2013 CME Annual meeting in multiple sclerosis “How to ... › sites › default › files › ne...Gavin Giovannoni Department of Neurology The Royal London Hospital Whitechapel,

2013 CME Annual meeting in multiple sclerosis

ldquoHow to translate new insights in MS into clinical practicerdquo

Istanbul TurkeyHighlights MayJune 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 ldquoHow to translate new insights in MS into clinical practicerdquo 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

1

Contents

Faculty 2

SESSION I MS before MS ndash differential diagnosis 3

SESSION II Treatment issues management today ndash part 1 4

SESSION III Treatment issues management today ndash part 2 5

SESSION IV How to implement recovery processes and brain plasticity 6

SESSION V Genetics ndash genomics ndash proteomics 8

SESSION VI Paediatric MS 9

References 10

2

FacultyDavid 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 Duumlsseldorf German

Ludwig Kappos Neurology and Department of Biomedicine University Hospital Basel Basel Switzerland

Rana Karabudak University Hospital Department of Neurology Neuroimmunology Unit Ankara Turkey

Bernd Kieseier Department of Neurology Heinrich-Heine University Duumlsseldorf Germany

Jeffrey A Kleim School of Biological and Health Systems Engineering Arizona State University Tempe USA

Dawn Langdon Department of Psychology Royal Holloway University of London London UK

Xavier Montalban Multiple Sclerosis Center of Catalonia Unit of Clinical Neuroimmunology Vall drsquoHebron University Hospital Barcelona Spain

Jorge Oksenberg Department of Neurology University of California at San Francisco (UCSF) San Francisco CA USA

Peter Rieckmann Bamberg Hospital and University of Erlange Bamberg Germany

Aksel Siva Department of Neurology Cerrahpasa School of Medicine of Istanbul University Istanbul Turkey

Maria Pia Sormani University of Genoa Genoa ItalyUnfortunately Professor Sormani was unable to attend the meeting

Elia Stupka Unit Center for Translational Genomics and Bioinformatics San Raffaele Scientific Institute Milan Italy

Silvia Tenembaum Department of Neurology National Pediatric Hospital ndash ldquoDr Juan Garrahanrdquo Buenos Aires Argentina

Alan J Thompson Department of Brain Repair and Rehabilitation Institute of Neurology University College London National Hospital for Neurology and Neurosurgery London UK

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

3

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 demyelination9

Marburgrsquos 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

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 constructed10

McDonald criteria

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

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 ndash 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 MS11 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

Diagnosis communication and patientsrsquo coping

strategies

Professor D Langdon pointed out that receiving a diagnosis of MS is a major event in a patientrsquos life with mood and quality of life (QoL) immediately affected12 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

SESSION I MS before MS ndash differential diagnosisEarly diagnosis (RISCIS)

Professor X Montalban opened with an overview of two difficult-to-diagnose early conditions radiologically isolated syndrome (RIS) and clinically isolated syndrome (CIS) Overall about 85 of patients with multiple sclerosis (MS) initially present with CIS12 which describes the first clinical manifestation of inflammation or demyelination in the central nervous system (CNS)

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 headache3 The real prevalence of subclinical MS is a matter of debate with historical autopsy studies from undiagnosed individuals showing a prevalence of ~014-6 while MRI studies have shown that 006 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 years3

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

Differential diagnosis MS and acquired demyelinating disorders

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

Balograversquos 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

Figure 1 Differential features of NMO and MS8

NMO MS

Course Monophasic or relapsing

Relapsing

Attack severity Severe Mild

MRI head Normal non-specific Multiple lesions

CSF cells Pleocytosis Rarely gt25 cells

CSF OGB Absent Present

Female 80ndash90 60ndash70

Pathology Prominent necrosis Demyelination

CSF cerebrospinal fluid OGB oligoclonal bands

Until we are able to definitively and reliably diagnose MS with a single

test we will always need diagnostic criteria

4

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

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 lsquothreatrsquo 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 patientndashphysician communication

SESSION II Treatment issues management today ndash part 1Do 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 ndash 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 lsquoreserversquo of functional tissue Patients who sustain a greater early reduction in their reserve are more likely to progress faster

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

Although interferon (IFN) beta and glatiramer acetate (GA) are recognized as the mainstay of treatment for relapsingndashremitting 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 studies13 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

Oral drugs

Professor L Kappos led the audience through a summary of the major new oral agents

All three major trials of fingolimod ndash two comparing with placebo one with intramuscular IFN beta-1a once weekly ndash 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 trials14-16 The FREEDOMS extension study also showed that the attenuating effect on brain atrophy persisted to 4 years16 The safety profile of fingolimod was also reassuring long-term data are however still required

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 progression1718 Positive MRI outcomes were also observed although the data on brain atrophy was less convincing The main tolerability issues were flushing and abdominal complaints

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 dose19 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 studies20 laquinomod was associated with a 21 reduction in ARR versus placebo (p=00005) 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

Antibodies in MS

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 placebo2122 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

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-1a2324

In the DAC HYP SELECT Phase IIb registration trial the humanized monoclonal antibody daclizumab resulted in a 50ndash54 reduction in the ARR versus placebo as well as significant reductions in disability progression25 The increase in CD56bright cell population after treatment predicted which patients would develop the fewest new T2 lesions suggesting potential as a therapeutic response marker26 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 RRMS27 Another CD20-targeted 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 relapses28 Ocrelizumab is currently in Phase III trials

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 MS29 and there are currently Phase I and II clinical trials underway in acute optic neuritis and RRMS

Monoclonal antibody therapy should allow almost surgical precision

for MS treatment

5

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 patientrsquos first therapy is a very individual one which must be made in consultation with the patient considering many factors

It is also important to recognize that MS is a serious disease and that treatment as early as possible is essential ndash the so-called lsquowindow of opportunityrsquo which has a profound impact on long-term outcomes is small (Figure 2)

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 agents3031 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 Ziemssen concluded by reminding the audience that the successful management of MS requires early treatment as ldquowhat is lost cannot be brought backrdquo 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

SESSION III Treatment issues management today ndash part 2Long-term benefit of current DMDs on disability progression experience from clinical trials and clinical practice

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 ndash 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

One example of the biases seen in LTFU studies comes from the 15-year LTFU study of GA32 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 GA33

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

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 death34 and it seems likely that other DMDs that impact the same short-term outcomes are also associated with similar benefits although this remains to be demonstrated

When and how to switch from one therapy to another

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 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 05 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

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 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

Neu

rolo

gica

l dis

abili

ty

lsquoWindow of opportunityrsquo

Latetreatment

Natural history

Late treatmentEarlytreatment

Early treatment

Figure 2 The concept of early treatment and the lsquowindow of opportunityrsquo

6

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 life-long nature of therapy Long-term treatment is associated with many risks which can be mitigated with patient education and careful monitoring

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 factors35 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

Fingolimod requires more work-up prior to initiation and during the first administration and is associated with more AEs particularly lymphopenia A lymphocyte count lt200 cellsmL 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 3ndash4 months after initiation of the drug an ophthalmological examination should be conducted around this time36 Fingolimod cessation usually results in resolution of oedema and return of vision

The most common AE with teriflunomide is hepatotoxicity37 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 1ndash2 months of its initiation which account for the majority of its AEs38 Natalizumab is associated with a risk of PML

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

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 ndash it is essential that the riskndashbenefit profiles of candidate treatments be carefully assessed for each patient

SESSION IV How to implement recovery processes and brain plasticityNew 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

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

In additional to behavioural rehabilitation techniques adjuvant therapies ndash such as drug treatment or electro-stimulation ndash can help to improve the neural signal component of plasticity

In summary therapy can optimize neural plasticity ndash 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

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 tissue39 Similarly there

A

B

Escalating therapy

Induction therapy

5th line therapy

4th line therapy

3rd line therapy

2nd line therapy

1st line therapy

Moreaggressiveapproach

BMT

AlemtuzumabRituximab

Mitoxantrone Cyclophosphamide

Natalizumab

IFN betas GALaquinimod BG-12 Teriflunomide italicFin

golimod

4th line therapy

3rd line therapy

2nd line therapy

1st line therapy

BMT

Combinationtherapy

Natalizumab IFN GALaquinimod Teriflunomide BG-12

Mitoxantrone CyclophosphamideFingolimod Alemtuzumab Rituximab

Figure 3 Concepts for (A) escalation and (B) induction therapy

While physicians should be attentive to the safety issues surrounding MS treatments the probability of

AEs should not mean that therapies are withheld

7

is no experimental evidence for neuroprotection with natalizumab despite its robust effect on disability progression22 Fingolimod also slows disability progression and may have an anti-inflammatory action that preserves brain tissue15 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 unclear1718

Laquinimod affects disability progression despite its lack of anti-inflammatory 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 trials2324 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

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

Cell therapy

Dr M Bacigaluppi gave an overview of the potential for stem cell therapy in MS

Different stem cell types have different potencies41 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 effective4243

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 III multinational MESEMS clinical trials

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 goal45

The multidisciplinary approach to neurorehabilitation

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 carers46

Resistance training in patients with MS increases patient activity with convincing effects on functional score muscle strength and mass while having no AEs47 ndash 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 ndash while there is evidence for this in MRI patient-reported and animal data interventional studies do not support this notion

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

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 ndash surprising given the effect that MS has on the working life of a patient with 50ndash80 of patients unemployed within 10 years of diagnosis48

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)

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 placebo49 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 tiredness50

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 MS51 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 promise52 Two randomized trials have investigated the use of desipramine and paroxetine to

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

8

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 mgday

SESSION V Genetics ndash genomics ndash proteomicsFrom 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

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 ndash 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 ndash 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 MS53

Work to further elucidate the role GRAMD1B plays in MS is currently ongoing

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 genomersquos function To pursue epigenetics further individual clinics can contribute by maintaining well-organized biobanks of DNA RNA and cells

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

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 areas54 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 15 of AEs could be avoided with the application of pharmacogenomics testing at the bedside54 ndash 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

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 treatment5556 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

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

EpsteinndashBarr virus (EBV) is associated with an increased risk of MS57 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 10000 unitsday should be taken The European food safety authority has already recognized that 4000 unitsday is a safe dosage but recommended daily allowances in many countries fall short of this amount

Smoking increases the risk of MS by 5058 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 industryrsquos acknowledgement that there was a link between smoking and death (1997)

Because of the large sample sizes needed for such studies

pharmacogenomics research in MS should ideally be restructured into

large international consortia

9

Education is key particularly in the children of patients with MS If approached at an early age (6ndash12 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

SESSION VI Paediatric MSEnvironmental and genetic factorsclinical phenotypes

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 06ndash166100000 and 21ndash26 of cases are diagnosed with MS5960 One major risk factor is age with patients older than 1185 years having a 606 risk of their syndrome being MS60

The disease course in children is relapsingndashremitting in 93ndash100 of patients with 60 relapsing in the first year61 ARR and T1 lesion burden tend to be greater in children than in adults62

Several risk factors for paediatric MS have been identified including second-hand smoke from parents63 Obesity is also a risk factor children with a very high body mass index have a relative risk of 37 for MS6465 EBV is also associated with a higher frequency of MS66-69

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

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 updated70

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)

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

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

Treatment recommendations for paediatric MS

Paediatric MS represents 3ndash10 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 strategies7172 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

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 ndash 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 riskndashbenefit ratio in paediatric patients and certainly more data are required to define the optimal strategies in this population

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

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 quality73

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 costndashbenefit analyses which can be useful in setting societal priorities ndash although it is important not to confuse costndashbenefit with efficacy

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

Figure 4 Examples of atypical neurological findings in children that may be suggestive of CNS diseases other than MS

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

LHON Leberrsquos hereditary optic neuropathy

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

10

References1 Comi G De Stefano N Freedman MS et al Comparison of

two dosing frequencies of subcutaneous interferon beta-1a in patients with a first clinical demyelinating event suggestive of multiple sclerosis (REFLEX) a phase 3 randomised controlled trial Lancet Neurol 2012 11 33-41

2 Kappos L Polman CH Freedman MS et al Treatment with interferon beta-1b delays conversion to clinically definite and McDonald MS in patients with clinically isolated syndromes Neurology 2006 67 1242-9

3 Granberg T Martola J Kristoffersen-Wiberg M et al Radiologically isolated syndrome - incidental magnetic resonance imaging findings suggestive of multiple sclerosis a systematic review Mult Scler 2013 19 271-80

4 Brinar VV Diagnostic and therapeutic dilemmas Clin Neurol Neurosurg 2004 106 180-6

5 Engell T A clinical patho-anatomical study of clinically silent multiple sclerosis Acta Neurol Scand 1989 79 428-30

6 Gilbert JJ Sadler M Unsuspected multiple sclerosis Arch Neurol 1983 40 533-6

7 Tienari PJ Salonen O Wikstrom J et al Familial multiple sclerosis MRI findings in clinically affected and unaffected siblings J Neurol Neurosurg Psychiatry 1992 55 883-6

8 Weinshenker BG Neuromyelitis optica what it is and what it might be Lancet 2003 361 889-90

9 Masaki K Suzuki SO Matsushita T et al Extensive loss of connexins in Balorsquos disease evidence for an auto-antibody-independent astrocytopathy via impaired astrocyte-oligodendrocytemyelin interaction Acta Neuropathol 2012 123 887-900

10 Marchioni E Tavazzi E Franciotta D Ravaglia S Recurrent ADEM versus MS differential diagnostic criteria Neurol Res 2008 30 74

11 Whiting P Harbord R Main C et al Accuracy of magnetic resonance imaging for the diagnosis of multiple sclerosis systematic review BMJ 2006 332 875-84

12 Mattarozzi K Vignatelli L Baldin E et al Effect of the disclosure of MS diagnosis on anxiety mood and quality of life of patients a prospective study Int J Clin Pract 2012 66 504-14

13 Compston A Coles A Multiple sclerosis Lancet 2002 359 1221-31

14 Cohen JA Barkhof F Comi G et al Oral fingolimod or intramuscular interferon for relapsing multiple sclerosis N Engl J Med 2010 362 402-15

15 Kappos L Radue EW OrsquoConnor P et al A placebo-controlled trial of oral fingolimod in relapsing multiple sclerosis N Engl J Med 2010 362 387-401

16 Kappos L Radue EW OrsquoConnor P Long-term efficacy and safety of fingolimod (FTY720) in relapsing-remitting multiple sclerosis (RRMS) results from the extension of the Phase III FREEDOMS study Neurology 2012 78 S41004

17 Fox RJ Miller DH Phillips JT et al Placebo-controlled phase 3 study of oral BG-12 or glatiramer in multiple sclerosis N Engl J Med 2012 367 1087-97

18 Gold R Kappos L Arnold DL et al Placebo-controlled phase 3 study of oral BG-12 for relapsing multiple sclerosis N Engl J Med 2012 367 1098-107

19 OrsquoConnor P Wolinsky JS Confavreux C et al Randomized trial of oral teriflunomide for relapsing multiple sclerosis N Engl J Med 2011 365 1293-303

20 Vollmer T Comi G Sorensen PS Clinical efficacy of laquinimod for the treatment of multiple sclerosis pooled analyses from the ALLEGRO and BRAVO Phase III trials Neurology 2012 78 S01007

21 Havrdova E Galetta S Hutchinson M et al Effect of natalizumab on clinical and radiological disease activity in multiple sclerosis a retrospective analysis of the Natalizumab Safety and Efficacy in Relapsing-Remitting Multiple Sclerosis (AFFIRM) study Lancet Neurol 2009 8 254-60

22 Polman CH OrsquoConnor PW Havrdova E et al A randomized placebo-controlled trial of natalizumab for relapsing multiple sclerosis N Engl J Med 2006 354 899-910

23 Cohen JA Coles AJ Arnold DL et al Alemtuzumab versus interferon beta 1a as first-line treatment for patients with relapsing-remitting multiple sclerosis a randomised controlled phase 3 trial Lancet 2012 380 1819-28

24 Coles AJ Twyman CL Arnold DL et al Alemtuzumab for patients with relapsing multiple sclerosis after disease-modifying therapy a randomised controlled phase 3 trial Lancet 2012 380 1829-39

25 Gold R Giovannoni G Selmaj K A randomized double-blind placebo-controlled study to evaluate the safety and efficacy of daclizumab HYP monotherapy in relapsing-remitting multiple sclerosis primary results of the SELECT trial Neurology 2012 78 S01005

26 Elkins J Sheridan J Amaravadi L CD56bright natural killer cell expansion predicts response to daclizumab HYP treatment in RRMS results of the SELECT trial Neurology 2012 78 S31004

27 Hauser SL Waubant E Arnold DL et al B-cell depletion with rituximab in relapsing-remitting multiple sclerosis N Engl J Med 2008 358 676-88

28 Kappos L Li D Calabresi PA et al Ocrelizumab in relapsing-remitting multiple sclerosis a phase 2 randomised placebo-controlled multicentre trial Lancet 2011 378 1779-87

29 Kotter MR Stadelmann C Hartung HP Enhancing remyelination in diseasendashcan we wrap it up Brain 2011 134 1882-900

30 Finkelsztejn A Gabbai AA Fragoso YD et al Latin American algorithm for treatment of relapsing-remitting multiple sclerosis using disease-modifying agents Arq Neuropsiquiatr 2012 70 799-806

31 Rio J Comabella M Montalban X Multiple sclerosis current treatment algorithms Curr Opin Neurol 2011 24 230-7

32 Ford C Goodman AD Johnson K et al Continuous long-term immunomodulatory therapy in relapsing multiple sclerosis results from the 15-year analysis of the US prospective open-label study of glatiramer acetate Mult Scler 2010 16 342-50

33 Johnson KP Brooks BR Ford CC et al Sustained clinical benefits of glatiramer acetate in relapsing multiple sclerosis patients observed for 6 years Copolymer 1 Multiple Sclerosis Study Group Mult Scler 2000 6 255-66

34 Goodin DS Reder AT Ebers GC et al Survival in MS a randomized cohort study 21 years after the start of the pivotal IFN beta-1b trial Neurology 2012 78 1315-22

35 Tremlett HL Oger J Elevated aminotransferases during treatment with interferon-beta for multiple sclerosis actions and outcomes Mult Scler 2004 10 298-301

11

36 Novartis Pharmaceuticals GILENYA prescribing information httpwwwpharmausnovartiscomproductpipdfgilenyapdf (Accessed 12 June 2013)

37 Tanasescu R Evangelou N Constantinescu CS Role of oral teriflunomide in the management of multiple sclerosis Neuropsychiatr Dis Treat 2013 9 539-53

38 Biogen Idec TECFIDERA (dimethyl fumarate) prescribing information httpwwwtecfideracompdfsfull-prescribing -informationpdf (Accessed 12 June 2013)

39 PRISMS Study Group Randomised double-blind placebo-controlled study of interferon beta-1a in relapsingremitting multiple sclerosis Lancet 1998 352 1498-504

40 Comi G Jeffery D Kappos L et al Placebo-controlled trial of oral laquinimod for multiple sclerosis N Engl J Med 2012 366 1000-9

41 Pluchino S Zanotti L Brini E et al Regeneration and repair in multiple sclerosis the role of cell transplantation Neurosci Lett 2009 456 101-6

42 Mancardi G Saccardi R Autologous haematopoietic stem-cell transplantation in multiple sclerosis Lancet Neurol 2008 7 626-36

43 Tyndall A Successes and failures of stem cell transplantation in autoimmune diseases Hematology Am Soc Hematol Educ Program 2011 2011 280-4

44 Pluchino S Quattrini A Brambilla E et al Injection of adult neurospheres induces recovery in a chronic model of multiple sclerosis Nature 2003 422 688-94

45 Taveggia C Feltri ML Wrabetz L Signals to promote myelin formation and repair Nat Rev Neurol 2010 6 276-87

46 Khan F Turner-Stokes L Ng L Kilpatrick T Multidisciplinary rehabilitation for adults with multiple sclerosis Cochrane Database Syst Rev 2007 2 CD006036

47 Dalgas U Stenager E Jakobsen J et al Resistance training improves muscle strength and functional capacity in multiple sclerosis Neurology 2009 73 1478-84

48 Rao SM Leo GJ Ellington L et al Cognitive dysfunction in multiple sclerosis II Impact on employment and social functioning Neurology 1991 41 692-6

49 Goodman AD Brown TR Krupp LB et al Sustained-release oral fampridine in multiple sclerosis a randomised double-blind controlled trial Lancet 2009 373 732-8

50 Zajicek J Fox P Sanders H et al Cannabinoids for treatment of spasticity and other symptoms related to multiple sclerosis (CAMS study) multicentre randomised placebo-controlled trial Lancet 2003 362 1517-26

51 Kalsi V Gonzales G Popat R et al Botulinum injections for the treatment of bladder symptoms of multiple sclerosis Ann Neurol 2007 62 452-7

52 Krupp LB Christodoulou C Melville P et al Donepezil improved memory in multiple sclerosis in a randomized clinical trial Neurology 2004 63 1579-85

53 Boneschi FM Esposito F Cittaro D A novel multiple sclerosis susceptibility variant in the GRAMD1B gene Neurology 2013 80 P05136

54 Schildcrout JS Denny JC Bowton E et al Optimizing drug outcomes through pharmacogenetics a case for preemptive genotyping Clin Pharmacol Ther 2012 92 235-42

55 Goertsches RH Zettl UK Hecker M Sieving treatment biomarkers from blood gene-expression profiles a pharmacogenomic update on two types of multiple sclerosis therapy Pharmacogenomics 2011 12 423-32

56 Vandenbroeck K Urcelay E Comabella M IFN-beta pharmacogenomics in multiple sclerosis Pharmacogenomics 2010 11 1137-48

57 Ascherio A Munger KL Environmental risk factors for multiple sclerosis Part I the role of infection Ann Neurol 2007 61 288-99

58 Handel AE Giovannoni G Ebers GC Ramagopalan SV Environmental factors and their timing in adult-onset multiple sclerosis Nat Rev Neurol 2010 6 156-66

59 Banwell B Kennedy J Sadovnick D et al Incidence of acquired demyelination of the CNS in Canadian children Neurology 2009 72 232-9

60 Banwell B Bar-Or A Arnold DL et al Clinical environmental and genetic determinants of multiple sclerosis in children with acute demyelination a prospective national cohort study Lancet Neurol 2011 10 436-45

61 Gorman MP Healy BC Polgar-Turcsanyi M Chitnis T Increased relapse rate in pediatric-onset compared with adult-onset multiple sclerosis Arch Neurol 2009 66 54-9

62 Yeh EA Weinstock-Guttman B Ramanathan M et al Magnetic resonance imaging characteristics of children and adults with paediatric-onset multiple sclerosis Brain 2009 132 3392-400

63 Mikaeloff Y Caridade G Tardieu M Suissa S Parental smoking at home and the risk of childhood-onset multiple sclerosis in children Brain 2007 130 2589-95

64 Langer-Gould A Brara SM Beaber BE Koebnick C Childhood obesity and risk of pediatric multiple sclerosis and clinically isolated syndrome Neurology 2013 80 548-52

65 Munger KL Chitnis T Ascherio A Body size and risk of MS in two cohorts of US women Neurology 2009 73 1543-50

66 Alotaibi S Kennedy J Tellier R et al Epstein-Barr virus in pediatric multiple sclerosis JAMA 2004 291 1875-9

67 Banwell B Tellier R Krupp L Viral exposures in pediatric multiple sclerosis preliminary data from a multinational collaborative study Mult Scler 2004 10(Suppl 5) S97-283

68 Pohl D Krone B Rostasy K et al High seroprevalence of Epstein-Barr virus in children with multiple sclerosis Neurology 2006 67 2063-5

69 Pohl D Rostasy K Jacobi C et al Intrathecal antibody production against Epstein-Barr and other neurotropic viruses in pediatric and adult onset multiple sclerosis J Neurol 2010 257 212-6

70 Krupp LB Tardieu M Amato MP et al International Pediatric Multiple Sclerosis Study Group criteria for pediatric multiple sclerosis and immune-mediated central nervous system demyelinating disorders revisions to the 2007 definitions Mult Scler 2013 doi 1011771352458513484547

71 Chitnis T Tenembaum S Banwell B et al Consensus statement evaluation of new and existing therapeutics for pediatric multiple sclerosis Mult Scler 2012 18 116-27

72 Ghezzi A Banwell B Boyko A et al The management of multiple sclerosis in children a European view Mult Scler 2010 16 1258-67

73 Goodin DS Disease-modifying therapy in MS a critical review of the literature Part II assessing efficacy and dose-response J Neurol 2004 251(Suppl 5) v50-6

12Copyright copy Serono Symposia International Foundation 2013 All rights reserved

Improving the patientrsquos life through medical educationwwwseronosymposiaorg

Serono Symposia International Foundation

Headquarters Serono Symposia International Foundation 14 Rue du Rhone 1204 Geneva Switzerland

Representative OfficeSalita di San Nicola da Tolentino 1B 00187 Rome Italy T +39064204131 F +3906420413677

2

FacultyDavid 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 Duumlsseldorf German

Ludwig Kappos Neurology and Department of Biomedicine University Hospital Basel Basel Switzerland

Rana Karabudak University Hospital Department of Neurology Neuroimmunology Unit Ankara Turkey

Bernd Kieseier Department of Neurology Heinrich-Heine University Duumlsseldorf Germany

Jeffrey A Kleim School of Biological and Health Systems Engineering Arizona State University Tempe USA

Dawn Langdon Department of Psychology Royal Holloway University of London London UK

Xavier Montalban Multiple Sclerosis Center of Catalonia Unit of Clinical Neuroimmunology Vall drsquoHebron University Hospital Barcelona Spain

Jorge Oksenberg Department of Neurology University of California at San Francisco (UCSF) San Francisco CA USA

Peter Rieckmann Bamberg Hospital and University of Erlange Bamberg Germany

Aksel Siva Department of Neurology Cerrahpasa School of Medicine of Istanbul University Istanbul Turkey

Maria Pia Sormani University of Genoa Genoa ItalyUnfortunately Professor Sormani was unable to attend the meeting

Elia Stupka Unit Center for Translational Genomics and Bioinformatics San Raffaele Scientific Institute Milan Italy

Silvia Tenembaum Department of Neurology National Pediatric Hospital ndash ldquoDr Juan Garrahanrdquo Buenos Aires Argentina

Alan J Thompson Department of Brain Repair and Rehabilitation Institute of Neurology University College London National Hospital for Neurology and Neurosurgery London UK

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

3




McDonald criteria





strategies











NMO MS


Relapsing










4







Oral drugs






Antibodies in MS







for MS treatment

5
















Neu

rolo

gica

l dis

abili

ty


Latetreatment

Natural history


Early treatment


6













Neuroprotection



A

B

Escalating therapy

Induction therapy

5th line therapy

4th line therapy

3rd line therapy

2nd line therapy

1st line therapy


BMT



Natalizumab


golimod

4th line therapy

3rd line therapy

2nd line therapy

1st line therapy

BMT

Combinationtherapy






7




Cell therapy












Symptoms management









8






















9





























NMO LHON





10





































11












































3




McDonald criteria





strategies











NMO MS


Relapsing










4







Oral drugs






Antibodies in MS







for MS treatment

5
















Neu

rolo

gica

l dis

abili

ty


Latetreatment

Natural history


Early treatment


6













Neuroprotection



A

B

Escalating therapy

Induction therapy

5th line therapy

4th line therapy

3rd line therapy

2nd line therapy

1st line therapy


BMT



Natalizumab


golimod

4th line therapy

3rd line therapy

2nd line therapy

1st line therapy

BMT

Combinationtherapy






7




Cell therapy












Symptoms management









8






















9





























NMO LHON





10





































11












































4







Oral drugs






Antibodies in MS







for MS treatment

5
















Neu

rolo

gica

l dis

abili

ty


Latetreatment

Natural history


Early treatment


6













Neuroprotection



A

B

Escalating therapy

Induction therapy

5th line therapy

4th line therapy

3rd line therapy

2nd line therapy

1st line therapy


BMT



Natalizumab


golimod

4th line therapy

3rd line therapy

2nd line therapy

1st line therapy

BMT

Combinationtherapy






7




Cell therapy












Symptoms management









8






















9





























NMO LHON





10





































11












































5
















Neu

rolo

gica

l dis

abili

ty


Latetreatment

Natural history


Early treatment


6













Neuroprotection



A

B

Escalating therapy

Induction therapy

5th line therapy

4th line therapy

3rd line therapy

2nd line therapy

1st line therapy


BMT



Natalizumab


golimod

4th line therapy

3rd line therapy

2nd line therapy

1st line therapy

BMT

Combinationtherapy






7




Cell therapy












Symptoms management









8






















9





























NMO LHON





10





































11












































6













Neuroprotection



A

B

Escalating therapy

Induction therapy

5th line therapy

4th line therapy

3rd line therapy

2nd line therapy

1st line therapy


BMT



Natalizumab


golimod

4th line therapy

3rd line therapy

2nd line therapy

1st line therapy

BMT

Combinationtherapy






7




Cell therapy












Symptoms management









8






















9





























NMO LHON





10





































11












































7




Cell therapy












Symptoms management









8






















9





























NMO LHON





10





































11












































8






















9





























NMO LHON





10





































11












































9





























NMO LHON





10





































11












































10





































11












































11

















































Documents

2013 CME Annual meeting in multiple sclerosis “How to ... › sites › default › files › ne...Gavin Giovannoni Department of Neurology The Royal London Hospital Whitechapel,