Meeting Report: 19th State of the Art Symposium 2017 by Medicalwriters

MEETING REPORT

TH STATE OF THE ART

SYMPOSIUM of the Swiss Multiple Sclerosis Society www.multiplesklerose.ch

MEETING REPORT SATURDAY, JANUARY 28TH, 2017 KKL, Luzern, Culture and Convention Centre

Lucerne, 28 January 2017

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GENERAL INFORMATION Venue KKL Luzern, Europaplatz 1, CH-6005 Lucerne www.kkl-luzern.ch

Programme committee Britta Engelhardt, Bern Adam Czaplinski, Zurich Tobias Derfuss, Basel Christian Kamm, Lucerne Patrice Lalive, Geneva Nadja Münzel, Nottwil Jürgen Pannek, Nottwil Myriam Schluep, Lausanne Chiara Zecca, Lugano

Organisation Swiss MS Society and its Scientifc Advisory Board

Contact Swiss MS Society, Josefstrasse 129, CH-8031 Zurich symposium@multiplesklerose.ch www.ms-state-of-the-art.ch

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TABLE OF CONTENTS

AGENDA 4 WELCOME FROM THE SWISS MS SOCIETY

NEUROREHABILITATION IN MS – TRYING TO MELT & SHAPE THEORY & PRACTICE OVER 30 YEARS

NEURO-UROLOGY – SUMMARY OF CURRENT TREATMENT & REHAB OPTIONS FOR PEOPLE WITH MS (PWMS)

NEUROPSYCHIATRIC ASPECTS OF MULTIPLE SCLEROSIS – AN UPDATE

CANNABINOIDS FOR PAIN AND SPASTICITY IN MS

Christoph Lotter

Jürg Kesselring

Jürgen Pannek

Pasquale Calabrese Claude Vaney

REHABILITATION – DOES IT ONLY START WITH VISIBLE IMPAIRMENT? 14 Regula Steinlin Egli

UPDATE ON NEW TREATMENTS

WORKSHOP A – NEW TOPICS IN NEUROREHABILITATION

WORKSHOP B – FATIGUE – DEFINITION, ASSESSMENT AND TREATMENT OPTIONS

WORKSHOP C – NEW TREATMENT OPTIONS FOR LOWER URINARY TRACT SYMPTOMS

WORKSHOP D – GAIT DISORDERS IN MS

Ludwig Kappos

Jens Bansi, Tim Vanbellingen

Lutz Achtnichts, Gianna Riccitelli

Brigitte Schurch, Nikolaus Veit-Rubin Gilles Allali, Ulrik Dalgas Aarhus

ABBREVIATIONS 26

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AGENDA

TIME

TOPIC

SPEAKER

10.00 – 10.10

Welcome from the Swiss MS Society

Dr Christoph Lotter, Zurich

10.10 – 10.40

Neurorehabilitation in MS – Trying to Melt & Shape Theory & Practice over 30 Years

Prof. Jürg Kesselring, Valens

10.40 – 11.10

Neuro-urology – Summary of Current Treatment & Rehab Options for PwMS

Prof. Jürgen Pannek, Nottwil

11:10 – 11:40

Neuropsychiatric Aspects of Multiple Sclerosis – an Update

Prof. Pasquale Calabrese, Basel

11.40 – 12.10

Coffee Break

12.10 – 12.35

Cannabinoids for Pain and Spasticity in MS

Dr Claude Vaney, Crans Montana

12.35 – 12.50

Rehabilitation – Does It Only Start with Visible Impairment?

Regula Steinlin Egli, Basel

12.50 – 13.15

Update on New Treatments

Prof. Ludwig Kappos, Basel

13.15 – 14.15

Lunch Workshop A – New Topics in Neurorehabilitation

Dr Bansi & Dr Vanbellingen

Workshop B – Fatigue – Definition, Assessment and Treatment Options

Dr Achtnichts & Dr Riccitelli

14.15 – 15.00

15.00 - 15.20

Coffee Break Workshop C – New Treatment Options for Lower Urinary Tract Symptoms

Dr Veit-Rubin & Prof. Schurch

Workshop D – Gait Disorders in MS

Dr Allali & Dr Dalgas

15.20 – 16.05

16.05

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Farewell Apero

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WELCOME FROM THE SWISS MS SOCIETY

CHRISTOPH LOTTER Zurich

Dr Christoph Lotter, the Vice Director of the Swiss MS Society, welcomed the attendees to the 19th State of the Art Symposium. He briefly presented the MS Society and highlighted that its aims are to find a cure for MS, end the discrimination and exclusion of people living with MS (PwMS), and improve their quality of life. In order to achieve these goals, the Swiss MS Society has created a strong multidisciplinary platform where people with MS, doctors, nurses, physiotherapists and other carers can network and collaborate. In addition, the

MS Society provides individual advocacy and financial counselling and aid to people with MS, encourages initiatives that foster social integration, provides support for family and carers, and finances research in the field of MS. Dr Lotter ended his presentation by reminding the audience that the neutral and independent characteristics of the MS Society could only be maintained, thanks to the help of generous donors.

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NEUROREHABILITATION IN MS – TRYING TO MELT & SHAPE THEORY & PRACTICE OVER 30 YEARS

JÜRG KESSELRING Valens

During the first presentation of the day, Prof. Kesselring from the Clinic of Valens presented his 30 years of experience in the field of MS. Prof. Kesselring has been interested in the rehabilitation of people with MS since 1980, when he was first introduced to the field of MS by Dr Ian McDonald. He was President of the Medical and Scientific Board of the Swiss MS Society from 1985 to 2000 and participated in the organisation of the first State of the Art Symposium in 1999. Prof. Kesselring was part of the research group that first characterised MS in Switzerland in 1994. They showed that one person was diagnosed with MS each day, and found a trend between late-onset or low-intensity childhood infectious diseases (measles, mumps, varicella, rubella) and MS development. Aetiological factors seemed to be present long before the onset of MS symptoms, most likely before puberty. Prof. Kesselring was also involved in multiple editions of a book, entitled “Magnetic Resonance Imaging in Multiple Sclerosis”, which describes the advancements of MRI research for MS diagnosis and characterisation. He was also present at the Scientific Symposium, held in Zurich in 1984, where the use of interferon (IFN) gamma in MS was discussed. Against the advice of experts, IFN gamma was tested as a potential treatment against MS and was found to worsen the disease. This led to the development of the gamma IFN antagonists as a disease-modifying drug for MS. Currently, the treatment landscape of MS is complex and composed of many different therapies that target relapse, immunemodulation, symptom relief and neurorehabilitation.

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Regarding neurorehabilitation, Prof. Kesselring presented his career-long experience and stressed the importance of working with a multidisciplinary team, centred around the people with MS, that involves carers, neurologists, nurses, physiotherapists, speech therapists, psychologists, etc. Clear, measurable and realistic goals should be defined and their achievement monitored through time. Prof. Kesselring highlighted that measuring progress in neurorehabilitation is often challenging. The concept of resilience and its four domains (physical, emotional, mental and spiritual) was introduced. Neuroplasticity – the ability of the brain to reorganise itself by forming new neural connections – could give access to increased resilience and should be trained in people with MS. The challenge lies in identifying ways to translate this theory into practical exercises and recommendations. At the Clinic of Valens, physical inactivity is considered a major risk factor. Training programmes, tailored to each patient’s condition regardless of the degree of fatigue or spasticity, have shown significant impact, not only on aerobic fitness, immunological parameters and cognitive function, but also on health perception, activity levels and quality of life. Additionally, the reduction of the Uhthoff’s syndrome through cooling was demonstrated, and cooling garments were mentioned that provide patients with a pragmatic tool to control heat-associated neurologic symptoms.

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To conclude, Prof. Kesselring gave the audience the three following take home messages: 1. The objective of neurorehabilitation is to encourage neuroplasticity 2. Neuroplasticity is central to learning and can be trained 3. Learning is most effective when tailored to the specific needs of each patient

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NEURO-UROLOGY – SUMMARY OF CURRENT TREATMENT & REHAB OPTIONS FOR PWMS

JÜRGEN PANNEK Nottwil

In his presentation, Prof. Pannek highlighted that symptoms that affect bladder or sexual function can have a profound impact on quality of life (QoL). Fifteen percent of people with MS (PwMS) already present with symptoms of neurogenic lower urinary tract dysfunction (NLUTD) at diagnosis. The incidence increases drastically over time, and almost all patients eventually develop NLUTD, which may be manifested by a variety of storage and voiding symptoms. People with MS may suffer from overactive bladders, leading to frequent urination with small amounts, problems emptying all the urine from the bladder, or even complete loss of bladder control. Symptoms of underactive bladder include increased residual urine or urinary retention, and the inability to sense when the bladder is full. In addition, NLUTD can be associated with urinary tract infections and secondary renal damage.

antimuscarinic drugs or external electrostimulation to reduce incontinence and the urge and voiding frequency. Minimally invasive therapies, like sacral neuromodulation or onabotulinum toxin (Botox®) injections into the bladder wall may be considered if first line treatment options fail.

Because the risk of renal damage correlates with the type of dysfunction, a thorough diagnosis and classification of NLUTD and the risk factors for renal damage are crucial in determining therapy goals. There is a broad spectrum of therapeutic options from which physicians can select the most appropriate one. While the main goals in patients with low risk of developing secondary renal damage are to control the symptoms and preserve or improve quality of life, the treatment of high-risk patients is based on urodynamic testing and must focus on avoiding future renal damage.

Symptoms of incomplete emptying of the bladder can have different causes: reduced bladder contractility, bladder outlet obstruction or impaired coordination between bladder contraction and sphincter relaxation. Depending on the underlying cause, therapy options may include pharmacological treatment, sacral neuromodulation or re-education of the pelvic floor and sphincter muscles.

Prof. Pannek outlined that patients with bladder overactivity and/or incontinence who are not able to undergo bladder training should be treated with

In case these treatment options are unsuccessful, some patients will need to periodically use a urinary catheter to keep the bladder from becoming too full and

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to avoid urine backflow to the kidneys. This so-called â&#x20AC;&#x2DC;intermittent self-catheterisationâ&#x20AC;&#x2122; can often be done by patients themselves. It is preferable to permanent indwelling catheters, because of reduced secondary complication rates and better quality of life. If permanent catheterisation cannot be avoided, suprapubic catheters are less prone to complications than transurethral catheters.

Prof. Pannek concluded his talk by stating that the disease course and symptoms of MS are different in every single patient. Therefore, a highly individualised, multidisciplinary treatment approach is needed to guarantee optimal care and to minimise long-term neuro-urologic consequences of MS.

Surgery may be required if all previous treatments have failed. There are different ways to approach this. One method is to create a way for urine to leave the body through an artificial opening (stoma). In another technique called bladder augmentation, the bladder is made larger to allow for safe storage of larger amounts of urine. Urinary tract infections are frequent in patients with NLUTD. There are no widely accepted guidelines on how to successfully prevent infections, but several regimens exist that may be useful in clinical practice. Sexual dysfunction has an important impact on quality of life in MS patients. Multiple medical and non-medical treatment options for erectile dysfunction exist. Nevertheless, premature ejaculation, loss of libido and loss of genital sensation remain challenges for the treating physician, and counselling of both patients and their partners is crucial in the treatment strategy.

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NEUROPSYCHIATRIC ASPECTS OF MULTIPLE SCLEROSIS – AN UPDATE

PASQUALE CALABRESE Basel

Prof. Calabrese began his presentation by explaining that the human brain is social and that it has evolved to allow for optimal collaboration between people. Its large number of densely interconnected and myelinated neurons allows humans to communicate in a complex way, have mental representations, memory systems, and emotional multiperspectivity. Brain atrophy and demyelination can disrupt these functions and have strong implications on social integration. Cognitive impairment (CI) is present in 40–60% of people with MS and often manifests as poor memory, and low speed and flexibility. Prof. Calabrese examined three common misbeliefs associated with CI in MS. 1.

Careful neuro-examination enables the detection of CI

A study published in 1999 showed that CI was only detected in 25% of cases when neuro-examination was based on the physician’s clinical impression. When examination was combined with screening, 73% of cases were detected. The best results were obtained with comprehensive testing (92% of cases with CI were detected).

MS is often called benign in patients who show mild or minimal disability (Expanded Disability Status Scale, EDSS, ≤3) for more than 15 years. Despite this common misbelief, almost half of these patients present CI, with symptoms including fatigue, depression, and lower societal and vocational activity. Prof. Calabrese showed data from a report published in 2012 that demonstrated that increasing disability, fatigue, depression and anxiety reduced work productivity and health-related quality of life in people with MS. Presenteeism – attending work despite not being able to perform – was reported in 47% of people with MS. Results that showed MS as a risk factor for job loss were also discussed. Additionally, work difficulties seem related to the loss of social cognitive abilities that allow adequate performance self-rating. In fact, interpreting signs sent by colleagues and superiors requires facial and gestural emotion recognition, traits that are often affected in people with CI. Even mild CI can have important consequences on social and community integration. 3.

Prof. Calabrese concluded that in MS, the neurologist’s clinical impressions are not sufficient to detect CI and that the development of reliable measuring tools is required.

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Patients with benign MS do not have CI

Neuropsychiatric problems should not be discussed in detail with people with MS to avoid stigmatising and alienating them

Prof. Calabrese highlighted that depression is the most common psychiatric comorbidity of MS, affecting almost 50% of people with MS in their lifetime. During

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the course of the disease, depression prevalence has two peaks: the first, at the time of diagnosis, and the second at a later phase, probably associated with loss of independence or with brain changes. Studies seem to show that people with a strong social network cope better and show a faster recovery than others without social support. Prof. Calabrese concluded his presentation by emphasising that mental health is paramount for physical health. In his experience, cognitive rehabilitation alone is less efficient at maintaining and even improving mental health than when it is in combination with physical exercise, lifestyle modifications through coaching, and psychosocial stimulation through social integration. He strongly advocated for a multidisciplinary approach to the management of MS.

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CANNABINOIDS FOR PAIN AND SPASTICITY IN MS

CLAUDE VANEY Crans Montana

One cornerstone of current long-term MS treatment is the alleviation of symptoms. Despite reports that the use of cannabis in medical therapy is effective in alleviating pain and spasticity, very few medications are discussed as controversially as cannabis, and many doctors are reluctant to prescribe the cannabis extracts that are on the market – i.e. nabiximols (Sativex®). Dr Vaney’s interest in using cannabis in medical therapy was sparked when he saw a 23-year-old MS patient who had to resort to cannabis to relieve his spasticity-related pain. At that time, evidence from clinical studies about the effect of delta-9-tetrahydrocannabinol (THC) in MS was sparse. Five years later, Dr Vaney designed and initiated one of the first large studies that compared oral cannabinoids to alleviate pain and spasticity in people with MS. The hemp plant contains over 60 different types of cannabinoid. Sativex® is marketed as a mouth spray and contains THC and cannabidiol (CBD), two of the main pharmacologically active compounds, in a 1:1 ratio. THC, the psychoactive substance in cannabis, also has antiemetic and analgesic properties and acts as a muscle relaxant. CBD exerts antipsychotic effects, therefore attenuating the psychoactive effect of THC. It was also shown to have anticonvulsive, anxiolytic, and neuroprotective properties.

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Effect on MS symptoms – spasticity and pain relief Despite the use of immunomodulatory drugs, MS remains a progressive disease with decreasing mobility. The three main problems affecting quality of life are the increasing grade of immobility, spasticity and neuropathic pain, as well as incontinence and bladder problems. A number of studies have shown significant subjective reductions of spasticity and neuropathic pain with orally administered cannabis extracts. Reduced urgency and fewer incontinence episodes were also observed. Additional data also indicated improved mobility (i.e. stride length and walking speed) with cannabinoids. Based on these results, nabiximols was licensed in several countries (e.g., Switzerland, UK or Canada). However, there is no evidence for a reduction of MS-associated tremor. As a potential drawback, there are some concerns that cannabinoids may exacerbate pre-existing cognitive problems.

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Impact on disease progression

Affordability / Price

In vitro evidence suggests a potential neuroprotective effect of cannabinoids – possibly through reduced release of glutamate. Animal experiments have corroborated these results by showing that mice without cannabis receptors develop substantial neurodegeneration after immune attacks. Unfortunately, it was not possible to confirm initial reports from large randomised clinical trials that showed a reduction of relapse rates during the first six months of cannabinoid use. The long-term disease progression rates were equivalent in both the cannabinoid and the placebo groups.

Depending on the actual product that is used, the daily price of medical cannabis ranges from ten to twenty Swiss francs. A prescription for narcotics/controlled substances is sufficient in the case of Sativex®. A special clearance from the Department of Public Health is required for the use of cannabinoid solutions or tinctures.

Tolerability – Side effects Drugs that are commonly used to reduce spasticity frequently induce sedation or muscle weakness. Cannabinoids, however, relieve spasticity without serious side effects. Clinical studies have shown that medical cannabis – with a reduced THC content of approximately 1% – is well-tolerated in the majority of patients. Nevertheless, suicidal tendencies and presence of psychiatric disorders are contraindications for cannabinoid use. However, in one of Dr Vaney’s studies, the drop-out rate was rather high (12%) and the dose had to be reduced in 26% of the patients due to poor tolerance.

Summary Taken together, there is moderate quality evidence to support the use of cannabinoids in relieving chronic pain, spasticity and bladder overactivity. Therefore, the pragmatic approach should be to consider cannabinoids if other treatment options do not adequately control spasticity or chronic pain.

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REHABILITATION – DOES IT ONLY START WITH VISIBLE IMPAIRMENT?

REGULA STEINLIN EGLI Basel

As a physiotherapist who specialises in MS, Ms Steinlin Egli often treats people with MS when they have already developed visible impairments. Many treating physicians are not aware of the benefits that early physical therapy can have on long-term quality of life and fail to refer people with MS to specialised physiotherapists in due time. Ms Steinlin Egli underlined that physiotherapy offers people with MS much more than massages and coordination training, for example appropriate training for relaxation or strength. During her presentations, she explored other lesser-known benefits of her field. The inactive lifestyle often observed in people with MS often comes from fear, based on a lack of information regarding the nature and frequency of exercises that are salutary. Through physiotherapy, people with MS can receive a personalised training programme with carefully planned resting time to avoid fatigue and recommendations, for example on appropriate garments for temperature control. Under appropriate conditions, sporting activities can be carried out in a sustainable way and improve quality of life in the long run. Another benefit of physiotherapy, if started early in the course of MS, is the possibility of detecting and addressing subtle symptoms before they become true risk factors. Likewise, as soon as the first signs of spasticity are observed, exercise can be modified to prevent reinforcing behaviours. Teaching people with MS exercises that can be done at home fosters self-management and perceived selfefficacy, which increase the likelihood of healthy life

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choices, motivation and compliance with medication. Once patients have learned strategies for home-based therapy, weekly visits to the physiotherapist are usually no longer required during early stages of the disease; exercise review and adaptation can be done less frequently. At the end of her presentation, Ms Steinlin Egli presented the Swiss association of physiotherapists who are specialised in MS – Fachgruppe Physiotherapie bei Multipler Sklerose – and encouraged all physicians present in the audience to refer their patients to a physiotherapist before visible impairments have developed.

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UPDATE ON NEW TREATMENTS

LUDWIG KAPPOS Basel

Traditionally, the concluding presentation of the plenary session is given by Prof. Kappos, who presents an overview of the recent advances in the treatment of MS. In the last year, promising data on new compounds to treat relapsing-remitting MS (RRMS) and, for the first time, progressive MS, were presented and published.

volume changes. Daclizumab is generally well-tolerated, but shows a slightly higher infection rate compared to interferon-beta 1a and skin reactions that warrant thorough monitoring.

The progress made in treating MS is based on the identification of appropriate drug targets through the interaction of basic and clinical research. With increasing understanding of the disease course of MS, more sensitive and accurate measures of treatment efficacy are developed, and innovative trial designs integrate the knowledge from previous studies. Since the last State of the Art Symposium, two compounds were approved by the health authorities. The novel treatment options include GlatiramylÂŽ, a new formulation of glatiramer acetate, and daclizumab (ZinbrytaÂŽ). Further therapeutics are expected to become available in the coming months.

Prof. Kappos presented recent data of selected compounds at various stages of clinical development. Ocrelizumab, an anti-B cell antibody is expected to gain approval by health authorities in the near future. Three phase III studies on the effect of ocrelizumab in relapsing MS (OPERA-1 and -2) and in primary progressive MS (ORATORIO) have recently been published.

Daclizumab Daclizumab is a monoclonal antibody that selectively binds to the a-subunit of the interleukin-2 receptor, and through this, exhibits an immunomodulatory function by inhibiting activated T-cell responses. Key results from the DECIDE study that compared daclizumab to interferon-beta 1a showed a statistically significant reduction in annualised relapse rate by 45% and a moderate deceleration on disability progression. In addition, daclizumab significantly reduced the number of new MRI-defined lesions and whole brain

Compounds in clinical development (Phase II/III)

The key findings of the OPERA trials were: highly significant reductions in disability progression and annual relapse rates when using ocrelizumab compared with three times weekly interferon-beta 1a injections, and a nearly complete prevention of newly occurring focal brain lesions. The incidence and spectrum of side effects were comparable to interferon, with a slight increase of infection rates in two years (58% vs. 52%), but not more serious adverse events (SAE). Ocrelizumab was the first compound to have shown a significant effect on disability progression for patients with primary progressive MS (PPMS) in a phase III study. Other compounds that were discussed included ofatumumab, an anti-CD-20 monoclonal antibody, that recently started phase III testing in RRMS, natalizumab which showed no clinical benefit compared with placebo for advanced secondary progressive MS (SPMS), and

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a new selective S1P1 and S1P5 modulator, siponimod. Siponimod was shown to have a statistically significant effect on disability progression compared with placebo in a large trial in advanced SPMS patients. In the last part of his overview, Prof. Kappos presented ongoing clinical research activities with neuroprotective and neurorestorative agents. High-dose biotin (MD1003) was shown to improve EDSS and Timed 25-foot walk test (TW25) scores in a phase II study with progressive forms of MS. Opicinumab (anti-LINGO-1) was associated with an improved conduction velocity in the optic nerve, thus demonstrating remyelination potential in one phase II study (RENEW). However, a second study (SYNERGY) did not confirm clinical benefit using a compound clinical outcome. The treatment landscape in MS is becoming more and more complex and the new compounds need to be incorporated into the therapy algorithms and daily clinical practice. For the first time, valuable treatment options are becoming available for progressive forms of MS and will certainly improve the outlook for people with MS.

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WORKSHOP A – NEW TOPICS IN NEUROREHABILITATION

JENS BANSI Valens

Despite the availability of disease-modifying pharmacological therapies and treatment options to control MS-associated symptoms, people with MS still develop severe neurological disabilities over the course of the disease that require non-pharmacological rehabilitation. Dr Bansi and Dr Vanbellingen gave an overview of the neurorehabilitation and exercise regimens that have become an integral part of MS therapy.

Getting the dosage right – the relevance of adequate training intensities during neurorehabilitation in PwMS In his opening talk, Dr Bansi discussed the role of exercise intensity during neurorehabilitation with people with MS and outlined the effect on cardiorespiratory fitness, cognition, fatigue and immune functions. It is known that chronic inactivity leads to higher levels of cumulative inflammation and neurodegeneration in people with MS. This suggests that exercise may be an alternative strategy to deter loss of function. It is also known that the level of exercise intensity might be of relevance. The key question is how to find the right amount and intensity of exercise for each individual patient and how this activity level can be quantified. Dr Bansi described how to design exercises to improve cardiorespiratory fitness in people with MS with different levels of impairment. Individuals with mild-to-moderate impairment can effectively exercise on a cycle ergometer. They can reach 80% of their maximal heart rate (HRmax) or maximal oxygen consumption (VO2 max) – a higher

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threshold than initially expected. Using a step-wise protocol to increase the watt-loading in increments of every second minute, the exercise quality can be quantified accurately. In the first exercise study using cognition as a primary endpoint, 65 patients with mild-moderate MS (EDSS 6.5) were allocated to either five-times weekly continuous cycling for 30 minutes at 70% of their HRmax, or three times weekly exercise at 85–90% HRmax for three consecutive intervals of two minutes. There were no changes in the subjective feeling between the two arms, but the high intensity group enjoyed the short intense work-out. They also performed better in an assessment of their cognitive performance than the group who exercised five times per week at lower intensities. There is evidence that high-intensity exercise is safe. A transient exacerbation of symptoms during less than 12 hours was seen in only one case. While high-intensity exercise in moderate MS is mostly restricted to cycling, people with milder forms of MS can efficiently work out with other forms of exercise (e.g., aquatic exercise, kickboxing or using a climbing wall) and also get positive effects on their gait quality and balance. Designing training programmes for individuals with severe impairment (EDSS >7.0) remains a challenge. Moderate endurance and resistance exercises are suitable, with augmented watt loading over time while remaining in the tolerable intensity range.

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Upper limb neurorehabilitation in MS In the second part of the workshop, Dr Vanbellingen gave an overview of the importance of reliable, feasible upper limb neurorehabilitation methods and therapeutic assessments. He also demonstrated that upper limb training has a positive impact on white matter structures. Apart from walking disabilities, fatigue and cognitive deficits, upper limb dysfunctions are the most important and most widespread deficit in people with MS. In mild forms of MS, 70% of patients suffer from upper limb dysfunction, while in advanced disease stages (EDSS >6.0), almost all patients are affected. Standardised upper limb assessment tests reliably measure therapeutic outcomes and utilise multidimensional parameters such as those in the framework suggested by the International Classification of Functioning, Disability and Health (ICF); these include strength, tactile sensation, spasticity, and ataxia, amongst others. Standardised screening tests for dexterity include flipping a coin between your fingers or the 9-hole peg test (9-HPT). These assessments evaluate different aspects of dexterity. People with MS can, for example, reach normal levels in a 9-HPT, but show dexterity deficits in the coin-flip test or vice versa. Other methods utilise patient questionnaires to assess dexterity (e.g., Arm Function in Multiple Sclerosis Questionnaire (AMSQ), or wearing wrist-band sensors that measure how often the upper limbs are used). At the

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Neurozentrum at the Luzerner Kantonsspital, a novel outcome checklist was developed. A multidisciplinary team of nurses, physiotherapists, neuropsychologists and others record assessment scores in a standardised fashion at the time of admission to the centre and before discharge of the patients. It is crucial that the tests are not too time-consuming to easily fit them into the therapeutic schedule. In addition, the Luzern ICF multidisciplinary scale was developed (LIMOS) to assess these dysfunctions. New tablet-based tests (e.g., electronic 9-HPT), Kinectbased systems, or robot-based assessments have recently been developed to measure outcomes. Direct task-oriented training seems to deliver the highest level of evidence for improvement of upper limb dysfunction, both on an activity level and on a subjective level, however, further dose-specific trials are needed. Recent data have also demonstrated that upper limb training has a positive impact, as it better preserves white matter density in the corpus callosum and the cortical-spinal tract, compared to no exercise.

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WORKSHOP B â&#x20AC;&#x201C; FATIGUE â&#x20AC;&#x201C; DEFINITION, ASSESSMENT AND TREATMENT OPTIONS

LUTZ ACHTNICHTS Aarau

Dr Riccitelli began this afternoon session explaining that fatigue is the most common comorbidity in MS, with more than 90% of people affected. It is considered by patients to be the most disabling symptom of their disease and is known to worsen with elevated temperatures, spasticity, stress and depression. The aetiology of fatigue remains unknown. Cortical and subcortical demyelination and axonal loss have been cited among the hypotheses, as well as neuroimmune dysregulation and neuroendocrine dysfunction. Despite its enormous prevalence, fatigue is not clearly defined in the literature, and what is difficult to describe is often difficult to diagnose. According to patients, fatigue is defined as excessive tiredness, malaise and weakness. Researchers and physicians define it as exercise-induced reduction of voluntary muscle activation and also recognise its subjective dimension: a lack of physical and mental energy. Dr Riccitelli highlighted the difference between performance fatigability and perceptions of fatigue; Perceived fatigue relates to subjective feelings of weariness, such as an increasing sense of effort, an imbalance between effort and performance, and exhaustion. On the other hand, fatigability is objectively assessed as the magnitude, or rate of change, of a measureable performance criterion over time relative to a reference value. During prolonged testing in MS patients, changes in objective cognitive performance can occur independently of subjective changes in perceived fatigue. A key aim of clinical research is the understanding of the

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relationship between fatigability and fatigue complaints. Trait fatigue is defined as a stable state that expresses the global status of patients while state fatigue is the transient condition characterised by a decreased performance during acute effort. She also mentioned that various secondary factors can cause fatigue or modulate its level (e.g., medications used to treat MS or lack of sleep caused by several MS-associated symptoms), thus increasing the challenge associated with fatigue assessment and quantification. Currently, the most widely-used assessment tools for fatigue measurement are subjective and based on patients self-reporting the frequency and severity of episodes. They can be unidimensional (typically based on an visual analogue scale) or multi-dimensional (taking into account the cognitive and motor/physical dimensions) and are practical for use in daily clinical practice. The social dimension is rarely included in these tools. Conversely, objective measures are not common and are limited to research. Fatigability is often measured during a prolonged physical task, and motor domain measures include peak force as well as the evolution of movement through time and space. To quantify the cognitive domain of fatigue, reaction time and accuracy are often measured and performance at a task is compared before and after a fatigue-inducing exercise.

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Dr Riccitelli finished her presentation by summarising a few key points that are useful for the management of fatigue symptoms in MS: •

•

Fatigue is not a unitary phenomenon. Rather, fatigue should be distinguished from related phenomena and its distinct domains identified. To distinguish fatigue from related phenomena, it should be recognised that altered perceptions of fatigue be either a primary or secondary manifestation of disease. It is important to screen for fatigue related phenomena in patients complaining of fatigue and to treat these issues when present. Performance fatigability and perceived fatigue are distinct from each other and may also be independent. For example, changes in cognitive performance can occur independently of changes in perceived fatigue. Causal factors that can influence fatigability or perceived fatigue should be identified. Such factors may be homeostatic and physiologic in the case of fatigue, while peripheral and central factors may influence fatigability. Finally, tools for assessing distinct domains and potential confounds of fatigue can support effective treatment plans for fatigue in MS.

Dr Achtnichts clarified that fatigue cannot be detected by conventional MRI. However, there seems to be a relationship between brain atrophy observed on MRI and fatigue.

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Among the most effective treatment options against fatigue, Dr Achtnichts cited physical exercise. Studies have demonstrated that 90 minutes of exercise per week are sufficient to improve quality of life significantly and that non-aerobic training seems more effective than the aerobic option. Mindfulness training has also shown positive effects on depression, anxiety and fatigue. Some studies have found that cognitive behavioural therapy has a positive effect on fatigue. Because finding a therapist is often challenging, online tools have been developed (such as Elevida) and will be launched soon. Electromagnetic therapies may also have a positive impact on fatigue, but neither Dr Achtnichts nor Dr Riccitelli reported having experience with it. Pharmacological treatments include amantadine, modafinil, aspirin, and 4-aminopyridine, as well as over-the-counter supplements such as vitamin B1, ginseng and vitamin D. Disease-modifying drugs like natalizumab, for example, also seem to improve fatigue, but so far, no specific studies have been carried out. Dr Achtnichts ended this workshop session by underlining the lack of clear clinical guidelines on how to treat and manage fatigue. He presented the recently published “Berlin Treatment Algorithm”, which contains recommendations for the treatment of MS-related fatigue (Veauthier C, et al. EPMA J. 2016;7:25) and encouraged other physicians to follow it.

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WORKSHOP C – NEW TREATMENT OPTIONS FOR LOWER URINARY TRACT SYMPTOMS

BRIGITTE SCHURCH Lausanne

Conservative management of lower urinary tract disorders in MS patients Prof. Schurch opened the workshop with a comprehensive overview of conservative management options for lower urinary tract dysfunctions (LUTD). The majority of people with MS develop LUTD over the course of the disease and the severity of symptoms increases with the duration of the disease. The exact nature of the disorder is dependent on the location of the neurological lesion(s). While suprapontine lesions are associated with storage symptoms, i.e. bladder overactivity, spinal lesions can lead to both storage and voiding symptoms through detrusor overactivity and detrusor sphincter dyssynergia. Sacral and infrasacral plaques are predominantly associated with voiding symptoms.

NIKOLAUS VEIT-RUBIN Lausanne

Unfortunately, disease-modifying therapies only have a limited impact on LUT symptoms and management of LUTD requires a long-term multidisciplinary approach. Oral agents, especially anti-muscarinics, are the firstline treatment. Their use may be associated with an increased risk of cognitive impairment. A variety of oral antimuscarinic agents with different abilities to cross the blood brain barrier (BBB) are available. To minimise central side effects, compounds that selectively bind to the M3 subclass of receptors (e.g. darifenacin) or that do not cross the BBB (e.g. trospium chloride) should be preferred. There is promising data showing increased storage capacity and decreased voiding frequency with a b3-adrenoreceptor agonist, but longer term data are required to confirm these findings. In case oral agents are poorly tolerated or inefficient, a variety of other therapeutic options are available. Multiple studies have shown that non-invasive posterior tibial nerve stimulation (PTNS) at the ankle level is efficient in inhibiting the voiding reflex in an overactive bladder and in improving urodynamic parameters (i.e. daytime frequency, nocturia, or voiding volume). Generally, the treatment is performed once a week for twelve sessions. If the therapy is efficient, it can be repeated indefinitely, based on need.

Lower urinary tract dysfunction in the neurological patient: clinical assessment and management – Panicker et al. Lancet Neurol. 2015; 14:720-32

An alternative approach to treating bladder overactivity is chemical neuromodulation using onabotulinum toxin A (Botox®) injections into multiple sites of the detrusor muscle. Data from initial studies suggest that two weeks after the injection procedure, 90% of patients become continent. The effect is long-lasting, with a median

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duration of 42 weeks until retreatment is requested. Randomised, placebo-controlled studies comparing 200 with 300 units of botulinum toxin did not reveal any differences in efficacy or duration of treatment effect. In over 75% of patients, incontinence improved by over 50%, and 40% of patients reached full continence. One problem associated with botulinum injections is the occurrence of urinary retention that requires intermittent catheterisation. Studies are ongoing to assess the efficacy of lowering the botulinum dose to reduce the catheterisation rate. Prof. Schurch recommended using 100 or 200 units, based on the individual patient’s disease parameters and preference.

Posterior tibial nerve stimulation (PTNS) – A new promising therapy option for LUTD In the second part of the workshop, Dr Veit-Rubin presented a 6-month multicentre study (OPTIMIST) that prospectively evaluated the efficacy and safety of a new implantable tibial nerve stimulation system (RenovaTM). The goal of neuromodulation is to stimulate peripheral nerves to obtain a central response. Various studies with percutaneous PTNS showed significant response rates of 60–80% in terms of day- and night-time voiding frequencies, voiding volume, and reduction of leakage episodes. Contraindications for PTNS include pregnancy, having a pacemaker or implanted defibrillator, tendency of bleeding, and peripheral nerve damage. The treatment is generally safe, with only a few, minor transient side effects at the insertion site of the needle.

19th State of the Art Symposium

According to the guidelines of the American Urological Association (AUA) and the National Institute for Health and Care Excellence (NICE), percutaneous neuromodulation is a third-line therapy option after failure of first-line behavioural therapies and secondline oral antimuscarinic medications. Studies have shown that PTNS effects are sustainable. Without any major safety concerns, the treatment can be repeated. Treatment frequencies range from 3-times weekly stimulations to fortnightly sessions. The major drawback of this maintenance therapy is the fact that patients have to repeatedly attend an in-patient procedure. To alleviate this need, the RENOVA nerve stimulator system device was developed. The patients receive a passive implant that is wirelessly powered and controlled from a wearable external unit. An electrode of 2.5 cm in length is implanted at the level of the ankle close to the area of the tibial nerve under local anaesthesia. Sensory and motor responses are tested, and the device is fastened with two stitches to the nerve fascia. In the OPTIMIST study, 36 patients with overactive bladders were implanted with the device at four centres. The primary endpoint was the incidence of system or procedure-related SAEs. Only one SAE that required removal of the implant occurred (inflammation of the implantation site). After six months, urinary incontinence had improved by at least 50% in 51.7% of patients, with 27.6% reporting no leakage episodes. In

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addition, the urgency, and the number of voids per day decreased significantly. In conclusion, the new RENOVA system offers a minimally invasive, MRI-compatible therapy option without the need for repeated invasive neuromodulations. At the time of writing, a large, multicentre trial is in progress to confirm the presented preliminary data.

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WORKSHOP D – GAIT DISORDERS IN MS

GILLES ALLALI Geneva

Gait disorders are very prevalent in people with MS. They tend to worsen with disease progression and advance more rapidly in people with progressive types of MS than in those with RRMS. Their impact on daily life is very large and patients report walking to be the most challenging aspect of their disease. Dr Allali opened this workshop session by explaining that gait impairment and cognitive dysfunction are interconnected and that measuring one can help to detect the other. Dr Allali defined gait as a multisystem that can be affected by MS-related factors, such as treatment side effects, or non-MS-related factors, such as comorbidities or environmental factors. Because gait disorders start early in the course of MS, careful and precise measurement of gait performance can help predict and avoid falls and other gait-associated adverse events. However, the most commonly used measurements (EDSS and gait speed) do not allow detection of the first signs of gait disorders. In healthy individuals, gait is characterised by randomly distributed stride length and time. Much like with aging-related gait disorders, early in the course of MS, stride time variability increases. This may represent an abnormal subclinical parameter. A study was presented that compared the power of gait variability versus EDSS in predicting falls. Those who fell during study duration had a history of previous falls, higher EDSS and different stride time variability than patients who did not fall. Statistically, stride variability was found to have higher predictive value than EDSS.

19th State of the Art Symposium

ULRIK DALGAS Aarhus

Gait variability is influenced by locomotor factors, visual and cognitive parameters, pain, and fear of falling. Fear of falling, which may be measured using the Falls Efficacy Scale, influences gain variability, especially during dual tasks – combined cognitive and physical activities like walking while counting. Postural control associated with memory and attention in people with MS is also influenced by fear of falling. Dr Allali showed a video recorded in his laboratory of a person walking in a straight line, without any measurable sign of a gait disorder. When asked to count backwards while walking, the same person was unable to perform the motor task and almost fell over. The study carried out by Dr Allali and his team has shown that, when unable to perform dual cognitive-motor tasks, people with MS tend to prioritise the cognitive task, which is making it unsafe in everyday life. People with MS should be trained early in the course of their disease to prioritise motor tasks. During the second half of the workshop, Dr Dalgas reviewed the properties of the instruments most commonly used to characterise gait in people with MS. The 6-minute walk test (6MWT), the timed 25-foot walk test (T25WT), and the 12-items MS walking scale (MSWS-12) were examined. While validity, reliability and minimal clinically important difference (MCID) were comparable between tests, responsiveness was highest with MSWS-12 and lowest with T25WT. Dr Dalgas also discussed variations in gait speed during 6MWT (and 10MWT). Variations were larger when people were instructed to walk at their “usual” or “self-

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selectedâ&#x20AC;? speed than if maximal speed was instructed. Variation in gait speed is substantially larger for slow walkers, which affects the interpretation of walking tests in these patients.

studies have shown fampridine to have a positive impact on gait in a subset of people with MS; however, further studies are required.

To close this workshop session, Dr Dalgas discussed treatment options for gait disorders. He highlighted the benefits of physical exercise on gait maintenance and on improvement of gait disorders and mentioned that

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ABBREVIATIONS

AE – Adverse events

OAB – Overactive bladder

BBB – Blood brain barrier

PPMS – Primary progressive MS

CBD – Cannabidiol

PTNS – Posterior tibial nerve stimulation

CI – Cognitive impairment

PwMS – Person/people with MS

CNS – Central nervous system

QoL – Quality of life

CSF – Cerebrospinal fluid

RRMS – Relapsing remitting MS

DMT – Disease modifying therapy

SAE – Severe adverse events

EDSS – Expanded Disability Status Scale

SPMS – Secondary progressive MS

IFN – Interferon

THC – Delta-9-tetrahydrocannabinol

MCID – Minimal clinically important difference

TW25 or T25WT – Timed 25-foot walk test

MRI – Magnetic resonance imaging

6MWT or 10MWT – 6 or 10-minute walk test

MS – Multiple sclerosis

9-HPT – 9-hole peg test

MSWS-12 – 12-item MS walking scale NLUTD – Neurogenic lower urinary tract dysfunction

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