references: Phases and Phenotypes of Multiple Sclerosis By Orhun H. Kantarci, MD. Diagnosis of Multiple Sclerosis By Jiwon Oh, MD, PhD, FRCPC Nature Reviews | Disease Primers Multiple sclerosis Massimo Filippi1,2*, Amit Bar- Or3, Fredrik Piehl4,5,6, Paolo Preziosa1,2, Alessandra Solari7, Sandra Vukusic8 and Maria A. Rocca1,2

1. MS DIAGNOSIS
By / Lobna Ahmed​

2. AGENDA
• ​MS clinical presentation.
• Diagnostic criteria.
• Emerging biomarkers.
• phases

3. MS CLINICAL
PRESENTATION
3

4. 4
Optic nerve Spinal cord
Brainstem Cerebellum
Cerebral
hemisphere
Typically, the onset of MS is
characterized by an initial
clinical attack (defined as CIS)
in ~85% of patients, which
consists of an unpredictable
episode of neurological
dysfunction owing to
demyelinating lesions in the
CNS.

5. CLINICAL RELAPSE
An episode that lasts for ≥24 hours and occur in the absence of fever,
infection or clinical features of encephalopathy (for example, altered
consciousness or epileptic
seizures).
5
Symptoms of a clinical relapse typically show an acute or sub-​acute onset,
worsen over days or weeks, reach a peak severity within 2–3 weeks and
remit to a variable degree.
Remission refers to the recovery phase, with some level of restoration of myelin
and axonal integrity. Maximum clinical recovery after a relapse generally
stabilizes within the first 3months and rarely continues beyond 6 months
following a relapse.

6. ASYMPTOMATIC
RELAPSE
Presents as subclinical
activity (new MRI lesions)
without symptoms.
6
Recovery in MRI lesions (symptomatic or
asymptomatic) can be defined as
resolution of enhancement, restoration
of diffusion characteristics, and
shrinkage in size of the MS lesion(s) on
MRI.
It is a recurrence of symptoms from a previous clinical
relapse or a subclinical lesion, likely indicates incomplete
recovery from the previous CNS insult.
Any stress to the CNS (eg, heat, infection, exercise, fatigue)
exceeding a threshold that the damaged CNS can sustain can
trigger a pseudorelapse.
If symptoms attributed to a pseudorelapse exceed the
arbitrary cutoff of 24 hours or do not start improving within
a few days despite identifying and intervening with a
potential trigger (eg, treatment of a urinary tract infection), an
MRI should be obtained to differentiate it from a symptomatic
relapse recurrent in the same location or close vicinity on the
same neural pathway.
PSEUDO
RELAPSE

7. 7
• Optic neuritis is the first neurological episode in
~25% of patients.
• During fundus oculi examination, the optic nerve
head appears normal if inflammation is limited to the
retrobulbar portion of the nerve, but approximately
one-​third of patients might have inflammation of the
optic disc (papillitis) and disc oedema owing to
anterior optic neuritis.
• Patients without visual complaints with suspected MS
should be evaluated for more subtle manifestations
of optic neuritis, such as an afferent pupillary
defect or abnormalities at paraclinical tests (for
example, visual evoked potentials, optical OCT or
MRI).
 Partial or total visual loss in
one eye.
 Central scotoma (a blind spot
in the visual field).
 Dyschromatopsia (deficiency
of colour vision).
 Pain within the orbit that is
worsened by eye movement.
Optic neuritis

8. 8
• Sensory symptoms are the first clinical
manifestation in up to 43% of patients with MS and
are mainly caused by myelitis or brainstem
syndromes.
• Sensory symptoms can temporarily worsen with
increased body temperature (known as Uhthoff
phenomenon).
 Paresthesia (commonly described
as numbness, tingling, pins-​and-
needles feeling, tightness,
coldness and/or swelling of the
limbs or trunk).
 Lhermitte sign(a transient
symptom described as an electric
shock radiating down the spine or
into the limbs with flexion of the
neck).
 Impairment of vibration and joint
position sensation, and reduced
pain and light touch perception.
Sensory
symptoms

9. 9
• Motor manifestations are the initial symptoms in 30–
40% of patients and affect almost all patients during
the course of the disease.
 Pyramidal signs (such as
Babinski sign, more
pronounced reflexes and
clonus).
 Paresis.
 Spasticity.
Motor
symptoms

10. 10
• Brainstem and cerebellar symptoms are present in
up to 70% of patients with MS.
 Nystagmus.
 Oscillopsia.
 Diplopia.
 Ataxia and gait imbalance.
 Decomposition of
movements.
 Dysarthria and dysphagia.
Infratentorial
symptoms

11. 11
Sphincteric and
sexual
dysfunction
 The extent of sphincter and sexual dysfunction often parallels the degree of motor
impairment in the lower extremities, and the dysfunction usually becomes permanent
late in the disease course, affecting 34–99% of patients.
 The most common symptom of bladder dysfunction is urinary urgency, but
hesitancy, frequency and urge incontinence can also occur.
 Constipation is more common than faecal incontinence, and men with MS often have
erectile dysfunction and impotence.

12. 12
Cognitive
symptoms
 Overall, 40–70% of patients with MS have cognitive impairment, which can
start in the earliest phases of the disease.
 Cognitive deficits can predict conversion to clinically definite MS in patients
with CIS, are more frequent and more pronounced in chronic progressive MS,
worsen over time and affect patients’ daily life activities.
 Common cognitive symptoms include impairment in information processing
speed, episodic memory, attention, efficiency of information processing and
executive function.

13. 13
Fatigue
 Fatigue can be associated with relapses and can persist after the attack has
subsided, but it can also be a feature of daily life and can be present for years.
 Several strings of evidence support the hypothesis of a central origin of MS-​related
fatigue owing to a dysfunction of cortico-​subcortical circuits, mainly involving
structural damage in fronto-​parietal regions and the basal ganglia.
 Sleep disorders (for example, insomnia, obstructive sleep apnea and restless legs
syndrome) are found in up to 54% of patients with MS and might also promote fatigue.

14. 14
Other symptoms
 Affective disturbance occurs in up to two-​thirds of patients, of which depression is the
most common manifestation.
 Pain is reported in up to 43% of patients and can include trigeminal neuralgia,
dysesthetic pain, back pain, visceral pain and painful tonic spasms.

15. DIAGNOSTIC
CRITERIA

16. RRMS
Schumacher
1965
• Typical MS-related demyelination.
• Objective evidence of CNS involvement.
• Dissemination in time.
• Dissemination in space.
• No better explanation.
16
Typical syndromes: optic
neuritis,
brainstem syndromes such as
internuclear ophthalmoplegia and
trigeminal neuralgia, cerebellar
syndromes, and transverse
myelitis.
Objective evidence: clinical, paraclinical,
or radiographic evidence of a corroborating
CNS lesion that would explain the
presenting symptoms.
Dissemination in space is defined as detection of
lesions in more than one distinct anatomic location
within the CNS. Multifocal CNS involvement is
characteristic of MS.
Dissemination in time requires confirmation
of new CNS lesions over time, suggesting an
ongoing disease process typical of MS rather than
a monophasic disease.

17. 17
McDonald’s
criteria
2017

18. 18
McDonald’s
criteria
2017
Role of MRI in diagnosis of multiple sclerosis
• Brain and spinal cord MRI remain the most useful paraclinical tests to aid
the diagnosis of MS and can substitute for clinical findings in the of DIS
or DIT in patients with a typical CIS.
• There was general agreement that, although spinal MRI is not mandatory
in all cases, it is advisable when:
 The presentation suggests a spinal cord localization.
 There is a primary progressive course.
 Considering MS in a population in which the disease is less common (eg,
older individuals or non-white populations).
 Additional data are needed to increase diagnostic confidence (eg, when brain
MRI findings only just fulfil the criteria for DIS).
• Spinal MRI seems to be less useful in the diagnosis of MS in children
than in adults.

19. 19
McDonald’s
criteria
2017
Role of MRI in diagnosis of multiple sclerosis

20. 20

21. 21
McDonald’s
criteria
2017
Role of CSF in diagnosis of multiple sclerosis
• The qualitative demonstration of two or more CSF specific oligoclonal bands
more reliably indicates intrathecal antibody synthesis than do other tests,
such as the IgG index.
• The sensitivity of oligoclonal band testing depends on the method used;
agarose gel electrophoresis with isoelectric focusing and immunoblotting or
immunofixation for IgG is the most sensitive approach at present.
• Importantly, analysis of paired CSF and serum samples is essential to
confirm that the oligoclonal bands are unique to CSF.
• The threshold for CSF examination should be low to increase diagnostic
confidence.
• CSF oligoclonal bands are not specific for MS and its absence don’t exclude
the diagnosis of MS.

22. 22
• CSF examination is strongly recommended in the
following situations:
 when clinical and MRI evidence is insufficient to support a diagnosis of MS
particularly if initiation of DMT is being considered.
 When there is a presentation other than a typical CIS, including a progressive
course at onset PPMS.
 When clinical, imaging, or laboratory features are atypical of MS.
 In populations in which MS is less common (eg, children, older individuals, or
non-white populations).

23. 23
2017 Revisions

24. 24
Cortical MRI
lesions
• Lesions within the cerebral cortex.
• Typically, special MRI techniques such as
DIR, phase-sensitive
• inversion recovery, and magnetisation-
prepared rapid acquisition with gradient
echo sequences are required to visualise
these lesions.
• The lesions detected by these techniques
are primarily of the leukocortical type;
subpial lesions are rarely detected.
• Care is needed to distinguish potential
cortical lesions from neuroimaging
artefacts.
• A T2-hyperintense
cerebral white matter
lesion abutting the cortex,
and not separated from it
by white matter.
Juxtacortical
MRI lesions
Peri -
ventricular
lesions
• A T2-hyperintense cerebral
white matter lesion abutting
the lateral ventricles without
white matter in between,
including lesions in the
corpus callosum but
excluding lesions in deep
grey matter structures.

25. 25
Original development of the
McDonald criteria and
subsequent revisions were
largely based on data from
adult white European and
North American populations
with a typical clinically
isolated syndrome and age
younger than 50 years.
The application of McDonald
criteria alone for diagnosis of
MS in patients with atypical
clinical presentations is not
recommended and further
clinical, laboratory, and
radiologic assessments
beyond the minimum
requirements of the McDonald
criteria are necessary to
confirm a
diagnosis of MS.
Criteria critique
The criteria are generally
most applicable to patients
who are 11 years of age or
older; special care is needed
in patients younger than
11 years old, in whom the
likelihood of multiple sclerosis
is lower.

26. PPMS 26
• The diagnostic criteria for primary progressive multiple sclerosis remain the same in
the 2017 McDonald criteria as those outlined in the 2010 McDonald criteria.
• The 2013 revised classification of the clinical phenotypes and disease course of MS
maintained the distinction between MS with an attack onset versus a progressive
course from onset.
• The revised classification incorporated further categorization as active or not
(based on recent clinical relapse or MRI lesion activity) and progressive or not
(based on clinical assessment of disability).

27. PPMS 27

28. Radiologically isolated syndrome
(RIS)
28
Individuals with RIS have a high likelihood of having MS
and might already exhibit evidence of putative
pathobiology, including fatigue, cognitive impairment, or
thalamic atrophy, and that postponing the diagnosis of MS
and initiation of DMT might increase the risk of disability.
Misdiagnosis is high in patients with MRI abnormalities
only, and that two-thirds of these patients will not receive
a diagnosis of multiple sclerosis within 5 years.

29. 29
McDonald’s
criteria
2017
The Panel reached a consensus to continue to require
clinical manifestations to make the diagnosis of MS and, as
in the 2010 McDonald criteria, to allow the use of historical
radiological evidence for DIS and DIT in patients with RIS
to support the diagnosis of MS once a typical CIS occurs.
Factors that increase the likelihood of patients with RIS
converting to MS based on retrospective studies include:
 Male sex.
 Age younger than 37 years.
 Presence of spinal cord lesions.
 Infratentorial lesions.
 CSF-specific OCB.
 The development of gadolinium-enhancing lesions on follow-
up MRI.

30. 30
Okuda DT, Mowry EM, Beheshtian A, et al.
Incidental MRI anomalies suggestive of
multiple
sclerosis: the radiologically isolated syndrome.
Neurology 2009;72(9):800-805. doi:10.1212/01.
wnl.0000335764.14513.1a

31. Solitary
sclerosis
31
Possible MS
McDonald’s
criteria
2017
Patients who have an inflammatory lesion of the cerebral white
matter, cervico-medullary junction, or spinal cord who develop
progressive disability that is clinically indistinguishable
from progressive forms of MS and who might have CSF-
specific OCB but have no clinical or radiological evidence of
new lesion formation. The Panel agreed that despite a
progressive
course, such patients do not satisfy the McDonald criteria
for MS , because they do not have DIS.
The 2010 McDonald criteria5 include a diagnostic category of
possible MS, defined as a suspicion of MS (ie, a patient with a
CIS but not meeting the full criteria). The Panel considered
expanding the category of possible MS to include patients with
atypical presentations, but did not reach a consensus.

32. 32
Environmental and lifestyle factors
Genetic factors
Clinical factors
Laboratoristic factors
Neuroradiological factors
Optical coherence tomography factors

33. 33

34. 34

35. 35

36. PHASES AND DISEASE
COURSE
36

37. 37
Current disease
course
classification in MS
Progression
Relapses
Interaction between two phenomena,
relapses and progression, describe
the disease course in MS. These
phenomena can overlap at different
stages in the disease.
MS high risk
phase
RR phase
Progressive
phase
Each phase is further defined as
active or inactive at any given
time.

38. 38
ACTIVE
New
symptomatic
relapses or
asymptomatic
MRI activity
INACTIVE
The absence of
active disease
for an more
arbitrarily
determined
time cutoff of 1
year or more.
NEDA

39. 39
The
evolving
concept of
NEDA

40. 40
Progression
Insidious and
irreversible
worsening of
neurologic
function due to
MS over years.
Pseudo-
progression
Accumulating
insidious
disability due to
factors
indirectly
related or
unrelated to MS
Worsening
disability
Worsening disability can be due to:
• The stepwise accumulation of neurologic deficit from
partially recovered relapses.
• The insidious accumulation of neurologic deficit from
progressive disease course.
• A combination of both, or other MS or non–MS-related
factors

41. 41

42. 42
Onset of the progressive phase of MS
seemingly is age dependent but
agnostic for disease duration and pre-
progressive
phase.
Once the progressive phase starts, the relapse-based
disability accumulation gives secondary progressive MS
and single-attack progressive MS a head start over
primary progressive MS at the time of progressive MS
onset leading to a higher starting point of disability.
DMT are efficacious early in MS, but the utility of
continuing them in patients older than age 60 should be
considered on an individual basis.

43. 43

44. 44

45. TYPICAL AND ATYPICAL / RED
FLAGS PRESENTATIONS
45

46. 46
Clinical

47. 47
MRI

48. 48
Laboratory
• Absence of CSF-specific oligoclonal bands.
• Significant CSF pleocytosis (eg, greater than 50 cells/mm3).
• Significantly elevated CSF protein (eg, greater than 100 mg/dL).
• Presence of atypical cells (neutrophils, eosinophils, other
atypical cells).

49. 49

50. 50
The segment of optic nerve involvement is usually short, unilateral and confined to the optic nerve
itself.
T1 post contrast Left
T1 Coronal Left T2 axial Left

51. 51

52. 52

53. 53

54. EMERGING
BIOMARKERS
• Central vein sign.
• Paramagnetic rim.
• Body fluids biomarkers.
• OCT.
• Grey matter damage.
54

55. CENTRAL VEIN SIGN
• When appropriate susceptibility-based MRI sequences are used, it is often possible to visualize
central veins within white matter lesions, which are thought to be suggestive of lesions that have
formed due to perivenular inflammation and demyelination, a pathologic hallmark of MS-related
lesions.
• Numerous studies have demonstrated that people with MS have a high proportion of white matter
lesions demonstrating the central vein sign.
55
The 40 % role
If more than 40 % of
white matter lesions
demonstrate the central
vein sign, the likelihood
of a diagnosis of MS is
quite high.
Select 3 Select 6
At least three lesions
have evidence of the
central vein sign on
specific MRI
sequences.
At least six lesions have
evidence of the central
vein sign on specific
MRI sequences.
Automated methods of central vein sign detection are also emerging.

56. 56
NAIMS
consensus
statment
 The venocentric distribution of lesions exists in all MS clinical phenotypes
(RRMS, SPMS and PPMS).
 When imaging is used to examine the proportion of MS lesions with a central vein,
the location of the lesion should be taken into account. Current evidence suggests
that the prevalence of central veins is highest in periventricular and deep white
matter lesions.
 The effects of comorbidities (such as vascular conditions) on the proportion of
lesions with a central vein in patients with MS should not be neglected.
 The available evidence from MRI studies indicates that in comparison to patients
with MS, individuals with AQP4-IgG-positive NMOSD, SAD (Behçet syndrome,
systemic lupus erythematosus and antiphospholipid syndrome), CSVD, Susac
syndrome and migraine have a significantly lower proportion of brain lesions
with a central vein.
SATI, Pascal, et al. The central vein sign and its clinical evaluation for the diagnosis of multiple sclerosis: a
consensus statement from the North American Imaging in Multiple Sclerosis Cooperative. Nature Reviews
Neurology, 2016, 12.12: 714-722.

57. 57
NAIMS
consensus
statment
Perivenous distribution of MS
lesions.
3 T FLAIR* (combined T2* weighted
MRI and FLAIR) images from four
individuals with a variety of neurological
conditions.

58. 58
NAIMS
consensus
statement
 Imaging of veins in the brain can be performed using T2*-based MRI
sequences at any magnetic field strength (1.5 T, 3 T or 7 T).
 Although T2* imaging is most sensitive at 7 T, a high detection rate can still
be achieved at clinical field strengths (1.5 T and 3 T) with optimized
sequences.
 Owing to the small dimensions of the central veins, images should be
acquired at the highest resolution possible. The use of submillimetre voxel
dimensions can be particularly helpful
 High-resolution isotropic T2*with 3D EPI is currently the most
promising acquisition to adequately detect central veins while preserving a
clinically compatible scan time.
SATI, Pascal, et al. The central vein sign and its clinical evaluation for the diagnosis of multiple sclerosis: a
consensus statement from the North American Imaging in Multiple Sclerosis Cooperative. Nature Reviews
Neurology, 2016, 12.12: 714-722.

59. 59
Examples of lesions with and without central veins.
a | Dawson’s finger-shaped lesion with a central vein running perpendicular to the sagittal plane.
b | Periventricular lesion with a hypointense rim located next to the atrium of the lateral ventricle.
c | Small finger-like lesion with a diameter slightly >3 mm in its short axis. The central vein is not as conspicuous as in previous examples, but it is still visible.
d | Small deep white matter lesion with diameter >3 mm and no visible central vein in any plane.
e | Small subcortical lesion with diameter >3 mm and no visible central vein in any plane.
f | Juxtacortical lesion with no visible central vein in any plane.
g | Small hyperintense area with diameter <3 mm located around a parenchymal vein.
h | Periventricular lesion with branching veins. i | Confluent lesions with multiple veins.

60. 60
NAIMS
consensus
statement

61. PARAMAGNETIC RIM LESIONS
• An imaging measure reflective of chronic, active lesions.
• This measure may be useful in diagnosing progressive forms of MS as studies have demonstrated that
patients with progressive MS and greater disability have a higher proportion of lesions demonstrating
paramagnetic rim lesions.
• However, because paramagnetic rim lesions are visualized even in RIS and early RRMS (much like the
central vein sign), future studies are needed before this measure can be used as an imaging biomarker in
clinical settings.
61

62. BODY FLUIDS BIOMARKERS
• Blood biomarkers such as serum neurofilament light chain and glial fibrillary acidic protein (GFAP)
have demonstrated utility in prognostication and in disease monitoring, however, these markers are not
specific for MS-related tissue injury in isolation and it is unclear if they are useful as diagnostic biomarkers.
62
Marker of
axonal
damage.
NfL
Marker of
astrocytes
damage.
GFAP

63. 63
• Neurofilaments are major components of the
axonal cytoskeleton, consisting of light (NfL),
intermediate and heavy chains that are released
from damaged neurons and axons in neurological
disorders.
• These neurofilament chains can be quantified in
the blood and CSF as a marker for neuroaxonal
damage in MS.
• Several studies have demonstrated that levels of
NfL in cerebrospinal fluid are higher in patients
with CIS who convert to MS and patients with
RIS who develop a first clinical attack.
NfL
• In addition, higher levels of NfL are associated with
greater disability, more frequent relapses, higher
numbers of T2-hyperintense and gadolinium enhancing
lesions on MRI and more severe brain atrophy.
• In patients with RRMS, higher levels of NfL predicted
more severe disability and evolution to SPMS after 14
years of follow-​up, whereas in patients with PPMS or
SPMS, levels of NfL predicted the annual EDSS
increase.

64. OPTICAL COHERENCE TOMOGRAPHY.
• OCT can generate high-​resolution images of the retina in a non-​invasive, rapid and reproducible
manner and in a multicenter setting.
• In MS, OCT might show asymptomatic optic nerve involvement in patients with CIS and might predict
conversion to MS.
• The combined ganglion cell-​inner plexiform layer and the retinal nerve fibre layer (RNFL) have been
the two most frequently studied layers of the retina in patients with MS.
• In patients with acute optic neuritis, dynamic modifications of RNFL thickness, characterized by an
initial increase owing to acute inflammatory oedema followed by atrophy within the subsequent 3–6
months, have been detected, therefore, the occurrence of substantial and irreversible damage is
detectable only after 6 months.
64

65. OPTICAL COHERENCE TOMOGRAPHY.
• Meta-​analyses of ​OCT studies have demonstrated RNFL thinning to be most marked in the temporal
quadrant, which is the receiving region for the macular fibres.
• In addition to the RNFL, technological advances in OCT have allowed the segmentation of other retinal
layers, such as the ganglion cell layer (GCL), which has been shown to have a different response to
optic neuritis attacks, as this layer has a faster onset of thinning without any acute phase oedema.
For this reason, macular GCL thickness has been proposed as a superior early indicator of neural
changes following optic neuritis.
• RNFL thinning has been shown in all MS phenotypes and can start in patients with CIS. RNFL is more
severe in patients with SPMS than in those with RRMS independent of a history of previous optic neuritis.
• Progression of RNFL and GCL thinning correlates with visual deficits and worsening disability. In
addition, correlations between OCT parameters and atrophy of the whole brain and grey matter as
detected using MRI have been observed.
65

66. GREY MATTER DAMAGE
• Improvements in MRI techniques have enabled the measurement of grey matter pathology in vivo,
including focal lesions, tissue loss and neuronal abnormalities.
• Focal lesions in the cortex are a distinctive feature in patients with MS, and the presence of at least
one cortical lesion identifies patients with CIS at higher risk of developing MS.
• Cortical lesions are highly specific for MS, as they have not been detected in other neurological
disorders that can mimic MS so far, such as NMOSD or migraine.
• The presence of both cortical lesions and grey matter atrophy are more pronounced in patients with
progressive MS and correlates with more severe disability.
• In addition, the quantification of cortical lesions and grey matter atrophy enables the long-​term
prognostication of worsening of disability and cognitive dysfunction.
66

67. THANK
YOU