Differential diagnosis of demyelinating diseases: what's new?

Acquired demyelinating disorders lead to overlapping visual, pyramidal, sensory, autonomic, and cerebellar deficits and may lead to severe disability. Early diagnosis and start of treatment are fundamental towards preventing further attacks and halting disability.

Objective:

In this paper we provide an updated overview of the differential diagnoses of acquired demyelinating disorders.

Methods:

We performed a critical targeted review of the diagnoses of the most prevalent demyelinating disorders: multiple sclerosis (MS), neuromyelitis optica spectrum disorders (NMOSD) and myelin oligodendrocyte glycoprotein antibody disease (MOGAD).

Results:

We discuss the workup, diagnostic criteria and new biomarkers currently being used for the diagnosis of these disease entities taking into account the particularities of the Brazilian population and healthcare system.

Conclusion:

A comprehensive analysis of medical history, physical examination, biomedical and imaging data should be performed to obtain differential diagnosis. Diagnostic criteria should be mindfully employed considering ethnic and environmental particularities of each patient.

Keywords:
Multiple Sclerosis; Neuromyelitis Optica; Myelin-Oligodendrocyte Glycoprotein; Diagnosis

Medical history
	Personal history of autoimmunity
	Family history of autoimmunity
	Presence of infectious or vaccinal triggers.
History of previous neurological symptoms.
Biomedical workup	Blood	Complete blood count, renal function, liver function, thyroid function
		Serologies (EBV, VZV, CMV, HIV, HTLV I/II, HBC, HCV, Syphillis)
		Rheumatologic profile (ANA, anti-Ro, anti-La, anti-DNA)
		AQP4-IgG
		Anti-MOG IgG
		Metabolic profile (Vitamin B12, Vitamin D, Folic acid)
	CSF	Total and differencial cell count
		Biochemical analysis (glucose, protein, lactate)
		Oligoclonal band profile
Image	Brain MRI
Image	Spinal cord MRI
Complementary tests	OCT
	VEP
	MEP/SEP

The 2017 McDonald criteria for diagnosis of multiple sclerosis in patients with an attack at onset99. Thompson AJ, Banwell BL, Barkhof F, Carroll WM, Coetzee T, Comi G, et al. Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria. Lancet Neurol. 2018 Feb 1;17(2):P162-73. https://doi.org/10.1016/S1474-4422(17)30470-2 https://doi.org/10.1016/S1474-4422(17)30...
Number of attacks	Number of lesions with objective clinical evidence	Additional data needed for a diagnosis of multiple sclerosis
≥2 clinical attacks	≥2	None
≥2 clinical attacks	1 (as well as clear-cut historical evidence of a previous attack involving a lesion in a distinct anatomical location	None
≥2 clinical attacks	1	Dissemination in space demonstrated by an additional clinical attack implicating a different CNS site or by MRI
1 clinical attack	≥2	Dissemination in time demonstrated by an additional clinical attack or by MRI OR demonstration of CSF-specific oligoclonal bands
1 clinical attack	1	Dissemination in space demonstrated by an additional clinical attack implicating a different CNS site or by MRI AND dissemination in time demonstrated by an additional clinical attack or by MRI OR demonstration of CSF-specific oligoclonal bands

2017 McDonald criteria for diagnosis of multiple sclerosis in patients with a disease course characterized by progression from onset (primary progressive multiple sclerosis)99. Thompson AJ, Banwell BL, Barkhof F, Carroll WM, Coetzee T, Comi G, et al. Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria. Lancet Neurol. 2018 Feb 1;17(2):P162-73. https://doi.org/10.1016/S1474-4422(17)30470-2 https://doi.org/10.1016/S1474-4422(17)30...
Primary progressive multiple sclerosis can be diagnosed in patients with:
1 year of disability progression (retrospectively or prospectively determined) independent of clinical relapse
Plus two of the following criteria:
One or more T2-hyperintense lesions characteristic of multiple sclerosis in one or more of the following brain regions: periventricular, cortical or juxtacortical, or infratentorial
Two or more T2-hyperintense lesions in the spinal cord
Presence of CSF-specific oligoclonal bands

International consensus diagnostic criteria for neuromyelitis optica spectrum disorders1010. Wingerchuk DM, Banwell B, Bennett JL, Cabre P, Carroll W, Chitnis T, et al. International consensus diagnostic criteria for neuromyelitis optica spectrum disorders. Neurology. 2015 Jul 14;85(2):177-89. https://doi.org/10.1212/WNL.0000000000001729 https://doi.org/10.1212/WNL.000000000000...
Diagnostic criteria for NMOSD with AQP4-IgG
1. At least 1 core clinical characteristic
2. Positive test for AQP4-IgG using best available detection method (cell-based assay strongly recommended)
3. Exclusion of alternative diagnoses
Diagnostic criteria for NMOSD without AQP4-IgG or NMOSD with unknown AQP4-IgG status
1. At least 2 core clinical characteristics occurring as a result of one or more clinical attacks and meeting all of the following requirements:
a. At least 1 core clinical characteristic must be optic neuritis, acute myelitis with LETM, or area postrema syndrome
b. Dissemination in space (2 or more different core clinical characteristics)
c. Fulfillment of additional MRI requirements, as applicable
2. Negative tests for AQP4-IgG using best available detection method, or testing unavailable
3. Exclusion of alternative diagnoses
Core clinical characteristics
1. Optic neuritis
2. Acute myelitis
3. Area postrema syndrome: episode of otherwise unexplained hiccups or nausea and vomiting
4. Acute brainstem syndrome
5. Symptomatic narcolepsy or acute diencephalic clinical syndrome with NMOSD-typical diencephalic MRI lesions
6. Symptomatic cerebral syndrome with NMOSD-typical brain lesions
Additional MRI requirements for NMOSD without AQP4-IgG and NMOSD with unknown AQP4-IgG status
1. Acute optic neuritis: requires brain MRI showing (a) normal findings or only nonspecific white matter lesions, OR (b) optic nerve MRI with T2-hyperintense lesion or T1-weighted gadolinium- enhancing lesion extending over .1/2 optic nerve length or involving optic chiasm
2. Acute myelitis: requires associated intramedullary MRI lesion extending over 3 contiguous segments (LETM) OR 3 contiguous segments of focal spinal cord atrophy in patients with history compatible with acute myelitis
3. Area postrema syndrome: requires associated dorsal medulla/area postrema lesions
4. Acute brainstem syndrome: requires associated periependymal brainstem lesions

Demographic, clinical, MRI and CSF features of MS, AQP4-IgG positive NMOSD and MOG-IgG associated disease. (Adapted from Hegen et al. Ther Adv Neurol Disord. 2020.)66. Hegen H, Reindl M. Recent developments in MOG-IgG associated neurological disorders. Ther Adv Neurol Disord. 2020 Jul 31;13:1756286420945135. https://doi.org/10.1177/1756286420945135 https://doi.org/10.1177/1756286420945135...
Disease
	MOGAD	AQP4-IgG positive NMOSD	MS
Epidemiology
Brazilian prevalence (per 100,000)	Unknown	0.37- 4.52	8.69
Demographics
Female:male ratio	1-2/1	8-9/1	3/1
Age at onset	More often in childhood than adulthood	>40 years	20-30 years
Clinical presentation
Clinical presentation	ADEM-like (ADEM, MDEM, ADEM-optic neuritis, encephalitis) or opticospinal (optic neuritis, myelitis) or brainstem encephalitis	Optic neuritis, myelitis, area postrema syndrome, brainstem syndrome, narcolepsy or acute diencephalic syndrome, cerebral syndrome with NMOSD-typical brain lesions	Optic neuritis, myelitis, brainstem or cerebellar syndrome, cognitive dysfunction and symptoms caused by involvement of other MS-typical brain regions
Disease course	Monophasic and recurrent (recurrence often presents as optic neuritis)	More often recurrent than monophasic	Relapsing-remitting or chronic progressive
Magnetic resonance imaging
Brain MRI	ADEM-like, atypical for MS (fluffy lesions or three lesions or fewer) or no brain lesions	Atypical for MS and/or lesions in the brainstem; or no brain lesions	Multiple focal white matter lesions, ovoid lesions adjacent to the lateral ventricles, Dawson fingers, U-fibre subcortical lesions, T1 hypointense lesions
Frequency of normal brain MRI at disease onset	Up to 50% (depending on type of manifestation; normal brain MRI often seen in optic neuritis)	Up 50%	NA
Spinal MRI	Long-segment lesions (>3 vertebral segments); typically involving thoracolumbar segment and conus; confined to grey matter (H sign); contrast-enhancement infrequent	Long-segment lesions (>3 vertebral segments); typically involving cervicothoracic segment; central cord predominance; contrast-enhancement frequent	Short-segment lesions (<3 vertebral segments); axial peripheral (dorsal/lateral column); contrast-enhancement frequent
Optic neuritis	Bilateral more often than unilateral, often anterior optic pathway, long lesion, often recurrent, severe, good recovery	Bilateral more often than unilateral, often posterior optic pathway, involvement of optic chiasma, long lesion, often recurrent, severe, often residual deficits	Unilateral more often than bilateral; short lesion, good recovery
Cerebrospinal fluid
Pleocytosis	Common (>70% of patients)	Common (>70% of patients)	Moderate (<50% of patients)
Cytology	Mononuclear, but neutrophils can occur (in up to ~50% of samples)	Mononuclear, but neutrophils can occur (in up to ~50% of samples)	Mononuclear
OCBs	Rare (<10-20% of patients)	Rare (<10% of patients)	Common (>90% of patients)
Optical coherence tomography
Axonal damage (assessed, e.g., by pRNFL decrease)	Moderate (per optic neuritis attack)	Severe (per optic neuritis attack)	Moderate (per optic neuritis attack)

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[1] Correspondence:
Tarso Adoni; Email: tarso@dfvneuro.com.br.