Journal of Autoimmunity 48-49 (2014) 134e142

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Journal of Autoimmunity
journal homepage: www.elsevier.com/locate/jautimm

Review

The diagnosis of multiple sclerosis and the various related

demyelinating syndromes: A critical review
Dimitrios Karussis*
Department of Neurology, Multiple Sclerosis Center and Laboratory of Neuroimmunology, The Agnes-Ginges Center for Neurogenetics,
Hadassah University Hospital, Jerusalem, Ein-Kerem, Israel

a r t i c l e i n f o a b s t r a c t

Article history: Multiple sclerosis (MS), is a chronic disease of the central nervous system (CNS) characterized by loss of
Received 7 October 2013 motor and sensory function, that results from immune-mediated inflammation, demyelination and
Accepted 13 November 2013 subsequent axonal damage. MS is one of the most common causes of neurological disability in young
adults. Several variants of MS (and CNS demyelinating syndromes in general) have been nowadays
Keywords: defined in an effort to increase the diagnostic accuracy, to identify the unique immunopathogenic
Multiple sclerosis (MS)
profile and to tailor treatment in each individual patient. These include the initial events of demye-
Diagnostic criteria
lination defined as clinically or radiologically isolated syndromes (CIS and RIS respectively), acute
Clinically isolated syndrome (CIS)
Radiologically isolated syndrome (RIS)
disseminated encephalomyelitis (ADEM) and its variants (acute hemorrhagic leukoencephalitis-AHL,
Neuromyelitis optica (NMO) Marburg variant, and Balo’s concentric sclerosis), Schilder’s sclerosis, transverse myelitis, neuromyelitis
Biomarkers optica (NMO and NMO spectrum of diseases), recurrent isolated optic neuritis and tumefactive
demyelination. The differentiation between them is not only a terminological matter but has important
implications on their management. For instance, certain patients with MS and prominent immuno-
pathogenetic involvement of B cells and autoantibodies, or with the neuromyelitic variants of demy-
elination, may not only not respond well but even deteriorate under some of the first-line treatments
for MS. The unique clinical and neuroradiological features, along with the immunological biomarkers
help to distinguish these cases from classical MS. The use of such immunological and imaging bio-
markers, will not only improve the accuracy of diagnosis but also contribute to the identification of the
patients with CIS or RIS who, are at greater risk for disability progression (worse prognosis) or, on the
contrary, will have a more benign course. This review summarizes in a critical way, the diagnostic
criteria (historical and updated) and the definitions/characteristics of MS of the various variants/
subtypes of CNS demyelinating syndromes.
Ó 2014 Elsevier Ltd. All rights reserved.

1. Introduction
Multiple sclerosis (MS), is a chronic disease of the central ner-
vous system (CNS) characterized by loss of motor and sensory
function, that results from immune-mediated inflammation,
demyelination and subsequent axonal damage [1e3]. The preva-
lence of the disease varies in different regions of the globe, ranging
from 15/100,000, to 250/100,000 [4]. According to WHO, it is
estimated that more than two million people worldwide suffer
from MS and the disease is one of the most common causes of
neurological disability in young adults. Clinically, most MS patients
experience recurrent episodes (relapses) of neurological
* Tel.: þ972 2 6776939.
E-mail addresses: dimitrios@hadassah.org.il, karus@ekmd.huji.ac.il.
impairment, but in most cases (60e80%) the course of the disease
becomes chronic and progressive with time, leading to cumulative
motor disability, and cognitive deficits.
Histologically, perivenular inflammatory lesions (consisting of
mononuclear infiltrations) are evident in the earlier phases of the
disease, resulting in demyelinating plaques, the pathological hall-
mark of MS [2]. Inflammation leads to damage of oligodendrocytes
and demyelination, disrupting the relay of neuronal signals in the
affected regions. As the disease progresses, disability and neuronal
damage [5] become permanent and irreversible.
It is widely accepted that the inflammatory process in MS is
caused or propagated by an autoimmune cascade, involving T-cells
(predominantly of the Th17 phenotype) which target myelin self
antigens [6,7], and possibly mediated by mechanisms of molecular
mimicry (cross-reactive antigens expressed by viruses or other
microorganisms, and myelin components) [8]. An alternative

0896-8411/$ e see front matter Ó 2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.jaut.2014.01.022
 D. Karussis / Journal of Autoimmunity 48-49 (2014) 134e142
hypothesis is that myelin-specific T-cells, which maybe naturally
present, expand to critical, pathogenic numbers [9], due to mal-
functioning immunoregulatory mechanisms (such as those
involving Th2, Th3, Tr1, Treg, and CD8þ T-cells).
Although the autoimmune hypothesis is supported by concrete
data (including the efficacy of immunomodulatory treatments), the
initial insult, which evokes the immune-mediated cascade, remains
obscure. Environmental, genetic and infectious factors appear to
play important roles in MS pathogenesis, similarly to those in other
autoimmune diseases. However, MS is not a homogenous disease
and there are several distinct immunopathological profiles of the
disease, including involvement of humoral immune mechanisms in
some of the MS patients [10]. Patients with MS have an increased
number of B-cells in the central nervous system (CNS), mainly
memory cells and plasmablasts [11]. Plasmablasts persist in the
cerebrospinal fluid (CSF) throughout the course of MS, and the
number of these cells correlates with the intrathecal IgG synthesis
(oligoclonal antibodies, one of the earmarks of MS diagnosis) and
with active inflammatory disease [11,12]. Moreover, B cells, plasma
cells, autoantibodies and complement, have been detected in MS
lesions [13,14], Additional indications for antibody-mediated
mechanisms in MS come from the presence of ectopic lymphoid
follicles in the CNS of the patients [15,16], especially those suffering
form progressive disease.
Several variants of MS (and CNS demyelinating syndromes in
general) have been nowadays defined [17] in an effort to increase
the diagnostic accuracy, to identify the unique immunopathogenic
profile (Table 1) and to tailor treatment. These include the initial
events of demyelination defined as clinically or radiologically iso-
lated syndromes (CIS and RIS respectively) [18e20], acute
disseminated encephalomyelitis (ADEM) [21,22] and its variants
(acute hemorrhagic leukoencephalitis-AHL, Marburg variant, and
Balo’s concentric sclerosis) [23e25,17], Schilder’s sclerosis [17,26],
transverse myelitis [27], neuromyelitis optica (NMO and NMO
spectrum of diseases), recurrent isolated optic neuritis [17] and
tumefactive demyelination [28] (a large, tumor-like demyelinating
lesion with surrounding edema) (Table 1). The differentiation be-
tween them is not only a terminological matter but has important
implications on their management. For instance, patients with type
II MS immunopathogenesis (according to Luccinetti’s clacification
[10]), where autontibodies seem to be more involved than T cells, or
with the neuromyelitic variants of demyelination (NMO spectrum
of diseases, associated with anti-aquaporin antibodies) [27,29e32],
may not only not respond well but even deteriorate under some of
the first-line treatments for MS (such as interferons) [33]. The
unique clinical and neuroradiological features (Table 1), along with
the use of immunological biomarkers (such as anti-AQP4 anti-
bodies) help to distinguish these cases from classical MS. The use of
such immunological and imaging biomarkers, will not only
improve the accuracy of diagnosis but also contribute to the iden-
tification of the patients with CIS or RIS who, are at greater risk for
disability progression (worse prognosis) or, on the contrary, will
have a more benign course.
2. Diagnostic criteria for MS
The original diagnostic criteria for MS were based on clinical
features suggestive of CNS demyelination. The oldest Schumacher
criteria called for 2 clinical relapses separated in time and space in
patients aged 10e50 years and with no better explanation for their
signs and symptoms [34]. The subsequent Poser criteria added to
the Schumacher definition laboratory/paraclinical parameters for
the diagnosis (the presence of oligoclonal bands-OCB in the CSF and
of abnormal/delayed responses of the visual and auditory evoked
potentials) [35] (Table 2). The crucial request in both criteria in
135
order to definitely diagnose MS, was the need for clinical (or lab-
oratory) evidence of dissemination in time and space (DIT/DIS), i.e.
the presence of symptoms affecting more than one discrete CNS
region and at more than one time point during the course of the
disease. Patients were accordingly subclassified as clinically defi-
nite or probable and laboratory supported definite or probable MS
(Table 2).
With the advance of neuroradiological techniques (MR im-
aging), the need for clinical evidence of DIT and DIS was partially
replaced by the radiological evidence of such dissemination.
Based on this principle, a committee headed by McDonald,
defined the new proposed criteria [36], which were lately revised
[37].
In general, the McDonald criteria focus on the integration of
clinical, laboratory, and radiographic data to establish a diagnosis of
MS. Similarly to the Poser criteria, the 2001 McDonald diagnostic
criteria require 2 clinical attacks varying in time and space to
establish a definite diagnosis of MS. DIT could be fulfilled by either
gadolinium (Gd)-enhancing lesion, or a new T2 lesion detected on
repeat MRI scanning performed 3 or more months after the base-
line study. DIT required either meeting the Barkhof/Tintore MRI
criteria (3 of the 4 criteria: 1 Gd enhancing or 9 T2 lesions, 1
juxtacortical, 1 infratentorial, and 3 periventricular lesions)
[38,39] or the presence of 2 silent T2-weighted brain lesions and
oligoclonal bands (OCBs) in the CSF. The sensitivity and specificity
of the 2001 McDonald criteria for prediction of conversion to MS in
1e3 years were high and could therefore establish the diagnosis of
MS after CIS earlier than the Poser criteria, more than doubling the
rate of MS diagnosis within the first year of disease [40,39]. The
revised 2005 criteria better underlined the significance of spinal
cord lesions for DIS criteria and allowed new T2-weighted lesions
on brain MRI after 30 days (rather than the previous time frame of 3
months) following the baseline MRI to establish DIT [41,42]. These
updated criteria led to an improvement in sensitivity compared
with the 2001 criteria (60% vs 47%), while retaining good specificity
(88% vs 91%) [43].
More recently, based on a large cohort study, Swanton et al.
[43,44] proposed less stringent MRI guidelines for the diagnosis of
MS, while improving sensitivity (72% vs 60%, respectively) and
maintaining similar specificity (about 90%). According to their
recommendations, DIS could be met by 1 lesions in at least 2 of
the following locations: spinal cord, infratentorial, periventricular,
or juxtacortical, with no requirement for Gd enhancing lesions. As
for DIT, the Swanton criteria required a new T2 lesion on any
follow-up MRI scan, irrespective of timing.
Based on the latter study and data from the MAGNIMS research
group [45e47], the McDonald criteria were revised in 2010 with
the intent of further simplification [37]. The 2010 McDonald
criteria require fewer MRI scans to establish the diagnosis of def-
inite MS. To meet the criteria for DIS, a patient must have 2 clinical
attacks in different CNS sites or one clinical attack accompanied by
fulfillment of Swanton’s radiographic criteria. Symptomatic MRI
lesions in the brain stem or spinal cord are excluded from the
lesion count for these MRI criteria. Gd-enhancement is not
necessary for DIS. According to the 2010 criteria, DIT requires a
new T2 or Gd-enhancing lesion on subsequent MRI (regardless of
timing from baseline scan) or the presence of both asymptomatic
Gd-enhancing lesions and nonenhancing lesions on the baseline
MRI (Table 2). Thus, the diagnosis of MS after one clinical attack
may now be established even based solely on the baseline MRI (if
both enhancing and non-enhancing lesions co-exist). CSF findings
do not replace the radiographic requirements for DIS according to
the McDonald 2010 criteria [37]. These revised criteria are
considered to have increased diagnostic sensitivity without
compromising specificity.
136
Table 1
MS and related demyelinating syndromes
Clinical syndrome
RIS
CIS
MS
ADEM
Tumefactive MS
Marburg type and
Balo concentric
sclerosis
Schilder disease
Acute hemorrhagic
leukoencephalitis
(AHL), acute hemorrhagic
leukoencephalomyelitis
(AHEM), and Hurst acute
necrotizing hemorrhagic
leukoencephalitis (ANHLE)
Neuromyelitis optica (NMO)
D. Karussis / Journal of Autoimmunity 48-49 (2014) 134e142
Definition
Incidentally detected MRI T2 bright foci suggestive of
demyelination in absence of clinical symptoms [18].
First clinical CNS demyelinating event lasting 24 h and
consistent with MS but isolated in time; may or may not be
isolated in space [19,20].
Chronic, multifocal demyelinating disease of the CNS with
clinical and/or radiological evidence of dissemination in time
and space.
A first ever clinical event with presumed inflammatory or
demyelinating cause, with an acute or subacute onset
affecting multifocal areas of the CNS. This is usually
polysymptomatic and includes encephalopathy. More
common in children [22,127e131].
Presents with at least one large (>2 cm) acute demyelinating
lesion, with accompanying edema, mass effect, and ring
enhancement. Clinical presentations vary by size and location
of the lesion and often include headache, confusion, aphasia,
apraxia, and seizures (which are atypical of CIS/MS) [28].
Considered variants of tumefactive MS, characterized by
severe (often lethal), rapidly evolving course, atypical
neuropathological changes, and distinct radiographic changes
[17,25].
Myelinoclastic diffuse sclerosis, usually characterized by a
single or 2 symmetrically arranged lesions measuring at least
2  3 cm with involvement of the centrum semiovale in
setting of symptoms unusual for MS [17,26].
Rare, severe, rapidly progressive inflammatory and
hemorrhagic demyelinating disorders of the CNS, considered
variants of ADEM [23,24,132,133].
Episodes of optic neuritis (often severe and bilateral leading to
fixed visual loss) and acute myelitis are the major criteria for
diagnosis and a contiguous spinal MRI lesion extending over
3 vertebral segments or NMO-IgG seropositive, are
secondary criteria for diagnosis. According to the modified
criteria, brain lesions may also be present in NMO.
CSF can show pleocytosis of >50 WBCs.
Additional characteristics and diagnostic criteria
RIS criteria [18]:
Presence of incidentally identified CNS white matter anomalies meeting
the following MRI criteria:
1. Ovoid, well-circumscribed, and homogeneous foci with or without
involvement of corpus callosum
2. T2 hyperintensities measuring >3mm and fulfilling the Barkhof
criteria (at least 3 out of 4) for dissemination in space
3. CNS white matter anomalies inconsistent with vascular pattern
B. No historical accounts of remitting clinical symptoms consistent with
neurologic dysfunction
C. MRI anomalies do not account for clinically apparent impairments in
social, occupational, or generalized areas of function
D. MRI anomalies not due to direct physiologic effects of substances
(recreational drug abuse, toxic
exposure) or medical condition
E. Exclusion of individuals with MRI phenotypes suggestive of
leukoaraiosis or extensive white matter pathology lacking involvement
of corpus callosum
F. The CNS MRI anomalies are not better accounted for by other disease
processes
In 85% involves the optic nerves, brainstem, or spinal cord. Multifocal
brain lesions are present on MRI in many patients with CIS; some have
additional abnormalities on quantitative MRI in otherwise normal-
appearing white and gray matter that suggest an extensive pathological
process [19].
Usually relapsing course (RRMS); in 60e80% of the cases the course
becomes progressive with time (SPMS). Primary progressive
(prevalence 10%), relapsing-progressive and benign forms also exist.
The median time from diagnosis of RRMS to SPMS is 10 years, and the
time from disease onset to requiring a cane to walk is 15e25 years.
More than 80% of the patients (40e50% in the first year of the disease)
have oligoclonal antibodies in the CSF (which is typically acellular and
with normal protein levels). Brain MRI pathologic in 95% of the patients.
Visual and/or brain stem-evoked potentials pathologic in 60e70%.
Presence of focal/multifocal lesion(s) predominantly affecting the white
(but also the gray) matter, without evidence of previous destructive
white matter changes, the occurrence of clinical/radiologic
improvement (although there may be residual deficits), and the absence
of other etiology that could explain the event. New or fluctuating
symptoms, signs, or MRI findings occurring within 3 months are
considered part of the initial acute event.
Lack of oligoclonal antibodies and the presence of several lymphocytes
in the CSF; early involvement of CNS gray matter areas; lack of
significant dissemination in space (in the case of relapsing ADEM;
usually only expansion of previously existing lesions occurs); presence
of fever, confusion and headache [22].
Marburg: numerous large multifocal demyelinating lesions in deep
white matter
Balo: concentric layers of partial demyelination alternating with bands
of demyelination. Alternating isointense and hypointense concentric
rings on T1-weighted images in MRI, partial enhancement limited to T1-
hypointense areas
Absence of OCBs in CSF
White matter lesions on MRI tending to be large and diffuse, with
edema and mass effect, as well as restricted diffusion in affected areas of
the brain.
CSF typically demonstrates elevations in WBCs, red blood cells, and
protein.
Revised NMO criteria ([29])
1. Optic neuritis
2. Acute myelitis
3. At least two of the following three supportive criteria:
i. Contiguous spinal cord MRI lesion
extending over at least 3 vertebral segments
ii. Onset brain MRI not meeting the
 D. Karussis / Journal of Autoimmunity 48-49 (2014) 134e142 137

Table 1 (continued )

Clinical syndrome Definition Additional characteristics and diagnostic criteria

The longitudinally extensive myelopathy usually affects the diagnostic criteria for MS
central part of the cord, and intractable hiccups, nausea, or iii. NMO-IgG seropositivity status
vomiting may be reported as a result of a periaqueductal
medullary lesion [27,31,29].
NMO spectrum (NMOS) Includes classical NMO, and:
a. Limited forms of NMO:
i. Idiopathic single or recurrent events of longitudinally
myelitis
(extending to ‡3 vertebral segments on
spinal MRI)
ii.Optic neuritis: recurrent or simultaneous bilateral
b. Asian optic-spinal MS
c. Optic neuritis or longitudinally extensive myelitis
associated with systemic autoimmune disease
d. Optic neuritis or myelitis associated with brain lesions
typical of NMO (hypothalamic, corpus callosal,
periventricular, or brainstem) [30,32].
Chronic relapsing isolated An immune-mediated optic neuropathy considered distinct Differs from MS-related optic neuropathy in that patients often
optic neuropathy (CRION) from CIS/MS. CRION, manifesting as recurrent or chronic experience more severe degree of visual loss, persistence of pain after
unilateral or bilateral vision loss [17]. onset of visual loss, and relapsing and steroid-dependent course of
symptoms. MRI does not show additional CNS lesions.
May, infrequently, develop into NMO or MS
Transverse myelitis Inflammation and demyelination across both sides of one It is mostly caused by infectious agents such as syphilis, measles, Lyme
level, or segment, of the spinal cord resulting in symptoms disease, varicella zoster, herpes simplex, cytomegalovirus, Epstein
of neurological disconnection and dysfunction below the eBarr, influenza, echovirus, human immunodeficiency virus (HIV),
level of the demyelinating area [27]. hepatitis A, rubella and mycoplasma, either directly or as a post-
infectious autoimmune process. It may be also induced by various
vaccinations or be idiopathic.
The latter may occasionally represent one (or the initial) attack of MS or
NMO. In MS, transverse myelitis is usually partial and does not affect the
whole extend of the spinal cord segment.

3. Clinical and laboratory predictors for conversion from CIS
to CDMS
3.1. Clinical and epidemiologic features
Certain demographic and clinical factors have been found to be
associated with a higher risk of conversion from CIS to CDMS:
i. Nonwhite race,
ii. Age less than 30 years,
iii. Involvement of fewer functional systems at first presentation
[48,49]
iv. Motor or multifocal symptoms,
v. High Expanded Disability Status Scale (EDSS) scores at
baseline [19,50,51],
vi. Smoking [52],
vii. Increased EpsteineBarr virus (EBV)-encoded nuclear antigen
1 titer [53].
3.2. Magnetic resonance imaging (MRI)
MRI is a critical tool for both the diagnosis of early MS (McDo-
nald criteria) and the prediction of its future course. MRI represents
a much more sensitive tool for the detection of the clinically silent
activity of MS, than the clinical history or neurological examination
alone [54]. Up to 70% of brain lesions [55,56] and 30% of spinal
lesions [57,58] develop without clinical evidence of relapse. New
silent lesions (that may be defined as “radiological relapses”)
appear up to 10 times more frequently than lesions associated with
clinical relapses [59e61]. More than half of CIS patients show 1 or
more clinically silent T2-bright abnormalities on their baseline
brain MRI [19,58,62,63], the presence and the number of which
may predict the risk of development of MS in the next 5e14 years
[58,60,64e66].
A brain MRI protocol that includes 3 plane scout, sagittal fast
FLAIR, axial fast spin echo proton density/T2, axial fast FLAIR, and
axial Gd enhanced T1 is recommended by the Consortium of
Multiple Sclerosis Centers (CMSC) to evaluate patients presenting
with possible CIS [67]. The CMSC guidelines recommend spinal
cord MRI in patients presenting with symptoms at the spinal cord
level or in patients with focal neurological signs and an equivocal
brain MRI if the diagnosis of MS is still being weighed.
The results of numerous studies assessing the risk of conversion
from CIS to CDMS, suggest that patients who have asymptomatic
brain MRI lesions at the time of presentation of CIS have a 60%e80%
chance of developing CDMS within 10 years, whereas those
without brain lesions carry a much lower risk (w20% risk)
[62,63,68e70]. In general, the number of lesions seems to be well
correlated with the risk of conversion to CDMS.
MRI parameters that may predict conversion to CDMS,
include:
i. The presence of multifocal homogenous or ring-enhancing
white matter lesions,
ii. T2-hyperintense lesions in the corpus callosum [71]
iii. T2-hyperintense lesions in the posterolateral compartment
of the spinal cord [72]
iv. Positivity for Barkhof criteria [134]
However, particularly in the very early stages of MS, the sole
use of MRI may introduce diagnostic errors due to low specificity.
Hyperintense lesions in the white matter of the CNS (sometimes
defined also as UBOs-unknown bright objects) can be detected in a
plethora of pathological conditions (including migraine, micro-
vascular disease and various connective tissue diseases) or even in a
small percentage of “healthy” individuals [73e75]. This is the
reason why the old diagnostic criterion introduced in the sixties by
Shumacker (“rule out other possible causes”), still appears in the
138 D. Karussis / Journal of Autoimmunity 48-49 (2014) 134e142

Table 2
Various diagnostic criteria for MS.

Schumacker committee 1. Clinical signs of problem in CNS

criteria (1965) 2. Evidence of two or more areas of CNS involvement
3. Evidence of white matter involvement
4. One of these: Two or more relapses (each lasting 24 h and separated by at least 1 month) or progression (slow or stepwise)
5. Patient should be between 10 and 50 yrs old at time of examination
6. No better explanation for patient’s symptoms and signs
Poser’s criteria (1983) 1. CDMS (clinically definite MS): two or more attacks (relapses), with clinical (neurological dysfunction demonstrable by neurological
examination) or paraclinical evidence (demonstrable by any test) of the existence of a non-clinical lesion in the CNS. At least one event
should be of clinical evidence.
2. LSDMS (laboratory supported definite MS): At least one attack and oligoclonal bands. i. two attacks (occurrence of a symptom of
neurological dysfunction for more than 24 h), and one evidence (clinical or paraclinical): ii. one attack
and two clinical evidences ; iii. one attack, one clinical and one paraclinical evidence.
3. CPMS (clinically probable MS). One attack. i. Two attacks and one clinical evidence ; ii. one attack and two
clinical evidences; iii. one attack, one clinical and one paraclinical evidence.
4. LSPMS (laboratory supported probable MS): Two attacks with no other evidence.
McDonald criteria (2001) Clinical presentation Additional data needed
* 2 or more attacks (relapses) None; clinical evidence will suffice (additional evidence desirable
* 2 or more objective clinical lesions but must be consistent with MS)
* 2 or more attacks Dissemination in space, demonstrated by:
* 1 objective clinical lesion * MRI
* or a positive CSF and 2 or more MRI lesions consistent with MS
* or further clinical attack involving different site
* 1 attack Dissemination in time, demonstrated by:
* 2 or more objective clinical lesions * MRI
* or second clinical attack
* 1 attack Dissemination in space demonstrated by:
* 1 objective clinical lesion (monosymptomatic * MRI
presentation) * or positive CSF and 2 or more MRI lesions consistent with MS

and
Dissemination in time demonstrated by:
* MRI
* or second clinical attack
Insidious neurological progression suggestive of MS One year of disease progression (retrospectively or prospectively
(primary progressive MS) determined) and two of the following:
a. Positive brain MRI (nine T2 lesions or four or more T2 lesions
with positive VEP)
b. Positive spinal cord MRI (two focal T2 lesions)
c. Positive CSF
Modified McDonald * 2 or more attacks Dissemination in space, demonstrated by:
criteria (2010) * 1 objective clinical lesion * MRI
* or positive CSF and 2 or more MRI lesions consistent with MS
* or further clinical attack involving different site.

New criteria: Dissemination in space (DIS) can be demonstrated by the

presence of 1 or more T2 lesions in at least 2 out of 4 of the following
areas of the CNS: Periventricular, Juxtacortical, Infratentorial, or Spinal
Cord.
* 1 attack Dissemination in time (DIT), demonstrated by:
* 2 or more objective clinical lesions * MRI
* or second clinical attack

New criteria: No longer need to have separate MRIs scans; Dissemination

in time can be demonstrated by: the simultaneous presence of asymptomatic
gadolinium(Gd)-enhancing and nonenhancing lesions at any time;
or new T2 and/or Gd-enhancing lesion(s) on follow-up MRI, irrespective
of its timing with reference to baseline scan; or await a second clinical
attack.
* 1 attack New criteria: Dissemination in space and time, demonstrated by:
* 1 objective clinical lesion (clinically isolated For DIS: 1 or more T2 lesions in at least 2 of 4 MS-typical regions of the
syndrome) CNS (periventricular, juxtacortical, infratentorial, or spinal cord); or
await second clinical attack implicating a different CNS site. For DIT:
Simultaneous presence of asymptomatic Gd-enhancing and nonenhancing
lesions at any time; or new T2 and/or GD-enhancing lesion(s) on follow-up
MRI, irrespective of its timing with reference to a baseline scan; or await
second clinical attack.
Insidious neurological progression suggestive of MS New criteria: One year of disease progression (retrospectively or
(primary progressive MS) prospectively determined) and two or three of the following:
1. Evidence of DIS in the brain based on 1 or more T2 lesions in the
MS -characteristic regions (periventricular, juxtacortical, or infratentorial)
2. Evidence of DIS in the spinal cord based on 2 or more T2 lesions in the cord
3. Positive CSF (isoelectric focusing evidence of oligoclonal bands and/or elevated
IgG index)
 D. Karussis / Journal of Autoimmunity 48-49 (2014) 134e142
2010-revised criteria by McDonald [37] and in the recent criteria for
RIS, stressing the need for analysis of the MRI data with care and
performance of a thorough differential diagnosis.
Conventional 1.5 T imaging does not capture the entire extent of
MS activity. For example, cortical lesions, recently found in nearly
40% of patients with early MS [76e78], can not be captured by
conventional 1.5 T scans and may be detected only on double
inversion recovery imaging [79,80] and on 7 T MRI [81e84]. The
presence of at least 1 cortical lesion in patients with CIS may help
identify those at high risk for conversion to CDMS [45,85,86].
Small studies using additional and more advanced MR tech-
niques such as magnetic resonance spectroscopy (MRS) and
magnetization transfer imaging (MTI) have shown that these
methods may help predict which CIS patients will convert to CDMS
[87e90].
3.3. Evoked potentials
Visual-evoked potentials (VEPs) are abnormal in 30% of patients
with CIS, regardless of clinical symptoms [91] and in >50% of pa-
tients with MS [92] who have no history or clinical evidence of optic
nerve dysfunction. Somatosensory-evoked potentials (SSEPs) and
brain stem auditory-evoked potentials (BAEPs) may also be used as
evidence of demyelination that is non-detectable clinically or on
MRI. Pelayo et al. [93] showed that if all 3 evoked potentials (VEP,
SSEP, and BAEP) are abnormal at the time of CIS, there is an
increased risk of developing moderate disability from MS that is
independent of MRI findings.
3.4. CSF studies
About 60e70% of patients with CIS and up to 90% of those with
MS have 2 or more immunoglobulin G (IgG) OCBs uniquely to the
CSF [19,94e100]. CSF OCB testing must be run in parallel with
sampling of serum obtained within 72 h of the lumbar puncture.
The preferred method of analysis with the highest sensitivity and
specificity for MS is isoelectric focusing on agarose gels, followed by
immunodetection by blotting or fixation [101]. Some 70e90% of MS
patients will have an elevated IgG index [95,102] and this may be in
conjunction with, or independent of the presence of OCB in the CSF.
The presence of 2 OCBs in the CSF has a positive predictive value
of 97%, a negative predictive value of 84%, a sensitivity of 91%, and a
specificity of 94% for developing relapsing remitting MS (RRMS)
after a CIS [103]. Tintore et al. [104] and Masjuan et al. [103] showed
that the presence of OCBs within 3 months of CIS nearly doubled
the risk of a second clinical attack over 50 months [105] or over 6
years [104] in the respective studies. On the other hand, CSF with
>50 white blood cells (WBCs)/mm3 or >100 mg/dL protein is rarely
observed in MS, and this should raise the possibility of an alter-
native diagnosis [36,106]. It is also important to bear in mind that
disorders other than MS may also be associated with the presence
of OCB and a high IgG index. The differential diagnosis for the
presence of OCBs in the CSF includes the Sjogren syndrome (75%e
90% of patients with neurological involvement), neurosarcoidosis
(40%e70%), systemic lupus erythematosus (30%e50%), Behcet dis-
ease (20%e50%), paraneoplastic disorders (5%e25%), antiglutamic
acid decarboxylase antibody syndromes (40%e70%), VogteKoyanagie
Harada syndrome (30%e60%), Hashimoto’s steroid-responsive
encephalopathy (25%e35%), subacute sclerosing panencephalitis
(100%), rubella encephalitis (100%), neurosyphilis (90%e95%),
neuroborreliosis (80%e90%), human immunodeficiency virus
infection (60%e80%), meningitis (5%e50%), adrenoleukodystrophy
(100%), ataxia telangiectasia (50%e60%), Leber hereditary optic
atrophy (5%e15%), CNS vascular disorders (5%e25%), and CNS
tumors (<5%) [95].
139
3.5. Additional immunological biomarkers
As MS pathogenesis involves mainly immune-mediated mech-
anisms, serum immune biomarkers are good candidates for the
diagnosis and prognosis of the disease, reflecting the presence,
nature and intensity of certain immune responses [107]. Also, from
a practical standpoint, tests for serum biomarkers [108] could prove
very useful, as blood is relatively simple to collect and the tests can
be easily repeated as a monitoring strategy [109e111]. Such bio-
markers may also be identified in the cerebrospinal fluid (CSF),
which is in closer proximity to the lesions in the CNS.
Biomarkers in conjunction with other prognostic criteria, such
as MRI, may help in the early identification of MS and stratify CIS
patients according to their risk for progression to CDMS. Such
classification rules may provide additional tools for the determi-
nation of the most appropriate treatment strategy for the individ-
ual patient [112e115].
Antibodies targeting myelin antigens are, naturally, one of the
most extensively studied serum biomarkers in MS. The presence of
IgM, against the extracellular domain of myelin oligodentrocyte
protein (MOG), together with antibodies specific for myelin basic
protein (MBP) in CIS patients, was shown to be highly predictive for
CDMS [116]. However, other studies testing the prognostic value of
anti-MOG and anti-MBP antibodies revealed controversial results
ranging from highly significant to totally non significant [116e122].
Antibodies targeting alpha-glucose-based antigens were found
to differentiate MS from other neurological diseases and to predict
progression to a more severe disease phenotype [109e111].
The B cell chemoattractant chemokine CXCL13 may also serve as
a prognostic marker in patients with CIS. In a recent study, the
serum and CSF levels of CXCL13 of CIS patients were examined
prospectively over 2 years. CXCL13 showed the best positive pre-
dictive value (PPV) for conversion to CDMS, of all the parameters
investigated, and this was further pronounced when combining it
with the Barkhof MRI criteria (80%).
Additional novel biomarkers for MS include osteopontin, TNFa,
various cytokines and chemokines and ab-crystalin. Neurofilament
protein subunits are also potential CSF biomarkers for disease
progression in MS, as their presence at high levels may reflect acute
axonal damage and imply a prognostic value for conversion from
CIS to CDMS [123e126].
In conclusion, substantial progress has been made during the
last decade in the diagnosis of MS. The use of clinical, radiological,
electrophysiological and immunological biomarkers has paved the
way for earlier diagnosis and earlier (and therefore more effective)
therapy [54]. Using these biomarkers, allows the replacement of the
time consuming “waiting for clinical activity” by paraclinical pa-
rameters that provide evidence of new activity of the disease and
its dissemination in time and space, an essential criterion for the
definite diagnosis of MS. Several variants of MS have been now
recognized by using these biomarkers, allowing tailoring of treat-
ment and more "personalised" medicine. Along with these ad-
vantages of the new diagnostic approach in MS, which is based on
the revised (heavily dependent on neuroimaging) criteria, some
reservations and concerns are raised as to whether a certain degree
of specificity may be lost, with physicians tending to treat the MRIs
rather than the patient.
References
[1] Compston A, Coles A. Multiple sclerosis. Lancet 2008 Oct 25;372(9648):
1502e17. PubMed PMID: 18970977. Epub 2008/10/31. eng.
[2] Frohman EM, Racke MK, Raine CS. Multiple sclerosisethe plaque and its
pathogenesis. N Engl J Med 2006 Mar 2;354(9):942e55. PubMed PMID:
16510748. Epub 2006/03/03. eng.
140 D. Karussis / Journal of Autoimmunity 48-49 (2014) 134e142
[3] Steinman L. Multiple sclerosis: a two-stage disease. Nat Immunol 2001
Sep;2(9):762e4. PubMed PMID: 11526378. Epub 2001/08/30. eng.
[4] Kingwell E, Marriott JJ, Jette N, Pringsheim T, Makhani N, Morrow SA, et al.
Incidence and prevalence of multiple sclerosis in Europe: a systematic re-
view. BMC Neurol 2013 Sep 26;13(1):128. PubMed PMID: 24070256. Epub
2013/09/28. Eng.
[5] Trapp BD, Peterson J, Ransohoff RM, Rudick R, Mork S, Bo L. Axonal tran-
section in the lesions of multiple sclerosis. N Engl J Med 1998 Jan 29;338(5):
278e85. PubMed PMID: 9445407. Epub 1998/01/29. eng.
[6] Allegretta M, Nicklas JA, Sriram S, Albertini RJ. T cells responsive to myelin
basic protein in patients with multiple sclerosis. Science 1990 Feb
9;247(4943):718e21. PubMed PMID: 1689076. Epub 1990/02/09. eng.
[7] Zhang J, Markovic-Plese S, Lacet B, Raus J, Weiner HL, Hafler DA. Increased
frequency of interleukin 2-responsive T cells specific for myelin basic protein
and proteolipid protein in peripheral blood and cerebrospinal fluid of pa-
tients with multiple sclerosis. J Exp Med 1994 Mar 1;179(3):973e84.
PubMed PMID: 7509366. Pubmed Central PMCID: 2191414. Epub 1994/03/
01. eng.
[8] Wucherpfennig KW, Strominger JL. Molecular mimicry in T cell-mediated
autoimmunity: viral peptides activate human T cell clones specific for
myelin basic protein. Cell 1995;80(7534214):695e705.
[9] Venken K, Hellings N, Hensen K, Rummens JL, Stinissen P. Memory
CD4þCD127high T cells from patients with multiple sclerosis produce IL-17
in response to myelin antigens. J Neuroimmunol 2010 Sep 14;226(1e2):
185e91. PubMed PMID: 20554330. Epub 2010/06/18. eng.
[10] Lucchinetti C, Bruck W, Parisi J, Scheithauer B, Rodriguez M, Lassmann H.
Heterogeneity of multiple sclerosis lesions: implications for the pathogenesis
of demyelination. Ann Neurol 2000 Jun;47(6):707e17. PubMed PMID:
10852536. Epub 2000/06/14. eng.
[11] Cepok S, Rosche B, Grummel V, Vogel F, Zhou D, Sayn J, et al. Short-lived
plasma blasts are the main B cell effector subset during the course of mul-
tiple sclerosis. Brain 2005 Jul;128(Pt 7):1667e76. PubMed PMID: 15800022.
Epub 2005/04/01. eng.
[12] Owens GP, Bennett JL, Gilden DH, Burgoon MP. The B cell response in mul-
tiple sclerosis. Neurol Res 2006 Apr;28(3):236e44. PubMed PMID:
16687047. Epub 2006/05/12. eng.
[13] Archelos JJ, Storch MK, Hartung HP. The role of B cells and autoantibodies in
multiple sclerosis. Ann Neurol 2000 Jun;47(6):694e706. PubMed PMID:
10852535. Epub 2000/06/14. eng.
[14] Prineas JW, Graham JS. Multiple sclerosis: capping of surface immunoglob-
ulin G on macrophages engaged in myelin breakdown. Ann Neurol 1981
Aug;10(2):149e58. PubMed PMID: 7025748. Epub 1981/08/01. eng.
[15] Magliozzi R, Howell O, Vora A, Serafini B, Nicholas R, Puopolo M, et al.
Meningeal B-cell follicles in secondary progressive multiple sclerosis asso-
ciate with early onset of disease and severe cortical pathology. Brain 2007
Apr;130(Pt 4):1089e104. PubMed PMID: 17438020. Epub 2007/04/18. eng.
[16] Serafini B, Rosicarelli B, Magliozzi R, Stigliano E, Aloisi F. Detection of ectopic
B-cell follicles with germinal centers in the meninges of patients with sec-
ondary progressive multiple sclerosis. Brain Pathol 2004 Apr;14(2):164e74.
PubMed PMID: 15193029. Epub 2004/06/15. eng.
[17] Zettl UK, Stuve O, Patejdl R. Immune-mediated CNS diseases: a review on
nosological classification and clinical features. Autoimmun Rev
2012;11(21619943):167e73.
[18] Okuda DT, Mowry EM, Beheshtian A, Waubant E, Baranzini SE, Goodin DS,
et al. Incidental MRI anomalies suggestive of multiple sclerosis: the radio-
logically isolated syndrome. Neurology 2009 Mar 3;72(9):800e5. PubMed
PMID: 19073949. Epub 2008/12/17. eng.
[19] Miller D, Barkhof F, Montalban X, Thompson A, Filippi M. Clinically isolated
syndromes suggestive of multiple sclerosis, part 2: non-conventional MRI,
recovery processes, and management. Lancet Neurol 2005 Jun;4(6):341e8.
PubMed PMID: 15907738. Epub 2005/05/24. eng.
[20] Miller D, Barkhof F, Montalban X, Thompson A, Filippi M. Clinically isolated
syndromes suggestive of multiple sclerosis, part I: natural history, patho-
genesis, diagnosis, and prognosis. Lancet Neurol 2005 May;4(5):281e8.
PubMed PMID: 15847841. Epub 2005/04/26. eng.
[21] Brinar VV, Habek M. Diagnostic imaging in acute disseminated encephalo-
myelitis. Expert Rev Neurother 2010;10(20187866):459e67.
[22] Menge T, Kieseier BC, Nessler S, Hemmer B, Hartung H-P, Stuve O. Acute
disseminated encephalomyelitis: an acute hit against the brain. Curr Opin
Neurol 2007;20(17495616):247e54.
[23] Kuperan S, Ostrow P, Landi MK, Bakshi R. Acute hemorrhagic leukoence-
phalitis vs ADEM: FLAIR MRI and neuropathology findings. Neurology
2003;60(12601124):721e2.
[24] Mader I, Wolff M, Niemann G, Kuker W. Acute haemorrhagic encephalo-
myelitis (AHEM): MRI findings. Neuropediatrics 2004;35(15127316):143e6.
[25] Susac JO, Daroff RB. Magnetic resonance images on Marburg variant.
J Neuroimaging 2005;15(15746237):206.
[26] Poser CM, Goutieres F, Carpentier MA, Aicardi J. Schilder’s myelinoclastic
diffuse sclerosis. Pediatrics 1986;77(3940347):107e12.
[27] Wingerchuk DM, Weinshenker BG. Acute disseminated encephalomyelitis,
transverse myelitis, and neuromyelitis optica. Contin (Minneap Minn) 2013
Aug;19(4 Multiple Sclerosis):944e67. PubMed PMID: 23917095. Epub 2013/
08/07. eng.
[28] Lucchinetti CF, Gavrilova RH, Metz I, Parisi JE, Scheithauer BW, Weigand S,
et al. Clinical and radiographic spectrum of pathologically confirmed
tumefactive multiple sclerosis. Brain 2008 Jul;131(Pt 7):1759e75. PubMed
PMID: 18535080. Pubmed Central PMCID: 2442427. Epub 2008/06/07. eng.
[29] Wingerchuk DM, Lennon VA, Pittock SJ, Lucchinetti CF, Weinshenker BG.
Revised diagnostic criteria for neuromyelitis optica. Neurology 2006 May
23;66(10):1485e9. PubMed PMID: 16717206. Epub 2006/05/24. eng.
[30] Wingerchuk DM. Neuromyelitis optica spectrum disorders. Contin (Minneap
Minn) 2010 Oct;16(5 Multiple Sclerosis):105e21. PubMed PMID: 22810601.
Epub 2010/10/01. eng.
[31] McKeon A, Fryer JP, Apiwattanakul M, Lennon VA, Hinson SR, Kryzer TJ, et al.
Diagnosis of neuromyelitis spectrum disorders: comparative sensitivities
and specificities of immunohistochemical and immunoprecipitation assays.
Arch Neurol 2009 Sep;66(9):1134e8. PubMed PMID: 19752303. Epub 2009/
09/16. eng.
[32] Wingerchuk DM, Lennon VA, Lucchinetti CF, Pittock SJ, Weinshenker BG. The
spectrum of neuromyelitis optica. Lancet Neurol 2007 Sep;6(9):805e15.
PubMed PMID: 17706564. Epub 2007/08/21. eng.
[33] Bomprezzi R, Powers JM, Shimizu J, Tsuji S, Weinshenker BG,
Wingerchuk DM. IFNbeta-1b may severely exacerbate Japanese opticspinal
MS in neuromyelitis optica spectrum: Japanese optic-spinal MS: is it MS or
neuromyelitis optica and does the answer dictate treatment? Neurology
2011 Jul 12;77(2):195. discussion -6. PubMed PMID: 21747078. Epub 2011/
07/13. eng.
[34] Schumacker GA, Beebe G, Kibler RF, Kurland LT, Kurtzke JF, McDowell F, et al.
Problems of Experimental Trials of therapy in multiple sclerosis: report by
the panel on the evaluation of experimental trials of therapy in multiple
sclerosis. Ann N Y Acad Sci 1965 Mar;31(122):552e68. PubMed PMID:
14313512. Epub 1965/03/31. eng.
[35] Poser CM, Paty DW, Scheinberg L, McDonald WI, Davis FA, Ebers GC, et al.
New diagnostic criteria for multiple sclerosis: guidelines for research pro-
tocols. Ann Neurol 1983 Mar;13(3):227e31. PubMed PMID: 6847134. Epub
1983/03/01. eng.
[36] McDonald WI, Compston A, Edan G, Goodkin D, Hartung HP, Lublin FD, et al.
Recommended diagnostic criteria for multiple sclerosis: guidelines from the
international panel on the diagnosis of multiple sclerosis. Ann Neurol 2001
Jul;50(1):121e7. PubMed PMID: 11456302. Epub 2001/07/18. eng.
[37] Polman CH, Reingold SC, Banwell B, Clanet M, Cohen JA, Filippi M, et al.
Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald
criteria. Ann Neurol 2011 Feb;69(2):292e302. PubMed PMID: 21387374.
Pubmed Central PMCID: 3084507. Epub 2011/03/10. eng.
[38] Barkhof F, Filippi M, Miller DH, Scheltens P, Campi A, Polman CH, et al.
Comparison of MRI criteria at first presentation to predict conversion to
clinically definite multiple sclerosis. Brain 1997 Nov;120(Pt 11):2059e69.
PubMed PMID: 9397021. Epub 1997/12/16. eng.
[39] Tintore M, Rovira A, Rio J, Nos C, Grive E, Sastre-Garriga J, et al. New diag-
nostic criteria for multiple sclerosis: application in first demyelinating
episode. Neurology 2003 Jan 14;60(1):27e30. PubMed PMID: 12525713.
Epub 2003/01/15. eng.
[40] Dalton CM, Brex PA, Miszkiel KA, Hickman SJ, MacManus DG, Plant GT, et al.
Application of the new McDonald criteria to patients with clinically isolated
syndromes suggestive of multiple sclerosis. Ann Neurol 2002 Jul;52(1):47e
53. PubMed PMID: 12112046. Epub 2002/07/12. eng.
[41] Polman C, Barkhof F, Sandberg-Wollheim M, Linde A, Nordle O, Nederman T.
Treatment with laquinimod reduces development of active MRI lesions in
relapsing MS. Neurology 2005 Mar 22;64(6):987e91. PubMed PMID:
15781813. Epub 2005/03/23. eng.
[42] Polman CH, Reingold SC, Edan G, Filippi M, Hartung HP, Kappos L, et al.
Diagnostic criteria for multiple sclerosis: 2005 revisions to the “McDonald
Criteria”. Ann Neurol 2005 Dec;58(6):840e6. PubMed PMID: 16283615.
Epub 2005/11/12. eng.
[43] Swanton JK, Rovira A, Tintore M, Altmann DR, Barkhof F, Filippi M, et al. MRI
criteria for multiple sclerosis in patients presenting with clinically isolated
syndromes: a multicentre retrospective study. Lancet Neurol 2007 Aug;6(8):
677e86. PubMed PMID: 17616439. Epub 2007/07/10. eng.
[44] Swanton JK, Fernando K, Dalton CM, Miszkiel KA, Thompson AJ, Plant GT,
et al. Modification of MRI criteria for multiple sclerosis in patients with
clinically isolated syndromes. J Neurol Neurosurg Psychiatr 2006 Jul;77(7):
830e3. PubMed PMID: 16043456. Pubmed Central PMCID: 2117493. Epub
2005/07/27. eng.
[45] Montalban X, Tintore M, Swanton J, Barkhof F, Fazekas F, Filippi M, et al. MRI
criteria for MS in patients with clinically isolated syndromes. Neurology
2010 Feb 2;74(5):427e34. PubMed PMID: 20054006. Epub 2010/01/08. eng.
[46] Rovira A, Pericot I, Alonso J, Rio J, Grive E, Montalban X. Serial diffusion-
weighted MR imaging and proton MR spectroscopy of acute large demye-
linating brain lesions: case report. AJNR Am J Neuroradiol
2002;23(12063231):989e94.
[47] Rovira A, Swanton J, Tintore M, Huerga E, Barkhof F, Filippi M, et al. A single,
early magnetic resonance imaging study in the diagnosis of multiple scle-
rosis. Arch Neurol 2009 May;66(5):587e92. PubMed PMID: 19433658. Epub
2009/05/13. eng.
[48] Mowry EM, Pesic M, Grimes B, Deen SR, Bacchetti P, Waubant E. Clinical
predictors of early second event in patients with clinically isolated syn-
drome. J Neurol 2009 Jul;256(7):1061e6. PubMed PMID: 19252775. Pubmed
Central PMCID: 2708331. Epub 2009/03/03. eng.
[49] West T, Wyatt M, High A, Bostrom A, Waubant E. Are initial demyelinating
event recovery and time to second event under differential control?
 D. Karussis / Journal of Autoimmunity 48-49 (2014) 134e142
Neurology 2006 Sep 12;67(5):809e13. PubMed PMID: 16966542. Epub
2006/09/13. eng.
[50] Achiron A, Barak Y. Multiple sclerosis-from probable to definite diagnosis: a
7-year prospective study. Arch Neurol 2000 Jul;57(7):974e9. PubMed PMID:
10891979. Epub 2000/07/13. eng.
[51] Comi G, Filippi M, Barkhof F, Durelli L, Edan G, Fernandez O, et al. Effect of
early interferon treatment on conversion to definite multiple sclerosis: a
randomised study. Lancet 2001 May 19;357(9268):1576e82. PubMed PMID:
11377645. Epub 2001/05/30. eng.
[52] Di Pauli F, Reindl M, Ehling R, Schautzer F, Gneiss C, Lutterotti A, et al.
Smoking is a risk factor for early conversion to clinically definite multiple
sclerosis. Mult Scler 2008 Sep;14(8):1026e30. PubMed PMID: 18632775.
Epub 2008/07/18. eng.
[53] Lunemann JD, Tintore M, Messmer B, Strowig T, Rovira A, Perkal H, et al.
Elevated Epstein-Barr virus-encoded nuclear antigen-1 immune responses
predict conversion to multiple sclerosis. Ann Neurol 2010 Feb;67(2):159e69.
PubMed PMID: 20225269. Pubmed Central PMCID: 2848293. Epub 2010/03/
13. eng.
[54] Rudick RA, Cutter G. MRI lesions: a surrogate for relapses in multiple scle-
rosis? Lancet Neurol 2013 Jul;12(7):628e30. PubMed PMID: 23743083. Epub
2013/06/08. eng.
[55] Jacobs L, Kinkel PR, Kinkel WR. Impact of nuclear magnetic resonance im-
aging on the assessment of multiple sclerosis patients. Semin Neurol 1986
Mar;6(1):24e32. PubMed PMID: 3503355. Epub 1986/03/01. eng.
[56] Ormerod IE, Miller DH, McDonald WI, du Boulay EP, Rudge P, Kendall BE,
et al. The role of NMR imaging in the assessment of multiple sclerosis and
isolated neurological lesions. A quantitative study. Brain 1987 Dec;110(Pt 6):
1579e616. PubMed PMID: 3427402. Epub 1987/12/01. eng.
[57] Dalton CM, Chard DT, Davies GR, Miszkiel KA, Altmann DR, Fernando K, et al.
Early development of multiple sclerosis is associated with progressive grey
matter atrophy in patients presenting with clinically isolated syndromes.
Brain 2004 May;127(Pt 5):1101e7. PubMed PMID: 14998914. Epub 2004/
03/05. eng.
[58] O’Riordan JI, Thompson AJ, Kingsley DP, MacManus DG, Kendall BE, Rudge P,
et al. The prognostic value of brain MRI in clinically isolated syndromes of
the CNS. A 10-year follow-up. Brain 1998 Mar;121(Pt 3):495e503. PubMed
PMID: 9549525. Epub 1998/04/29. eng.
[59] Isaac C, Li DK, Genton M, Jardine C, Grochowski E, Palmer M, et al. Multiple
sclerosis: a serial study using MRI in relapsing patients. Neurology 1988
Oct;38(10):1511e5. PubMed PMID: 3419593. Epub 1988/10/01. eng.
[60] Kappos L, Stadt D, Ratzka M, Keil W, Schneiderbanger-Grygier S, Heitzer T,
et al. Magnetic resonance imaging in the evaluation of treatment in multiple
sclerosis. Neuroradiology 1988;30(4):299e302. PubMed PMID: 3050587.
Epub 1988/01/01. eng.
[61] Willoughby EW, Grochowski E, Li DK, Oger J, Kastrukoff LF, Paty DW. Serial
magnetic resonance scanning in multiple sclerosis: a second prospective
study in relapsing patients. Ann Neurol 1989 Jan;25(1):43e9. PubMed PMID:
2913928. Epub 1989/01/01. eng.
[62] Brex PA, Ciccarelli O, O’Riordan JI, Sailer M, Thompson AJ, Miller DH.
A longitudinal study of abnormalities on MRI and disability from multiple
sclerosis. N Engl J Med 2002 Jan 17;346(3):158e64. PubMed PMID:
11796849. Epub 2002/01/18. eng.
[63] Frohman EM, Goodin DS, Calabresi PA, Corboy JR, Coyle PK, Filippi M, et al.
The utility of MRI in suspected MS: report of the therapeutics and technology
assessment subcommittee of the American Academy of Neurology.
Neurology 2003 Sep 9;61(5):602e11. PubMed PMID: 12963748. Epub 2003/
09/10. eng.
[64] Ghezzi A, Martinelli V, Torri V, Zaffaroni M, Rodegher M, Comi G, et al. Long-
term follow-up of isolated optic neuritis: the risk of developing multiple
sclerosis, its outcome, and the prognostic role of paraclinical tests. J Neurol
1999 Sep;246(9):770e5. PubMed PMID: 10525973. Epub 1999/10/20. eng.
[65] Miller DH, Ormerod IE, McDonald WI, MacManus DG, Kendall BE,
Kingsley DP, et al. The early risk of multiple sclerosis after optic neuritis.
J Neurol Neurosurg Psychiatr 1988 Dec;51(12):1569e71. PubMed PMID:
3221224. Pubmed Central PMCID: 1032775. Epub 1988/12/01. eng.
[66] Morrissey SP, Miller DH, Kendall BE, Kingsley DP, Kelly MA, Francis DA, et al.
The significance of brain magnetic resonance imaging abnormalities at
presentation with clinically isolated syndromes suggestive of multiple scle-
rosis. A 5-year follow-up study. Brain 1993 Feb;116(Pt 1):135e46. PubMed
PMID: 8453454. Epub 1993/02/01. eng.
[67] Simon JH, Li D, Traboulsee A, Coyle PK, Arnold DL, Barkhof F, et al. Stan-
dardized MR imaging protocol for multiple sclerosis: consortium of MS
centers consensus guidelines. AJNR Am J Neuroradiol 2006 Feb;27(2):455e
61. PubMed PMID: 16484429. Epub 2006/02/18. eng.
[68] Beck RW, Trobe JD, Moke PS, Gal RL, Xing D, Bhatti MT, et al. High- and
low-risk profiles for the development of multiple sclerosis within 10 years
after optic neuritis: experience of the optic neuritis treatment trial. Arch
Ophthalmol 2003 Jul;121(7):944e9. PubMed PMID: 12860795. Epub 2003/
07/16. eng.
[69] Minneboo A, Barkhof F, Polman CH, Uitdehaag BM, Knol DL, Castelijns JA.
Infratentorial lesions predict long-term disability in patients with initial
findings suggestive of multiple sclerosis. Arch Neurol 2004 Feb;61(2):217e
21. PubMed PMID: 14967769. Epub 2004/02/18. eng.
[70] Scott TF, Kassab SL, Singh S. Acute partial transverse myelitis with normal
cerebral magnetic resonance imaging: transition rate to clinically definite
141
multiple sclerosis. Mult Scler 2005 Aug;11(4):373e7. PubMed PMID:
16042216. Epub 2005/07/27. eng.
[71] Zivadinov R, Cox JL. Neuroimaging in multiple sclerosis. Int Rev Neurobiol
2007;79:449e74. PubMed PMID: 17531854. Epub 2007/05/29. eng.
[72] Cordonnier C, de Seze J, Breteau G, Ferriby D, Michelin E, Stojkovic T, et al.
Prospective study of patients presenting with acute partial transverse
myelopathy. J Neurol 2003 Dec;250(12):1447e52. PubMed PMID: 14673577.
Epub 2003/12/16. eng.
[73] Kruit MC, van Buchem MA, Hofman PA, Bakkers JT, Terwindt GM,
Ferrari MD, et al. Migraine as a risk factor for subclinical brain lesions.
J Am Med Assoc 2004 Jan 28;291(4):427e34. PubMed PMID: 14747499.
Epub 2004/01/30. eng.
[74] Morris Z, Whiteley WN, Longstreth Jr WT, Weber F, Lee YC, Tsushima Y, et al.
Incidental findings on brain magnetic resonance imaging: systematic review
and meta-analysis. BMJ 2009;339:b3016. PubMed PMID: 19687093. Pubmed
Central PMCID: 2728201. Epub 2009/08/19. eng.
[75] Vernooij MW, Ikram MA, Tanghe HL, Vincent AJ, Hofman A, Krestin GP, et al.
Incidental findings on brain MRI in the general population. N Engl J Med 2007
Nov 1;357(18):1821e8. PubMed PMID: 17978290. Epub 2007/11/06. eng.
[76] Roemer SF, Scheithauer BW, Varnavas GG, Lucchinetti CF. Tumefactive
demyelination and glioblastoma: a rare collision lesion. Clin Neuropathol 2011
Jul-Aug;30(4):186e91. PubMed PMID: 21726504. Epub 2011/07/06. eng.
[77] Calabrese M, Filippi M, Gallo P. Cortical lesions in multiple sclerosis. Nat
Rev Neurol 2010 Aug;6(8):438e44. PubMed PMID: 20625376. Epub 2010/
07/14. eng.
[78] Lucchinetti CF, Popescu BF, Bunyan RF, Moll NM, Roemer SF, Lassmann H,
et al. Inflammatory cortical demyelination in early multiple sclerosis. N Engl J
Med 2011 Dec 8;365(23):2188e97. PubMed PMID: 22150037. Pubmed
Central PMCID: 3282172. Epub 2011/12/14. eng.
[79] Calabrese M, De Stefano N, Atzori M, Bernardi V, Mattisi I, Barachino L, et al.
Detection of cortical inflammatory lesions by double inversion recovery
magnetic resonance imaging in patients with multiple sclerosis. Arch Neurol
2007 Oct;64(10):1416e22. PubMed PMID: 17923625. Epub 2007/10/10. eng.
[80] Nelson F, Poonawalla AH, Hou P, Huang F, Wolinsky JS, Narayana PA.
Improved identification of intracortical lesions in multiple sclerosis with
phase-sensitive inversion recovery in combination with fast double inver-
sion recovery MR imaging. AJNR Am J Neuroradiol 2007 Oct;28(9):1645e9.
PubMed PMID: 17885241. Epub 2007/09/22. eng.
[81] Hasan KM, Narayana PA. Magnetic resonance imaging-based quantitative
iron mapping at 7-tesla remains to be elusive in multiple sclerosis. Ann
Neurol 2009 Dec;66(6):867. author reply PubMed PMID: 20035512. Epub
2009/12/26. eng.
[82] Hammond KE, Metcalf M, Carvajal L, Okuda DT, Srinivasan R, Vigneron D,
et al. Quantitative in vivo magnetic resonance imaging of multiple sclerosis
at 7 Tesla with sensitivity to iron. Ann Neurol 2008 Dec;64(6):707e13.
PubMed PMID: 19107998. Epub 2008/12/25. eng.
[83] Kangarlu A, Bourekas EC, Ray-Chaudhury A, Rammohan KW. Cerebral
cortical lesions in multiple sclerosis detected by MR imaging at 8 Tesla. AJNR
Am J Neuroradiol 2007 Feb;28(2):262e6. PubMed PMID: 17296991. Epub
2007/02/14. eng.
[84] Mainero C, Benner T, Radding A, van der Kouwe A, Jensen R, Rosen BR, et al.
In vivo imaging of cortical pathology in multiple sclerosis using ultra-high
field MRI. Neurology 2009 Sep 22;73(12):941e8. PubMed PMID:
19641168. Pubmed Central PMCID: 2754332. Epub 2009/07/31. eng.
[85] Calabrese M, Rocca MA, Atzori M, Mattisi I, Favaretto A, Perini P, et al. A 3-
year magnetic resonance imaging study of cortical lesions in relapse-onset
multiple sclerosis. Ann Neurol 2010 Mar;67(3):376e83. PubMed PMID:
20373349. Epub 2010/04/08. eng.
[86] Filippi M, Rocca MA, Calabrese M, Sormani MP, Rinaldi F, Perini P, et al.
Intracortical lesions: relevance for new MRI diagnostic criteria for multiple
sclerosis. Neurology 2010 Nov 30;75(22):1988e94. PubMed PMID:
21115953. Epub 2010/12/01. eng.
[87] Wattjes MP, Harzheim M, Lutterbey GG, Bogdanow M, Schild HH, Traber F.
High field MR imaging and 1H-MR spectroscopy in clinically isolated syn-
dromes suggestive of multiple sclerosis: correlation between metabolic al-
terations and diagnostic MR imaging criteria. J Neurol 2008 Jan;255(1):56e
63. PubMed PMID: 18080854. Epub 2007/12/18. eng.
[88] Filippi M, Inglese M, Rovaris M, Sormani MP, Horsfield P, Iannucci PG, et al.
Magnetization transfer imaging to monitor the evolution of MS: a 1-year
follow-up study. Neurology 2000 Oct 10;55(7):940e6. PubMed PMID:
11061248. Epub 2000/11/04. eng.
[89] Iannucci G, Tortorella C, Rovaris M, Sormani MP, Comi G, Filippi M. Prog-
nostic value of MR and magnetization transfer imaging findings in patients
with clinically isolated syndromes suggestive of multiple sclerosis at pre-
sentation. AJNR Am J Neuroradiol 2000 JuneJul;21(6):1034e8. PubMed
PMID: 10871009. Epub 2000/06/28. eng.
[90] Wattjes MP, Harzheim M, Lutterbey GG, Hojati F, Simon B, Schmidt S, et al.
Does high field MRI allow an earlier diagnosis of multiple sclerosis? J Neurol
2008 Aug;255(8):1159e63. PubMed PMID: 18446305. Epub 2008/05/01. eng.
[91] Rot U, Mesec A. Clinical, MRI, CSF and electrophysiological findings in
different stages of multiple sclerosis. Clin Neurol Neurosurg 2006
Mar;108(3):271e4. PubMed PMID: 16378679. Epub 2005/12/28. eng.
[92] Bradley WG, Daroff RB, Fenichel GM, Jankovic J, Mazziotta JC. Neurology in
clinical practice. Clinical neurophysiology: electroencephalography and
evoked potentials. 5th ed. Philadelphia, PA: Elseiver Inc; 2008.
142 D. Karussis / Journal of Autoimmunity 48-49 (2014) 134e142
[93] Pelayo R, Montalban X, Minoves T, Moncho D, Rio J, Nos C, et al. Do multi-
modal evoked potentials add information to MRI in clinically isolated syn-
dromes? Mult Scler 2010 Jan;16(1):55e61. PubMed PMID: 19995838. Epub
2009/12/10. eng.
[94] Avasarala JR, Cross AH, Trotter JL. Oligoclonal band number as a marker for
prognosis in multiple sclerosis. Arch Neurol 2001 Dec;58(12):2044e5.
PubMed PMID: 11735778. Epub 2001/12/26. eng.
[95] Awad A, Hemmer B, Hartung HP, Kieseier B, Bennett JL, Stuve O. Analyses of
cerebrospinal fluid in the diagnosis and monitoring of multiple sclerosis.
J Neuroimmunol 2010 Feb 26;219(1e2):1e7. PubMed PMID: 19782408.
Epub 2009/09/29. eng.
[96] Paolino E, Fainardi E, Ruppi P, Tola MR, Govoni V, Casetta I, et al. A prospective
study on the predictive value of CSF oligoclonal bands and MRI in acute
isolated neurological syndromes for subsequent progression to multiple
sclerosis. J Neurol Neurosurg Psychiatr 1996 May;60(5):572e5. PubMed
PMID: 8778266. Pubmed Central PMCID: 486374. Epub 1996/05/01. eng.
[97] Polman C, Kappos L, Freedman MS, Edan G, Hartung HP, Miller DH, et al.
Subgroups of the BENEFIT study: risk of developing MS and treatment effect
of interferon beta-1b. J Neurol 2008 Apr;255(4):480e7. PubMed PMID:
18004635. Epub 2007/11/16. eng.
[98] Sastre-Garriga J, Tintore M, Rovira A, Grive E, Pericot I, Comabella M, et al.
Conversion to multiple sclerosis after a clinically isolated syndrome of the
brainstem: cranial magnetic resonance imaging, cerebrospinal fluid and
neurophysiological findings. Mult Scler 2003 Feb;9(1):39e43. PubMed
PMID: 12617267. Epub 2003/03/06. eng.
[99] Tintore M, Rovira A, Brieva L, Grive E, Jardi R, Borras C, et al. Isolated
demyelinating syndromes: comparison of CSF oligoclonal bands and
different MR imaging criteria to predict conversion to CDMS. Mult Scler 2001
Dec;7(6):359e63. PubMed PMID: 11795456. Epub 2002/01/25. eng.
[100] Zipoli V, Hakiki B, Portaccio E, Lolli F, Siracusa G, Giannini M, et al. The
contribution of cerebrospinal fluid oligoclonal bands to the early diagnosis of
multiple sclerosis. Mult Scler 2009 Apr;15(4):472e8. PubMed PMID:
19153171. Epub 2009/01/21. eng.
[101] Freedman MS, Thompson EJ, Deisenhammer F, Giovannoni G, Grimsley G,
Keir G, et al. Recommended standard of cerebrospinal fluid analysis in the
diagnosis of multiple sclerosis: a consensus statement. Arch Neurol 2005
Jun;62(6):865e70. PubMed PMID: 15956157. Epub 2005/06/16. eng.
[102] Link H, Huang YM. Oligoclonal bands in multiple sclerosis cerebrospinal fluid:
an update on methodology and clinical usefulness. J Neuroimmunol 2006
Nov;180(1e2):17e28. PubMed PMID: 16945427. Epub 2006/09/02. eng.
[103] Masjuan J, Alvarez-Cermeno JC, Garcia-Barragan N, Diaz-Sanchez M,
Espino M, Sadaba MC, et al. Clinically isolated syndromes: a new oligoclonal
band test accurately predicts conversion to MS. Neurology 2006 Feb
28;66(4):576e8. PubMed PMID: 16505315. Epub 2006/03/01. eng.
[104] Tintore M, Rovira A, Rio J, Tur C, Pelayo R, Nos C, et al. Do oligoclonal bands add
information to MRI in first attacks of multiple sclerosis? Neurology 2008 Mar
25;70(13 Pt 2):1079e83. PubMed PMID: 17881717. Epub 2007/09/21. eng.
[105] Martino D, Branson JA, Church AJ, Candler PM, Livrea P, Giovannoni G, et al.
Soluble adhesion molecules in acute disseminated encephalomyelitis.
Pediatr Neurol 2005;33(16194723):255e8.
[106] Trapp BD, Nave KA. Multiple sclerosis: an immune or neurodegenerative
disorder? Annu Rev Neurosci 2008;31:247e69. PubMed PMID: 18558855.
Epub 2008/06/19. eng.
[107] Hawa M, Beyan H, Leslie RD. Principles of autoantibodies as disease-specific
markers. Autoimmunity 2004 Jun;37(4):253e6. PubMed PMID: 15518036.
Epub 2004/11/03. eng.
[108] Prince HE. Biomarkers for diagnosing and monitoring autoimmune diseases.
Biomarkers 2005 Nov;10(Suppl. 1):S44e9. PubMed PMID: 16298911. Epub
2005/11/22. eng.
[109] Schwarz M, Spector L, Gortler M, Weisshaus O, Glass-Marmor L, Karni A,
et al. Serum anti-Glc(alpha1,4)Glc(alpha) antibodies as a biomarker for
relapsing-remitting multiple sclerosis. J Neurol Sci 2006 May 15;244(1e2):
59e68. PubMed PMID: 16480743. Epub 2006/02/17. eng.
[110] Freedman MS, Laks J, Dotan N, Altstock RT, Dukler A, Sindic CJ. Anti-alpha-
glucose-based glycan IgM antibodies predict relapse activity in multiple
sclerosis after the first neurological event. Mult Scler 2009 Apr;15(4):422e
30. PubMed PMID: 19324980. Pubmed Central PMCID: 2850589. Epub 2009/
03/28. eng.
[111] Brettschneider J, Jaskowski TD, Tumani H, Abdul S, Husebye D, Seraj H, et al.
Serum anti-GAGA4 IgM antibodies differentiate relapsing remitting and
secondary progressive multiple sclerosis from primary progressive multiple
sclerosis and other neurological diseases. J Neuroimmunol 2009 Dec
10;217(1e2):95e101. PubMed PMID: 19879655. Epub 2009/11/03. eng.
[112] Rudick RA, Polman CH. Current approaches to the identification and manage-
ment of breakthrough disease in patients with multiple sclerosis. Lancet Neurol
2009 Jun;8(6):545e59. PubMed PMID: 19446274. Epub 2009/05/19. eng.
[113] Rudick RA, Cohen JA, Weinstock-Guttman B, Kinkel RP, Ransohoff RM.
Management of multiple sclerosis. N Engl J Med 1997 Nov 27;337(22):1604e
11. PubMed PMID: 9371858. Epub 1997/11/27. eng.
[114] Jacobs LD, Beck RW, Simon JH, Kinkel RP, Brownscheidle CM, Murray TJ, et al.
Intramuscular interferon beta-1a therapy initiated during a first demyelin-
ating event in multiple sclerosis. CHAMPS Study Group. N Engl J Med 2000
Sep 28;343(13):898e904. PubMed PMID: 11006365. Epub 2000/09/28. eng.
[115] Kappos L, Freedman MS, Polman CH, Edan G, Hartung HP, Miller DH, et al.
Effect of early versus delayed interferon beta-1b treatment on disability after
a first clinical event suggestive of multiple sclerosis: a 3-year follow-up
analysis of the BENEFIT study. Lancet 2007 Aug 4;370(9585):389e97.
PubMed PMID: 17679016. Epub 2007/08/07. eng.
[116] Berger T, Rubner P, Schautzer F, Egg R, Ulmer H, Mayringer I, et al. Anti-
myelin antibodies as a predictor of clinically definite multiple sclerosis after
a first demyelinating event. N Engl J Med 2003 Jul 10;349(2):139e45.
PubMed PMID: 12853586. Epub 2003/07/11. eng.
[117] Tomassini V, De Giglio L, Reindl M, Russo P, Pestalozza I, Pantano P, et al.
Anti-myelin antibodies predict the clinical outcome after a first episode
suggestive of MS. Mult Scler 2007 Nov;13(9):1086e94. PubMed PMID:
17468447. Epub 2007/05/01. eng.
[118] Greeve I, Sellner J, Lauterburg T, Walker U, Rosler KM, Mattle HP. Anti-
myelin antibodies in clinically isolated syndrome indicate the risk of mul-
tiple sclerosis in a Swiss cohort. Acta Neurol Scand 2007 Oct;116(4):207e10.
PubMed PMID: 17824895. Epub 2007/09/11. eng.
[119] Lim ET, Berger T, Reindl M, Dalton CM, Fernando K, Keir G, et al. Anti-myelin
antibodies do not allow earlier diagnosis of multiple sclerosis. Mult Scler
2005 Aug;11(4):492e4. PubMed PMID: 16042235. Epub 2005/07/27. eng.
[120] Kuhle J, Lindberg RL, Regeniter A, Mehling M, Hoffmann F, Reindl M, et al.
Antimyelin antibodies in clinically isolated syndromes correlate with
inflammation in MRI and CSF. J Neurol 2007 Feb;254(2):160e8. PubMed
PMID: 17334662. Epub 2007/03/06. eng.
[121] Kuhle J, Pohl C, Mehling M, Edan G, Freedman MS, Hartung HP, et al. Lack of
association between antimyelin antibodies and progression to multiple
sclerosis. N Engl J Med 2007 Jan 25;356(4):371e8. PubMed PMID: 17251533.
Epub 2007/01/26. eng.
[122] Pelayo R, Tintore M, Montalban X, Rovira A, Espejo C, Reindl M, et al. Anti-
myelin antibodies with no progression to multiple sclerosis. N Engl J Med
2007 Jan 25;356(4):426e8. PubMed PMID: 17251547. Epub 2007/01/26. eng.
[123] Teunissen CE, Khalil M. Neurofilaments as biomarkers in multiple sclerosis.
Mult Scler 2012 May;18(5):552e6. PubMed PMID: 22492131. Epub 2012/04/
12. eng.
[124] Teunissen CE, Iacobaeus E, Khademi M, Brundin L, Norgren N, Koel-
Simmelink MJ, et al. Combination of CSF N-acetylaspartate and neurofila-
ments in multiple sclerosis. Neurology 2009 Apr 14;72(15):1322e9. PubMed
PMID: 19365053. Epub 2009/04/15. eng.
[125] Fialova L, Bartos A, Svarcova J, Zimova D, Kotoucova J, Malbohan I. Serum and
cerebrospinal fluid light neurofilaments and antibodies against them in
clinically isolated syndrome and multiple sclerosis. J Neuroimmunol 2013
Sep 15;262(1e2):113e20. PubMed PMID: 23870535. Epub 2013/07/23. eng.
[126] Fialova L, Bartos A, Svarcova J, Zimova D, Kotoucova J. Serum and cerebro-
spinal fluid heavy neurofilaments and antibodies against them in early
multiple sclerosis. J Neuroimmunol 2013 Jun 15;259(1e2):81e7. PubMed
PMID: 23632043. Epub 2013/05/02. eng.
[127] Caldemeyer KS, Smith RR, Harris TM, Edwards MK. MRI in acute dissemi-
nated encephalomyelitis. Neuroradiology 1994;36(8041443):216e20.
[128] Dale RC, de Sousa C, Chong WK, Cox TC, Harding B, Neville BG. Acute
disseminated encephalomyelitis, multiphasic disseminated encephalomy-
elitis and multiple sclerosis in children. Brain 2000 Dec;123(Pt 12):2407e22.
PubMed PMID: 11099444. Epub 2000/12/02. eng.
[129] Mikaeloff Y, Caridade G, Husson B, Suissa S, Tardieu M. Acute disseminated
encephalomyelitis cohort study: prognostic factors for relapse. Eur J Paediatr
Neurol 2007;11(17188007):90e5.
[130] Murthy SNK, Faden HS, Cohen ME, Bakshi R. Acute disseminated encepha-
lomyelitis in children. Pediatrics 2002;110(12165620).
[131] Tardieu M, Mikaeloff Y. What is acute disseminated encephalomyelitis
(ADEM)? Eur J Paediatr Neurol 2004;8(15341905):239e42.
[132] Rosman NP, Gottlieb SM, Bernstein CA. Acute hemorrhagic leukoencephali-
tis: recovery and reversal of magnetic resonance imaging findings in a child.
J Child Neurol 1997;12(9373802):448e54.
[133] Wong AM, Simon EM, Zimmerman RA, Wang HS, Toh CH, Ng SH. Acute
necrotizing encephalopathy of childhood: correlation of MR findings and
clinical outcome. AJNR Am J Neuroradiol 2006;27(17032866):1919e23.
[134] D’Alessandro R, Vignatelli L, Lugaresi A, Baldin E, Granella F, Tola MR, et al.
Risk of multiple sclerosis following clinically isolated syndrome: a 4-year
prospective study. J Neurol 2013;260(6):1583e93. http://dx.doi.org/
10.1007/s00415-013-6838-x. Epub 2013 Feb 3.