Multiple Sclerosis Lecture Slides PDF (UNSW, November 2022)

11/11/22 MULTIPLE SCLEROSIS Pathogenesis & Management Phu Hoang, PhD Senior Physiotherapist, MS Consultant, MS Australia Limited (MSL) Senior Research Fellow, Neuroscience Research Australia Conjoint Lecturer, UNSW Clinical Fellow – Australian Catholic University UNSW –EP – November 2012 1 Overv...

11/11/22 MULTIPLE SCLEROSIS Pathogenesis & Management Phu Hoang, PhD Senior Physiotherapist, MS Consultant, MS Australia Limited (MSL) Senior Research Fellow, Neuroscience Research Australia Conjoint Lecturer, UNSW Clinical Fellow – Australian Catholic University UNSW –EP – November 2012 1 Overview 1. An overview on prevalence & pathogenesis of MS 2. Common problems impacting mobility in MS ü Muscle weakness ü Spasticity ü Fatigue ü Structural and Functional changes q Joint contracture q Foot drop q Knee hyperextension 3. Strategies to improve mobility in MS UNSW –EP – November 2012 2 What is Multiple Sclerosis? ü Chronic neurodegenerative disease affecting central nervous system(CNS) ü Demyelination: destruction of the myelin insulation covering nerve fiber - disruption of transmission of information in the CNS ü Cortical lesions and deep grey matter lesions - decrease in grey matter (volume loss) – closely associated with physical and cognitive changes ü Progressive and unpredictable ü Exact cause remains unknown ü No cure ü ~26,000 – F:M = 3:1 ü 10 new cases/week - ~ 500 cases/year Carswell's Classical 1838 Illustration of "a peculiar diseased state of the spinal cord and pons", chiefly set apart by "a remarkable lesion of the spinal cord". UNSW –EP – November 2012 3 1 11/11/22 Prevalence of MS in Australia Prevalence 2010 = 95.5 Prevalence 2017 = 103.7 Reflect global trends and, likely reflects the increased survival of PwMS 50 new cases /week UNSW –EP – November 2012 4 World Map of MS MS Atlas - 2020 UNSW –EP – November 2012 5 How does a person get MS? Infectious agents (e.g. Epston-Barr virus) Other risk factors: gender, family history, smoking Genetic predisposition Abnormal immunological response M S Environmental factor Worsening factors: Lack of sleep, infections (flu), depression, smoking UNSW –EP – November 2012 6 2 11/11/22 Diagnosis of MS? Preclinical CIS Relapse-Remitting Secondary Progressive Clinical Threshold Atrophy and Axonal Degeneration Total lesion load Number of lesions McDonald Poser UNSW –EP – November 2012 7 Type of MS Clinically Isolated Syndrome Relapse forms of MS - RMS Relapse-Remitting MS Secondary Progressive Progressive forms of MS - PMS Primary Progressive MS • • • Active – Experiencing relapses of neurological symptoms – New or enlarging lesions visible on MRI Inactive/Stable - No apparent relapse or progression is noted Worsening – Experiencing an increase in neurological dysfunction or disability as a result of either relapses or progression. UNSW –EP – November 2012 8 Current Disease Modifying Therapies (DMTs) in MS - Oral tablets - 4 Brand name Aubagio® Gilenya® Mavenclad® Tecfidera® Generic name teriflunomide fingolimod cladribine tablets dimethyl fumarate Indications RRMS RRMS & Relapsing SPMS RRMS RRMS PBS Yes Yes (1/11/2019 Yes for 0.25mg (1/1/2019) capsules) Yes Side-effects Reduced lymphocytes, Reduced lymphocytes, abnormal liver enzyme levels abnormal liver enzyme levels Progressive Multifocal Leukoencephal opathy (PML) – JVC virus Reduced lymphocytes, UNSW –EP – November 2012 9 3 11/11/22 Current Disease Modifying Therapies in MS - Injection - 5 Brand name Avonex® Plegridy® Rebif® Generic name interferon b- interferon b- glatiramer 1a 1b acetate Betaferon® Copaxone® interferon b-1a interferon b-1a Indications RRMS RRMS & SPMS RRMS RRMS RRMS PBS Yes Yes Yes Yes Side-effects ‘flu-like’ symptoms ‘flu-like’ symptoms pain in the joints, sore muscles, feeling of weakness, itching, yellowing of skin, nausea, tiredness Injection site reactions redness, swelling, bruising, pain; flu-like symptoms dizziness UNSW –EP – November 2012 10 Current Disease Modifying Therapies in MS - Infusion - 3 Brand name Lemtrada® Ocrevus® Tysabri® Generic name alemtuzumab ocrelizumab natalizumab Indications RRMS RRMS & PPMS RRMS PBS Yes Yes – RRMS only No - PPMS Yes From 1/11/2019 for Paediatric patients Side-effects ‘flu-like’ symptoms ‘flu-like’ symptoms Progressive Multifocal Leukoencephalopathy (PML) Injection site reactions UNSW –EP – November 2012 11 Summary of the effectiveness of DMDs Tomas Kalincik et al., Neurology, 96 (5), 2/2021 UNSW –EP – November 2012 12 4 11/11/22 AUTOLOGOUS HAEMATOPOIETIC STEM CELL TRANSPLANT (AHSCT or HSCT) What is it? intensive form of treatment, involves 5 steps: 1/ release bone marrow stem cells, 2/ collecting AHSC,3/ freezing, 4/chemotherapy, 5/return AHSC back by infusion Evidence of effectiveness? not yet been tested in sufficiently large gold-standard, randomised controlled trials Australian AHSCT trial? 20 RRMS + 15 SPMS over 3 years. 60% no evidence of disease activity (70% RRMS), 73% no disability progression, 37% significant improvement in disability. 8 show disease continued to progress, 34% required RBC transfusion & 49% required platelet transfusion Summary • • • promising treatment for MS – aggressive – high risks Available in private Centres with different criteria and safety standards. ?? Effectiveness vs other treatments vs no treatment UNSW –EP – November 2012 13 The expanded Disability Status Score (EDSS) UNSW –EP – November 2012 14 Disease Steps in MS !""""#$%&'(" )""""*+(,"-+.'/+(+01"23+.+/(1"'/4$%&'("5'+06 7""""*$,8%'08"-+.'/+(+01"23+.+/(1"'/4$%&'("5'+06 9"""":'%(1";'48"27<"=880"$%">?@"&808%."A+0B$C0"D'486 E""""F'08";'48"2G"7<"=880"A+0B$C0"D'486 <""""H+('08%'("ICJJ$%0"2488,8,"0$"A'(K"7<"=8806 @""""LB88(DB'+%"2&'1"/8"'"=8A".08J.6 M""""M4D('..+=+'/(8 !"#"$ %&'($)'*++,)'-%./"$"01)'2,344,*5,,6 UNSW –EP – November 2012 15 5 11/11/22 Low physical activity level in people with MS The cumulative evidence suggests that individuals with MS are less physically active than non-diseased populations. (Motl, R. W., et al. (2005). "Physical activity and multiple sclerosis: a metaanalysis." Mult Scler 11(4): 459-463) UNSW –EP – November 2012 16 MS vs. Healthy controls Individuals with MS compared with Healthy controls ICF level Muscle strength4 Muscle fibres/ muscle mass2 9 BODY FUNCTIONS Cardiorespiratory fitness2 3 Risk of cardiovascular diseases2 4 Cognitive impairment6 Depression2 2 Fatigue8 Physical activity level1 6 Functional capacity/walking1 6 ACTIVITY Balance9 ,2 0 Falls2 0 ,3 3 Quality of life1 2 PARTICIPATION Employment11 UNSW –EP – November 2012 17 Symptoms of MS Source: USF Health - University of South Florida UNSW –EP – November 2012 18 6 11/11/22 Patient perception of bodily functions in MS Heesen et al., 2008 UNSW –EP – November 2012 19 Physical activity and exercise for people MS UNSW –EP – November 2012 20 Physical activity and exercise for people MS UNSW –EP – November 2012 21 7 11/11/22 Impaired mobility in MS – is there a clinical pattern? UNSW –EP – November 2012 22 Clinical features of impaired walking gait in MS 1/ Symptoms of Upper Motor Neuron Syndrome • Positive symptoms q Increased passive resistance to stretch Spasticity q Flexor spasms Only seen in advanced MS q Clonus Ankle joint/joint contracture ☑ • Negative symptoms q Weakness Lower limb & Flexors first ☑ q Incoordination ☑ q Fatigability ☑ 2/ Ankle joint contracture, foot drop, knee hyperextension ☑ UNSW –EP – November 2012 23 Muscle weakness ü *$.0"D$&&$4"D$&J('+40"/1"NA*I ü O8,CD8,"'/+(+01"0$"J%$,CD8"(838(."$="&C.D(8"=$%D8 ü P00%+/C08,"0$ o !"#$%&'()*$*%(+",-.-$/Q"""+%-0"/($*()*$*%(#"1%*#"2((()*$*%(1#-$( %".%1-$)"#$(&#+(((()&3-)&'()*$*%(1#-$(,-%-#4(%&$" o +-/1/"5-#+1."+(.6&#4"/(-#(.*)7*/-$-*#(&#+(.*#$%&.$-'"(,-8%"/(&#+((( )1/.'"()&// o 9*$*%5,&$-41"(:(+".'-#"(-#(0*'1#$&%;(,*%."(+1%-#4(/1/$&-#"+( .*#$%&.$-*#/(<"=4=(+"$"%-*%&$-#4(>&'?-#4@ UNSW –EP – November 2012 24 8 11/11/22 Muscle weakness ü F$A8%"(+&/"'==8D08,"=+%.0""" ü :.J8D+'((1"=(8R$%. '4,"B+J"'/,CD0$%. o S+J"=(8R$%." o T488"=(8R$%. o P4K(8",$%.+=(8R$%. ü UDDC%."38%1"8'%(1""2A+4,$A"$JJ$%0C4+016 UNSW –EP – November 2012 25 Prevalence of weakness Proportion of participants with muscle weakness (defined as muscle manual testing score ≤ 3/5) in one or more muscles in each disease step. Greyed areas are 95% confidence intervals. (Hoang et al, Disability and Rehabilitation, 2014; 36(19): 1588–1593) UNSW –EP – November 2012 26 Can weakness be improved? ü Yes! ü “Strong evidence in favour of exercise therapy compared to no exercise therapy in terms of muscle power function” (Rietberg et al, 2005_Cochrane systematic review) ü Compelling evidence is provided, that progressive resistant training performed over sufficiently long periods, improves functional capacity. (Kjolhede et al, Mult Scler 2015, 21:599-611) ü Clinical observations!! UNSW –EP – November 2012 27 9 11/11/22 Impaired/adaptive gait due to weakness UNSW –EP – November 2012 28 6 months later – strength/gait training UNSW –EP – November 2012 29 Spasticity in MS - a common and difficult problem to manage Proportion of participants with spasticity in each disease step. Greyed areas are 95% confidence intervals. (Hoang et al, Disability and Rehabilitation, 2013 under review) UNSW –EP – November 2012 30 10 11/11/22 Spasticity in MS UNSW –EP – November 2012 31 Spastic walking gait UNSW –EP – November 2012 32 Impaired mobility due to clonus UNSW –EP – November 2012 33 11 11/11/22 Management of spasticity ü Pharmacological: Oral Baclofen**, Diazepam, Intrathecal Baclofen (ITB, marijuana-based pharmaceutical* ü Botox – some temporary effects but not clinical meaningful ü More invasive: neurosurgical approach* ü Physiotherapy** UNSW –EP – November 2012 34 Oral anti-spastic agents ü Most commonly used: baclofen ü Often fail to provide adequate symptomatic control ü Factors to consider • Side effects: Benefits vs. Harmful side effects • Is it necessary? Affects functions? • Appropriate dosage? Frequency? ü New medication: Sativex®: • Marijuana-based – mouth spray – can be used with Baclofen • TGA approved (Novartis Pharmaceutical)- not yet available in Australia UNSW –EP – November 2012 35 Spasticity – evidence of physiotherapy ü Exercises: Hydrotherapy Unloaded leg cycling, passive stretch, eccentric exercise ü Physical modalities: ?FES; ?massage, ? Whole body vibration? (Huang, M., et al., 2017) ü There is 'low level' evidence for non-pharmacological interventions such as physical activities given in conjunction with other interventions (Amatya et al. (2013 Cochrane Database Syst Rev 2) UNSW –EP – November 2012 36 12 11/11/22 Spastic gait due to spasticity in the thigh UNSW –EP – November 2012 37 Proprioceptive Neuromuscular facilitation or PNF • Margaret Knott PT, and Herman Kabat MD in the 1940's to treat neurological dysfunctions • Promoting flexibility, developing muscular strength and endurance, improving joint stability or increasing neuromuscular control and coordination, PNF is a valuable part of every rehabilitation program. UNSW –EP – November 2012 38 Temporary effects of PNF UNSW –EP – November 2012 39 13 11/11/22 Temporary effects of WBV UNSW –EP – November 2012 40 Management of spasticity in MS - summary • Difficult problem – working on case-to-case • With appropriate patients, antispastic treatment, including pharmacotherapy and physiotherapy rehabilitation, may provide benefits (Oreja-Guevara et al., 2013) • Physiotherapy interventions may provide temporary benefits: ü PNF ü Vibration (under investigation) ü Eccentric exercises (under investigation) UNSW –EP – November 2012 41 DISCUSSION UNSW –EP – November 2012 42 14 11/11/22 Fatigue – another common problem in MS • Fatigue - one of the most debilitating symptoms in MS ü 65 - 80% ü Physical or mental weariness; lack of energy ü Daily basis, comes on easily and suddenly ü May occur early in the morning, even after a restful night’s sleep ü Tends to worsen as the day progresses ü Tends to be aggravated by heat and humidity*** • Management ü Aerobic exercise ü Medication: amantadine UNSW –EP – November 2012 43 Muscle Fatigue – another common problem in MS • Muscle fatigue in MS? ü Physical performance deteriorates after a period of time ü A few minutes to > 30 minutes ü Both central and peripheral origin • Management? ü Rest (few seconds to minutes) ü Assistive device (dictus band, AFO, stick, etc) ü Exercise (improve both central drives and peripheral changes) ü ? Medication: Fampyra UNSW –EP – November 2012 44 Heat-related Fatigue – another common problem in MS • Heat-related fatigue in MS? ü Heat intolerance ü Uhthoff’s phenomenon - a rise in core temperature of ~0.5˚C induces heat-related fatigue ü Cooling: stay inside, cooling vest, fan during exercise etc. UNSW –EP – November 2012 45 15 11/11/22 Cold fluid ingestion prolongs time to exhaustion in PwMS exercising in the heat * UNSW –EP – November 2012 46 Ankle joint contracture UNSW –EP – November 2012 47 Joint contracture Proportion of participants with joint contracture in each disease step. Greyed areas are 95% confidence intervals. (Hoang et al, Disability and Rehabilitation, 2014; 36(19): 1588–1593) UNSW –EP – November 2012 48 16 11/11/22 Prevalence of joint contractures UNSW –EP – November 2012 49 Eccentric exercise UNSW –EP – November 2012 50 Eccentric exercise UNSW –EP – November 2012 51 17 11/11/22 Preliminary results Changes in passive range of motion after 12 weeks eccentric training 90 Ankle angle Ankle angle 100 90 80 70 60 S1 S2 Baseline S3 S4 S5 Changes in active range of motion after 12 weeks eccentric raining 80 70 60 50 One week post training 11°± 5° S1 S2 Baseline S3 S4 S5 One week post training 10°±7° UNSW –EP – November 2012 52 Foot drop as consequence of muscle weakness DICTUS Band UNSW –EP – November 2012 53 Foot drop UNSW –EP – November 2012 54 18 11/11/22 Foot drop & Knee hyper-extension UNSW –EP – November 2012 55 Foot drop & Knee hyper-extension UNSW –EP – November 2012 56 Discussion UNSW –EP – November 2012 57 19 11/11/22 Falls in MS – highly prevalent UNSW –EP – November 2012 58 Falls in MS – highly prevalent UNSW –EP – November 2012 59 Falls in MS – highly prevalent UNSW –EP – November 2012 60 20 11/11/22 About 60% Pw will fall in next 3 months 600 500 N = 537 Fallers ≤ 1 (N = 300 or 56% ) 400 Frequent fallers ≥2 (N = 197 or 37% ) 300 200 100 0 Au s Sw e de n UK US A To ta l UNSW –EP – November 2012 61 Results UNSW –EP – November 2012 62 Step Training to improve balance UNSW –EP – November 2012 63 21 11/11/22 Interventions to reduce falls in MS I-FIMS q ACT – Sydney – Melbourne - Hobart q Completed recruitment 9/2019: N= 469 – Intervention = 237; Control = 232 q Intervention: Home based Smart Stepping Mat – at least 120 min/week in 6 months q Control: normal physical activities & exercises (same as Intervention) q Primary outcomes: Falls incidents in 12 months via monthly Falls Calendars UNSW –EP – November 2012 64 Interventions to reduce falls in MS I-FIMS – key findings q Significantly reduced the rate of falls in participants who completed >1 hour stepping exercises per week (IRR=0.62, 95% CI=0.39-0.98). q Significantly reduced stepping decision and movement times UNSW –EP – November 2012 65 SUMMARY • Impaired mobility/walking gait in MS can be improved • The early the treatments the better • Exercise for people with MS need to address multifactorial problems including underlying positive and negative features of UMN syndrome and associated problems such as joint contractures, foot drop, knee hyperextension • Long-term commitment is necessary giving the chronic and progressive natures of the problems • Recommended reading: ESSA position statement on exercise and people with mild and moderate multiple sclerosis UNSW –EP – November 2012 66 22 11/11/22 What Exercises? (EDSS ≤ 6.5) Aerobic exercise training Resistance exercise training Frequency Intensity* 2-3 sessions /week 40-60% of maximum predicted heart rate or 40-60% of VO2max or RPE =11-13** 2-3 sessions/week Initially 1 set of 8-15 repetitions (70-80% of 1RM) Time Initially, 10-30 minutes per session. 2-4 minutes rest between sets to avoid muscle fatigue. Type Bicycle ergometry, arm-leg ergometry, arm Weight machines, free weights, cable pulleys; ergometry elliptical trainer. Rowing and Or body weight exercises (e.g. sit-to-stand), elastic running for those with low EDSS resistance bands, aquatic exercises and calisthenics Progression Gradually increase to at least 30 minutes per session Increase towards 2- 4 sets of 8-15 repetitions (75-80 % of 1RM) depending on individual tolerance. 5-10 exercises Progress to up to 5 sessions /week, up to 40 minutes each at 70% VO2max or 80% maximum predicted heart rate and RPE approaching 15 out of 20. Clinicians may also consider prescribing high intensity aerobic interval training, i.e. alternate periods of intense activity with intervals of less intense activity (i.e. active periods of lower exercise intensity or periods of rest), as a method to employ progressive overload. UNSW –EP – November 2012 67 What Exercises? (EDSS ≤ 6.5) Combined training • • • • Stretching*** • • • Special considerations • • • • • Well-tolerated in individuals with MS Recommended that it is performed on alternate days with equal proportions of resistance and aerobic training If performed on the same day, begin with resistance training before proceeding with aerobic training Apply frequency, intensity, time, type and progression as recommended for each type of exercise above Recommended for people with MS with EDSS 6.5 or over or those with spasticity (often observed in the calf muscle or knee extensors) or joint contractures (often observed in the ankle) Stretching can be performed in a long sitting position or weight bearing position (standing frame or using a wedge) or in prone posture for knee extensors Duration: 5 - 10 minutes Recommended that all exercise training, especially resistance exercise, should be initiated and continued under supervision by clinical exercise professionals. If there are barriers to undertaking supervised exercise, at least two sessions supervised by clinical exercise professionals should be completed before recommending individuals with MS to undertake home-based unsupervised training program or at least until the person with MS is comfortable and safe with a home-based training program. Regular review is recommended. Adjust levels of exercise difficulties to accommodate fatigue. Some individuals with MS experience “exercise intolerance”. In these cases, exercise prescription may focus on purely maintaining functional mobility. Reduce exercise intensity during acute exacerbation of symptoms. Minimise the impact of exercise-induced heat-intolerance by taking cold drinks and/or exercise in a ventilated, air-conditioned environment. UNSW –EP – November 2012 68 Dr Paterson’s story UNSW –EP – November 2012 69 23 11/11/22 THANK YOU FOR YOUR ATTENTION UNSW –EP – November 2012 70 24