Radiologic Differential Diagnosis of Multiple Sclerosis

Inflammatory demyelinating diseases of the central nervous system cause considerable disability across the age spectrum. Multiple sclerosis (MS), aquaporin-4 antibody–positive neuromyelitis optica spectrum disorder (AQP4+ NMOSD), and myelin oligodendrocyte protein antibody–associated disease (MOGAD) are the most common of these disorders.^1-3 Distinguishing among MS, AQP4+ NMOSD, and MOGAD is imperative to clinical practice, as each of these diseases has its own prognosis and therapeutic options.

Diagnostic criteria for MS,⁴ AQP4+ NMOSD,⁵ and MOGAD⁶ integrate clinical and paraclinical data to help clinicians distinguish among these disorders. In addition to clinical and serologic antibody testing results, radiographic features associated with these disorders can be useful in diagnosis. MRI is a fast, noninvasive diagnostic tool that can help identify individuals who may benefit from the timely administration of disease-specific therapies. 

Inherent to the challenges in differentiating MS, AQP4+ NMOSD, MOGAD, and other lesional diseases of the brain and spine is the overlapping location of lesions among these disorders. The 2024 McDonald criteria updates⁴ for diagnosis of MS recognizes 5 anatomic locations for demonstrating dissemination in space: periventricular, juxtacortical or cortical, infratentorial, spinal cord, and the newly added optic nerve. The core clinical criteria for AQP4+ NMOSD diagnosis⁵ are optic neuritis (ON), acute myelitis, area postrema syndrome (APS), acute brainstem syndrome, symptomatic narcolepsy or acute diencephalic syndrome, and symptomatic cerebral syndrome. The MOGAD diagnostic criteria⁶ recognize presentations of ON, acute myelitis, acute disseminated encephalomyelitis (ADEM), cerebral focal syndromes, infratentorial syndromes, and cerebral cortical encephalitis with seizures. These overlapping features in the clinical criteria of MS, AQP4+ NMOSD, and MOGAD highlight the need for a strong understanding of the radiographic features to distinguish among these diseases.

This review provides a guide for distinguishing the radiographic features of MS, AQP4+ NMOSD, and MOGAD (Table 1). We highlight the distinctive presentations of each of these disorders and clarify how a diagnosis can be suspected even when an attack affects a common topography.

Major Distinguishing Features of MS, AQP4+ NMOSD, and MOGAD
Several radiographic features of MS, AQP4+ NMOSD, and MOGAD are unique to each disorder. First, asymptomatic lesions are more typical of MS and are rare in AQP4+ NMOSD or MOGAD.^7-9 Asymptomatic lesions are one reason why regular MRI scans are an important part of monitoring disease activity and treatment effectiveness in people with MS.¹⁰ Second, APS and diencephalon syndrome are more characteristic of AQP4+ NMOSD compared with MS and MOGAD. APS is one of the most common manifestations in individuals with AQP4+ NMOSD, presenting in up to 40% of individuals.¹¹ Third, ADEM and cortical encephalitis with seizures are more typical of MOGAD compared with MS and AQP4+ NMOSD.⁶ Typical ADEM lesions observed on MRI scans are T2 hyperintense, large, globular, and poorly demarcated, involving gray–white junctions and deep gray, cortical, or infratentorial structures.¹² Cortical encephalitis with seizures can appear as linear T2-hyperintense or gadolinium-enhancing lesions that follow the cortical ribbon.⁶ Fluid-attenuated inversion recovery (FLAIR) sequences can also highlight the leptomeningeal involvement of encephalitis.⁶

Distinguishing Common Topographies in MS, AQP4-NMOSD, and MOGAD

Optic Neuritis
Radiographic features that help distinguish ON presentations are length, bilaterality, and perineural involvement of lesions. MS-related ON typically affects retrobulbar optic nerve segments unilaterally, with short-segment involvement (<50% of nerve length) and mild enhancement.⁹ In AQP4+ NMOSD ON, characteristic T2-hyperintense and gadolinium-enhancing lesions involve bilateral optic nerves, posterior optic nerves with extension into the chiasm, or long segments of single optic nerves.⁵ Typical presentations of MOGAD ON include T2 hyperintensities and gadolinium enhancement of the optic nerve perineurium, as well as simultaneous lesions of both optic nerves and long-segment lesions that may include the optic nerve head.^6,9 Bilateral simultaneous involvement of the optic nerves are more common in MOGAD than in MS and marginally more common than in AQP4+ NMOSD.⁶

Supratentorial Lesions
Brain MS lesions typically appear asymmetrically as ovoid T2-hyperintense foci oriented perpendicular to the ventricular surface, creating pathognomonic “Dawson fingers” following medullary veins.¹³ Lesions are typically 3 to 10 mm, although tumefactive presentations exceeding 2 cm can occur.¹³ Acute lesions may demonstrate incomplete rim or nodular enhancement following gadolinium-based contrast agent administration; however, this feature only persists in new lesions for 2 to 3 weeks.¹³ The presence of T1-hypointense black holes indicates severe tissue destruction with axonal loss.¹⁴ Periventricular lesions, which are not specific to MS, are lesions that directly contact the lateral ventricles with no intervening normal-appearing white matter, including corpus callosal lesions that border the ventricles.¹³ Juxtacortical lesions, which affect subcortical U-fibers and abut cortical gray matter, and cortical lesions are particularly characteristic of MS and help distinguish MS from small vessel ischemic disease.¹³

In AQP4+ NMOSD cerebral syndromes, more specific patterns are those that span much of the corpus callosum and can be extensive, with splenial (arch-bridge sign) or corticospinal tract involvement.⁹ Cerebral MOGAD lesions are often bilateral, may be large, and can have poorly defined edges, although rarely the small juxtacortical or periventricular lesions seen in people with MS are present in MOGAD.⁶ MOGAD also rarely presents with T1-hypointense black holes.⁶ On follow-up, lesions resolve far more often in MOGAD than in AQP4+ NMOSD or MS.⁶

Brainstem and Infratentorial Lesions
MS infratentorial lesions, including those affecting the brainstem, cerebellar peduncles, and cerebellum, typically appear more diffuse and less T2 hyperintense than supratentorial lesions.¹³ Many of the acute brainstem syndromes in AQP4+ NMOSD include T2-hyperintense and gadolinium-enhancing lesions adjacent to the fourth ventricle or other ependymal surfaces, some of which might lead to APS.⁵ Like supratentorial MOGAD lesions, infratentorial MOGAD lesions are often bilateral, are relatively large, and have poorly defined edges.⁶ Overall, AQP4+ NMOSD and MOGAD brain lesions are difficult to distinguish from one another.⁶

Myelitis
Features that help distinguish MS, AQP4+ NMOSD, and MOGAD myelitis are the length and axial location of lesions. MS cord lesions are typically short-segment, well demarcated, less than half the axial cross-sectional area, and located peripherally in the lateral or posterior columns.¹⁵ In AQP4+ NMOSD acute myelitis, the characteristic presentation is longitudinally extensive transverse myelitis (LETM), defined as lesions that span >3 vertebral segments with cord swelling, T1-hypointense core, and gadolinium enhancement.⁵ Although the more common presentation is LETM, short-segment transverse myelitis in AQP4+ NMOSD is possible, and can even be the presenting sign.¹⁶ MOGAD lesions are often T2-hyperintense and gadolinium-enhancing LETM, although a minority of individuals can exhibit normal MRI results at onset or short-segment transverse myelitis.⁶ On axial imaging, MOGAD myelitis can present as central T2-hyperintense lesions restricted to the gray matter (displaying the H sign), which can help distinguish MOGAD myelitis from other causes of LETM.⁶ In addition, involvement of the conus medullaris can help distinguish MOGAD from MS and AQP4+ NMOSD.⁶

Advanced Imaging Features for Distinguishing MS From AQP4+ NMOSD and MOGAD

Central Vein Sign and Paramagnetic Rim Lesions
Many of the advancements in identifying specific radiographic features that differentiate MS from other diseases have focused on supratentorial lesions. The 2024 McDonald criteria updates for MS diagnosis incorporate central vein sign (CVS) and paramagnetic rim lesions (PRLs) as optional, highly specific tools for the diagnosis of MS (Table 2).^17-21 The CVS, visible on susceptibility-weighted imaging, identifies the perivenular MS lesion. Fulfillment of the Select-6 rule supports MS diagnosis in certain clinical scenarios. Select-6 is positive if ≥6 lesions have a CVS, or if there are <10 lesions and most of these lesions have a CVS.^17,20 Chronic-active MS lesions consist of an inactive core surrounded by activated, iron-laden microglia, and susceptibility-weighted imaging can identify these PRLs even at the earliest stages of disease.²² Although PRLs are highly specific for MS, their reported sensitivity varies widely.²³ CVS and PRLs are uncommon in AQP4+ NMOSD, MOGAD, and other inflammatory disorders of the central nervous system, although these radiographic features can be present in these disorders.²¹

Optimal Detection of Distinguishing Radiographic Features of MS
Advanced MRI techniques should be applied when conventional lesion topography does not, by itself, secure MS diagnosis, or when comorbidities increase the risk of misclassification. Brain MRI acquisition should follow the 2024 Magnetic Resonance Imaging in MS–Consortium of Multiple Sclerosis Centers–North American Imaging in MS Cooperative consensus¹³ to improve detection of CVS, PRLs, juxtacortical lesions, and cortical lesions, all of which are more specific to MS. Sequences included in this consensus include FLAIR, susceptibility-sensitive sequences, double inversion recovery,²⁴ and phase-sensitive inversion recovery sequences.¹⁷ Beyond identification of these supratentorial features, other dedicated orbit and spinal cord sequences are suggested for sufficient sampling of other topographies.¹⁴

Summary
MS, AQP4+ NMOSD, and MOGAD are inflammatory disorders with many overlapping clinical and radiographic features. Despite the considerable overlap in imaging findings, optimized MRI techniques can help distinguish disease-specific features, allowing for more targeted and timely treatment in individuals with these disorders.