Atypical or red flag presentations for multiple sclerosis

Atypical or red flag presentations	Diagnostic considerations
General
Deficit developing within minutes	Ischemic stroke; seizure
Fevers, weight loss, night sweats, alopecia, and synovitis	Infection; systemic vasculitis; SLE
Livedo reticularis, early trimester abortions, and thrombotic events	Antiphospholipid syndrome
Headache or meningismus	ADEM, cerebral venous thrombosis; chronic meningitis; lymphoma; glioma; vasculitis; SLE
Gradually progressive course from onset	HTLV-1; adrenomyeloneuropathy; adrenoleukodystrophy; metachromatic leukodystrophy; vitamin B12 deficiency
Onset before age 20 years	Mitochondrial encephalomyopathy; leukodystrophy; Friedrich ataxia
Onset after age 50 years	Cerebral infarction; cerebral amyloid angiopathy; lymphoma
Supratentorial
Encephalopathy (alterations in awareness and coma)	ADEM; PRES; MOG-EM; infectious/autoimmune encephalitis
Hemianopsia and cortical blindness	Ischemic stroke; PRES; neoplasm; PML
Insidious cognitive decline	Neurodegenerative disorders; genetic leukoencephalopathy and leukodystrophy
Seizures	Whipple disease; vasculitis; metastases
Cranial nerves
Progressive optic neuritis	Neoplasm; neurosarcoidosis; LHON
Altitudinal deficit and monocular blindness	Ischemic optic neuropathy
Clinically severe or simultaneous bilateral optic neuritis	NMOSD; MOG-EM
Neuroretinitis and uveitis	NMOSD
Multiple cranial neuropathies or polyradiculopathy	Chronic meningitis; including neurosarcoidosis and tuberculosis; Lyme disease
Brainstem
Insidiously progressive brainstem symptoms, especially with persistent enhancement on MRI	Neurosarcoidosis; histiocytosis; Behçet syndrome; malignancy; Whipple disease; tuberculosis; CLIPPERS
Intractable nausea and vomiting or intractable hiccups (compatible with area postrema syndrome)	NMOSD; MOG-EM
Cerebellum
Progressive cerebellar symptoms	Spinocerebellar ataxia; autoimmune/paraneoplastic syndromes
Spinal cord
Anterior spinal syndrome	Ischemia
Complete transverse myelitis	NMOSD; idiopathic myelitis; ADEM
Radiculitis	Infection; neurosarcoidosis; carcinomatosis/lymphomatosis
Progressive spastic paraparesis	HTLV-1; HIV; cobalamin deficiency; PLS; cervical spondylotic myelopathy; dAVF; adrenomyeloneuropathy; progressive solitary sclerosis
Longitudinally extensive spinal cord lesion	NMOSD; MOG-EM

SLE: systemic lupus erythematosus; ADEM: acute disseminated encephalomyelitis; HTLV-1: human T-lymphotropic virus type 1; PRES: posterior reversible encephalopathy syndrome; MOG-EM: myelin oligodendrocyte glycoprotein immunoglobulin G autoantibody-associated encephalomyelitis; PML: progressive multifocal leukoencephalopathy; LHON: Leber hereditary optic atrophy; NMOSD: neuromyelitis optica spectrum disorder; MRI: magnetic resonance imaging; CLIPPERS: chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids; PLS: primary lateral sclerosis; dAVF: dural arteriovenous fistula.

Adapted from: Toledano M, Weinshenker BG, Solomon AJ. A Clinical Approach to the Differential Diagnosis of Multiple Sclerosis. Curr Neurol Neurosci Rep 2015; 15:57.

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Atypical or red flag presentations for multiple sclerosis