MOUNT SINAI JOURNAL OF MEDICINE 78:268–279, 2011 268

Multiple Sclerosis:
Where Will We Be in 2020?
Aaron E. Miller, MD
Mount Sinai School of Medicine, New York, NY

OUTLINE like forever. Remarkable progress has been made

with regard to multiple sclerosis (MS), especially in
DIAGNOSIS the area of therapeutics, in the last couple of decades.
CAUSES AND RISK FACTORS Will the next 10 years see similar advances? This arti-
PROGNOSIS cle will address current issues regarding MS and offer
TREATMENT some predictions about where we might be at the
Treatment of Relapsing Forms of conclusion of the second decade of the 21st century.
Multiple Sclerosis
Treatment of Progressive Forms of
Multiple Sclerosis DIAGNOSIS
Chronic Cerebrospinal Venous
Insufficiency For many decades, the diagnosis of MS has been
CONCLUSION predicated, irrespective of the specific criteria in a
particular diagnostic scheme, on the demonstration
ABSTRACT of ‘‘dissemination in time and space.’’ This dictum
requires that symptoms or signs have to reflect
The past decade has seen a surge of research inter- disease activity at multiple points in time and involve-
est in multiple sclerosis and an accelerated expan-
ment of multiple discrete areas of the central nervous
sion of investigative efforts into multiple sclerosis
therapeutics. Investigators have continued dissect- system (CNS). Virtually all proposed criteria for the
ing the complex immunological perturbations that diagnosis of MS also included the caveat that there is
may contribute to the disease and made major no better explanation for the clinical syndrome.
advances in understanding the genetics of multiple A major development in the diagnosis of MS
sclerosis. This article addresses current investiga- was the publication in 2001 of the diagnostic crite-
tive issues and offers predictions about where the ria established by an international panel convened
understanding and treatment of multiple sclerosis by the National Multiple Sclerosis Society, subse-
may stand at the end of the 21st century’s second quently known as the McDonald criteria after the late
decade. Mt Sinai J Med 78:268–279, 2011.  2011 chairman of that panel, W. Ian McDonald.1 These cri-
Mount Sinai School of Medicine teria were the first to incorporate magnetic resonance
imaging (MRI) parameters into the diagnostic scheme,
Key Words: genetics, immunology, MS, multiple
sclerosis, therapeutics. allowing their utilization for demonstration of dissem-
ination in space or time, or both. The requirement for
In the perspective of history, a decade seems like dissemination in space made use of criteria initially
merely a fleeting moment. On the other hand, for suggested by Barkhof and subsequently modified
people with a serious chronic disease it can seem by Tintore. To fulfill the requirements (subsequently
widely known as the Barkhof criteria) for dissemina-
tion in space, the MRI had to demonstrate at least 3
of the following 4 criteria:
Address Correspondence to:
1. ≥9 T2-hyperintense lesions or ≥1 gadolinium-
Aaron E. Miller enhancing lesions.
Mount Sinai School of Medicine 2. ≥1 infratentorial lesions.
New York, NY 3. ≥1 juxtacortical lesions (ie, at the gray-white
Email: aaron.miller@mssm.edu junction).
4. ≥3 periventricular lesions.

Published online in Wiley Online Library (wileyonlinelibrary.com).

DOI:10.1002/msj.20242

 2011 Mount Sinai School of Medicine

MOUNT SINAI JOURNAL OF MEDICINE
In 2005 the panel published revised criteria.2 These
included some minor revisions in the use of MRI
for dissemination in space (allowing a spinal cord
lesion to be counted as an infratentorial lesion and
permitting all discrete T2 lesions in the spinal cord to
be included among the 9 T2 hyperintensities needed
to satisfy one of the requirement options), but also
a major change that simplified the demonstration of
dissemination in time. Two options are available.
The first is the demonstration of a new gadolinium-
enhancing lesion on a scan performed at ≥3 months
after the initial onset of clinical symptoms (provided
it was not in an area likely responsible for the clinical
symptoms). The second option is the demonstration
of any new lesion on an MRI performed any time
after a reference scan that was performed ≥30 days
after the clinical onset. These changes were simpler
to fulfill and allowed earlier diagnosis, increasing
sensitivity while sacrificing very little in specificity.
Recently, a European MS MRI consortium (Mag-
netic Imaging in MS [MAGNIMS]) proposed yet
simpler criteria3 designating dissemination in space
when the MRI shows ≥1 lesion in at least 2 of
4 characteristic locations: juxtacortical, periventric-
ular, infratentorial, or spinal cord. They simplified
the criteria for dissemination in time by accepting
the occurrence of any new lesion developing at any
time after a reference scan that was performed at
any time in reference to the initial clinical episode.
Furthermore, the MAGNIMS criteria also permit the
fulfillment of the criteria of dissemination in time by
a single MRI scan that simultaneously demonstrates
both T2 hyperintense lesion(s) and ≥1 gadolinium-
enhancing lesion, based on the presumption that the
contrast-enhancing lesion represents current disease
activity and the T2-hyperintense lesions represent
past activity. Though this option for designating
dissemination in time has relatively low sensitivity
(45%), it has good specificity (86%) and simplifies
the diagnostic process when present.
The international panel met again in Dublin in
2010 and made further revisions to the McDonald
criteria which incorporated the MAGNIMS criteria.
I do not believe we will see further significant
revisions in the diagnostic process over the next
decade. I do not expect that refinements in MRI
technology will lead to clinical utilization that would
further alter the recommendations for dissemination
in space and time. The only other development that
could potentially alter the diagnostic scheme would
be the discovery of reliable biomarkers, something
that could be reliably measured in a bodily fluid,
preferably blood or urine rather than cerebrospinal
269
I do not believe we will see further
significant revisions in the
diagnostic process over the next
decade.
fluid. Despite intense interest in this subject, nothing
looms on the horizon that will likely be of diagnostic
value.
CAUSES AND RISK FACTORS
To give the bottom line first, I do not think we will
be substantially further along in a decade in our
understanding the root cause of MS, because I do not
believe there is a single ‘‘cause’’ of MS. Increasingly
To give the bottom line first, I do
not think we will be substantially
further along in a decade in our
understanding the root cause of
multiple sclerosis (MS), because I
do not believe there is a single
‘‘cause’’ of MS.
the evidence suggests that the disease results from
a complex interplay of genetic and environmental
factors that are unlikely to be the same in any 2
individuals. Specifically, investigators have searched
for years for a specific viral etiology. Occasional
claims of the identification of a particular agent have
subsequently been refuted, and, given the sophis-
tication of modern biological techniques, it seems
very unlikely that a novel causative agent will be
discovered. In recent years extensive attention has
been paid to the potential role of Epstein-Barr virus
(EBV).4 – 8 Exposure to this virus does seem to convey
some increased risk for the development of MS. For
example, MS is more common in patients who have
had clinical mononucleosis5,6 and the prevalence of
positive serology to EBV is higher among patients
with MS than in controls.8 However, the near ubiq-
uity of this viral infection and failure to find the virus
itself in the brains of most patients with MS makes it
highly improbable that EBV is directly involved as a
causal agent.
In the first decade of the 21st century, vita-
min D has garnered considerable attention among
MS researchers. A variety of evidence suggests that
vitamin D deficiency may be a risk factor for the
development of the disease.9,10 However, currently
the data, principally on the basis of epidemiological
DOI:10.1002/MSJ
270 A. E. MILLER: MULTIPLE SCLEROSIS: WHERE WILL WE BE IN 2020?
surveys or studies, only indicate potential association
between a lack of vitamin D, rather than a causal
role. In a large case-control study among US military
personnel, MS was significantly less prevalent in the
group whose banked serum samples, obtained prior
to the diagnosis of MS, were in the highest quintile
of vitamin D levels.11
Latitudinal differences in the prevalence of MS,
with the disease much more common in popula-
tions living farther away from the equator, have long
been recognized. One way to link this observation
with vitamin D is the suggestion that the latitudinal
difference reflects variation in the amount of sun-
light, specifically ultraviolet (UV) light exposure, the
population receives. Individuals in more temperate
latitudes receive less UV exposure, in turn resulting
in lower levels of vitamin D, because sunlight is a
major factor in the body’s synthesis of vitamin D. Sur-
veys of individuals within the same geographical area
suggest that those individuals with more sun expo-
sure are less likely to develop MS.12 In a Tasmanian
study, the amount of UV exposure was estimated
based on the extent of actinic damage to the skin,
demonstrated on skin biopsy, and children who had
more extensive actinic damage were less likely to
develop MS.13 Other epidemiological evidence does,
however, cast some doubt on the role of vitamin D,
or at least that of sun exposure. The prevalence of MS
in the island nation of Malta is approximately 13 per
100,000,14 which is dramatically different from that in
Enna, Sicily, where the prevalence was determined to
be 120 per 100,000.15 It seems highly improbable that
there is significant difference in average sun exposure
between the populations living in these 2 closely geo-
graphically situated Mediterranean islands, although
other indeterminate risk factors may distinguish these
2 populations.
It is virtually certainly that by 2020 we will not
have further definitive evidence about the role of vita-
min D as an MS risk factor. That determination would
It is virtually certainly that by 2020
we will not have further definitive
evidence about the role of
vitamin D as a
MS risk factor. That determination
would require following
an enormously large cohort
for several decades, a theoretically
feasible, but practically
daunting and financially
overwhelming undertaking.
DOI:10.1002/MSJ
require following an enormously large cohort for sev-
eral decades, a theoretically feasible, but practically
daunting and financially overwhelming undertaking.
What about the role of supplemental vitamin D
in reducing the relapse rate or disability progression
in people who already have MS? The answer to
this question is currently unknown. Many physicians
caring for people with MS have begun to recommend
that their patients take supplemental vitamin D. If
one assumes that a minimum desired serum level of
vitamin D is 30 ng/mL, then one finds that one-third
to one-half of the population in temperate countries
has levels below 20 ng/mL.10 Generally speaking,
supplementation with daily oral vitamin D between
1000 and 4000 (average 2000) IU will bring most
people to at least the minimum level.
A trial to determine whether supplemental vita-
min D is beneficial to people with MS would seem
relatively easy to design. Here, however, a major bar-
rier to completion of a study of statistically adequate
power is likely to be cost. Given the widespread exis-
tence of increasingly effective therapies, the demon-
stration of the value of adding vitamin D will likely
require a study with a very large sample size. A
more manageable sample size would be sufficient
in a randomized, placebo-controlled trial. However,
such a trial would be currently unethical, at least
in most well-developed countries, because of the
availability of at least partially effective treatments.
To perform an adequate trial in patients already on
disease-modifying therapy (DMT) would require a
very large sum of money, the availability of which
is quite problematic in view of absence of a profit
motive for the demonstration of the utility of vita-
min D supplementation. I predict, therefore, that the
current practice of recommending supplemental vita-
min D for people with MS will continue, because
of its apparent safety and potential benefit for such
other issues as bone health. However, I believe that
in 2020 we will neither know specifically whether
such a recommendation has an impact on the course
of MS, nor what an ideal serum level is.
Recent years have seen an explosion of inter-
est and research into genetic aspects of MS. Clearly,
genetic influences are important for the develop-
ment of MS. For example, the concordance rate in
monozygotic twins is approximately 30%, far exceed-
ing the prevalence rate in the general population
(eg, approximately 1/1000 in temperate latitudes of
the Northern Hemisphere) or the lifetime risk in
first-degree relatives, including dizygotic twins, of
about 2%–5%.16 The converse of this observation,
of course, is that the discordance rate is 70%, indi-
cating that any genetic risk must be augmented by
some presumably stochastic environmental event in
MOUNT SINAI JOURNAL OF MEDICINE
order to trigger the development of MS in a particular
individual.
For many years, the importance of the associa-
tion with major histocompatibility loci in MS has been
recognized. Specifically, the relationship between MS
and HLA DRB*1501 remains by far the most impor-
tant genetic connection. Very recently, a series of
genome-wide association studies (GWAS) conducted
by a number of large international groups has uncov-
ered ≥15 susceptibility alleles.17 – 19 Each of these
allelic variations conveys an added risk, but with very
low odds ratios, ranging from 1.04 to 1.33. Therefore,
even the presence of many of these alleles in an
individual conveys little added risk, likely no more
than 2%.
Efforts are ongoing to make use of this genetic
information in the clinical setting. Nonetheless, I sus-
pect that the clinician in 2020 will still find little,
if any, meaningful guidance from the genetic infor-
mation about individual patients. Indeed, knowledge
Efforts are ongoing to make use of
genetic information in the clinical
setting. Nonetheless, I suspect that
the clinician in 2020 will still find
little, if any, meaningful guidance
from the genetic information
about individual patients.
of the strongest genetic association, that with HLA
DRB*1501, has been known for years and has had no
impact on clinical practice. Adding the limited impact
of the other allelic risk loci seems unlikely to change
this situation. Perhaps the greatest importance to be
derived from the GWAS so far has been the recog-
nition that virtually all of the identified risk loci are
related to the immunological system. This informa-
tion may lead to further unraveling of the role of the
immune system in the pathogenesis of MS.
PROGNOSIS
Customarily, physicians answer MS patients who
inquire about their prognosis by professing their
inability to predict an individual’s course because the
disease has so much variability and ‘‘every patient
is different.’’ To be sure, we currently lack the abil-
ity to precisely forecast an individual’s course with
MS, and that will likely remain true a decade from
now. Nonetheless, with regard to other medical con-
ditions, physicians commonly utilize statistical data
about prognosis to make treatment decisions and
271
Table 1. Negative Prognostic Features in MS.
Clinical
1. Motor, brainstem, or cerebellar involvement in initial
attack
2. Bladder or bowel involvement with initial attack
3. Incomplete recovery from initial attack
4. Short interval (<2 years) between first and second
attacks
MRI
1. ≥10 T2-hyperintense lesions on initial MRI
2. Posterior fossa involvement
Abbreviations: MRI, magnetic resonance imaging;
MS, multiple sclerosis.
to offer patients some guidance about what they
are more or less likely to experience in the future.
I believe that we already have considerable informa-
tion available to inform prognosis (Table 1) and that
over the next decade we will continue to recognize
other clues to the expected course of MS. Utilizing
this information will become increasingly important,
I believe that we already have
considerable information
available to inform prognosis and
that over the next decade we will
continue to recognize other clues
to the expected course of MS.
as physicians may need to choose between drugs that
are potentially more effective but carry greater risk
and those whose efficacy may be lower but whose
safety profile is better.
Currently, even the very first episode of what is
likely to be MS, the so-called clinically isolated syn-
drome (CIS), offers some prognostic information. The
nature of that initial attack has implications. Patients
whose attack involves the brainstem or, especially,
motor function, have a worse prognosis, on average,
than those with sensory episodes. If the initial attack
involves urinary dysfunction, admittedly a relatively
infrequent occurrence, studies consistently demon-
strate a worse prognosis. Multiple studies support the
observation that failure to make a complete recovery
from the initial clinical episode portends a bleaker
future.20,21
Early MRI data are undergoing increasing
scrutiny for prognostic implications. Recent studies
suggest that even the initial MRI can provide impor-
tant information about the future. In a well-studied
British cohort, patients who had ≥10 T2-hyperintense
lesions on their initial MRI scan fared considerably
worse than those with fewer lesions.22 Such patients
DOI:10.1002/MSJ
272 A. E. MILLER: MULTIPLE SCLEROSIS: WHERE WILL WE BE IN 2020?
had a median Expanded Disability Status Scale (EDSS)
score of 6 (meaning they required unilateral assis-
tance to walk) at 20 years. Nearly 50% of these
patients had reached an EDSS of 6, compared with
<20% of patients with ≤3 lesions. Another study has
shown that the presence of 3 or 4 positive Barkhof
criteria on the initial scan has a moderate correlation
with the EDSS at 5 years.
As the patient evolves to a diagnosis of definitive
MS, additional information may inform the progno-
sis. Studies have consistently demonstrated that the
interval between the first 2 MS attacks augurs the
future course.20,23 Those patients with a short initial
interattack interval (<2 years in most studies) have a
worse prognosis than those who go a longer period
between the first and second attacks. In one of the
largest MS databases studied over a long period of
time, in Lyon, France, patients with an initial interat-
tack interval of <2 years reached an EDSS score of
4 (generally, a point at which the distance a person
can walk is clearly becoming limited) at a median
of 6.6 years, compared with 9.6 years to reach that
milestone for those who went 2 to 5 years between
attacks and 16.1 years for those who took >5 years.23
Putting such information together, then, as we
approach patients over the next decade, it seems that
a more aggressive therapeutic approach would be
warranted, for example, for a patient with clinically
definite MS who has had an initial motor attack, leav-
ing her with a residual paresis of 1 leg, followed by a
brainstem attack 6 months later and whose initial MRI
meets all 4 Barkhof criteria, with 20 T2-hyperintense
lesions, including involvement of the brainstem and
spinal cord. In contrast, a less-ominous course would
be implied in a patient who has had an episode
of mild optic neuritis with full recovery, followed
7 years later by a minor sensory relapse, who has
a normal neurological examination and whose MRI
reveals only 5 T2-hyperintense lesions confined to
the cerebral white matter.
During the next decade, new imaging techniques
will evolve and improvements in current research
techniques are likely to occur. However, given the
current lack of standardization of the specific imaging
protocols and their unavailability for routine clinical
use, as well as the length of follow-up needed to
acquire prognostic information, it is unlikely that
they will contribute significantly to a better ability
to forecast individual outcomes by 2020. The quest
for biomarkers as surrogates that would contribute
to accurate forecasting of individual prognosis is a
vigorous area of investigation. Thus far, no strong
candidate has emerged, and I suspect that this holy
grail will remain elusive over the next decade with
regard to application to a specific MS patient.
DOI:10.1002/MSJ
TREATMENT
Treatment of Relapsing Forms of
Multiple Sclerosis
For more than a decade, the mainstay of treatment
to modify the course of MS has been injectable ther-
apy with either interferon-β (IFN-β) or glatiramer
acetate (GA). Two other parenteral agents, mitox-
antrone and natalizumab, are on the market, but are
generally reserved for patients who are having an
unsatisfactory response to or are not tolerating the
self-injected DMTs. Three preparations of IFN-β are
available (in historical order of US Food and Drug
Administration approval): subcutaneous (SC) IFN-β-
1b, administered every other day; intramuscular (IM)
IFN-β-1a, administered weekly; and SC IFN-β-1a,
administered 3× weekly. Although the mechanisms
of action of IFN-β and GA are imprecisely known,
and their adverse-event profiles differ, the efficacy
of the 2 classes of DMTs appears to be comparable,
perhaps with the caveat that weekly IM IFN-β may
be somewhat less effective than the more frequently
administered IFN-β preparations. Mitoxantrone, an
immunosuppressive agent, is currently the only drug
approved for the treatment of secondary progressive
MS (SPMS) without relapses (it is also approved for
worsening relapsing forms). It is infrequently used
because of its potential for serious adverse events,
including cardiotoxicity and drug-related leukemia.
Natalizumab is a monoclonal antibody directed
against α4β1 integrin, an adhesion molecule on the
surface of lymphocytes.24 Interaction of this adhesion
molecule with its complementary receptor vascular
cell adhesion protein 1 on the vascular endothelium
enables the lymphocyte to be arrested at the vascular
wall, a necessary step for penetration into the CNS.
Natalizumab was originally marketed in late 2004,
but was voluntarily removed in early 2005 because
of the discovery of 2 cases of progressive multifo-
cal leukoencephalopathy (PML),25,26 an opportunistic
viral infection of the brain caused by JC virus (JCV),
in study patients treated with the drug for MS and an
additional case in an individual receiving the agent for
Crohn’s disease. The drug was brought back to mar-
ket in the summer of 2006 with a risk evaluation and
mitigation strategy to try to facilitate the early recogni-
tion of PML. Since its reintroduction, 75 more patients
with PML have been identified among >75,000 who
have received natalizumab. The risk of PML increases
with duration of exposure, at least up to 2 years
of treatment. No case of PML has yet occurred
with usage of natalizumab for <14 months, and the
incidence for all patients receiving ≥24 infusions
is 1.97/1000 (95% confidence interval: 1.51–2.53).
MOUNT SINAI JOURNAL OF MEDICINE
However, the rate does not appear to continue to
increase with exposure for >2 years. Because of this
risk, use of natalizumab is recommended for patients
who are not having a satisfactory response to the first-
line injectable therapies or are not tolerating them.
Use of a recently developed antibody assay for
JCV suggests that only slightly more than half of the
patients treated with natalizumab have antibody to
JCV.27
So far, in all 23 natalizumab-treated patients for
whom serum was available, antibody titers have been
positive. If these observations hold up with further
study, there would probably be a major impact on
the clinical use of natalizumab, as antibody negativ-
ity would imply extremely low risk of PML (patients
do convert to antibody positivity at a low annual
rate, so repeated testing would be necessary). Con-
versely, the presence of antibodies would mean that
a patient on the drug was at a considerably higher
risk for PML than we currently believe, at least after
prolonged exposure to the treatment. Soon after the
introduction of IFN-β-1b, patients began to ask their
physicians, ‘‘When will there be a pill?’’ Despite the
very benign safety profiles of IFN-β and GA, clearly
most patients would prefer to have an oral medi-
cation. Many patients experience both physical and
psychological discomfort from the repeated injec-
tions. Often, because of underlying changes to the
SC tissue, patients experience increasing difficulty
with their injections after prolonged usage. In par-
ticular, GA may cause prominent focal lipoatrophy,
sometimes resulting in cosmetically unsightly ‘‘div-
ots’’ in the injected areas after extended treatment.
This is especially true in women.
Fortunately, we are now seeing the dawn of oral
therapy for MS. The first oral agent, fingolimod, was
approved by the FDA in September 2010. A new class
of MS DMT, fingolimod is a sphingosine-1-phosphate
receptor (S1PR) modulator. The drug acts as a func-
tional antagonist of the S1PR, thereby preventing
egress of lymphocytes from the lymph nodes (albeit
sparing central memory T cells) and thus keeping
them from doing damage in the CNS. Fingolimod
may also have a direct neuroprotective effect within
the CNS.
Administered once daily, the drug was approved
based on two positive phase III trials. The first
reported was a 1-year trial against an active compara-
tor, weekly IM IFN-β-1a, in which patients receiving
fingolimod at what is now the marketed dose of
0.5 mg experienced fewer than half the number
of relapses that occurred in the IFN-β-1a group.28
The pivotal randomized, double-blind, placebo-
controlled trial, known as the Efficacy and Safety
of Fingolimod in Patients With Relapsing-Remitting
273
Multiple Sclerosis (FREEDOMS) 1, resulted in a
>50% reduction in annualized relapse rate for both
the 0.5-mg and 1.25-mg doses of fingolimod that
were studied in the trial.29 The fingolimod-treated
patients also experienced significant benefit on sev-
eral MRI parameters, including new T2-lesion vol-
ume, gadolinium-enhanced lesions, and brain vol-
ume, as well as a statistically significant reduction in
sustained disability progression.
Fingolimod treatment was associated with some
potentially significant adverse events. Bradycardia,
rarely clinically significant, occurred with the first
dose, and prescribing information instructs healthcare
providers to monitor patients for 6 hours at the initial
dosing and also recommends obtaining an electro-
cardiogram prior to prescribing the drug in patients
using antiarrhythmics including β-blockers and cal-
cium channel blockers, those with cardiac risk factors
(second-degree or higher atrioventricular blocks, sick
sinus syndrome, prolonged QT interval, ischemic car-
diac disease, or congestive heart failure), and those
who on examination have a slow or irregular heart-
beat. Macular edema occurred in 0.4% of patients,
albeit usually in the patients treated with the 1.25-mg
dose of fingolimod, resulting in the recommendation
that patients undergo baseline ophthalmic evaluation
and repeat examination 3 to 4 months later. Concern
about herpes infections, especially varicella zoster,
has led to the recommendation that patients not be
started on fingolimod unless they have had chicken
pox or varicella immunization. Liver function tests
and complete blood counts need to be monitored.
Cladribine, a purine nucleoside analogue that
is a potent lymphocyte-depleting agent, has had a
positive phase III trial, reducing relapse rate by well
over 50% compared with placebo.30 The drug was
dosed for several days in each of 2 or 4 monthly
cycles (low and high dose, respectively), and then
treatment was not repeated until 12 months after
the initial cycle. The agent is currently approved in
Russia and Australia, but the European Medicines
Agency recently rejected the application, citing con-
cerns about 4 cases of cancer that occurred in the
trial. A decision by the FDA is pending.
Teriflunomide, a drug that interferes with pyrim-
idine synthesis, met its primary endpoint of a reduc-
tion of annualized relapse rate (ARR), as reported
at a recent international MS meeting. Both the 7-
and 14-mg single daily doses tested achieved relapse
rate reductions of approximately 31%, as well as sig-
nificant reductions in total T2-lesion volume.31 The
higher dose also produced a statistically significant
reduction of nearly 30% in the development of sus-
tained disability progression. Confirmatory studies
DOI:10.1002/MSJ
274 A. E. MILLER: MULTIPLE SCLEROSIS: WHERE WILL WE BE IN 2020?
are in progress. The safety profile appears favorable,
although elevations of liver enzymes may occur.
Two other oral agents, fumarate and laquini-
mod, are nearing completion of phase III trials. Both
agents are likely to have good safety profiles, based
on their phase II data.32,33 In addition, fumarate has
been marketed in Germany for years for the treat-
ment of psoriasis, without the significant occurrence
of serious adverse events. The exact mechanisms of
action of these drugs is uncertain. The major ques-
tion that must be answered is whether these agents
will prove effective. In the phase II trials, both agents
reduced MRI activity, although the laquinimod results
were less pronounced than what has been seen with
several other drugs. Each drug showed only a trend
to reducing relapse activity in the phase II trials, but
such studies are not powered to expect statistically
significant results on this parameter.
In addition to these promising oral agents, sev-
eral parenteral monoclonal antibodies are undergo-
ing phase III trials. Rituximab, a chimeric antibody
directed against the CD20 antigen on B cells, had a
positive phase II trial several years ago.34 However,
its further development for MS was halted in favor of
a more fully humanized anti-CD20 antibody known
as ocrelizumab. Results of a phase II trial of this agent
were recently reported and, like rituximab, produced
robust reduction in MRI activity and also statisti-
cally significant reduction in relapse rate, despite the
power limitations of the phase II trial.35 The drug is
expected to soon undergo phase III testing.
Alemtuzumab, a monoclonal antibody directed
against the CD52 antigen present on both T and
B lymphocytes, is a potent immunosuppressive
agent. Because the treatment is associated with
very prolonged depletion of lymphocytes, it is
administered for several days followed by a hiatus
of 1 year before the next course of therapy. In
a phase II/III trial against SC IFN-β-1a, treatment
with the agent resulted in a remarkably low
ARR of 0.11 in patients treated with 12 mg/day
and 0.05 in patients who received 24 mg/day.36
Unfortunately, the trial was marked by some
serious adverse experiences. Most notably, 6 cases
of immune thrombocytopenic purpura, the first
of which resulted in a fatal brain hemorrhage,
occurred among the 222 patients who received
alemtuzumab. In addition, 49 patients receiving the
monoclonal antibody developed abnormalities of
thyroid function. Despite these risks, phase III trials
are currently in progress.
A third monoclonal antibody, daclizumab, is also
currently in phase III trials. This agent is directed
against the α subunit (CD25) of the high-affinity
interleukin-2 receptor and results in inhibition of
DOI:10.1002/MSJ
activated T cells. Current evidence suggests that
CD25 antagonism causes expansion of a regulatory
subset of natural killer cells, CD56 bright cells, which
presumably lyse autologous activated T cells. In
a phase II trial, the higher dose of daclizumab,
2 mg/kg SC every 2 weeks, added to treatment
with weekly IM IFN-β-a, reduced the number of
total new and enlarging gadolinium-enhanced lesions
developing between weeks 8 and 24 by 72%
compared with the addition of placebo.37 A trend in
ARR favored daclizumab but did not reach statistical
significance.
Currently available and prospective DMTs are
summarized in Table 2. I believe that by 2020,
oral treatment of MS will be the mainstay of ther-
apy. I predict that S1PR modulation will ultimately
be determined to be an effective and relatively
safe therapy. Fingolimod may be the most widely
used therapy; although, depending on the speed
of development, it might be supplanted by more
receptor-selective S1PR modulators. Many patients,
however, may initially be treated with an oral agent
with a better safety profile but perhaps somewhat
lesser efficacy, such as teriflunomide, fumarate, or
laquinimod, and switched to the more potent agent
if they experience breakthrough disease. I believe
that cladribine, if approved, will be prescribed less
frequently because of its very-long-lasting depletion
of lymphocytes, as well as concerns about reproduc-
tive risk. I also expect the monoclonal antibodies
to have a smaller role in the overall management
I believe that by 2020, oral
treatment of MS will be the
mainstay of therapy. Fingolimod
may be the most widely used
therapy; although, depending on
the speed of development, it might
be supplanted by more
receptor-selective S1PR
modulators. Many patients,
however, may initially be treated
with an oral agent with a better
safety profile but perhaps
somewhat lesser efficacy, such as
teriflunomide, fumarate, or
laquinimod, and switched to the
more potent agent if they
experience breakthrough disease.
MOUNT SINAI JOURNAL OF MEDICINE 275

Table 2. Current and Prospective MS DMTs.

Route of
Drug Name Administration Mechanism of Action FDA Status
IFN-β-1a IM Multiple Approved
IFN-β-1a SC Multiple Approved
IFN-β-1b SC Multiple Approved
Glatiramer acetate SC Switch from Th1 to Th2 predominance; Approved
?Increase Treg cells
Mitoxantrone IV Multiple immunosuppressant functions, Approved
including inhibition of T-cell activation
Natalizumab IV Selective adhesion molecule inhibitor Approved
Fingolimod Oral S1PR modulator Approved
Cladribine Oral Purine nucleoside analogue; depletes Pending
lymphocytes
Teriflunomide Oral Pyrimidine synthesis inhibition in 1 phase III trial positive
lymphocytes
Laquinimod Oral ?Th1 to Th2 shift 1 phase III trial positive
Fumarate (BG-12) Oral Uncertain Phase III trials pending
Rituximab/ocrelizumab IV Anti-CD20 antibody; depletes B cells Phase II trial positive
Alemtuzumab IV Anti-CD52 antibody; depletes T and B Phase II/III trial positive;
cells phase III trial pending
Daclizumab SC Anti-CD25, component of high-affinity Phase III trials pending
IL-2 receptor; inhibits activated T cells

Abbreviations: DMT, disease-modifying therapy; FDA, US Food and Drug Administration; IFN-β, interferon β;
IL-2, interleukin-2; IM, intramuscular; IV, intravenous; MS, multiple sclerosis; S1PR, sphingosine-1-phosphate receptor;
SC, subcutaneous; Th, T helper cell; Treg, regulatory T cells.

of MS, primarily because of greater concerns about
the potential for opportunistic infections (particularly
with ocrelizumab or alemtuzumab) or, particularly in
the case of alemtuzumab, other autoimmune phe-
nomena. In addition, treatment with alemtuzumab is
a double-edged sword. On the one hand, the treat-
ment regimen is attractive, requiring only a few days
of intravenous infusion annually, but the fact that
the effects of the treatment are of very prolonged
duration and irreversible is concerning.
I anticipate that by 2020 the use of self-
administered injectable medications–the IFN-βs or
GA–will be minimal, principally because of the
advent of better-accepted oral agents that match or
exceed these current frontline therapies in efficacy
I anticipate that by 2020 the use
of self-administered injectable
medications–the interferons or
glatiramer acetate–will be
minimal, principally because
of the advent of better-accepted
oral agents that match or exceed
these current frontline therapies
in efficacy while carrying an
acceptable safety profile.
while carrying an acceptable safety profile. Possibly,
combination therapy with one or another of the oral
agents and either IFN-β or GA will be employed in
some patients whose disease is not fully controlled
by the single drug. Patients taking injectable ther-
apy today almost universally would prefer the option
of oral therapy, or even infrequently administered
infusions, as they almost invariably experience dis-
comfort with the injections and increasing difficulty
because of tissue changes associated with prolonged
usage of these drugs.
Treatment of Progressive Forms of
Multiple Sclerosis
Developing successful treatment of progressive forms
of MS, both SPMS and primary progressive (PPMS),
has been an unmet challenge and remains a crit-
ical need. Currently mitoxantrone, an immunosup-
pressive agent, is the only drug approved for the
treatment of SPMS (without relapses), and it is not
widely used because of the potential serious risks of
drug-induced leukemia and cardiotoxicity.
No drug has so far had a positive trial for
the treatment of PPMS. A trial of GA showed a
trend in favor of benefit, but could not demonstrate
statistical significance. The trial was hampered
by the fact that the placebo group failed to
progress to the extent anticipated when the trial

DOI:10.1002/MSJ
276 A. E. MILLER: MULTIPLE SCLEROSIS: WHERE WILL WE BE IN 2020?
was powered.38 A post hoc analysis suggested
that males had benefited from the treatment. In
another recent trial for PPMS patients comparing
rituximab with placebo, the primary endpoint of
confirmed progression was not achieved.39 However,
the data suggested benefit for younger patients
and those with continued evidence of inflammation
as indicated by gadolinium-enhancing lesions on
MRI.
The progressive stage of MS, be it in SPMS or
PPMS, appears to be principally associated with a
process that is neurodegenerative or influenced by
the innate immune system, rather than the more evi-
dent inflammation that is seen in relapsing-remitting
disease. Nonetheless, some patients with SPMS do
continue to have relapses and to develop new lesions
on MRI, including gadolinium-enhancing lesions. In
clinical trials of PPMS, some patients also continue to
develop enhancing lesions.
I predict that an ongoing trial of fingolimod in
PPMS will be positive, resulting in the approval of
the first drug for PPMS. I believe this not necessarily
I predict that an ongoing trial of
fingolimod in primary progressive
multiple sclerosis will be positive,
resulting in the approval of the
first drug for PPMS.
because fingolimod has a greater impact on neu-
rodegeneration (though it may) than other agents,
but rather because the design of the phase III trials
favors the inclusion of patients with a more inflam-
matory profile than other trials in PPMS have. The
trial limits entry to patients who have had evidence of
PPMS for ≤10 years and also requires evidence of dis-
ease progression in each of the 2 years prior to entry.
These criteria favor a population with greater disease
activity and, I believe, will increase the likelihood of
a favorable outcome in the trial.
The prospects of success in SPMS are uncer-
tain over the next decade. Progress has also been
hampered by the absence of surrogate markers for
progression, necessitating long follow-up of patients
in clinical trials. The search for predictive surro-
gate markers for progression, either imaging mea-
sures or biomarkers, will continue. Nonetheless,
we are likely to see trials of some of the more
active anti-inflammatory agents, which may again, for
the reasons cited above, possibly result in positive
trials.
DOI:10.1002/MSJ
Chronic Cerebrospinal Venous
Insufficiency
In 2009, a vascular surgeon, Professor Paulo Zam-
boni of Ferrara, Italy, reported an association of what
he claimed were venous abnormalities detected by
ultrasound in patients with MS.40 He defined the syn-
drome of chronic cerebrospinal venous insufficiency
(CCSVI) as the situation in which at least 2 of 5
criteria were present:
• Reflux in internal jugular veins (IJV) or vertebral
veins (VVs).
• Reflux in intracranial veins or sinuses.
• Detection of stenoses in IJVs.
• Absence of Doppler signal in IJV and/or VV.
• Cross-sectional area of IJV greater sitting than
supine.
He claimed that CCSVI existed in 100% of 65 MS
patients and none of 235 control patients, and postu-
lated that the condition caused MS. Zamboni further
based this speculation on the belief that CCSVI led
to the deposition of iron in the brain, which in turn
promoted an inflammatory, demyelinating process.
In a subsequent paper, he reported that interven-
tions to repair these venous abnormalities resulted
in improvement in patients with MS, using a pro-
cedure that he provocatively termed the ‘‘liberation
procedure.’’41 He did, however, note that ‘‘restenosis’’
of the IJV occurred in 47% of cases.
The Zamboni claims created a firestorm in the
MS community, fueled by the promotion of his
ideas by the mainstream media, especially in Canada.
Demands for the liberation procedure reached a fever
pitch, fanned by huge numbers of Internet bloggers.
The causal relationship between CCSVI and MS was
considered highly unlikely by most MS scientists and
clinical specialists. The all-or-none results claimed by
Zamboni strained credulity. Critics pointed out the
fact that ultrasound evaluation of the cerebral venous
system was significantly operator-dependent and that
no uniform anatomy of that system existed. They
emphasized the redundancy of the venous drainage
of the brain and the fact that surgeons operating on
the head and neck, particularly for tumors, commonly
ligated the IJVs without untoward effects. In addition,
they noted the absence of the clinical signs usually
associated with blocked venous drainage and pointed
out that, although iron deposition is increased in the
brains of people with MS, it is also found in patients
with other neurodegenerative diseases. It is also pos-
sible that even if the association of CCSVI with MS
were true, it might be a result of the disease, rather
than a cause.
MOUNT SINAI JOURNAL OF MEDICINE
Despite this widespread skepticism, the National
Multiple Sclerosis Society and the Multiple Sclerosis
Society of Canada, driven by their desire to explore
any possibility of finding a cause or cure of MS and
the intensity of the demand for procedures to ‘‘open’’
the veins, requested proposals to study CCSVI. An
international multidisciplinary panel recommended
funding of several studies, currently underway,
designed to confirm or refute the Zamboni findings,
as well as to extend the studies to other methods
of investigating the venous system in patients with
MS, including those very early in the course of the
disease.
Subsequent to the original Zamboni reports,
deaths associated with the use of venous stents
have been reported, as well as some other seri-
ous complications. The occurrence of a death from
intracerebral hemorrhage and the need for open heart
surgery because of migration of a stent to the heart
led Stanford University to ban performance of the
procedure.42 Recently, another death occurred in a
patient who underwent the procedure in Costa Rica.43
A number of investigators have now reported finding
either a much lower frequency of CCSVI in patients
with MS and a much greater number in controls, or
no significant difference at all between MS patients
and control subjects.35,44,45
By 2020, the concept of CCSVI will likely have
been discredited as a plausible cause of MS. Nonethe-
less, as we have seen with other claims, such as
the refuted notion that dental amalgams cause MS
and their removal effects improvement, I expect that
some patients will continue to seek procedures to
‘‘open’’ their venous systems. Furthermore, I expect
that within the next decade some other claim about
the cause and cure of MS will capture the pub-
lic fancy, just as others have done over the years.
Sadly, such situations tend to divert patients from
By 2020, the concept of
cerebrospinal venous insufficiency
will likely have been discredited
as a plausible cause of multiple
sclerosis. Furthermore, I expect
that within the next decade some
other claim about the cause and
cure of multiple sclerosis will
capture the public fancy, just as
others have done over the years.
legitimate, scientifically proven treatments (even
if only partially successful) and may result in
277
expenditure of research dollars that could be better
used for other studies.
CONCLUSION
The past decade has seen a surge of research interest
in MS and an incredible expansion of investigative
efforts in MS therapeutics. Continued dissection
of the complex immunological perturbations that
may contribute to the disease has occurred. Major
advances in understanding the genetics of MS have
been made and are continuing rapidly. I expect that
the current decade will be characterized by continued
intense exploration of this enigmatic disorder with
further advances in our understanding of the disease
and additional progress in its treatment.
DISCLOSURES
Potential conflict of interest: Nothing to report.
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