin-4 (AQP4) antibodies in NMOSD, which primarily target astrocytes, MOG antibodies directly affect oligodendrocytes, producing a different pattern of tissue damage. Histopathological analyses of MOGAD lesions reveal perivenous demyelination with relative preservation of astrocytes, distinguishing it from NMOSD and MS.

The immune response in MOGAD is largely humoral, with immunoglobulin G1 (IgG1) subclass antibodies playing a central role. These antibodies activate complement pathways and recruit immune cells, leading to inflammation and myelin destruction. However, complement deposition in MOGAD lesions appears less pronounced than in NMOSD, suggesting that antibody-dependent cellular cytotoxicity (ADCC) and macrophage-mediated phagocytosis may be the dominant mechanisms. Autopsy studies and experimental models highlight macrophage infiltration and microglial activation as key features of MOGAD pathology.

Neurological Manifestations

MOGAD primarily affects the optic nerves, spinal cord, and brain. Optic neuritis is a common presentation, often causing unilateral or bilateral vision loss, eye pain, and impaired color perception. Unlike MS, where optic neuritis typically involves retrobulbar inflammation, MOGAD-related optic neuritis frequently affects the anterior optic nerve, leading to pronounced optic disc swelling. This can be misinterpreted as papilledema, complicating diagnosis. Patients often experience severe visual impairment during acute episodes but generally recover better than those with aquaporin-4 antibody-positive NMOSD.

Spinal cord involvement presents as acute transverse myelitis, causing motor, sensory, and autonomic dysfunction. Lesions tend to be longitudinally extensive, spanning three or more vertebral segments, though shorter lesions can also occur. Symptoms include limb weakness, paresthesia, and bladder or bowel dysfunction. Compared to NMOSD, MOGAD-associated myelitis lacks severe necrotic features and has a more favorable recovery. However, relapses can lead to cumulative disability if they affect the same spinal regions. Imaging reveals T2-hyperintense lesions in the central gray matter of the spinal cord, aiding differentiation from other demyelinating disorders.

Brain and brainstem involvement can cause encephalopathy, ataxia, and cranial nerve deficits. Lesions are often transient and poorly defined, affecting cortical, subcortical, and deep white matter regions. In pediatric cases, MOGAD may present as acute disseminated encephalomyelitis (ADEM), characterized by widespread brain inflammation, altered mental status, and multifocal neurological deficits. Children with ADEM often exhibit drowsiness, irritability, and seizures, reflecting diffuse cortical involvement. In adults, brainstem attacks can lead to oculomotor disturbances, dysphagia, and respiratory complications, particularly if the medulla is affected. These episodes can be severe but generally resolve more completely than NMOSD-related brainstem syndromes.

Diagnostic Approaches

Diagnosing MOGAD requires clinical evaluation, imaging, and serological testing. Given its overlap with MS and NMOSD, recognizing symptom patterns and lesion characteristics is crucial. MOGAD lesions often appear in the deep and subcortical white matter and frequently resolve over time without leaving persistent black holes or significant atrophy, distinguishing it from MS.

Magnetic resonance imaging (MRI) plays a central role, with optic nerve involvement being a key feature. MOGAD-related optic neuritis typically presents with anterior optic nerve swelling, contrasting with the retrobulbar inflammation seen in MS. Spinal cord lesions often extend across multiple vertebral segments but, unlike NMOSD, are more centrally located within the gray matter. Brain lesions vary widely, with some resembling ADEM, particularly in children. Diffusion-weighted imaging may help differentiate MOGAD from other demyelinating conditions, as lesions exhibit less restricted diffusion than ischemic or necrotic processes.

Serological testing for MOG antibodies is the definitive diagnostic method. The most reliable assay is the live cell-based immunofluorescence test, which detects immunoglobulin G (IgG) antibodies against full-length human MOG protein. Enzyme-linked immunosorbent assays (ELISA) and fixed cell-based assays are less specific and can yield false positives. A positive MOG-IgG test in the right clinical and radiological context strongly supports the diagnosis, but antibody titers can fluctuate, and seroreversion has been observed, complicating long-term monitoring.

Relapse Patterns

MOGAD follows an unpredictable course, with some patients experiencing a single episode and others developing a relapsing pattern. Unlike MS, where relapses accumulate over time, MOGAD attacks are typically discrete events without ongoing progression between episodes. Studies indicate that 30–50% of patients experience at least one relapse within the first few years. While some remain in remission, others suffer multiple recurrences, particularly without long-term immunotherapy.

Certain features influence relapse risk. Patients with optic neuritis or transverse myelitis are more likely to experience recurrent episodes than those with a monophasic ADEM course. Bilateral optic neuritis at onset is associated with an increased risk of subsequent attacks, often leading to cumulative visual impairment. Persistent antibody positivity does not always predict recurrence, complicating long-term prognostication.

Therapeutic Strategies

Managing MOGAD involves acute treatment during relapses and long-term strategies to prevent recurrence. Acute attacks are typically treated with high-dose intravenous methylprednisolone (IVMP), administered at 1,000 mg per day for three to five days. If corticosteroids are insufficient, therapeutic plasma exchange (PLEX) is used to remove circulating MOG antibodies. Early PLEX intervention improves visual and motor outcomes, particularly in severe optic neuritis or transverse myelitis. Intravenous immunoglobulin (IVIG) has shown promising results in corticosteroid-resistant cases.

For high-risk patients, long-term immunotherapy prevents relapses. Unlike NMOSD, where B-cell depletion therapies like rituximab are highly effective, MOGAD responds inconsistently to these agents. Instead, IVIG, mycophenolate mofetil, and azathioprine are commonly used, with IVIG showing particular efficacy. A multicenter study found that IVIG maintenance therapy significantly reduced recurrence, especially in those with frequent attacks. The choice of therapy depends on relapse severity, tolerability, and patient preference. Some individuals with a monophasic course may not require ongoing immunosuppression, but close monitoring is essential, as relapses can occur even after prolonged remission.

Differences From NMOSD

MOGAD and NMOSD share overlapping clinical features, but distinct pathological and radiological differences help differentiate them. MOGAD is mediated by antibodies against myelin oligodendrocyte glycoprotein, while NMOSD is associated with aquaporin-4 (AQP4) antibodies. This distinction results in unique patterns of tissue damage, with NMOSD exhibiting extensive astrocyte destruction and necrotic lesions, while MOGAD lesions tend to have more reversible inflammation.

MRI characteristics provide additional clues. NMOSD lesions are often more destructive, with longitudinally extensive spinal cord involvement extending into the central canal and periependymal regions. In contrast, MOGAD spinal cord lesions are more centered in the gray matter. Optic neuritis in NMOSD frequently leads to severe, permanent visual impairment, whereas MOGAD-associated optic neuritis, though often bilateral, generally has a better recovery. Brain lesions in NMOSD follow a periependymal pattern around the third and fourth ventricles, while MOGAD lesions are more variable, often resembling ADEM. Serological testing for AQP4 and MOG antibodies ensures accurate diagnosis and appropriate treatment.

Pediatric And Adult Presentations

MOGAD differs between pediatric and adult populations in clinical presentation, relapse propensity, and long-term outcomes. Children are more likely to present with ADEM, characterized by widespread brain inflammation, encephalopathy, and multifocal neurological deficits. Pediatric patients with ADEM-associated MOGAD generally experience a monophasic course, with many recovering fully. However, recurrent attacks can occur, particularly with initial optic neuritis or myelitis.

In adults, MOGAD more frequently manifests as recurrent optic neuritis, transverse myelitis, or brainstem syndromes. Unlike pediatric cases, adult-onset MOGAD has a higher likelihood of a relapsing course. Optic neuritis in adults is often severe and bilateral, though visual recovery is generally better than in NMOSD. Persistent disability increases with repeated episodes, making early recognition and preventive treatment essential. Understanding these age-specific differences helps guide diagnosis and management.