The Multiple Sclerosis Differential Diagnosis Consortium has published consensus recommendations on the differential diagnosis of multiple sclerosis (Solomon et al. Lancet Neurol 2023;22:750-768). This version updates recommendations published 15 years ago (Miller et al. Mult Scler 2008;14:1157-1174).

Recent reports have indicated that 24-30% of cases of suspected MS have an alternative diagnosis (Yamout et al. Mult Scler Relat Disord 2017;18:85-89. Calabrese et al. Neurology 2019;92:e2527-e2537). Common MS mimics include migraine, fibromyalgia, nonspecific neurologic symptoms with abnormal MRI, psychiatric disorders and neuromyelitis optica spectrum disorder (Solomon et al. Neurology 2016;87:1393-1399).

The following is a summary of ‘red flags’ identified by the group that may suggest an alternative diagnosis to MS or the need for further investigations.

Optic neuritis: The absence of findings indicative of an optic nerve lesion (e.g. unilateral central scotoma, relative afferent pupillary defect, loss of colour vision) may suggest an alternative diagnosis. Red flags include hyperacute onset (within minutes) with no pain; simultaneous bilateral vision loss; visual loss over a period >2 weeks; severe visual loss (20/200 or worse); severe optic disc edema; and retro-orbital pain. Atypical MRI findings include bilateral or longitudinally extensive optic nerve lesions; optic nerve sheath enhancement; and normal orbital MRI. Severe peripapillary retinal nerve fibre layer (pRNFL) or ganglion cell-inner plexiform layer (GCIPL) thinning after a single ON attack is suggestive of NMOSD or MOGAD. (See also Bennett et al. Lancet Neurol 2023;22:89-100.)

Brainstem or cerebellar syndromes: Findings such as bulbar muscle weakness, complete gaze palsy, bilateral cranial nerve involvement and intractable nausea, vomiting or hiccups may suggest an alternative diagnosis. Consider other neurological disorders in cases of hearing loss and paroxysmal dysarthria with ataxia (rare in MS) or trigeminal neuralgia in the absence of other clinical/MRI findings suggestive of MS. Red flag: worsening of an acute brainstem or cerebellar syndrome >4 weeks. MS lesions are typically located at the surface of the brainstem or the fourth ventricle, in the cerebral peduncles, paramedian medulla, cerebellar peduncles and cerebellar white matter. MS lesions are usually round or ovoid and gadolinium enhancement is generally nodular or ring-like. Consider an alternative diagnosis if lesions are in other locations or have a different morphology or pattern of enhancement. Consider an inflammatory or infectious cause if contrast enhancement in the brainstem or cerebellum persists >3 months.

Myelitis: Red flags include hyperacute severe myelopathy (max. deficits within a few hours); absence of reflexes and flaccid tone; and severe acute myelitis associated with loss of ambulation and neurogenic bladder requiring catheterization. Consider an alternative diagnosis if there is worsening of acute-onset myelitis after 4 weeks. MRI findings suggestive of an alternative diagnosis include longitudinally extensive spinal cord lesions (>3 segments) or long segments of spinal-cord atrophy; and lesions selectively involving the SC grey matter, anterior spinal cord or anterior horn cells. A finding of T2 hyperintense lesions that completely resolve is suggestive of MOGAD.