What is brain health? Gavin Giovannoni Barts and The London
What is brain health?
Gavin GiovannoniBarts and The London
DisclosuresProfessor Giovannoni has received personal compensation for participating on Advisory Boards in relation to clinical trial design, trial steering committees and data and safety monitoring committees from: Abbvie, Bayer-Schering Healthcare, Biogen-Idec, Canbex, Eisai, Elan, Fiveprime, Genzyme, Genentech, GSK, GW Pharma, Ironwood, Merck-Serono, Novartis, Pfizer, Roche, Sanofi-Aventis, Synthon BV, Teva, UCB Pharma and Vertex Pharmaceuticals.
Regarding www.ms-res.org survey results in this presentation: please note that no personal identifiers were collected as part of these surveys and that by completing the surveys participants consented for their anonymous data to be analysed and presented by Professor Giovannoni.
Professor Giovannoni would like to acknowledge and thank several companies for making available data slides on natalizumab and alemtuzumab for this presentation.
Reasoning by analogy
Images courtesy of Professor Gavin Giovannoni /
ESRFend-stage renal failure
Images courtesy of Professor Gavin Giovannoni /
Epstein Bar Virus
Genetics
Vitamin D
Smoking
Risks
Adverse events
DifferentialDiagnosis
At risk
RIS CIS
Minimal impairment
Moderateimpairment
Severeimpairment
Terminal
Phase
MRI
EvokedPotentials
Lumbar puncture
BloodTests
DiagnosticCriteria
Cognition
Depression
Fatigue
Bladder
Bowel
Sexual dysfunction Tremor
PainSwallowing
SpasticityFalls
Balance problems Insomnia
Restless legsFertility
Clinical trials
Gait
Pressuresores
Oscillopsia
Emotionallability
Seizures
Gastrostomy
Rehab
Suprapubiccatheter Intrathecal
baclofen
Physio-therapy
Speech therapy
OccupationalTherapy
Functional neurosurgery
Colostomy
Tendonotomy
Studying
EmploymentRelationships
Travel
Vaccination
Anxiety
Driving
Nurse specialists
Family counselling
Relapses
1st line2nd line
Maintenance Escalation Induction
Monitoring
Disease-free
Disease progression
DMTs
Side Effects
Advanced Directive
Exercise
Diet
AlternativeMedicine
PregnancyBreastFeeding
Research
Insurance
Visual loss
PalliativeCare
Assistedsuicide
Socialservices
Legalaid
Genetic counselling
PreventionDiagnosis
DMTSymptomatic
Therapist
Terminal
CounsellingAn holistic approach to MS
Intrathecalphenol
Fractures
Movement disorders
Osteopaenia
Brain atrophy
Hearing loss
Tinnitus
Photophobia
Hiccoughs
DVLA
Neuroprotection
Psychosis
Depersonaliation
BrainHealth
CognitiveReserve
Sudden death
SuicideOCD
Narcolepsy
ApnoeaCarers
Respite
Hospice
Respite
Dignitas
Advanced Directive
Rhiztomy
Rhiztomy
Wheelchair
Walking aids
Blood/Organdonation
Brain donation
Exercise therapy
NABs
Autoimmunity
Infections
Outcome measures
WebResources
Pathogenesis
Doublevision
What isMS?
NEDA
T2TOCT
Neurofilaments
JCV statusPharma
Anaesthesia
Early intervention and long-term prognosis
www.msbrainhealth.orgImage reproduced with permission from Giovannoni G, et al. Brain health: Time matters in multiple sclerosis. 2015 Available at www.msbrainhealth.org/report Accessed 26 May 2016.
Incr
easi
ng d
isab
ility
Time
Intervention at diagnosis
Intervention later
Potentialrange ofoutcomes
No treatment
Later intervention
Intervention at diagnosis
Responsibility
Who should take responsibility?
• The person with MS?
• The HCP or neurologist?
• The healthcare system?
• The regulators?
• Society?
HCP, healthcare practitioner; MS, multiple sclerosis.
Neuro-restoration
Remyelination
Neuroprotection
Anti-inflammatory
Therapeutic pyramid
Anti-ageing
Brain Health Initiative
• Smoking• Exercise• Diet• Alcohol• Sleep• Co-morbidities• Infections• Concomitant medications
• ? Menopause / HRT
MS-specific
MS non-specific
What is brain health?
Relapses
Unreported relapses
Clinical disease progression
Subclinical relapses: focal MRI activity
Focal gray and white matter lesions not detected by MRI
Brain atrophy
Spinal fluid neurofilament levels
Etc.
Clinical activity
Focal MRI activity
Hidden focal and diffuse MRI activity
Microscopic or biochemical pathology
Biomarkers
NEDA
END-
ORGA
N DA
MAG
E
MS Specific Targets: MS Iceberg
MRI, magnetic resonance imaging; NEDA, no evidence of disease activity. Images reproduced with permission from: http://multiple-sclerosis-research.blogspot.com/2015/07/cortical-lesions-and-cognitive-ability.html Accessed 27 May 2016.
13
Rapid adoption of innovations has the potential to improve MS care
Reproduced and adapted from Rogers EM. Diffusion of innovation. New York: Simon and Schuster, 2003
100
80
60
40
20
0
Pro
porti
on o
f ado
pter
s (%
)
Innovators
Early adopters
Majority adopters
Late adopters
Laggards
30% tipping point
Time
14
Slow adoption of innovations results in healthcare inequity
Per
form
ance
Time1 2
1st line
2nd and 3rd line
Old
New
Newer3rd line
2nd line
1st line
15
0 20 40 60 80 100
Large disparities exist in access to disease-modifying therapies
DMT, disease-modifying therapy. 1. Hollingworth S et al. J Clin Neurosci 2014;21:2083–7; 2. World Bank, 2015. http://data.worldbank.org/indicator/SP.POP.TOTL; 3. MSIF, 2013. http://www.atlasofms.org; 4. Wilsdon T et al. 2013. http://crai.com/sites/default/files/publications/CRA-Biogen-Access-to-MS-Treatment-Final-Report.pdf. Figure reproduced from Giovannoni G et al. Brain health: time matters in multiple sclerosis. Available at: www.msbrainhealth.org
Newer DMTEstablished DMTNo DMT
All people with MS (%)
All data are from 2013
4
4
4
4
4
4
4
4
4
4
4
4
4
1–3
Established DMTsDMTs approved for relapsing forms of MS during the 1990s and reformulations or generic versions of these substances
Newer DMTsDMTs approved for relapsing forms of MS that have a different mechanism of action from established DMTs
16
Brain health: time matters in multiple sclerosis – a policy report
■ Brain health perspective■ Multidisciplinary international
author group■ Structured discussions
during 2015 ■ Evidence-based consensus
recommendations on:□ diagnosis□ therapeutic strategies□ access to treatment
www.msbrainhealth.org
International policy initiative
DMT, disease-modifying therapy. Images used with permission from Giovannoni G, et al. Brain health: Time matters in multiple sclerosis. 2015 www.msbrainhealth.org/report. Accessed 26 May 2016.
Stroke or brain attack: ‘time really is brain’
Passive Active
Defining the therapeutic target
Relapses
Unreported relapses
Clinical disease progression
Subclinical relapses: focal MRI activity
Focal gray and white matter lesions not detected by MRI
Brain atrophy
Spinal fluid neurofilament levels
Etc.
Clinical activity
Focal MRI activity
Hidden focal and diffuse MRI activity
Microscopic or biochemical pathology
Biomarkers
NEDA
END-
ORG
AN D
AMAG
E
MS Specific Targets: MS Iceberg
MRI, magnetic resonance imaging; NEDA, no evidence of disease activity. Images reproduced with permission from: http://multiple-sclerosis-research.blogspot.com/2015/07/cortical-lesions-and-cognitive-ability.html Accessed 27 May 2016.
Treatment effect on disability predicted by effect on T2-lesion load and brain atrophy
Meta-analysis of treatment effect on EDSS worsening (y) vs effects on MRI lesions and brain atrophy, individually or combined, in 13 placebo-controlled RRMS trials (13,500 patients)
Sormani MP et al. Ann Neurol. 2014;75:43-49.
BARTS-MS T2T-NEDA ALGORITHM
T2T = treating-to-target; NEDA = no evident disease activity
Choose therapy
A B C
Define the individual’s MS
Treatment failure?
• Patient’s preferences?• Your choice?
Individual measures:• Evidence of disease activity?• Tolerability/safety?• Adherence?• Drug or inhibitory markers,
e.g. NABs?
Monitoring
• MS prognosis based on clinical and MRI indices
• Life style and goals • Shared goals for therapy
Rebaseline
Rebaselining:• IFNβ, natalizumab, fingolimod,
teriflunomide, Dimethyl-Fumarate=3-6 months
• Glatiramer acetate=9 months• Alemtuzumab=24 months
Choose a therapeutic strategy
Maintenance-escalation Induction
Choose therapy
X Z
Rebaseline
Monitoring
Initiate or Switch or Escalate Rx Complete course / Re-treat
Breakthrough disease
Y
• Patient’s preferences?• Your choice?
NoYes Yes
• Only one licensed induction therapy at present
Ifn-β = interferon-beta; NABs = neutralizing antibodies; Rx = treatment;Giovannoni G et al. Multiple Sclerosis and Related Disorders 2015;4;329-33
Rheumatoid arthritisEnd-stage joint disease
Baseline Month 6
Month 12 Month 18
Baseline Month 6
Month 12 Month 18
Patient 1 Patient 2
End-organ damage
www.ms-res.org
Does the biology of MS change with time?
TOP: earlier natalizumab treatment favours annualised relapse rate outcomes
P values from a negative binomial regression model adjusted for gender, baseline EDSS score (<3.0 vs ≥3.0l), relapse status in the prior year (≤1 vs >1), prior DMT use (<3 vs ≥3), disease duration (<8 vs ≥8 years), and treatment duration (≥3 vs <3 years), except for the factor of interest. Error bars represent 95% CIs.DMT=disease-modifying therapy; CI=confidence interval.Wiendl et al. Presented at ENS; June 8–11, 2013; Barcelona, Spain,. P372.
NEDA outcomes with alemtuzumab:3-year follow-up of the CARE-MS studies
MRI, magnetic resonance image; CI, confidence interval.Adapted from Havrdova E et al. Presented on ACTRIMS/ECTRIMS, 2014, FC1.4.
↑32.2%P=0.0062
↑45.8%P<0.0001
CARE-MS I: NEDA by year
SC IFNB-1aALEM 12 mg
174369
170 356
—349
SC IFNB-1aALEM 12 mg
187405
173434
— 393
↑61.2%P<0.0001
CARE-MS II: NEDA by year
↑84.3%P<0.0001
Meningeal B-cell follicles in secondary progressive multiple sclerosis associate with early onset of disease and severe cortical pathology
Magliozzi et al. Brain 2007; 130:1089-1104.
Cortical and white matter demyelination
FemaleAge 47 yearsMS for 30 years
Proportion of cortex demyelinated=
59%
Schmierer-Lab, Blizard Institute
Intrathecal Antibody Response
local OCBs
local & systemic OCBs
systemic OCBs
normal / polyclonal
CSFSerum
Intrathecal or central compartment
Systemic or peripheral compartment
C
S
C
S
C
S
C
S
Meningeal Perivascular
Time is brain!
Stroke or brain attack: ‘time really is brain’
Passive Active
www.msbrainhealth.org
www.msbrainhealth.org
Baseline Month 6
Month 12 Month 18
Baseline Month 6
Month 12 Month 18
www.msbrainhealth.org
Neuro-restoration
Remyelination
Neuroprotection
Anti-inflammatory
Therapeutic pyramid
Anti-ageing
Brain Health Initiative
• Smoking• Exercise• Diet• Alcohol• Sleep• Co-morbidities• Infections• Concomitant medications
• ? Menopause / HRT
MS-specific
MS non-specific
Brain Health
Walk the talk!
2016Brain Health
Challenge
Barts-MS☑ Treat-2-Target
☑ Lifestyle
☑ Co-morbidities
☑ Wellness
☑ Treat-2-Target
☑ Prognosis
☑ Active MS
☑ Treatment
☑ Re-baselining
☑ Monitoring
☑ NEDA
#ThinkHand 95%
clinicspeak.com
clinicspeak.com
☑ Lifestyle
☑ Diet & supplements
☑ Exercise
☑ Smoking
☑ Alcohol
☑ Sleep
☑ Stress
Lifestyle modification in MS
John Saxton Department of Sport, Exercise and Rehabilitation Northumbria UniversityNewcastle Upon Tyne, UK
Morphological(Body
composition)
Cardio-respiratory
Metabolic
Motor
Immunological
Molecular
Muscular
Depression
Anxiety
Stress
Self-esteem
Cognitive function
Mood states
Locus of control
Perceived fatigue
Perceived ability to cope
PerceivedPhysical
attractiveness
Social integration
Enjoyment of life
Physiological Psychosocial
Health is a state of complete physical, mental and social well-being and not merely the absence of disease or
infirmity (WHO)
Positive side effects
Rietberg MB et al. (2004). Exercise therapy for multiple sclerosis. Cochrane Database of Systematic Reviews.
Strong evidence in favour of exercise therapy vs no exercise therapy in terms of:• Muscle power function• Exercise tolerance• Mobility-related activities
Exercise therapy is well tolerated
No evidence for a positive impact of exercise therapy on symptoms of fatigue
Cognitive dysfunction • Cognitive dysfunction is observed in up to 65% of PwMS and impacts
employability, activities of daily living, social and family functions and overall quality of life (Feinstein et al., Mult Scler Relat Dis 2013, 2: 4-12)
Systematic review: Sandroff et al., Neuropsychol Rev: Epub 22 July 2016
• Collectively, there is insufficient well-designed research to definitively conclude that exercise, physical activity, and physical fitness are effective for improving cognition in MS.
• Promising evidence from non-randomised trials may be useful for informing the development of better intervention research.
• Very common amongst PwMS: Annual prevalence rate of 20% and lifetime prevalence rate of 50% (Sadnovick et al., Neurology 1996, 46:628-632)
Cross-sectional study of 2459 PwMS: Taylor et al. BMC Psychiatry 2014, 14:327:
• Poor diet, low levels of exercise, obesity, smoking, marked social isolation and taking interferon were associated with greater depression risk in PwMS, whereas use of omega-3 FA and vitamin D supplements, frequent fish consumption, moderate alcohol consumption and meditation reduced depression risk.
Depression
Exercise prescription
F-I-T-TPRINCIPLE
TYPE
FREQUENCY
TIME
INTENSITY
Challenges for exercise studies in MS• Fatigue• Relapse• Heterogeneous range of symptoms, disabilities• Heat sensitivity• Flexible approach needed• Control of exercise stimulus
“Exercise training programs have traditionally been discouraged in the MS population because of the belief that they might exacerbate fatigue and other MS symptoms. To the contrary, recent studies have demonstrated positive effects of physical therapy and increased physical activity in reducing pain and improving mobility in MS patients.”
Filipi et al. (2010); Int J MS Care 12, 6–12.
Aerobic exercise studies
Resistance exercise studies Combined studies Other exercise
studies
Study design 8 x RCTs2 x Non-controlled1 x Controlled
2 x Non-controlled trials1 x RCT
3 x RCTs2 x Non-controlled
2 x Non-controlled
N 8 – 112 8 – 38 10 – 95 4 – 31
Exercise modality Arm/leg ergometryTreadmill/home walking
Machine exercises1 x upper & lower extremities2 x lower extremities only
Circuit training; combinations of aerobic, resistance, stretching and/or balance exercises
2 x Acquatic therapy
Total duration/ frequency
4-26 weeks / 1-5 x per week
8-10 weeks / 2 x per week
8-26 weeks / 2-5 x per week 8-12 weeks / 2-3 x per week
Intensity/volume Typically 30 min @ 55-80% VO2 max or predicted HRmax
1-4 sets of 8-15 reps (progressive based on Rep Max / MVC)
30 – 90 min per session No details given
Main results FSS: x x x x x √ MFIS: √MFI: √
Qualitative interviews: √MFIS: √FSS & MFI: √
FSS: xChalder: √MFI: xQualitative interviews: √ + xMFIS: √
Chalder physical: √MFIS: √
Notes Of the 5 largest controlled trials (N=39-112), 3 reported improvements in fatigue.
Key points
• Heterogeneous findings between studies• Studies have not targeted patients who are
experiencing significant levels of fatigue• Only a few studies have evaluated fatigue as
the primary outcome measure• Only 12/21 studies were RCTs• Choice of fatigue scale may have some
bearing on the results
☑ Co-morbidities
☑ Obesity☑ Hypertension☑ Glucose☑ Cholesterol☑ Smoking☑ Sleep disorders☑ Infections☑ Falls☑ Depression & anxiety☑ Con-medications
Comorbidities in Multiple Sclerosis
Ruth Ann Marrie, MD, PhDProfessor of Medicine & Community
Health SciencesUniversity of Manitoba
Winnipeg, Canada
Psychiatric Comorbidity is Common• Depression
– Up to 50% lifetime prev. (3X higher than gen pop’n)
– 12-month prev. 14% (vs. 5.9-7.3% in gen pop’n)
• Anxiety– up to 35% lifetime prevalence
– Generalized anxiety disorder, social phobias
• Other disorders → less studied– Bipolar disorder: 5%
– Psychosis: 0.9-1%
• Under-diagnosed & undertreatedMarrie RA et al. MSJ 2015;21:305-317
Most Common Physical Comorbidities in MS
• Hypertension* 18.6% (13.9-23.2%)• Hyperlipidemia 10.9% (5.6-16.1%)• Chronic lung disease 10.0% (0-20.9%)• Irritable bowel syndrome 12.2%
• Thyroid disease 6.4% (0.19-12.7%)• Psoriasis 7.7%
*leading causes of disability in gen. pop’n are hypertension, arthritis, back/ spine problems, lung disease, and heart disease
Marrie RA et al. MSJ 2015;21:263-281
Comorbidity is common at diagnosis• 4 Canadian provinces: 23,382 incident MS cases & 116,638
matched controls
Marrie RA et al. Neurology 2016;86:1279-1286
Vascular Comorbidity Accelerates Disability Progression!
Neurology 2010;74:1041–1047
HR 1.68; 1.51-1.87 (accounting for disability at dx, SES, race, tx…)
Median difference 6 years
Hospitalization rates & comorbidity status
No. MS pop’n
0 1.01 1.32 (0.96-1.83)
2 1.80 (1.35-2.40)3 2.11 (1.58-2.83)
≥4 3.65 (2.78-4.78)
Implications I• Comorbidity common in MS & affects outcomes• Consider when developing plans of care
• MS Team needs to be involved in: – diagnosis & management of comorbidity → depression,
anxiety, vascular in particular– educate patients & families
• Health promotion (next talk)– Address health behaviors: smoking, diet, weight,
physical activity– Preventive care
Conclusion
• Comorbidity is common in MS
• Associated with broad range of adverse
outcomes: disability, QOL, hospitalizations,
mortality
• Affects treatment choices & responses
• Requires team approach, and possibly changes
in models of care to achieve optimal outcomes
☑ Wellness
☑ Intellectual
☑ Emotional
☑ Physical
☑ Social
☑ Spiritual
☑ Occupational
☑ Environmental
Rheumatoid arthritisEnd-stage joint disease
Images courtesy of Professor Gavin Giovannoni and http://www.hopkinsarthritis.org/arthritis-info/rheumatoid-arthritis/ra-symptoms/
What next?
Example intervention
Specificintervention
Specificintervention
Specificintervention
Specificintervention
Improve accessto DMTs by…
Contributing factor
Early diagnosis
Aim: maximize lifelong brain health in people with MS and improve
outcomes
Contributing factor
MRI monitoring
Contributing factor
Optimize treatment for each individual
Action effect methodology is iterative; the diagram develops as different stakeholders are engaged
Engage with a wide range of stakeholders to gain buy-in and to agree on an overall aim, desired outcomes and
measure concepts
DMT treatment rates
The diagram acts as a ‘road map’ – a starting point for pilot projects in specific
healthcare systems
Local application
A quality improvement approach to measure local adoption of the recommendations
Agree on the overall aim, aspirations and scope
Agree on factors that contribute to the aim
Interventions are changes made to achieve the aim
Measure concept, are we seeing
improvement in a process/outcome?
Cause/effect arrow
Local application
M M M
M
M
M
M
MS Brain Health – a potential ‘tripadvisor’ for MS …
msAdvisor
msAdvisor Barts-MS, Royal London HospitalWhitechapel, London E1 1BB
Overall
Diagnosis
Monitoring
DMTs
Co-morbidities
Education
Relapses
62 reviews
38.6 days
868 MSers
54%
8.3 days
1211 MSers
187 reviews
Contact Staff Services For you search
Conclusions• MS is a bad disease
• Mortality, disability, unemployment, divorce, cognitive impairment, etc.
• On average early effective therapy is the only realistic option of preventing end-organ damage • NEDA and T2T are current treatment target (zero tolerance)• Beyond NEDA we need to target end-organ damage (brain atrophy,
CSF NF levels, etc.)• Brain Health initiative
• Are you prepared to join the challenge?• Pledge your support?• Be an early adopter?• Walk the talk?
www.ms-res.org
www.clinicspeak.com
www.msbrainhealth.org
@GavinGiovannoni
Thank You!