small vessel disease and post stroke cognitive impairment
TRANSCRIPT
Small vessel disease and post stroke
cognitive impairment
Dr Fergus Doubal
Stroke Association Clinical Senior Lecturer
Consultant Stroke Physician and Geriatrician
Royal Infirmary of Edinburgh
Outline
bull What is small vessel disease
bull Why does it happen
bull Why does it matter including links between stroke and dementia
bull How should I manage patients with SVD
Cerebral Small Vessel Disease
Recent small
subcortical
infarct
White
matter
lesions
Perivascular
SpacesMicrobleeds
25 of stroke
Age
Hypertension
Disability
Cognitive impairment
Dementia
Stroke risk
depression inflammation amyloid
Lacune
DWI FLAIR FLAIR T2 T2GRE
lsquosilentrsquostroke
Small Vessel Disease lesions
Largely Variable Terminology
Slide courtesy J Wardlaw
Radiological features of Silent CVD
Wardlaw JM Smith EE Biessels GJ et al Neuroimaging standards for research into small vessel disease and its contribution to ageing and neurodegeneration The Lancet Neurology 201312822-838
Radiological changes of ldquonon silentrdquo SVD
Lacunar stroke
ICHMicroinfarcts
Will better technology find moremarkers
Features also visible on CT
R L
atrophy
old infarct
WMH
lacune
Thinning of overlying
cortex
Acute small subcortical
infarct may
bull cavitate
bull disappear
bull stay a WMH
bull expand
bull affect the cortex
bull affect the brainstem
and spinal cord
WMH can
bull increase
bull shrink
bull white matter atrophy
bull cortical atrophy
Lacunes and
microbleeds also
appear and disappear
Small vessel disease effects are diffuse and dynamic
Wardlaw JAHA 2015 METACOHORTS Alz Dem 2016
Wallerian
degeneration
ldquoNormalrdquo white matter
is diffusely abnormal
closer to lesions as
lesions increase
Reasons for variability reversibility incompletely understood
Small vessel disease links stroke and dementia
Dementia Stroke
Imaging defines SVD
Unknown causes SVD
Endothelial Damage
Inflammation
Impaired Glymphatic
Drainage
Vessel Stiffening
Vessel Occlusion
lsquoSmall Vessel Diseasersquo matters to patients (JLA)
Poor blood vessels worse Alzheimerrsquos
lsquoLacunarrsquo
Stroke
3 million per year worldwide
35000 per year in the UK
Up to 16 million dementias
worldwide
Few die
A fifth are left dependent
A third have cognitive impairment
Balance and walking problems
Mood ndash common cause of depression at
older ages
20-25
Vascular
Dementia25-45
Stroke leads to dementia
7-30 in 1st year after stroke severity pre-existing cognitive decline
Stroke Cognitive impairment
Prediction of dementia is difficult
bull lsquoDementiarsquo tests focus on memory ndash other abilities are more affected
bull Tests often too long and tiring
bull Patients may not be able to do some tests after stroke
bull Donrsquot account for previous cognitive ability but this is the strongest predictor of cognitive problems after stroke
bull REGARDS cohort in US
bull 24000 pts gt45yrs fu from 2003 for 6 yrs
bull Investigated acute and chronic cognition post stroke
bull Global cognition ndash SIS (six item screener)bull Executive functioning and memory
500 patients had stroke
JAMA 2015
Results
Incident stroke
Acute significant decline in global cognition and
memory
Accelerated decline in global cognition and
executive function
Cognitive decline predicts stroke
bull 930 men in Sweden without strokebull 13 years follow-up
bull Worse performance on a lsquojoin the dotsrsquo test predicted stroke
Cognitive decline predicts Stroke
fastest
slowest
Leiden 85+ Study 480 subjects 85 years
In the very elderly cognition predicts stroke better than vascular risk factors
Cognitive decline predicts stroke
Sabayan B et al Stroke 2013441866-1871
Vascular risk score Memory test
Cognition impaired after even minor stroke
Patients n=135 1 year after with minor stroke
median age 66 (IQR 56-75)
17 ACE-R lt82 (lsquodementiarsquo)
R p
Age -031 0001
Pre-morbid IQ 092 lt00001(National Adult Reading Test)
WMH score 158 003
Not NIHSS old stroke lesion
location lacunar vs non-lacunar
etc
Makin et al 2014
Idyll Zealot Gist Superfluous
Simile Deny Ache Banal
Naiumlve Depot Beatify Facade
Catacomb Equivocal Gauche Placebo
Deacutetente Heir Aeon Puerperal
Chord Sidereal Quadruped Aver
Rarefy Bouquet Abstemious Rarefy
Topiary Radix Debt Assignate
Capon Thyme Drachma Sidereal
Topiary Prelate Demesne Syncope
Labile Procreate Subtle Gaoled
Courteous Gouge Hiatus Psalm
Campanile Leviathan Aisle Cellist
White matter hyperintensities
mild
severe
Age 50-69 7 70-89 17 +
risk of dementia
Debette BMJ 2010
ldquoTotal SVD burdenrdquo and cognition
Staals Neurology 2014 +Neurology Patient page
Staals NBA 2015 Karema Mol Psych 2015
Simple sum score or more complex
latent variable model
Higher SVD burden associated with
Poorer general cognitive ability
Full score β -008 p=002
Without WMH β -01 p=04
Staals et al Neurology 2014 NBA 2015
bull Working party consensus
bull Recommends cognitive screeningbull Examples are MOCA or the Oxford Cognitive Screen
RCP 2016
SVD Treatment options ndash consider aim
bull No specific SVD treatments
bull Case 1 ndash Asymptomatic
bull Case 2 ndash Lacunar stroke
bull Case 3 ndash Co-incidental SVD
Smith EE Saposnik G Biessels GJ et al Prevention of stroke in patients with
silent cerebrovascular disease A Scientific Statement for healthcare
professionals from the American Heart AssociationAmerican Stroke
Association Stroke 201748e44-e71
Case 1 Asymptomatic patient
bull 70 yr old man golfer (18 holes)
bull Well
bull Headachehead injury
bull Incidental finding
bull Is this really ldquosilentrdquo
bull Revert to primary prevention risk factor control
Treatment and prevention
Treat vascular risk factors
High blood pressure ++
Diabetes +
High cholesterol +
Smoking ++
But Impact may
differ at different ages
eg BP may be more
important in 40s ndash
60s than 70s ndash 90s
But All common vascular risk factors combined only
explain a small proportion of the burden of brain
vascular disease and so far trials of risk factor
reduction have been disappointing
Case 2 Lacunar stroke patient
bull 65 yr old female
bull Left sided weakness
bull Is there enough evidence to manage her differently from other ischaemic strokes
bull Many studies included lacunar stroke patients but did not adequately report subtype findings
bull Few studies in lacunar stroke
SPS3 trial
Benavente NEJM 2012 Benavente Lancet Neurol 2013
N=3000 patients with lacunar stroke and baseline MRI scans
Intensive blood pressure control no significant benefit on strokemortality
(but fewer ICH)
Dual antiplatelet (clopasp) therapy harmful and stopped early
Lower than expected stroke incidence
Case 3 Co-incidental SVD
bull 80 yr with atrial fibrillation - CHADSVASC2 3
MRI shows microbleeds
bull 70 yr with acute MCA infarct ndash 2 hours ago
MRICT show white matter disease
Anticoagulation and other therapies in patients with silent microbleeds
It is reasonable to provide anticoagulation therapy to patients with microbleeds when there is an indication
(eg AF)
When anticoagulation is needed a novel oral anticoagulant is preferred over warfarin
Percutaneous closure of the left atrial appendage could be considered as an alternative to anticoagulation
It is reasonable to provide antiplatelet therapy to patients with microbleeds when there is an indication
MRI screening for microbleeds is not needed before the initiation of antithrombotic therapies
Individuals with silent microbleeds are at increased future risk of both ischemic stroke and ICH
Implement preventive care recommended by AHAASA guidelines for primary prevention of ischemic stroke
It is reasonable to provide preventive care recommended by AHAASA guidelines for prevention of ICH
Suggestions for Clinical Care in Patients with Microbleeds
Acute ischemic stroke due to RMCA occlusion
Multiple microbleeds on SWI
77 year woman
Plan of management
NIHSS 16
a) No thrombolysis or antithromboticsb) Aspirinc) IV tPA 09 mgkg then thrombectomyd) IV tPA 06 mgkg then EVTe) Straight to EVT without tPA
Microbleed Scenario Acute Ischemic Stroke
Slide adapted from E Smith
Risk for sICH after TPA
bull Meta-analysis of 8 cohort studies with data on cerebral microbleeds and risk for post-tPA sICH
bull Pooled OR 287 for ICH post TPA in the presence of microbleeds
bull Unclear whether 56 risk increase for sICH outweighs
12 risk reduction for ischemic stroke disability expected
from tPA
Charidimou A et al Neurology 201585927-924
Safety of acute ischemic stroke therapy in patients with silent microbleeds
It is reasonable to administer intravenous alteplase to patients with acute ischemic stroke and
evidence of microbleeds if it is otherwise indicated
It is reasonable to perform endovascular thrombectomy in patients with acute ischemic stroke and
evidence of microbleeds
In acute ischemic stroke patients with microbleeds bypassing intravenous alteplase therapy to
proceed directly to endovascular thrombectomy is an unproven strategy
Clinical Suggestions for Acute Ischemic
Stroke
Therapy in Patients with Microbleeds
Other SVD treatment targets
Weak blood vessel lining strengthen cell junctions
Poor blood vessel function increase nitric oxide
lsquoInflammationrsquo anti-inflammatory
Statins nitrates pentoxyfiline cilostazol dipyridamole etc
Trials are ongoing eg LACI-1 LACI-2 PRESERVE
Salt exercise green vegetables nutrient bars
RCTs of cilostazol and nitrates in SVD
n=446012 weeksEdinburghNottingham
n=4001 yrJuly 2017gt30 UK centres
TolerabilityCVR measuresPulse wave analysis
1 Cilostazol2 Nitrate3 Both early4 Both late
Clinical outcomesMRI at one year
1 Cilostazol2 Nitrate3 Both4 Neither
SVD trials
bull Difficult ndash heterogenous patient groups
bull Low stroke recurrence rate (3 pa)
bull Cognitive testing time consuming
bull Do they measure the correct outcomes
For now
Apply guideline treatments
bull Lower blood pressure
bull Lower lipids
bull Use antiplatelet drugs but not ASA+Clop long term
bull Lifestyle advise ndash smoking salt reduction exercise
bull Trials of existing agents and novel agents
bull More animal data to lead to human trials
Conclusions
bull SVD important defined by imaging
bull Silent may not be silent
bull Stroke and dementia linked
bull Treatment options at present limited
Outline
bull What is small vessel disease
bull Why does it happen
bull Why does it matter including links between stroke and dementia
bull How should I manage patients with SVD
Cerebral Small Vessel Disease
Recent small
subcortical
infarct
White
matter
lesions
Perivascular
SpacesMicrobleeds
25 of stroke
Age
Hypertension
Disability
Cognitive impairment
Dementia
Stroke risk
depression inflammation amyloid
Lacune
DWI FLAIR FLAIR T2 T2GRE
lsquosilentrsquostroke
Small Vessel Disease lesions
Largely Variable Terminology
Slide courtesy J Wardlaw
Radiological features of Silent CVD
Wardlaw JM Smith EE Biessels GJ et al Neuroimaging standards for research into small vessel disease and its contribution to ageing and neurodegeneration The Lancet Neurology 201312822-838
Radiological changes of ldquonon silentrdquo SVD
Lacunar stroke
ICHMicroinfarcts
Will better technology find moremarkers
Features also visible on CT
R L
atrophy
old infarct
WMH
lacune
Thinning of overlying
cortex
Acute small subcortical
infarct may
bull cavitate
bull disappear
bull stay a WMH
bull expand
bull affect the cortex
bull affect the brainstem
and spinal cord
WMH can
bull increase
bull shrink
bull white matter atrophy
bull cortical atrophy
Lacunes and
microbleeds also
appear and disappear
Small vessel disease effects are diffuse and dynamic
Wardlaw JAHA 2015 METACOHORTS Alz Dem 2016
Wallerian
degeneration
ldquoNormalrdquo white matter
is diffusely abnormal
closer to lesions as
lesions increase
Reasons for variability reversibility incompletely understood
Small vessel disease links stroke and dementia
Dementia Stroke
Imaging defines SVD
Unknown causes SVD
Endothelial Damage
Inflammation
Impaired Glymphatic
Drainage
Vessel Stiffening
Vessel Occlusion
lsquoSmall Vessel Diseasersquo matters to patients (JLA)
Poor blood vessels worse Alzheimerrsquos
lsquoLacunarrsquo
Stroke
3 million per year worldwide
35000 per year in the UK
Up to 16 million dementias
worldwide
Few die
A fifth are left dependent
A third have cognitive impairment
Balance and walking problems
Mood ndash common cause of depression at
older ages
20-25
Vascular
Dementia25-45
Stroke leads to dementia
7-30 in 1st year after stroke severity pre-existing cognitive decline
Stroke Cognitive impairment
Prediction of dementia is difficult
bull lsquoDementiarsquo tests focus on memory ndash other abilities are more affected
bull Tests often too long and tiring
bull Patients may not be able to do some tests after stroke
bull Donrsquot account for previous cognitive ability but this is the strongest predictor of cognitive problems after stroke
bull REGARDS cohort in US
bull 24000 pts gt45yrs fu from 2003 for 6 yrs
bull Investigated acute and chronic cognition post stroke
bull Global cognition ndash SIS (six item screener)bull Executive functioning and memory
500 patients had stroke
JAMA 2015
Results
Incident stroke
Acute significant decline in global cognition and
memory
Accelerated decline in global cognition and
executive function
Cognitive decline predicts stroke
bull 930 men in Sweden without strokebull 13 years follow-up
bull Worse performance on a lsquojoin the dotsrsquo test predicted stroke
Cognitive decline predicts Stroke
fastest
slowest
Leiden 85+ Study 480 subjects 85 years
In the very elderly cognition predicts stroke better than vascular risk factors
Cognitive decline predicts stroke
Sabayan B et al Stroke 2013441866-1871
Vascular risk score Memory test
Cognition impaired after even minor stroke
Patients n=135 1 year after with minor stroke
median age 66 (IQR 56-75)
17 ACE-R lt82 (lsquodementiarsquo)
R p
Age -031 0001
Pre-morbid IQ 092 lt00001(National Adult Reading Test)
WMH score 158 003
Not NIHSS old stroke lesion
location lacunar vs non-lacunar
etc
Makin et al 2014
Idyll Zealot Gist Superfluous
Simile Deny Ache Banal
Naiumlve Depot Beatify Facade
Catacomb Equivocal Gauche Placebo
Deacutetente Heir Aeon Puerperal
Chord Sidereal Quadruped Aver
Rarefy Bouquet Abstemious Rarefy
Topiary Radix Debt Assignate
Capon Thyme Drachma Sidereal
Topiary Prelate Demesne Syncope
Labile Procreate Subtle Gaoled
Courteous Gouge Hiatus Psalm
Campanile Leviathan Aisle Cellist
White matter hyperintensities
mild
severe
Age 50-69 7 70-89 17 +
risk of dementia
Debette BMJ 2010
ldquoTotal SVD burdenrdquo and cognition
Staals Neurology 2014 +Neurology Patient page
Staals NBA 2015 Karema Mol Psych 2015
Simple sum score or more complex
latent variable model
Higher SVD burden associated with
Poorer general cognitive ability
Full score β -008 p=002
Without WMH β -01 p=04
Staals et al Neurology 2014 NBA 2015
bull Working party consensus
bull Recommends cognitive screeningbull Examples are MOCA or the Oxford Cognitive Screen
RCP 2016
SVD Treatment options ndash consider aim
bull No specific SVD treatments
bull Case 1 ndash Asymptomatic
bull Case 2 ndash Lacunar stroke
bull Case 3 ndash Co-incidental SVD
Smith EE Saposnik G Biessels GJ et al Prevention of stroke in patients with
silent cerebrovascular disease A Scientific Statement for healthcare
professionals from the American Heart AssociationAmerican Stroke
Association Stroke 201748e44-e71
Case 1 Asymptomatic patient
bull 70 yr old man golfer (18 holes)
bull Well
bull Headachehead injury
bull Incidental finding
bull Is this really ldquosilentrdquo
bull Revert to primary prevention risk factor control
Treatment and prevention
Treat vascular risk factors
High blood pressure ++
Diabetes +
High cholesterol +
Smoking ++
But Impact may
differ at different ages
eg BP may be more
important in 40s ndash
60s than 70s ndash 90s
But All common vascular risk factors combined only
explain a small proportion of the burden of brain
vascular disease and so far trials of risk factor
reduction have been disappointing
Case 2 Lacunar stroke patient
bull 65 yr old female
bull Left sided weakness
bull Is there enough evidence to manage her differently from other ischaemic strokes
bull Many studies included lacunar stroke patients but did not adequately report subtype findings
bull Few studies in lacunar stroke
SPS3 trial
Benavente NEJM 2012 Benavente Lancet Neurol 2013
N=3000 patients with lacunar stroke and baseline MRI scans
Intensive blood pressure control no significant benefit on strokemortality
(but fewer ICH)
Dual antiplatelet (clopasp) therapy harmful and stopped early
Lower than expected stroke incidence
Case 3 Co-incidental SVD
bull 80 yr with atrial fibrillation - CHADSVASC2 3
MRI shows microbleeds
bull 70 yr with acute MCA infarct ndash 2 hours ago
MRICT show white matter disease
Anticoagulation and other therapies in patients with silent microbleeds
It is reasonable to provide anticoagulation therapy to patients with microbleeds when there is an indication
(eg AF)
When anticoagulation is needed a novel oral anticoagulant is preferred over warfarin
Percutaneous closure of the left atrial appendage could be considered as an alternative to anticoagulation
It is reasonable to provide antiplatelet therapy to patients with microbleeds when there is an indication
MRI screening for microbleeds is not needed before the initiation of antithrombotic therapies
Individuals with silent microbleeds are at increased future risk of both ischemic stroke and ICH
Implement preventive care recommended by AHAASA guidelines for primary prevention of ischemic stroke
It is reasonable to provide preventive care recommended by AHAASA guidelines for prevention of ICH
Suggestions for Clinical Care in Patients with Microbleeds
Acute ischemic stroke due to RMCA occlusion
Multiple microbleeds on SWI
77 year woman
Plan of management
NIHSS 16
a) No thrombolysis or antithromboticsb) Aspirinc) IV tPA 09 mgkg then thrombectomyd) IV tPA 06 mgkg then EVTe) Straight to EVT without tPA
Microbleed Scenario Acute Ischemic Stroke
Slide adapted from E Smith
Risk for sICH after TPA
bull Meta-analysis of 8 cohort studies with data on cerebral microbleeds and risk for post-tPA sICH
bull Pooled OR 287 for ICH post TPA in the presence of microbleeds
bull Unclear whether 56 risk increase for sICH outweighs
12 risk reduction for ischemic stroke disability expected
from tPA
Charidimou A et al Neurology 201585927-924
Safety of acute ischemic stroke therapy in patients with silent microbleeds
It is reasonable to administer intravenous alteplase to patients with acute ischemic stroke and
evidence of microbleeds if it is otherwise indicated
It is reasonable to perform endovascular thrombectomy in patients with acute ischemic stroke and
evidence of microbleeds
In acute ischemic stroke patients with microbleeds bypassing intravenous alteplase therapy to
proceed directly to endovascular thrombectomy is an unproven strategy
Clinical Suggestions for Acute Ischemic
Stroke
Therapy in Patients with Microbleeds
Other SVD treatment targets
Weak blood vessel lining strengthen cell junctions
Poor blood vessel function increase nitric oxide
lsquoInflammationrsquo anti-inflammatory
Statins nitrates pentoxyfiline cilostazol dipyridamole etc
Trials are ongoing eg LACI-1 LACI-2 PRESERVE
Salt exercise green vegetables nutrient bars
RCTs of cilostazol and nitrates in SVD
n=446012 weeksEdinburghNottingham
n=4001 yrJuly 2017gt30 UK centres
TolerabilityCVR measuresPulse wave analysis
1 Cilostazol2 Nitrate3 Both early4 Both late
Clinical outcomesMRI at one year
1 Cilostazol2 Nitrate3 Both4 Neither
SVD trials
bull Difficult ndash heterogenous patient groups
bull Low stroke recurrence rate (3 pa)
bull Cognitive testing time consuming
bull Do they measure the correct outcomes
For now
Apply guideline treatments
bull Lower blood pressure
bull Lower lipids
bull Use antiplatelet drugs but not ASA+Clop long term
bull Lifestyle advise ndash smoking salt reduction exercise
bull Trials of existing agents and novel agents
bull More animal data to lead to human trials
Conclusions
bull SVD important defined by imaging
bull Silent may not be silent
bull Stroke and dementia linked
bull Treatment options at present limited
Cerebral Small Vessel Disease
Recent small
subcortical
infarct
White
matter
lesions
Perivascular
SpacesMicrobleeds
25 of stroke
Age
Hypertension
Disability
Cognitive impairment
Dementia
Stroke risk
depression inflammation amyloid
Lacune
DWI FLAIR FLAIR T2 T2GRE
lsquosilentrsquostroke
Small Vessel Disease lesions
Largely Variable Terminology
Slide courtesy J Wardlaw
Radiological features of Silent CVD
Wardlaw JM Smith EE Biessels GJ et al Neuroimaging standards for research into small vessel disease and its contribution to ageing and neurodegeneration The Lancet Neurology 201312822-838
Radiological changes of ldquonon silentrdquo SVD
Lacunar stroke
ICHMicroinfarcts
Will better technology find moremarkers
Features also visible on CT
R L
atrophy
old infarct
WMH
lacune
Thinning of overlying
cortex
Acute small subcortical
infarct may
bull cavitate
bull disappear
bull stay a WMH
bull expand
bull affect the cortex
bull affect the brainstem
and spinal cord
WMH can
bull increase
bull shrink
bull white matter atrophy
bull cortical atrophy
Lacunes and
microbleeds also
appear and disappear
Small vessel disease effects are diffuse and dynamic
Wardlaw JAHA 2015 METACOHORTS Alz Dem 2016
Wallerian
degeneration
ldquoNormalrdquo white matter
is diffusely abnormal
closer to lesions as
lesions increase
Reasons for variability reversibility incompletely understood
Small vessel disease links stroke and dementia
Dementia Stroke
Imaging defines SVD
Unknown causes SVD
Endothelial Damage
Inflammation
Impaired Glymphatic
Drainage
Vessel Stiffening
Vessel Occlusion
lsquoSmall Vessel Diseasersquo matters to patients (JLA)
Poor blood vessels worse Alzheimerrsquos
lsquoLacunarrsquo
Stroke
3 million per year worldwide
35000 per year in the UK
Up to 16 million dementias
worldwide
Few die
A fifth are left dependent
A third have cognitive impairment
Balance and walking problems
Mood ndash common cause of depression at
older ages
20-25
Vascular
Dementia25-45
Stroke leads to dementia
7-30 in 1st year after stroke severity pre-existing cognitive decline
Stroke Cognitive impairment
Prediction of dementia is difficult
bull lsquoDementiarsquo tests focus on memory ndash other abilities are more affected
bull Tests often too long and tiring
bull Patients may not be able to do some tests after stroke
bull Donrsquot account for previous cognitive ability but this is the strongest predictor of cognitive problems after stroke
bull REGARDS cohort in US
bull 24000 pts gt45yrs fu from 2003 for 6 yrs
bull Investigated acute and chronic cognition post stroke
bull Global cognition ndash SIS (six item screener)bull Executive functioning and memory
500 patients had stroke
JAMA 2015
Results
Incident stroke
Acute significant decline in global cognition and
memory
Accelerated decline in global cognition and
executive function
Cognitive decline predicts stroke
bull 930 men in Sweden without strokebull 13 years follow-up
bull Worse performance on a lsquojoin the dotsrsquo test predicted stroke
Cognitive decline predicts Stroke
fastest
slowest
Leiden 85+ Study 480 subjects 85 years
In the very elderly cognition predicts stroke better than vascular risk factors
Cognitive decline predicts stroke
Sabayan B et al Stroke 2013441866-1871
Vascular risk score Memory test
Cognition impaired after even minor stroke
Patients n=135 1 year after with minor stroke
median age 66 (IQR 56-75)
17 ACE-R lt82 (lsquodementiarsquo)
R p
Age -031 0001
Pre-morbid IQ 092 lt00001(National Adult Reading Test)
WMH score 158 003
Not NIHSS old stroke lesion
location lacunar vs non-lacunar
etc
Makin et al 2014
Idyll Zealot Gist Superfluous
Simile Deny Ache Banal
Naiumlve Depot Beatify Facade
Catacomb Equivocal Gauche Placebo
Deacutetente Heir Aeon Puerperal
Chord Sidereal Quadruped Aver
Rarefy Bouquet Abstemious Rarefy
Topiary Radix Debt Assignate
Capon Thyme Drachma Sidereal
Topiary Prelate Demesne Syncope
Labile Procreate Subtle Gaoled
Courteous Gouge Hiatus Psalm
Campanile Leviathan Aisle Cellist
White matter hyperintensities
mild
severe
Age 50-69 7 70-89 17 +
risk of dementia
Debette BMJ 2010
ldquoTotal SVD burdenrdquo and cognition
Staals Neurology 2014 +Neurology Patient page
Staals NBA 2015 Karema Mol Psych 2015
Simple sum score or more complex
latent variable model
Higher SVD burden associated with
Poorer general cognitive ability
Full score β -008 p=002
Without WMH β -01 p=04
Staals et al Neurology 2014 NBA 2015
bull Working party consensus
bull Recommends cognitive screeningbull Examples are MOCA or the Oxford Cognitive Screen
RCP 2016
SVD Treatment options ndash consider aim
bull No specific SVD treatments
bull Case 1 ndash Asymptomatic
bull Case 2 ndash Lacunar stroke
bull Case 3 ndash Co-incidental SVD
Smith EE Saposnik G Biessels GJ et al Prevention of stroke in patients with
silent cerebrovascular disease A Scientific Statement for healthcare
professionals from the American Heart AssociationAmerican Stroke
Association Stroke 201748e44-e71
Case 1 Asymptomatic patient
bull 70 yr old man golfer (18 holes)
bull Well
bull Headachehead injury
bull Incidental finding
bull Is this really ldquosilentrdquo
bull Revert to primary prevention risk factor control
Treatment and prevention
Treat vascular risk factors
High blood pressure ++
Diabetes +
High cholesterol +
Smoking ++
But Impact may
differ at different ages
eg BP may be more
important in 40s ndash
60s than 70s ndash 90s
But All common vascular risk factors combined only
explain a small proportion of the burden of brain
vascular disease and so far trials of risk factor
reduction have been disappointing
Case 2 Lacunar stroke patient
bull 65 yr old female
bull Left sided weakness
bull Is there enough evidence to manage her differently from other ischaemic strokes
bull Many studies included lacunar stroke patients but did not adequately report subtype findings
bull Few studies in lacunar stroke
SPS3 trial
Benavente NEJM 2012 Benavente Lancet Neurol 2013
N=3000 patients with lacunar stroke and baseline MRI scans
Intensive blood pressure control no significant benefit on strokemortality
(but fewer ICH)
Dual antiplatelet (clopasp) therapy harmful and stopped early
Lower than expected stroke incidence
Case 3 Co-incidental SVD
bull 80 yr with atrial fibrillation - CHADSVASC2 3
MRI shows microbleeds
bull 70 yr with acute MCA infarct ndash 2 hours ago
MRICT show white matter disease
Anticoagulation and other therapies in patients with silent microbleeds
It is reasonable to provide anticoagulation therapy to patients with microbleeds when there is an indication
(eg AF)
When anticoagulation is needed a novel oral anticoagulant is preferred over warfarin
Percutaneous closure of the left atrial appendage could be considered as an alternative to anticoagulation
It is reasonable to provide antiplatelet therapy to patients with microbleeds when there is an indication
MRI screening for microbleeds is not needed before the initiation of antithrombotic therapies
Individuals with silent microbleeds are at increased future risk of both ischemic stroke and ICH
Implement preventive care recommended by AHAASA guidelines for primary prevention of ischemic stroke
It is reasonable to provide preventive care recommended by AHAASA guidelines for prevention of ICH
Suggestions for Clinical Care in Patients with Microbleeds
Acute ischemic stroke due to RMCA occlusion
Multiple microbleeds on SWI
77 year woman
Plan of management
NIHSS 16
a) No thrombolysis or antithromboticsb) Aspirinc) IV tPA 09 mgkg then thrombectomyd) IV tPA 06 mgkg then EVTe) Straight to EVT without tPA
Microbleed Scenario Acute Ischemic Stroke
Slide adapted from E Smith
Risk for sICH after TPA
bull Meta-analysis of 8 cohort studies with data on cerebral microbleeds and risk for post-tPA sICH
bull Pooled OR 287 for ICH post TPA in the presence of microbleeds
bull Unclear whether 56 risk increase for sICH outweighs
12 risk reduction for ischemic stroke disability expected
from tPA
Charidimou A et al Neurology 201585927-924
Safety of acute ischemic stroke therapy in patients with silent microbleeds
It is reasonable to administer intravenous alteplase to patients with acute ischemic stroke and
evidence of microbleeds if it is otherwise indicated
It is reasonable to perform endovascular thrombectomy in patients with acute ischemic stroke and
evidence of microbleeds
In acute ischemic stroke patients with microbleeds bypassing intravenous alteplase therapy to
proceed directly to endovascular thrombectomy is an unproven strategy
Clinical Suggestions for Acute Ischemic
Stroke
Therapy in Patients with Microbleeds
Other SVD treatment targets
Weak blood vessel lining strengthen cell junctions
Poor blood vessel function increase nitric oxide
lsquoInflammationrsquo anti-inflammatory
Statins nitrates pentoxyfiline cilostazol dipyridamole etc
Trials are ongoing eg LACI-1 LACI-2 PRESERVE
Salt exercise green vegetables nutrient bars
RCTs of cilostazol and nitrates in SVD
n=446012 weeksEdinburghNottingham
n=4001 yrJuly 2017gt30 UK centres
TolerabilityCVR measuresPulse wave analysis
1 Cilostazol2 Nitrate3 Both early4 Both late
Clinical outcomesMRI at one year
1 Cilostazol2 Nitrate3 Both4 Neither
SVD trials
bull Difficult ndash heterogenous patient groups
bull Low stroke recurrence rate (3 pa)
bull Cognitive testing time consuming
bull Do they measure the correct outcomes
For now
Apply guideline treatments
bull Lower blood pressure
bull Lower lipids
bull Use antiplatelet drugs but not ASA+Clop long term
bull Lifestyle advise ndash smoking salt reduction exercise
bull Trials of existing agents and novel agents
bull More animal data to lead to human trials
Conclusions
bull SVD important defined by imaging
bull Silent may not be silent
bull Stroke and dementia linked
bull Treatment options at present limited
Recent small
subcortical
infarct
White
matter
lesions
Perivascular
SpacesMicrobleeds
25 of stroke
Age
Hypertension
Disability
Cognitive impairment
Dementia
Stroke risk
depression inflammation amyloid
Lacune
DWI FLAIR FLAIR T2 T2GRE
lsquosilentrsquostroke
Small Vessel Disease lesions
Largely Variable Terminology
Slide courtesy J Wardlaw
Radiological features of Silent CVD
Wardlaw JM Smith EE Biessels GJ et al Neuroimaging standards for research into small vessel disease and its contribution to ageing and neurodegeneration The Lancet Neurology 201312822-838
Radiological changes of ldquonon silentrdquo SVD
Lacunar stroke
ICHMicroinfarcts
Will better technology find moremarkers
Features also visible on CT
R L
atrophy
old infarct
WMH
lacune
Thinning of overlying
cortex
Acute small subcortical
infarct may
bull cavitate
bull disappear
bull stay a WMH
bull expand
bull affect the cortex
bull affect the brainstem
and spinal cord
WMH can
bull increase
bull shrink
bull white matter atrophy
bull cortical atrophy
Lacunes and
microbleeds also
appear and disappear
Small vessel disease effects are diffuse and dynamic
Wardlaw JAHA 2015 METACOHORTS Alz Dem 2016
Wallerian
degeneration
ldquoNormalrdquo white matter
is diffusely abnormal
closer to lesions as
lesions increase
Reasons for variability reversibility incompletely understood
Small vessel disease links stroke and dementia
Dementia Stroke
Imaging defines SVD
Unknown causes SVD
Endothelial Damage
Inflammation
Impaired Glymphatic
Drainage
Vessel Stiffening
Vessel Occlusion
lsquoSmall Vessel Diseasersquo matters to patients (JLA)
Poor blood vessels worse Alzheimerrsquos
lsquoLacunarrsquo
Stroke
3 million per year worldwide
35000 per year in the UK
Up to 16 million dementias
worldwide
Few die
A fifth are left dependent
A third have cognitive impairment
Balance and walking problems
Mood ndash common cause of depression at
older ages
20-25
Vascular
Dementia25-45
Stroke leads to dementia
7-30 in 1st year after stroke severity pre-existing cognitive decline
Stroke Cognitive impairment
Prediction of dementia is difficult
bull lsquoDementiarsquo tests focus on memory ndash other abilities are more affected
bull Tests often too long and tiring
bull Patients may not be able to do some tests after stroke
bull Donrsquot account for previous cognitive ability but this is the strongest predictor of cognitive problems after stroke
bull REGARDS cohort in US
bull 24000 pts gt45yrs fu from 2003 for 6 yrs
bull Investigated acute and chronic cognition post stroke
bull Global cognition ndash SIS (six item screener)bull Executive functioning and memory
500 patients had stroke
JAMA 2015
Results
Incident stroke
Acute significant decline in global cognition and
memory
Accelerated decline in global cognition and
executive function
Cognitive decline predicts stroke
bull 930 men in Sweden without strokebull 13 years follow-up
bull Worse performance on a lsquojoin the dotsrsquo test predicted stroke
Cognitive decline predicts Stroke
fastest
slowest
Leiden 85+ Study 480 subjects 85 years
In the very elderly cognition predicts stroke better than vascular risk factors
Cognitive decline predicts stroke
Sabayan B et al Stroke 2013441866-1871
Vascular risk score Memory test
Cognition impaired after even minor stroke
Patients n=135 1 year after with minor stroke
median age 66 (IQR 56-75)
17 ACE-R lt82 (lsquodementiarsquo)
R p
Age -031 0001
Pre-morbid IQ 092 lt00001(National Adult Reading Test)
WMH score 158 003
Not NIHSS old stroke lesion
location lacunar vs non-lacunar
etc
Makin et al 2014
Idyll Zealot Gist Superfluous
Simile Deny Ache Banal
Naiumlve Depot Beatify Facade
Catacomb Equivocal Gauche Placebo
Deacutetente Heir Aeon Puerperal
Chord Sidereal Quadruped Aver
Rarefy Bouquet Abstemious Rarefy
Topiary Radix Debt Assignate
Capon Thyme Drachma Sidereal
Topiary Prelate Demesne Syncope
Labile Procreate Subtle Gaoled
Courteous Gouge Hiatus Psalm
Campanile Leviathan Aisle Cellist
White matter hyperintensities
mild
severe
Age 50-69 7 70-89 17 +
risk of dementia
Debette BMJ 2010
ldquoTotal SVD burdenrdquo and cognition
Staals Neurology 2014 +Neurology Patient page
Staals NBA 2015 Karema Mol Psych 2015
Simple sum score or more complex
latent variable model
Higher SVD burden associated with
Poorer general cognitive ability
Full score β -008 p=002
Without WMH β -01 p=04
Staals et al Neurology 2014 NBA 2015
bull Working party consensus
bull Recommends cognitive screeningbull Examples are MOCA or the Oxford Cognitive Screen
RCP 2016
SVD Treatment options ndash consider aim
bull No specific SVD treatments
bull Case 1 ndash Asymptomatic
bull Case 2 ndash Lacunar stroke
bull Case 3 ndash Co-incidental SVD
Smith EE Saposnik G Biessels GJ et al Prevention of stroke in patients with
silent cerebrovascular disease A Scientific Statement for healthcare
professionals from the American Heart AssociationAmerican Stroke
Association Stroke 201748e44-e71
Case 1 Asymptomatic patient
bull 70 yr old man golfer (18 holes)
bull Well
bull Headachehead injury
bull Incidental finding
bull Is this really ldquosilentrdquo
bull Revert to primary prevention risk factor control
Treatment and prevention
Treat vascular risk factors
High blood pressure ++
Diabetes +
High cholesterol +
Smoking ++
But Impact may
differ at different ages
eg BP may be more
important in 40s ndash
60s than 70s ndash 90s
But All common vascular risk factors combined only
explain a small proportion of the burden of brain
vascular disease and so far trials of risk factor
reduction have been disappointing
Case 2 Lacunar stroke patient
bull 65 yr old female
bull Left sided weakness
bull Is there enough evidence to manage her differently from other ischaemic strokes
bull Many studies included lacunar stroke patients but did not adequately report subtype findings
bull Few studies in lacunar stroke
SPS3 trial
Benavente NEJM 2012 Benavente Lancet Neurol 2013
N=3000 patients with lacunar stroke and baseline MRI scans
Intensive blood pressure control no significant benefit on strokemortality
(but fewer ICH)
Dual antiplatelet (clopasp) therapy harmful and stopped early
Lower than expected stroke incidence
Case 3 Co-incidental SVD
bull 80 yr with atrial fibrillation - CHADSVASC2 3
MRI shows microbleeds
bull 70 yr with acute MCA infarct ndash 2 hours ago
MRICT show white matter disease
Anticoagulation and other therapies in patients with silent microbleeds
It is reasonable to provide anticoagulation therapy to patients with microbleeds when there is an indication
(eg AF)
When anticoagulation is needed a novel oral anticoagulant is preferred over warfarin
Percutaneous closure of the left atrial appendage could be considered as an alternative to anticoagulation
It is reasonable to provide antiplatelet therapy to patients with microbleeds when there is an indication
MRI screening for microbleeds is not needed before the initiation of antithrombotic therapies
Individuals with silent microbleeds are at increased future risk of both ischemic stroke and ICH
Implement preventive care recommended by AHAASA guidelines for primary prevention of ischemic stroke
It is reasonable to provide preventive care recommended by AHAASA guidelines for prevention of ICH
Suggestions for Clinical Care in Patients with Microbleeds
Acute ischemic stroke due to RMCA occlusion
Multiple microbleeds on SWI
77 year woman
Plan of management
NIHSS 16
a) No thrombolysis or antithromboticsb) Aspirinc) IV tPA 09 mgkg then thrombectomyd) IV tPA 06 mgkg then EVTe) Straight to EVT without tPA
Microbleed Scenario Acute Ischemic Stroke
Slide adapted from E Smith
Risk for sICH after TPA
bull Meta-analysis of 8 cohort studies with data on cerebral microbleeds and risk for post-tPA sICH
bull Pooled OR 287 for ICH post TPA in the presence of microbleeds
bull Unclear whether 56 risk increase for sICH outweighs
12 risk reduction for ischemic stroke disability expected
from tPA
Charidimou A et al Neurology 201585927-924
Safety of acute ischemic stroke therapy in patients with silent microbleeds
It is reasonable to administer intravenous alteplase to patients with acute ischemic stroke and
evidence of microbleeds if it is otherwise indicated
It is reasonable to perform endovascular thrombectomy in patients with acute ischemic stroke and
evidence of microbleeds
In acute ischemic stroke patients with microbleeds bypassing intravenous alteplase therapy to
proceed directly to endovascular thrombectomy is an unproven strategy
Clinical Suggestions for Acute Ischemic
Stroke
Therapy in Patients with Microbleeds
Other SVD treatment targets
Weak blood vessel lining strengthen cell junctions
Poor blood vessel function increase nitric oxide
lsquoInflammationrsquo anti-inflammatory
Statins nitrates pentoxyfiline cilostazol dipyridamole etc
Trials are ongoing eg LACI-1 LACI-2 PRESERVE
Salt exercise green vegetables nutrient bars
RCTs of cilostazol and nitrates in SVD
n=446012 weeksEdinburghNottingham
n=4001 yrJuly 2017gt30 UK centres
TolerabilityCVR measuresPulse wave analysis
1 Cilostazol2 Nitrate3 Both early4 Both late
Clinical outcomesMRI at one year
1 Cilostazol2 Nitrate3 Both4 Neither
SVD trials
bull Difficult ndash heterogenous patient groups
bull Low stroke recurrence rate (3 pa)
bull Cognitive testing time consuming
bull Do they measure the correct outcomes
For now
Apply guideline treatments
bull Lower blood pressure
bull Lower lipids
bull Use antiplatelet drugs but not ASA+Clop long term
bull Lifestyle advise ndash smoking salt reduction exercise
bull Trials of existing agents and novel agents
bull More animal data to lead to human trials
Conclusions
bull SVD important defined by imaging
bull Silent may not be silent
bull Stroke and dementia linked
bull Treatment options at present limited
Largely Variable Terminology
Slide courtesy J Wardlaw
Radiological features of Silent CVD
Wardlaw JM Smith EE Biessels GJ et al Neuroimaging standards for research into small vessel disease and its contribution to ageing and neurodegeneration The Lancet Neurology 201312822-838
Radiological changes of ldquonon silentrdquo SVD
Lacunar stroke
ICHMicroinfarcts
Will better technology find moremarkers
Features also visible on CT
R L
atrophy
old infarct
WMH
lacune
Thinning of overlying
cortex
Acute small subcortical
infarct may
bull cavitate
bull disappear
bull stay a WMH
bull expand
bull affect the cortex
bull affect the brainstem
and spinal cord
WMH can
bull increase
bull shrink
bull white matter atrophy
bull cortical atrophy
Lacunes and
microbleeds also
appear and disappear
Small vessel disease effects are diffuse and dynamic
Wardlaw JAHA 2015 METACOHORTS Alz Dem 2016
Wallerian
degeneration
ldquoNormalrdquo white matter
is diffusely abnormal
closer to lesions as
lesions increase
Reasons for variability reversibility incompletely understood
Small vessel disease links stroke and dementia
Dementia Stroke
Imaging defines SVD
Unknown causes SVD
Endothelial Damage
Inflammation
Impaired Glymphatic
Drainage
Vessel Stiffening
Vessel Occlusion
lsquoSmall Vessel Diseasersquo matters to patients (JLA)
Poor blood vessels worse Alzheimerrsquos
lsquoLacunarrsquo
Stroke
3 million per year worldwide
35000 per year in the UK
Up to 16 million dementias
worldwide
Few die
A fifth are left dependent
A third have cognitive impairment
Balance and walking problems
Mood ndash common cause of depression at
older ages
20-25
Vascular
Dementia25-45
Stroke leads to dementia
7-30 in 1st year after stroke severity pre-existing cognitive decline
Stroke Cognitive impairment
Prediction of dementia is difficult
bull lsquoDementiarsquo tests focus on memory ndash other abilities are more affected
bull Tests often too long and tiring
bull Patients may not be able to do some tests after stroke
bull Donrsquot account for previous cognitive ability but this is the strongest predictor of cognitive problems after stroke
bull REGARDS cohort in US
bull 24000 pts gt45yrs fu from 2003 for 6 yrs
bull Investigated acute and chronic cognition post stroke
bull Global cognition ndash SIS (six item screener)bull Executive functioning and memory
500 patients had stroke
JAMA 2015
Results
Incident stroke
Acute significant decline in global cognition and
memory
Accelerated decline in global cognition and
executive function
Cognitive decline predicts stroke
bull 930 men in Sweden without strokebull 13 years follow-up
bull Worse performance on a lsquojoin the dotsrsquo test predicted stroke
Cognitive decline predicts Stroke
fastest
slowest
Leiden 85+ Study 480 subjects 85 years
In the very elderly cognition predicts stroke better than vascular risk factors
Cognitive decline predicts stroke
Sabayan B et al Stroke 2013441866-1871
Vascular risk score Memory test
Cognition impaired after even minor stroke
Patients n=135 1 year after with minor stroke
median age 66 (IQR 56-75)
17 ACE-R lt82 (lsquodementiarsquo)
R p
Age -031 0001
Pre-morbid IQ 092 lt00001(National Adult Reading Test)
WMH score 158 003
Not NIHSS old stroke lesion
location lacunar vs non-lacunar
etc
Makin et al 2014
Idyll Zealot Gist Superfluous
Simile Deny Ache Banal
Naiumlve Depot Beatify Facade
Catacomb Equivocal Gauche Placebo
Deacutetente Heir Aeon Puerperal
Chord Sidereal Quadruped Aver
Rarefy Bouquet Abstemious Rarefy
Topiary Radix Debt Assignate
Capon Thyme Drachma Sidereal
Topiary Prelate Demesne Syncope
Labile Procreate Subtle Gaoled
Courteous Gouge Hiatus Psalm
Campanile Leviathan Aisle Cellist
White matter hyperintensities
mild
severe
Age 50-69 7 70-89 17 +
risk of dementia
Debette BMJ 2010
ldquoTotal SVD burdenrdquo and cognition
Staals Neurology 2014 +Neurology Patient page
Staals NBA 2015 Karema Mol Psych 2015
Simple sum score or more complex
latent variable model
Higher SVD burden associated with
Poorer general cognitive ability
Full score β -008 p=002
Without WMH β -01 p=04
Staals et al Neurology 2014 NBA 2015
bull Working party consensus
bull Recommends cognitive screeningbull Examples are MOCA or the Oxford Cognitive Screen
RCP 2016
SVD Treatment options ndash consider aim
bull No specific SVD treatments
bull Case 1 ndash Asymptomatic
bull Case 2 ndash Lacunar stroke
bull Case 3 ndash Co-incidental SVD
Smith EE Saposnik G Biessels GJ et al Prevention of stroke in patients with
silent cerebrovascular disease A Scientific Statement for healthcare
professionals from the American Heart AssociationAmerican Stroke
Association Stroke 201748e44-e71
Case 1 Asymptomatic patient
bull 70 yr old man golfer (18 holes)
bull Well
bull Headachehead injury
bull Incidental finding
bull Is this really ldquosilentrdquo
bull Revert to primary prevention risk factor control
Treatment and prevention
Treat vascular risk factors
High blood pressure ++
Diabetes +
High cholesterol +
Smoking ++
But Impact may
differ at different ages
eg BP may be more
important in 40s ndash
60s than 70s ndash 90s
But All common vascular risk factors combined only
explain a small proportion of the burden of brain
vascular disease and so far trials of risk factor
reduction have been disappointing
Case 2 Lacunar stroke patient
bull 65 yr old female
bull Left sided weakness
bull Is there enough evidence to manage her differently from other ischaemic strokes
bull Many studies included lacunar stroke patients but did not adequately report subtype findings
bull Few studies in lacunar stroke
SPS3 trial
Benavente NEJM 2012 Benavente Lancet Neurol 2013
N=3000 patients with lacunar stroke and baseline MRI scans
Intensive blood pressure control no significant benefit on strokemortality
(but fewer ICH)
Dual antiplatelet (clopasp) therapy harmful and stopped early
Lower than expected stroke incidence
Case 3 Co-incidental SVD
bull 80 yr with atrial fibrillation - CHADSVASC2 3
MRI shows microbleeds
bull 70 yr with acute MCA infarct ndash 2 hours ago
MRICT show white matter disease
Anticoagulation and other therapies in patients with silent microbleeds
It is reasonable to provide anticoagulation therapy to patients with microbleeds when there is an indication
(eg AF)
When anticoagulation is needed a novel oral anticoagulant is preferred over warfarin
Percutaneous closure of the left atrial appendage could be considered as an alternative to anticoagulation
It is reasonable to provide antiplatelet therapy to patients with microbleeds when there is an indication
MRI screening for microbleeds is not needed before the initiation of antithrombotic therapies
Individuals with silent microbleeds are at increased future risk of both ischemic stroke and ICH
Implement preventive care recommended by AHAASA guidelines for primary prevention of ischemic stroke
It is reasonable to provide preventive care recommended by AHAASA guidelines for prevention of ICH
Suggestions for Clinical Care in Patients with Microbleeds
Acute ischemic stroke due to RMCA occlusion
Multiple microbleeds on SWI
77 year woman
Plan of management
NIHSS 16
a) No thrombolysis or antithromboticsb) Aspirinc) IV tPA 09 mgkg then thrombectomyd) IV tPA 06 mgkg then EVTe) Straight to EVT without tPA
Microbleed Scenario Acute Ischemic Stroke
Slide adapted from E Smith
Risk for sICH after TPA
bull Meta-analysis of 8 cohort studies with data on cerebral microbleeds and risk for post-tPA sICH
bull Pooled OR 287 for ICH post TPA in the presence of microbleeds
bull Unclear whether 56 risk increase for sICH outweighs
12 risk reduction for ischemic stroke disability expected
from tPA
Charidimou A et al Neurology 201585927-924
Safety of acute ischemic stroke therapy in patients with silent microbleeds
It is reasonable to administer intravenous alteplase to patients with acute ischemic stroke and
evidence of microbleeds if it is otherwise indicated
It is reasonable to perform endovascular thrombectomy in patients with acute ischemic stroke and
evidence of microbleeds
In acute ischemic stroke patients with microbleeds bypassing intravenous alteplase therapy to
proceed directly to endovascular thrombectomy is an unproven strategy
Clinical Suggestions for Acute Ischemic
Stroke
Therapy in Patients with Microbleeds
Other SVD treatment targets
Weak blood vessel lining strengthen cell junctions
Poor blood vessel function increase nitric oxide
lsquoInflammationrsquo anti-inflammatory
Statins nitrates pentoxyfiline cilostazol dipyridamole etc
Trials are ongoing eg LACI-1 LACI-2 PRESERVE
Salt exercise green vegetables nutrient bars
RCTs of cilostazol and nitrates in SVD
n=446012 weeksEdinburghNottingham
n=4001 yrJuly 2017gt30 UK centres
TolerabilityCVR measuresPulse wave analysis
1 Cilostazol2 Nitrate3 Both early4 Both late
Clinical outcomesMRI at one year
1 Cilostazol2 Nitrate3 Both4 Neither
SVD trials
bull Difficult ndash heterogenous patient groups
bull Low stroke recurrence rate (3 pa)
bull Cognitive testing time consuming
bull Do they measure the correct outcomes
For now
Apply guideline treatments
bull Lower blood pressure
bull Lower lipids
bull Use antiplatelet drugs but not ASA+Clop long term
bull Lifestyle advise ndash smoking salt reduction exercise
bull Trials of existing agents and novel agents
bull More animal data to lead to human trials
Conclusions
bull SVD important defined by imaging
bull Silent may not be silent
bull Stroke and dementia linked
bull Treatment options at present limited
Radiological features of Silent CVD
Wardlaw JM Smith EE Biessels GJ et al Neuroimaging standards for research into small vessel disease and its contribution to ageing and neurodegeneration The Lancet Neurology 201312822-838
Radiological changes of ldquonon silentrdquo SVD
Lacunar stroke
ICHMicroinfarcts
Will better technology find moremarkers
Features also visible on CT
R L
atrophy
old infarct
WMH
lacune
Thinning of overlying
cortex
Acute small subcortical
infarct may
bull cavitate
bull disappear
bull stay a WMH
bull expand
bull affect the cortex
bull affect the brainstem
and spinal cord
WMH can
bull increase
bull shrink
bull white matter atrophy
bull cortical atrophy
Lacunes and
microbleeds also
appear and disappear
Small vessel disease effects are diffuse and dynamic
Wardlaw JAHA 2015 METACOHORTS Alz Dem 2016
Wallerian
degeneration
ldquoNormalrdquo white matter
is diffusely abnormal
closer to lesions as
lesions increase
Reasons for variability reversibility incompletely understood
Small vessel disease links stroke and dementia
Dementia Stroke
Imaging defines SVD
Unknown causes SVD
Endothelial Damage
Inflammation
Impaired Glymphatic
Drainage
Vessel Stiffening
Vessel Occlusion
lsquoSmall Vessel Diseasersquo matters to patients (JLA)
Poor blood vessels worse Alzheimerrsquos
lsquoLacunarrsquo
Stroke
3 million per year worldwide
35000 per year in the UK
Up to 16 million dementias
worldwide
Few die
A fifth are left dependent
A third have cognitive impairment
Balance and walking problems
Mood ndash common cause of depression at
older ages
20-25
Vascular
Dementia25-45
Stroke leads to dementia
7-30 in 1st year after stroke severity pre-existing cognitive decline
Stroke Cognitive impairment
Prediction of dementia is difficult
bull lsquoDementiarsquo tests focus on memory ndash other abilities are more affected
bull Tests often too long and tiring
bull Patients may not be able to do some tests after stroke
bull Donrsquot account for previous cognitive ability but this is the strongest predictor of cognitive problems after stroke
bull REGARDS cohort in US
bull 24000 pts gt45yrs fu from 2003 for 6 yrs
bull Investigated acute and chronic cognition post stroke
bull Global cognition ndash SIS (six item screener)bull Executive functioning and memory
500 patients had stroke
JAMA 2015
Results
Incident stroke
Acute significant decline in global cognition and
memory
Accelerated decline in global cognition and
executive function
Cognitive decline predicts stroke
bull 930 men in Sweden without strokebull 13 years follow-up
bull Worse performance on a lsquojoin the dotsrsquo test predicted stroke
Cognitive decline predicts Stroke
fastest
slowest
Leiden 85+ Study 480 subjects 85 years
In the very elderly cognition predicts stroke better than vascular risk factors
Cognitive decline predicts stroke
Sabayan B et al Stroke 2013441866-1871
Vascular risk score Memory test
Cognition impaired after even minor stroke
Patients n=135 1 year after with minor stroke
median age 66 (IQR 56-75)
17 ACE-R lt82 (lsquodementiarsquo)
R p
Age -031 0001
Pre-morbid IQ 092 lt00001(National Adult Reading Test)
WMH score 158 003
Not NIHSS old stroke lesion
location lacunar vs non-lacunar
etc
Makin et al 2014
Idyll Zealot Gist Superfluous
Simile Deny Ache Banal
Naiumlve Depot Beatify Facade
Catacomb Equivocal Gauche Placebo
Deacutetente Heir Aeon Puerperal
Chord Sidereal Quadruped Aver
Rarefy Bouquet Abstemious Rarefy
Topiary Radix Debt Assignate
Capon Thyme Drachma Sidereal
Topiary Prelate Demesne Syncope
Labile Procreate Subtle Gaoled
Courteous Gouge Hiatus Psalm
Campanile Leviathan Aisle Cellist
White matter hyperintensities
mild
severe
Age 50-69 7 70-89 17 +
risk of dementia
Debette BMJ 2010
ldquoTotal SVD burdenrdquo and cognition
Staals Neurology 2014 +Neurology Patient page
Staals NBA 2015 Karema Mol Psych 2015
Simple sum score or more complex
latent variable model
Higher SVD burden associated with
Poorer general cognitive ability
Full score β -008 p=002
Without WMH β -01 p=04
Staals et al Neurology 2014 NBA 2015
bull Working party consensus
bull Recommends cognitive screeningbull Examples are MOCA or the Oxford Cognitive Screen
RCP 2016
SVD Treatment options ndash consider aim
bull No specific SVD treatments
bull Case 1 ndash Asymptomatic
bull Case 2 ndash Lacunar stroke
bull Case 3 ndash Co-incidental SVD
Smith EE Saposnik G Biessels GJ et al Prevention of stroke in patients with
silent cerebrovascular disease A Scientific Statement for healthcare
professionals from the American Heart AssociationAmerican Stroke
Association Stroke 201748e44-e71
Case 1 Asymptomatic patient
bull 70 yr old man golfer (18 holes)
bull Well
bull Headachehead injury
bull Incidental finding
bull Is this really ldquosilentrdquo
bull Revert to primary prevention risk factor control
Treatment and prevention
Treat vascular risk factors
High blood pressure ++
Diabetes +
High cholesterol +
Smoking ++
But Impact may
differ at different ages
eg BP may be more
important in 40s ndash
60s than 70s ndash 90s
But All common vascular risk factors combined only
explain a small proportion of the burden of brain
vascular disease and so far trials of risk factor
reduction have been disappointing
Case 2 Lacunar stroke patient
bull 65 yr old female
bull Left sided weakness
bull Is there enough evidence to manage her differently from other ischaemic strokes
bull Many studies included lacunar stroke patients but did not adequately report subtype findings
bull Few studies in lacunar stroke
SPS3 trial
Benavente NEJM 2012 Benavente Lancet Neurol 2013
N=3000 patients with lacunar stroke and baseline MRI scans
Intensive blood pressure control no significant benefit on strokemortality
(but fewer ICH)
Dual antiplatelet (clopasp) therapy harmful and stopped early
Lower than expected stroke incidence
Case 3 Co-incidental SVD
bull 80 yr with atrial fibrillation - CHADSVASC2 3
MRI shows microbleeds
bull 70 yr with acute MCA infarct ndash 2 hours ago
MRICT show white matter disease
Anticoagulation and other therapies in patients with silent microbleeds
It is reasonable to provide anticoagulation therapy to patients with microbleeds when there is an indication
(eg AF)
When anticoagulation is needed a novel oral anticoagulant is preferred over warfarin
Percutaneous closure of the left atrial appendage could be considered as an alternative to anticoagulation
It is reasonable to provide antiplatelet therapy to patients with microbleeds when there is an indication
MRI screening for microbleeds is not needed before the initiation of antithrombotic therapies
Individuals with silent microbleeds are at increased future risk of both ischemic stroke and ICH
Implement preventive care recommended by AHAASA guidelines for primary prevention of ischemic stroke
It is reasonable to provide preventive care recommended by AHAASA guidelines for prevention of ICH
Suggestions for Clinical Care in Patients with Microbleeds
Acute ischemic stroke due to RMCA occlusion
Multiple microbleeds on SWI
77 year woman
Plan of management
NIHSS 16
a) No thrombolysis or antithromboticsb) Aspirinc) IV tPA 09 mgkg then thrombectomyd) IV tPA 06 mgkg then EVTe) Straight to EVT without tPA
Microbleed Scenario Acute Ischemic Stroke
Slide adapted from E Smith
Risk for sICH after TPA
bull Meta-analysis of 8 cohort studies with data on cerebral microbleeds and risk for post-tPA sICH
bull Pooled OR 287 for ICH post TPA in the presence of microbleeds
bull Unclear whether 56 risk increase for sICH outweighs
12 risk reduction for ischemic stroke disability expected
from tPA
Charidimou A et al Neurology 201585927-924
Safety of acute ischemic stroke therapy in patients with silent microbleeds
It is reasonable to administer intravenous alteplase to patients with acute ischemic stroke and
evidence of microbleeds if it is otherwise indicated
It is reasonable to perform endovascular thrombectomy in patients with acute ischemic stroke and
evidence of microbleeds
In acute ischemic stroke patients with microbleeds bypassing intravenous alteplase therapy to
proceed directly to endovascular thrombectomy is an unproven strategy
Clinical Suggestions for Acute Ischemic
Stroke
Therapy in Patients with Microbleeds
Other SVD treatment targets
Weak blood vessel lining strengthen cell junctions
Poor blood vessel function increase nitric oxide
lsquoInflammationrsquo anti-inflammatory
Statins nitrates pentoxyfiline cilostazol dipyridamole etc
Trials are ongoing eg LACI-1 LACI-2 PRESERVE
Salt exercise green vegetables nutrient bars
RCTs of cilostazol and nitrates in SVD
n=446012 weeksEdinburghNottingham
n=4001 yrJuly 2017gt30 UK centres
TolerabilityCVR measuresPulse wave analysis
1 Cilostazol2 Nitrate3 Both early4 Both late
Clinical outcomesMRI at one year
1 Cilostazol2 Nitrate3 Both4 Neither
SVD trials
bull Difficult ndash heterogenous patient groups
bull Low stroke recurrence rate (3 pa)
bull Cognitive testing time consuming
bull Do they measure the correct outcomes
For now
Apply guideline treatments
bull Lower blood pressure
bull Lower lipids
bull Use antiplatelet drugs but not ASA+Clop long term
bull Lifestyle advise ndash smoking salt reduction exercise
bull Trials of existing agents and novel agents
bull More animal data to lead to human trials
Conclusions
bull SVD important defined by imaging
bull Silent may not be silent
bull Stroke and dementia linked
bull Treatment options at present limited
Radiological changes of ldquonon silentrdquo SVD
Lacunar stroke
ICHMicroinfarcts
Will better technology find moremarkers
Features also visible on CT
R L
atrophy
old infarct
WMH
lacune
Thinning of overlying
cortex
Acute small subcortical
infarct may
bull cavitate
bull disappear
bull stay a WMH
bull expand
bull affect the cortex
bull affect the brainstem
and spinal cord
WMH can
bull increase
bull shrink
bull white matter atrophy
bull cortical atrophy
Lacunes and
microbleeds also
appear and disappear
Small vessel disease effects are diffuse and dynamic
Wardlaw JAHA 2015 METACOHORTS Alz Dem 2016
Wallerian
degeneration
ldquoNormalrdquo white matter
is diffusely abnormal
closer to lesions as
lesions increase
Reasons for variability reversibility incompletely understood
Small vessel disease links stroke and dementia
Dementia Stroke
Imaging defines SVD
Unknown causes SVD
Endothelial Damage
Inflammation
Impaired Glymphatic
Drainage
Vessel Stiffening
Vessel Occlusion
lsquoSmall Vessel Diseasersquo matters to patients (JLA)
Poor blood vessels worse Alzheimerrsquos
lsquoLacunarrsquo
Stroke
3 million per year worldwide
35000 per year in the UK
Up to 16 million dementias
worldwide
Few die
A fifth are left dependent
A third have cognitive impairment
Balance and walking problems
Mood ndash common cause of depression at
older ages
20-25
Vascular
Dementia25-45
Stroke leads to dementia
7-30 in 1st year after stroke severity pre-existing cognitive decline
Stroke Cognitive impairment
Prediction of dementia is difficult
bull lsquoDementiarsquo tests focus on memory ndash other abilities are more affected
bull Tests often too long and tiring
bull Patients may not be able to do some tests after stroke
bull Donrsquot account for previous cognitive ability but this is the strongest predictor of cognitive problems after stroke
bull REGARDS cohort in US
bull 24000 pts gt45yrs fu from 2003 for 6 yrs
bull Investigated acute and chronic cognition post stroke
bull Global cognition ndash SIS (six item screener)bull Executive functioning and memory
500 patients had stroke
JAMA 2015
Results
Incident stroke
Acute significant decline in global cognition and
memory
Accelerated decline in global cognition and
executive function
Cognitive decline predicts stroke
bull 930 men in Sweden without strokebull 13 years follow-up
bull Worse performance on a lsquojoin the dotsrsquo test predicted stroke
Cognitive decline predicts Stroke
fastest
slowest
Leiden 85+ Study 480 subjects 85 years
In the very elderly cognition predicts stroke better than vascular risk factors
Cognitive decline predicts stroke
Sabayan B et al Stroke 2013441866-1871
Vascular risk score Memory test
Cognition impaired after even minor stroke
Patients n=135 1 year after with minor stroke
median age 66 (IQR 56-75)
17 ACE-R lt82 (lsquodementiarsquo)
R p
Age -031 0001
Pre-morbid IQ 092 lt00001(National Adult Reading Test)
WMH score 158 003
Not NIHSS old stroke lesion
location lacunar vs non-lacunar
etc
Makin et al 2014
Idyll Zealot Gist Superfluous
Simile Deny Ache Banal
Naiumlve Depot Beatify Facade
Catacomb Equivocal Gauche Placebo
Deacutetente Heir Aeon Puerperal
Chord Sidereal Quadruped Aver
Rarefy Bouquet Abstemious Rarefy
Topiary Radix Debt Assignate
Capon Thyme Drachma Sidereal
Topiary Prelate Demesne Syncope
Labile Procreate Subtle Gaoled
Courteous Gouge Hiatus Psalm
Campanile Leviathan Aisle Cellist
White matter hyperintensities
mild
severe
Age 50-69 7 70-89 17 +
risk of dementia
Debette BMJ 2010
ldquoTotal SVD burdenrdquo and cognition
Staals Neurology 2014 +Neurology Patient page
Staals NBA 2015 Karema Mol Psych 2015
Simple sum score or more complex
latent variable model
Higher SVD burden associated with
Poorer general cognitive ability
Full score β -008 p=002
Without WMH β -01 p=04
Staals et al Neurology 2014 NBA 2015
bull Working party consensus
bull Recommends cognitive screeningbull Examples are MOCA or the Oxford Cognitive Screen
RCP 2016
SVD Treatment options ndash consider aim
bull No specific SVD treatments
bull Case 1 ndash Asymptomatic
bull Case 2 ndash Lacunar stroke
bull Case 3 ndash Co-incidental SVD
Smith EE Saposnik G Biessels GJ et al Prevention of stroke in patients with
silent cerebrovascular disease A Scientific Statement for healthcare
professionals from the American Heart AssociationAmerican Stroke
Association Stroke 201748e44-e71
Case 1 Asymptomatic patient
bull 70 yr old man golfer (18 holes)
bull Well
bull Headachehead injury
bull Incidental finding
bull Is this really ldquosilentrdquo
bull Revert to primary prevention risk factor control
Treatment and prevention
Treat vascular risk factors
High blood pressure ++
Diabetes +
High cholesterol +
Smoking ++
But Impact may
differ at different ages
eg BP may be more
important in 40s ndash
60s than 70s ndash 90s
But All common vascular risk factors combined only
explain a small proportion of the burden of brain
vascular disease and so far trials of risk factor
reduction have been disappointing
Case 2 Lacunar stroke patient
bull 65 yr old female
bull Left sided weakness
bull Is there enough evidence to manage her differently from other ischaemic strokes
bull Many studies included lacunar stroke patients but did not adequately report subtype findings
bull Few studies in lacunar stroke
SPS3 trial
Benavente NEJM 2012 Benavente Lancet Neurol 2013
N=3000 patients with lacunar stroke and baseline MRI scans
Intensive blood pressure control no significant benefit on strokemortality
(but fewer ICH)
Dual antiplatelet (clopasp) therapy harmful and stopped early
Lower than expected stroke incidence
Case 3 Co-incidental SVD
bull 80 yr with atrial fibrillation - CHADSVASC2 3
MRI shows microbleeds
bull 70 yr with acute MCA infarct ndash 2 hours ago
MRICT show white matter disease
Anticoagulation and other therapies in patients with silent microbleeds
It is reasonable to provide anticoagulation therapy to patients with microbleeds when there is an indication
(eg AF)
When anticoagulation is needed a novel oral anticoagulant is preferred over warfarin
Percutaneous closure of the left atrial appendage could be considered as an alternative to anticoagulation
It is reasonable to provide antiplatelet therapy to patients with microbleeds when there is an indication
MRI screening for microbleeds is not needed before the initiation of antithrombotic therapies
Individuals with silent microbleeds are at increased future risk of both ischemic stroke and ICH
Implement preventive care recommended by AHAASA guidelines for primary prevention of ischemic stroke
It is reasonable to provide preventive care recommended by AHAASA guidelines for prevention of ICH
Suggestions for Clinical Care in Patients with Microbleeds
Acute ischemic stroke due to RMCA occlusion
Multiple microbleeds on SWI
77 year woman
Plan of management
NIHSS 16
a) No thrombolysis or antithromboticsb) Aspirinc) IV tPA 09 mgkg then thrombectomyd) IV tPA 06 mgkg then EVTe) Straight to EVT without tPA
Microbleed Scenario Acute Ischemic Stroke
Slide adapted from E Smith
Risk for sICH after TPA
bull Meta-analysis of 8 cohort studies with data on cerebral microbleeds and risk for post-tPA sICH
bull Pooled OR 287 for ICH post TPA in the presence of microbleeds
bull Unclear whether 56 risk increase for sICH outweighs
12 risk reduction for ischemic stroke disability expected
from tPA
Charidimou A et al Neurology 201585927-924
Safety of acute ischemic stroke therapy in patients with silent microbleeds
It is reasonable to administer intravenous alteplase to patients with acute ischemic stroke and
evidence of microbleeds if it is otherwise indicated
It is reasonable to perform endovascular thrombectomy in patients with acute ischemic stroke and
evidence of microbleeds
In acute ischemic stroke patients with microbleeds bypassing intravenous alteplase therapy to
proceed directly to endovascular thrombectomy is an unproven strategy
Clinical Suggestions for Acute Ischemic
Stroke
Therapy in Patients with Microbleeds
Other SVD treatment targets
Weak blood vessel lining strengthen cell junctions
Poor blood vessel function increase nitric oxide
lsquoInflammationrsquo anti-inflammatory
Statins nitrates pentoxyfiline cilostazol dipyridamole etc
Trials are ongoing eg LACI-1 LACI-2 PRESERVE
Salt exercise green vegetables nutrient bars
RCTs of cilostazol and nitrates in SVD
n=446012 weeksEdinburghNottingham
n=4001 yrJuly 2017gt30 UK centres
TolerabilityCVR measuresPulse wave analysis
1 Cilostazol2 Nitrate3 Both early4 Both late
Clinical outcomesMRI at one year
1 Cilostazol2 Nitrate3 Both4 Neither
SVD trials
bull Difficult ndash heterogenous patient groups
bull Low stroke recurrence rate (3 pa)
bull Cognitive testing time consuming
bull Do they measure the correct outcomes
For now
Apply guideline treatments
bull Lower blood pressure
bull Lower lipids
bull Use antiplatelet drugs but not ASA+Clop long term
bull Lifestyle advise ndash smoking salt reduction exercise
bull Trials of existing agents and novel agents
bull More animal data to lead to human trials
Conclusions
bull SVD important defined by imaging
bull Silent may not be silent
bull Stroke and dementia linked
bull Treatment options at present limited
Features also visible on CT
R L
atrophy
old infarct
WMH
lacune
Thinning of overlying
cortex
Acute small subcortical
infarct may
bull cavitate
bull disappear
bull stay a WMH
bull expand
bull affect the cortex
bull affect the brainstem
and spinal cord
WMH can
bull increase
bull shrink
bull white matter atrophy
bull cortical atrophy
Lacunes and
microbleeds also
appear and disappear
Small vessel disease effects are diffuse and dynamic
Wardlaw JAHA 2015 METACOHORTS Alz Dem 2016
Wallerian
degeneration
ldquoNormalrdquo white matter
is diffusely abnormal
closer to lesions as
lesions increase
Reasons for variability reversibility incompletely understood
Small vessel disease links stroke and dementia
Dementia Stroke
Imaging defines SVD
Unknown causes SVD
Endothelial Damage
Inflammation
Impaired Glymphatic
Drainage
Vessel Stiffening
Vessel Occlusion
lsquoSmall Vessel Diseasersquo matters to patients (JLA)
Poor blood vessels worse Alzheimerrsquos
lsquoLacunarrsquo
Stroke
3 million per year worldwide
35000 per year in the UK
Up to 16 million dementias
worldwide
Few die
A fifth are left dependent
A third have cognitive impairment
Balance and walking problems
Mood ndash common cause of depression at
older ages
20-25
Vascular
Dementia25-45
Stroke leads to dementia
7-30 in 1st year after stroke severity pre-existing cognitive decline
Stroke Cognitive impairment
Prediction of dementia is difficult
bull lsquoDementiarsquo tests focus on memory ndash other abilities are more affected
bull Tests often too long and tiring
bull Patients may not be able to do some tests after stroke
bull Donrsquot account for previous cognitive ability but this is the strongest predictor of cognitive problems after stroke
bull REGARDS cohort in US
bull 24000 pts gt45yrs fu from 2003 for 6 yrs
bull Investigated acute and chronic cognition post stroke
bull Global cognition ndash SIS (six item screener)bull Executive functioning and memory
500 patients had stroke
JAMA 2015
Results
Incident stroke
Acute significant decline in global cognition and
memory
Accelerated decline in global cognition and
executive function
Cognitive decline predicts stroke
bull 930 men in Sweden without strokebull 13 years follow-up
bull Worse performance on a lsquojoin the dotsrsquo test predicted stroke
Cognitive decline predicts Stroke
fastest
slowest
Leiden 85+ Study 480 subjects 85 years
In the very elderly cognition predicts stroke better than vascular risk factors
Cognitive decline predicts stroke
Sabayan B et al Stroke 2013441866-1871
Vascular risk score Memory test
Cognition impaired after even minor stroke
Patients n=135 1 year after with minor stroke
median age 66 (IQR 56-75)
17 ACE-R lt82 (lsquodementiarsquo)
R p
Age -031 0001
Pre-morbid IQ 092 lt00001(National Adult Reading Test)
WMH score 158 003
Not NIHSS old stroke lesion
location lacunar vs non-lacunar
etc
Makin et al 2014
Idyll Zealot Gist Superfluous
Simile Deny Ache Banal
Naiumlve Depot Beatify Facade
Catacomb Equivocal Gauche Placebo
Deacutetente Heir Aeon Puerperal
Chord Sidereal Quadruped Aver
Rarefy Bouquet Abstemious Rarefy
Topiary Radix Debt Assignate
Capon Thyme Drachma Sidereal
Topiary Prelate Demesne Syncope
Labile Procreate Subtle Gaoled
Courteous Gouge Hiatus Psalm
Campanile Leviathan Aisle Cellist
White matter hyperintensities
mild
severe
Age 50-69 7 70-89 17 +
risk of dementia
Debette BMJ 2010
ldquoTotal SVD burdenrdquo and cognition
Staals Neurology 2014 +Neurology Patient page
Staals NBA 2015 Karema Mol Psych 2015
Simple sum score or more complex
latent variable model
Higher SVD burden associated with
Poorer general cognitive ability
Full score β -008 p=002
Without WMH β -01 p=04
Staals et al Neurology 2014 NBA 2015
bull Working party consensus
bull Recommends cognitive screeningbull Examples are MOCA or the Oxford Cognitive Screen
RCP 2016
SVD Treatment options ndash consider aim
bull No specific SVD treatments
bull Case 1 ndash Asymptomatic
bull Case 2 ndash Lacunar stroke
bull Case 3 ndash Co-incidental SVD
Smith EE Saposnik G Biessels GJ et al Prevention of stroke in patients with
silent cerebrovascular disease A Scientific Statement for healthcare
professionals from the American Heart AssociationAmerican Stroke
Association Stroke 201748e44-e71
Case 1 Asymptomatic patient
bull 70 yr old man golfer (18 holes)
bull Well
bull Headachehead injury
bull Incidental finding
bull Is this really ldquosilentrdquo
bull Revert to primary prevention risk factor control
Treatment and prevention
Treat vascular risk factors
High blood pressure ++
Diabetes +
High cholesterol +
Smoking ++
But Impact may
differ at different ages
eg BP may be more
important in 40s ndash
60s than 70s ndash 90s
But All common vascular risk factors combined only
explain a small proportion of the burden of brain
vascular disease and so far trials of risk factor
reduction have been disappointing
Case 2 Lacunar stroke patient
bull 65 yr old female
bull Left sided weakness
bull Is there enough evidence to manage her differently from other ischaemic strokes
bull Many studies included lacunar stroke patients but did not adequately report subtype findings
bull Few studies in lacunar stroke
SPS3 trial
Benavente NEJM 2012 Benavente Lancet Neurol 2013
N=3000 patients with lacunar stroke and baseline MRI scans
Intensive blood pressure control no significant benefit on strokemortality
(but fewer ICH)
Dual antiplatelet (clopasp) therapy harmful and stopped early
Lower than expected stroke incidence
Case 3 Co-incidental SVD
bull 80 yr with atrial fibrillation - CHADSVASC2 3
MRI shows microbleeds
bull 70 yr with acute MCA infarct ndash 2 hours ago
MRICT show white matter disease
Anticoagulation and other therapies in patients with silent microbleeds
It is reasonable to provide anticoagulation therapy to patients with microbleeds when there is an indication
(eg AF)
When anticoagulation is needed a novel oral anticoagulant is preferred over warfarin
Percutaneous closure of the left atrial appendage could be considered as an alternative to anticoagulation
It is reasonable to provide antiplatelet therapy to patients with microbleeds when there is an indication
MRI screening for microbleeds is not needed before the initiation of antithrombotic therapies
Individuals with silent microbleeds are at increased future risk of both ischemic stroke and ICH
Implement preventive care recommended by AHAASA guidelines for primary prevention of ischemic stroke
It is reasonable to provide preventive care recommended by AHAASA guidelines for prevention of ICH
Suggestions for Clinical Care in Patients with Microbleeds
Acute ischemic stroke due to RMCA occlusion
Multiple microbleeds on SWI
77 year woman
Plan of management
NIHSS 16
a) No thrombolysis or antithromboticsb) Aspirinc) IV tPA 09 mgkg then thrombectomyd) IV tPA 06 mgkg then EVTe) Straight to EVT without tPA
Microbleed Scenario Acute Ischemic Stroke
Slide adapted from E Smith
Risk for sICH after TPA
bull Meta-analysis of 8 cohort studies with data on cerebral microbleeds and risk for post-tPA sICH
bull Pooled OR 287 for ICH post TPA in the presence of microbleeds
bull Unclear whether 56 risk increase for sICH outweighs
12 risk reduction for ischemic stroke disability expected
from tPA
Charidimou A et al Neurology 201585927-924
Safety of acute ischemic stroke therapy in patients with silent microbleeds
It is reasonable to administer intravenous alteplase to patients with acute ischemic stroke and
evidence of microbleeds if it is otherwise indicated
It is reasonable to perform endovascular thrombectomy in patients with acute ischemic stroke and
evidence of microbleeds
In acute ischemic stroke patients with microbleeds bypassing intravenous alteplase therapy to
proceed directly to endovascular thrombectomy is an unproven strategy
Clinical Suggestions for Acute Ischemic
Stroke
Therapy in Patients with Microbleeds
Other SVD treatment targets
Weak blood vessel lining strengthen cell junctions
Poor blood vessel function increase nitric oxide
lsquoInflammationrsquo anti-inflammatory
Statins nitrates pentoxyfiline cilostazol dipyridamole etc
Trials are ongoing eg LACI-1 LACI-2 PRESERVE
Salt exercise green vegetables nutrient bars
RCTs of cilostazol and nitrates in SVD
n=446012 weeksEdinburghNottingham
n=4001 yrJuly 2017gt30 UK centres
TolerabilityCVR measuresPulse wave analysis
1 Cilostazol2 Nitrate3 Both early4 Both late
Clinical outcomesMRI at one year
1 Cilostazol2 Nitrate3 Both4 Neither
SVD trials
bull Difficult ndash heterogenous patient groups
bull Low stroke recurrence rate (3 pa)
bull Cognitive testing time consuming
bull Do they measure the correct outcomes
For now
Apply guideline treatments
bull Lower blood pressure
bull Lower lipids
bull Use antiplatelet drugs but not ASA+Clop long term
bull Lifestyle advise ndash smoking salt reduction exercise
bull Trials of existing agents and novel agents
bull More animal data to lead to human trials
Conclusions
bull SVD important defined by imaging
bull Silent may not be silent
bull Stroke and dementia linked
bull Treatment options at present limited
Thinning of overlying
cortex
Acute small subcortical
infarct may
bull cavitate
bull disappear
bull stay a WMH
bull expand
bull affect the cortex
bull affect the brainstem
and spinal cord
WMH can
bull increase
bull shrink
bull white matter atrophy
bull cortical atrophy
Lacunes and
microbleeds also
appear and disappear
Small vessel disease effects are diffuse and dynamic
Wardlaw JAHA 2015 METACOHORTS Alz Dem 2016
Wallerian
degeneration
ldquoNormalrdquo white matter
is diffusely abnormal
closer to lesions as
lesions increase
Reasons for variability reversibility incompletely understood
Small vessel disease links stroke and dementia
Dementia Stroke
Imaging defines SVD
Unknown causes SVD
Endothelial Damage
Inflammation
Impaired Glymphatic
Drainage
Vessel Stiffening
Vessel Occlusion
lsquoSmall Vessel Diseasersquo matters to patients (JLA)
Poor blood vessels worse Alzheimerrsquos
lsquoLacunarrsquo
Stroke
3 million per year worldwide
35000 per year in the UK
Up to 16 million dementias
worldwide
Few die
A fifth are left dependent
A third have cognitive impairment
Balance and walking problems
Mood ndash common cause of depression at
older ages
20-25
Vascular
Dementia25-45
Stroke leads to dementia
7-30 in 1st year after stroke severity pre-existing cognitive decline
Stroke Cognitive impairment
Prediction of dementia is difficult
bull lsquoDementiarsquo tests focus on memory ndash other abilities are more affected
bull Tests often too long and tiring
bull Patients may not be able to do some tests after stroke
bull Donrsquot account for previous cognitive ability but this is the strongest predictor of cognitive problems after stroke
bull REGARDS cohort in US
bull 24000 pts gt45yrs fu from 2003 for 6 yrs
bull Investigated acute and chronic cognition post stroke
bull Global cognition ndash SIS (six item screener)bull Executive functioning and memory
500 patients had stroke
JAMA 2015
Results
Incident stroke
Acute significant decline in global cognition and
memory
Accelerated decline in global cognition and
executive function
Cognitive decline predicts stroke
bull 930 men in Sweden without strokebull 13 years follow-up
bull Worse performance on a lsquojoin the dotsrsquo test predicted stroke
Cognitive decline predicts Stroke
fastest
slowest
Leiden 85+ Study 480 subjects 85 years
In the very elderly cognition predicts stroke better than vascular risk factors
Cognitive decline predicts stroke
Sabayan B et al Stroke 2013441866-1871
Vascular risk score Memory test
Cognition impaired after even minor stroke
Patients n=135 1 year after with minor stroke
median age 66 (IQR 56-75)
17 ACE-R lt82 (lsquodementiarsquo)
R p
Age -031 0001
Pre-morbid IQ 092 lt00001(National Adult Reading Test)
WMH score 158 003
Not NIHSS old stroke lesion
location lacunar vs non-lacunar
etc
Makin et al 2014
Idyll Zealot Gist Superfluous
Simile Deny Ache Banal
Naiumlve Depot Beatify Facade
Catacomb Equivocal Gauche Placebo
Deacutetente Heir Aeon Puerperal
Chord Sidereal Quadruped Aver
Rarefy Bouquet Abstemious Rarefy
Topiary Radix Debt Assignate
Capon Thyme Drachma Sidereal
Topiary Prelate Demesne Syncope
Labile Procreate Subtle Gaoled
Courteous Gouge Hiatus Psalm
Campanile Leviathan Aisle Cellist
White matter hyperintensities
mild
severe
Age 50-69 7 70-89 17 +
risk of dementia
Debette BMJ 2010
ldquoTotal SVD burdenrdquo and cognition
Staals Neurology 2014 +Neurology Patient page
Staals NBA 2015 Karema Mol Psych 2015
Simple sum score or more complex
latent variable model
Higher SVD burden associated with
Poorer general cognitive ability
Full score β -008 p=002
Without WMH β -01 p=04
Staals et al Neurology 2014 NBA 2015
bull Working party consensus
bull Recommends cognitive screeningbull Examples are MOCA or the Oxford Cognitive Screen
RCP 2016
SVD Treatment options ndash consider aim
bull No specific SVD treatments
bull Case 1 ndash Asymptomatic
bull Case 2 ndash Lacunar stroke
bull Case 3 ndash Co-incidental SVD
Smith EE Saposnik G Biessels GJ et al Prevention of stroke in patients with
silent cerebrovascular disease A Scientific Statement for healthcare
professionals from the American Heart AssociationAmerican Stroke
Association Stroke 201748e44-e71
Case 1 Asymptomatic patient
bull 70 yr old man golfer (18 holes)
bull Well
bull Headachehead injury
bull Incidental finding
bull Is this really ldquosilentrdquo
bull Revert to primary prevention risk factor control
Treatment and prevention
Treat vascular risk factors
High blood pressure ++
Diabetes +
High cholesterol +
Smoking ++
But Impact may
differ at different ages
eg BP may be more
important in 40s ndash
60s than 70s ndash 90s
But All common vascular risk factors combined only
explain a small proportion of the burden of brain
vascular disease and so far trials of risk factor
reduction have been disappointing
Case 2 Lacunar stroke patient
bull 65 yr old female
bull Left sided weakness
bull Is there enough evidence to manage her differently from other ischaemic strokes
bull Many studies included lacunar stroke patients but did not adequately report subtype findings
bull Few studies in lacunar stroke
SPS3 trial
Benavente NEJM 2012 Benavente Lancet Neurol 2013
N=3000 patients with lacunar stroke and baseline MRI scans
Intensive blood pressure control no significant benefit on strokemortality
(but fewer ICH)
Dual antiplatelet (clopasp) therapy harmful and stopped early
Lower than expected stroke incidence
Case 3 Co-incidental SVD
bull 80 yr with atrial fibrillation - CHADSVASC2 3
MRI shows microbleeds
bull 70 yr with acute MCA infarct ndash 2 hours ago
MRICT show white matter disease
Anticoagulation and other therapies in patients with silent microbleeds
It is reasonable to provide anticoagulation therapy to patients with microbleeds when there is an indication
(eg AF)
When anticoagulation is needed a novel oral anticoagulant is preferred over warfarin
Percutaneous closure of the left atrial appendage could be considered as an alternative to anticoagulation
It is reasonable to provide antiplatelet therapy to patients with microbleeds when there is an indication
MRI screening for microbleeds is not needed before the initiation of antithrombotic therapies
Individuals with silent microbleeds are at increased future risk of both ischemic stroke and ICH
Implement preventive care recommended by AHAASA guidelines for primary prevention of ischemic stroke
It is reasonable to provide preventive care recommended by AHAASA guidelines for prevention of ICH
Suggestions for Clinical Care in Patients with Microbleeds
Acute ischemic stroke due to RMCA occlusion
Multiple microbleeds on SWI
77 year woman
Plan of management
NIHSS 16
a) No thrombolysis or antithromboticsb) Aspirinc) IV tPA 09 mgkg then thrombectomyd) IV tPA 06 mgkg then EVTe) Straight to EVT without tPA
Microbleed Scenario Acute Ischemic Stroke
Slide adapted from E Smith
Risk for sICH after TPA
bull Meta-analysis of 8 cohort studies with data on cerebral microbleeds and risk for post-tPA sICH
bull Pooled OR 287 for ICH post TPA in the presence of microbleeds
bull Unclear whether 56 risk increase for sICH outweighs
12 risk reduction for ischemic stroke disability expected
from tPA
Charidimou A et al Neurology 201585927-924
Safety of acute ischemic stroke therapy in patients with silent microbleeds
It is reasonable to administer intravenous alteplase to patients with acute ischemic stroke and
evidence of microbleeds if it is otherwise indicated
It is reasonable to perform endovascular thrombectomy in patients with acute ischemic stroke and
evidence of microbleeds
In acute ischemic stroke patients with microbleeds bypassing intravenous alteplase therapy to
proceed directly to endovascular thrombectomy is an unproven strategy
Clinical Suggestions for Acute Ischemic
Stroke
Therapy in Patients with Microbleeds
Other SVD treatment targets
Weak blood vessel lining strengthen cell junctions
Poor blood vessel function increase nitric oxide
lsquoInflammationrsquo anti-inflammatory
Statins nitrates pentoxyfiline cilostazol dipyridamole etc
Trials are ongoing eg LACI-1 LACI-2 PRESERVE
Salt exercise green vegetables nutrient bars
RCTs of cilostazol and nitrates in SVD
n=446012 weeksEdinburghNottingham
n=4001 yrJuly 2017gt30 UK centres
TolerabilityCVR measuresPulse wave analysis
1 Cilostazol2 Nitrate3 Both early4 Both late
Clinical outcomesMRI at one year
1 Cilostazol2 Nitrate3 Both4 Neither
SVD trials
bull Difficult ndash heterogenous patient groups
bull Low stroke recurrence rate (3 pa)
bull Cognitive testing time consuming
bull Do they measure the correct outcomes
For now
Apply guideline treatments
bull Lower blood pressure
bull Lower lipids
bull Use antiplatelet drugs but not ASA+Clop long term
bull Lifestyle advise ndash smoking salt reduction exercise
bull Trials of existing agents and novel agents
bull More animal data to lead to human trials
Conclusions
bull SVD important defined by imaging
bull Silent may not be silent
bull Stroke and dementia linked
bull Treatment options at present limited
Small vessel disease links stroke and dementia
Dementia Stroke
Imaging defines SVD
Unknown causes SVD
Endothelial Damage
Inflammation
Impaired Glymphatic
Drainage
Vessel Stiffening
Vessel Occlusion
lsquoSmall Vessel Diseasersquo matters to patients (JLA)
Poor blood vessels worse Alzheimerrsquos
lsquoLacunarrsquo
Stroke
3 million per year worldwide
35000 per year in the UK
Up to 16 million dementias
worldwide
Few die
A fifth are left dependent
A third have cognitive impairment
Balance and walking problems
Mood ndash common cause of depression at
older ages
20-25
Vascular
Dementia25-45
Stroke leads to dementia
7-30 in 1st year after stroke severity pre-existing cognitive decline
Stroke Cognitive impairment
Prediction of dementia is difficult
bull lsquoDementiarsquo tests focus on memory ndash other abilities are more affected
bull Tests often too long and tiring
bull Patients may not be able to do some tests after stroke
bull Donrsquot account for previous cognitive ability but this is the strongest predictor of cognitive problems after stroke
bull REGARDS cohort in US
bull 24000 pts gt45yrs fu from 2003 for 6 yrs
bull Investigated acute and chronic cognition post stroke
bull Global cognition ndash SIS (six item screener)bull Executive functioning and memory
500 patients had stroke
JAMA 2015
Results
Incident stroke
Acute significant decline in global cognition and
memory
Accelerated decline in global cognition and
executive function
Cognitive decline predicts stroke
bull 930 men in Sweden without strokebull 13 years follow-up
bull Worse performance on a lsquojoin the dotsrsquo test predicted stroke
Cognitive decline predicts Stroke
fastest
slowest
Leiden 85+ Study 480 subjects 85 years
In the very elderly cognition predicts stroke better than vascular risk factors
Cognitive decline predicts stroke
Sabayan B et al Stroke 2013441866-1871
Vascular risk score Memory test
Cognition impaired after even minor stroke
Patients n=135 1 year after with minor stroke
median age 66 (IQR 56-75)
17 ACE-R lt82 (lsquodementiarsquo)
R p
Age -031 0001
Pre-morbid IQ 092 lt00001(National Adult Reading Test)
WMH score 158 003
Not NIHSS old stroke lesion
location lacunar vs non-lacunar
etc
Makin et al 2014
Idyll Zealot Gist Superfluous
Simile Deny Ache Banal
Naiumlve Depot Beatify Facade
Catacomb Equivocal Gauche Placebo
Deacutetente Heir Aeon Puerperal
Chord Sidereal Quadruped Aver
Rarefy Bouquet Abstemious Rarefy
Topiary Radix Debt Assignate
Capon Thyme Drachma Sidereal
Topiary Prelate Demesne Syncope
Labile Procreate Subtle Gaoled
Courteous Gouge Hiatus Psalm
Campanile Leviathan Aisle Cellist
White matter hyperintensities
mild
severe
Age 50-69 7 70-89 17 +
risk of dementia
Debette BMJ 2010
ldquoTotal SVD burdenrdquo and cognition
Staals Neurology 2014 +Neurology Patient page
Staals NBA 2015 Karema Mol Psych 2015
Simple sum score or more complex
latent variable model
Higher SVD burden associated with
Poorer general cognitive ability
Full score β -008 p=002
Without WMH β -01 p=04
Staals et al Neurology 2014 NBA 2015
bull Working party consensus
bull Recommends cognitive screeningbull Examples are MOCA or the Oxford Cognitive Screen
RCP 2016
SVD Treatment options ndash consider aim
bull No specific SVD treatments
bull Case 1 ndash Asymptomatic
bull Case 2 ndash Lacunar stroke
bull Case 3 ndash Co-incidental SVD
Smith EE Saposnik G Biessels GJ et al Prevention of stroke in patients with
silent cerebrovascular disease A Scientific Statement for healthcare
professionals from the American Heart AssociationAmerican Stroke
Association Stroke 201748e44-e71
Case 1 Asymptomatic patient
bull 70 yr old man golfer (18 holes)
bull Well
bull Headachehead injury
bull Incidental finding
bull Is this really ldquosilentrdquo
bull Revert to primary prevention risk factor control
Treatment and prevention
Treat vascular risk factors
High blood pressure ++
Diabetes +
High cholesterol +
Smoking ++
But Impact may
differ at different ages
eg BP may be more
important in 40s ndash
60s than 70s ndash 90s
But All common vascular risk factors combined only
explain a small proportion of the burden of brain
vascular disease and so far trials of risk factor
reduction have been disappointing
Case 2 Lacunar stroke patient
bull 65 yr old female
bull Left sided weakness
bull Is there enough evidence to manage her differently from other ischaemic strokes
bull Many studies included lacunar stroke patients but did not adequately report subtype findings
bull Few studies in lacunar stroke
SPS3 trial
Benavente NEJM 2012 Benavente Lancet Neurol 2013
N=3000 patients with lacunar stroke and baseline MRI scans
Intensive blood pressure control no significant benefit on strokemortality
(but fewer ICH)
Dual antiplatelet (clopasp) therapy harmful and stopped early
Lower than expected stroke incidence
Case 3 Co-incidental SVD
bull 80 yr with atrial fibrillation - CHADSVASC2 3
MRI shows microbleeds
bull 70 yr with acute MCA infarct ndash 2 hours ago
MRICT show white matter disease
Anticoagulation and other therapies in patients with silent microbleeds
It is reasonable to provide anticoagulation therapy to patients with microbleeds when there is an indication
(eg AF)
When anticoagulation is needed a novel oral anticoagulant is preferred over warfarin
Percutaneous closure of the left atrial appendage could be considered as an alternative to anticoagulation
It is reasonable to provide antiplatelet therapy to patients with microbleeds when there is an indication
MRI screening for microbleeds is not needed before the initiation of antithrombotic therapies
Individuals with silent microbleeds are at increased future risk of both ischemic stroke and ICH
Implement preventive care recommended by AHAASA guidelines for primary prevention of ischemic stroke
It is reasonable to provide preventive care recommended by AHAASA guidelines for prevention of ICH
Suggestions for Clinical Care in Patients with Microbleeds
Acute ischemic stroke due to RMCA occlusion
Multiple microbleeds on SWI
77 year woman
Plan of management
NIHSS 16
a) No thrombolysis or antithromboticsb) Aspirinc) IV tPA 09 mgkg then thrombectomyd) IV tPA 06 mgkg then EVTe) Straight to EVT without tPA
Microbleed Scenario Acute Ischemic Stroke
Slide adapted from E Smith
Risk for sICH after TPA
bull Meta-analysis of 8 cohort studies with data on cerebral microbleeds and risk for post-tPA sICH
bull Pooled OR 287 for ICH post TPA in the presence of microbleeds
bull Unclear whether 56 risk increase for sICH outweighs
12 risk reduction for ischemic stroke disability expected
from tPA
Charidimou A et al Neurology 201585927-924
Safety of acute ischemic stroke therapy in patients with silent microbleeds
It is reasonable to administer intravenous alteplase to patients with acute ischemic stroke and
evidence of microbleeds if it is otherwise indicated
It is reasonable to perform endovascular thrombectomy in patients with acute ischemic stroke and
evidence of microbleeds
In acute ischemic stroke patients with microbleeds bypassing intravenous alteplase therapy to
proceed directly to endovascular thrombectomy is an unproven strategy
Clinical Suggestions for Acute Ischemic
Stroke
Therapy in Patients with Microbleeds
Other SVD treatment targets
Weak blood vessel lining strengthen cell junctions
Poor blood vessel function increase nitric oxide
lsquoInflammationrsquo anti-inflammatory
Statins nitrates pentoxyfiline cilostazol dipyridamole etc
Trials are ongoing eg LACI-1 LACI-2 PRESERVE
Salt exercise green vegetables nutrient bars
RCTs of cilostazol and nitrates in SVD
n=446012 weeksEdinburghNottingham
n=4001 yrJuly 2017gt30 UK centres
TolerabilityCVR measuresPulse wave analysis
1 Cilostazol2 Nitrate3 Both early4 Both late
Clinical outcomesMRI at one year
1 Cilostazol2 Nitrate3 Both4 Neither
SVD trials
bull Difficult ndash heterogenous patient groups
bull Low stroke recurrence rate (3 pa)
bull Cognitive testing time consuming
bull Do they measure the correct outcomes
For now
Apply guideline treatments
bull Lower blood pressure
bull Lower lipids
bull Use antiplatelet drugs but not ASA+Clop long term
bull Lifestyle advise ndash smoking salt reduction exercise
bull Trials of existing agents and novel agents
bull More animal data to lead to human trials
Conclusions
bull SVD important defined by imaging
bull Silent may not be silent
bull Stroke and dementia linked
bull Treatment options at present limited
Unknown causes SVD
Endothelial Damage
Inflammation
Impaired Glymphatic
Drainage
Vessel Stiffening
Vessel Occlusion
lsquoSmall Vessel Diseasersquo matters to patients (JLA)
Poor blood vessels worse Alzheimerrsquos
lsquoLacunarrsquo
Stroke
3 million per year worldwide
35000 per year in the UK
Up to 16 million dementias
worldwide
Few die
A fifth are left dependent
A third have cognitive impairment
Balance and walking problems
Mood ndash common cause of depression at
older ages
20-25
Vascular
Dementia25-45
Stroke leads to dementia
7-30 in 1st year after stroke severity pre-existing cognitive decline
Stroke Cognitive impairment
Prediction of dementia is difficult
bull lsquoDementiarsquo tests focus on memory ndash other abilities are more affected
bull Tests often too long and tiring
bull Patients may not be able to do some tests after stroke
bull Donrsquot account for previous cognitive ability but this is the strongest predictor of cognitive problems after stroke
bull REGARDS cohort in US
bull 24000 pts gt45yrs fu from 2003 for 6 yrs
bull Investigated acute and chronic cognition post stroke
bull Global cognition ndash SIS (six item screener)bull Executive functioning and memory
500 patients had stroke
JAMA 2015
Results
Incident stroke
Acute significant decline in global cognition and
memory
Accelerated decline in global cognition and
executive function
Cognitive decline predicts stroke
bull 930 men in Sweden without strokebull 13 years follow-up
bull Worse performance on a lsquojoin the dotsrsquo test predicted stroke
Cognitive decline predicts Stroke
fastest
slowest
Leiden 85+ Study 480 subjects 85 years
In the very elderly cognition predicts stroke better than vascular risk factors
Cognitive decline predicts stroke
Sabayan B et al Stroke 2013441866-1871
Vascular risk score Memory test
Cognition impaired after even minor stroke
Patients n=135 1 year after with minor stroke
median age 66 (IQR 56-75)
17 ACE-R lt82 (lsquodementiarsquo)
R p
Age -031 0001
Pre-morbid IQ 092 lt00001(National Adult Reading Test)
WMH score 158 003
Not NIHSS old stroke lesion
location lacunar vs non-lacunar
etc
Makin et al 2014
Idyll Zealot Gist Superfluous
Simile Deny Ache Banal
Naiumlve Depot Beatify Facade
Catacomb Equivocal Gauche Placebo
Deacutetente Heir Aeon Puerperal
Chord Sidereal Quadruped Aver
Rarefy Bouquet Abstemious Rarefy
Topiary Radix Debt Assignate
Capon Thyme Drachma Sidereal
Topiary Prelate Demesne Syncope
Labile Procreate Subtle Gaoled
Courteous Gouge Hiatus Psalm
Campanile Leviathan Aisle Cellist
White matter hyperintensities
mild
severe
Age 50-69 7 70-89 17 +
risk of dementia
Debette BMJ 2010
ldquoTotal SVD burdenrdquo and cognition
Staals Neurology 2014 +Neurology Patient page
Staals NBA 2015 Karema Mol Psych 2015
Simple sum score or more complex
latent variable model
Higher SVD burden associated with
Poorer general cognitive ability
Full score β -008 p=002
Without WMH β -01 p=04
Staals et al Neurology 2014 NBA 2015
bull Working party consensus
bull Recommends cognitive screeningbull Examples are MOCA or the Oxford Cognitive Screen
RCP 2016
SVD Treatment options ndash consider aim
bull No specific SVD treatments
bull Case 1 ndash Asymptomatic
bull Case 2 ndash Lacunar stroke
bull Case 3 ndash Co-incidental SVD
Smith EE Saposnik G Biessels GJ et al Prevention of stroke in patients with
silent cerebrovascular disease A Scientific Statement for healthcare
professionals from the American Heart AssociationAmerican Stroke
Association Stroke 201748e44-e71
Case 1 Asymptomatic patient
bull 70 yr old man golfer (18 holes)
bull Well
bull Headachehead injury
bull Incidental finding
bull Is this really ldquosilentrdquo
bull Revert to primary prevention risk factor control
Treatment and prevention
Treat vascular risk factors
High blood pressure ++
Diabetes +
High cholesterol +
Smoking ++
But Impact may
differ at different ages
eg BP may be more
important in 40s ndash
60s than 70s ndash 90s
But All common vascular risk factors combined only
explain a small proportion of the burden of brain
vascular disease and so far trials of risk factor
reduction have been disappointing
Case 2 Lacunar stroke patient
bull 65 yr old female
bull Left sided weakness
bull Is there enough evidence to manage her differently from other ischaemic strokes
bull Many studies included lacunar stroke patients but did not adequately report subtype findings
bull Few studies in lacunar stroke
SPS3 trial
Benavente NEJM 2012 Benavente Lancet Neurol 2013
N=3000 patients with lacunar stroke and baseline MRI scans
Intensive blood pressure control no significant benefit on strokemortality
(but fewer ICH)
Dual antiplatelet (clopasp) therapy harmful and stopped early
Lower than expected stroke incidence
Case 3 Co-incidental SVD
bull 80 yr with atrial fibrillation - CHADSVASC2 3
MRI shows microbleeds
bull 70 yr with acute MCA infarct ndash 2 hours ago
MRICT show white matter disease
Anticoagulation and other therapies in patients with silent microbleeds
It is reasonable to provide anticoagulation therapy to patients with microbleeds when there is an indication
(eg AF)
When anticoagulation is needed a novel oral anticoagulant is preferred over warfarin
Percutaneous closure of the left atrial appendage could be considered as an alternative to anticoagulation
It is reasonable to provide antiplatelet therapy to patients with microbleeds when there is an indication
MRI screening for microbleeds is not needed before the initiation of antithrombotic therapies
Individuals with silent microbleeds are at increased future risk of both ischemic stroke and ICH
Implement preventive care recommended by AHAASA guidelines for primary prevention of ischemic stroke
It is reasonable to provide preventive care recommended by AHAASA guidelines for prevention of ICH
Suggestions for Clinical Care in Patients with Microbleeds
Acute ischemic stroke due to RMCA occlusion
Multiple microbleeds on SWI
77 year woman
Plan of management
NIHSS 16
a) No thrombolysis or antithromboticsb) Aspirinc) IV tPA 09 mgkg then thrombectomyd) IV tPA 06 mgkg then EVTe) Straight to EVT without tPA
Microbleed Scenario Acute Ischemic Stroke
Slide adapted from E Smith
Risk for sICH after TPA
bull Meta-analysis of 8 cohort studies with data on cerebral microbleeds and risk for post-tPA sICH
bull Pooled OR 287 for ICH post TPA in the presence of microbleeds
bull Unclear whether 56 risk increase for sICH outweighs
12 risk reduction for ischemic stroke disability expected
from tPA
Charidimou A et al Neurology 201585927-924
Safety of acute ischemic stroke therapy in patients with silent microbleeds
It is reasonable to administer intravenous alteplase to patients with acute ischemic stroke and
evidence of microbleeds if it is otherwise indicated
It is reasonable to perform endovascular thrombectomy in patients with acute ischemic stroke and
evidence of microbleeds
In acute ischemic stroke patients with microbleeds bypassing intravenous alteplase therapy to
proceed directly to endovascular thrombectomy is an unproven strategy
Clinical Suggestions for Acute Ischemic
Stroke
Therapy in Patients with Microbleeds
Other SVD treatment targets
Weak blood vessel lining strengthen cell junctions
Poor blood vessel function increase nitric oxide
lsquoInflammationrsquo anti-inflammatory
Statins nitrates pentoxyfiline cilostazol dipyridamole etc
Trials are ongoing eg LACI-1 LACI-2 PRESERVE
Salt exercise green vegetables nutrient bars
RCTs of cilostazol and nitrates in SVD
n=446012 weeksEdinburghNottingham
n=4001 yrJuly 2017gt30 UK centres
TolerabilityCVR measuresPulse wave analysis
1 Cilostazol2 Nitrate3 Both early4 Both late
Clinical outcomesMRI at one year
1 Cilostazol2 Nitrate3 Both4 Neither
SVD trials
bull Difficult ndash heterogenous patient groups
bull Low stroke recurrence rate (3 pa)
bull Cognitive testing time consuming
bull Do they measure the correct outcomes
For now
Apply guideline treatments
bull Lower blood pressure
bull Lower lipids
bull Use antiplatelet drugs but not ASA+Clop long term
bull Lifestyle advise ndash smoking salt reduction exercise
bull Trials of existing agents and novel agents
bull More animal data to lead to human trials
Conclusions
bull SVD important defined by imaging
bull Silent may not be silent
bull Stroke and dementia linked
bull Treatment options at present limited
lsquoSmall Vessel Diseasersquo matters to patients (JLA)
Poor blood vessels worse Alzheimerrsquos
lsquoLacunarrsquo
Stroke
3 million per year worldwide
35000 per year in the UK
Up to 16 million dementias
worldwide
Few die
A fifth are left dependent
A third have cognitive impairment
Balance and walking problems
Mood ndash common cause of depression at
older ages
20-25
Vascular
Dementia25-45
Stroke leads to dementia
7-30 in 1st year after stroke severity pre-existing cognitive decline
Stroke Cognitive impairment
Prediction of dementia is difficult
bull lsquoDementiarsquo tests focus on memory ndash other abilities are more affected
bull Tests often too long and tiring
bull Patients may not be able to do some tests after stroke
bull Donrsquot account for previous cognitive ability but this is the strongest predictor of cognitive problems after stroke
bull REGARDS cohort in US
bull 24000 pts gt45yrs fu from 2003 for 6 yrs
bull Investigated acute and chronic cognition post stroke
bull Global cognition ndash SIS (six item screener)bull Executive functioning and memory
500 patients had stroke
JAMA 2015
Results
Incident stroke
Acute significant decline in global cognition and
memory
Accelerated decline in global cognition and
executive function
Cognitive decline predicts stroke
bull 930 men in Sweden without strokebull 13 years follow-up
bull Worse performance on a lsquojoin the dotsrsquo test predicted stroke
Cognitive decline predicts Stroke
fastest
slowest
Leiden 85+ Study 480 subjects 85 years
In the very elderly cognition predicts stroke better than vascular risk factors
Cognitive decline predicts stroke
Sabayan B et al Stroke 2013441866-1871
Vascular risk score Memory test
Cognition impaired after even minor stroke
Patients n=135 1 year after with minor stroke
median age 66 (IQR 56-75)
17 ACE-R lt82 (lsquodementiarsquo)
R p
Age -031 0001
Pre-morbid IQ 092 lt00001(National Adult Reading Test)
WMH score 158 003
Not NIHSS old stroke lesion
location lacunar vs non-lacunar
etc
Makin et al 2014
Idyll Zealot Gist Superfluous
Simile Deny Ache Banal
Naiumlve Depot Beatify Facade
Catacomb Equivocal Gauche Placebo
Deacutetente Heir Aeon Puerperal
Chord Sidereal Quadruped Aver
Rarefy Bouquet Abstemious Rarefy
Topiary Radix Debt Assignate
Capon Thyme Drachma Sidereal
Topiary Prelate Demesne Syncope
Labile Procreate Subtle Gaoled
Courteous Gouge Hiatus Psalm
Campanile Leviathan Aisle Cellist
White matter hyperintensities
mild
severe
Age 50-69 7 70-89 17 +
risk of dementia
Debette BMJ 2010
ldquoTotal SVD burdenrdquo and cognition
Staals Neurology 2014 +Neurology Patient page
Staals NBA 2015 Karema Mol Psych 2015
Simple sum score or more complex
latent variable model
Higher SVD burden associated with
Poorer general cognitive ability
Full score β -008 p=002
Without WMH β -01 p=04
Staals et al Neurology 2014 NBA 2015
bull Working party consensus
bull Recommends cognitive screeningbull Examples are MOCA or the Oxford Cognitive Screen
RCP 2016
SVD Treatment options ndash consider aim
bull No specific SVD treatments
bull Case 1 ndash Asymptomatic
bull Case 2 ndash Lacunar stroke
bull Case 3 ndash Co-incidental SVD
Smith EE Saposnik G Biessels GJ et al Prevention of stroke in patients with
silent cerebrovascular disease A Scientific Statement for healthcare
professionals from the American Heart AssociationAmerican Stroke
Association Stroke 201748e44-e71
Case 1 Asymptomatic patient
bull 70 yr old man golfer (18 holes)
bull Well
bull Headachehead injury
bull Incidental finding
bull Is this really ldquosilentrdquo
bull Revert to primary prevention risk factor control
Treatment and prevention
Treat vascular risk factors
High blood pressure ++
Diabetes +
High cholesterol +
Smoking ++
But Impact may
differ at different ages
eg BP may be more
important in 40s ndash
60s than 70s ndash 90s
But All common vascular risk factors combined only
explain a small proportion of the burden of brain
vascular disease and so far trials of risk factor
reduction have been disappointing
Case 2 Lacunar stroke patient
bull 65 yr old female
bull Left sided weakness
bull Is there enough evidence to manage her differently from other ischaemic strokes
bull Many studies included lacunar stroke patients but did not adequately report subtype findings
bull Few studies in lacunar stroke
SPS3 trial
Benavente NEJM 2012 Benavente Lancet Neurol 2013
N=3000 patients with lacunar stroke and baseline MRI scans
Intensive blood pressure control no significant benefit on strokemortality
(but fewer ICH)
Dual antiplatelet (clopasp) therapy harmful and stopped early
Lower than expected stroke incidence
Case 3 Co-incidental SVD
bull 80 yr with atrial fibrillation - CHADSVASC2 3
MRI shows microbleeds
bull 70 yr with acute MCA infarct ndash 2 hours ago
MRICT show white matter disease
Anticoagulation and other therapies in patients with silent microbleeds
It is reasonable to provide anticoagulation therapy to patients with microbleeds when there is an indication
(eg AF)
When anticoagulation is needed a novel oral anticoagulant is preferred over warfarin
Percutaneous closure of the left atrial appendage could be considered as an alternative to anticoagulation
It is reasonable to provide antiplatelet therapy to patients with microbleeds when there is an indication
MRI screening for microbleeds is not needed before the initiation of antithrombotic therapies
Individuals with silent microbleeds are at increased future risk of both ischemic stroke and ICH
Implement preventive care recommended by AHAASA guidelines for primary prevention of ischemic stroke
It is reasonable to provide preventive care recommended by AHAASA guidelines for prevention of ICH
Suggestions for Clinical Care in Patients with Microbleeds
Acute ischemic stroke due to RMCA occlusion
Multiple microbleeds on SWI
77 year woman
Plan of management
NIHSS 16
a) No thrombolysis or antithromboticsb) Aspirinc) IV tPA 09 mgkg then thrombectomyd) IV tPA 06 mgkg then EVTe) Straight to EVT without tPA
Microbleed Scenario Acute Ischemic Stroke
Slide adapted from E Smith
Risk for sICH after TPA
bull Meta-analysis of 8 cohort studies with data on cerebral microbleeds and risk for post-tPA sICH
bull Pooled OR 287 for ICH post TPA in the presence of microbleeds
bull Unclear whether 56 risk increase for sICH outweighs
12 risk reduction for ischemic stroke disability expected
from tPA
Charidimou A et al Neurology 201585927-924
Safety of acute ischemic stroke therapy in patients with silent microbleeds
It is reasonable to administer intravenous alteplase to patients with acute ischemic stroke and
evidence of microbleeds if it is otherwise indicated
It is reasonable to perform endovascular thrombectomy in patients with acute ischemic stroke and
evidence of microbleeds
In acute ischemic stroke patients with microbleeds bypassing intravenous alteplase therapy to
proceed directly to endovascular thrombectomy is an unproven strategy
Clinical Suggestions for Acute Ischemic
Stroke
Therapy in Patients with Microbleeds
Other SVD treatment targets
Weak blood vessel lining strengthen cell junctions
Poor blood vessel function increase nitric oxide
lsquoInflammationrsquo anti-inflammatory
Statins nitrates pentoxyfiline cilostazol dipyridamole etc
Trials are ongoing eg LACI-1 LACI-2 PRESERVE
Salt exercise green vegetables nutrient bars
RCTs of cilostazol and nitrates in SVD
n=446012 weeksEdinburghNottingham
n=4001 yrJuly 2017gt30 UK centres
TolerabilityCVR measuresPulse wave analysis
1 Cilostazol2 Nitrate3 Both early4 Both late
Clinical outcomesMRI at one year
1 Cilostazol2 Nitrate3 Both4 Neither
SVD trials
bull Difficult ndash heterogenous patient groups
bull Low stroke recurrence rate (3 pa)
bull Cognitive testing time consuming
bull Do they measure the correct outcomes
For now
Apply guideline treatments
bull Lower blood pressure
bull Lower lipids
bull Use antiplatelet drugs but not ASA+Clop long term
bull Lifestyle advise ndash smoking salt reduction exercise
bull Trials of existing agents and novel agents
bull More animal data to lead to human trials
Conclusions
bull SVD important defined by imaging
bull Silent may not be silent
bull Stroke and dementia linked
bull Treatment options at present limited
Stroke leads to dementia
7-30 in 1st year after stroke severity pre-existing cognitive decline
Stroke Cognitive impairment
Prediction of dementia is difficult
bull lsquoDementiarsquo tests focus on memory ndash other abilities are more affected
bull Tests often too long and tiring
bull Patients may not be able to do some tests after stroke
bull Donrsquot account for previous cognitive ability but this is the strongest predictor of cognitive problems after stroke
bull REGARDS cohort in US
bull 24000 pts gt45yrs fu from 2003 for 6 yrs
bull Investigated acute and chronic cognition post stroke
bull Global cognition ndash SIS (six item screener)bull Executive functioning and memory
500 patients had stroke
JAMA 2015
Results
Incident stroke
Acute significant decline in global cognition and
memory
Accelerated decline in global cognition and
executive function
Cognitive decline predicts stroke
bull 930 men in Sweden without strokebull 13 years follow-up
bull Worse performance on a lsquojoin the dotsrsquo test predicted stroke
Cognitive decline predicts Stroke
fastest
slowest
Leiden 85+ Study 480 subjects 85 years
In the very elderly cognition predicts stroke better than vascular risk factors
Cognitive decline predicts stroke
Sabayan B et al Stroke 2013441866-1871
Vascular risk score Memory test
Cognition impaired after even minor stroke
Patients n=135 1 year after with minor stroke
median age 66 (IQR 56-75)
17 ACE-R lt82 (lsquodementiarsquo)
R p
Age -031 0001
Pre-morbid IQ 092 lt00001(National Adult Reading Test)
WMH score 158 003
Not NIHSS old stroke lesion
location lacunar vs non-lacunar
etc
Makin et al 2014
Idyll Zealot Gist Superfluous
Simile Deny Ache Banal
Naiumlve Depot Beatify Facade
Catacomb Equivocal Gauche Placebo
Deacutetente Heir Aeon Puerperal
Chord Sidereal Quadruped Aver
Rarefy Bouquet Abstemious Rarefy
Topiary Radix Debt Assignate
Capon Thyme Drachma Sidereal
Topiary Prelate Demesne Syncope
Labile Procreate Subtle Gaoled
Courteous Gouge Hiatus Psalm
Campanile Leviathan Aisle Cellist
White matter hyperintensities
mild
severe
Age 50-69 7 70-89 17 +
risk of dementia
Debette BMJ 2010
ldquoTotal SVD burdenrdquo and cognition
Staals Neurology 2014 +Neurology Patient page
Staals NBA 2015 Karema Mol Psych 2015
Simple sum score or more complex
latent variable model
Higher SVD burden associated with
Poorer general cognitive ability
Full score β -008 p=002
Without WMH β -01 p=04
Staals et al Neurology 2014 NBA 2015
bull Working party consensus
bull Recommends cognitive screeningbull Examples are MOCA or the Oxford Cognitive Screen
RCP 2016
SVD Treatment options ndash consider aim
bull No specific SVD treatments
bull Case 1 ndash Asymptomatic
bull Case 2 ndash Lacunar stroke
bull Case 3 ndash Co-incidental SVD
Smith EE Saposnik G Biessels GJ et al Prevention of stroke in patients with
silent cerebrovascular disease A Scientific Statement for healthcare
professionals from the American Heart AssociationAmerican Stroke
Association Stroke 201748e44-e71
Case 1 Asymptomatic patient
bull 70 yr old man golfer (18 holes)
bull Well
bull Headachehead injury
bull Incidental finding
bull Is this really ldquosilentrdquo
bull Revert to primary prevention risk factor control
Treatment and prevention
Treat vascular risk factors
High blood pressure ++
Diabetes +
High cholesterol +
Smoking ++
But Impact may
differ at different ages
eg BP may be more
important in 40s ndash
60s than 70s ndash 90s
But All common vascular risk factors combined only
explain a small proportion of the burden of brain
vascular disease and so far trials of risk factor
reduction have been disappointing
Case 2 Lacunar stroke patient
bull 65 yr old female
bull Left sided weakness
bull Is there enough evidence to manage her differently from other ischaemic strokes
bull Many studies included lacunar stroke patients but did not adequately report subtype findings
bull Few studies in lacunar stroke
SPS3 trial
Benavente NEJM 2012 Benavente Lancet Neurol 2013
N=3000 patients with lacunar stroke and baseline MRI scans
Intensive blood pressure control no significant benefit on strokemortality
(but fewer ICH)
Dual antiplatelet (clopasp) therapy harmful and stopped early
Lower than expected stroke incidence
Case 3 Co-incidental SVD
bull 80 yr with atrial fibrillation - CHADSVASC2 3
MRI shows microbleeds
bull 70 yr with acute MCA infarct ndash 2 hours ago
MRICT show white matter disease
Anticoagulation and other therapies in patients with silent microbleeds
It is reasonable to provide anticoagulation therapy to patients with microbleeds when there is an indication
(eg AF)
When anticoagulation is needed a novel oral anticoagulant is preferred over warfarin
Percutaneous closure of the left atrial appendage could be considered as an alternative to anticoagulation
It is reasonable to provide antiplatelet therapy to patients with microbleeds when there is an indication
MRI screening for microbleeds is not needed before the initiation of antithrombotic therapies
Individuals with silent microbleeds are at increased future risk of both ischemic stroke and ICH
Implement preventive care recommended by AHAASA guidelines for primary prevention of ischemic stroke
It is reasonable to provide preventive care recommended by AHAASA guidelines for prevention of ICH
Suggestions for Clinical Care in Patients with Microbleeds
Acute ischemic stroke due to RMCA occlusion
Multiple microbleeds on SWI
77 year woman
Plan of management
NIHSS 16
a) No thrombolysis or antithromboticsb) Aspirinc) IV tPA 09 mgkg then thrombectomyd) IV tPA 06 mgkg then EVTe) Straight to EVT without tPA
Microbleed Scenario Acute Ischemic Stroke
Slide adapted from E Smith
Risk for sICH after TPA
bull Meta-analysis of 8 cohort studies with data on cerebral microbleeds and risk for post-tPA sICH
bull Pooled OR 287 for ICH post TPA in the presence of microbleeds
bull Unclear whether 56 risk increase for sICH outweighs
12 risk reduction for ischemic stroke disability expected
from tPA
Charidimou A et al Neurology 201585927-924
Safety of acute ischemic stroke therapy in patients with silent microbleeds
It is reasonable to administer intravenous alteplase to patients with acute ischemic stroke and
evidence of microbleeds if it is otherwise indicated
It is reasonable to perform endovascular thrombectomy in patients with acute ischemic stroke and
evidence of microbleeds
In acute ischemic stroke patients with microbleeds bypassing intravenous alteplase therapy to
proceed directly to endovascular thrombectomy is an unproven strategy
Clinical Suggestions for Acute Ischemic
Stroke
Therapy in Patients with Microbleeds
Other SVD treatment targets
Weak blood vessel lining strengthen cell junctions
Poor blood vessel function increase nitric oxide
lsquoInflammationrsquo anti-inflammatory
Statins nitrates pentoxyfiline cilostazol dipyridamole etc
Trials are ongoing eg LACI-1 LACI-2 PRESERVE
Salt exercise green vegetables nutrient bars
RCTs of cilostazol and nitrates in SVD
n=446012 weeksEdinburghNottingham
n=4001 yrJuly 2017gt30 UK centres
TolerabilityCVR measuresPulse wave analysis
1 Cilostazol2 Nitrate3 Both early4 Both late
Clinical outcomesMRI at one year
1 Cilostazol2 Nitrate3 Both4 Neither
SVD trials
bull Difficult ndash heterogenous patient groups
bull Low stroke recurrence rate (3 pa)
bull Cognitive testing time consuming
bull Do they measure the correct outcomes
For now
Apply guideline treatments
bull Lower blood pressure
bull Lower lipids
bull Use antiplatelet drugs but not ASA+Clop long term
bull Lifestyle advise ndash smoking salt reduction exercise
bull Trials of existing agents and novel agents
bull More animal data to lead to human trials
Conclusions
bull SVD important defined by imaging
bull Silent may not be silent
bull Stroke and dementia linked
bull Treatment options at present limited
Prediction of dementia is difficult
bull lsquoDementiarsquo tests focus on memory ndash other abilities are more affected
bull Tests often too long and tiring
bull Patients may not be able to do some tests after stroke
bull Donrsquot account for previous cognitive ability but this is the strongest predictor of cognitive problems after stroke
bull REGARDS cohort in US
bull 24000 pts gt45yrs fu from 2003 for 6 yrs
bull Investigated acute and chronic cognition post stroke
bull Global cognition ndash SIS (six item screener)bull Executive functioning and memory
500 patients had stroke
JAMA 2015
Results
Incident stroke
Acute significant decline in global cognition and
memory
Accelerated decline in global cognition and
executive function
Cognitive decline predicts stroke
bull 930 men in Sweden without strokebull 13 years follow-up
bull Worse performance on a lsquojoin the dotsrsquo test predicted stroke
Cognitive decline predicts Stroke
fastest
slowest
Leiden 85+ Study 480 subjects 85 years
In the very elderly cognition predicts stroke better than vascular risk factors
Cognitive decline predicts stroke
Sabayan B et al Stroke 2013441866-1871
Vascular risk score Memory test
Cognition impaired after even minor stroke
Patients n=135 1 year after with minor stroke
median age 66 (IQR 56-75)
17 ACE-R lt82 (lsquodementiarsquo)
R p
Age -031 0001
Pre-morbid IQ 092 lt00001(National Adult Reading Test)
WMH score 158 003
Not NIHSS old stroke lesion
location lacunar vs non-lacunar
etc
Makin et al 2014
Idyll Zealot Gist Superfluous
Simile Deny Ache Banal
Naiumlve Depot Beatify Facade
Catacomb Equivocal Gauche Placebo
Deacutetente Heir Aeon Puerperal
Chord Sidereal Quadruped Aver
Rarefy Bouquet Abstemious Rarefy
Topiary Radix Debt Assignate
Capon Thyme Drachma Sidereal
Topiary Prelate Demesne Syncope
Labile Procreate Subtle Gaoled
Courteous Gouge Hiatus Psalm
Campanile Leviathan Aisle Cellist
White matter hyperintensities
mild
severe
Age 50-69 7 70-89 17 +
risk of dementia
Debette BMJ 2010
ldquoTotal SVD burdenrdquo and cognition
Staals Neurology 2014 +Neurology Patient page
Staals NBA 2015 Karema Mol Psych 2015
Simple sum score or more complex
latent variable model
Higher SVD burden associated with
Poorer general cognitive ability
Full score β -008 p=002
Without WMH β -01 p=04
Staals et al Neurology 2014 NBA 2015
bull Working party consensus
bull Recommends cognitive screeningbull Examples are MOCA or the Oxford Cognitive Screen
RCP 2016
SVD Treatment options ndash consider aim
bull No specific SVD treatments
bull Case 1 ndash Asymptomatic
bull Case 2 ndash Lacunar stroke
bull Case 3 ndash Co-incidental SVD
Smith EE Saposnik G Biessels GJ et al Prevention of stroke in patients with
silent cerebrovascular disease A Scientific Statement for healthcare
professionals from the American Heart AssociationAmerican Stroke
Association Stroke 201748e44-e71
Case 1 Asymptomatic patient
bull 70 yr old man golfer (18 holes)
bull Well
bull Headachehead injury
bull Incidental finding
bull Is this really ldquosilentrdquo
bull Revert to primary prevention risk factor control
Treatment and prevention
Treat vascular risk factors
High blood pressure ++
Diabetes +
High cholesterol +
Smoking ++
But Impact may
differ at different ages
eg BP may be more
important in 40s ndash
60s than 70s ndash 90s
But All common vascular risk factors combined only
explain a small proportion of the burden of brain
vascular disease and so far trials of risk factor
reduction have been disappointing
Case 2 Lacunar stroke patient
bull 65 yr old female
bull Left sided weakness
bull Is there enough evidence to manage her differently from other ischaemic strokes
bull Many studies included lacunar stroke patients but did not adequately report subtype findings
bull Few studies in lacunar stroke
SPS3 trial
Benavente NEJM 2012 Benavente Lancet Neurol 2013
N=3000 patients with lacunar stroke and baseline MRI scans
Intensive blood pressure control no significant benefit on strokemortality
(but fewer ICH)
Dual antiplatelet (clopasp) therapy harmful and stopped early
Lower than expected stroke incidence
Case 3 Co-incidental SVD
bull 80 yr with atrial fibrillation - CHADSVASC2 3
MRI shows microbleeds
bull 70 yr with acute MCA infarct ndash 2 hours ago
MRICT show white matter disease
Anticoagulation and other therapies in patients with silent microbleeds
It is reasonable to provide anticoagulation therapy to patients with microbleeds when there is an indication
(eg AF)
When anticoagulation is needed a novel oral anticoagulant is preferred over warfarin
Percutaneous closure of the left atrial appendage could be considered as an alternative to anticoagulation
It is reasonable to provide antiplatelet therapy to patients with microbleeds when there is an indication
MRI screening for microbleeds is not needed before the initiation of antithrombotic therapies
Individuals with silent microbleeds are at increased future risk of both ischemic stroke and ICH
Implement preventive care recommended by AHAASA guidelines for primary prevention of ischemic stroke
It is reasonable to provide preventive care recommended by AHAASA guidelines for prevention of ICH
Suggestions for Clinical Care in Patients with Microbleeds
Acute ischemic stroke due to RMCA occlusion
Multiple microbleeds on SWI
77 year woman
Plan of management
NIHSS 16
a) No thrombolysis or antithromboticsb) Aspirinc) IV tPA 09 mgkg then thrombectomyd) IV tPA 06 mgkg then EVTe) Straight to EVT without tPA
Microbleed Scenario Acute Ischemic Stroke
Slide adapted from E Smith
Risk for sICH after TPA
bull Meta-analysis of 8 cohort studies with data on cerebral microbleeds and risk for post-tPA sICH
bull Pooled OR 287 for ICH post TPA in the presence of microbleeds
bull Unclear whether 56 risk increase for sICH outweighs
12 risk reduction for ischemic stroke disability expected
from tPA
Charidimou A et al Neurology 201585927-924
Safety of acute ischemic stroke therapy in patients with silent microbleeds
It is reasonable to administer intravenous alteplase to patients with acute ischemic stroke and
evidence of microbleeds if it is otherwise indicated
It is reasonable to perform endovascular thrombectomy in patients with acute ischemic stroke and
evidence of microbleeds
In acute ischemic stroke patients with microbleeds bypassing intravenous alteplase therapy to
proceed directly to endovascular thrombectomy is an unproven strategy
Clinical Suggestions for Acute Ischemic
Stroke
Therapy in Patients with Microbleeds
Other SVD treatment targets
Weak blood vessel lining strengthen cell junctions
Poor blood vessel function increase nitric oxide
lsquoInflammationrsquo anti-inflammatory
Statins nitrates pentoxyfiline cilostazol dipyridamole etc
Trials are ongoing eg LACI-1 LACI-2 PRESERVE
Salt exercise green vegetables nutrient bars
RCTs of cilostazol and nitrates in SVD
n=446012 weeksEdinburghNottingham
n=4001 yrJuly 2017gt30 UK centres
TolerabilityCVR measuresPulse wave analysis
1 Cilostazol2 Nitrate3 Both early4 Both late
Clinical outcomesMRI at one year
1 Cilostazol2 Nitrate3 Both4 Neither
SVD trials
bull Difficult ndash heterogenous patient groups
bull Low stroke recurrence rate (3 pa)
bull Cognitive testing time consuming
bull Do they measure the correct outcomes
For now
Apply guideline treatments
bull Lower blood pressure
bull Lower lipids
bull Use antiplatelet drugs but not ASA+Clop long term
bull Lifestyle advise ndash smoking salt reduction exercise
bull Trials of existing agents and novel agents
bull More animal data to lead to human trials
Conclusions
bull SVD important defined by imaging
bull Silent may not be silent
bull Stroke and dementia linked
bull Treatment options at present limited
bull REGARDS cohort in US
bull 24000 pts gt45yrs fu from 2003 for 6 yrs
bull Investigated acute and chronic cognition post stroke
bull Global cognition ndash SIS (six item screener)bull Executive functioning and memory
500 patients had stroke
JAMA 2015
Results
Incident stroke
Acute significant decline in global cognition and
memory
Accelerated decline in global cognition and
executive function
Cognitive decline predicts stroke
bull 930 men in Sweden without strokebull 13 years follow-up
bull Worse performance on a lsquojoin the dotsrsquo test predicted stroke
Cognitive decline predicts Stroke
fastest
slowest
Leiden 85+ Study 480 subjects 85 years
In the very elderly cognition predicts stroke better than vascular risk factors
Cognitive decline predicts stroke
Sabayan B et al Stroke 2013441866-1871
Vascular risk score Memory test
Cognition impaired after even minor stroke
Patients n=135 1 year after with minor stroke
median age 66 (IQR 56-75)
17 ACE-R lt82 (lsquodementiarsquo)
R p
Age -031 0001
Pre-morbid IQ 092 lt00001(National Adult Reading Test)
WMH score 158 003
Not NIHSS old stroke lesion
location lacunar vs non-lacunar
etc
Makin et al 2014
Idyll Zealot Gist Superfluous
Simile Deny Ache Banal
Naiumlve Depot Beatify Facade
Catacomb Equivocal Gauche Placebo
Deacutetente Heir Aeon Puerperal
Chord Sidereal Quadruped Aver
Rarefy Bouquet Abstemious Rarefy
Topiary Radix Debt Assignate
Capon Thyme Drachma Sidereal
Topiary Prelate Demesne Syncope
Labile Procreate Subtle Gaoled
Courteous Gouge Hiatus Psalm
Campanile Leviathan Aisle Cellist
White matter hyperintensities
mild
severe
Age 50-69 7 70-89 17 +
risk of dementia
Debette BMJ 2010
ldquoTotal SVD burdenrdquo and cognition
Staals Neurology 2014 +Neurology Patient page
Staals NBA 2015 Karema Mol Psych 2015
Simple sum score or more complex
latent variable model
Higher SVD burden associated with
Poorer general cognitive ability
Full score β -008 p=002
Without WMH β -01 p=04
Staals et al Neurology 2014 NBA 2015
bull Working party consensus
bull Recommends cognitive screeningbull Examples are MOCA or the Oxford Cognitive Screen
RCP 2016
SVD Treatment options ndash consider aim
bull No specific SVD treatments
bull Case 1 ndash Asymptomatic
bull Case 2 ndash Lacunar stroke
bull Case 3 ndash Co-incidental SVD
Smith EE Saposnik G Biessels GJ et al Prevention of stroke in patients with
silent cerebrovascular disease A Scientific Statement for healthcare
professionals from the American Heart AssociationAmerican Stroke
Association Stroke 201748e44-e71
Case 1 Asymptomatic patient
bull 70 yr old man golfer (18 holes)
bull Well
bull Headachehead injury
bull Incidental finding
bull Is this really ldquosilentrdquo
bull Revert to primary prevention risk factor control
Treatment and prevention
Treat vascular risk factors
High blood pressure ++
Diabetes +
High cholesterol +
Smoking ++
But Impact may
differ at different ages
eg BP may be more
important in 40s ndash
60s than 70s ndash 90s
But All common vascular risk factors combined only
explain a small proportion of the burden of brain
vascular disease and so far trials of risk factor
reduction have been disappointing
Case 2 Lacunar stroke patient
bull 65 yr old female
bull Left sided weakness
bull Is there enough evidence to manage her differently from other ischaemic strokes
bull Many studies included lacunar stroke patients but did not adequately report subtype findings
bull Few studies in lacunar stroke
SPS3 trial
Benavente NEJM 2012 Benavente Lancet Neurol 2013
N=3000 patients with lacunar stroke and baseline MRI scans
Intensive blood pressure control no significant benefit on strokemortality
(but fewer ICH)
Dual antiplatelet (clopasp) therapy harmful and stopped early
Lower than expected stroke incidence
Case 3 Co-incidental SVD
bull 80 yr with atrial fibrillation - CHADSVASC2 3
MRI shows microbleeds
bull 70 yr with acute MCA infarct ndash 2 hours ago
MRICT show white matter disease
Anticoagulation and other therapies in patients with silent microbleeds
It is reasonable to provide anticoagulation therapy to patients with microbleeds when there is an indication
(eg AF)
When anticoagulation is needed a novel oral anticoagulant is preferred over warfarin
Percutaneous closure of the left atrial appendage could be considered as an alternative to anticoagulation
It is reasonable to provide antiplatelet therapy to patients with microbleeds when there is an indication
MRI screening for microbleeds is not needed before the initiation of antithrombotic therapies
Individuals with silent microbleeds are at increased future risk of both ischemic stroke and ICH
Implement preventive care recommended by AHAASA guidelines for primary prevention of ischemic stroke
It is reasonable to provide preventive care recommended by AHAASA guidelines for prevention of ICH
Suggestions for Clinical Care in Patients with Microbleeds
Acute ischemic stroke due to RMCA occlusion
Multiple microbleeds on SWI
77 year woman
Plan of management
NIHSS 16
a) No thrombolysis or antithromboticsb) Aspirinc) IV tPA 09 mgkg then thrombectomyd) IV tPA 06 mgkg then EVTe) Straight to EVT without tPA
Microbleed Scenario Acute Ischemic Stroke
Slide adapted from E Smith
Risk for sICH after TPA
bull Meta-analysis of 8 cohort studies with data on cerebral microbleeds and risk for post-tPA sICH
bull Pooled OR 287 for ICH post TPA in the presence of microbleeds
bull Unclear whether 56 risk increase for sICH outweighs
12 risk reduction for ischemic stroke disability expected
from tPA
Charidimou A et al Neurology 201585927-924
Safety of acute ischemic stroke therapy in patients with silent microbleeds
It is reasonable to administer intravenous alteplase to patients with acute ischemic stroke and
evidence of microbleeds if it is otherwise indicated
It is reasonable to perform endovascular thrombectomy in patients with acute ischemic stroke and
evidence of microbleeds
In acute ischemic stroke patients with microbleeds bypassing intravenous alteplase therapy to
proceed directly to endovascular thrombectomy is an unproven strategy
Clinical Suggestions for Acute Ischemic
Stroke
Therapy in Patients with Microbleeds
Other SVD treatment targets
Weak blood vessel lining strengthen cell junctions
Poor blood vessel function increase nitric oxide
lsquoInflammationrsquo anti-inflammatory
Statins nitrates pentoxyfiline cilostazol dipyridamole etc
Trials are ongoing eg LACI-1 LACI-2 PRESERVE
Salt exercise green vegetables nutrient bars
RCTs of cilostazol and nitrates in SVD
n=446012 weeksEdinburghNottingham
n=4001 yrJuly 2017gt30 UK centres
TolerabilityCVR measuresPulse wave analysis
1 Cilostazol2 Nitrate3 Both early4 Both late
Clinical outcomesMRI at one year
1 Cilostazol2 Nitrate3 Both4 Neither
SVD trials
bull Difficult ndash heterogenous patient groups
bull Low stroke recurrence rate (3 pa)
bull Cognitive testing time consuming
bull Do they measure the correct outcomes
For now
Apply guideline treatments
bull Lower blood pressure
bull Lower lipids
bull Use antiplatelet drugs but not ASA+Clop long term
bull Lifestyle advise ndash smoking salt reduction exercise
bull Trials of existing agents and novel agents
bull More animal data to lead to human trials
Conclusions
bull SVD important defined by imaging
bull Silent may not be silent
bull Stroke and dementia linked
bull Treatment options at present limited
Results
Incident stroke
Acute significant decline in global cognition and
memory
Accelerated decline in global cognition and
executive function
Cognitive decline predicts stroke
bull 930 men in Sweden without strokebull 13 years follow-up
bull Worse performance on a lsquojoin the dotsrsquo test predicted stroke
Cognitive decline predicts Stroke
fastest
slowest
Leiden 85+ Study 480 subjects 85 years
In the very elderly cognition predicts stroke better than vascular risk factors
Cognitive decline predicts stroke
Sabayan B et al Stroke 2013441866-1871
Vascular risk score Memory test
Cognition impaired after even minor stroke
Patients n=135 1 year after with minor stroke
median age 66 (IQR 56-75)
17 ACE-R lt82 (lsquodementiarsquo)
R p
Age -031 0001
Pre-morbid IQ 092 lt00001(National Adult Reading Test)
WMH score 158 003
Not NIHSS old stroke lesion
location lacunar vs non-lacunar
etc
Makin et al 2014
Idyll Zealot Gist Superfluous
Simile Deny Ache Banal
Naiumlve Depot Beatify Facade
Catacomb Equivocal Gauche Placebo
Deacutetente Heir Aeon Puerperal
Chord Sidereal Quadruped Aver
Rarefy Bouquet Abstemious Rarefy
Topiary Radix Debt Assignate
Capon Thyme Drachma Sidereal
Topiary Prelate Demesne Syncope
Labile Procreate Subtle Gaoled
Courteous Gouge Hiatus Psalm
Campanile Leviathan Aisle Cellist
White matter hyperintensities
mild
severe
Age 50-69 7 70-89 17 +
risk of dementia
Debette BMJ 2010
ldquoTotal SVD burdenrdquo and cognition
Staals Neurology 2014 +Neurology Patient page
Staals NBA 2015 Karema Mol Psych 2015
Simple sum score or more complex
latent variable model
Higher SVD burden associated with
Poorer general cognitive ability
Full score β -008 p=002
Without WMH β -01 p=04
Staals et al Neurology 2014 NBA 2015
bull Working party consensus
bull Recommends cognitive screeningbull Examples are MOCA or the Oxford Cognitive Screen
RCP 2016
SVD Treatment options ndash consider aim
bull No specific SVD treatments
bull Case 1 ndash Asymptomatic
bull Case 2 ndash Lacunar stroke
bull Case 3 ndash Co-incidental SVD
Smith EE Saposnik G Biessels GJ et al Prevention of stroke in patients with
silent cerebrovascular disease A Scientific Statement for healthcare
professionals from the American Heart AssociationAmerican Stroke
Association Stroke 201748e44-e71
Case 1 Asymptomatic patient
bull 70 yr old man golfer (18 holes)
bull Well
bull Headachehead injury
bull Incidental finding
bull Is this really ldquosilentrdquo
bull Revert to primary prevention risk factor control
Treatment and prevention
Treat vascular risk factors
High blood pressure ++
Diabetes +
High cholesterol +
Smoking ++
But Impact may
differ at different ages
eg BP may be more
important in 40s ndash
60s than 70s ndash 90s
But All common vascular risk factors combined only
explain a small proportion of the burden of brain
vascular disease and so far trials of risk factor
reduction have been disappointing
Case 2 Lacunar stroke patient
bull 65 yr old female
bull Left sided weakness
bull Is there enough evidence to manage her differently from other ischaemic strokes
bull Many studies included lacunar stroke patients but did not adequately report subtype findings
bull Few studies in lacunar stroke
SPS3 trial
Benavente NEJM 2012 Benavente Lancet Neurol 2013
N=3000 patients with lacunar stroke and baseline MRI scans
Intensive blood pressure control no significant benefit on strokemortality
(but fewer ICH)
Dual antiplatelet (clopasp) therapy harmful and stopped early
Lower than expected stroke incidence
Case 3 Co-incidental SVD
bull 80 yr with atrial fibrillation - CHADSVASC2 3
MRI shows microbleeds
bull 70 yr with acute MCA infarct ndash 2 hours ago
MRICT show white matter disease
Anticoagulation and other therapies in patients with silent microbleeds
It is reasonable to provide anticoagulation therapy to patients with microbleeds when there is an indication
(eg AF)
When anticoagulation is needed a novel oral anticoagulant is preferred over warfarin
Percutaneous closure of the left atrial appendage could be considered as an alternative to anticoagulation
It is reasonable to provide antiplatelet therapy to patients with microbleeds when there is an indication
MRI screening for microbleeds is not needed before the initiation of antithrombotic therapies
Individuals with silent microbleeds are at increased future risk of both ischemic stroke and ICH
Implement preventive care recommended by AHAASA guidelines for primary prevention of ischemic stroke
It is reasonable to provide preventive care recommended by AHAASA guidelines for prevention of ICH
Suggestions for Clinical Care in Patients with Microbleeds
Acute ischemic stroke due to RMCA occlusion
Multiple microbleeds on SWI
77 year woman
Plan of management
NIHSS 16
a) No thrombolysis or antithromboticsb) Aspirinc) IV tPA 09 mgkg then thrombectomyd) IV tPA 06 mgkg then EVTe) Straight to EVT without tPA
Microbleed Scenario Acute Ischemic Stroke
Slide adapted from E Smith
Risk for sICH after TPA
bull Meta-analysis of 8 cohort studies with data on cerebral microbleeds and risk for post-tPA sICH
bull Pooled OR 287 for ICH post TPA in the presence of microbleeds
bull Unclear whether 56 risk increase for sICH outweighs
12 risk reduction for ischemic stroke disability expected
from tPA
Charidimou A et al Neurology 201585927-924
Safety of acute ischemic stroke therapy in patients with silent microbleeds
It is reasonable to administer intravenous alteplase to patients with acute ischemic stroke and
evidence of microbleeds if it is otherwise indicated
It is reasonable to perform endovascular thrombectomy in patients with acute ischemic stroke and
evidence of microbleeds
In acute ischemic stroke patients with microbleeds bypassing intravenous alteplase therapy to
proceed directly to endovascular thrombectomy is an unproven strategy
Clinical Suggestions for Acute Ischemic
Stroke
Therapy in Patients with Microbleeds
Other SVD treatment targets
Weak blood vessel lining strengthen cell junctions
Poor blood vessel function increase nitric oxide
lsquoInflammationrsquo anti-inflammatory
Statins nitrates pentoxyfiline cilostazol dipyridamole etc
Trials are ongoing eg LACI-1 LACI-2 PRESERVE
Salt exercise green vegetables nutrient bars
RCTs of cilostazol and nitrates in SVD
n=446012 weeksEdinburghNottingham
n=4001 yrJuly 2017gt30 UK centres
TolerabilityCVR measuresPulse wave analysis
1 Cilostazol2 Nitrate3 Both early4 Both late
Clinical outcomesMRI at one year
1 Cilostazol2 Nitrate3 Both4 Neither
SVD trials
bull Difficult ndash heterogenous patient groups
bull Low stroke recurrence rate (3 pa)
bull Cognitive testing time consuming
bull Do they measure the correct outcomes
For now
Apply guideline treatments
bull Lower blood pressure
bull Lower lipids
bull Use antiplatelet drugs but not ASA+Clop long term
bull Lifestyle advise ndash smoking salt reduction exercise
bull Trials of existing agents and novel agents
bull More animal data to lead to human trials
Conclusions
bull SVD important defined by imaging
bull Silent may not be silent
bull Stroke and dementia linked
bull Treatment options at present limited
Cognitive decline predicts stroke
bull 930 men in Sweden without strokebull 13 years follow-up
bull Worse performance on a lsquojoin the dotsrsquo test predicted stroke
Cognitive decline predicts Stroke
fastest
slowest
Leiden 85+ Study 480 subjects 85 years
In the very elderly cognition predicts stroke better than vascular risk factors
Cognitive decline predicts stroke
Sabayan B et al Stroke 2013441866-1871
Vascular risk score Memory test
Cognition impaired after even minor stroke
Patients n=135 1 year after with minor stroke
median age 66 (IQR 56-75)
17 ACE-R lt82 (lsquodementiarsquo)
R p
Age -031 0001
Pre-morbid IQ 092 lt00001(National Adult Reading Test)
WMH score 158 003
Not NIHSS old stroke lesion
location lacunar vs non-lacunar
etc
Makin et al 2014
Idyll Zealot Gist Superfluous
Simile Deny Ache Banal
Naiumlve Depot Beatify Facade
Catacomb Equivocal Gauche Placebo
Deacutetente Heir Aeon Puerperal
Chord Sidereal Quadruped Aver
Rarefy Bouquet Abstemious Rarefy
Topiary Radix Debt Assignate
Capon Thyme Drachma Sidereal
Topiary Prelate Demesne Syncope
Labile Procreate Subtle Gaoled
Courteous Gouge Hiatus Psalm
Campanile Leviathan Aisle Cellist
White matter hyperintensities
mild
severe
Age 50-69 7 70-89 17 +
risk of dementia
Debette BMJ 2010
ldquoTotal SVD burdenrdquo and cognition
Staals Neurology 2014 +Neurology Patient page
Staals NBA 2015 Karema Mol Psych 2015
Simple sum score or more complex
latent variable model
Higher SVD burden associated with
Poorer general cognitive ability
Full score β -008 p=002
Without WMH β -01 p=04
Staals et al Neurology 2014 NBA 2015
bull Working party consensus
bull Recommends cognitive screeningbull Examples are MOCA or the Oxford Cognitive Screen
RCP 2016
SVD Treatment options ndash consider aim
bull No specific SVD treatments
bull Case 1 ndash Asymptomatic
bull Case 2 ndash Lacunar stroke
bull Case 3 ndash Co-incidental SVD
Smith EE Saposnik G Biessels GJ et al Prevention of stroke in patients with
silent cerebrovascular disease A Scientific Statement for healthcare
professionals from the American Heart AssociationAmerican Stroke
Association Stroke 201748e44-e71
Case 1 Asymptomatic patient
bull 70 yr old man golfer (18 holes)
bull Well
bull Headachehead injury
bull Incidental finding
bull Is this really ldquosilentrdquo
bull Revert to primary prevention risk factor control
Treatment and prevention
Treat vascular risk factors
High blood pressure ++
Diabetes +
High cholesterol +
Smoking ++
But Impact may
differ at different ages
eg BP may be more
important in 40s ndash
60s than 70s ndash 90s
But All common vascular risk factors combined only
explain a small proportion of the burden of brain
vascular disease and so far trials of risk factor
reduction have been disappointing
Case 2 Lacunar stroke patient
bull 65 yr old female
bull Left sided weakness
bull Is there enough evidence to manage her differently from other ischaemic strokes
bull Many studies included lacunar stroke patients but did not adequately report subtype findings
bull Few studies in lacunar stroke
SPS3 trial
Benavente NEJM 2012 Benavente Lancet Neurol 2013
N=3000 patients with lacunar stroke and baseline MRI scans
Intensive blood pressure control no significant benefit on strokemortality
(but fewer ICH)
Dual antiplatelet (clopasp) therapy harmful and stopped early
Lower than expected stroke incidence
Case 3 Co-incidental SVD
bull 80 yr with atrial fibrillation - CHADSVASC2 3
MRI shows microbleeds
bull 70 yr with acute MCA infarct ndash 2 hours ago
MRICT show white matter disease
Anticoagulation and other therapies in patients with silent microbleeds
It is reasonable to provide anticoagulation therapy to patients with microbleeds when there is an indication
(eg AF)
When anticoagulation is needed a novel oral anticoagulant is preferred over warfarin
Percutaneous closure of the left atrial appendage could be considered as an alternative to anticoagulation
It is reasonable to provide antiplatelet therapy to patients with microbleeds when there is an indication
MRI screening for microbleeds is not needed before the initiation of antithrombotic therapies
Individuals with silent microbleeds are at increased future risk of both ischemic stroke and ICH
Implement preventive care recommended by AHAASA guidelines for primary prevention of ischemic stroke
It is reasonable to provide preventive care recommended by AHAASA guidelines for prevention of ICH
Suggestions for Clinical Care in Patients with Microbleeds
Acute ischemic stroke due to RMCA occlusion
Multiple microbleeds on SWI
77 year woman
Plan of management
NIHSS 16
a) No thrombolysis or antithromboticsb) Aspirinc) IV tPA 09 mgkg then thrombectomyd) IV tPA 06 mgkg then EVTe) Straight to EVT without tPA
Microbleed Scenario Acute Ischemic Stroke
Slide adapted from E Smith
Risk for sICH after TPA
bull Meta-analysis of 8 cohort studies with data on cerebral microbleeds and risk for post-tPA sICH
bull Pooled OR 287 for ICH post TPA in the presence of microbleeds
bull Unclear whether 56 risk increase for sICH outweighs
12 risk reduction for ischemic stroke disability expected
from tPA
Charidimou A et al Neurology 201585927-924
Safety of acute ischemic stroke therapy in patients with silent microbleeds
It is reasonable to administer intravenous alteplase to patients with acute ischemic stroke and
evidence of microbleeds if it is otherwise indicated
It is reasonable to perform endovascular thrombectomy in patients with acute ischemic stroke and
evidence of microbleeds
In acute ischemic stroke patients with microbleeds bypassing intravenous alteplase therapy to
proceed directly to endovascular thrombectomy is an unproven strategy
Clinical Suggestions for Acute Ischemic
Stroke
Therapy in Patients with Microbleeds
Other SVD treatment targets
Weak blood vessel lining strengthen cell junctions
Poor blood vessel function increase nitric oxide
lsquoInflammationrsquo anti-inflammatory
Statins nitrates pentoxyfiline cilostazol dipyridamole etc
Trials are ongoing eg LACI-1 LACI-2 PRESERVE
Salt exercise green vegetables nutrient bars
RCTs of cilostazol and nitrates in SVD
n=446012 weeksEdinburghNottingham
n=4001 yrJuly 2017gt30 UK centres
TolerabilityCVR measuresPulse wave analysis
1 Cilostazol2 Nitrate3 Both early4 Both late
Clinical outcomesMRI at one year
1 Cilostazol2 Nitrate3 Both4 Neither
SVD trials
bull Difficult ndash heterogenous patient groups
bull Low stroke recurrence rate (3 pa)
bull Cognitive testing time consuming
bull Do they measure the correct outcomes
For now
Apply guideline treatments
bull Lower blood pressure
bull Lower lipids
bull Use antiplatelet drugs but not ASA+Clop long term
bull Lifestyle advise ndash smoking salt reduction exercise
bull Trials of existing agents and novel agents
bull More animal data to lead to human trials
Conclusions
bull SVD important defined by imaging
bull Silent may not be silent
bull Stroke and dementia linked
bull Treatment options at present limited
Leiden 85+ Study 480 subjects 85 years
In the very elderly cognition predicts stroke better than vascular risk factors
Cognitive decline predicts stroke
Sabayan B et al Stroke 2013441866-1871
Vascular risk score Memory test
Cognition impaired after even minor stroke
Patients n=135 1 year after with minor stroke
median age 66 (IQR 56-75)
17 ACE-R lt82 (lsquodementiarsquo)
R p
Age -031 0001
Pre-morbid IQ 092 lt00001(National Adult Reading Test)
WMH score 158 003
Not NIHSS old stroke lesion
location lacunar vs non-lacunar
etc
Makin et al 2014
Idyll Zealot Gist Superfluous
Simile Deny Ache Banal
Naiumlve Depot Beatify Facade
Catacomb Equivocal Gauche Placebo
Deacutetente Heir Aeon Puerperal
Chord Sidereal Quadruped Aver
Rarefy Bouquet Abstemious Rarefy
Topiary Radix Debt Assignate
Capon Thyme Drachma Sidereal
Topiary Prelate Demesne Syncope
Labile Procreate Subtle Gaoled
Courteous Gouge Hiatus Psalm
Campanile Leviathan Aisle Cellist
White matter hyperintensities
mild
severe
Age 50-69 7 70-89 17 +
risk of dementia
Debette BMJ 2010
ldquoTotal SVD burdenrdquo and cognition
Staals Neurology 2014 +Neurology Patient page
Staals NBA 2015 Karema Mol Psych 2015
Simple sum score or more complex
latent variable model
Higher SVD burden associated with
Poorer general cognitive ability
Full score β -008 p=002
Without WMH β -01 p=04
Staals et al Neurology 2014 NBA 2015
bull Working party consensus
bull Recommends cognitive screeningbull Examples are MOCA or the Oxford Cognitive Screen
RCP 2016
SVD Treatment options ndash consider aim
bull No specific SVD treatments
bull Case 1 ndash Asymptomatic
bull Case 2 ndash Lacunar stroke
bull Case 3 ndash Co-incidental SVD
Smith EE Saposnik G Biessels GJ et al Prevention of stroke in patients with
silent cerebrovascular disease A Scientific Statement for healthcare
professionals from the American Heart AssociationAmerican Stroke
Association Stroke 201748e44-e71
Case 1 Asymptomatic patient
bull 70 yr old man golfer (18 holes)
bull Well
bull Headachehead injury
bull Incidental finding
bull Is this really ldquosilentrdquo
bull Revert to primary prevention risk factor control
Treatment and prevention
Treat vascular risk factors
High blood pressure ++
Diabetes +
High cholesterol +
Smoking ++
But Impact may
differ at different ages
eg BP may be more
important in 40s ndash
60s than 70s ndash 90s
But All common vascular risk factors combined only
explain a small proportion of the burden of brain
vascular disease and so far trials of risk factor
reduction have been disappointing
Case 2 Lacunar stroke patient
bull 65 yr old female
bull Left sided weakness
bull Is there enough evidence to manage her differently from other ischaemic strokes
bull Many studies included lacunar stroke patients but did not adequately report subtype findings
bull Few studies in lacunar stroke
SPS3 trial
Benavente NEJM 2012 Benavente Lancet Neurol 2013
N=3000 patients with lacunar stroke and baseline MRI scans
Intensive blood pressure control no significant benefit on strokemortality
(but fewer ICH)
Dual antiplatelet (clopasp) therapy harmful and stopped early
Lower than expected stroke incidence
Case 3 Co-incidental SVD
bull 80 yr with atrial fibrillation - CHADSVASC2 3
MRI shows microbleeds
bull 70 yr with acute MCA infarct ndash 2 hours ago
MRICT show white matter disease
Anticoagulation and other therapies in patients with silent microbleeds
It is reasonable to provide anticoagulation therapy to patients with microbleeds when there is an indication
(eg AF)
When anticoagulation is needed a novel oral anticoagulant is preferred over warfarin
Percutaneous closure of the left atrial appendage could be considered as an alternative to anticoagulation
It is reasonable to provide antiplatelet therapy to patients with microbleeds when there is an indication
MRI screening for microbleeds is not needed before the initiation of antithrombotic therapies
Individuals with silent microbleeds are at increased future risk of both ischemic stroke and ICH
Implement preventive care recommended by AHAASA guidelines for primary prevention of ischemic stroke
It is reasonable to provide preventive care recommended by AHAASA guidelines for prevention of ICH
Suggestions for Clinical Care in Patients with Microbleeds
Acute ischemic stroke due to RMCA occlusion
Multiple microbleeds on SWI
77 year woman
Plan of management
NIHSS 16
a) No thrombolysis or antithromboticsb) Aspirinc) IV tPA 09 mgkg then thrombectomyd) IV tPA 06 mgkg then EVTe) Straight to EVT without tPA
Microbleed Scenario Acute Ischemic Stroke
Slide adapted from E Smith
Risk for sICH after TPA
bull Meta-analysis of 8 cohort studies with data on cerebral microbleeds and risk for post-tPA sICH
bull Pooled OR 287 for ICH post TPA in the presence of microbleeds
bull Unclear whether 56 risk increase for sICH outweighs
12 risk reduction for ischemic stroke disability expected
from tPA
Charidimou A et al Neurology 201585927-924
Safety of acute ischemic stroke therapy in patients with silent microbleeds
It is reasonable to administer intravenous alteplase to patients with acute ischemic stroke and
evidence of microbleeds if it is otherwise indicated
It is reasonable to perform endovascular thrombectomy in patients with acute ischemic stroke and
evidence of microbleeds
In acute ischemic stroke patients with microbleeds bypassing intravenous alteplase therapy to
proceed directly to endovascular thrombectomy is an unproven strategy
Clinical Suggestions for Acute Ischemic
Stroke
Therapy in Patients with Microbleeds
Other SVD treatment targets
Weak blood vessel lining strengthen cell junctions
Poor blood vessel function increase nitric oxide
lsquoInflammationrsquo anti-inflammatory
Statins nitrates pentoxyfiline cilostazol dipyridamole etc
Trials are ongoing eg LACI-1 LACI-2 PRESERVE
Salt exercise green vegetables nutrient bars
RCTs of cilostazol and nitrates in SVD
n=446012 weeksEdinburghNottingham
n=4001 yrJuly 2017gt30 UK centres
TolerabilityCVR measuresPulse wave analysis
1 Cilostazol2 Nitrate3 Both early4 Both late
Clinical outcomesMRI at one year
1 Cilostazol2 Nitrate3 Both4 Neither
SVD trials
bull Difficult ndash heterogenous patient groups
bull Low stroke recurrence rate (3 pa)
bull Cognitive testing time consuming
bull Do they measure the correct outcomes
For now
Apply guideline treatments
bull Lower blood pressure
bull Lower lipids
bull Use antiplatelet drugs but not ASA+Clop long term
bull Lifestyle advise ndash smoking salt reduction exercise
bull Trials of existing agents and novel agents
bull More animal data to lead to human trials
Conclusions
bull SVD important defined by imaging
bull Silent may not be silent
bull Stroke and dementia linked
bull Treatment options at present limited
Cognition impaired after even minor stroke
Patients n=135 1 year after with minor stroke
median age 66 (IQR 56-75)
17 ACE-R lt82 (lsquodementiarsquo)
R p
Age -031 0001
Pre-morbid IQ 092 lt00001(National Adult Reading Test)
WMH score 158 003
Not NIHSS old stroke lesion
location lacunar vs non-lacunar
etc
Makin et al 2014
Idyll Zealot Gist Superfluous
Simile Deny Ache Banal
Naiumlve Depot Beatify Facade
Catacomb Equivocal Gauche Placebo
Deacutetente Heir Aeon Puerperal
Chord Sidereal Quadruped Aver
Rarefy Bouquet Abstemious Rarefy
Topiary Radix Debt Assignate
Capon Thyme Drachma Sidereal
Topiary Prelate Demesne Syncope
Labile Procreate Subtle Gaoled
Courteous Gouge Hiatus Psalm
Campanile Leviathan Aisle Cellist
White matter hyperintensities
mild
severe
Age 50-69 7 70-89 17 +
risk of dementia
Debette BMJ 2010
ldquoTotal SVD burdenrdquo and cognition
Staals Neurology 2014 +Neurology Patient page
Staals NBA 2015 Karema Mol Psych 2015
Simple sum score or more complex
latent variable model
Higher SVD burden associated with
Poorer general cognitive ability
Full score β -008 p=002
Without WMH β -01 p=04
Staals et al Neurology 2014 NBA 2015
bull Working party consensus
bull Recommends cognitive screeningbull Examples are MOCA or the Oxford Cognitive Screen
RCP 2016
SVD Treatment options ndash consider aim
bull No specific SVD treatments
bull Case 1 ndash Asymptomatic
bull Case 2 ndash Lacunar stroke
bull Case 3 ndash Co-incidental SVD
Smith EE Saposnik G Biessels GJ et al Prevention of stroke in patients with
silent cerebrovascular disease A Scientific Statement for healthcare
professionals from the American Heart AssociationAmerican Stroke
Association Stroke 201748e44-e71
Case 1 Asymptomatic patient
bull 70 yr old man golfer (18 holes)
bull Well
bull Headachehead injury
bull Incidental finding
bull Is this really ldquosilentrdquo
bull Revert to primary prevention risk factor control
Treatment and prevention
Treat vascular risk factors
High blood pressure ++
Diabetes +
High cholesterol +
Smoking ++
But Impact may
differ at different ages
eg BP may be more
important in 40s ndash
60s than 70s ndash 90s
But All common vascular risk factors combined only
explain a small proportion of the burden of brain
vascular disease and so far trials of risk factor
reduction have been disappointing
Case 2 Lacunar stroke patient
bull 65 yr old female
bull Left sided weakness
bull Is there enough evidence to manage her differently from other ischaemic strokes
bull Many studies included lacunar stroke patients but did not adequately report subtype findings
bull Few studies in lacunar stroke
SPS3 trial
Benavente NEJM 2012 Benavente Lancet Neurol 2013
N=3000 patients with lacunar stroke and baseline MRI scans
Intensive blood pressure control no significant benefit on strokemortality
(but fewer ICH)
Dual antiplatelet (clopasp) therapy harmful and stopped early
Lower than expected stroke incidence
Case 3 Co-incidental SVD
bull 80 yr with atrial fibrillation - CHADSVASC2 3
MRI shows microbleeds
bull 70 yr with acute MCA infarct ndash 2 hours ago
MRICT show white matter disease
Anticoagulation and other therapies in patients with silent microbleeds
It is reasonable to provide anticoagulation therapy to patients with microbleeds when there is an indication
(eg AF)
When anticoagulation is needed a novel oral anticoagulant is preferred over warfarin
Percutaneous closure of the left atrial appendage could be considered as an alternative to anticoagulation
It is reasonable to provide antiplatelet therapy to patients with microbleeds when there is an indication
MRI screening for microbleeds is not needed before the initiation of antithrombotic therapies
Individuals with silent microbleeds are at increased future risk of both ischemic stroke and ICH
Implement preventive care recommended by AHAASA guidelines for primary prevention of ischemic stroke
It is reasonable to provide preventive care recommended by AHAASA guidelines for prevention of ICH
Suggestions for Clinical Care in Patients with Microbleeds
Acute ischemic stroke due to RMCA occlusion
Multiple microbleeds on SWI
77 year woman
Plan of management
NIHSS 16
a) No thrombolysis or antithromboticsb) Aspirinc) IV tPA 09 mgkg then thrombectomyd) IV tPA 06 mgkg then EVTe) Straight to EVT without tPA
Microbleed Scenario Acute Ischemic Stroke
Slide adapted from E Smith
Risk for sICH after TPA
bull Meta-analysis of 8 cohort studies with data on cerebral microbleeds and risk for post-tPA sICH
bull Pooled OR 287 for ICH post TPA in the presence of microbleeds
bull Unclear whether 56 risk increase for sICH outweighs
12 risk reduction for ischemic stroke disability expected
from tPA
Charidimou A et al Neurology 201585927-924
Safety of acute ischemic stroke therapy in patients with silent microbleeds
It is reasonable to administer intravenous alteplase to patients with acute ischemic stroke and
evidence of microbleeds if it is otherwise indicated
It is reasonable to perform endovascular thrombectomy in patients with acute ischemic stroke and
evidence of microbleeds
In acute ischemic stroke patients with microbleeds bypassing intravenous alteplase therapy to
proceed directly to endovascular thrombectomy is an unproven strategy
Clinical Suggestions for Acute Ischemic
Stroke
Therapy in Patients with Microbleeds
Other SVD treatment targets
Weak blood vessel lining strengthen cell junctions
Poor blood vessel function increase nitric oxide
lsquoInflammationrsquo anti-inflammatory
Statins nitrates pentoxyfiline cilostazol dipyridamole etc
Trials are ongoing eg LACI-1 LACI-2 PRESERVE
Salt exercise green vegetables nutrient bars
RCTs of cilostazol and nitrates in SVD
n=446012 weeksEdinburghNottingham
n=4001 yrJuly 2017gt30 UK centres
TolerabilityCVR measuresPulse wave analysis
1 Cilostazol2 Nitrate3 Both early4 Both late
Clinical outcomesMRI at one year
1 Cilostazol2 Nitrate3 Both4 Neither
SVD trials
bull Difficult ndash heterogenous patient groups
bull Low stroke recurrence rate (3 pa)
bull Cognitive testing time consuming
bull Do they measure the correct outcomes
For now
Apply guideline treatments
bull Lower blood pressure
bull Lower lipids
bull Use antiplatelet drugs but not ASA+Clop long term
bull Lifestyle advise ndash smoking salt reduction exercise
bull Trials of existing agents and novel agents
bull More animal data to lead to human trials
Conclusions
bull SVD important defined by imaging
bull Silent may not be silent
bull Stroke and dementia linked
bull Treatment options at present limited
White matter hyperintensities
mild
severe
Age 50-69 7 70-89 17 +
risk of dementia
Debette BMJ 2010
ldquoTotal SVD burdenrdquo and cognition
Staals Neurology 2014 +Neurology Patient page
Staals NBA 2015 Karema Mol Psych 2015
Simple sum score or more complex
latent variable model
Higher SVD burden associated with
Poorer general cognitive ability
Full score β -008 p=002
Without WMH β -01 p=04
Staals et al Neurology 2014 NBA 2015
bull Working party consensus
bull Recommends cognitive screeningbull Examples are MOCA or the Oxford Cognitive Screen
RCP 2016
SVD Treatment options ndash consider aim
bull No specific SVD treatments
bull Case 1 ndash Asymptomatic
bull Case 2 ndash Lacunar stroke
bull Case 3 ndash Co-incidental SVD
Smith EE Saposnik G Biessels GJ et al Prevention of stroke in patients with
silent cerebrovascular disease A Scientific Statement for healthcare
professionals from the American Heart AssociationAmerican Stroke
Association Stroke 201748e44-e71
Case 1 Asymptomatic patient
bull 70 yr old man golfer (18 holes)
bull Well
bull Headachehead injury
bull Incidental finding
bull Is this really ldquosilentrdquo
bull Revert to primary prevention risk factor control
Treatment and prevention
Treat vascular risk factors
High blood pressure ++
Diabetes +
High cholesterol +
Smoking ++
But Impact may
differ at different ages
eg BP may be more
important in 40s ndash
60s than 70s ndash 90s
But All common vascular risk factors combined only
explain a small proportion of the burden of brain
vascular disease and so far trials of risk factor
reduction have been disappointing
Case 2 Lacunar stroke patient
bull 65 yr old female
bull Left sided weakness
bull Is there enough evidence to manage her differently from other ischaemic strokes
bull Many studies included lacunar stroke patients but did not adequately report subtype findings
bull Few studies in lacunar stroke
SPS3 trial
Benavente NEJM 2012 Benavente Lancet Neurol 2013
N=3000 patients with lacunar stroke and baseline MRI scans
Intensive blood pressure control no significant benefit on strokemortality
(but fewer ICH)
Dual antiplatelet (clopasp) therapy harmful and stopped early
Lower than expected stroke incidence
Case 3 Co-incidental SVD
bull 80 yr with atrial fibrillation - CHADSVASC2 3
MRI shows microbleeds
bull 70 yr with acute MCA infarct ndash 2 hours ago
MRICT show white matter disease
Anticoagulation and other therapies in patients with silent microbleeds
It is reasonable to provide anticoagulation therapy to patients with microbleeds when there is an indication
(eg AF)
When anticoagulation is needed a novel oral anticoagulant is preferred over warfarin
Percutaneous closure of the left atrial appendage could be considered as an alternative to anticoagulation
It is reasonable to provide antiplatelet therapy to patients with microbleeds when there is an indication
MRI screening for microbleeds is not needed before the initiation of antithrombotic therapies
Individuals with silent microbleeds are at increased future risk of both ischemic stroke and ICH
Implement preventive care recommended by AHAASA guidelines for primary prevention of ischemic stroke
It is reasonable to provide preventive care recommended by AHAASA guidelines for prevention of ICH
Suggestions for Clinical Care in Patients with Microbleeds
Acute ischemic stroke due to RMCA occlusion
Multiple microbleeds on SWI
77 year woman
Plan of management
NIHSS 16
a) No thrombolysis or antithromboticsb) Aspirinc) IV tPA 09 mgkg then thrombectomyd) IV tPA 06 mgkg then EVTe) Straight to EVT without tPA
Microbleed Scenario Acute Ischemic Stroke
Slide adapted from E Smith
Risk for sICH after TPA
bull Meta-analysis of 8 cohort studies with data on cerebral microbleeds and risk for post-tPA sICH
bull Pooled OR 287 for ICH post TPA in the presence of microbleeds
bull Unclear whether 56 risk increase for sICH outweighs
12 risk reduction for ischemic stroke disability expected
from tPA
Charidimou A et al Neurology 201585927-924
Safety of acute ischemic stroke therapy in patients with silent microbleeds
It is reasonable to administer intravenous alteplase to patients with acute ischemic stroke and
evidence of microbleeds if it is otherwise indicated
It is reasonable to perform endovascular thrombectomy in patients with acute ischemic stroke and
evidence of microbleeds
In acute ischemic stroke patients with microbleeds bypassing intravenous alteplase therapy to
proceed directly to endovascular thrombectomy is an unproven strategy
Clinical Suggestions for Acute Ischemic
Stroke
Therapy in Patients with Microbleeds
Other SVD treatment targets
Weak blood vessel lining strengthen cell junctions
Poor blood vessel function increase nitric oxide
lsquoInflammationrsquo anti-inflammatory
Statins nitrates pentoxyfiline cilostazol dipyridamole etc
Trials are ongoing eg LACI-1 LACI-2 PRESERVE
Salt exercise green vegetables nutrient bars
RCTs of cilostazol and nitrates in SVD
n=446012 weeksEdinburghNottingham
n=4001 yrJuly 2017gt30 UK centres
TolerabilityCVR measuresPulse wave analysis
1 Cilostazol2 Nitrate3 Both early4 Both late
Clinical outcomesMRI at one year
1 Cilostazol2 Nitrate3 Both4 Neither
SVD trials
bull Difficult ndash heterogenous patient groups
bull Low stroke recurrence rate (3 pa)
bull Cognitive testing time consuming
bull Do they measure the correct outcomes
For now
Apply guideline treatments
bull Lower blood pressure
bull Lower lipids
bull Use antiplatelet drugs but not ASA+Clop long term
bull Lifestyle advise ndash smoking salt reduction exercise
bull Trials of existing agents and novel agents
bull More animal data to lead to human trials
Conclusions
bull SVD important defined by imaging
bull Silent may not be silent
bull Stroke and dementia linked
bull Treatment options at present limited
ldquoTotal SVD burdenrdquo and cognition
Staals Neurology 2014 +Neurology Patient page
Staals NBA 2015 Karema Mol Psych 2015
Simple sum score or more complex
latent variable model
Higher SVD burden associated with
Poorer general cognitive ability
Full score β -008 p=002
Without WMH β -01 p=04
Staals et al Neurology 2014 NBA 2015
bull Working party consensus
bull Recommends cognitive screeningbull Examples are MOCA or the Oxford Cognitive Screen
RCP 2016
SVD Treatment options ndash consider aim
bull No specific SVD treatments
bull Case 1 ndash Asymptomatic
bull Case 2 ndash Lacunar stroke
bull Case 3 ndash Co-incidental SVD
Smith EE Saposnik G Biessels GJ et al Prevention of stroke in patients with
silent cerebrovascular disease A Scientific Statement for healthcare
professionals from the American Heart AssociationAmerican Stroke
Association Stroke 201748e44-e71
Case 1 Asymptomatic patient
bull 70 yr old man golfer (18 holes)
bull Well
bull Headachehead injury
bull Incidental finding
bull Is this really ldquosilentrdquo
bull Revert to primary prevention risk factor control
Treatment and prevention
Treat vascular risk factors
High blood pressure ++
Diabetes +
High cholesterol +
Smoking ++
But Impact may
differ at different ages
eg BP may be more
important in 40s ndash
60s than 70s ndash 90s
But All common vascular risk factors combined only
explain a small proportion of the burden of brain
vascular disease and so far trials of risk factor
reduction have been disappointing
Case 2 Lacunar stroke patient
bull 65 yr old female
bull Left sided weakness
bull Is there enough evidence to manage her differently from other ischaemic strokes
bull Many studies included lacunar stroke patients but did not adequately report subtype findings
bull Few studies in lacunar stroke
SPS3 trial
Benavente NEJM 2012 Benavente Lancet Neurol 2013
N=3000 patients with lacunar stroke and baseline MRI scans
Intensive blood pressure control no significant benefit on strokemortality
(but fewer ICH)
Dual antiplatelet (clopasp) therapy harmful and stopped early
Lower than expected stroke incidence
Case 3 Co-incidental SVD
bull 80 yr with atrial fibrillation - CHADSVASC2 3
MRI shows microbleeds
bull 70 yr with acute MCA infarct ndash 2 hours ago
MRICT show white matter disease
Anticoagulation and other therapies in patients with silent microbleeds
It is reasonable to provide anticoagulation therapy to patients with microbleeds when there is an indication
(eg AF)
When anticoagulation is needed a novel oral anticoagulant is preferred over warfarin
Percutaneous closure of the left atrial appendage could be considered as an alternative to anticoagulation
It is reasonable to provide antiplatelet therapy to patients with microbleeds when there is an indication
MRI screening for microbleeds is not needed before the initiation of antithrombotic therapies
Individuals with silent microbleeds are at increased future risk of both ischemic stroke and ICH
Implement preventive care recommended by AHAASA guidelines for primary prevention of ischemic stroke
It is reasonable to provide preventive care recommended by AHAASA guidelines for prevention of ICH
Suggestions for Clinical Care in Patients with Microbleeds
Acute ischemic stroke due to RMCA occlusion
Multiple microbleeds on SWI
77 year woman
Plan of management
NIHSS 16
a) No thrombolysis or antithromboticsb) Aspirinc) IV tPA 09 mgkg then thrombectomyd) IV tPA 06 mgkg then EVTe) Straight to EVT without tPA
Microbleed Scenario Acute Ischemic Stroke
Slide adapted from E Smith
Risk for sICH after TPA
bull Meta-analysis of 8 cohort studies with data on cerebral microbleeds and risk for post-tPA sICH
bull Pooled OR 287 for ICH post TPA in the presence of microbleeds
bull Unclear whether 56 risk increase for sICH outweighs
12 risk reduction for ischemic stroke disability expected
from tPA
Charidimou A et al Neurology 201585927-924
Safety of acute ischemic stroke therapy in patients with silent microbleeds
It is reasonable to administer intravenous alteplase to patients with acute ischemic stroke and
evidence of microbleeds if it is otherwise indicated
It is reasonable to perform endovascular thrombectomy in patients with acute ischemic stroke and
evidence of microbleeds
In acute ischemic stroke patients with microbleeds bypassing intravenous alteplase therapy to
proceed directly to endovascular thrombectomy is an unproven strategy
Clinical Suggestions for Acute Ischemic
Stroke
Therapy in Patients with Microbleeds
Other SVD treatment targets
Weak blood vessel lining strengthen cell junctions
Poor blood vessel function increase nitric oxide
lsquoInflammationrsquo anti-inflammatory
Statins nitrates pentoxyfiline cilostazol dipyridamole etc
Trials are ongoing eg LACI-1 LACI-2 PRESERVE
Salt exercise green vegetables nutrient bars
RCTs of cilostazol and nitrates in SVD
n=446012 weeksEdinburghNottingham
n=4001 yrJuly 2017gt30 UK centres
TolerabilityCVR measuresPulse wave analysis
1 Cilostazol2 Nitrate3 Both early4 Both late
Clinical outcomesMRI at one year
1 Cilostazol2 Nitrate3 Both4 Neither
SVD trials
bull Difficult ndash heterogenous patient groups
bull Low stroke recurrence rate (3 pa)
bull Cognitive testing time consuming
bull Do they measure the correct outcomes
For now
Apply guideline treatments
bull Lower blood pressure
bull Lower lipids
bull Use antiplatelet drugs but not ASA+Clop long term
bull Lifestyle advise ndash smoking salt reduction exercise
bull Trials of existing agents and novel agents
bull More animal data to lead to human trials
Conclusions
bull SVD important defined by imaging
bull Silent may not be silent
bull Stroke and dementia linked
bull Treatment options at present limited
bull Working party consensus
bull Recommends cognitive screeningbull Examples are MOCA or the Oxford Cognitive Screen
RCP 2016
SVD Treatment options ndash consider aim
bull No specific SVD treatments
bull Case 1 ndash Asymptomatic
bull Case 2 ndash Lacunar stroke
bull Case 3 ndash Co-incidental SVD
Smith EE Saposnik G Biessels GJ et al Prevention of stroke in patients with
silent cerebrovascular disease A Scientific Statement for healthcare
professionals from the American Heart AssociationAmerican Stroke
Association Stroke 201748e44-e71
Case 1 Asymptomatic patient
bull 70 yr old man golfer (18 holes)
bull Well
bull Headachehead injury
bull Incidental finding
bull Is this really ldquosilentrdquo
bull Revert to primary prevention risk factor control
Treatment and prevention
Treat vascular risk factors
High blood pressure ++
Diabetes +
High cholesterol +
Smoking ++
But Impact may
differ at different ages
eg BP may be more
important in 40s ndash
60s than 70s ndash 90s
But All common vascular risk factors combined only
explain a small proportion of the burden of brain
vascular disease and so far trials of risk factor
reduction have been disappointing
Case 2 Lacunar stroke patient
bull 65 yr old female
bull Left sided weakness
bull Is there enough evidence to manage her differently from other ischaemic strokes
bull Many studies included lacunar stroke patients but did not adequately report subtype findings
bull Few studies in lacunar stroke
SPS3 trial
Benavente NEJM 2012 Benavente Lancet Neurol 2013
N=3000 patients with lacunar stroke and baseline MRI scans
Intensive blood pressure control no significant benefit on strokemortality
(but fewer ICH)
Dual antiplatelet (clopasp) therapy harmful and stopped early
Lower than expected stroke incidence
Case 3 Co-incidental SVD
bull 80 yr with atrial fibrillation - CHADSVASC2 3
MRI shows microbleeds
bull 70 yr with acute MCA infarct ndash 2 hours ago
MRICT show white matter disease
Anticoagulation and other therapies in patients with silent microbleeds
It is reasonable to provide anticoagulation therapy to patients with microbleeds when there is an indication
(eg AF)
When anticoagulation is needed a novel oral anticoagulant is preferred over warfarin
Percutaneous closure of the left atrial appendage could be considered as an alternative to anticoagulation
It is reasonable to provide antiplatelet therapy to patients with microbleeds when there is an indication
MRI screening for microbleeds is not needed before the initiation of antithrombotic therapies
Individuals with silent microbleeds are at increased future risk of both ischemic stroke and ICH
Implement preventive care recommended by AHAASA guidelines for primary prevention of ischemic stroke
It is reasonable to provide preventive care recommended by AHAASA guidelines for prevention of ICH
Suggestions for Clinical Care in Patients with Microbleeds
Acute ischemic stroke due to RMCA occlusion
Multiple microbleeds on SWI
77 year woman
Plan of management
NIHSS 16
a) No thrombolysis or antithromboticsb) Aspirinc) IV tPA 09 mgkg then thrombectomyd) IV tPA 06 mgkg then EVTe) Straight to EVT without tPA
Microbleed Scenario Acute Ischemic Stroke
Slide adapted from E Smith
Risk for sICH after TPA
bull Meta-analysis of 8 cohort studies with data on cerebral microbleeds and risk for post-tPA sICH
bull Pooled OR 287 for ICH post TPA in the presence of microbleeds
bull Unclear whether 56 risk increase for sICH outweighs
12 risk reduction for ischemic stroke disability expected
from tPA
Charidimou A et al Neurology 201585927-924
Safety of acute ischemic stroke therapy in patients with silent microbleeds
It is reasonable to administer intravenous alteplase to patients with acute ischemic stroke and
evidence of microbleeds if it is otherwise indicated
It is reasonable to perform endovascular thrombectomy in patients with acute ischemic stroke and
evidence of microbleeds
In acute ischemic stroke patients with microbleeds bypassing intravenous alteplase therapy to
proceed directly to endovascular thrombectomy is an unproven strategy
Clinical Suggestions for Acute Ischemic
Stroke
Therapy in Patients with Microbleeds
Other SVD treatment targets
Weak blood vessel lining strengthen cell junctions
Poor blood vessel function increase nitric oxide
lsquoInflammationrsquo anti-inflammatory
Statins nitrates pentoxyfiline cilostazol dipyridamole etc
Trials are ongoing eg LACI-1 LACI-2 PRESERVE
Salt exercise green vegetables nutrient bars
RCTs of cilostazol and nitrates in SVD
n=446012 weeksEdinburghNottingham
n=4001 yrJuly 2017gt30 UK centres
TolerabilityCVR measuresPulse wave analysis
1 Cilostazol2 Nitrate3 Both early4 Both late
Clinical outcomesMRI at one year
1 Cilostazol2 Nitrate3 Both4 Neither
SVD trials
bull Difficult ndash heterogenous patient groups
bull Low stroke recurrence rate (3 pa)
bull Cognitive testing time consuming
bull Do they measure the correct outcomes
For now
Apply guideline treatments
bull Lower blood pressure
bull Lower lipids
bull Use antiplatelet drugs but not ASA+Clop long term
bull Lifestyle advise ndash smoking salt reduction exercise
bull Trials of existing agents and novel agents
bull More animal data to lead to human trials
Conclusions
bull SVD important defined by imaging
bull Silent may not be silent
bull Stroke and dementia linked
bull Treatment options at present limited
SVD Treatment options ndash consider aim
bull No specific SVD treatments
bull Case 1 ndash Asymptomatic
bull Case 2 ndash Lacunar stroke
bull Case 3 ndash Co-incidental SVD
Smith EE Saposnik G Biessels GJ et al Prevention of stroke in patients with
silent cerebrovascular disease A Scientific Statement for healthcare
professionals from the American Heart AssociationAmerican Stroke
Association Stroke 201748e44-e71
Case 1 Asymptomatic patient
bull 70 yr old man golfer (18 holes)
bull Well
bull Headachehead injury
bull Incidental finding
bull Is this really ldquosilentrdquo
bull Revert to primary prevention risk factor control
Treatment and prevention
Treat vascular risk factors
High blood pressure ++
Diabetes +
High cholesterol +
Smoking ++
But Impact may
differ at different ages
eg BP may be more
important in 40s ndash
60s than 70s ndash 90s
But All common vascular risk factors combined only
explain a small proportion of the burden of brain
vascular disease and so far trials of risk factor
reduction have been disappointing
Case 2 Lacunar stroke patient
bull 65 yr old female
bull Left sided weakness
bull Is there enough evidence to manage her differently from other ischaemic strokes
bull Many studies included lacunar stroke patients but did not adequately report subtype findings
bull Few studies in lacunar stroke
SPS3 trial
Benavente NEJM 2012 Benavente Lancet Neurol 2013
N=3000 patients with lacunar stroke and baseline MRI scans
Intensive blood pressure control no significant benefit on strokemortality
(but fewer ICH)
Dual antiplatelet (clopasp) therapy harmful and stopped early
Lower than expected stroke incidence
Case 3 Co-incidental SVD
bull 80 yr with atrial fibrillation - CHADSVASC2 3
MRI shows microbleeds
bull 70 yr with acute MCA infarct ndash 2 hours ago
MRICT show white matter disease
Anticoagulation and other therapies in patients with silent microbleeds
It is reasonable to provide anticoagulation therapy to patients with microbleeds when there is an indication
(eg AF)
When anticoagulation is needed a novel oral anticoagulant is preferred over warfarin
Percutaneous closure of the left atrial appendage could be considered as an alternative to anticoagulation
It is reasonable to provide antiplatelet therapy to patients with microbleeds when there is an indication
MRI screening for microbleeds is not needed before the initiation of antithrombotic therapies
Individuals with silent microbleeds are at increased future risk of both ischemic stroke and ICH
Implement preventive care recommended by AHAASA guidelines for primary prevention of ischemic stroke
It is reasonable to provide preventive care recommended by AHAASA guidelines for prevention of ICH
Suggestions for Clinical Care in Patients with Microbleeds
Acute ischemic stroke due to RMCA occlusion
Multiple microbleeds on SWI
77 year woman
Plan of management
NIHSS 16
a) No thrombolysis or antithromboticsb) Aspirinc) IV tPA 09 mgkg then thrombectomyd) IV tPA 06 mgkg then EVTe) Straight to EVT without tPA
Microbleed Scenario Acute Ischemic Stroke
Slide adapted from E Smith
Risk for sICH after TPA
bull Meta-analysis of 8 cohort studies with data on cerebral microbleeds and risk for post-tPA sICH
bull Pooled OR 287 for ICH post TPA in the presence of microbleeds
bull Unclear whether 56 risk increase for sICH outweighs
12 risk reduction for ischemic stroke disability expected
from tPA
Charidimou A et al Neurology 201585927-924
Safety of acute ischemic stroke therapy in patients with silent microbleeds
It is reasonable to administer intravenous alteplase to patients with acute ischemic stroke and
evidence of microbleeds if it is otherwise indicated
It is reasonable to perform endovascular thrombectomy in patients with acute ischemic stroke and
evidence of microbleeds
In acute ischemic stroke patients with microbleeds bypassing intravenous alteplase therapy to
proceed directly to endovascular thrombectomy is an unproven strategy
Clinical Suggestions for Acute Ischemic
Stroke
Therapy in Patients with Microbleeds
Other SVD treatment targets
Weak blood vessel lining strengthen cell junctions
Poor blood vessel function increase nitric oxide
lsquoInflammationrsquo anti-inflammatory
Statins nitrates pentoxyfiline cilostazol dipyridamole etc
Trials are ongoing eg LACI-1 LACI-2 PRESERVE
Salt exercise green vegetables nutrient bars
RCTs of cilostazol and nitrates in SVD
n=446012 weeksEdinburghNottingham
n=4001 yrJuly 2017gt30 UK centres
TolerabilityCVR measuresPulse wave analysis
1 Cilostazol2 Nitrate3 Both early4 Both late
Clinical outcomesMRI at one year
1 Cilostazol2 Nitrate3 Both4 Neither
SVD trials
bull Difficult ndash heterogenous patient groups
bull Low stroke recurrence rate (3 pa)
bull Cognitive testing time consuming
bull Do they measure the correct outcomes
For now
Apply guideline treatments
bull Lower blood pressure
bull Lower lipids
bull Use antiplatelet drugs but not ASA+Clop long term
bull Lifestyle advise ndash smoking salt reduction exercise
bull Trials of existing agents and novel agents
bull More animal data to lead to human trials
Conclusions
bull SVD important defined by imaging
bull Silent may not be silent
bull Stroke and dementia linked
bull Treatment options at present limited
Smith EE Saposnik G Biessels GJ et al Prevention of stroke in patients with
silent cerebrovascular disease A Scientific Statement for healthcare
professionals from the American Heart AssociationAmerican Stroke
Association Stroke 201748e44-e71
Case 1 Asymptomatic patient
bull 70 yr old man golfer (18 holes)
bull Well
bull Headachehead injury
bull Incidental finding
bull Is this really ldquosilentrdquo
bull Revert to primary prevention risk factor control
Treatment and prevention
Treat vascular risk factors
High blood pressure ++
Diabetes +
High cholesterol +
Smoking ++
But Impact may
differ at different ages
eg BP may be more
important in 40s ndash
60s than 70s ndash 90s
But All common vascular risk factors combined only
explain a small proportion of the burden of brain
vascular disease and so far trials of risk factor
reduction have been disappointing
Case 2 Lacunar stroke patient
bull 65 yr old female
bull Left sided weakness
bull Is there enough evidence to manage her differently from other ischaemic strokes
bull Many studies included lacunar stroke patients but did not adequately report subtype findings
bull Few studies in lacunar stroke
SPS3 trial
Benavente NEJM 2012 Benavente Lancet Neurol 2013
N=3000 patients with lacunar stroke and baseline MRI scans
Intensive blood pressure control no significant benefit on strokemortality
(but fewer ICH)
Dual antiplatelet (clopasp) therapy harmful and stopped early
Lower than expected stroke incidence
Case 3 Co-incidental SVD
bull 80 yr with atrial fibrillation - CHADSVASC2 3
MRI shows microbleeds
bull 70 yr with acute MCA infarct ndash 2 hours ago
MRICT show white matter disease
Anticoagulation and other therapies in patients with silent microbleeds
It is reasonable to provide anticoagulation therapy to patients with microbleeds when there is an indication
(eg AF)
When anticoagulation is needed a novel oral anticoagulant is preferred over warfarin
Percutaneous closure of the left atrial appendage could be considered as an alternative to anticoagulation
It is reasonable to provide antiplatelet therapy to patients with microbleeds when there is an indication
MRI screening for microbleeds is not needed before the initiation of antithrombotic therapies
Individuals with silent microbleeds are at increased future risk of both ischemic stroke and ICH
Implement preventive care recommended by AHAASA guidelines for primary prevention of ischemic stroke
It is reasonable to provide preventive care recommended by AHAASA guidelines for prevention of ICH
Suggestions for Clinical Care in Patients with Microbleeds
Acute ischemic stroke due to RMCA occlusion
Multiple microbleeds on SWI
77 year woman
Plan of management
NIHSS 16
a) No thrombolysis or antithromboticsb) Aspirinc) IV tPA 09 mgkg then thrombectomyd) IV tPA 06 mgkg then EVTe) Straight to EVT without tPA
Microbleed Scenario Acute Ischemic Stroke
Slide adapted from E Smith
Risk for sICH after TPA
bull Meta-analysis of 8 cohort studies with data on cerebral microbleeds and risk for post-tPA sICH
bull Pooled OR 287 for ICH post TPA in the presence of microbleeds
bull Unclear whether 56 risk increase for sICH outweighs
12 risk reduction for ischemic stroke disability expected
from tPA
Charidimou A et al Neurology 201585927-924
Safety of acute ischemic stroke therapy in patients with silent microbleeds
It is reasonable to administer intravenous alteplase to patients with acute ischemic stroke and
evidence of microbleeds if it is otherwise indicated
It is reasonable to perform endovascular thrombectomy in patients with acute ischemic stroke and
evidence of microbleeds
In acute ischemic stroke patients with microbleeds bypassing intravenous alteplase therapy to
proceed directly to endovascular thrombectomy is an unproven strategy
Clinical Suggestions for Acute Ischemic
Stroke
Therapy in Patients with Microbleeds
Other SVD treatment targets
Weak blood vessel lining strengthen cell junctions
Poor blood vessel function increase nitric oxide
lsquoInflammationrsquo anti-inflammatory
Statins nitrates pentoxyfiline cilostazol dipyridamole etc
Trials are ongoing eg LACI-1 LACI-2 PRESERVE
Salt exercise green vegetables nutrient bars
RCTs of cilostazol and nitrates in SVD
n=446012 weeksEdinburghNottingham
n=4001 yrJuly 2017gt30 UK centres
TolerabilityCVR measuresPulse wave analysis
1 Cilostazol2 Nitrate3 Both early4 Both late
Clinical outcomesMRI at one year
1 Cilostazol2 Nitrate3 Both4 Neither
SVD trials
bull Difficult ndash heterogenous patient groups
bull Low stroke recurrence rate (3 pa)
bull Cognitive testing time consuming
bull Do they measure the correct outcomes
For now
Apply guideline treatments
bull Lower blood pressure
bull Lower lipids
bull Use antiplatelet drugs but not ASA+Clop long term
bull Lifestyle advise ndash smoking salt reduction exercise
bull Trials of existing agents and novel agents
bull More animal data to lead to human trials
Conclusions
bull SVD important defined by imaging
bull Silent may not be silent
bull Stroke and dementia linked
bull Treatment options at present limited
Case 1 Asymptomatic patient
bull 70 yr old man golfer (18 holes)
bull Well
bull Headachehead injury
bull Incidental finding
bull Is this really ldquosilentrdquo
bull Revert to primary prevention risk factor control
Treatment and prevention
Treat vascular risk factors
High blood pressure ++
Diabetes +
High cholesterol +
Smoking ++
But Impact may
differ at different ages
eg BP may be more
important in 40s ndash
60s than 70s ndash 90s
But All common vascular risk factors combined only
explain a small proportion of the burden of brain
vascular disease and so far trials of risk factor
reduction have been disappointing
Case 2 Lacunar stroke patient
bull 65 yr old female
bull Left sided weakness
bull Is there enough evidence to manage her differently from other ischaemic strokes
bull Many studies included lacunar stroke patients but did not adequately report subtype findings
bull Few studies in lacunar stroke
SPS3 trial
Benavente NEJM 2012 Benavente Lancet Neurol 2013
N=3000 patients with lacunar stroke and baseline MRI scans
Intensive blood pressure control no significant benefit on strokemortality
(but fewer ICH)
Dual antiplatelet (clopasp) therapy harmful and stopped early
Lower than expected stroke incidence
Case 3 Co-incidental SVD
bull 80 yr with atrial fibrillation - CHADSVASC2 3
MRI shows microbleeds
bull 70 yr with acute MCA infarct ndash 2 hours ago
MRICT show white matter disease
Anticoagulation and other therapies in patients with silent microbleeds
It is reasonable to provide anticoagulation therapy to patients with microbleeds when there is an indication
(eg AF)
When anticoagulation is needed a novel oral anticoagulant is preferred over warfarin
Percutaneous closure of the left atrial appendage could be considered as an alternative to anticoagulation
It is reasonable to provide antiplatelet therapy to patients with microbleeds when there is an indication
MRI screening for microbleeds is not needed before the initiation of antithrombotic therapies
Individuals with silent microbleeds are at increased future risk of both ischemic stroke and ICH
Implement preventive care recommended by AHAASA guidelines for primary prevention of ischemic stroke
It is reasonable to provide preventive care recommended by AHAASA guidelines for prevention of ICH
Suggestions for Clinical Care in Patients with Microbleeds
Acute ischemic stroke due to RMCA occlusion
Multiple microbleeds on SWI
77 year woman
Plan of management
NIHSS 16
a) No thrombolysis or antithromboticsb) Aspirinc) IV tPA 09 mgkg then thrombectomyd) IV tPA 06 mgkg then EVTe) Straight to EVT without tPA
Microbleed Scenario Acute Ischemic Stroke
Slide adapted from E Smith
Risk for sICH after TPA
bull Meta-analysis of 8 cohort studies with data on cerebral microbleeds and risk for post-tPA sICH
bull Pooled OR 287 for ICH post TPA in the presence of microbleeds
bull Unclear whether 56 risk increase for sICH outweighs
12 risk reduction for ischemic stroke disability expected
from tPA
Charidimou A et al Neurology 201585927-924
Safety of acute ischemic stroke therapy in patients with silent microbleeds
It is reasonable to administer intravenous alteplase to patients with acute ischemic stroke and
evidence of microbleeds if it is otherwise indicated
It is reasonable to perform endovascular thrombectomy in patients with acute ischemic stroke and
evidence of microbleeds
In acute ischemic stroke patients with microbleeds bypassing intravenous alteplase therapy to
proceed directly to endovascular thrombectomy is an unproven strategy
Clinical Suggestions for Acute Ischemic
Stroke
Therapy in Patients with Microbleeds
Other SVD treatment targets
Weak blood vessel lining strengthen cell junctions
Poor blood vessel function increase nitric oxide
lsquoInflammationrsquo anti-inflammatory
Statins nitrates pentoxyfiline cilostazol dipyridamole etc
Trials are ongoing eg LACI-1 LACI-2 PRESERVE
Salt exercise green vegetables nutrient bars
RCTs of cilostazol and nitrates in SVD
n=446012 weeksEdinburghNottingham
n=4001 yrJuly 2017gt30 UK centres
TolerabilityCVR measuresPulse wave analysis
1 Cilostazol2 Nitrate3 Both early4 Both late
Clinical outcomesMRI at one year
1 Cilostazol2 Nitrate3 Both4 Neither
SVD trials
bull Difficult ndash heterogenous patient groups
bull Low stroke recurrence rate (3 pa)
bull Cognitive testing time consuming
bull Do they measure the correct outcomes
For now
Apply guideline treatments
bull Lower blood pressure
bull Lower lipids
bull Use antiplatelet drugs but not ASA+Clop long term
bull Lifestyle advise ndash smoking salt reduction exercise
bull Trials of existing agents and novel agents
bull More animal data to lead to human trials
Conclusions
bull SVD important defined by imaging
bull Silent may not be silent
bull Stroke and dementia linked
bull Treatment options at present limited
Treatment and prevention
Treat vascular risk factors
High blood pressure ++
Diabetes +
High cholesterol +
Smoking ++
But Impact may
differ at different ages
eg BP may be more
important in 40s ndash
60s than 70s ndash 90s
But All common vascular risk factors combined only
explain a small proportion of the burden of brain
vascular disease and so far trials of risk factor
reduction have been disappointing
Case 2 Lacunar stroke patient
bull 65 yr old female
bull Left sided weakness
bull Is there enough evidence to manage her differently from other ischaemic strokes
bull Many studies included lacunar stroke patients but did not adequately report subtype findings
bull Few studies in lacunar stroke
SPS3 trial
Benavente NEJM 2012 Benavente Lancet Neurol 2013
N=3000 patients with lacunar stroke and baseline MRI scans
Intensive blood pressure control no significant benefit on strokemortality
(but fewer ICH)
Dual antiplatelet (clopasp) therapy harmful and stopped early
Lower than expected stroke incidence
Case 3 Co-incidental SVD
bull 80 yr with atrial fibrillation - CHADSVASC2 3
MRI shows microbleeds
bull 70 yr with acute MCA infarct ndash 2 hours ago
MRICT show white matter disease
Anticoagulation and other therapies in patients with silent microbleeds
It is reasonable to provide anticoagulation therapy to patients with microbleeds when there is an indication
(eg AF)
When anticoagulation is needed a novel oral anticoagulant is preferred over warfarin
Percutaneous closure of the left atrial appendage could be considered as an alternative to anticoagulation
It is reasonable to provide antiplatelet therapy to patients with microbleeds when there is an indication
MRI screening for microbleeds is not needed before the initiation of antithrombotic therapies
Individuals with silent microbleeds are at increased future risk of both ischemic stroke and ICH
Implement preventive care recommended by AHAASA guidelines for primary prevention of ischemic stroke
It is reasonable to provide preventive care recommended by AHAASA guidelines for prevention of ICH
Suggestions for Clinical Care in Patients with Microbleeds
Acute ischemic stroke due to RMCA occlusion
Multiple microbleeds on SWI
77 year woman
Plan of management
NIHSS 16
a) No thrombolysis or antithromboticsb) Aspirinc) IV tPA 09 mgkg then thrombectomyd) IV tPA 06 mgkg then EVTe) Straight to EVT without tPA
Microbleed Scenario Acute Ischemic Stroke
Slide adapted from E Smith
Risk for sICH after TPA
bull Meta-analysis of 8 cohort studies with data on cerebral microbleeds and risk for post-tPA sICH
bull Pooled OR 287 for ICH post TPA in the presence of microbleeds
bull Unclear whether 56 risk increase for sICH outweighs
12 risk reduction for ischemic stroke disability expected
from tPA
Charidimou A et al Neurology 201585927-924
Safety of acute ischemic stroke therapy in patients with silent microbleeds
It is reasonable to administer intravenous alteplase to patients with acute ischemic stroke and
evidence of microbleeds if it is otherwise indicated
It is reasonable to perform endovascular thrombectomy in patients with acute ischemic stroke and
evidence of microbleeds
In acute ischemic stroke patients with microbleeds bypassing intravenous alteplase therapy to
proceed directly to endovascular thrombectomy is an unproven strategy
Clinical Suggestions for Acute Ischemic
Stroke
Therapy in Patients with Microbleeds
Other SVD treatment targets
Weak blood vessel lining strengthen cell junctions
Poor blood vessel function increase nitric oxide
lsquoInflammationrsquo anti-inflammatory
Statins nitrates pentoxyfiline cilostazol dipyridamole etc
Trials are ongoing eg LACI-1 LACI-2 PRESERVE
Salt exercise green vegetables nutrient bars
RCTs of cilostazol and nitrates in SVD
n=446012 weeksEdinburghNottingham
n=4001 yrJuly 2017gt30 UK centres
TolerabilityCVR measuresPulse wave analysis
1 Cilostazol2 Nitrate3 Both early4 Both late
Clinical outcomesMRI at one year
1 Cilostazol2 Nitrate3 Both4 Neither
SVD trials
bull Difficult ndash heterogenous patient groups
bull Low stroke recurrence rate (3 pa)
bull Cognitive testing time consuming
bull Do they measure the correct outcomes
For now
Apply guideline treatments
bull Lower blood pressure
bull Lower lipids
bull Use antiplatelet drugs but not ASA+Clop long term
bull Lifestyle advise ndash smoking salt reduction exercise
bull Trials of existing agents and novel agents
bull More animal data to lead to human trials
Conclusions
bull SVD important defined by imaging
bull Silent may not be silent
bull Stroke and dementia linked
bull Treatment options at present limited
Case 2 Lacunar stroke patient
bull 65 yr old female
bull Left sided weakness
bull Is there enough evidence to manage her differently from other ischaemic strokes
bull Many studies included lacunar stroke patients but did not adequately report subtype findings
bull Few studies in lacunar stroke
SPS3 trial
Benavente NEJM 2012 Benavente Lancet Neurol 2013
N=3000 patients with lacunar stroke and baseline MRI scans
Intensive blood pressure control no significant benefit on strokemortality
(but fewer ICH)
Dual antiplatelet (clopasp) therapy harmful and stopped early
Lower than expected stroke incidence
Case 3 Co-incidental SVD
bull 80 yr with atrial fibrillation - CHADSVASC2 3
MRI shows microbleeds
bull 70 yr with acute MCA infarct ndash 2 hours ago
MRICT show white matter disease
Anticoagulation and other therapies in patients with silent microbleeds
It is reasonable to provide anticoagulation therapy to patients with microbleeds when there is an indication
(eg AF)
When anticoagulation is needed a novel oral anticoagulant is preferred over warfarin
Percutaneous closure of the left atrial appendage could be considered as an alternative to anticoagulation
It is reasonable to provide antiplatelet therapy to patients with microbleeds when there is an indication
MRI screening for microbleeds is not needed before the initiation of antithrombotic therapies
Individuals with silent microbleeds are at increased future risk of both ischemic stroke and ICH
Implement preventive care recommended by AHAASA guidelines for primary prevention of ischemic stroke
It is reasonable to provide preventive care recommended by AHAASA guidelines for prevention of ICH
Suggestions for Clinical Care in Patients with Microbleeds
Acute ischemic stroke due to RMCA occlusion
Multiple microbleeds on SWI
77 year woman
Plan of management
NIHSS 16
a) No thrombolysis or antithromboticsb) Aspirinc) IV tPA 09 mgkg then thrombectomyd) IV tPA 06 mgkg then EVTe) Straight to EVT without tPA
Microbleed Scenario Acute Ischemic Stroke
Slide adapted from E Smith
Risk for sICH after TPA
bull Meta-analysis of 8 cohort studies with data on cerebral microbleeds and risk for post-tPA sICH
bull Pooled OR 287 for ICH post TPA in the presence of microbleeds
bull Unclear whether 56 risk increase for sICH outweighs
12 risk reduction for ischemic stroke disability expected
from tPA
Charidimou A et al Neurology 201585927-924
Safety of acute ischemic stroke therapy in patients with silent microbleeds
It is reasonable to administer intravenous alteplase to patients with acute ischemic stroke and
evidence of microbleeds if it is otherwise indicated
It is reasonable to perform endovascular thrombectomy in patients with acute ischemic stroke and
evidence of microbleeds
In acute ischemic stroke patients with microbleeds bypassing intravenous alteplase therapy to
proceed directly to endovascular thrombectomy is an unproven strategy
Clinical Suggestions for Acute Ischemic
Stroke
Therapy in Patients with Microbleeds
Other SVD treatment targets
Weak blood vessel lining strengthen cell junctions
Poor blood vessel function increase nitric oxide
lsquoInflammationrsquo anti-inflammatory
Statins nitrates pentoxyfiline cilostazol dipyridamole etc
Trials are ongoing eg LACI-1 LACI-2 PRESERVE
Salt exercise green vegetables nutrient bars
RCTs of cilostazol and nitrates in SVD
n=446012 weeksEdinburghNottingham
n=4001 yrJuly 2017gt30 UK centres
TolerabilityCVR measuresPulse wave analysis
1 Cilostazol2 Nitrate3 Both early4 Both late
Clinical outcomesMRI at one year
1 Cilostazol2 Nitrate3 Both4 Neither
SVD trials
bull Difficult ndash heterogenous patient groups
bull Low stroke recurrence rate (3 pa)
bull Cognitive testing time consuming
bull Do they measure the correct outcomes
For now
Apply guideline treatments
bull Lower blood pressure
bull Lower lipids
bull Use antiplatelet drugs but not ASA+Clop long term
bull Lifestyle advise ndash smoking salt reduction exercise
bull Trials of existing agents and novel agents
bull More animal data to lead to human trials
Conclusions
bull SVD important defined by imaging
bull Silent may not be silent
bull Stroke and dementia linked
bull Treatment options at present limited
SPS3 trial
Benavente NEJM 2012 Benavente Lancet Neurol 2013
N=3000 patients with lacunar stroke and baseline MRI scans
Intensive blood pressure control no significant benefit on strokemortality
(but fewer ICH)
Dual antiplatelet (clopasp) therapy harmful and stopped early
Lower than expected stroke incidence
Case 3 Co-incidental SVD
bull 80 yr with atrial fibrillation - CHADSVASC2 3
MRI shows microbleeds
bull 70 yr with acute MCA infarct ndash 2 hours ago
MRICT show white matter disease
Anticoagulation and other therapies in patients with silent microbleeds
It is reasonable to provide anticoagulation therapy to patients with microbleeds when there is an indication
(eg AF)
When anticoagulation is needed a novel oral anticoagulant is preferred over warfarin
Percutaneous closure of the left atrial appendage could be considered as an alternative to anticoagulation
It is reasonable to provide antiplatelet therapy to patients with microbleeds when there is an indication
MRI screening for microbleeds is not needed before the initiation of antithrombotic therapies
Individuals with silent microbleeds are at increased future risk of both ischemic stroke and ICH
Implement preventive care recommended by AHAASA guidelines for primary prevention of ischemic stroke
It is reasonable to provide preventive care recommended by AHAASA guidelines for prevention of ICH
Suggestions for Clinical Care in Patients with Microbleeds
Acute ischemic stroke due to RMCA occlusion
Multiple microbleeds on SWI
77 year woman
Plan of management
NIHSS 16
a) No thrombolysis or antithromboticsb) Aspirinc) IV tPA 09 mgkg then thrombectomyd) IV tPA 06 mgkg then EVTe) Straight to EVT without tPA
Microbleed Scenario Acute Ischemic Stroke
Slide adapted from E Smith
Risk for sICH after TPA
bull Meta-analysis of 8 cohort studies with data on cerebral microbleeds and risk for post-tPA sICH
bull Pooled OR 287 for ICH post TPA in the presence of microbleeds
bull Unclear whether 56 risk increase for sICH outweighs
12 risk reduction for ischemic stroke disability expected
from tPA
Charidimou A et al Neurology 201585927-924
Safety of acute ischemic stroke therapy in patients with silent microbleeds
It is reasonable to administer intravenous alteplase to patients with acute ischemic stroke and
evidence of microbleeds if it is otherwise indicated
It is reasonable to perform endovascular thrombectomy in patients with acute ischemic stroke and
evidence of microbleeds
In acute ischemic stroke patients with microbleeds bypassing intravenous alteplase therapy to
proceed directly to endovascular thrombectomy is an unproven strategy
Clinical Suggestions for Acute Ischemic
Stroke
Therapy in Patients with Microbleeds
Other SVD treatment targets
Weak blood vessel lining strengthen cell junctions
Poor blood vessel function increase nitric oxide
lsquoInflammationrsquo anti-inflammatory
Statins nitrates pentoxyfiline cilostazol dipyridamole etc
Trials are ongoing eg LACI-1 LACI-2 PRESERVE
Salt exercise green vegetables nutrient bars
RCTs of cilostazol and nitrates in SVD
n=446012 weeksEdinburghNottingham
n=4001 yrJuly 2017gt30 UK centres
TolerabilityCVR measuresPulse wave analysis
1 Cilostazol2 Nitrate3 Both early4 Both late
Clinical outcomesMRI at one year
1 Cilostazol2 Nitrate3 Both4 Neither
SVD trials
bull Difficult ndash heterogenous patient groups
bull Low stroke recurrence rate (3 pa)
bull Cognitive testing time consuming
bull Do they measure the correct outcomes
For now
Apply guideline treatments
bull Lower blood pressure
bull Lower lipids
bull Use antiplatelet drugs but not ASA+Clop long term
bull Lifestyle advise ndash smoking salt reduction exercise
bull Trials of existing agents and novel agents
bull More animal data to lead to human trials
Conclusions
bull SVD important defined by imaging
bull Silent may not be silent
bull Stroke and dementia linked
bull Treatment options at present limited
Case 3 Co-incidental SVD
bull 80 yr with atrial fibrillation - CHADSVASC2 3
MRI shows microbleeds
bull 70 yr with acute MCA infarct ndash 2 hours ago
MRICT show white matter disease
Anticoagulation and other therapies in patients with silent microbleeds
It is reasonable to provide anticoagulation therapy to patients with microbleeds when there is an indication
(eg AF)
When anticoagulation is needed a novel oral anticoagulant is preferred over warfarin
Percutaneous closure of the left atrial appendage could be considered as an alternative to anticoagulation
It is reasonable to provide antiplatelet therapy to patients with microbleeds when there is an indication
MRI screening for microbleeds is not needed before the initiation of antithrombotic therapies
Individuals with silent microbleeds are at increased future risk of both ischemic stroke and ICH
Implement preventive care recommended by AHAASA guidelines for primary prevention of ischemic stroke
It is reasonable to provide preventive care recommended by AHAASA guidelines for prevention of ICH
Suggestions for Clinical Care in Patients with Microbleeds
Acute ischemic stroke due to RMCA occlusion
Multiple microbleeds on SWI
77 year woman
Plan of management
NIHSS 16
a) No thrombolysis or antithromboticsb) Aspirinc) IV tPA 09 mgkg then thrombectomyd) IV tPA 06 mgkg then EVTe) Straight to EVT without tPA
Microbleed Scenario Acute Ischemic Stroke
Slide adapted from E Smith
Risk for sICH after TPA
bull Meta-analysis of 8 cohort studies with data on cerebral microbleeds and risk for post-tPA sICH
bull Pooled OR 287 for ICH post TPA in the presence of microbleeds
bull Unclear whether 56 risk increase for sICH outweighs
12 risk reduction for ischemic stroke disability expected
from tPA
Charidimou A et al Neurology 201585927-924
Safety of acute ischemic stroke therapy in patients with silent microbleeds
It is reasonable to administer intravenous alteplase to patients with acute ischemic stroke and
evidence of microbleeds if it is otherwise indicated
It is reasonable to perform endovascular thrombectomy in patients with acute ischemic stroke and
evidence of microbleeds
In acute ischemic stroke patients with microbleeds bypassing intravenous alteplase therapy to
proceed directly to endovascular thrombectomy is an unproven strategy
Clinical Suggestions for Acute Ischemic
Stroke
Therapy in Patients with Microbleeds
Other SVD treatment targets
Weak blood vessel lining strengthen cell junctions
Poor blood vessel function increase nitric oxide
lsquoInflammationrsquo anti-inflammatory
Statins nitrates pentoxyfiline cilostazol dipyridamole etc
Trials are ongoing eg LACI-1 LACI-2 PRESERVE
Salt exercise green vegetables nutrient bars
RCTs of cilostazol and nitrates in SVD
n=446012 weeksEdinburghNottingham
n=4001 yrJuly 2017gt30 UK centres
TolerabilityCVR measuresPulse wave analysis
1 Cilostazol2 Nitrate3 Both early4 Both late
Clinical outcomesMRI at one year
1 Cilostazol2 Nitrate3 Both4 Neither
SVD trials
bull Difficult ndash heterogenous patient groups
bull Low stroke recurrence rate (3 pa)
bull Cognitive testing time consuming
bull Do they measure the correct outcomes
For now
Apply guideline treatments
bull Lower blood pressure
bull Lower lipids
bull Use antiplatelet drugs but not ASA+Clop long term
bull Lifestyle advise ndash smoking salt reduction exercise
bull Trials of existing agents and novel agents
bull More animal data to lead to human trials
Conclusions
bull SVD important defined by imaging
bull Silent may not be silent
bull Stroke and dementia linked
bull Treatment options at present limited
Anticoagulation and other therapies in patients with silent microbleeds
It is reasonable to provide anticoagulation therapy to patients with microbleeds when there is an indication
(eg AF)
When anticoagulation is needed a novel oral anticoagulant is preferred over warfarin
Percutaneous closure of the left atrial appendage could be considered as an alternative to anticoagulation
It is reasonable to provide antiplatelet therapy to patients with microbleeds when there is an indication
MRI screening for microbleeds is not needed before the initiation of antithrombotic therapies
Individuals with silent microbleeds are at increased future risk of both ischemic stroke and ICH
Implement preventive care recommended by AHAASA guidelines for primary prevention of ischemic stroke
It is reasonable to provide preventive care recommended by AHAASA guidelines for prevention of ICH
Suggestions for Clinical Care in Patients with Microbleeds
Acute ischemic stroke due to RMCA occlusion
Multiple microbleeds on SWI
77 year woman
Plan of management
NIHSS 16
a) No thrombolysis or antithromboticsb) Aspirinc) IV tPA 09 mgkg then thrombectomyd) IV tPA 06 mgkg then EVTe) Straight to EVT without tPA
Microbleed Scenario Acute Ischemic Stroke
Slide adapted from E Smith
Risk for sICH after TPA
bull Meta-analysis of 8 cohort studies with data on cerebral microbleeds and risk for post-tPA sICH
bull Pooled OR 287 for ICH post TPA in the presence of microbleeds
bull Unclear whether 56 risk increase for sICH outweighs
12 risk reduction for ischemic stroke disability expected
from tPA
Charidimou A et al Neurology 201585927-924
Safety of acute ischemic stroke therapy in patients with silent microbleeds
It is reasonable to administer intravenous alteplase to patients with acute ischemic stroke and
evidence of microbleeds if it is otherwise indicated
It is reasonable to perform endovascular thrombectomy in patients with acute ischemic stroke and
evidence of microbleeds
In acute ischemic stroke patients with microbleeds bypassing intravenous alteplase therapy to
proceed directly to endovascular thrombectomy is an unproven strategy
Clinical Suggestions for Acute Ischemic
Stroke
Therapy in Patients with Microbleeds
Other SVD treatment targets
Weak blood vessel lining strengthen cell junctions
Poor blood vessel function increase nitric oxide
lsquoInflammationrsquo anti-inflammatory
Statins nitrates pentoxyfiline cilostazol dipyridamole etc
Trials are ongoing eg LACI-1 LACI-2 PRESERVE
Salt exercise green vegetables nutrient bars
RCTs of cilostazol and nitrates in SVD
n=446012 weeksEdinburghNottingham
n=4001 yrJuly 2017gt30 UK centres
TolerabilityCVR measuresPulse wave analysis
1 Cilostazol2 Nitrate3 Both early4 Both late
Clinical outcomesMRI at one year
1 Cilostazol2 Nitrate3 Both4 Neither
SVD trials
bull Difficult ndash heterogenous patient groups
bull Low stroke recurrence rate (3 pa)
bull Cognitive testing time consuming
bull Do they measure the correct outcomes
For now
Apply guideline treatments
bull Lower blood pressure
bull Lower lipids
bull Use antiplatelet drugs but not ASA+Clop long term
bull Lifestyle advise ndash smoking salt reduction exercise
bull Trials of existing agents and novel agents
bull More animal data to lead to human trials
Conclusions
bull SVD important defined by imaging
bull Silent may not be silent
bull Stroke and dementia linked
bull Treatment options at present limited
Acute ischemic stroke due to RMCA occlusion
Multiple microbleeds on SWI
77 year woman
Plan of management
NIHSS 16
a) No thrombolysis or antithromboticsb) Aspirinc) IV tPA 09 mgkg then thrombectomyd) IV tPA 06 mgkg then EVTe) Straight to EVT without tPA
Microbleed Scenario Acute Ischemic Stroke
Slide adapted from E Smith
Risk for sICH after TPA
bull Meta-analysis of 8 cohort studies with data on cerebral microbleeds and risk for post-tPA sICH
bull Pooled OR 287 for ICH post TPA in the presence of microbleeds
bull Unclear whether 56 risk increase for sICH outweighs
12 risk reduction for ischemic stroke disability expected
from tPA
Charidimou A et al Neurology 201585927-924
Safety of acute ischemic stroke therapy in patients with silent microbleeds
It is reasonable to administer intravenous alteplase to patients with acute ischemic stroke and
evidence of microbleeds if it is otherwise indicated
It is reasonable to perform endovascular thrombectomy in patients with acute ischemic stroke and
evidence of microbleeds
In acute ischemic stroke patients with microbleeds bypassing intravenous alteplase therapy to
proceed directly to endovascular thrombectomy is an unproven strategy
Clinical Suggestions for Acute Ischemic
Stroke
Therapy in Patients with Microbleeds
Other SVD treatment targets
Weak blood vessel lining strengthen cell junctions
Poor blood vessel function increase nitric oxide
lsquoInflammationrsquo anti-inflammatory
Statins nitrates pentoxyfiline cilostazol dipyridamole etc
Trials are ongoing eg LACI-1 LACI-2 PRESERVE
Salt exercise green vegetables nutrient bars
RCTs of cilostazol and nitrates in SVD
n=446012 weeksEdinburghNottingham
n=4001 yrJuly 2017gt30 UK centres
TolerabilityCVR measuresPulse wave analysis
1 Cilostazol2 Nitrate3 Both early4 Both late
Clinical outcomesMRI at one year
1 Cilostazol2 Nitrate3 Both4 Neither
SVD trials
bull Difficult ndash heterogenous patient groups
bull Low stroke recurrence rate (3 pa)
bull Cognitive testing time consuming
bull Do they measure the correct outcomes
For now
Apply guideline treatments
bull Lower blood pressure
bull Lower lipids
bull Use antiplatelet drugs but not ASA+Clop long term
bull Lifestyle advise ndash smoking salt reduction exercise
bull Trials of existing agents and novel agents
bull More animal data to lead to human trials
Conclusions
bull SVD important defined by imaging
bull Silent may not be silent
bull Stroke and dementia linked
bull Treatment options at present limited
Risk for sICH after TPA
bull Meta-analysis of 8 cohort studies with data on cerebral microbleeds and risk for post-tPA sICH
bull Pooled OR 287 for ICH post TPA in the presence of microbleeds
bull Unclear whether 56 risk increase for sICH outweighs
12 risk reduction for ischemic stroke disability expected
from tPA
Charidimou A et al Neurology 201585927-924
Safety of acute ischemic stroke therapy in patients with silent microbleeds
It is reasonable to administer intravenous alteplase to patients with acute ischemic stroke and
evidence of microbleeds if it is otherwise indicated
It is reasonable to perform endovascular thrombectomy in patients with acute ischemic stroke and
evidence of microbleeds
In acute ischemic stroke patients with microbleeds bypassing intravenous alteplase therapy to
proceed directly to endovascular thrombectomy is an unproven strategy
Clinical Suggestions for Acute Ischemic
Stroke
Therapy in Patients with Microbleeds
Other SVD treatment targets
Weak blood vessel lining strengthen cell junctions
Poor blood vessel function increase nitric oxide
lsquoInflammationrsquo anti-inflammatory
Statins nitrates pentoxyfiline cilostazol dipyridamole etc
Trials are ongoing eg LACI-1 LACI-2 PRESERVE
Salt exercise green vegetables nutrient bars
RCTs of cilostazol and nitrates in SVD
n=446012 weeksEdinburghNottingham
n=4001 yrJuly 2017gt30 UK centres
TolerabilityCVR measuresPulse wave analysis
1 Cilostazol2 Nitrate3 Both early4 Both late
Clinical outcomesMRI at one year
1 Cilostazol2 Nitrate3 Both4 Neither
SVD trials
bull Difficult ndash heterogenous patient groups
bull Low stroke recurrence rate (3 pa)
bull Cognitive testing time consuming
bull Do they measure the correct outcomes
For now
Apply guideline treatments
bull Lower blood pressure
bull Lower lipids
bull Use antiplatelet drugs but not ASA+Clop long term
bull Lifestyle advise ndash smoking salt reduction exercise
bull Trials of existing agents and novel agents
bull More animal data to lead to human trials
Conclusions
bull SVD important defined by imaging
bull Silent may not be silent
bull Stroke and dementia linked
bull Treatment options at present limited
Safety of acute ischemic stroke therapy in patients with silent microbleeds
It is reasonable to administer intravenous alteplase to patients with acute ischemic stroke and
evidence of microbleeds if it is otherwise indicated
It is reasonable to perform endovascular thrombectomy in patients with acute ischemic stroke and
evidence of microbleeds
In acute ischemic stroke patients with microbleeds bypassing intravenous alteplase therapy to
proceed directly to endovascular thrombectomy is an unproven strategy
Clinical Suggestions for Acute Ischemic
Stroke
Therapy in Patients with Microbleeds
Other SVD treatment targets
Weak blood vessel lining strengthen cell junctions
Poor blood vessel function increase nitric oxide
lsquoInflammationrsquo anti-inflammatory
Statins nitrates pentoxyfiline cilostazol dipyridamole etc
Trials are ongoing eg LACI-1 LACI-2 PRESERVE
Salt exercise green vegetables nutrient bars
RCTs of cilostazol and nitrates in SVD
n=446012 weeksEdinburghNottingham
n=4001 yrJuly 2017gt30 UK centres
TolerabilityCVR measuresPulse wave analysis
1 Cilostazol2 Nitrate3 Both early4 Both late
Clinical outcomesMRI at one year
1 Cilostazol2 Nitrate3 Both4 Neither
SVD trials
bull Difficult ndash heterogenous patient groups
bull Low stroke recurrence rate (3 pa)
bull Cognitive testing time consuming
bull Do they measure the correct outcomes
For now
Apply guideline treatments
bull Lower blood pressure
bull Lower lipids
bull Use antiplatelet drugs but not ASA+Clop long term
bull Lifestyle advise ndash smoking salt reduction exercise
bull Trials of existing agents and novel agents
bull More animal data to lead to human trials
Conclusions
bull SVD important defined by imaging
bull Silent may not be silent
bull Stroke and dementia linked
bull Treatment options at present limited
Other SVD treatment targets
Weak blood vessel lining strengthen cell junctions
Poor blood vessel function increase nitric oxide
lsquoInflammationrsquo anti-inflammatory
Statins nitrates pentoxyfiline cilostazol dipyridamole etc
Trials are ongoing eg LACI-1 LACI-2 PRESERVE
Salt exercise green vegetables nutrient bars
RCTs of cilostazol and nitrates in SVD
n=446012 weeksEdinburghNottingham
n=4001 yrJuly 2017gt30 UK centres
TolerabilityCVR measuresPulse wave analysis
1 Cilostazol2 Nitrate3 Both early4 Both late
Clinical outcomesMRI at one year
1 Cilostazol2 Nitrate3 Both4 Neither
SVD trials
bull Difficult ndash heterogenous patient groups
bull Low stroke recurrence rate (3 pa)
bull Cognitive testing time consuming
bull Do they measure the correct outcomes
For now
Apply guideline treatments
bull Lower blood pressure
bull Lower lipids
bull Use antiplatelet drugs but not ASA+Clop long term
bull Lifestyle advise ndash smoking salt reduction exercise
bull Trials of existing agents and novel agents
bull More animal data to lead to human trials
Conclusions
bull SVD important defined by imaging
bull Silent may not be silent
bull Stroke and dementia linked
bull Treatment options at present limited
RCTs of cilostazol and nitrates in SVD
n=446012 weeksEdinburghNottingham
n=4001 yrJuly 2017gt30 UK centres
TolerabilityCVR measuresPulse wave analysis
1 Cilostazol2 Nitrate3 Both early4 Both late
Clinical outcomesMRI at one year
1 Cilostazol2 Nitrate3 Both4 Neither
SVD trials
bull Difficult ndash heterogenous patient groups
bull Low stroke recurrence rate (3 pa)
bull Cognitive testing time consuming
bull Do they measure the correct outcomes
For now
Apply guideline treatments
bull Lower blood pressure
bull Lower lipids
bull Use antiplatelet drugs but not ASA+Clop long term
bull Lifestyle advise ndash smoking salt reduction exercise
bull Trials of existing agents and novel agents
bull More animal data to lead to human trials
Conclusions
bull SVD important defined by imaging
bull Silent may not be silent
bull Stroke and dementia linked
bull Treatment options at present limited
SVD trials
bull Difficult ndash heterogenous patient groups
bull Low stroke recurrence rate (3 pa)
bull Cognitive testing time consuming
bull Do they measure the correct outcomes
For now
Apply guideline treatments
bull Lower blood pressure
bull Lower lipids
bull Use antiplatelet drugs but not ASA+Clop long term
bull Lifestyle advise ndash smoking salt reduction exercise
bull Trials of existing agents and novel agents
bull More animal data to lead to human trials
Conclusions
bull SVD important defined by imaging
bull Silent may not be silent
bull Stroke and dementia linked
bull Treatment options at present limited
For now
Apply guideline treatments
bull Lower blood pressure
bull Lower lipids
bull Use antiplatelet drugs but not ASA+Clop long term
bull Lifestyle advise ndash smoking salt reduction exercise
bull Trials of existing agents and novel agents
bull More animal data to lead to human trials
Conclusions
bull SVD important defined by imaging
bull Silent may not be silent
bull Stroke and dementia linked
bull Treatment options at present limited
Conclusions
bull SVD important defined by imaging
bull Silent may not be silent
bull Stroke and dementia linked
bull Treatment options at present limited