Table 2.

Clinical Features of MOGAD [2–5, 14, 15, 18–31]

Clinical Feature	Distinguishing Characteristics	Key Diagnostic Pearls
Optic Neuritis	ON is the most frequent manifestation of MOGAD, and recurrent ON occurs in 30–50% of cases. Incident cases may be unilateral or bilateral, but bilateral simultaneous optic nerve involvement is more likely to be seen in MOGAD than MS. Vision loss is usually severe at the nadir and is often heralded by pain or headache. Moderate to severe optic disk edema is more common with MOGAD than MS or NMOSD. MOGAD ON is typically steroid responsive and is associated with good recovery, despite OCT evidence of significant neuro-axonal injury. It is reasonable to test for MOG-IgG in ON cases characterized by bilateral simultaneous optic nerve involvement, recurrent ON events, quick steroid responsivity, and/or significant optic disk swelling. The propensity for MOG-IgG in pediatric cases (up to 50%) makes serological testing a reasonable component of the routine evaluation for ON in this patient population	Optic neuritis may be over-diagnosed if critical features of the history and examination are not interpreted correctly. It is important to clarify whether patient have recurrent patterns of pain that suggest an underlying primary headache disorder, since overweighting pain in the absence of vision loss has been identified as a cause of overdiagnosis in patients referred for ON evaluation. It is also imperative to look for the presence of a RAPD in unilateral or asymmetrically severe ON cases. Mimics for MOGAD ON include ON related to MS, NMOSD, or other etiologies. Anterior ischemic optic neuropathy is far more common than MOGAD ON and presents with similar features of optic disk edema. Cases of non-arteritic AION however are frequently not associated with pain, affect older patients, do not demonstrate MRI enhancement of the optic nerve, and show less robust visual recovery. Leber hereditary optic neuropathy may present sporadically with pseudo-optic disk edema and severe vision loss. Yet, vision loss in LHON is painless and generally not associated with MRI enhancement of the optic nerve. Similarly, drugs including immune checkpoint inhibitors, and TNF alpha blockers may cause optic nerve injury, and must be checked for during history-taking. Inflammatory optic neuropathies caused by sarcoid and other systemic diseases may mimic MOGAD ON. Lymphomatous optic neuropathy may present with optic disk edema and show acute steroid responsivity. Fulminant IIH, particularly in children could be mistaken for MOGAD. To determine MOGAD diagnosis, symptoms derived from history, and careful review of MRI (and venography) imaging features will be critical to avoid delaying appropriate management
Acute Myelitis	Cases of MOGAD myelitis may be preceded by a viral illness. Patients may experience weakness, a sensory level, bladder/bowel dysfunction, and (over time) spasticity. Motor recovery tends to be relatively good, but sexual and sphincter dysfunction may persist. In 10% of MOGAD myelitis cases, the MRI may appear normal at symptom onset. Conversely, patients with MOGAD may have LETM lesions like NMOSD; spinal lesions may involve any part of the cord from the medulla to the conus, and shorter segmental lesions may occur. A minority of individuals may manifest features resembling acute flaccid myelitis (with areflexia) instead of the more common upper motor neuron syndrome. Gadolinium enhancement is uncommon and subtle when present. One imaging feature that may help diagnose MOGAD myelitis is disproportionate spinal cord gray matter involvement, visualized as an “H pattern” in the axial plane and a linear central T2 hyper-intensity in the sagittal plane. In contrast to MS, a burden of asymptomatic spinal cord lesions is relatively uncommon. Spinal imaging abnormalities often resolve after clinical recovery which is a distinguishing feature of MOGAD	Acute myelitis may be caused by a myriad of CNS inflammatory syndromes including sarcoidosis, MS, NMOSD and tumors. Cases of imaging negative myelitis have been not only been associated MOGAD, but also with COVID infection. Longitudinal T2 weighted MRI spinal cord lesions have also been described in other etiologies, such as LHON and biotinidase deficiencies. MOGAD myelitis cases differ from enterovirus D68–associated acute flaccid myelitis, because the former tend to respond well to short-term immunotherapy
Cerebral Cortical Encephalitis (Often with Seizures)	MOGAD patients may present with focal encephalitis characterized by fever, decreased consciousness, seizures, and focal weakness. Patients may manifest the FLAMES (unilateral cortical FLAIR hyper-intense Lesions in Anti-MOG-associated Encephalitis with Seizures) phenotype. MRI may also reveal enhancement of overlying meninges	In the setting of suspected encephalitis patients should be evaluated for other infectious and inflammatory causes, including anti-NMDA receptor encephalitis given that patients may have an overlap syndrome with dual serum positivity to MOG-IgG and NMDA receptors antibodies
ADEM	ADEM is the most common presentation of MOGAD in young children and MOG-IgG may be found in up to half of children presenting with this clinical phenotype. An infectious prodrome may precede onset of ADEM manifestations. Clinical findings include fever, headaches, irritability, fatigue, encephalopathy, seizures, brainstem/cerebellar dysfunction, and other neurologic symptoms. Clinical and radiological features typically resolve in the majority of MOGAD patients, but deficits may persist in ADEM patients who develop MRI features of a leukodystrophy	ADEM is the most common presenting feature of MOGAD in children but represents only 5–6% of adult presentations. Regardless of age, other causes of encephalopathy should be excluded in cases of ADEM. Since children with MOGAD are highly likely to present with ADEM, it is reasonable to test for MOG-IgG in pediatric patients presenting with encephalitic or encephalopathic features, particularly those aged less than 12 years
Autoimmune/Atypical Encephalitis	Some MOGAD patients do not fulfill ADEM criteria or exhibit a clear-cut focal encephalitis syndrome (FLAMES). Instead, these patients may present with altered consciousness, seizures, or a brainstem syndrome. Rarely, patients may exhibit minimal brain MRI changes, despite dramatic clinical phenotypes that may include refractory status epilepticus. For this reason, it is reasonable to check for MOG-IgG in cases of suspected autoimmune or atypical encephalitis	The usual suspects for infectious (bacterial, viral, and fungal) encephalitis, paraneoplastic syndromes and other autoimmune encephalitis subtypes should be considered as part of the diagnostic evaluation
CLIPPERS	MOGAD may (rarely) show a predilection for pontine involvement. Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) has been associated with MOGAD. The diagnosis requires evidence of subacute pontocerebellar dysfunction, without peripheral nerve involvement, that is responsive to steroids. On MRI, small, homogeneous gadolinium-enhancing nodules are visible in the pons and cerebellum with matching T2 lesions. Spinal cord lesions may also be seen. Gadolinium enhancement resolves with steroid therapy	Many cases of CLIPPERS remain idiopathic. Other causes of a CLIPPERS-like phenotype include MS, primary angiitis of the CNS, primary CNS lymphoma, and CNS lymphomatoid granulomatosis
Brainstem and Cerebellar Syndromes	Brainstem involvement is seen in up to 30% of MOGAD patients and may be a risk factor for a higher disability over time. Patients may present with weakness, cranial nerve deficits (diplopia in particular), ataxia, hypoventilation syndrome, and impaired consciousness. Area postrema syndrome (APS), while much rarer than in NMOSD, has also been described in MOGAD patients, but is usually not found in isolation. Finally, MOGAD can mimic infective rhomboencephalitis when a patient presents with fever, CSF leukocytosis, brainstem enhancing lesions and leptomeningeal enhancement	Brainstem and cerebellar lesions are seen in numerous CNS inflammatory disorders including MS and NMOSD. It is important to exclude other potential causes. Isolated attacks involving the brainstem, cerebellum, or both may be less frequent in MOGAD than MS, but not different to that seen in NMOSD. The presence of diffuse middle cerebellar peduncle MRI lesions favors MOGAD over other contending etiologies. Involvement of the brainstem, cerebellum, or both is common in MOGAD but usually occurs as a component of a multifocal CNS attack rather than in isolation
Cerebral Monofocal or Multifocal Demyelinating Lesions with Clinical Deficits	Examples of mono-focal or multifocal deficits may be accompanied by MRI T2 hyper-intense lesions in the middle cerebellar peduncle, around the fourth ventricle, supratentorial white matter, cortical juxtacortical regions, and deep gray nuclei. Tumefactive lesions may occur	This category of deficits included in the proposed criteria for MOGAD is somewhat nonspecific. For this reason, a high degree of vigilance is needed to exclude alternative diagnoses. Well circumscribed lesions on MRI in a pattern consistent with MS, particularly when accompanied by CSF OCB would be atypical for MOGAD and suggest MS as an alternative diagnosis
Papilledema and Raised Intracranial Pressure	Rarely MOGAD has been associated with a syndrome of raised intracranial pressure with vision loss. Raised ICP can occur in the context of ADEM, and tumefactive lesions may rarely lead to subfalcine and tentorial herniation	Mechanisms of raised intracranial pressure include inflammation, cerebral venous sinus thrombosis, mass effect or coincidental IIH. Understanding the mechanism will inform the most suitable therapeutic strategy
Progressive Leukodystrophies	Rarely, patients (usually pediatric) seropositive for MOG-IgG present with cranial MRI features suggestive on an inherited leukodystrophy. Immunotherapy may help stabilize these cases	Leukodystrophies can be caused by a myriad of causes including genetic disorders, infections, drug effects, mitochondrial syndromes, and metabolic dysregulation, and alternative causes need to be ruled out. Patients with a history of immunosuppression need to be evaluated for PML
Peripheral Nervous System Syndromes	AIDP, myeloradiculitis, multifocal motor neuropathy, brachial neuritis, migrant sensory neuritis, combined central and peripheral demyelination, and paresthesias with limb pain have been rarely reported in MOGAD patients with CNS findings	The differential for these entities is quite broad. Investigations need to be tailored to exclude more common causes of these syndromes
CNS Vasculitis Association	Rare cases of histologically proven CNS vasculitis associated with seropositive MOG-IgG status have been reported. Affected individuals presented with fever, headache, confusion, and focal neurologic deficits	The strength of this association is not entirely clear, yet a strong association with MOG-IgG could help target immunotherapy
Uveitis	Rare cases of anterior, intermediate, and posterior uveitis, affecting one or both eyes have been linked to MOGAD	The differential diagnosis for uveitis is broad, and many cases remain idiopathic. A standard uveitic work-up to exclude other causes (TB, sarcoid, syphilis, HSV, CMV, VZV, inflammatory bowel disease, lymphoma, HLA-B27-related disease, toxoplasmosis) should be considered
Cranial Neuropathies	Cranial neuropathy is an emerging clinical phenotype in MOGAD, and patients may have features of both central and peripheral nervous system involvement, with the trigeminal nerve being the most affected nerve	Cranial neuropathies are common with ischemic, inflammation, compression, and demyelinating etiologies in the differential diagnosis. MOG-IgG antibody testing in patients with cranial neuropathies is warranted in the appropriate clinical setting. However, because this is a rare MOGAD phenotype, caution in concluding a diagnosis of MOGAD is recommended, especially if the MOG-IgG titer is low. Alternative diagnoses must be ruled out
Ocular Flutter/Opsoclonus Myoclonus (OMS)	OMS is a rare autoimmune neurological entity caused by antibodies against specific surface antigens on neuronal cells. Features include rapid multidirectional conjugate eye movement, ataxia, and myoclonus. OMS has been rarely reported in MOGAD	MOGAD has been implicated in OMS and serum MOG-IgG should be included in the diagnostic evaluation, in the appropriate clinical setting. Other causes of OMS including tumors, paraneoplastic conditions, and autoimmune processes – all of which need to be excluded
Non-Optic Nerve Ophthalmic Issues	Ulcerative keratitis, acute macular neuro-retinopathy, neuro-retinitis, venous stasis retinopathy, large pre-retinal macular hemorrhage, and orbital inflammatory syndromes have been reported in MOGAD	It is possible that more non-optic nerve-related findings may be associated with seropositive MOG-IgG status. Alternatively, a bystander effect of MOG seropositivity also needs to be considered in the evaluation of these conditions

ON optic neuritis, ADEM acute disseminated encephalomyelitis, OCT  Optical coherence tomography, MRI magnetic resonance imaging, FLAIR  fluid-attenuated inversion recovery, LETM longitudinal extensive transverse myelitis, TNF alpha Tumor necrosis factor alpha, FLAMES Lesions in Anti-MOG-associated Encephalitis with Seizures, LHON Leber hereditary optic neuropathy, CLIPPERS chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids, APS area postrema syndrome, CNS central nervous System, CSF  cerebral spinal fluid, OCB oligo-clonal banding, ICP intracranial pressure, PE plasma exchange, IVIG = intravenous immune globulin, MS multiple sclerosis, PML  progressive multifocal leukoencephalopathy, IIH  idiopathic intracranial hypertension, PNS peripheral nervous system, TB tuberculosis, HSV herpes simplex virus, CMV cytomegalovirus, VZV varicella zoster virus, HLA-B27 human leukocyte antigen B27, OMS ocular flutter/opsoclonus myoclonus