1. health and fitness
2. disease

2013 CME Annual meeting in multiple sclerosis
“How to translate new insights
in MS into clinical practice”
Istanbul, Turkey
Highlights: May/June 2013
More than 400 delegates from all over the world gathered at the Ceylan Intercontinental Hotel in Istanbul, Turkey, to listen
to a distinguished faculty discuss the latest advances in multiple sclerosis (MS) research and how these new insights can be
translated into clinical practice and improved patient outcomes.
Professor Giancarlo Comi, President of the Scientific Committee of the Serono Symposia International Foundation, opened the
meeting, “How to translate new insights in MS into clinical practice”, by welcoming the participants and giving an overview
of the purposes and activities of the foundation. Following Professor Comi, Professor David Bates, co-chair of the meeting,
welcomed the first speaker.
Contents
Faculty
2
SESSION I: MS before MS – differential diagnosis
3
SESSION II: Treatment issues management today – part 1
4
SESSION III: Treatment issues management today – part 2
5
SESSION IV: How to implement recovery processes and brain plasticity
6
SESSION V: Genetics – genomics – proteomics
8
SESSION VI: Paediatric MS
9
10
References
1
Faculty
David Bates (Chair)
Department of Neurology
Royal Victoria Infirmary
Newcastle upon Tyne, UK
Magnhild Sandberg-Wollheim (Chair)
Department of Neurology
Lund University Hospital
Lund, Sweden
Marco Bacigaluppi
Neuroimmunology Unit
Department of Neurology
Institute of Experimental Neurology
Vita-Salute San Raffaele University
Milan, Italy
Giancarlo Comi
Department of Neurology
Institute of Experimental Neurology
Vita-Salute San Raffaele University
Milan, Italy
Angelo Ghezzi
Multiple Sclerosis Centre
Gallarate Hospital
Gallarate, Italy
Gavin Giovannoni
Department of Neurology
The Royal London Hospital
Whitechapel, London, UK
Douglas Goodin
UCSF Multiple Sclerosis Center
University of California San Francisco
San Francisco, CA, USA
David Hafler
Department of Neurology
Yale School of Medicine
New Haven, CT, USA
Hans-Peter Hartung
Department of Neurology
Heinrich-Heine University
Düsseldorf, German
Ludwig Kappos
Neurology and Department of
Biomedicine
University Hospital Basel
Basel, Switzerland
Rana Karabudak
University Hospital Department of
Neurology
Neuroimmunology Unit
Ankara, Turkey
Dawn Langdon
Department of Psychology
Royal Holloway
University of London
London, UK
Elia Stupka
Unit Center for Translational
Genomics and Bioinformatics
San Raffaele Scientific Institute
Milan, Italy
Xavier Montalban
Multiple Sclerosis Center of
Catalonia
Unit of Clinical Neuroimmunology
Vall d’Hebron University Hospital
Barcelona, Spain
Silvia Tenembaum
Department of Neurology
National Pediatric Hospital –
“Dr Juan Garrahan”
Buenos Aires, Argentina
Jorge Oksenberg
Department of Neurology
University of California at San
Francisco (UCSF)
San Francisco, CA, USA
Alan J. Thompson
Department of Brain Repair and
Rehabilitation
Institute of Neurology
University College London
National Hospital for Neurology
and Neurosurgery
London, UK
Peter Rieckmann
Bamberg Hospital and
University of Erlange
Bamberg, Germany
Aksel Siva
Department of Neurology
Cerrahpasa School of Medicine of
Istanbul University
Istanbul, Turkey
Bernd Kieseier
Department of Neurology
Heinrich-Heine University
Düsseldorf, Germany
Jeffrey A. Kleim
School of Biological and
Health Systems Engineering
Arizona State University
Tempe, USA
Maria Pia Sormani
University of Genoa
Genoa, Italy
Unfortunately, Professor Sormani was
unable to attend the meeting
2
Ann Yeh
Pediatric MS and Demyelinating
Disorders Center
Division of Neurology
Hospital for Sick Children
University of Toronto
Toronto, Canada
Tjalf Ziemssen
MS Center Dresden
Neurological University Clinic
Dresden, Germany
SESSION I: MS before MS –
differential diagnosis
behavioural dysfunction, aphasia and seizure, and death in weeks
or months. Typical MRI findings on T1-weighted images show
lesions with alternating concentric rings of active demyelination.9
Marburg’s disease is a very severe fulminating monophasic
condition, characterized by overwhelming attacks and death within
a few weeks. Immediate, aggressive treatment is required, for
example, with mitoxantrone.
Early diagnosis (RIS/CIS)
Professor X. Montalban opened with an overview of two difficultto-diagnose early conditions, radiologically isolated syndrome
(RIS) and clinically isolated syndrome (CIS). Overall, about 85% of
patients with multiple sclerosis (MS) initially present with CIS,1,2
which describes the first clinical manifestation of inflammation or
demyelination in the central nervous system (CNS).
Paediatric acute disseminated encephalomyelitis (ADEM) is a
multifocal, clinical CNS event caused by presumed inflammatory
demyelination and characterized by encephalopathy that cannot be
explained by fever. Brain MRI shows diffuse, bilateral lesions; T1
hypointense lesions in the white matter are rare, while deep grey
matter lesions in the thalamus or basal ganglia can be present. A
diagnostic algorithm for differential diagnosis of ADEM and MS has
been constructed.10
Preclinical MS (or RIS) describes asymptomatic lesions typical of
MS found on a magnetic resonance imaging (MRI) scan that has
been performed for other reasons, most commonly for headache.3
The real prevalence of subclinical MS is a matter of debate, with
historical autopsy studies from undiagnosed individuals showing a
prevalence of ~0.1%,4-6 while MRI studies have shown that 0.06%
of healthy individuals had definite demyelination suggestive of MS
(rising to 11% among asymptomatic siblings of patients with MS).7
In a systematic review of RIS cohorts, approximately two-thirds of
patients showed radiological progression, and one third developed
neurological symptoms during a mean follow-up of up to 5 years.3
Professor D. Bates presented a summary of the current version of
the McDonald criteria, which was last refined in 2010 to integrate
MRI, include primary progressive MS, clarify definitions and
simplify classification, all with the aim of assisting in the diagnosis
of MS earlier and with greater reliability.
Management of RIS is still a matter of great debate and treatment
guidelines for early signs of MS vary between countries. Some
neurologists advocate disease-modifying drugs (DMDs) with only
MRI evidence of MS pathology, while others state that treatment is
only appropriate with clinical conversion and treatment guidelines.
One possible recommendation is that DMDs for RIS should be
considered when there is dissemination in space (DIS) and in time
(DIT), as defined by the McDonald 2010 criteria, or if prognosis is
a concern, particularly if the patient develops cognitive symptoms
or if there is evidence of brain atrophy and black holes on the MRI.
D
ifferential diagnosis:
demyelinating disorders
MS
and
According to the McDonald criteria, an MS attack is an episode of
neurological disturbance that lasts for at least 24 hours and has
objective signs – and, indeed, the criteria preclude the diagnosis
of MS in the absence of clinical signs. Additionally, while MRI has
been claimed by some to be a relatively poor diagnostic tool for the
diagnosis of MS,11 both DIS and DIT are required.
Professor Bates concluded by stating that when we change the
diagnostic criteria for MS, we change the characteristics of the
disease itself. Starting with the Poser criteria in the 1990s, we
have gradually begun to enlarge the cohort of patients diagnosed
with MS, allowing identification of patients both at earlier stages of
disease and with more benign MS. As a result, the characteristics
of patient cohorts enrolled in clinical trials have changed, which
makes comparison of data over time more difficult. In the future,
we must be able to adapt and evolve the diagnostic criteria
dynamically, especially as we understand more about brain
atrophy, and as MRI technology continues to improve. But, until we
are able to definitively and reliably diagnose MS with a single test,
we will always need diagnostic criteria.
acquired
Professor G. Comi described several neurological conditions that
are readily mistaken for MS, making differential diagnosis difficult.
Neuromyelitis optica (NMO) is the first CNS white matter
inflammatory disease that has been demonstrated to be associated
with a specific antibody, NMO immunoglobulin G. The discovery of
this biomarker suggests that NMO should be considered a clinical
entity distinct from MS, with a variety of clinical phenotypes that
also includes more limited forms such as recurrent longitudinally
extensive transverse myelitis and recurrent optic neuritis. NMO
and the limited forms can all show the same initial clinical
presentation and neuroradiological findings similar to MS, posing
a problem for the physician, although there are key differences that
can guide the differential diagnosis (Figure 1).8
NMO
MS
Monophasic or
relapsing
Relapsing
Severe
Mild
MRI head
Normal, non-specific
Multiple lesions
CSF cells
Pleocytosis
Rarely >25 cells
CSF OGB
Absent
Present
Female
80–90%
60–70%
Prominent necrosis
Demyelination
Course
Attack severity
Pathology
McDonald criteria
Until we are able to definitively
and
reliably diagnose MS with a single
test, we will always need
diagnostic criteria.
Diagnosis communication and patients’ coping
strategies
Professor D. Langdon pointed out that receiving a diagnosis of MS
is a major event in a patient’s life, with mood and quality of life
(QoL) immediately affected.12 Anxiety and uncertainty about the
future appear to be the most important and difficult aspects of
the diagnosis to deal with, and although these effects ameliorate
over time, one study reported that ~20% of patients experience
symptoms of post-traumatic stress disorder post-diagnosis. Most
neurologists believe that they have a good perception of their
ability to manage this difficult communication process, but if the
diagnosis is communicated in an inadequate manner, the patient
will feel isolated and helpless. Therefore, it is important that the
information imparted is tailored to the individual, with simple and
direct language, with the physician acknowledging the uncertainty
and worry that the diagnosis brings. Increasingly, patients find
CSF, cerebrospinal fluid; OGB, oligoclonal bands.
Figure 1. Differential features of NMO and MS.8
Balò’s concentric sclerosis is a rare demyelinating condition
that can affect young adults. It can be monophasic or relapsing,
and is characterized by headache, severe paresis, cognitive and
3
their own information online, which may be inaccurate and have
a negative impact, so it is important to provide guidance to more
appropriate sources of information.
The DEFINE and CONFIRM studies compared BG-12 with placebo
and GA, respectively. A stable effect on ARR was observed in both,
although only the DEFINE trial showed an effect on disability
progression.17,18 Positive MRI outcomes were also observed,
although the data on brain atrophy was less convincing. The main
tolerability issues were flushing and abdominal complaints.
Several practical coping strategies can help patients with early
stage MS adjust to their diagnosis. These include social support,
a positive mental attitude and a clear aim to carry on with their
life. Indeed, many patients reach a point where their MS co-exists
with an acceptable QoL and emotional well-being, although
this may be negatively impacted by the on-going ‘threat’ of MS,
including the loss of ability to walk, drive and work, and decreased
independence. In conclusion, Dr Langdon suggested that the
biggest issue for patients was the uncertainty surrounding their
disease, rather than with the diagnosis itself, and more work is
needed to optimize the logistical difficulties surrounding diagnosis
and patient–physician communication.
In the Phase III TEMSO and TOWER studies, teriflunomide 7 or
14 mg was associated with a significant reduction in ARR versus
placebo; in the TOWER study, the effect was greater with the
higher dose.19 The 14 mg dose had a significant effect on disability
progression in both trials. The safety profile of teriflunomide was
similar to that of placebo.
In a pooled analysis of the ALLEGRO and BRAVO studies,20
laquinomod was associated with a 21% reduction in ARR versus
placebo (p=0.0005) and a significant reduction in disability
progression and brain atrophy rate. Laquinimod also had a benign
safety profile, suggesting that it may be possible to use higher
doses than those currently under investigation in order to achieve
better efficacy.
SESSION II: Treatment issues
management today – part 1
Do IFNs and GA still have a role in MS?
Opening the second session, Professor P. Rieckmann reminded the
audience that the earlier treatment for MS is initiated, the better
the results seen – but early treatment requires early diagnosis
and agents that are as safe and effective as possible. Relapses
and MRI activity in the first few years may not translate into
immediate disability, thanks to neuronal plasticity and redundancy,
but accumulated axonal loss, which may start early in the disease
course, depletes the ‘reserve’ of functional tissue. Patients who
sustain a greater early reduction in their reserve are more likely
to progress faster.
Monoclonal antibody therapy, explained Professor H.-P. Hartung,
should allow almost surgical precision for treatment. Natalizumab
is currently the only monoclonal antibody approved for the treatment
of MS, and is highly effective, with one trial finding 37% of treated
patients having no disease activity over 2 years, versus only 7%
with placebo.21,22 Natalizumab is generally well tolerated, although
it is associated with an increased risk of progressive multifocal
leukoencephalopahty (PML). However, factors associated with
a higher risk of PML have now been identified, including prior
history of immunosuppressive therapy, duration of treatment and
JC virus status, thus allowing a risk stratification that may guide
treatment decision.
From diagnosis and treatment initiation, it is essential to educate
the patient about their disease and the treatment options available,
as this will positively impact patient adherence. Hidden problems
such as depression must also be identified, and non-medication
options such as physical and occupational therapy can be
considered alongside pharmacotherapy.
Antibodies in MS
Alemtuzumab is an antibody targeted to CD52, which selectively
and precipitously depletes mature lymphocytes and removes
autoreactive cells from the circulation. In the CARE-MS-I and
CARE-MS-II trials, alemtuzumab was associated with a significantly
improved relapse-free survival, and in CARE-MS-II, with improved
disability outcomes, versus IFN beta-1a.23,24
Although interferon (IFN) beta and glatiramer acetate (GA) are
recognized as the mainstay of treatment for relapsing–remitting
MS (RRMS), data on these agents come mostly from early clinical
trials whose populations tended to have more advanced MS than
those of more recent studies.13 This disparity in patient populations
makes it difficult to compare data on IFN beta and GA with those for
newer drugs. However, unlike the newer drugs, data are available
for IFN beta and GA on the treatment of a wide range of disease
stages, including CIS and progressive phases. The resulting CIS
indications mean that these agents remain the treatment of choice
for very early therapy. Additionally, extensive long-term follow-up
data for both agents mean that IFN beta and GA have well-known,
long-term safety profiles. Although oral administration of MS
therapy may be perceived as an advantage, constant improvement
of delivery devices means that, now, most patients are able to cope
with injected IFN beta and GA treatment.
In the DAC HYP SELECT Phase IIb registration trial, the humanized
monoclonal antibody daclizumab resulted in a 50–54% reduction
in the ARR versus placebo, as well as significant reductions in
disability progression.25 The increase in CD56bright cell population
after treatment predicted which patients would develop the fewest
new T2 lesions, suggesting potential as a therapeutic response
marker.26 Its use requires careful monitoring so that potentially
serious side effects (autoimmunity against the thyroid gland, and
less frequently, against platelets in immune thrombocytopenia)
can be identified early and treated effectively.
In a Phase II trial, the CD20-targeted antibody rituximab resulted
in sustained depletion of CD20 cells in RRMS.27 Another CD20targeted molecule, ocrelizumab, resulted in a significant reduction
in the number of new T1 gadolinium-enhancing lesions versus
placebo at Week 96 in a Phase II trial, as well as significant
reductions in the number of new clinical relapses.28 Ocrelizumab
is currently in Phase III trials.
Oral drugs
Finally, the anti-LINGO-1 antibody BIIB033 is under investigation
for promoting remyelination and repair. LINGO is a negative
regulator of myelination; anti-LINGO-1 promotes remyelination
in animal models of MS,29 and there are currently Phase I and II
clinical trials underway in acute optic neuritis and RRMS.
Professor L. Kappos led the audience through a summary of the
major new oral agents.
All three major trials of fingolimod – two comparing with placebo,
one with intramuscular IFN beta-1a once weekly – showed
significant improvements in annualized relapse rate (ARR), time
to relapse and the proportion of patients free from relapse; the
effect on disability progression was only significant in one of the
two placebo-controlled trials.14-16 The FREEDOMS extension study
also showed that the attenuating effect on brain atrophy persisted
to 4 years.16 The safety profile of fingolimod was also reassuring;
long-term data are, however, still required.
4
Monoclonal antibody therapy
should allow almost surgical precision
for MS treatment.
One example of the biases seen in LTFU studies comes from the
15-year LTFU study of GA,32 in which 40% of the original cohort of
251 randomized patients was ascertained by 15 years. Here there
was a clear informed censoring bias, with patients who refused to
participate in the LTFU having twice the number of relapses and
twice the disability progression of those who elected to continue
with GA.33
When and how to start a therapy
Concluding the morning sessions, Professor T. Ziemssen stressed
that the decision on when and how to start a patient’s first therapy
is a very individual one, which must be made in consultation with
the patient, considering many factors.
Neurological disability
It is also important to recognize that MS is a serious disease, and
that treatment as early as possible is essential – the so-called
‘window of opportunity’, which has a profound impact on long-term
outcomes, is small (Figure 2).
‘Window of
opportunity’
Early
treatment
Late
treatment
Several strategies exist for limiting the sources of bias in analyses
of LTFU data. For ascertainment bias, follow-up must be as
complete as possible, with direct comparison of baseline and
on-randomized treatment characteristics of those patients in the
LTFU versus those not in the LTFU. Informed censoring bias may
be countered by using the percentage of total possible time on
therapy to assess exposure, rather than absolute time on therapy.
Propensity scoring limits treatment selection bias by adjusting for
the likelihood that a particular treatment will be selected based
on available patient characteristics. Finally, bias introduced by
multiple testing can be avoided by creating a single model and
applying adjustments to p-values according to the number of
predictors tested in that model.
Natural history
With regard to specific therapies, there is reasonably strong
evidence that IFN beta therapy is associated with a long-term
benefit on measures such as conversion to secondary progressive
MS, progression of unremitting disability and premature death,34
and it seems likely that other DMDs that impact the same shortterm outcomes are also associated with similar benefits, although
this remains to be demonstrated.
Late treatment
Early treatment
Figure 2. The concept of early treatment and the ‘window of opportunity’.
When and how to switch from one therapy to another
While treatment guidelines exist and are helpful, they are often
difficult to put into clinical practice. Treatment algorithms are
perhaps more useful, particularly when it comes to using more
active or aggressive agents,30,31 but there are little hard clinical data
on the benefits of different treatment concepts such as induction
or escalation. Certainly, more active drugs such as alemtuzumab
are associated with higher risks for the patient, so the treatment
decision for these types of agents certainly must be based on
individual cases.
Professor G. Comi stated that in order to fully optimize therapy
for the individual we must know when to start treatment, what
treatment to start with, be able to detect non-responders quickly
and know how best to change treatment. Indeed, when choosing
a new therapy, it is important to balance risk versus benefit in the
treatment decision. The balance of disease activity and burden
versus treatment burden is complex, as each drug has its own
benefits and risks and each patient responds differently.
Professor Ziemssen concluded by reminding the audience that the
successful management of MS requires early treatment, as “what
is lost cannot be brought back.” A compromise exists between
efficacy and safety, particularly with more active agents, and while
we continue to need scientific data, we also need to continue to
gather valuable clinical experience to help build our evidence for
optimal treatment selection and timing.
Professor Comi defined the criteria for response to treatment into
three categories: full response, where there is no relapse during
therapy and no MRI activity; non-response, where the ARR during
treatment is greater than 0.5, or there are two active lesions on
a single MRI scan or at least four cumulative action lesions; or
partial response, which falls somewhere between. Patients who
are full responders can stay on treatment, while the remainder may
require a treatment switch. Several factors may predict response
to treatment, including clinical and demographic characteristics,
MRI activity, laboratory measures and pharmacogenomics. Evoked
potentials may also be an important predictive tool, as baseline
abnormalities predict the treatment response to first-line DMDs.
SESSION III: Treatment issues
management today – part 2
Long-term benefit of current DMDs on disability
progression: experience from clinical trials and
clinical practice
Two approaches for switching therapy are escalation and induction.
In escalation, first-line treatment consists of well-established
therapies such as IFN beta and GA, moving to increasingly
aggressive therapies as required. With an induction approach,
an aggressive therapy such as mitoxantrone or alemtuzumab in
the future is used initially for a limited time period, essentially
resetting the immune system. This is then followed by long-term
maintenance therapy with a less potent but less risky therapy
(Figure 3). Various treatment algorithms have been developed to
aid physicians in the treatment switching decision.
In his lecture, Professor D. Goodin stressed that the principal
therapeutic goal of DMDs in MS is to reduce the likelihood of
long-term physical and cognitive disability – and it is, therefore,
imperative to conduct long-term studies. However, long-term
follow-up (LTFU) studies are fraught with difficulties, including bias
from treatment selection (where therapeutic effect is dependent
on patient selection characteristics), ascertainment (where
therapeutic effect is dependent on characteristics of participating
patients) and informed censoring (where there is an inflated
estimate of therapeutic benefit because patients doing well
continue therapy while patients for whom therapy is failing switch
or stop therapy). In addition, it is difficult to identify prognostic
factors for later disability.
In conclusion, Professor Comi stated that it is important to
remember that while prognostic information is available to orient
treatment choice, we are still unable to fully predict which patients
will respond to various different treatments.
5
A
Escalating therapy
5th line therapy
BMT
4th line therapy
Alemtuzumab
Rituximab
3rd line therapy
1st line therapy
B
4th line therapy
In conclusion, while physicians should be attentive to the safety
issues surrounding MS treatments, the probability of AEs should
not mean that therapies are withheld – it is essential that the
risk–benefit profiles of candidate treatments be carefully assessed
for each patient.
More
aggressive
approach
im
od
Mitoxantrone / Cyclophosphamide
Fi
ng
ol
2nd line therapy
in patients who are anti-JC virus antibody positive, mainly with a
high index; other risk stratification tools are available, based on
the duration of treatment and prior use of immunosuppressants.
Natalizumab
While physicians should be attentive
to the safety issues surrounding
MS treatments, the probability of
AEs should not mean that therapies
are withheld.
IFN betas / GA
Laquinimod / BG-12 / Teriflunomide italic
Induction therapy
BMT
3rd line therapy
Combination
therapy
2nd line therapy
Natalizumab / IFN / GA
Laquinimod / Teriflunomide / BG-12
1st line therapy
Mitoxantrone / Cyclophosphamide
Fingolimod / Alemtuzumab / Rituximab
SESSION IV: How to implement
recovery processes and brain
plasticity
New biological basis of rehabilitation
Professor J. Kleim opened the final session of Day 1 by introducing
recovery medicine as an exciting new frontier of neuroscience. The
brain is a highly dynamic organ capable of significant plasticity,
which allows it to overcome a certain degree of functional
impairment and injury. The capacity of the residual tissue to
maintain function, as observed in MS, results in a non-linear
relationship between brain and spinal cord damage and function.
Eventually, however, the capacity for compensation is exhausted.
Figure 3. Concepts for (A) escalation and (B) induction therapy.
How to detect and monitor safety issues
Professor A. Siva discussed the issues surrounding the safety
of MS treatments, which are of particular interest given the lifelong nature of therapy. Long-term treatment is associated with
many risks, which can be mitigated with patient education and
careful monitoring.
In order to promote neurorehabilitation, we can optimize both
behavioural and neural signals. Key to this approach is the concept
of repetition of motor tasks, which has been shown to induce
neural plasticity in stroke patients with remarkable improvements
in function. Such techniques can be applied to rehabilitation in MS.
The most common adverse events (AEs) with IFN beta treatment
are flu-like symptoms and injection-site reactions, although
these rarely require treatment switching. Temporary elevation
of liver enzymes are also frequently observed, for which there
are a number of known risk factors.35 Prior to initiation of IFN
beta therapy, a full laboratory work-up is required; once therapy
has been initiated, complete blood count and liver function tests
should be conducted monthly for the first 3 months, then every
3 months thereafter for the first year, with annual assessments of
thyroid function and auto-antibodies. GA is associated with more
injection-site reactions than IFN beta, but for both of these drugs,
their long-term safety profiles are well known.
In additional to behavioural rehabilitation techniques, adjuvant
therapies – such as drug treatment or electro-stimulation – can
help to improve the neural signal component of plasticity.
In summary, therapy can optimize neural plasticity – to achieve the
best results, task repetition and intensity must be maximized and
targeted to specific functions that are salient to the patient. As MS
treatments improve, slowing or even ceasing disease progression,
rehabilitation will become even more important to change brain
function and improve patient outcomes.
Fingolimod requires more work-up prior to initiation and during the
first administration and is associated with more AEs, particularly
lymphopenia. A lymphocyte count <200 cells/mL requires treatment
interruption in order to prevent an increased risk of infection. Mean
lymphocyte counts generally return to normal range approximately
45 days after discontinuation. Additionally, because of the potential
risk of bradycardia and atrioventricular block, all patients require
electrocardiography monitoring during the first administration.
Macular oedema, although its risk is very low, can occur, especially
in patients with a history of uveitis or diabetes mellitus. As the
onset of macular oedema is typically within 3–4 months after
initiation of the drug, an ophthalmological examination should be
conducted around this time.36 Fingolimod cessation usually results
in resolution of oedema and return of vision.
Neuroprotection
Neuroprotection is a hot topic in MS, explained Professor B.
Kieseier, but so far results from animal models have proven difficult
to translate into human studies. In MS, effective suppression of
inflammation does not limit brain atrophy or protect from clinical
progression once the cascade of events leading to tissue injury is
established. Although we can achieve indirect neuroprotection with
immunosuppressive agents early in the disease course, there is no
current evidence that direct neuroprotection is possible with any of
the current armamentarium of DMDs in the clinical setting.
GA has shown some evidence of neuroprotective activity in
culture experiments, but these have not translated into clinical
studies. Likewise, while in vitro studies show that IFN beta may
promote release of neurotrophic factors, there is a lack of clinical
evidence, although the reduction in disability progression versus
placebo seen in the PRISMS trial suggests that there is indirect
neuroprotection with preservation of brain tissue.39 Similarly, there
The most common AE with teriflunomide is hepatotoxicity,37 and
liver function tests, potassium, creatinine, complete blood count
and uric acid levels should be monitored. Another new agent,
BG-12, is associated with gastrointestinal side effects and flushing
within the first 1–2 months of its initiation, which account for the
majority of its AEs.38 Natalizumab is associated with a risk of PML
6
The multidisciplinary approach to neurorehabilitation
is no experimental evidence for neuroprotection with natalizumab,
despite its robust effect on disability progression.22 Fingolimod also
slows disability progression and may have an anti-inflammatory
action that preserves brain tissue.15 BG-12, which showed some
evidence of neuroprotection in animal models and tissue cultures,
has not demonstrated this effect in patients, and its impact on
disability is unclear.17,18
Rehabilitation, explained Professor A. Thompson, is defined as
both an educational process and an active process of change by
which a person who has become disabled acquires and uses the
knowledge and skills necessary for optimal physical, psychological
and social function. Although it is difficult to assess interventions for
rehabilitation, a Cochrane review of multidisciplinary rehabilitation
identified seven randomized controlled trials that showed evidence
for durable gains in patient activity and participation, with some
evidence in gains in QoL and benefit to carers.46
Laquinimod affects disability progression, despite its lack of antiinflammatory action40; it is possible that it has a direct protective
effect on astrocytes. Alemtuzumab had positive effects on disability
progression in both the CARE-MS-I and CARE-MS-II trials,23,24
with some evidence that it induced the release of neurotrophic
factors. However, the results of this trial show an effect clearly
driven by very potent anti-inflammatory activity, not an actual
neuroprotective effect.
Resistance training in patients with MS increases patient activity,
with convincing effects on functional score, muscle strength and
mass, while having no AEs47 – all despite a long-held belief that
exercise is not good for patients with MS, making symptoms
worse when instead they should be focused on preserving energy.
However, it is unclear whether disease progression can itself be
slowed through exercise – while there is evidence for this in MRI,
patient-reported, and animal data, interventional studies do not
support this notion.
Ideally, we would have an MS treatment that would repair and
regenerate the brain, but this goal is a long way from achievement.
However, while available immunotherapies do not exhibit a direct
neuroprotective effect, early rescue of neurons and axons from
a toxic environment with DMDs may represent one of the key
mechanisms by which beneficial effects are achieved.
Several new approaches have been developed to improve
neurorehabilitation in patients with MS. Telecare systems, where
patients with MS are empowered to self-manage and avoid visits to
their physicians by using a remote care system utilizing dedicated
call centres staffed by specialist nurses, video-based clinics and
email support, have been shown to work extremely well.
Although we can achieve
indirect neuroprotection with
immunosuppressive agents early in
the disease course, there is no current
evidence that direct neuroprotection
is possible with any of the current
armamentarium of DMDs in the
clinical setting.
Cognitive impairment in MS is frequently underestimated, and
rehabilitation in this area is a challenge. Even diagnosis can
be problematic, as cognitive decline can be subtle, and patients
with a high cognitive reserve are protected from the effects of
brain atrophy.
Finally, vocational rehabilitation is important, but appears to be
a somewhat neglected strategy – surprising, given the effect that
MS has on the working life of a patient, with 50–80% of patients
unemployed within 10 years of diagnosis.48
Cell therapy
Dr M. Bacigaluppi gave an overview of the potential for stem cell
therapy in MS.
Symptoms management
Professor A. Thompson focused on three different areas of MS
symptom management: motor symptoms (including weakness,
mobility and spasticity), bladder dysfunction and cognitive
dysfunction (including mood disturbance and fatigue).
Different stem cell types have different potencies,41 and it is
possible to take differentiated cells from a patient and transform
them into pluripotent stem cells. Although this allows a promising
avenue of research for MS treatment, safety concerns remain,
particularly the development of neoplasms upon transplantation.
Therefore, only multipotent stem cells have been used thus far
and investigational therapies based on autologous haematopoietic
stem cell transplantation for MS and other severe autoimmune
diseases have proved clinically effective.42,43
Sustained-release oral dalfampridine is effective for the treatment
of MS-related motor symptoms, resulting in a significant and
consistent improvement in mean walking speed versus placebo,49
independent of baseline characteristics and concomitant
immunomodulatory therapy. Management strategies for motor
spasticity, caused by abnormal muscle tone resulted from
decreased descending inhibitory input and increased ascending
sensory excitation, are more complex, but various pharmacological
therapies are effective, including agents with a general effect, such
as baclofen, tizanidine, dantrolene, benzodiazepines, gabapentin
and cannabinoids, focal treatment with botulinum toxin and
regional nerve blocks, and finally intrathecal baclofen and phenol.
In the placebo-controlled CAMS study of cannabis extract, there
was a perceived benefit across several category rating scales,
including spasticity, sleep, pain and spasm, while there was no
benefit in terms of irritability, depression and tiredness.50
Neuronal precursor cells (NPCs), sourced from foetal brain tissue,
are another cell therapy approach. Transplanted NPCs exhibit
pathotropism, localizing areas of CNS inflammation, where they
promote remyelination44; in animal models, NPC treatment has
produced symptomatic improvement. However, NPCs are limited
by their source, which by its nature prevents autologous transplant.
Attempts have been made to derive NPCs from pluripotent stem
cells, created from skin cells taken by biopsy and reprogrammed.
These reprogrammed cells show the same characteristics as adult
NPCs, and in animal models have shown the same efficacy.
Mesenchymal stem cells (MSCs) can be easily isolated from any
connective tissue, representing an enormous advantage for obtaining
autologous cells. MSCs exert profound immunomodulatory effects,
reducing dendritic cells and increasing regulatory T cells, and
are currently being investigated in the Phase I/II multinational
MESEMS clinical trials.
Many pharmacological treatments are available for treatment of
bladder dysfunction, including desmopressin and onabotulinum-A
toxin. Onabotulinum-A toxin resulted in an improvement in urinary
urgency, frequency, incontinence and QoL in 43 patients with MS,51
requiring retreatment after a median of 42 weeks.
Several randomized trials have investigated the treatment of
memory problems associated with MS with various agents,
including donepezil, rivastigmine, memantine and ginkgo biloba; of
these, donepezil has shown the most promise.52 Two randomized
trials have investigated the use of desipramine and paroxetine to
Stem cells, therefore, represent an important form of MS
treatment, with cells derived from different tissues inducing
immunomodulation, resulting in indirect remyelination and
ultimately neuroprotection, a key treatment goal.45
7
and by keeping track of familial cases of the disease. Extreme or
unusual cases may be worth pursuing with genome sequencing,
such as MS with very early onset, very unusual symptom severity
or symptom combinations, and rapid progression.
treat depression in MS, both of which showed active treatment to
be effective in this population. Finally, fatigue, a major issue in
MS, can be difficult to manage, with many other factors such as
chronic pain and poor nutrition, as well as treatments themselves,
exacerbating the issue. Although currently no medicines have a
strong evidence base, some small clinical benefit may arise from
amantadine 200 mg/day.
Pharmacogenetics and pharmacogenomics
Continuing the discussion of the genetics of MS, Professor J.
Oksenberg defined pharmacogenomics as the study of how genetic
variation affects the response to drugs. Pharmacogenomics can
play an important role in identifying responders and non-responders
to medications, allowing optimization and personalization of
treatment. Moreover, drug response heterogeneity may reflect
distinct pathogenic mechanisms in different individuals with similar
phenotypes, and pharmacogenomics may also uncover novel
therapeutic targets. Additionally, as seen in other disease areas,54
pre-emptive genotyping can help identify preventable adverse
reactions to drugs. A recent study from Vanderbilt University
using a limited panel of drugs showed that approximately 1.5% of
AEs could be avoided with the application of pharmacogenomics
testing at the bedside54 – only a small effect, but important on
a per-patient basis. Indeed, about 10% of approved drugs now
contain pharmacogenomics data and recommendations in the
product label.
SESSION V: Genetics –
genomics – proteomics
From genotype to biology in MS
Opening the second day of the meeting, Professor D. Hafler
gave an overview of the genetics of MS and how they relate to
the phenotype seen in the clinic. Autoimmune diseases like MS
are not the result of mutations, but of common allelic variations,
each of which have only a small effect on disease risk but have a
cumulative biological impact. A number of common allelic variants
have so far been tabulated, revealing patterns of risk shared across
different immune-mediated diseases. Unfortunately, creation of
epigenetic maps and their analysis takes years, although several
genes, such as the Treg transcriptome in regulatory T cells, appear
to have a defect in MS. Additionally, MS susceptibility alleles have
been identified, including rs2300747.
Pharmacogenomic research in MS faces a number of specific
challenges. While studies in this area will provide useful information
for the selection of patient-matched therapy to maximize efficacy
and minimize AEs, MS is a complex disease, involving multiple genes
with individual modest effects, as well as the possible contribution
of rare mutations that may be responsible for individual responses
to treatment.55,56 The design of pharmacogenetic studies in MS
must, therefore, take many different factors into consideration,
foremost of which is ensuring an adequate sample size to provide
sufficient study power. Because of the large sample sizes needed
for such studies, pharmacogenomics research should ideally be
restructured into large international consortia.
The environment also has an impact on MS genomics. The
consumption of a high-salt diet drives autoimmune disease by
inducing pathogenic Th17 cells and the production of inflammatory
cytokines, and worsens disease in animal models of MS. Several
critical effector genes are induced by salt consumption, suggesting
that our high-salt diet contributes to the prevalence of MS –
although, importantly, it is highly unlikely that salt is the only
environmental factor.
As with other chronic autoimmune diseases, the pathogenesis
and progression of MS involves multiple genes with small effects
interacting with multiple environmental factors. It may be possible
in the future to predict disease risk or MS type with genetic
markers, leading to the suggestion that we may need to redefine
how we discuss disease, basing classifications around genetic
architecture and gene expression instead of organ systems and
their treatment.
Beyond genetics: integrating next generation
sequencing-based approaches
Following this introduction, Professor E. Stupka gave an overview of
a new approach in genetics applied to complex disorders, so-called
next generation genetic sequencing, which allows sequencing
of entire genomes in a few days. From limited samples, a vast
amount of information can be gathered, allowing investigation of
epigenomics. Next generation sequencing allows investigation
of a complex disease such as MS through the family trees of
affected families, quickly sequencing exons or whole genomes
to find causal variants – indeed, using such multi-omics familial
profiling, MS soon looks like a standard genetic disease, with
several genes and patterns of expression identified that convey risk
of MS. One example is the GRAMD1B gene, which is expressed in
the brain and the immune system, although little is known about
its function. An extremely rare novel variant is associated with
MS, with all subjects homozygous for the variant having MS.53
Work to further elucidate the role GRAMD1B plays in MS is
currently ongoing.
Because of the large sample
sizes needed for such studies,
pharmacogenomics research in MS
should ideally be restructured into
large international consortia.
How to translate knowledge into practice?
Professor G. Giovannoni concluded the session on MS genetics by
summarizing three examples of environmental and behavioural
factors that may interact with the genomic factors associated with
MS, and how these may be modified to mitigate the prevalence of MS.
Epstein–Barr virus (EBV) is associated with an increased risk of
MS,57 and although it is currently unclear how we might prevent
EBV infection, such a strategy in future could reduce the risk of
MS in many people.
It is clear that a relationship exists between MS and ultraviolet
light exposure. To become replete in vitamin D, and to maintain
immune function, ideally up to 10,000 units/day should be taken.
The European food safety authority has already recognized that
4000 units/day is a safe dosage but recommended daily allowances
in many countries fall short of this amount.
Smoking increases the risk of MS by 50%,58 but it is difficult to stop
young people taking up smoking, and there is still a worldwide
epidemic. Indeed, smoking is a strong example of the difficulties
in putting knowledge into practice, with 43 years elapsing between
the first reports of mortality in doctors who smoked (1954) and the
tobacco industry’s acknowledgement that there was a link between
smoking and death (1997).
Clearly, epigenetic analysis is becoming increasingly important to
help understand a complex disease like MS, and so far we have
only tapped into a small part of the human genome’s function.
To pursue epigenetics further, individual clinics can contribute
by maintaining well-organized biobanks of DNA, RNA and cells,
8
Education is key, particularly in the children of patients with MS.
If approached at an early age (6–12 years), it may be possible to
ingrain positive behaviours, such as adhering to a schedule of
vitamin D supplementation and refraining from smoking. While
MS is a complex disease, it is clear there are steps that can
be taken now, without waiting for data from clinical trials or
recommendations from public health authorities.
than in adult-onset MS, with more severe acute axonal damage.
MS in children has a progressive cognitive impact, and irreversible
disability is usually reached at an earlier age than in adult patients.
Paediatric MS represents 3–10% of the entire MS population,
explained Professor A. Ghezzi. While there have been few
randomized controlled trials investigating the use of DMDs in
children, first-line MS drugs are frequently used to treat children
and adolescents. Data on the use of DMDs in paediatric MS
comes mostly from observational studies, although two recent
consensus papers have critically reviewed the evidence and
proposed treatment strategies.71,72 The use of immunomodulators
in paediatric MS is effective and appears to be well tolerated; it is
recommended that treatment is initiated early in children with MS,
rather than delayed until adulthood.
SESSION VI: Paediatric MS
Environmental
phenotypes
and
genetic
factors/clinical
Opening the final session, Professor A. Yeh reviewed the clinical
phenotypes of paediatric MS, and its associated risk factors.
Paediatric demyelinating syndromes have an incidence of 0.6–
1.66/100,000, and 21–26% of cases are diagnosed with MS.59,60 One
major risk factor is age, with patients older than 11.85 years having
a 60.6% risk of their syndrome being MS.60
There are several options for second-line therapy in paediatric
patients. Natalizumab appears to be well tolerated and effective.
Mitoxantrone is also effective, although the IPMSSG discourages
the use of this agent in children owing to the risks of cardiotoxicity
and leukaemia. There is considerable experience with the use of
cyclophosphamide in other paediatric autoimmune diseases, and
while it is a viable option for some patients, close monitoring of
severe AEs should be a priority. Fingolimod, while approved for
the treatment of adult patients with MS, has no data regarding
the safety, efficacy and dosing in children – in particular, there are
concerns over its effects on thymic T-cell maturation and egress.
In general, second-line treatment should be considered within
the context of the risk–benefit ratio in paediatric patients, and
certainly more data are required to define the optimal strategies
in this population.
The disease course in children is relapsing–remitting in 93–100%
of patients, with 60% relapsing in the first year61; ARR and T1 lesion
burden tend to be greater in children than in adults.62
Several risk factors for paediatric MS have been identified,
including second-hand smoke from parents.63 Obesity is also
a risk factor; children with a very high body mass index have a
relative risk of 3.7 for MS.64,65 EBV is also associated with a higher
frequency of MS.66-69
Future work in paediatric MS will involve correlation of MRI and
structural lesions with outcomes, and investigation of DMDs,
cognitive rehabilitation, interventions for fatigue and depression,
and the role of remyelination strategies. Additionally, long-term
outcomes must be studied, along with functional outcomes related
to school.
The use of immunomodulators in
paediatric MS is effective and appears
to be well tolerated; it is recommended
that treatment is initiated early, rather
than delayed until adulthood.
How difficult is the diagnosis of MS in children?
Diagnosis of childhood MS is challenging because signs and
symptoms tend to be different from those seen in adults, limiting
the utility of established diagnostic criteria, explained Professor S.
Tenembaum. However, recommendations for diagnosis in children
are broadly based on the McDonald criteria, with no lower age
limit. As with adult MS, MRI findings can now be used to meet the
DIS and DIT requirements, except in the context of an ADEM-like
presentation and in children younger than 12 years. Additionally,
the International Paediatric MS Study Group (IPMSSG) criteria for
paediatric MS and immune-mediated CNS inflammatory disorders
were recently updated.70
Critical analysis of clinical trials: assessing
therapeutic value
Closing the 2013 meeting, Professor D. Goodin returned to
discuss issues surrounding the interpretation of statistical output
from clinical trials, reminding the audience of the concepts and
definitions of significance, effect size and bias. Post hoc data
manipulation and inadvertent introduction of bias can affect the
design, conduct and analysis of clinical trial data, eroding its value
as evidence-based medicine. We must, therefore, interpret trial
results with caution before applying them to clinical practice.
It is important to differentiate MS from other MS-like diseases in
children. In particular, several atypical neurological findings may be
suggestive of other conditions in this patient population (Figure 4).
Atypical neurological findings
Considerations
Hearing loss
Susac syndrome
Headache
CNS vasculitis, Susac syndrome
Hypothalamic symptoms
NMO, neurosarcoidosis
Brain stem syndrome
NMO, pontine glioma
Longitudinal extensive
myelopathy
NMO, B12 or copper deficiency,
Alexander disease (juvenile)
Severe or recurrent optic
neuropathy
NMO, LHON
Treatment recommendations for paediatric MS
To accurately assess clinical trial data, studies can be classified
into four groups, based on various study characteristics. In tandem
with this, the level of evidence from clinical trials can be pooled and
classified into three primary levels of recommendation, depending
upon the pool of trial data available and its quality.73
Figure 4. Examples of atypical neurological findings in children that may be
suggestive of CNS diseases other than MS.
Finally, Professor Goodin outlined the comparative strengths
and weaknesses of methods used to compare the efficacy of
MS drugs using data from different trials. Comparing relative
risks of outcomes is a reasonably transparent approach, but can
exaggerate small differences. The number needed to treat has
the advantage of being an absolute, rather than relative measure,
and has the clear advantage of being applicable to cost–benefit
analyses, which can be useful in setting societal priorities –
although it is important not to confuse cost–benefit with efficacy.
Early diagnosis is also essential in children, as the disease occurs
during key periods of brain growth, active primary myelination and
maturation of neural networks. MS disease activity is also higher
Professor Goodin concluded that, although all statistical
methodologies have their advantages and disadvantages, caution
should be exercised when comparing trials in the absence of
head-to-head studies.
LHON, Leber’s hereditary optic neuropathy
9
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