The document discusses the importance of carefully considering alternative diagnoses to multiple sclerosis (MS) when evaluating patients. Common causes of MS misdiagnosis include nonspecific white matter abnormalities on brain MRI and vague neurological symptoms. Other disorders like neuromyelitis optica spectrum disorders, acute disseminated encephalomyelitis, and inherited disorders can mimic MS clinically and radiologically. A thorough evaluation of demographic, clinical, laboratory, and imaging factors is necessary to avoid misdiagnosis, as an MS diagnosis has significant implications for treatment.

1. Osama Ragab
Neurology MD
Tanta University

2. In recent years, several studies confirmed the issue
of incorrect MS diagnosis.
Currently, the most common cause of MS
misdiagnosis:
Nonspecific brain MRI white matter
abnormalities
The presence of vague or nonspecific neurologic
symptoms considered to be related to MS.

3.  In fact, up to one-third of “normal” people aged 20
to 45, had transient neurologic symptoms, such as
visual changes , weakness, poor balance, and
speech difficulties of no clinical significance.
When they have a number of nonspecific white
matter spots on their brain MRI, they easily may
be misdiagnosed as having MS .

4. Another major issue in the diagnosis and differential
diagnosis of MS is a large number of other disorders that
may mimic MS, such:
Neuromyelitis optica spectrum disorders (NMOSD), acute
disseminated encephalomyelitis (ADEM), several
inherited disorders, infectious, neoplastic, or vascular
disorders .

5. Unfortunately, a significant number of practising
neurologists find a clinical history and MRI findings
sufficient to make a diagnosis of MS.
However, the CSF is not only important in supporting the
diagnosis, but at times it may reveal unexpected findings,
such as a high level of protein, a low glucose level, or
elevated number of cells, when the diagnosis of MS then
needs to be questioned.

6.  we need to “think twice” either before making or confirming a
diagnosis of MS.
 These “think twice” warnings will be summarized as:
 Demographic.
Clinical
 Laboratory.
Imaging .

7. All possible in MS, but other diseases should be ruled out first!
Childhood-onset (age <16)
[consider dysmyelinating diseases]
Late-onset (age > 50)
[ischemic diseases and other vasculopathies with secondary demyelinating changes]
Strong family history >3 family members have identical MRI
abnormalities
[consider genetic diseases]

8.  All possible in MS, but first other diseases should be ruled out!
Acute (stroke like) onset (acute hemiparesis; acute optic
neuropathy [ON])
Unexpected course! [Fulminant/rapidly progressive course]
Onset with atypical symptoms for MS [impaired
consciousness, cognitive deficits, aphasia, apraxia, seizures,
extrapyramidal signs]
Clinical stereotype! [Attacks originating always from the same
central nervous system (CNS) region]

9.  All possible in MS, but first other diseases should be ruled out!
Progressive and lateralized/mono-symptomatic disease .
Lack of typical MS symptoms in a patient with a long-
standing CNS disease [eg, none of ON, bladder problems,
sensory symptoms, Lhermitte]
No documented response to IVMP at any time [likely to be
noninflammatory disease, non-MS]

10.  There are no blood or other tests that are diagnostic for MS.
 Positive antinuclear antibody (ANA) testing was found in 30.4% of
patients with MS, but the titers were mostly low (1:320).
 Low vitamin B12 have been reported in up to 19.4% of patients with
MS.
 Reactive Lyme serology in patients with MS has been shown to be
up to 7%.
 Elevated serum ACE levels were also reported in 23% of patients
with MS .

11.  Selective autoantibodies that may be studied in patients who
present with suspected atypical demyelinating syndromes
 AQP4-immunoglobulin (Ig)G
 aMOG-IgG
 aNMDAr-IgG and other Abs for autoimmune encephalopathies
 Antibody panel for vasculitic/collagen disorders (antinuclear
antibodies, adsDNA; RF; Sjogren syndrome; ACl)
 Antibody panel for paraneoplastic disorders
 Antibodies for infectious disorders

12. Normal CSF (no oligoclonal bands [OCBs], normal IgG
and IgG index): start thinking twice
OCB (-VE): less likely to be MS
Cells up to 50/mL in MS, but already when more than 20
to 50 start thinking twice; >50: neuro-infectious!
Protein up to 90 mg/dL in MS, but already when more
than 60, start thinking twice!

13. Albumin CSF/serum ratio (QAlb): normal or slightly
increased, when elevated (together with increased cells)
think more of infections or leptomeningeal metastases, as
well as acute and chronic demyelinating polyneuropathies
and spinal stenosis
Glucose: normal in MS; if low, consider bacterial or viral
meningo-encephalitis, also may be leptomeningeal
metastatic infiltration

14. Very small lesions (<3 mm) [NSWMA; Vasculopathies;
Migraine]
Absence of ovoid lesions [NSWMA; Vasculopathies; Migraine]
No or only a few juxtacortical and/or periventricular
lesions [NSWMA; Vasculopathies; Migraine]
Absence of posterior fossa, corpus callosum and spinal
cord lesions [NSWMA]
Symmetrical/semi-symmetrical lesions [NSWMA; inherited
disorders including CADASIL]

15. Disproportionally large corpus callosum lesions [Susac’s;
NMOSD; malignant primary bain tumors and lymphoma]
No change in successive MRIs – all MRIs are the same!
[NSWMA]
No gadolinium enhancement in any MRI [NSWMA;
Migraine, -most- genetic disorders]
Persistent gadolinium enhancement in all MRIs [vascular
lesions e.g., venous developmental anomalies]

16. Family members with similar “identical” MRI! [genetic
disorders]
Lesions with prominent mass effect [Tumors, some
infections]
Up/downward (edematous) extension of large brainstem
lesion/s [NBD; tumors]
Longitudinally extensive spinal cord lesions [NMOSD;
MOG-myelopathies; Neuro-sarcoidosis;NBD; spinal cord
vascular malformations/ dural fistula; tumors]

18.  It is well known that people with migraine are more likely to have
white matter abnormalities (WMA) that may be seen in the
posterior fossa structures .
 These WMAs may increase in time .
 The supratentorial lesions in migraine are mostly subcortical,
rather than periventricular and less likely to be juxtacortical.

19.  (A–F) Two patients with migraine
and NSWMAs on MRI. (A–D)
 An MRI study done for headaches
and visual symptoms reveals
bilateral mostly subcortica
semisymmetrical NSWMAs in an
umbrellalike distribution!

20. The multisystem disorders caused by a variety of genetic
defects will result in a number of inherited disorders, such
as lysosomal storage disorders, several mitochondrial
diseases, and several other neurometabolic disorders.
Multisystem involvement, a positive family history,
involvement in some of both cortical and deep gray matter
in a nonvascular pattern in addition to the
semisymmetrical or symmetric white matter involvement,
should raise the suspicion of such disorders.

21.  The MRI findings suggest genetic disorders:
 Symmetric-appearing white matter involvement of the cerebral
hemispheres
 Cerebral involvement limited to long tracts (mostly within the
post internal capsule and brain stem)
 Spinal cord involvement limited to long tracts: longitudinal
lesions
 T1 hyperintensities of thalamic pulvinar
 T2 (symmetric) hyperintensities of dentate nucleus
 Multiple subcortical cystic cavitation

22. Leukoencephalopathy with brainstem and
spinal cord involvement and high (or
normal) lactate.
MRI discloses inhomogeneous and spotty
cerebral white matter abnormalities within
the periventricular and deep cerebral white
matter, sparing the temporal lobes and the
U-fibers, posterior corpus callosum, and
posterior internal capsule.
Selective pyramidal tract involvement and
cerebellar connections are involved as well
as the intraparenchymal trajectories of the
trigeminal nerve and long tract involvement
of the spinal cord.

23. The type of MRI involvement, the strong family history, and genetic
testing are diagnostic.
The lesions involve bilaterally the U-fibers, the basal ganglia,
external capsule, insular regions, and commonly in the form of
lacunar like infarcts within the corona radiata and subcortical
regions.
The anterior part of the temporal lobes and the frontal pole juxta-
subcortical lesions together with external capsule involvement,
should bring CADASIL to the top of the differential diagnosis list.

24.  MRI shows almost the typical
imaging pattern of CADASIL, the
lesions involve the anterior part
of the temporal lobes, as well as
the frontal pole juxta-subcortical
lesions together with external
capsule. The U-fibers and the
basal ganglia, as well as the
corona radiata and subcortical
regions are also involved.

25.  Leber hereditary ON (LHON), which is a maternally
inherited bilateral ON, has its onset in teenage and is
the most common of this group of disorders.
 Although the major neurologic manifestation in LHON
is an acute or subacute onset of painless ON that
affects both eyes successively,
 In a recent study, it was shown that one-fourth of
patients with LHON were found to have an MRI
appearance typical of MS.

26. It is small-vessel diseases that may be
confused both clinically and by MRI
with MS, but the presence of large
infarcts together with T1-hyperintense
signal abnormalities in the pulvinar
nuclei are characteristic.

28.  corpus callosum lesions in MS and they frequently seen at the
genu and body of the callosum with their origin at calloso-
septal interface, and initially as small separate lesions .
 Susac is apresenting typically with a triad of encephalopathy,
retinopathy, and hearing loss.
 MRI shows disproportionally large/cluster of corpus callosum
lesions and limited hemispheric lesions,

29.  Corpus callosum lesions. (A) A
patient with MS whose MRI
shows a few and relatively small
well-demarcated corpus callosum
lesions (this patient had many
hemispheric lesions and at other
sites consistent for MS). (B) A
patient with Susac disease,
whose MRI shows
disproportionally large and a
cluster of corpus callosum lesions
(he had a limited number of
hemispheric lesions).

30.  Marchiafava- Bignami disease, involves the middle layers of genu
and splenium.
 High-grade gliomas and brain lymphoma also may involve the
corpus callosum and more frequently at the genu and splenium, they
are large lesions extending across the corpus callosum and cross the
midline .
 Brain NMO may also involve the entire corpus callosum
(longitudinally extensive corpus callosum lesion!) but more
frequently will affect the splenium .

31.  Gliomatosis cerebri also may involve the corpus callosum together by bilateral
patchy or large brain lesions.
 ADEM is another atypical inflammatory disease that can involve the corpus
callosum largely as well.
 Occasionally, tumefactive MS may spread across the corpus callosum in a
“butterfly” configuration, simulating an infiltrative astrocytoma or lymphoma.

32.  SVD are mostly subcortical and are not
involve the “U-fibers” ,the corpus callosum,
or the spinal cord.
 T2-hyperintense rims around the ventricles,
known as “caps and bands” should not be
confused with periventricular lesions of MS.
 SVD do not have an ovoid shape and do not
enhance unless in the acute/subacute phase.

33.  PVSs that occur in almost all locations and most
commonly in the deep gray matter, midbrain, fontal
subcortical regions, but also in the corpus callosum.
 PVSs are hyperintense on T2-weighted imaging
(T2WI), hypointense (isointense with CSF) on T1-
weighted imaging.

35.  Demyelinating-inflammatory lesions larger than 20 mm are referred
to as tumefactive demyelinating lesions (TDLs).
 TDLs are mostly focal, well-demarcated, hyperintense on T2WI.
 Most, TDLs show gadolinium enhancement, with most having either
an open-ring or closed-ring pattern, and a few showing
heterogeneous enhancement patterns.
 when the mass effect is disproportionally large than the lesion size,
think twice.

36.  MRI of a patient with biopsy-
proven tumefactive lesion. An 18-
year-old woman develops subacute
right-sided hemiparesis.
 MRI study shows a large
tumefactive lesion, with very little
perifocal edema and almost no
mass effect.
 A biopsy confirms inflammatory
demyelinating pathology.

38.  The MRI in PCNSV are bilateral cortical and subcortical multiple
infarctions, within large-artery and branch-artery territories and
others limited to small arteries, resulting in multiple subcortical
infarctions.
 Multiple microhemorrhages, multiple small/punctate enhancing
lesions, large single-enhancing and multiple-enhancing
mass/tumefactive lesions, and leptomeningeal enhancement all may
be seen.
 Spinal cord involvement, has been reported in patients with
PCNSV.

39. The MRI is lesions are located within
the brainstem, are large with no
distinct borders and have a tendency
to extend to the diencephalic
structures and basal ganglia.
The posterior fossa–brain stem lesions
are more discrete and smaller in MS,
whereas juxtacortical and
periventricular lesions are less likely
in CNS-NBD.

40.  Parenchymal involvement may be seen in NS, not
uncommonly involving the pituitary gland and the
hypothalamus.
 In patients with NS, parenchymal lesions seen on
MRI, which may be due to granulomas and
ischemia or inflammation due to granulomatous
vasculitis, may mimic MS plaques.

41.  cerebral toxoplasmosis are
hyperintense on T2/FLAIR
images and hypointense on
T1 images, often show
ring-enhancement with
perilesional edema.
 They are likely to be in the
juxta-cortical region and
also frequently in the basal
ganglia, with "eccentric
target sign”

43.  When it is a “short-segment spinal cord lesion” [fewer than 3
vertebral segments]
 Radiologically isolated syndromes.
 MS-myelitis
 Transverse myelitis (idiopathic inflammatory-demyelinative)
 Short-segment or recovering NMO/NMOSD: myelitis
 Myelitis associated with systemic vasculitic or collagen tissue
disorders Tumors (ie, astrocytoma; ependymoma)
 Infectious disorders

44.  When it is a “longitudinally extensive spinal cord lesion” [more than
3 vertebral segments]
 NMO/NMOSD: myelitis
 Transverse myelitis
 MS: multiple short-segment lesions in contiguity suggestive .
 Myelitis associated with systemic vasculitides .
 Metabolic-toxic myelopathies (B12)
 spinal venous dural fistula or other vascular malformations
 Tumors (ie, astrocytoma; ependymoma)
 Infectious disorders (ie, viral, tuberculosis, Lyme)

45. Subacute combined degeneration
Myelopathy due to dural fistula

46.  Currently, as the incidence of MS increases, the number of
misdiagnosed cases as MS and the patients who have the disease
but are misdiagnosed for something else, is also arising.
 So we need to be highly alert and be aware of all clinical, laboratory,
and imaging features and pitfalls.
 We also need to be extremely careful when we see a patient who
already has received a diagnosis of MS, and first we should confirm
that diagnosis ourselves, before proceeding further.