Series

Multiple sclerosis 1
Diagnosis of multiple sclerosis: progress and challenges
Wallace J Brownlee, Todd A Hardy, Franz Fazekas, David H Miller

Lancet 2017; 389: 1336–46 The diagnosis of multiple sclerosis is based on neurological symptoms and signs, alongside evidence of dissemination
Published Online of CNS lesions in space and time. MRI is often sufficient to confirm the diagnosis when characteristic lesions
November 23, 2016 accompany a typical clinical syndrome, but in some patients, further supportive information is obtained from
http://dx.doi.org/10.1016/
cerebrospinal fluid examination and neurophysiological testing. Differentiation is important from other diseases in
S0140-6736(16)30959-X
which demyelination is a feature (eg, neuromyelitis optica spectrum disorder and acute disseminated
This is the first in a Series of
three papers about multiple encephalomyelitis) and from non-demyelinating disorders such as chronic small vessel disease and other
sclerosis inflammatory, granulomatous, infective, metabolic, and genetic causes that can mimic multiple sclerosis. Advances
Queen Square Multiple in MRI and serological and genetic testing have greatly increased accuracy in distinguishing multiple sclerosis from
Sclerosis Centre, University these disorders, but misdiagnosis can occur. In this Series paper we explore the progress and challenges in the
College London (UCL) Institute
diagnosis of multiple sclerosis with reference to diagnostic criteria, important differential diagnoses, controversies
of Neurology, London, UK
(W J Brownlee FRACP, and uncertainties, and future prospects.
Prof D H Miller FMedSci);
Neuroimmunology Clinic, Introduction progressive multiple sclerosis typically presents at an
Concord Hospital and Brain &
Multiple sclerosis is a chronic, immune-mediated, older age than does relapsing-remitting multiple
Mind Centre, University of
Sydney, Sydney, NSW, Australia demyelinating disorder of the CNS. It can present with sclerosis (mean age at onset 40 years) and there is no sex
(T A Hardy PhD); Department of changes in sensation, mobility, balance, sphincter bias. People with relapsing-remitting multiple sclerosis
Neurology, Medical University function, vision, and cognition. Although the course is may develop a progressive course with time (secondary
of Graz, Graz, Austria
highly variable, many people develop irreversible progressive multiple sclerosis) with a gradual increase in
(Prof F Fazekas MD); and
National Institute for Health disability and multiple sclerosis remains a major cause disability with or without relapses.2
Research University College of neurological disability in young adults. The disease is An early and accurate diagnosis of multiple sclerosis is
London Hospitals Biomedical classified as either relapsing-remitting or primary essential because there are now effective treatments for
Research Centre, London, UK
progressive based on the initial disease course. Relapsing- relapsing-remitting multiple sclerosis. Diagnosis is
(Prof D H Miller)
remitting multiple sclerosis is more common, affecting based on the presence of clinical symptoms and signs
Correspondence to:
Dr Wallace Brownlee, National 85–90% of patients with multiple sclerosis, and is and findings on MRI, which is highly sensitive to detect
Hospital for Neurology and characterised by relapses (episodes of neurological characteristic CNS lesions.1 Advances in MRI, serological
Neurosurgery, University College dysfunction lasting at least 24 h in the absence of fever or and genetic testing have improved the diagnosis of other
London, London, WC1E 6BT, UK
infection1) followed by periods of remission. Recovery disorders that can be mistaken for multiple sclerosis.
w.brownlee@ucl.ac.uk
from relapses is variable and can be incomplete.2 A major discovery was the association between
Relapsing-remitting multiple sclerosis typically affects neuromyelitis optica spectrum disorder and serum
young adults (mean age at onset 30 years) and women aquaporin 4 IgG (AQP4-IgG), confirming that it is a
are affected three times more often than are men.3 different disease from multiple sclerosis and needs
Evidence suggests that the incidence of relapsing- distinct treatment.4
remitting multiple sclerosis might be increasing, In this, the first in a Series of papers about multiple
particularly in women.3 Primary progressive multiple sclerosis, we discuss the diagnosis of multiple sclerosis,
sclerosis (10–15% of patievnts) is characterised by an including the approach to investigation of patients with
insidious, slowly progressive increase in neurological suspected disease and diagnostic criteria and their
disability over time, usually without relapses.2 Primary application in clinical practice. We discuss key differential
diagnoses with particular focus on other idiopathic
inflammatory disorders, including acute disseminated
Search strategy and selection criteria encephalomyelitis and neuromyelitis optica spectrum
We searched MEDLINE and Embase with the search terms disorder. Finally, we consider areas of controversy and
“multiple sclerosis”, “neuromyelitis optica”, “acute uncertainty and the potential for future changes in
disseminated encephalomyelitis”, “diagnosis”, “diagnostic diagnostic criteria.
criteria”, and “differential diagnosis” for papers published in
English between Jan 1, 1995, and May 15, 2016. We sought Diagnosis
additional articles from the reference lists of relevant articles. Presenting symptoms
We gave priority to new studies published in the past 5 years. The initial presentation of multiple sclerosis varies
Where appropriate, we reference review articles to provide according to both the location of lesions and the type of
more detailed information on individual topics. symptom onset (relapsing or progressive). Patients can
present to a broad range of doctors depending on the

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nature of their symptoms (eg, general practitioners or

family doctors, ophthalmologists, and orthopaedic Panel 1: Typical presentations of relapsing-remitting
surgeons) and if multiple sclerosis is suspected, prompt multiple sclerosis and selected atypical or red flag
referral to a neurologist is needed. presentations that are more suggestive of an alternative
Panel 1 shows some common presenting symptoms diagnosis
and signs of multiple sclerosis and selected others that Typical presentations
are less common and suggestive of an alternative • Acute unilateral optic neuritis
diagnosis. A first episode of neurological dysfunction, • Double vision due to an internuclear ophthalmoplegia or
presumably due to relapsing-remitting multiple sclerosis, sixth nerve palsy*
is called a clinically isolated syndrome.2,5 Common • Facial sensory loss or trigeminal neuralgia*
clinically isolated syndrome presentations include acute • Cerebellar ataxia and nystagmus
unilateral optic neuritis, a partial myelitis, or a brainstem • Partial myelopathy
syndrome.5 Clinical features that suggest demyelination • Sensory symptoms in a CNS pattern
as the cause of such an episode include age younger than • Lhermitte’s symptom
40 years, an acute or subacute onset over hours to days, • Asymmetric limb weakness
maximal deficit within 4 weeks of onset, and spontaneous • Urge incontinence or erectile dysfunction
remission. The onset of primary progressive multiple
sclerosis by contrast is characterised by slowly progressive Atypical or red flag presentations
symptoms, most often an asymmetric paraparesis that • Bilateral optic neuritis or unilateral optic neuritis with a
evolves over months or years,6 or, less commonly, a poor visual recovery
progressive hemiparesis or cerebellar ataxia or very • Complete gaze palsy or fluctuating ophthalmoparesis
rarely, visual failure or dementia.6 • Intractable nausea, vomiting, or hiccups
In assessing a patient with suspected multiple sclerosis, • Complete transverse myelopathy with bilateral motor and
it is important to determine the onset and evolution of sensory involvement
their symptoms and to seek details of previous • Encephalopathy
neurological symptoms that could indicate an earlier • Subacute cognitive decline
unrecognised attack and thus help to establish the • Headache or meningism
diagnosis and disease course (relapsing or progressive • Isolated fatigue or asthenia
onset). Neurological examination is important to localise • Constitutional symptoms
the site of involvement in the CNS and can provide *In a young adult (<40 years of age).
evidence of other lesions—eg, pathologically brisk
reflexes or an extensor plantar response in a patient with
optic neuritis. segments and are often eccentrically placed abutting the
pial surface. Brain and spinal cord lesions might show
Investigation approaches enhancement after the administration of gadolinium
When a patient presents with symptoms or signs that (figure).
could indicate multiple sclerosis, an MRI is highly The MAGNIMS network has proposed a standardised
recommended because an abnormal brain MRI is MRI protocol to assist in the diagnosis of multiple
present in nearly all patients with established multiple sclerosis.12 As well as brain images with an axial
sclerosis7 and in more than 80% of patients with orientation, obtaining a sagittal T2 fluid-attenuated
clinically isolated syndrome who develop multiple inversion recovery sequence is recommended by
sclerosis.8 MRI is also helpful to exclude other MAGNIMS and others to detect juxtacortical and corpus
pathologies (eg, a compressive lesion in a patient with a callosum lesions and to help differentiate multiple
progressive myelopathy) or to identify abnormalities that sclerosis from other disorders.12,13 A post-contrast
suggest an alternative diagnosis (eg, leptomeningeal T1-weighted scan is recommended in patients with brain
enhancement or a longitudinally extensive spinal cord MRI lesions to assist in diagnosis and differential
lesion). diagnosis.12 Spinal cord MRI is recommended in patients
Brain MRI typically shows multifocal T2-hyperintense with myelopathy or when MRI brain findings are not
white matter lesions in characteristic locations diagnostic of multiple sclerosis.12
(figure): periventricular (including the corpus callosum), In most patients with typical clinical and MRI findings,
juxtacortical (abutting the cerebral cortex), and examination of cerebrospinal fluid (CSF) is not usually
infratentorial regions.9 On T1-weighted images, lesions necessary, but can provide supportive evidence of
might appear hypointense (so-called black holes). Spinal multiple sclerosis. CSF findings include a normal or
cord lesions occur in 80–90% of patients with established mildly raised white cell count (<25 cells per cm³;
multiple sclerosis and up to half of patients with predominantly lymphocytes) and protein (usually
clinically isolated syndrome, most often in the cervical <1 g/L), a raised IgG index, and IgG oligoclonal bands
cord.10,11 Lesions extend over one or two vertebral not present in serum.14 Qualitative assessment of IgG

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A B E F

C D

G H

Figure: Typical multiple sclerosis lesions in the brain and spinal cord
Lesions shown with arrows. Axial brain MRI scans show multiple periventricular lesions (A) with contrast enhancement of one lesion (B), juxtacortical lesions (C),
and infratentorial lesions (D). Sagittal (E, F) and axial (G, H) scans with a cervical spinal cord lesion showing contrast enhancement in F and H.

using isoelectric focusing and immunofixation is the might be indicated if the history, examination, or MRI
best method to detect oligoclonal bands,14 which are findings are atypical.
found in up to 90% of people with multiple sclerosis
(less often in patients with clinically isolated syndrome).15 Diagnostic criteria and their clinical application
Oligoclonal bands can sometimes be present in patients The diagnosis of multiple sclerosis requires objective
with other neuroinflammatory disorders and their evidence of CNS lesions disseminated in time and
presence needs to be interpreted carefully. Neuro­ space, and also importantly that there is no better
physiological testing of evoked potentials in visual, explanation for the clinical presentation and that
sensory, or auditory pathways can also provide supportive alternative diagnoses are considered and excluded.1
evidence of multiple sclerosis through identification of a Historically, dissemination in time and space has been
clinically silent lesion in the CNS, indicating based on clinical findings alone, requiring two separate
dissemination in space. A prolonged latency and well attacks with signs of two or more lesions.18 Using the
preserved waveform on evoked potential testing is McDonald 2010 criteria (panel 2), a diagnosis of multiple
suggestive of demyelination, but is not specific.16 sclerosis can still be made on clinical grounds alone;
Laboratory investigations are often requested as part of however, MRI is used to provide evidence for
the diagnostic work-up for multiple sclerosis. Routine dissemination in time and space, including in patients
testing for systemic autoimmune diseases has a very low with clinically isolated syndrome.1 For relapsing-
yield in patients with presentations typical of multiple remitting multiple sclerosis, MRI evidence of
sclerosis.17 Non-specific antibodies are frequently dissemination in space requires at least one T2 lesion in
detected that might not be clinically relevant, with low- at least two of four sites, periventricular, juxtacortical,
titre antinuclear antibodies (ANA) particularly prevalent and infratentorial regions and the spinal cord (figure),
in patients with multiple sclerosis.17 Further targeted with symptomatic lesions in the brainstem and spinal
laboratory tests to exclude mimics of multiple sclerosis cord excluded.1 Dissemination in time requires either

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asymptomatic gadolinium-enhancing and non-

enhancing lesions on the same MRI scan or a new Panel 2: McDonald 2010 diagnostic criteria for multiple sclerosis, with bullet points
lesion on a follow-up scan.1 Using the McDonald 2010 showing additional evidence required
criteria, a diagnosis of relapsing-remitting multiple At least two attacks with objective clinical evidence of at least two lesions
sclerosis can be made in up to a third of patients with None
clinically isolated syndrome with a single MRI scan.19
The McDonald criteria provide separate recommend- At least two attacks with objective clinical evidence of one lesion
ations for the diagnosis of primary progressive multiple Dissemination in space shown by:
sclerosis, which includes testing for CSF abnormalities • At least one T2 lesion in at least two of four areas of the CNS typically affected in
in addition to MRI.1 Brain T2 lesion load tends to be demyelination: periventricular, juxtacortical, infratentorial, and spinal cord
lower in primary progressive multiple sclerosis6 and the • Further clinical attack at a different site
combination of MRI and CSF findings provides a higher One attack with objective clinical evidence of at least two lesions
sensitivity than MRI alone.20 Dissemination in space in Dissemination in time shown by:
suspected primary progressive multiple sclerosis • Simultaneous presence of asymptomatic gadolinium-enhancing and non-enhancing
requires two or more of the following: at least one lesions on a single scan or a new T2 and/or gadolinium-enhancing lesion on
T2 brain lesion in at least one of three sites typically follow-up MRI
affected in multiple sclerosis (periventricular, • Second clinical attack
juxtacortical, and infratentorial); at least two T2 spinal
cord lesions; and positive CSF (at least two oligoclonal One attack with objective clinical evidence of one lesion
bands not present in serum, raised IgG index, or both). Dissemination in space shown by:
Progressive worsening over a period of at least 12 months • At least one T2 lesion in at least two of four areas of the CNS typically affected in
provides evidence of dissemination in time. demyelination: periventricular, juxtacortical, infratentorial, and spinal cord
The McDonald 2010 criteria are easily applied in a • Second clinical attack at a different site
clinical setting and allow for an earlier diagnosis of Dissemination in time shown by:
multiple sclerosis.19 However, there are important • Simultaneous presence of asymptomatic gadolinium-enhancing and non-enhancing
caveats when using MRI criteria. The criteria are lesions on a single scan or a new T2 and/or gadolinium-enhancing lesion on
intended for diagnosis of patients in whom multiple follow-up MRI
sclerosis is clinically suspected, rather than to • Second clinical attack
differentiate multiple sclerosis from other neurological 1 year of disease progression (retrospectively or prospectively determined)
disorders. MRI in patients with small vessel Presence of two of:
cerebrovascular disease, other inflammatory disorders, • At least one T2 brain lesion in at least one multiple sclerosis-characteristic region:
and non-inflammatory disorders affecting white matter periventricular, juxtacortical, or infratentorial
(tables 1, 2), and even in healthy people (especially in • At least two T2 spinal cord lesions
older age groups), might show brain lesions that fulfil • Positive CSF (at least two oligoclonal bands not present in serum, elevated IgG index,
MRI criteria for multiple sclerosis.21–24 The McDonald or both)
MRI criteria were developed and tested after a clinically
isolated syndrome in patients with symptoms typical of Modified from Polman and colleagues.1

multiple sclerosis (eg, unilateral optic neuritis) and

they should not be applied to patients with non-specific demyelinating lesions that characterise radiologically
neurological symptoms such as paraesthesia, dizziness, isolated syndrome need to be carefully differentiated
or headache, in whom the diagnosis is much less from small vessel cerebrovascular disease and non-
likely.23 Additionally, MRI criteria were tested and specific white matter lesions (the latter being common in
validated in European populations with a high people with migraine21,24).
incidence of multiple sclerosis,25 although studies A third of patients with radiologically isolated syndrome
investigating the McDonald 2010 criteria in cohorts will develop clinical symptoms of multiple sclerosis in
with clinically isolated syndrome in Latin America26 5 years of follow-up (either a relapse or progressive
and Asia27 have reported a similarly good performance. symptoms).29 Younger age, male sex, and gadolinium-
Finally, the diagnosis of multiple sclerosis should be enhancing, cortical, or spinal cord lesions might be
made only by a neurologist taking into account the associated with an increased risk of developing multiple
clinical picture, MRI findings, and the results of any sclerosis.29–31 There are no accepted diagnostic criteria for
other investigations. radiologically isolated syndrome, but the Okuda 2009
criteria28 have been used in research studies and can also
The radiologically isolated syndrome be applied in a clinical setting. These criteria consider
The widespread use of MRI means incidental findings only dissemination in space and are more stringent than
suggestive of multiple sclerosis are sometimes identified the McDonald criteria, taking into account lesion size
in people who have no clinical symptoms, referred to as and morphology, as well as location, to differentiate
a radiologically isolated syndrome.28 The typical asymptomatic demyelinating lesions from other white

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Clinical features MRI findings CSF findings Other investigations

Neuromyelitis optica Optic neuritis, especially bilateral or with Longitudinally extensive optic nerve lesions Mild CSF pleocytosis AQP4-IgG; MOG-IgG;
spectrum disorder poor visual recovery; transverse myelitis; (involving >50% of the optic nerve) with or without sometimes with neutrophils sometimes OCT
intractable nausea and vomiting; extension into the optic chiasm; brain lesions in or eosinophils; OCBs present
paroxysmal tonic spasms diencephalon, dorsal midbrain, or periependymal in 20% of patients
regions; cloud-like enhancement; longitudinally
extensive spinal cord lesions extending over three or
more vertebral segments
Neurosarcoidosis Optic neuropathy and myelopathy; facial Meningeal enhancement; enhancement of the optic OCBs sometimes present; Serum ACE concentration; chest
palsy; early relapse after stopping steroids; nerve sheath; persistent, nodular enhancement raised CSF ACE (not sensitive or radiograph, HRCT, lung function
with or without systemic involvement within lesions; enlarged lacrimal glands specific for neurosarcoidosis) tests; CT/PET scan; slit-lamp
examination; tissue biopsy
CNS vasculitis Headache; acute CNS syndromes including Punctate or larger lesions in the grey and white OCBs sometimes present Serum ANCA (systemic vasculitis);
(primary or hemiparesis and ataxia; early cognitive matter, often enhancing, sometimes with restricted tissue biopsy at systemic site or
secondary) impairment; with or without systemic diffusion and evidence of microhaemorrhages brain biopsy (if possible)
involvement
Susac’s syndrome Encephalopathy, visual loss, deafness “Snow-ball” lesions in the corpus callosum associated OCBs usually absent Fluorescein angiogram looking
with restricted diffusion in the acute phase and then for branch retinal artery
T1-hypointensity; also icicle and spoke lesions occlusions; OCT; audiometry
CADASIL Migraine, especially with complex or Extensive white matter abnormalities; prominent OCBs absent Testing for NOTCH3 gene
prolonged aura; recurrent acute involvement of the temporal poles and external capsule mutation; skin biopsy
hemiparesis and other vascular syndromes;
neuropsychiatric disturbance; dementia
Connective tissue Optic neuritis; longitudinally extensive Variable OCBs usually absent Serological testing: ANA, ENA,
disorders (systemic transverse myelitis; systemic involvement; antiphospholipid antibodies;
lupus erythematosus, recurrent miscarriage, thrombosis AQP4-IgG
SjÖgren’s syndrome, (antiphospholipid syndrome)
antiphospholipid
syndrome)
BehÇet’s disease Brainstem syndrome; myelopathy (rare); Mass-like enhancing lesions, predilection for the Significant pleocytosis (white Pathergy testing; HLA typing
oral and genital ulceration; intraocular midbrain, thalami, and internal capsules count >50 cells per cm³), might
inflammation be neutrophil predominant;
OCBs usually absent
CLIPPERS Subacute ataxia, double vision, and slurred Punctate gadolinium-enhancing lesions within the OCBs sometimes present Brain biopsy
speech; early relapse after stopping steroids brainstem and cerebellum; with or without lesions in
the basal ganglia, supratentorial white matter, and
spinal cord
Leber’s hereditary Bilateral sequential optic neuropathies Normal or might show white matter lesions OCBs absent Genetic testing
optic neuropathy with poor visual recovery; more common (Harding’s disease)
in men than in women

CSF=cerebrospinal fluid. OCBs=oligoclonal bands. AQP4=aquaporin 4. MOG=myelin oligodendrocyte glycoprotein. OCT=optical coherence tomography. ACE=angiotensin-converting enzyme.
HRCT=high resolution CT. ANCA=antineutrophil cytoplasmic antibodies. CADASIL=cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy. ANA=antinuclear antibodies.
ENA=extractable nuclear antigen. CLIPPERS=chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids.

Table 1: Differential diagnosis of multiple sclerosis: selected disorders with a relapsing-remitting course

matter lesions. A diagnosis of multiple sclerosis should large, confluent, T2-hyperintense lesions that show
only be made in a patient who has symptoms suggestive remarkable resolution on follow-up scans.33 Clinical
of demyelination.2 However, patients with radiologically features and MRI findings might be suggestive of
isolated syndrome are at risk of developing multiple acute disseminated encephalomyelitis. Older children
sclerosis and should be counselled and offered follow-up (≥12 years of age) usually present with clinical features and
as appropriate. MRI findings similar to adults with clinically isolated
syndrome.32,34 The McDonald 2010 criteria have been tested
Multiple sclerosis in special populations in children with clinically isolated syndrome and have
Children similar sensitivity and specificity for the development of
Up to 5% of patients with multiple sclerosis develop their multiple sclerosis as they do for adult populations35 but
first symptoms in childhood, and these are almost always should not be applied in the setting of encephalopathy (ie,
those of relapsing-remitting multiple sclerosis.32 In acute disseminated encephalomyelitis).32
younger children (<12 years of age) multiple sclerosis can
present differently from in adolescents and adults; Older adults
encephalopathy, multifocal neurological deficits (often People presenting with multiple sclerosis after the age of
with prominent brainstem or cerebellar involvement), and 50 years are typically classified as having late-onset
seizures are more common.32 MRI findings can include multiple sclerosis.36 In this age group, men are

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Clinical features MRI findings CSF findings Other investigations

HTLV1-associated Progressive myelopathy; residence or travel to an Spinal cord atrophy (thoracic more than cervical); OCBs sometimes CSF HTLV1 antibody testing
myelopathy endemic area (especially West Indies or Japan) T2-hyperintense brain lesions in some patients present
Dural arteriovenous fistula Subacute, progressive myelopathy Extensive spinal cord T2-hyperintensity often OCBs absent Spinal angiography
extending to the conus, with or without gadolinium
enhancement; dilated veins over the dorsal surface of
the cord (often subtle); brain MRI normal
Nutritional myelopathy Subacute progressive myelopathy or T2-hyperintensity upper cervical cord classically OCBs absent Serum B12, methylmalonic
(vitamin B12 or copper myeloneuropathy; optic atrophy (severe B12 affecting the posterior columns; brain MRI normal acid; serum copper levels,
deficiency) deficiency); anaemia or pancytopenia caeruloplasmin
Primary lateral sclerosis (or Spastic quadriparesis or hemiparesis; with or without MRI normal or showing T2-hyperintensity in the OCBs absent Electromyography looking
upper motor neuron bulbar involvement; with or without development of corticospinal tracts for lower motor neuron
predominant ALS) lower motor neuron signs involvement
Leukodystrophies: Progressive myelopathy (adrenomyeloneuropathy, Highly variable; diffuse, symmetrical T2-hyperintensity OCBs absent Very-long-chain fatty acids
adrenomyeloneuropathy; Krabbe’s); bulbar symptoms, ataxia (Alexander’s sparing subcortical U fibres; with posterior hemispheric (adrenomyeloneuropathy);
Krabbe’s disease; Alexander’s disease); early cognitive impairment (hereditary predominance (adrenomyeloneuropathy); spinal cord genetic testing available for
disease; hereditary diffuse diffuse leukoencephalopathy with axonal spheroids) MRI normal or showing atrophy some leukodystrophies
leukoencephalopathy with
axonal spheroids
Hereditary spastic paraplegia Slowly progressive myelopathy (spasticity greater Spinal cord atrophy; supratentorial and infratentorial OCBs absent Genetic testing
(especially SPG5) than weakness) with or without other neurological white matter lesions (SPG5); atrophy of the corpus
symptoms and family history callosum
Spinocerebellar ataxias Progressive cerebellar ataxia, with or without other Early, prominent cerebellar, with or without spinal OCBs absent Genetic testing
neurological symptoms and family history cord, atrophy

CSF=cerebrospinal fluid. HTLV1=human T-lymphotropic virus type 1. OCB=oligoclonal band. ALS=amyotrophic lateral sclerosis.

Table 2: Differential diagnosis of multiple sclerosis: selected disorders with a progressive course

over-represented and a progressive onset is more predict outcome; the presence of typical multiple
common. Establishing a diagnosis of multiple sclerosis sclerosis lesions and a closed-ring enhancement pattern
can be more difficult in older adults because white matter have been associated with a higher risk of multiple
lesions due to small vessel cerebrovascular disease are sclerosis.38 Atypical demyelinating lesions are also seen
often found on brain MRI.7,37 A stringent interpretation of in neuromyelitis optica spectrum disorder and acute
brain MRI criteria is mandatory and spinal cord MRI is disseminated encephalomyelitis.41
helpful because spinal cord lesions do not occur with
healthy ageing.11 A CSF examination for oligoclonal bands Differential diagnosis of multiple sclerosis
can be particularly helpful in older adults, as might visual Alternative diagnoses
evoked potentials. Studies investigating MRI criteria for a The differential diagnosis of multiple sclerosis is broad
diagnosis of multiple sclerosis have typically excluded and many neurologists use the approach of identifying
patients older than 50 years and the McDonald criteria so-called red flag clinical, imaging, or other laboratory
have not been investigated in this group. features that suggest an alternative diagnosis.42 The
differential diagnosis depends on the clinical
Atypical demyelinating lesions presentation, with different considerations in patients
Brain lesions in multiple sclerosis are typically small with relapsing or progressive courses. These disorders
(<1 cm diameter) and ovoid with a homogeneous include several closely related idiopathic inflammatory
signal on T2-weighted sequences.9 Occasionally, CNS diseases (tables 1, 2), along with a range of other
multiple sclerosis presents with atypical demyelinating disorders that can involve white matter (eg, inherited
lesions, which are characterised by their large size (>2 cm leukodystrophies, vasculopathies, and metabolic
diameter, sometimes with peri-lesional oedema and disorders), and other neuroinflammatory diseases (eg,
mass effect), enhancement pattern (open-ring or closed- sarcoidosis, vasculitis, and Behcet’s disease).
ring enhancement), or morphology (infiltrative or
heterogeneous appearance including concentric Acute disseminated encephalomyelitis
rings).38–40 These lesions might have the appearance of a Acute disseminated encephalomyelitis is an inflammatory
neoplasm (glioma or primary CNS lymphoma) or demyelinating disorder of the CNS, distinct from multiple
infection (brain abscess or progressive multifocal sclerosis, that occurs mainly in children and is rare in
leukoencephalopathy), sometimes necessitating brain adults. Patients present with multifocal neurological
biopsy. Although some patients who present with atypical deficits and encephalopathy, sometimes with a history of
demyelinating lesions have a monophasic course, antecedent infection or vaccination. MRI findings can
30–60% develop multiple sclerosis.38,40 MRI might help to include large (>1–2 cm), bilateral, white matter lesions

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and deep grey matter lesions and contrast enhancement.42 longitudinally extensive spinal cord lesions on MRI (at
CSF findings include a lymphocytic pleocytosis and raised least three vertebral bodies) with prominent involvement
protein. CSF oligoclonal bands might be present only of the central cord (appendix),49 by contrast to multiple
transiently. The clinical, imaging, and laboratory features sclerosis in which lesions are usually short (one or two
of acute disseminated encephalomyelitis and multiple vertebral bodies) and located peripherally. Brain
sclerosis overlap and diagnostic criteria emphasise the involvement also occurs in neuromyelitis optica spectrum
requirement of encephalopathy (altered level of disorder especially in areas rich in AQPA 4 such as the
consciousness, behavioural, or cognitive change) in dorsal medulla or area postrema (where lesions can cause
making the diagnosis of acute disseminated encephalo- intractable nausea, vomiting, and hiccups), diencephalon,
See Online for appendix myelitis (appendix).32 Acute disseminated encephalo­ and periependymal regions of the corpus callosum and
myelitis is almost always monophasic; however, an third and fourth ventricles (appendix).49 Some patients
encephalopathic acute disseminated encephalomyelitis- with neuromyelitis optica spectrum disorder have brain
like illness can sometimes be the first presentation of lesions that can be difficult to distinguish from multiple
multiple sclerosis in both children32,34 and adults,43 and sclerosis, with up to a quarter fulfilling Barkhof criteria.51
diagnostic criteria for acute disseminated encephalo­ CSF test results occasionally show features distinct from
myelitis remain imperfect. multiple sclerosis (white cell counts higher than 50 cells
per cm³ and neutrophils or eosinophils higher than
Neuromyelitis optica spectrum disorder 5 cells per cm³); however, a mild CSF pleocytosis is more
Neuromyelitis optica spectrum disorder is an common (white cell count lower than 25 cells per cm³).52
inflammatory astrocytopathy of the CNS with clinical By contrast with multiple sclerosis, CSF oligoclonal bands
and radiological features that overlap with multiple are uncommon in patients with neuromyelitis optica
sclerosis.4 The identification of a pathogenic IgG antibody spectrum disorder (<20% of patients).52
directed against aquaporin 4 (AQP4-IgG) has established About 70% of patients with relapsing neuromyelitis
neuromyelitis optica spectrum disorder as a specific optica spectrum disorder are AQP4-IgG-positive, with
disease entity that needs to be differentiated from the sensitivity increased with the use of cell-based rather
multiple sclerosis because of important differences in than ELISA assays.53,54 AQP4-IgG is highly specific for
prognosis and treatment.44,45 Neuromyelitis optica neuromyelitis optica spectrum disorder, although false
spectrum disorder is about 100-times less common than positives occur in up to 0·5% of patients with multiple
multiple sclerosis in European and North American sclerosis using ELISA assays, potentially resulting in
populations, but is relatively more common in Asian and misdiagnosis.54,55 A recently identified subgroup of
African populations, in which multiple sclerosis is less AQP4-IgG-seronegative patients have antibodies against
common.46 Neuromyelitis optica spectrum disorder myelin oligodendrocyte glycoprotein (MOG-IgG)56 and
shows a strong sex bias (female:male ratio up to 9:1) and might have a more favourable course.50,57 MOG-IgG is
a mean age at onset of 39 years,46 although all age groups also found in some patients with acute disseminated
can be affected including children and elderly people. A encephalomyelitis (particularly in children), and in acute
history of autoimmunity including thyroid disease and disseminated encephalomyelitis followed by optic
connective tissue disorders (eg, systemic lupus neuritis, and isolated or recurrent optic neuritis.58,59 It is
erythematosus and Sjogren’s syndrome) is not not clear whether MOG-IgG-associated inflammatory
uncommon.45 Most patients with neuromyelitis optica demyelinating syndromes will remain part of
spectrum disorder have a relapsing course with neuromyelitis optica spectrum disorder or be considered
accumulation of disability over time related to poor as a distinct nosological entity in the future.60
recovery from individual attacks and a secondary Diagnostic criteria for neuromyelitis optica spectrum
progressive course is rare.45,47 An accurate diagnosis of disorder were updated in 2015 (appendix).4 The diagnostic
neuromyelitis optica spectrum disorder is essential criteria are more stringent in AQP4-IgG-negative patients,
because prompt treatment of acute attacks and long-term requiring at least two attacks affecting different sites, one
immunosuppression seem to reduce disability, whereas of which must be optic neuritis, myelitis, or an area
conventional treatments for multiple sclerosis might postrema syndrome.
aggravate neuromyelitis optica spectrum disorder.44,48 Although the first attack of neuromyelitis optica
The core clinical features of neuromyelitis optica spectrum disorder can mimic clinically isolated syndrome
spectrum disorder are optic neuritis and transverse (eg, acute unilateral optic neuritis or short-segment partial
myelitis. Compared with in multiple sclerosis, optic myelitis61), routine testing for AQP4-IgG in patients with
neuritis in neuromyelitis optica spectrum disorder is clinically isolated syndrome in populations with a high
more likely to be bilateral (either simultaneous or rapidly incidence of multiple sclerosis and low incidence of
sequential) and associated with poor visual recovery. neuromyelitis optica spectrum disorder has a very low
Characteristic lesions are those extending over more than yield and is not recommended.62 A first demyelinating
half the length of the optic nerve, and sometimes into the event suggestive of neuromyelitis optica spectrum disorder
optic chiasm.49,50 Attacks of myelitis are associated with (eg, severe or bilateral optic neuritis, longitudinally

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extensive transverse myelitis, and area postrema and Drug Administration and the European Medicines
syndrome) should always mandate testing for AQP4-IgG Agency are investigating the clinical significance of
and facilitates an earlier diagnosis and treatment. gadolinium deposits in the brain reported in some
patients after the repeated use of gadolinium-based
Misdiagnosis of multiple sclerosis contrast agents.69,70 At this time, safety concerns should
Rates of misdiagnosis of multiple sclerosis might be as not preclude the use of gadolinium-based contrast agents
high as 10%.63 In a survey of multiple sclerosis specialist for diagnostic purposes, but they should be considered
neurologists in the USA, 95% of respondents had seen when monitoring patients with multiple sclerosis.
one or more patients in the previous year who had been MRI criteria for multiple sclerosis require a balance
misdiagnosed with multiple sclerosis, many of whom between sensitivity (diagnosing multiple sclerosis at an
were being treated inappropriately with disease- early stage) and specificity (making an accurate
modifying therapies. The major disorders identified that diagnosis). The optimum balance of sensitivity and
were misdiagnosed as multiple sclerosis were small specificity using MRI criteria is uncertain. Using the
vessel cerebrovascular disease, migraine, fibromyalgia, McDonald criteria, multiple sclerosis is being diagnosed
and functional neurological disorders.64 These disorders substantially earlier than with the use of clinical criteria
usually present quite differently to multiple sclerosis alone, facilitating earlier treatment.19 However, the
and reasons for misdiagnosis included misinterpretation criteria are intended to provide diagnostic, rather than
of clinical findings (symptoms not typical of prognostic, information. Conventional brain MRI
demyelination or absence of objective neurological findings around the time of diagnosis are only modestly
signs) and inappropriate application of MRI criteria.63 predictive of long-term disability8 and there is uncertainty
The application of McDonald criteria and the diagnosis as to the extent to which criteria for diagnosis and
of multiple sclerosis should be undertaken by treatment should be linked. The McDonald criteria
neurologists who are familiar with multiple sclerosis identify a subgroup of patients with a single attack and
with additional expert advice when needed (eg, MRI MRI evidence of dissemination in time and space who
review by a neuroradiologist). do not experience further relapses even with long-term
follow-up.71 This group would previously have been
Controversies and areas of uncertainty considered to have clinically isolated syndrome rather
Although there has been major progress in the diagnosis than multiple sclerosis. The changes to the diagnostic
of multiple sclerosis, areas of uncertainty remain. The criteria might be favourably shifting the apparent long-
role of spinal cord imaging65 and CSF examination66 term outcome of multiple sclerosis (the so-called Will
in diagnosis is particularly controversial. Guidelines Rogers phenomenon), independent of any effect of
recommend spinal cord MRI in patients with symptoms disease-modifying treatments.72
of myelopathy or when brain MRI findings are not
diagnostic of multiple sclerosis.12 However, spinal cord Conclusions and future perspectives
lesions can be very helpful in making a diagnosis of Current diagnostic criteria for multiple sclerosis integrate
multiple sclerosis (cord lesions do not occur with healthy clinical and MRI findings and enable an earlier and more
ageing or cerebrovascular disease11 and provide additional reliable diagnosis of multiple sclerosis than with clinical
evidence of dissemination in space10) and might provide findings alone, potentially facilitating earlier treatment.
important prognostic information.67 Therefore, routine The criteria are best applied in an individual patient
imaging of the whole spinal cord in all patients with when there are typical symptoms and signs of multiple
suspected multiple sclerosis has been proposed.68 The sclerosis and when relevant differential diagnoses have
McDonald 2010 criteria do not mandate a CSF been excluded. Further supportive information from
examination and there is much variation between CSF and evoked potentials can be obtained if diagnostic
neurologists as to how often a lumbar puncture is done in uncertainty remains.
the diagnosis of multiple sclerosis.66 The sensitivity of Despite the current usefulness of the McDonald
oligoclonal bands is lower than 100% and might be criteria, the MAGNIMS network have recently proposed
substantially lower in people with a first demyelinating a number of modifications, such as inclusion of optic
event,15 when a lumbar puncture is most likely to be done. nerve, cortical, and symptomatic lesions in dissemination
However, oligoclonal bands might provide additional in space and standardisation of dissemination in space
prognostic information15 and increase diagnostic criteria for relapsing-remitting multiple sclerosis,
confidence, especially when considering long-term primary progressive multiple sclerosis, and radiologically
disease-modifying treatment. isolated syndrome.68 Some of these recommendations
Gadolinium-enhancing lesions provide evidence for are evidence-based73,74 and others are based on expert
dissemination in time and can also assist in differential consensus. These and other changes to the diagnostic
diagnosis.1,12 Guidelines recommend a post-contrast criteria for multiple sclerosis will be considered at a
T1-weighted scan as part of the diagnostic evaluation of meeting of the International Panel on Nov 3–5, 2016, and
patients with suspected multiple sclerosis.12 The US Food will be published in 2017.

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Further iterations of the McDonald criteria could allow from Biogen Idec, Novartis, Mitsubishi Pharma Europe, and Bayer
for inclusion of new and emerging MRI techniques with Schering Pharma and compensation through payments to his employer
for performing central MRI analysis of multiple sclerosis trials from
improved pathological specificity.12,68 Cortical grey matter Biogen Idec, Novartis, and Apitope. WJB declares no competing interests.
is frequently involved in multiple sclerosis pathologically,
Acknowledgments
but cortical lesions are rarely visualised on conventional We thank Kate Brunskill from the Queen Square Library, Archive &
MRI sequences and are better seen using double Museum (London, UK) for planning and conducting the literature
inversion recovery (DIR) or phase-sensitive inversion search. The Queen Square Multiple Sclerosis Centre at UCL Institute of
recovery (PSIR) techniques.73,75 Cortical grey matter Neurology is supported by the United Kingdom MS Society and
UCL-UCLH Biomedical Research Centre.
lesions could be helpful in making a diagnosis of
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