Table 4.

Established and Emerging Biomarkers to help Diagnose MOGAD, Monitor Disease Activity, and Prognosticate Recovery [2–5, 9, 12, 14, 43–51]

Biomarker	Key Points	Considerations
Serology
MOG-IgG	Live cell-based assays (CBA) using full-length human MOG are optimal for MOGAD evaluation. The sensitivity of fixed CBA is lower when compared to the live CBA, yet fixed CBA is still superior to other non-CBAs, such as ELISA, which cannot reliably identify MOG-IgG. Testing for MOG IgG with either an IgG Fc or IgG1 specific secondary antibody is recommended, as is use of an IgG (heavy and light) secondary antibody. Serum testing for MOG-IgG is preferred over CSF, but CSF sampling may be considered in patients with clinical and MRI features suggestive of MOGAD who have negative results on serum testing. Anti-MOG antibodies titers may fluctuate, and sometimes increase during disease exacerbations. While persistent MOG-IgG seropositivity is associated with an increased risk of relapse, it is difficult to tailor treatment to MOG-IgG titers as patients may remain seropositive while relapse-free for years. Alternatively, patients may become seronegative during follow-up but then seroconvert back to a positive status at the time of relapse. It is uncommon to become seropositive when baseline serology for MOG IgG is negative	False positive MOG IgG results may occur, particularly when patients lack clinical or MRI features of MOGAD. It has been reported that MOG-IgG was detected in approximately 1% of patients with other neurologic diseases and generally at low titers. For borderline or low titer results, consider repeat testing. When MOG IgG co-exists with a variety of other autoantibodies, consider the specificity of the result, as it may represent a bystander effect and not true MOGAD
Serum Neurofilament Light (sNFL) Chain	sNFL, a scaffolding protein in the neuronal cytoskeleton, has shown promise in detecting relapses in NMOSD and may be an indicator of disease severity in MOGAD	As a biomarker, sNfL may be useful in quantifying relapse severity, however sNfL levels do not necessarily differ between patients with NMOSD, MS, or MOGAD. sNfL levels may also be elevated in various pathological (CNS inflammatory syndromes) and physiological states (aging, fever)
Magnetic Resonance Imaging
Optic Nerve	Features may include longitudinal optic nerve involvement (> 50% of optic nerve length, involving orbital, canalicular, and intracranial regions), optic disk edema, peri-neural optic nerve sheath enhancement, and simultaneous bilateral involvement	The detection of optic nerve lesions relies upon dedicated orbital imaging, with fat suppressed T2 images and gadolinium enhanced T1W views or short tau inversion recovery sequences. Otherwise, poor visualization of findings may occur particularly when imaging is delayed over a month or more. It is noteworthy that other inflammatory and infiltrative conditions can cause similar MRI findings. Lesion enhancement persisting beyond 6 months would be unusual for MOGAD as would failure to respond to steroids
Spinal Cord	Most lesions are T2 hyper-intense and centrally located, often restricted to the gray matter producing the so-called “H” sign on axial views. Involvement of the conus and thickening and enhancement of the dorsal nerve roots have been described in MOGAD. Contrast enhancement is seen in half of patients with transverse myelitis	Most patients with MOGAD have visible T2 lesions on MRI but 10% may be imaging negative (acutely). Patients with MOGAD-related myelitis may have LETM akin to NMOSD, which can cause diagnostic confusion. Spinal lesions related to MOGAD tend to resolve and failure to do so should prompt concern, and reinvestigations for an alternative diagnosis. Different than that seen in MS, is that accumulating spinal cord lesions independent of attacks is uncommon. Note that bilateral vision loss and LETM have been described in LHON
Brain	Brain imaging may be normal initially for patients with ON or myelitis. MOGAD lesions are often bilateral poorly defined and appear large with deep gray matter involvement. In the brainstem, involvement of the pons and middle cerebellar peduncles is observed	Area postrema involvement is uncommon in MOGAD. MRI findings of well circumscribed T2 lesions meeting criteria dissemination of space for MS would be a red flag for MOGAD diagnosis, as would lesion enhancement > 6 months. Brain lesions in MOGAD often resolve over time, unlike MS
Cerebrospinal Fluid
Cellular Constituents	CSF pleocytosis may be seen particularly during attacks, and elevations in protein are also observed. During attacks, CSF may show evidence of a pleocytosis particularly in patients with myelitis, brainstem, and multifocal relapses, more so than optic neuritis events	CSF pleocytosis is not specific for any CNS inflammatory condition and can be seen across a variety of disorders. Results need to be interpreted in the appropriate clinical context
Oligoclonal Bands (OCBs)	OCBS are detected in up to 20% of MOGAD cases	OCB are common in MS (found in 85% of cases) but less frequently observed in AQP4-IgG seropositive NMOSD and MOGAD. In MOGAD, they may be occasionally found but may also be transient
MOG IgG	Occasional CSF MOG IgG can be used to confirm diagnosis when serum MOG IgG is falsely negative	CSF sensitivity for MOG IgG is generally low
Optical Coherence Tomography
Peripapillary RNFL (pRNFL)	Approximately 3–6 months after acute ON, there is progressive thinning of the peri-papillary RNFL thickness, but this does not distinguish ON cases caused by MOGAD, MS, or NMOSD. One distinguishing feature of MOGAD ON is the extent of optic disk swelling seen acutely, sometimes with associated hemorrhage. Accordingly, mean pRNFL measures for MOGAD ON patients tend to be higher than MS ON patients, such that a baseline measure of 118 microns may prove to be a useful cut-off to distinguish MOGAD ON patients from MS ON. Moreover, MOGAD ON patients often have at least 10 microns of inter-eye asymmetry (with higher values in the ON eyes) compared to MS ON patients	Many acute optic neuropathies including inflammatory and ischemic (non-arteritic anterior ischemic optic neuropathy) insults may present with significant optic disk swelling and pRNFL thickening at symptom onset. It is therefore important to ensure that MOGAD patients have a classical clinical phenotype, ideally with good radiological and corresponding serological evidence of disease
Macular GCIPL	In acute ON, the first sign of neuro-axonal injury tends to be thinning of the macular GCIPL, but this is not specific for MOGAD	Due to floor effects of the OCT technology, it is challenging to detect new evidence of ganglion layer injury in the setting of prior injury, even with recurrent ON attacks
OCT-Angiography	MOGAD may be associated with significant decreases in vascular density. It is thought that peripheral vessel density might predict the visual outcomes in MOGAD patients [52, 53]	OCT-A changes may not be specific for MOGAD and need to be interpreted in the appropriate clinical context