Abstract
Teaching Courses
TC1 - Current controversy in management: Interactive case discussion
1Icahn School of Medicine at Mount Sinai, Neurology, New York, NY, United States, 2University Hospital Vall d’Hebron, Neurology-Neuroimmunology, Barcelona, Spain
Two highly experienced MS physicians address a series of highly controversial issues in the management of patients with MS, using the format of case discussions with an audience response system to enable participants to express their own opinions about management and to compare them immediately with those of their peers, as well as the faculty. The course will be very practical, particularly emphasizing treatment decisions.
The faculty will address selection of specific disease-modifying therapy (DMT) for individual patients, emphasizing prognostic factors and risk-benefit analysis, particularly with regard to the use of natalizumab. They will also indicate their approach to the current controversy surrounding management of risk factors, including Vitamin D, smoking, and dietary factors, including salt. The course will also address the difficult decisions about when to switch DMT and what agent(s) to consider. In a discussion of progressive MS, the faculty will not only discuss the controversial use of DMTs, but will also review important areas of symptom management. Should clinicians prescribe cannabinoids for spasticity or pain? Is the use of fampridine (dalfampridine) worthwhile for gait disturbance? Is there a role for cognitive rehabilitation in patients with MS?
Controversy is not confined to therapeutics alone. Diagnostic issues such as the radiologically isolated syndrome and clinically isolated syndrome will be considered. The classification of MS phenotypes as relapsing-remitting, secondary progressive, primary progressive, and progressive-relapsing, widely used for nearly 20 years, has recently been revised. The faculty will bring course participants up to speed on this brand new schema.
By the end of the course, participants will have gained greater understanding of these areas of clinical controversy. They will have made their own decisions and seen how these compare with those of their peers and of the faculty. Registrants will have better insight into the nuances of DMT selection, the new diagnostic classification, and specific symptom management. They will also gain greater understanding of which clinical areas have more controversy than consensus and vice versa.
TC2 - How do I choose the correct disease-modifying treatment?
TC2.1 Treating CIS and early RRMS: pros and cons
1Stanford University, Neurology, Stanford, CA, United States
The 2010 McDonald diagnostic criteria for MS allow us to be able to diagnose MS accurately and more rapidly than in the past with fewer clinical attacks and fewer MRIs. This has created the opportunity to treat patients with disease-modifying therapy (DMT) early in their disease course. Clinically isolated syndrome (CIS) is a central nervous system demyelinating event isolated in time that is compatible with the possible future development of MS. Patients that present with a CIS raise challenging questions regarding when to initiate therapy. Early risk stratification for conversion to MS helps with treatment decisions. Several clinical trials of DMTs in CIS patients have shown that four of the first-line injectable DMTs delay the conversion to clinically definite MS (CDMS) and reduce the number of new MRI lesions. This has encouraged some neurologists to recommend initiating DMTs for CIS patients. We will review the current definitions of CIS and CDMS, possible neurodiagnostics that can assist in risk stratification, and the evidence demonstrating possible benefits DMTs may afford both groups of patients. We will also consider the possible risks doctors and their patients take on with early DMT initiation.
TC2.2 Choosing the right treatment for the right patient
1Cleveland Clinic, Mellen Center for MS, Cleveland, OH, United States
Despite few head-to-head comparison treatment trials, the comparability of many long-term MS disease modifying agents is emerging, which in turn is helping to guide treatment choice. Patients need to develop appropriate expectations regarding the anticipated benefits of therapy. Despite apparent differences in efficacy at the population level, predictors of treatment response at the individual patient level are generally lacking. However, risk stratification has become an important component in choosing treatment in individual patients. Risk mitigation strategies can be used to reduce the chances of many serious complications associated with MS disease modifying therapies. Risk mitigation includes assessments prior to treatment initiation and over the course of treatment. With the ultimate goal of personalized disease management, risk mitigation has become an important aspect of MS care with current medications, and its importance is expected to continue as new therapies are introduced. Additionally, the high cost of MS therapies has led local payers to implement policies with significant impact on the availability of specific MS therapies.
TC2.3 When and how should MS treatment be switched or escalated
1Heinrich-Heine University, Dept. of Neurology, Duesseldorf, Germany
In the past, immunotherapy for MS was dominated by a selection of different interferon-β preparations and glatiramer acetate providing a similar level of efficacy in terms of reducing relapse rate and slowing disease progression. A few years ago natalizumab, the first monoclonal antibody used in neurology, was introduced for the treatment of MS, opening a new era of immunotherapy. Ever since a good number of new drugs have broadened our therapeutic armamentarium, some addressing the unmet need of an oral application: fingolimod, a selective S1P receptor antagonist; teriflunomide, the active metabolite of leflunomide, noncompetitively and reversibly inhibiting the mitochondrial enzyme dihydro-orotate dehydrogenase (DHODH); alemtuzumab, a humanized monoclonal antibody rapidly depleting CD52+ cells of the lymphoid lineage from the peripheral blood. All these new therapies differ in their mode of action, mode of application, clinical efficacy and risk-benefit profiles. Neurologists treating MS today are confronted with the challenge to choose the right drug for the right patient at the right time. Patients in daily practice differ from those selected for clinical trials. Thus, treatment algorithms, as discussed that might be of help to prompt therapeutic decisions. This presentation will address the evidence and clinical experience given for making treatment choices for patients with MS.
TC3 - Symptom management
TC3.1 Symptom management - focus on gait impairment
1University of Rochester, Neurology, Rochester, NY, United States
Impairments of motor functions resulting in gait abnormalities are among the commonest and most dreaded problems caused by MS. This portion of the course will concentrate on symptom management and therapy of weakness, spasticity, and imbalance affecting gait. We will discuss integrated approaches including physical therapy, assistive devices, exercise, and pharmacologic management.
TC3.2 Effective management of spasticity
1University College London, Institute of Neurology, London, United Kingdom
Spasticity is a frequent and poorly managed symptom seen in over 50% of people with MS. It is inextricably linked to the upper motor neuron syndrome and is therefore usually associated with weakness and complicated by flexor and extensor spasms and clonus. It can result in pain, contractures and reduced mobility if not managed effectively and consistently over time. Effective treatment must be firmly based on education and active self-management. An understanding of the factors which may aggravate spasticity is a critical first step. A multi-disciplinary approach incorporating nurse specialist, physiotherapist and physician and focused on the individual needs and optimizing function and quality of life is fundamental. An exercise/stretching regime combined with appropriate use of oral agents forms the core of the approach to mild/moderate spasticity. More invasive treatments, may then be added depending on whether the spasticity is focal (unusual) or generalized. The increasing number of treatment options warrants an active and expert management program driven by evidence-based expert guidance. There remains an urgent need for more effective and better tolerated oral agents for this disabling and poorly managed symptom.
TC3.3 Exercise therapy as symptomatic treatment
1Aarhus University, Public Health, Aarhus C, Denmark
For many years patients with MS were recommended to avoid exercise therapy (ET). This advice was given because it was noted that ET could worsen symptoms and induce fatigue. Today we know that the worsening of symptoms is a temporary phenomenon and that ET is safe with minimal risk of adverse events and side effects. Furthermore, ET has a broad range of beneficial effects covering both physiological and psychological aspects, which often improves health and quality of life. Moreover, ETs are able to positively impact a number of frequent MS symptoms. ET covers a number of different exercise modalities ranging from resistance training (RT) at the one end to aerobic training (AT) at the other end. Both RT and AT are safe, and induce numerous beneficial effects, that do, however, differ markedly in some respects. Despite the numerous beneficial effects most studies that include a follow up period have shown that when MS patients leave the study setting the attained effects tend to disappear, strongly suggesting that long-term adherence is a major problem that needs to be addressed further. Also, research focusing on barriers and facilitators towards a more active physical lifestyle in MS patients, needs more attention in future studies. Taken together ET is one of the most promising non-pharmacological treatments in MS, being safe and having numerous beneficial physiological and psychological effects.
TC4 - Management during pregnancy
1BWH, Department of Neurology, Division of MS, Harvard Medical School, Department of Neurology, Director, Women’s Health Program, Brookline, MA, United States
2Department of Neurology, St, Josef Hospital, Ruhr University Bochum, Bochum, Germany
MS is the most common neurologic disease among women of reproductive age. Historically, women with MS have been discouraged from becoming pregnant. Today, we have reliable data regarding reciprocal influences of MS and pregnancy. While the relapse rate is decreased during pregnancy, it is increased after birth. Newer data suggests that the relapse rate is also increasing after unsuccessful artificial reproductive techniques. New disease modifying therapies and their effects on pregnancy safety bring forth additional levels of management complexities. Overall, patients with MS should receive appropriate support and guidance from their neurologist about family planning, disease management, lactation and other aspects of prospective motherhood. This course will cover safety of the current MS medications during conception/pregnancy and breastfeeding. We will propose and discuss optimal conception timing and pregnancy and post- partum management algorithms for MS patients with various disease severity. The data on the influence of breastfeeding on MS course, and issues related to psycho-social aspects of postpartum MS care will also be elucidated.
TC 5 - Clinically isolated syndromes (CIS)
TC5.1 Radiologically isolated syndrome: pre-symptomatic MS?
1University of Texas Southwestern Medical Center, Neurology & Neurotherapeutics, Dallas, TX, United States
MS is a common cause of severe neurological disability in young adults, resulting from autoimmune interruption of both myelin and axons within the central nervous system (CNS). The diagnosis is made by fulfilling both spatial criteria, by meeting the requisite number of lesions within the brain and spinal cord, along with criteria for time, by demonstrating a history of at least a second clinical attack or the development of a new MS lesion on MRI after a seminal neurological event. Similar to many other chronic diseases, signs of impending disease may be observed in the months to years preceding the formal diagnosis. At times, healthy individuals who do not exhibit or have an existing history of neurological dysfunction commonly have brain MRI studies performed for a reason other than for the evaluation of MS that reveal unexpected anomalies highly suggestive of in situ demyelinating plaques given their size, location, and morphology. The radiologically isolated syndrome (RIS) is a recently described MS subtype that precedes the first clinical attack and diagnosis of MS. This relevant cohort of individuals, when properly characterized, appears to be at risk for future demyelinating events. The discovery of the first visible manifestation of MS creates intersecting neuro-ethical, social, and medical management challenges of immediate and long-term consequence for healthcare providers, in addition to offering scientific opportunities to deconstruct the early events preceding first symptom development related to CNS demyelination. With the increasing use of non-invasive diagnostic imaging studies of the brain being performed throughout the world for medical and research purposes, and the potential risk of the “over-diagnosis” of RIS by healthcare professionals, a comprehensive understanding of this relevant group of individuals and common radiological mimics is needed. Here we discuss the diagnostic criteria for RIS, provide an overview of the current scientific data related to the risk for a seminal demyelinating event, and will highlight the challenges related to the proper classification of subjects and existing controversies, along with reviewing new scientific efforts aimed at improving disease characterization.
TC5.2 Predicting outcome of adults and children with CIS
University College London, Institute of Neurology, London, United Kingdom
About 30% of patients with CIS present a second clinical attack within one year from onset, leading to the diagnosis of clinically-definite MS (CDMS). The majority of patients who convert to CDMS do so within the first 5 years. The aim of this talk is to review and discuss the clinical, blood, cerebrospinal fluid and MRI markers that are risk factors for conversion to MS in adults, and are used in clinical practice to inform people with CIS about their prognosis. Predictors of a diagnosis of MS in children with CIS will be discussed. Finally, predictors of long-term clinical outcome will be presented.
TC5.3 How can we treat and manage CIS patients?
1MS Center of Catalonia,Vall d’Hebron University Hospital, Neurology/Neuroimmunology Department, Barcelona, Spain
The McDonald diagnostic criteria have allowed the formal diagnosis of MS in patients presenting with clinically isolated syndromes (CIS). Evidence from research suggests that many patients with CIS or early MS should be treated with disease-modifying drugs (DMDs) at an early stage, since disease experience during the first few years are likely to have significant impact on the long-term evolution of the disease. We will review simple clinical, radiological and biological tools that can be applied in our daily practice to better estimate the long-term prognosis of the individual patients. Demographics and topography are low-impact prognostic factors, presence of oligoclonal bands is a medium-impact and brain MRI is a high-impact prognostic factor. Five randomized clinical trials with β-interferons and glatiramer acetate performed in patients with a clinically isolated syndrome and abnormal brain MRI have shown a significant decrease in the risk of having a second attack. Extension studies have confirmed the long-term benefit of early treatment in terms of delaying the appearance of a second attack. The effect of these DMDs on disability in studies performed in real life conditions has been more controversial, although some have shown a benefit in reducing the risk to develop secondary progressive MS others have not been able to confirm this hallmark. DMDs as well as new oral drugs have also shown a greater benefit when used earlier in the disease course. It is concluded that the time to introduce treatment is critically important for outcome and that early treatment seems to be associated with better outcomes.
TC6 - Neuromyelitis optica (NMO)
TC6.1 Diagnostic criteria for neuromyelitis optica: an update
1Mayo Clinic, Neurology, Rochester, MN, United States
The concept of an opticospinal form of demyelinating disease distinct from MS entered the modern era in the mid-1990’s. MRI of the spinal cord and autoantibodies targeting aquaporin-4 (AQP4-IgG) facilitated definition of an opticospinal inflammatory disease distinct from MS. Current neuromyelitis optica (NMO) diagnostic criteria require at least one episode of optic neuritis and myelitis and 2 of 3 additional characteristics: normal brain MRI at initial presentation; T2-weighted spinal cord MRI lesion extending over 3 vertebral segments at the time of a myelitis episode; detection of AQP4-IgG (Wingerchuk et al, 2006). NMO is a worldwide disease. Although the proportion of MS-like illness attributable to NMO is greater in Asian countries than in the west, the absolute prevalence is similar. AQP4-IgG is detectable in many patients with recurrent myelitis or recurrent optic neuritis who don’t satisfy NMO criteria. Certain cerebral syndromes not previously recognized to be associated with NMO were found to occur in AQP4-IgG seropositive patients and patients with otherwise typical NMO including lesions of the area postrema or hypothalamus, longitudinally extensive corpus callosum lesions, and long corticospinal tract lesions in the corona radiata and brainstem. Collectively, optic neuritis and myelitis syndromes not satisfying traditional NMO criteria and NMO-typical brain syndromes and lesions in AQP4-IgG seropositive individuals are referred to as NMO spectrum disorders (NMOSD). Studies from service testing laboratories reveal that the vast majority of AQP4-IgG seropositive patients have had optic neuritis and myelitis or a well-accepted signature syndrome of NMOSD, such as intractable vomiting or hiccough, although the spectrum of clinical associations is constrained by referral bias of samples.
An international panel has proposed new criteria that eliminate distinctions between NMO and NMOSD. NMOSD may be diagnosed after a single compatible syndrome of NMO in AQP4-IgG seropositive patients. AQP4-IgG seronegative NMOSD is heterogeneous and defined more rigorously than seropositive (evidence of dissemination in space; at least one “signature” syndrome [optic neuritis, longitudinally extensive myelitis or intractable vomiting/hiccup]). False positive results may occur with AQP4 assays, especially the ELISA assay, currently in wide use. Patients should not be diagnosed with NMOSD in the absence of compatible clinical and radiological characteristics.
TC6.2 AQP4 antibody-seronegative NMOSD: the clinical dilemma
1Tohoku University Graduate School of Medicine, Department of MS Therapeutics, Sendai, Japan
MS is less prevalent in Asia than in Western countries. Before the discovery of aquaporin-4 (AQP4)-IgG, patients with severe optic neuritis and transverse myelitis were often diagnosed with “opticospinal” MS (OSMS), and OSMS was reported as a unique type of MS in Asians. On the other hand, cases with brain lesions were classified as “conventional” MS (CMS) even if they had severe optic neuritis and transverse myelitis. However, clinical studies mainly based on longitudinally extensive spinal cord lesions (LESCL) (> 3 vertebral segments) and AQP4-IgG seropositivity revealed that both OSMS and CMS included NMOSD as well as MS, Thus Asian MS, OSMS, and CMS are misleading terms and now discouraged. If patients have core manifestation(s) of NMOSD and are AQP4-IgG-seropositive, making the diagnosis of NMOSD is relatively easy, but some patients with clinical features of NMOSD are consistently seronegative despite the use of highly sensitive cell-based assays of AQP4-IgG. Other than NMOSD, LESCL can develop in a variety of etiologies, and thus rigorous differential diagnosis at onset is essential. Features of AQP4-IgG-seronegative NMO/NMOSD include no female preponderance, less relapses, simultaneous development of optic neuritis and longitudinally extensive transverse myelitis at onset, and milder functional disability. Additionally, 10% of patients with NMOSD fulfill the Barkhof MRI criteria for MS, but some brain lesions such as the presence of a subcortical U-fiber lesion and a Dawson’s finger-type lesion can distinguish MS from NMOSD.
Recent studies with cell-based assays showed that a fraction of patients with AQP4-IgG-seronegative NMOSD are myelin oligodendrocyte glycoprotein (MOG)-IgG-seropositive. In addition to the features mentioned above, simultaneous, bilateral optic neuritis and lumbosacral myelitis are often seen in MOG-IgG- seropositive disease. Pathological and experimental studies suggest that astrocytopathy is the primary and predominant pathology of AQP4-IgG-seropositive NMOSD, but it is intriguing to know if MOG-IgG-seropositive NMOSD is a demyelinating disease.
Management of AQP4-IgG-seronegative NMOSD has not been established. But generally, compared to AQP4-IgG-seropositive disease, plasma exchange is not often need as a rescue therapy of acute exacerbation. Some patients may have monophasic disease, but in relapsing disease, immunosuppressive drugs are often administered. Efficacy of MS drugs like interferon-beta is unknown.
TC6.3 Treatments in NMO: current algorithms, future therapies and trial designs
1Oxford University Hospitals Trust, Oxford, United Kingdom
In contrast to MS, the disability incurred in neuromyelitis optica and its spectrum disorders is solely relapse associated. Thus urgent aggressive relapse treatment is indicated in addition to long-term relapse prevention. Acute relapses should be treated with high dose intravenous corticosteroids, backed up by plasma exchange (and possibly intravenous immunoglobulins) in patients not responding adequately. Long-term strategies for relapse prevention include prednisolone and/or azathioprine, mycophenolate mofetil, methotrexate and the anti-CD20; rituximab. Breakthrough relapses despite an adequate therapeutic trial in terms of dosage and length of treatment, or intolerance, should lead to a change in the treatment regime.
Many future promising pharmacological agents are being developed and include; aquaporin 4 antibody binding blockade, inhibition of complement, destruction of lymphocytes expressing the CD19/20 surface proteins and targeting the IL-6 pathway. Trial design is a challenge because current standard therapies are not backed by high level evidence. Regulatory bodies requiring placebo controlled studies may be of concern to some due to the risk of relapse in the untreated group. Add-on studies and direct head to head studies are alternative designs. A combination of these strategies may be required to identify where these treatments fit into the NMO therapeutic armamentarium. Because relapses are more likely to cause permanent disability in NMO than in MS, time to relapse may be a more suitable outcome in NMO than relapse rate. The visual and spinal cord focus of pathology may require disability outcomes to be modified.
TC7 - Imaging small parts of the nervous system (MAGNIMS)
TC7.1 Optic nerve imaging: pathophysiological insights
1UCL Institute of Neurology, Brain Repair and Rehabilitation, London, United Kingdom
We will focus on the role of MRI in helping to understand pathophysiological mechanisms of damage and recovery after optic neuritis and in MS. I will begin by explaining the challenges of MRI in optic nerve imaging and then go on to explain how more conventional MRI techniques using contrast have improved our understanding of the disease. I will talk about the role of FLAIR imaging in determining the degree of swelling or thinning of the optic nerve and then move on to more advanced MRI techniques such as magnetization transfer imaging and diffusion weighted and tensor imaging.
TC7.2 Deep grey matter: current and new technologies
1Hospital San Raffaele, Neuroimaging Research Unit, Milan, Italy
MS is often considered a white matter (WM) inflammatory demyelinating disease, but evidence now suggests that deep gray matter (GM) damage is frequent and extensive in this condition. Deep GM damage has been described from the earliest stages of the disease, in patients with clinically isolated syndromes (CIS), yet it is more pronounced in patients with the progressive disease clinical phenotypes. Several mechanisms are likely to contribute to such a deep GM involvement including primary damage to the GM, with demyelination and neuroaxonal loss, as well as secondary phenomena due to the progressive accumulation of WM damage. Imaging of GM damage, and in particular deep GM damage, in MS remains challenging. However, with the introduction of advanced MRI techniques, ultra high-field scanners and novel methods of analysis, our ability to assess such damage and its clinical relevance has markedly improved. Several MRI studies have shown that focal lesions occur in deep GM, including the thalamus and hippocampus. The thalamus seems to be one of the initial and preferential sites of damage in MS, since atrophy at this level has been consistently found in patients with CIS and pediatric MS. Notably, thalamic atrophy has been correlated with physical disability, cognitive impairment and fatigue.
Quantitative MR techniques have detected reduced magnetization transfer ratio and diffusivity abnormalities in deep GM. These abnormalities, which reflect microstructural tissue alterations, are at least partially correlated with clinical disability, cognitive impairment, brain volume loss and WM lesion load. Functional MRI (fMRI) has shown changes in MS brain, during both active tasks and at resting state. Altered functional activations might initially represent adaptive mechanisms to compensate for distributed brain damage, but later on, functional maladaptation might further contribute to clinical worsening. Network-based analysis of structural and functional connections show that MS patients have a distributed pattern of connectivity abnormalities also involving deep GM, which is related to T2 lesion burden and the severity of clinical impairment. This lecture will discuss the actual challenges, the most recent advances and the upcoming strategies useful for the evaluation of deep GM involvement in MS.
TC7.3 Imaging the small parts of the nervous system: spinal cord
1National Institute of Neurological Disorders and Stroke, NIH, Translational Neuroradiology Unit, Bethesda, MD, United States
The spinal cord is heavily affected in MS. At least 90% of MS cases have inflammatory demyelinating lesions in the spinal cord. MRI detects cord lesions in most cases at the time of diagnosis, and establishing their presence fulfills one of the 2010 McDonald criteria for dissemination in space. Damage to the cord, including both focal demyelination and neuroaxonal degeneration, contributes massively to disability, particularly in the progressive stage of the disease. Finally, the spinal cord is an attractive target structure for studies that seek to elucidate the functional correlates of MRI-visualized tissue damage in MS. Unfortunately, despite its importance, spinal cord imaging has proved to be especially challenging for a variety of technical reasons. As such, it’s potential value for the care of the MS patient, and for improving understanding of the disease in general, is underappreciated.
In this talk, I will describe recent improvements in spinal cord structural MRI as applied to MS and will show how those improvements can be used to detect lesions more reliably. I will also describe approaches to measuring spinal cord atrophy, which has proved to be a relatively strong marker of disease progression. Finally, I will show how quantitative MRI techniques that are sensitive to tissue structure on a subvoxel level, such as diffusion-weighted and magnetization-transfer imaging can be useful adjuncts to improved structural imaging techniques despite being pathologically nonspecific.
TC8 - Update in pediatric MS
TC8.1 Diagnosis of MS and acute demyelinating disorders in children
1Great Ormond Street Hospital for Children, London, United Kingdom
MS and other recurrent demyelinating disorders presenting in individuals less than 18 years of age are rare. Unlike in adults, where an episode of demyelination almost always heralds the onset of MS, in young people an episode of acute demyelination is frequently not the start of MS. Thus a comprehensive knowledge of the variety of different presentation that can occur and an awareness of some of the common mimics is essential for accurate diagnosis, correct classification and the provision of appropriate treatment.
In this talk, I shall use a case-based approach to help individuals make an accurate diagnosis of Pediatric Onset MS (POMS) or one of the related demyelinating syndromes. I shall also discuss the revised 2012 Consensus Definitions recently published from the International Pediatric MS Study Group (IPMSSG). Included in the talk will also be discussion of some of the antibody driven disorders such as NMO and NMO spectrum disorder and MOG positive demyelination which provide challenges both diagnostically and for treatment.
TC8.2 Emerging therapies and clinical trials in pediatric MS
1Harvard Medical School, Massachusetts General Hospital, Partners Pediatric MS Center, Boston, MA, United States
There are currently no FDA approved disease modifying treatments for pediatric MS and only limited approval for beta-inteferons in adolescents by the EMA. The aim of this talk is to summarize the goals of disease-modifying treatment for children with MS, and to review the available data on currently used treatments. In addition, new initiatives in clinical trials in pediatric MS will be presented. Example cases and treatment management scenarios will be discussed.
TC8.3 MRI: role in assessment of MS disease activity and disease impact in patients with MS onset during childhood
1The Children’s Hospital of Philadelphia, University of Pennsylvania, Neurology and Pediatrics, Philadelphia, PA, United States
The role of MRI in the diagnosis of MS is well-established in adult-onset disease. The last 5 years have seen several studies illustrating the importance of MRI in the diagnosis of MS in children and adolescents. The presence of multiple clinically silent lesions in CNS locations commonly involved in MS, the presence at onset of lesions that appear chronic (as defined by persistent T1 hypointensity), and the early and prominent involvement of the brainstem are key findings in pediatric MS patients. The absence of such findings also has powerful negative predictive implications, providing reassurance to families of children destined for a monophasic demyelinating illness. Serial MRI studies have illustrated the rate of accrual of new lesions in pediatric MS patients, although the number of such studies remains very small and the number of children studied through rigorous protocols is very limited. To date, serial MRI findings have shown a rate of new lesion accrual that is relatively similar to that of adult MS patients, provided that both groups are evaluated in the first few years of disease. Analyses of brain volume in pediatric MS patients have not only demonstrated a reduced brain size for age, but an even greater reduction in thalamic volume compared to age-matched healthy children. The reduction in brain and thalamic volume associates with cognitive impairment, indicating that the MRI findings are of clinical significance. Findings on serial brain growth will be presented at the meeting. Lacking to date is data relating to the role of MRI in therapeutic clinical trials in pediatric MS. The next few years will see the first clinical trials in the pediatric MS population. While key data to be gained regarding treatment efficacy is the primary objective of such trials, the data gleaned from the trial-related MRI scans will inform not only on the MRI features of pediatric MS in larger cohorts, but also on the utility of MRI as an outcome metric. The implications and considerations of MRI findings in pediatric clinical trials will be presented to generate discussion of this important and emerging topic in pediatric MS.
TC9 - Differential diagnoses and diagnostic dilemmas
TC9.1 Diagnostic approach to MS
1University of Lille, Neurology, Lille, France
Diagnostic approach to MS includes clinical and paraclinical assessments emphasizing the need to demonstrate dissemination in time and dissemination in space and to exclude alternative diagnoses. The recent revised McDonald criteria allow a more rapid diagnosis of MS and earlier treatment. Although diagnosis of MS can be made on clinical grounds alone, MRI can support, implement or even replace some clinical criteria. In some cases CSF analysis can help with a high degree of diagnostic accuracy. Diagnostic approaches have identify some clinical and paraclinical red flags that should signal particular caution. It is extremely important to differentiate MS from recurrent and multiphasic disseminated encephalomyelitis because of the increasing availability of disease-modifying drugs, and the pressure to initiate treatment as quickly as possible, even after what has been labeled a clinically isolated symptom suggestive of MS. Some potential biomarkers in the serum have been identified but none of them can be used in routine clinical practice for a positive diagnosis. However, a screening for antibodies is recommended in patients with atypical clinical or radiological signs. New MRI sequences as double-inversion recovery are in some cases useful, showing in MS small cortical lesions. High-field MRI studies have shown that penetrating veins can be detected in most MS lesions using T2 weighted or susceptibility-weighted imaging. Future studies must address the feasibility of imaging such veins in a clinically practical context. However the specificity of this biomarker is unknown. The introduction of some biological or radiological tests as a complementary tool in current diagnostic procedures will be discussed.
TC9.2 Red flags in MS: zebras or horses?
1New York University Langone Medical Center, Neurology, New York, NY, United States
The differential diagnosis of MS is broad. There are a variety of demographic features, clinical findings and imaging characteristics that may suggest an alternative diagnosis. In this talk, we will use a case based approach to examine some of those “red flags” to the diagnosis of MS. Some telltale signs of the visual system will be emphasized.
TC9.3 MS differential diagnoses
1University of California San Francisco, Neurology and Pediatrics, San Francisco, CA, United States
The presentation will highlight differential diagnoses that can mimic MS. The emphasis will be on those disorders that can present clinically or on MRI scans like MS.
TC10 - Neuroimmunology in relation to MS pathophysiology and immunotherapy
TC10.1 Inadequate activation of T cells in MS: possible mechanisms involved
1Toulouse University, Immunology, Toulouse, France
Based on genetic data, on study of the CSF and on post-mortem examination of CNS samples from MS patients, T cells are thought to play a major deleterious role in the disease process. Animal models, such as experimental autoimmune encephalitis (EAE), have strengthened this idea as T cells are necessary and sufficient for disease development in this model. Stimulation of immunity (with interferon-gamma) aggravates the MS disease course, while current therapies aiming at blocking T cell penetration to the CNS (or physically eliminating most T cells) have clear beneficial effects. Collectively, these data point to T cells as major contributors of CNS tissue damage during MS. However, the factors that initiate this inappropriate immune reaction in MS are not clearly identified. New information originating from genetic studies and from studies of the EAE model has however provided new hypotheses that will be detailed. The involvement of CD4 T cells subsets (Th1, Th17, T follicular helper cells, and regulatory T cells) and data implicating CD8 T cells shed new light in the disease immunopathology and also add an additional layer of complexity. Once in the CNS, CD4 and CD8 T cells might contribute to tissue damage through different mechanisms. Selective inhibition of the pathogenic T cell subsets (or population) would be an attractive therapeutic development and current research is heading this way.
TC10.2 Contribution of B cell: T cell interactions to CNS inflammation in MS
1Montreal Neurological Institute and Hospital, McGill University, Montreal, QC, Canada
While studies into the immune pathophysiology of MS continue to highlight roles of effector and regulatory T cell subsets, several Phase 2 studies of selective B cell depletion have reported robust decreases in new relapses, indicating that B cells play important roles in the development of new MS disease activity. This benefit appears to reflect, at least in part, non-antibody dependent roles of B cells. This talk will review emerging data related to the elucidation of novel disease-implicated B cell subsets, highlighting the diversity of their (pro-inflammatory and anti-inflammatory) responses, and abnormalities of distinct B cell subsets identified in MS patients. We will consider how aberrant B cell:T cell interactions are likely to contribute to MS relapsing disease activity, and how B cells may also be involved in compartmentalized inflammation within the MS CNS, of potential relevance for mechanisms if progressive disease.
TC10.3 Immune cell trafficking to the CNS, mechanisms and therapeutic implications
1Stanford University, Neurology and Neurological Sciences, Stanford, CA, United States
MS is an autoimmune inflammatory CNS demyelinating disorder that causes permanent neurologic disability. The CNS is an immune privileged under physiological conditions, however, in MS, entry of immune cells into the CNS results in inflammation, tissue damage and neurodegeneration. Understanding the mechanisms that govern immune cell trafficking into the CNS will result in development of effective MS therapies. In order for promote immune cell entry into the CNS, cells in the peripheral immune system require going through an activation process, exit into the systemic circulation, follow cues to home to the CNS and pass though the blood-brain barrier (BBB). This complex process is orchestrated by multiple cellular and soluble mediators in a coordinated fashion. We will be discussing factors that determine immune cell activation in the peripheral immune system, how activated cells exit into the systemic circulation and home to the CNS via the BBB. Several currently available MS therapies target one or more of these check points. Understanding how this process is regulated will shed light on development of effective therapies that will modulate neuroinflammation in MS.
TC11 - MRI issues in clinical practice (MAGNIMS)
TC11.1 Lesions: can we go beyond counts and volumes?
1University of Siena, Siena, Italy
The pathology in MS is characterized by the presence of focal lesions in the brain and spinal cord. The number and volume of the white matter lesion has been widely used to diagnose and monitor patients with MS. However, both counting and volume assessment of lesions correlate relatively weakly with clinical measures. This is due, at least in part, to the fact that these measures do not take into account the relevance of the location where lesions occur. Also the notion that lesions are heterogeneous, and therefore may reflect very different tissue damage is neglected when only number and volume of lesion are measured. During this course the importance of lesion location for the development of physical and cognitive disability will be discussed. The value of lesion mapping, which has shown to be a very powerful tool for studying distribution and probability of occurrence of brain lesions will be also reviewed. Furthermore, the relevance of heterogeneity and its underlying difference in tissue damage will be considered. In this context, the importance of recognizing and monitoring hypointense lesions is discussed. The advantage of monitoring voxel-wise lesion evolution by using magnetization transfer imaging will be considered.
TC11.2 Brain atrophy: an outcome measure in clinical studies
1Cleveland Clinic, Biomedical Engineering, Cleveland, OH, United States
MRI studies over the past 15 years have revealed that brain atrophy begins early in MS and progresses at a faster rate than normal aging. Like most aspects of MS, the rate and pattern of brain tissue loss varies greatly between individuals and over time. Brain volume changes arise from a complex combination of pathologic and physiologic processes. However, to a large extent, brain atrophy is believed to reflect the most destructive aspects of MS pathology, such as axonal loss, chronic demyelination, and neurodegeneration. This interpretation is supported by cross-sectional and predictive associations between atrophy and disability that are relatively robust. Almost all clinical trials of MS drugs have included brain atrophy as an outcome measure. The results of most trials suggest that reducing inflammatory activity leads to a subsequent slowing of brain atrophy, or secondary neuroprotection. Ongoing studies are focused on discerning the mechanisms of brain tissue loss, defining the differences in gray versus white matter atrophy, and improving understanding of the effects of processes such as inflammation, de- and re-myelination, and gliosis on brain volume measurements in MS.
TC11.3 Imaging biomarkers of normal-appearing brain
1Yale University, Departments of Neurology and Radiology, New Haven, CT, United States
MR and histopathological correlative studies support the use of quantitative MR and metabolite imaging methods to assess pathologically relevant injury in the brain of MS patients. Conventional MRI is sensitive to focal white matter lesions and is being used daily in clinical practice but unfortunately does not reveal the extent of damage in white matter areas outside of focal inflammatory demyelinated lesions (NAWM). T1/T2 relaxation, magnetization, diffusion, susceptibility, and spectroscopic methods at 1.5T/3T strengths, including methods developed at 7T, have revealed significant abnormalities at all stages of the disease. The amount of injury is variable between patients. The changes are consistent with diffuse demyelination, axonal damage, and gliosis along with what appears to be the presence of inflammation with associated increase in water content. Despite the difficulty of using these methods in clinical practice, several clinical validation studies using longitudinal patient datasets have established an association between in vivo NAWM abnormalities and long term measures of disease progression. The transition of these imaging methods from research experiments to routine clinical practice remains very challenging but some are showing promise in research trials evaluating MS disease-modifying therapies.
TC12 - Neuro-opthalmology update
TC12.1 Visual manifestations of CNS demyelinating disorders
1University of Calgary/Hotchkiss Brain Institute, Clinical Neurosciences and Surgery, Calgary, AB, Canada
This presentation implements a case-based format to highlight afferent and efferent visual pathway features of MS and other inflammatory demyelinating syndromes of the central nervous system (CNS) including neuromyelitis optica (NMO) and chronic relapsing inflammatory optic neuropathy (CRION). This talk will “set the stage” and review clinical syndromes and neuro- ophthalmic testing techniques expanded upon in the lectures that follow. As part of the core content of the presentation, an approach to the detection, localization, and management of optic neuritis (ON), retrogeniculate visual pathway lesions, internuclear ophthalmoplegia (INO) and other brainstem demyelinating syndromes, ocular motor cranial nerve palsies, acquired patterns of nystagmus and vestibular imbalance will be provided. Moreover, the role of emerging visual function testing methods and ocular imaging technologies will be described, including but not limited to: low contrast letter acuity, binocular summation, motion perception, multifocal visual evoked potentials (mfVEP), and optical coherence tomography (OCT). By the conclusion of this presentation, participants will have been provided a detailed review of how neuro-ophthalmic manifestations of CNS demyelinating disorders may be diagnosed and treated. In addition, course participants will be able to identify the merits of the afferent visual pathway (AVP) model of CNS demyelination, through which pathogenic mechanisms of injury may be better elucidated.
TC12.3 Neuromyelitis optica: new diagnostic criteria enlarge the spectrum
1CHU de Strasbourg, Strasbourg, France
Neuromyelitis optica (NMO) is an immune-mediated disorder of the central nervous system (CNS) in which the optic nerves and the spinal cord are preferentially involved. A marker of the disease has been identified in the serum of most patients which binds to aquaporin-4 (AQP4), a water channel protein highly expressed in the astrocytic foot processes in the blood-brain barrier. Recently, it has been shown that the disease encompasses a broader spectrum of clinical and imaging phenotypic manifestations such as the limited forms of the disease [seropositive patients with just one of the index events, either recurrent or bilateral optic neuritis, or longitudinally extensive transverse myelitis (LETM)]; brainstem, hypothalamic, and cerebral syndromes in association with optic neuritis and LETM; and the association of typical NMO with other systemic autoimmune disorders. This phenotypic spectrum is known as NMO spectrum disorders (NMOSD). In this presentation we will highlight visual manifestations of NMOSD, review new diagnostic criteria for this clinical spectrum, and provide an approach to management.
TC12.3 The role of visual outcomes in MS clinical trials
1New York University School of Medicine, Neurology, New York, NY, United States
This talk summarizes points from the previous lectures, and provides a “future directions” perspective by briefly highlighting the role visual outcome measures in MS trials including: low contrast letter acuity, contrast sensitivity, binocular summation and inhibition, multifocal visual evoked potential testing, and optical coherence tomography.
TC13 - Assesing the drug efficacy: Challenges in study design
TC13.1 Assessing drug efficacy: challenges in study design
1Icahn School of Medicine at Mount Sinai, Corinne Goldsmith Dickinson Center for MS, New York, NY, United States
Over the past 30 years, the field (and science) of MS clinical trials has expanded dramatically, leading to approval of new agents that modify disease course. The process has been iterative, with improved understanding of the metrics and techniques needed for successful studies honed after analysis of each succeeding study. Development of anti-inflammatory molecules has benefited from a highly efficient phase II proof of principle design utilizing frequent MRI analysis of new disease activity, which has been highly predictive of successful phase III studies of a clinical outcome. The current challenges to advancing clinical trial design involve the robustness of our clinical outcomes in phase III studies. These have included measures of relapse frequency and advancing impairment/disability. Measuring relapses has been a successful metric but is now challenged by a decreasing relapse rate across all groups and the successful reduction in relapses seen in recent MS studies. Measures of disability have always been problematic, but recent trial designs and regulatory concerns have highlighted issues with this approach. While most studies have utilized the EDSS, there are many issues with this metric, including its lack of linearity and non-informative fluctuation. The MSFC has been proposed as an alternative, but has not gained much traction nor has it performed well in most studies. Efforts are underway to develop improved versions of both the EDSS and the MSFC. For the future, we need to develop better patient reported outcomes employable across multiple trials. Perhaps the biggest challenge facing us at this time is the need for reliable trial designs for progressive disease and restorative therapies, at both the level of proof of principle and pivotal study. Proof of principle for progressive studies will most likely require validation of a reliable MRI metric of tissue loss. Current studies have utilized measures of brain volume with varying degrees of success, as exploratory outcomes in anti-inflammatory trials. For phase II testing of a neuroprotective molecule, these volumetric assessments will need to be more robust and hopefully as successful at predicting phase III success as the MRI measures of disease activity have been in predicting clinical success for anti-inflammatory molecules. Phase III challenges for progressive MS studies will be challenged further by the problems we currently have with reliable clinical measures of progressive disease.
TC13.2 Assessing treatment efficacy in MS: observational studies vs clinical trials
1University of Genoa, Genoa, Italy
The gold standard for measuring a treatment effect is the randomized clinical trial, whose duration is typically 2-3 years in MS. The long-term effect of a drug in MS can be assessed only thru trials extensions or using observational studies, taking advantage of data from registries or large single centers databases. The main limitation of observational studies is an unavoidable selection bias, introduced when the intervention is not randomly assigned. The use of propensity score methods can balance the comparison groups with respect to baseline covariates, but cannot correct for unmeasurable confounding factors. Long-term extensions of clinical trials are free from selection biases due to randomization, but they can only provide an assessment of early versus delayed treatment effect. These methodological issues will be presented and an analysis of how they have been managed in different observational and extension studies assessing long-term effect of interferon-beta in MS will be discussed.
TC13.3 Investigator initiated vs industry sponsored studies, which and when - randomized trials in the active treatment era
1University of Alabama at Birmingham, School of Public Health, Biostatistics, Birmingham, AL, United States
Many trials in MS have evolved from the pharmaceutical industry and partnerships with academics. Working together is getting more difficult as conflict of interest rules evolve, but key questions must also be asked to address the pressing research questions of today. While placebo controlled trials are the fastest and most cost effective way to identify efficacy of treatments, they may no longer address the questions of essential importance to clinicians and payors. In this course we discuss decisions that must be considered in designing trials of the future. The most important design element being what is the question being asked?
Topics to be discussed include:
How many treatment groups, what endpoints are suitable, deciding the duration of the trials - the importance of long term outcomes, what are the benefits and risks of adaptive trials, the role and elements of cost effectiveness, and can we find more frugal approaches to doing trials.
TC14 - Neuropsychiatric manifestations and cognitive impairment
TC14.1 The manifestations of cognitive and psychiatric disorders in MS and assessment strategies
1University at Buffalo, Neurology, Buffalo, NY, United States
Cognitive impairment and psychiatric symptoms are common in MS patients. As there are increasingly more treatment options for these comorbidities, the need for routine assessment is paramount. The purpose of this first session is to review the cognitive and neuropsychiatric disorders that are most relevant for MS patients, and how best to assess them. MS associated cognitive deficits were documented in the late 19th century but not formally studied until neuropsychological tests were applied in the 1970s. Steve Rao is credited with the first large sample study showing that roughly 50% of patients have cognitive impairment. This general finding was repeatedly replicated although the frequency of impairment is higher in patients with more progressive course, and lower in patients with early disease. The domains of information processing speed and memory are most frequently involved. In recent work, we and others have shown that brief tests in these domains can be easily applied in the clinical setting. The tests results are also relevant as shown by correlation with meaningful outcomes such as brain MRI, driving, maintenance of employment, and the frequency of work problems among employed patients.
The most common neuropsychiatric symptom is depression, either in the form of major depression or more often adjustment disorder with depressed mood. Fortunately, MS associated depression is often treatable. It is critical then that patients be screened for depression using one of several validated strategies in the form of a brief questionnaire or screening question administered by the patient’s doctor. A much rarer affect disorder is euphoria sclerotica, first described by Charcot in 1877. Unlike depression, this condition is most often associated with severe cognitive impairment or dementia. The syndrome is characterized by childlike cheerfulness coupled with poor insight and impulsive behavior patterns. This lecture will cover a published structured interview method for evaluating caregiver perspectives on this and other severe mood disorders. Finally, the assessment of personality traits will also be discussed as our recent work has shown that personality moderates the relationship between brain atrophy in MS and both cognition and affect disorder.
TC14.2 Treatment of disorders of mood and affect in MS patients
1University of Toronto, Department of Psychiatry, Toronto, ON, Canada
Depression in MS can be treated with either antidepressant medication or psychotherapy. Notwithstanding the frequency with which depression occurs in MS, there are few medication treatment trials, only two of which are endorsed by a Cochrane Review. Desipramine, an older tricyclic antidepressant (TCA) and paroxetine, a newer selective serotonin reuptake inhibitor (SSRI) were both found to have modest benefits in treating depressed MS patients. Side effects with both drugs were reported to limit dosage and contribute to poor compliance. Common adverse reactions included sedation, dry mouth, constipation and sexual dysfunction. Of the various psychotherapies, a second Cochrane review concluded that cognitive behavior therapy (CBT) was effective in treating depression. One study that compared CBT to the SSRI sertraline at various doses found that the two treatments were equally effective for patients with moderately severe depression. Of note is that CBT can be successfully administered over the telephone to MS patients, thereby making it particularly attractive to individuals with mobility difficulties who struggle to attend clinic. Mindfulness based therapy is also reported to alleviate depression in MS. In patients with severe depression who have not responded to medication and CBT and where suicide may be a concern, electroconvulsive therapy can be given. Side effects here can include memory impairment and a possible relapse in the MS. Pseudobulbar affect responds well to many different medications including low dose amitriptyline, various SSRI drugs and levodopa. More recently a combination of dextromethorphan and quinidine was found to be effective as well. One advantage to this treatment is that it spares the sexual problems that may occur with TCA and SSRI medications. Of note is that all antidepressant medications (TCAs and SSRIs) may reduce or turn off pseudobulbar affect within 48-72 hours whereas the same treatment usually takes approximately two weeks to lift low mood. There are no MS related treatment trials of bipolar affective disorder and as such, general psychiatry based guidelines must be followed, with the usual neuropsychiatry dosage advice of “start low and go slow” given patient sensitivity to side effects. Mood stabilizing medication (lithium carbonate, valproic acid) may have to be augmented with benzodiazepines if sedation is required and antipsychotic medication if delusions and hallucinations are present.
TC14.3 Treatment of cognitive dysfunction in MS patients
1University of Florence, Department Neurosciences, Florence, Italy
This lecture reviews key evidence on pharmacological approaches and cognitive rehabilitation and highlight the most promising results. The disease modifying drugs (DMDs) have the potential to positively influence the cognitive outcome of the patients by acting on some key pathogenic mechanisms of MS-related cognitive impairment. However, evidence in the field is limited. Interpretation of available data is complicated by issues largely related to methodological problems of study design and execution. Data from trials with beta-interferons in clinically isolated syndromes and early relapsing MS suggest that early treatment may be the most efficient strategy to prevent cognitive dysfunction. Post-marketing data also support the effect of beta interferons and natalizumab in improving the subject cognitive outcome, whereas studies with other new agents are under way. Studies based on symptomatic treatments have included the use of Alzheimer’s drugs (donepezil, rivastigmine, memantine), mainly with negative or inconsistent results, symptomatic treatments for fatigue (dopamine, pemoline, modafinil), potassium channel blockers (4-aminoyridine, 3-4 diaminopyridine) and psychostimulants (l-amphetamine, methylphenidate). Again, the evidence is limited and some preliminary positive results obtained with modafinil or a few psychostimulants wait for confirmation in larger, more rigorous trials. As for cognitive rehabilitation, most published studies have targeted learning and memory, followed by attention and executive functions, whereas there is no study specifically addressing processing speed deficits. The format of rehabilitation programs is heterogeneous; most often based on computerized training programs or behavioral techniques. Some of the studies suffer from serious methodological limitations. However, some well-designed studies using computerized training programs or cognitive behavioral techniques do show some evidence of improvement with specific and rather intensive interventions, particularly in the field of memory and attention. Moreover, proof of concept studies using functional MRI support these positive findings and suggest that cognitive rehabilitation could enhance plasticity in the brain. In conclusion, the treatment and prevention of cognitive impairment in MS needs to remain a key research focus, identifying new interventions and improving clinical trial methodology.