cerebral small vessel disease - rcp london
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Cerebral small vessel disease
What is it
What are the clinical syndromes
How do we diagnose it
What is the pathophysiology
New insights from genetics
Possible therapies
Small Vessel disease
Changes in the small perforating arteries arterioles and venules
Age-related and hypertension-related small vessel diseases and cerebral
amyloid angiopathy are the most common forms distal arterioles of
perforating deep vessels
Recognised by imaging appearances best seen with MRI
Clinically important as associated with increased risk of stroke dementia and
death
Clinical Presentations
Asymptomatic white matter disease found on MRI imaging
Presenting with cognitive impairment in the memory service
Presenting with fallsgait disturbance
Presenting with a lacunar stroke syndrome
Cerebrovasc Dis 201132(6)577-588 Epub 2011 Dec 1
2001-2011 A Decade of the LADIS (Leukoaraiosis And DISability) Study What Have We Learned about White Matter Changes and Small-Vessel Disease
The LADIS Study Group Poggesi A Pantoni L Inzitari D Fazekas F Ferro J OBrien J Hennerici M Scheltens P Erkinjuntti T Visser M Langhorne P Chabriat H Waldemar G Wallin A Wahlund A
Small vessel disease ndashprognostic marker
Triples risk of stroke doubles risk of dementia and increases risk of death
Radiological markers of small vessel
disease
main difference between
symptomatic and silent cerebral
infarcts are their size and location
STRIVE-Standards for Reporting and
Imaging of small Vessel disease
STRIVE STandards for Reporting and Imaging of Small Vessel
Disease
Cerebral Microbleeds
CMBs are small (2 to 5 mm) hypointense lesions on paramagnetic sensitive MR sequences such as T2-weighted gradient-echo (GRE) or susceptibility-weighted sequences They are most often located in the cortico-subcortical junction deep grey or white matter in the cerebral hemispheres brainstem and cerebellum
Cerebral microbleeds potential imaging markers of bleeding-prone small vessel arteriopathies in particular small vessel disease related to hypertension and to cerebral amyloid angiopathy
A number of association studies have been published suggesting that presence of microbleeds negatively influence a large number of early and long-term outcomes after TIA ischemic stroke and intracerebral hemorrhage
However these findings are not yet so firmly established that they should be used to influence clinical decision making on acute and secondary preventive therapies in TIA and stroke
Lacunar stroke
OCSP LACI- pure motor deficit pure sensorysensorimotor or ataxic hemiparesis
Lacunar ischaemic stroke is defined as a stroke that is attributable to a recent
small infarct lt15 (or some say 2) cm diameter in the white matter basal ganglia
pons or brainstem and is consistent with a lacunar clinical syndrome
derived from French for ldquo a small fluid-filled cavityrdquo that was thought to mark the
healed stage of a small deep brain infarct
Oxfordshire Community Stroke Project (OCSP) classification which uses only
clinical features to diagnose the stroke subtype can predict correctly the size and
location of a recent brain infarct on imaging in 75ndash80 of patients with stroke
however up to 20 of acute lacunar infarcts can present with cortical symptoms
and conversely cortical infarcts can present with lacunar syndromes
Possible mechanisms of lacunar
infarction
Pathophysiology-insights from the
Spontaneously hypertensive stroke prone rat
model early endothelial damage in small vessels leads to a compromised bloodndashbrain
barrier
Leakage of plasma into tissue surrounding blood vessels
Activation of inflammation microthrombosis
Local vessel occlusion and hypoperfusion
Local vessel occlusion and rupture causing microbleeds
Illustration of how blood brain-barrier might become more permeable and cause damage to surrounding neurons and glial cells
JM Wardlaw et al Stroke 200334806-812
Genetic causes of hereditary small
vessel disease
Cerebral small vessel disease is considered hereditary in about 5 of patients and is characterized by lacunar infarcts and white matter hyperintensities on MRI Several monogenic hereditary diseases causing cerebral small vessel disease and stroke have been identified
CADASIL CARASIL collagen type IV mutations (including PADMAL) retinal vasculopathy with cerebral leukodystrophy Fabry disease hereditary cerebral hemorrhage with amyloidosis and forkhead box C1 mutations
These monogenic disorders are often characterized by early-age stroke but also by migraine mood disturbances vascular dementia and often gait disturbances Some also present with extra-cerebral manifestations such as microangiopathy of the eyes and kidneys Many present with clinically recognizable syndromes
Possible therapeutic interventions
Blood brain barrier modulation
both cGMP (dipyridamole) and cAMP (cilostazol pentoxifylline) modulators
can improve BBB integrity at least in experimental studies
Nitric oxide donors
Aggressive versus standard BP lowering (PRESERVE Trial)
Combination cilostazol and ISMN (LACI-2 trial)
Pharmacological treatment and prevention of cerebral small vessel disease a
review of potential interventions International Journal of Stroke
Volume 10 Issue 4 pages 469-478 2 MAR 2015 DOI 101111ijs12466
Summary of clinical manifestations
What do we already know and what
future study results awaited
TARDIS-dual antiplatelets to be avoided as excess harm
CROMIS
PRESERVE
BRIDGE
RESTART
SoSTART
The End
Pantoni L Cerebral small vessel disease from pathogenesis and clinical
characteristics to therapeutic challenges Lancet Neurol (2010) 9689ndash
701101016S1474-4422(10)70104-6
Hugh Markus-genetics
Joanna Wardlaw-MRI imaging
Philip Bath-therapeutics
CROMIS-UCL Pof Werring
RESTART and SoSTART-Edinburgh
Small Vessel disease
Changes in the small perforating arteries arterioles and venules
Age-related and hypertension-related small vessel diseases and cerebral
amyloid angiopathy are the most common forms distal arterioles of
perforating deep vessels
Recognised by imaging appearances best seen with MRI
Clinically important as associated with increased risk of stroke dementia and
death
Clinical Presentations
Asymptomatic white matter disease found on MRI imaging
Presenting with cognitive impairment in the memory service
Presenting with fallsgait disturbance
Presenting with a lacunar stroke syndrome
Cerebrovasc Dis 201132(6)577-588 Epub 2011 Dec 1
2001-2011 A Decade of the LADIS (Leukoaraiosis And DISability) Study What Have We Learned about White Matter Changes and Small-Vessel Disease
The LADIS Study Group Poggesi A Pantoni L Inzitari D Fazekas F Ferro J OBrien J Hennerici M Scheltens P Erkinjuntti T Visser M Langhorne P Chabriat H Waldemar G Wallin A Wahlund A
Small vessel disease ndashprognostic marker
Triples risk of stroke doubles risk of dementia and increases risk of death
Radiological markers of small vessel
disease
main difference between
symptomatic and silent cerebral
infarcts are their size and location
STRIVE-Standards for Reporting and
Imaging of small Vessel disease
STRIVE STandards for Reporting and Imaging of Small Vessel
Disease
Cerebral Microbleeds
CMBs are small (2 to 5 mm) hypointense lesions on paramagnetic sensitive MR sequences such as T2-weighted gradient-echo (GRE) or susceptibility-weighted sequences They are most often located in the cortico-subcortical junction deep grey or white matter in the cerebral hemispheres brainstem and cerebellum
Cerebral microbleeds potential imaging markers of bleeding-prone small vessel arteriopathies in particular small vessel disease related to hypertension and to cerebral amyloid angiopathy
A number of association studies have been published suggesting that presence of microbleeds negatively influence a large number of early and long-term outcomes after TIA ischemic stroke and intracerebral hemorrhage
However these findings are not yet so firmly established that they should be used to influence clinical decision making on acute and secondary preventive therapies in TIA and stroke
Lacunar stroke
OCSP LACI- pure motor deficit pure sensorysensorimotor or ataxic hemiparesis
Lacunar ischaemic stroke is defined as a stroke that is attributable to a recent
small infarct lt15 (or some say 2) cm diameter in the white matter basal ganglia
pons or brainstem and is consistent with a lacunar clinical syndrome
derived from French for ldquo a small fluid-filled cavityrdquo that was thought to mark the
healed stage of a small deep brain infarct
Oxfordshire Community Stroke Project (OCSP) classification which uses only
clinical features to diagnose the stroke subtype can predict correctly the size and
location of a recent brain infarct on imaging in 75ndash80 of patients with stroke
however up to 20 of acute lacunar infarcts can present with cortical symptoms
and conversely cortical infarcts can present with lacunar syndromes
Possible mechanisms of lacunar
infarction
Pathophysiology-insights from the
Spontaneously hypertensive stroke prone rat
model early endothelial damage in small vessels leads to a compromised bloodndashbrain
barrier
Leakage of plasma into tissue surrounding blood vessels
Activation of inflammation microthrombosis
Local vessel occlusion and hypoperfusion
Local vessel occlusion and rupture causing microbleeds
Illustration of how blood brain-barrier might become more permeable and cause damage to surrounding neurons and glial cells
JM Wardlaw et al Stroke 200334806-812
Genetic causes of hereditary small
vessel disease
Cerebral small vessel disease is considered hereditary in about 5 of patients and is characterized by lacunar infarcts and white matter hyperintensities on MRI Several monogenic hereditary diseases causing cerebral small vessel disease and stroke have been identified
CADASIL CARASIL collagen type IV mutations (including PADMAL) retinal vasculopathy with cerebral leukodystrophy Fabry disease hereditary cerebral hemorrhage with amyloidosis and forkhead box C1 mutations
These monogenic disorders are often characterized by early-age stroke but also by migraine mood disturbances vascular dementia and often gait disturbances Some also present with extra-cerebral manifestations such as microangiopathy of the eyes and kidneys Many present with clinically recognizable syndromes
Possible therapeutic interventions
Blood brain barrier modulation
both cGMP (dipyridamole) and cAMP (cilostazol pentoxifylline) modulators
can improve BBB integrity at least in experimental studies
Nitric oxide donors
Aggressive versus standard BP lowering (PRESERVE Trial)
Combination cilostazol and ISMN (LACI-2 trial)
Pharmacological treatment and prevention of cerebral small vessel disease a
review of potential interventions International Journal of Stroke
Volume 10 Issue 4 pages 469-478 2 MAR 2015 DOI 101111ijs12466
Summary of clinical manifestations
What do we already know and what
future study results awaited
TARDIS-dual antiplatelets to be avoided as excess harm
CROMIS
PRESERVE
BRIDGE
RESTART
SoSTART
The End
Pantoni L Cerebral small vessel disease from pathogenesis and clinical
characteristics to therapeutic challenges Lancet Neurol (2010) 9689ndash
701101016S1474-4422(10)70104-6
Hugh Markus-genetics
Joanna Wardlaw-MRI imaging
Philip Bath-therapeutics
CROMIS-UCL Pof Werring
RESTART and SoSTART-Edinburgh
Clinical Presentations
Asymptomatic white matter disease found on MRI imaging
Presenting with cognitive impairment in the memory service
Presenting with fallsgait disturbance
Presenting with a lacunar stroke syndrome
Cerebrovasc Dis 201132(6)577-588 Epub 2011 Dec 1
2001-2011 A Decade of the LADIS (Leukoaraiosis And DISability) Study What Have We Learned about White Matter Changes and Small-Vessel Disease
The LADIS Study Group Poggesi A Pantoni L Inzitari D Fazekas F Ferro J OBrien J Hennerici M Scheltens P Erkinjuntti T Visser M Langhorne P Chabriat H Waldemar G Wallin A Wahlund A
Small vessel disease ndashprognostic marker
Triples risk of stroke doubles risk of dementia and increases risk of death
Radiological markers of small vessel
disease
main difference between
symptomatic and silent cerebral
infarcts are their size and location
STRIVE-Standards for Reporting and
Imaging of small Vessel disease
STRIVE STandards for Reporting and Imaging of Small Vessel
Disease
Cerebral Microbleeds
CMBs are small (2 to 5 mm) hypointense lesions on paramagnetic sensitive MR sequences such as T2-weighted gradient-echo (GRE) or susceptibility-weighted sequences They are most often located in the cortico-subcortical junction deep grey or white matter in the cerebral hemispheres brainstem and cerebellum
Cerebral microbleeds potential imaging markers of bleeding-prone small vessel arteriopathies in particular small vessel disease related to hypertension and to cerebral amyloid angiopathy
A number of association studies have been published suggesting that presence of microbleeds negatively influence a large number of early and long-term outcomes after TIA ischemic stroke and intracerebral hemorrhage
However these findings are not yet so firmly established that they should be used to influence clinical decision making on acute and secondary preventive therapies in TIA and stroke
Lacunar stroke
OCSP LACI- pure motor deficit pure sensorysensorimotor or ataxic hemiparesis
Lacunar ischaemic stroke is defined as a stroke that is attributable to a recent
small infarct lt15 (or some say 2) cm diameter in the white matter basal ganglia
pons or brainstem and is consistent with a lacunar clinical syndrome
derived from French for ldquo a small fluid-filled cavityrdquo that was thought to mark the
healed stage of a small deep brain infarct
Oxfordshire Community Stroke Project (OCSP) classification which uses only
clinical features to diagnose the stroke subtype can predict correctly the size and
location of a recent brain infarct on imaging in 75ndash80 of patients with stroke
however up to 20 of acute lacunar infarcts can present with cortical symptoms
and conversely cortical infarcts can present with lacunar syndromes
Possible mechanisms of lacunar
infarction
Pathophysiology-insights from the
Spontaneously hypertensive stroke prone rat
model early endothelial damage in small vessels leads to a compromised bloodndashbrain
barrier
Leakage of plasma into tissue surrounding blood vessels
Activation of inflammation microthrombosis
Local vessel occlusion and hypoperfusion
Local vessel occlusion and rupture causing microbleeds
Illustration of how blood brain-barrier might become more permeable and cause damage to surrounding neurons and glial cells
JM Wardlaw et al Stroke 200334806-812
Genetic causes of hereditary small
vessel disease
Cerebral small vessel disease is considered hereditary in about 5 of patients and is characterized by lacunar infarcts and white matter hyperintensities on MRI Several monogenic hereditary diseases causing cerebral small vessel disease and stroke have been identified
CADASIL CARASIL collagen type IV mutations (including PADMAL) retinal vasculopathy with cerebral leukodystrophy Fabry disease hereditary cerebral hemorrhage with amyloidosis and forkhead box C1 mutations
These monogenic disorders are often characterized by early-age stroke but also by migraine mood disturbances vascular dementia and often gait disturbances Some also present with extra-cerebral manifestations such as microangiopathy of the eyes and kidneys Many present with clinically recognizable syndromes
Possible therapeutic interventions
Blood brain barrier modulation
both cGMP (dipyridamole) and cAMP (cilostazol pentoxifylline) modulators
can improve BBB integrity at least in experimental studies
Nitric oxide donors
Aggressive versus standard BP lowering (PRESERVE Trial)
Combination cilostazol and ISMN (LACI-2 trial)
Pharmacological treatment and prevention of cerebral small vessel disease a
review of potential interventions International Journal of Stroke
Volume 10 Issue 4 pages 469-478 2 MAR 2015 DOI 101111ijs12466
Summary of clinical manifestations
What do we already know and what
future study results awaited
TARDIS-dual antiplatelets to be avoided as excess harm
CROMIS
PRESERVE
BRIDGE
RESTART
SoSTART
The End
Pantoni L Cerebral small vessel disease from pathogenesis and clinical
characteristics to therapeutic challenges Lancet Neurol (2010) 9689ndash
701101016S1474-4422(10)70104-6
Hugh Markus-genetics
Joanna Wardlaw-MRI imaging
Philip Bath-therapeutics
CROMIS-UCL Pof Werring
RESTART and SoSTART-Edinburgh
Small vessel disease ndashprognostic marker
Triples risk of stroke doubles risk of dementia and increases risk of death
Radiological markers of small vessel
disease
main difference between
symptomatic and silent cerebral
infarcts are their size and location
STRIVE-Standards for Reporting and
Imaging of small Vessel disease
STRIVE STandards for Reporting and Imaging of Small Vessel
Disease
Cerebral Microbleeds
CMBs are small (2 to 5 mm) hypointense lesions on paramagnetic sensitive MR sequences such as T2-weighted gradient-echo (GRE) or susceptibility-weighted sequences They are most often located in the cortico-subcortical junction deep grey or white matter in the cerebral hemispheres brainstem and cerebellum
Cerebral microbleeds potential imaging markers of bleeding-prone small vessel arteriopathies in particular small vessel disease related to hypertension and to cerebral amyloid angiopathy
A number of association studies have been published suggesting that presence of microbleeds negatively influence a large number of early and long-term outcomes after TIA ischemic stroke and intracerebral hemorrhage
However these findings are not yet so firmly established that they should be used to influence clinical decision making on acute and secondary preventive therapies in TIA and stroke
Lacunar stroke
OCSP LACI- pure motor deficit pure sensorysensorimotor or ataxic hemiparesis
Lacunar ischaemic stroke is defined as a stroke that is attributable to a recent
small infarct lt15 (or some say 2) cm diameter in the white matter basal ganglia
pons or brainstem and is consistent with a lacunar clinical syndrome
derived from French for ldquo a small fluid-filled cavityrdquo that was thought to mark the
healed stage of a small deep brain infarct
Oxfordshire Community Stroke Project (OCSP) classification which uses only
clinical features to diagnose the stroke subtype can predict correctly the size and
location of a recent brain infarct on imaging in 75ndash80 of patients with stroke
however up to 20 of acute lacunar infarcts can present with cortical symptoms
and conversely cortical infarcts can present with lacunar syndromes
Possible mechanisms of lacunar
infarction
Pathophysiology-insights from the
Spontaneously hypertensive stroke prone rat
model early endothelial damage in small vessels leads to a compromised bloodndashbrain
barrier
Leakage of plasma into tissue surrounding blood vessels
Activation of inflammation microthrombosis
Local vessel occlusion and hypoperfusion
Local vessel occlusion and rupture causing microbleeds
Illustration of how blood brain-barrier might become more permeable and cause damage to surrounding neurons and glial cells
JM Wardlaw et al Stroke 200334806-812
Genetic causes of hereditary small
vessel disease
Cerebral small vessel disease is considered hereditary in about 5 of patients and is characterized by lacunar infarcts and white matter hyperintensities on MRI Several monogenic hereditary diseases causing cerebral small vessel disease and stroke have been identified
CADASIL CARASIL collagen type IV mutations (including PADMAL) retinal vasculopathy with cerebral leukodystrophy Fabry disease hereditary cerebral hemorrhage with amyloidosis and forkhead box C1 mutations
These monogenic disorders are often characterized by early-age stroke but also by migraine mood disturbances vascular dementia and often gait disturbances Some also present with extra-cerebral manifestations such as microangiopathy of the eyes and kidneys Many present with clinically recognizable syndromes
Possible therapeutic interventions
Blood brain barrier modulation
both cGMP (dipyridamole) and cAMP (cilostazol pentoxifylline) modulators
can improve BBB integrity at least in experimental studies
Nitric oxide donors
Aggressive versus standard BP lowering (PRESERVE Trial)
Combination cilostazol and ISMN (LACI-2 trial)
Pharmacological treatment and prevention of cerebral small vessel disease a
review of potential interventions International Journal of Stroke
Volume 10 Issue 4 pages 469-478 2 MAR 2015 DOI 101111ijs12466
Summary of clinical manifestations
What do we already know and what
future study results awaited
TARDIS-dual antiplatelets to be avoided as excess harm
CROMIS
PRESERVE
BRIDGE
RESTART
SoSTART
The End
Pantoni L Cerebral small vessel disease from pathogenesis and clinical
characteristics to therapeutic challenges Lancet Neurol (2010) 9689ndash
701101016S1474-4422(10)70104-6
Hugh Markus-genetics
Joanna Wardlaw-MRI imaging
Philip Bath-therapeutics
CROMIS-UCL Pof Werring
RESTART and SoSTART-Edinburgh
Radiological markers of small vessel
disease
main difference between
symptomatic and silent cerebral
infarcts are their size and location
STRIVE-Standards for Reporting and
Imaging of small Vessel disease
STRIVE STandards for Reporting and Imaging of Small Vessel
Disease
Cerebral Microbleeds
CMBs are small (2 to 5 mm) hypointense lesions on paramagnetic sensitive MR sequences such as T2-weighted gradient-echo (GRE) or susceptibility-weighted sequences They are most often located in the cortico-subcortical junction deep grey or white matter in the cerebral hemispheres brainstem and cerebellum
Cerebral microbleeds potential imaging markers of bleeding-prone small vessel arteriopathies in particular small vessel disease related to hypertension and to cerebral amyloid angiopathy
A number of association studies have been published suggesting that presence of microbleeds negatively influence a large number of early and long-term outcomes after TIA ischemic stroke and intracerebral hemorrhage
However these findings are not yet so firmly established that they should be used to influence clinical decision making on acute and secondary preventive therapies in TIA and stroke
Lacunar stroke
OCSP LACI- pure motor deficit pure sensorysensorimotor or ataxic hemiparesis
Lacunar ischaemic stroke is defined as a stroke that is attributable to a recent
small infarct lt15 (or some say 2) cm diameter in the white matter basal ganglia
pons or brainstem and is consistent with a lacunar clinical syndrome
derived from French for ldquo a small fluid-filled cavityrdquo that was thought to mark the
healed stage of a small deep brain infarct
Oxfordshire Community Stroke Project (OCSP) classification which uses only
clinical features to diagnose the stroke subtype can predict correctly the size and
location of a recent brain infarct on imaging in 75ndash80 of patients with stroke
however up to 20 of acute lacunar infarcts can present with cortical symptoms
and conversely cortical infarcts can present with lacunar syndromes
Possible mechanisms of lacunar
infarction
Pathophysiology-insights from the
Spontaneously hypertensive stroke prone rat
model early endothelial damage in small vessels leads to a compromised bloodndashbrain
barrier
Leakage of plasma into tissue surrounding blood vessels
Activation of inflammation microthrombosis
Local vessel occlusion and hypoperfusion
Local vessel occlusion and rupture causing microbleeds
Illustration of how blood brain-barrier might become more permeable and cause damage to surrounding neurons and glial cells
JM Wardlaw et al Stroke 200334806-812
Genetic causes of hereditary small
vessel disease
Cerebral small vessel disease is considered hereditary in about 5 of patients and is characterized by lacunar infarcts and white matter hyperintensities on MRI Several monogenic hereditary diseases causing cerebral small vessel disease and stroke have been identified
CADASIL CARASIL collagen type IV mutations (including PADMAL) retinal vasculopathy with cerebral leukodystrophy Fabry disease hereditary cerebral hemorrhage with amyloidosis and forkhead box C1 mutations
These monogenic disorders are often characterized by early-age stroke but also by migraine mood disturbances vascular dementia and often gait disturbances Some also present with extra-cerebral manifestations such as microangiopathy of the eyes and kidneys Many present with clinically recognizable syndromes
Possible therapeutic interventions
Blood brain barrier modulation
both cGMP (dipyridamole) and cAMP (cilostazol pentoxifylline) modulators
can improve BBB integrity at least in experimental studies
Nitric oxide donors
Aggressive versus standard BP lowering (PRESERVE Trial)
Combination cilostazol and ISMN (LACI-2 trial)
Pharmacological treatment and prevention of cerebral small vessel disease a
review of potential interventions International Journal of Stroke
Volume 10 Issue 4 pages 469-478 2 MAR 2015 DOI 101111ijs12466
Summary of clinical manifestations
What do we already know and what
future study results awaited
TARDIS-dual antiplatelets to be avoided as excess harm
CROMIS
PRESERVE
BRIDGE
RESTART
SoSTART
The End
Pantoni L Cerebral small vessel disease from pathogenesis and clinical
characteristics to therapeutic challenges Lancet Neurol (2010) 9689ndash
701101016S1474-4422(10)70104-6
Hugh Markus-genetics
Joanna Wardlaw-MRI imaging
Philip Bath-therapeutics
CROMIS-UCL Pof Werring
RESTART and SoSTART-Edinburgh
Cerebral Microbleeds
CMBs are small (2 to 5 mm) hypointense lesions on paramagnetic sensitive MR sequences such as T2-weighted gradient-echo (GRE) or susceptibility-weighted sequences They are most often located in the cortico-subcortical junction deep grey or white matter in the cerebral hemispheres brainstem and cerebellum
Cerebral microbleeds potential imaging markers of bleeding-prone small vessel arteriopathies in particular small vessel disease related to hypertension and to cerebral amyloid angiopathy
A number of association studies have been published suggesting that presence of microbleeds negatively influence a large number of early and long-term outcomes after TIA ischemic stroke and intracerebral hemorrhage
However these findings are not yet so firmly established that they should be used to influence clinical decision making on acute and secondary preventive therapies in TIA and stroke
Lacunar stroke
OCSP LACI- pure motor deficit pure sensorysensorimotor or ataxic hemiparesis
Lacunar ischaemic stroke is defined as a stroke that is attributable to a recent
small infarct lt15 (or some say 2) cm diameter in the white matter basal ganglia
pons or brainstem and is consistent with a lacunar clinical syndrome
derived from French for ldquo a small fluid-filled cavityrdquo that was thought to mark the
healed stage of a small deep brain infarct
Oxfordshire Community Stroke Project (OCSP) classification which uses only
clinical features to diagnose the stroke subtype can predict correctly the size and
location of a recent brain infarct on imaging in 75ndash80 of patients with stroke
however up to 20 of acute lacunar infarcts can present with cortical symptoms
and conversely cortical infarcts can present with lacunar syndromes
Possible mechanisms of lacunar
infarction
Pathophysiology-insights from the
Spontaneously hypertensive stroke prone rat
model early endothelial damage in small vessels leads to a compromised bloodndashbrain
barrier
Leakage of plasma into tissue surrounding blood vessels
Activation of inflammation microthrombosis
Local vessel occlusion and hypoperfusion
Local vessel occlusion and rupture causing microbleeds
Illustration of how blood brain-barrier might become more permeable and cause damage to surrounding neurons and glial cells
JM Wardlaw et al Stroke 200334806-812
Genetic causes of hereditary small
vessel disease
Cerebral small vessel disease is considered hereditary in about 5 of patients and is characterized by lacunar infarcts and white matter hyperintensities on MRI Several monogenic hereditary diseases causing cerebral small vessel disease and stroke have been identified
CADASIL CARASIL collagen type IV mutations (including PADMAL) retinal vasculopathy with cerebral leukodystrophy Fabry disease hereditary cerebral hemorrhage with amyloidosis and forkhead box C1 mutations
These monogenic disorders are often characterized by early-age stroke but also by migraine mood disturbances vascular dementia and often gait disturbances Some also present with extra-cerebral manifestations such as microangiopathy of the eyes and kidneys Many present with clinically recognizable syndromes
Possible therapeutic interventions
Blood brain barrier modulation
both cGMP (dipyridamole) and cAMP (cilostazol pentoxifylline) modulators
can improve BBB integrity at least in experimental studies
Nitric oxide donors
Aggressive versus standard BP lowering (PRESERVE Trial)
Combination cilostazol and ISMN (LACI-2 trial)
Pharmacological treatment and prevention of cerebral small vessel disease a
review of potential interventions International Journal of Stroke
Volume 10 Issue 4 pages 469-478 2 MAR 2015 DOI 101111ijs12466
Summary of clinical manifestations
What do we already know and what
future study results awaited
TARDIS-dual antiplatelets to be avoided as excess harm
CROMIS
PRESERVE
BRIDGE
RESTART
SoSTART
The End
Pantoni L Cerebral small vessel disease from pathogenesis and clinical
characteristics to therapeutic challenges Lancet Neurol (2010) 9689ndash
701101016S1474-4422(10)70104-6
Hugh Markus-genetics
Joanna Wardlaw-MRI imaging
Philip Bath-therapeutics
CROMIS-UCL Pof Werring
RESTART and SoSTART-Edinburgh
Lacunar stroke
OCSP LACI- pure motor deficit pure sensorysensorimotor or ataxic hemiparesis
Lacunar ischaemic stroke is defined as a stroke that is attributable to a recent
small infarct lt15 (or some say 2) cm diameter in the white matter basal ganglia
pons or brainstem and is consistent with a lacunar clinical syndrome
derived from French for ldquo a small fluid-filled cavityrdquo that was thought to mark the
healed stage of a small deep brain infarct
Oxfordshire Community Stroke Project (OCSP) classification which uses only
clinical features to diagnose the stroke subtype can predict correctly the size and
location of a recent brain infarct on imaging in 75ndash80 of patients with stroke
however up to 20 of acute lacunar infarcts can present with cortical symptoms
and conversely cortical infarcts can present with lacunar syndromes
Possible mechanisms of lacunar
infarction
Pathophysiology-insights from the
Spontaneously hypertensive stroke prone rat
model early endothelial damage in small vessels leads to a compromised bloodndashbrain
barrier
Leakage of plasma into tissue surrounding blood vessels
Activation of inflammation microthrombosis
Local vessel occlusion and hypoperfusion
Local vessel occlusion and rupture causing microbleeds
Illustration of how blood brain-barrier might become more permeable and cause damage to surrounding neurons and glial cells
JM Wardlaw et al Stroke 200334806-812
Genetic causes of hereditary small
vessel disease
Cerebral small vessel disease is considered hereditary in about 5 of patients and is characterized by lacunar infarcts and white matter hyperintensities on MRI Several monogenic hereditary diseases causing cerebral small vessel disease and stroke have been identified
CADASIL CARASIL collagen type IV mutations (including PADMAL) retinal vasculopathy with cerebral leukodystrophy Fabry disease hereditary cerebral hemorrhage with amyloidosis and forkhead box C1 mutations
These monogenic disorders are often characterized by early-age stroke but also by migraine mood disturbances vascular dementia and often gait disturbances Some also present with extra-cerebral manifestations such as microangiopathy of the eyes and kidneys Many present with clinically recognizable syndromes
Possible therapeutic interventions
Blood brain barrier modulation
both cGMP (dipyridamole) and cAMP (cilostazol pentoxifylline) modulators
can improve BBB integrity at least in experimental studies
Nitric oxide donors
Aggressive versus standard BP lowering (PRESERVE Trial)
Combination cilostazol and ISMN (LACI-2 trial)
Pharmacological treatment and prevention of cerebral small vessel disease a
review of potential interventions International Journal of Stroke
Volume 10 Issue 4 pages 469-478 2 MAR 2015 DOI 101111ijs12466
Summary of clinical manifestations
What do we already know and what
future study results awaited
TARDIS-dual antiplatelets to be avoided as excess harm
CROMIS
PRESERVE
BRIDGE
RESTART
SoSTART
The End
Pantoni L Cerebral small vessel disease from pathogenesis and clinical
characteristics to therapeutic challenges Lancet Neurol (2010) 9689ndash
701101016S1474-4422(10)70104-6
Hugh Markus-genetics
Joanna Wardlaw-MRI imaging
Philip Bath-therapeutics
CROMIS-UCL Pof Werring
RESTART and SoSTART-Edinburgh
Possible mechanisms of lacunar
infarction
Pathophysiology-insights from the
Spontaneously hypertensive stroke prone rat
model early endothelial damage in small vessels leads to a compromised bloodndashbrain
barrier
Leakage of plasma into tissue surrounding blood vessels
Activation of inflammation microthrombosis
Local vessel occlusion and hypoperfusion
Local vessel occlusion and rupture causing microbleeds
Illustration of how blood brain-barrier might become more permeable and cause damage to surrounding neurons and glial cells
JM Wardlaw et al Stroke 200334806-812
Genetic causes of hereditary small
vessel disease
Cerebral small vessel disease is considered hereditary in about 5 of patients and is characterized by lacunar infarcts and white matter hyperintensities on MRI Several monogenic hereditary diseases causing cerebral small vessel disease and stroke have been identified
CADASIL CARASIL collagen type IV mutations (including PADMAL) retinal vasculopathy with cerebral leukodystrophy Fabry disease hereditary cerebral hemorrhage with amyloidosis and forkhead box C1 mutations
These monogenic disorders are often characterized by early-age stroke but also by migraine mood disturbances vascular dementia and often gait disturbances Some also present with extra-cerebral manifestations such as microangiopathy of the eyes and kidneys Many present with clinically recognizable syndromes
Possible therapeutic interventions
Blood brain barrier modulation
both cGMP (dipyridamole) and cAMP (cilostazol pentoxifylline) modulators
can improve BBB integrity at least in experimental studies
Nitric oxide donors
Aggressive versus standard BP lowering (PRESERVE Trial)
Combination cilostazol and ISMN (LACI-2 trial)
Pharmacological treatment and prevention of cerebral small vessel disease a
review of potential interventions International Journal of Stroke
Volume 10 Issue 4 pages 469-478 2 MAR 2015 DOI 101111ijs12466
Summary of clinical manifestations
What do we already know and what
future study results awaited
TARDIS-dual antiplatelets to be avoided as excess harm
CROMIS
PRESERVE
BRIDGE
RESTART
SoSTART
The End
Pantoni L Cerebral small vessel disease from pathogenesis and clinical
characteristics to therapeutic challenges Lancet Neurol (2010) 9689ndash
701101016S1474-4422(10)70104-6
Hugh Markus-genetics
Joanna Wardlaw-MRI imaging
Philip Bath-therapeutics
CROMIS-UCL Pof Werring
RESTART and SoSTART-Edinburgh
Pathophysiology-insights from the
Spontaneously hypertensive stroke prone rat
model early endothelial damage in small vessels leads to a compromised bloodndashbrain
barrier
Leakage of plasma into tissue surrounding blood vessels
Activation of inflammation microthrombosis
Local vessel occlusion and hypoperfusion
Local vessel occlusion and rupture causing microbleeds
Illustration of how blood brain-barrier might become more permeable and cause damage to surrounding neurons and glial cells
JM Wardlaw et al Stroke 200334806-812
Genetic causes of hereditary small
vessel disease
Cerebral small vessel disease is considered hereditary in about 5 of patients and is characterized by lacunar infarcts and white matter hyperintensities on MRI Several monogenic hereditary diseases causing cerebral small vessel disease and stroke have been identified
CADASIL CARASIL collagen type IV mutations (including PADMAL) retinal vasculopathy with cerebral leukodystrophy Fabry disease hereditary cerebral hemorrhage with amyloidosis and forkhead box C1 mutations
These monogenic disorders are often characterized by early-age stroke but also by migraine mood disturbances vascular dementia and often gait disturbances Some also present with extra-cerebral manifestations such as microangiopathy of the eyes and kidneys Many present with clinically recognizable syndromes
Possible therapeutic interventions
Blood brain barrier modulation
both cGMP (dipyridamole) and cAMP (cilostazol pentoxifylline) modulators
can improve BBB integrity at least in experimental studies
Nitric oxide donors
Aggressive versus standard BP lowering (PRESERVE Trial)
Combination cilostazol and ISMN (LACI-2 trial)
Pharmacological treatment and prevention of cerebral small vessel disease a
review of potential interventions International Journal of Stroke
Volume 10 Issue 4 pages 469-478 2 MAR 2015 DOI 101111ijs12466
Summary of clinical manifestations
What do we already know and what
future study results awaited
TARDIS-dual antiplatelets to be avoided as excess harm
CROMIS
PRESERVE
BRIDGE
RESTART
SoSTART
The End
Pantoni L Cerebral small vessel disease from pathogenesis and clinical
characteristics to therapeutic challenges Lancet Neurol (2010) 9689ndash
701101016S1474-4422(10)70104-6
Hugh Markus-genetics
Joanna Wardlaw-MRI imaging
Philip Bath-therapeutics
CROMIS-UCL Pof Werring
RESTART and SoSTART-Edinburgh
Illustration of how blood brain-barrier might become more permeable and cause damage to surrounding neurons and glial cells
JM Wardlaw et al Stroke 200334806-812
Genetic causes of hereditary small
vessel disease
Cerebral small vessel disease is considered hereditary in about 5 of patients and is characterized by lacunar infarcts and white matter hyperintensities on MRI Several monogenic hereditary diseases causing cerebral small vessel disease and stroke have been identified
CADASIL CARASIL collagen type IV mutations (including PADMAL) retinal vasculopathy with cerebral leukodystrophy Fabry disease hereditary cerebral hemorrhage with amyloidosis and forkhead box C1 mutations
These monogenic disorders are often characterized by early-age stroke but also by migraine mood disturbances vascular dementia and often gait disturbances Some also present with extra-cerebral manifestations such as microangiopathy of the eyes and kidneys Many present with clinically recognizable syndromes
Possible therapeutic interventions
Blood brain barrier modulation
both cGMP (dipyridamole) and cAMP (cilostazol pentoxifylline) modulators
can improve BBB integrity at least in experimental studies
Nitric oxide donors
Aggressive versus standard BP lowering (PRESERVE Trial)
Combination cilostazol and ISMN (LACI-2 trial)
Pharmacological treatment and prevention of cerebral small vessel disease a
review of potential interventions International Journal of Stroke
Volume 10 Issue 4 pages 469-478 2 MAR 2015 DOI 101111ijs12466
Summary of clinical manifestations
What do we already know and what
future study results awaited
TARDIS-dual antiplatelets to be avoided as excess harm
CROMIS
PRESERVE
BRIDGE
RESTART
SoSTART
The End
Pantoni L Cerebral small vessel disease from pathogenesis and clinical
characteristics to therapeutic challenges Lancet Neurol (2010) 9689ndash
701101016S1474-4422(10)70104-6
Hugh Markus-genetics
Joanna Wardlaw-MRI imaging
Philip Bath-therapeutics
CROMIS-UCL Pof Werring
RESTART and SoSTART-Edinburgh
Genetic causes of hereditary small
vessel disease
Cerebral small vessel disease is considered hereditary in about 5 of patients and is characterized by lacunar infarcts and white matter hyperintensities on MRI Several monogenic hereditary diseases causing cerebral small vessel disease and stroke have been identified
CADASIL CARASIL collagen type IV mutations (including PADMAL) retinal vasculopathy with cerebral leukodystrophy Fabry disease hereditary cerebral hemorrhage with amyloidosis and forkhead box C1 mutations
These monogenic disorders are often characterized by early-age stroke but also by migraine mood disturbances vascular dementia and often gait disturbances Some also present with extra-cerebral manifestations such as microangiopathy of the eyes and kidneys Many present with clinically recognizable syndromes
Possible therapeutic interventions
Blood brain barrier modulation
both cGMP (dipyridamole) and cAMP (cilostazol pentoxifylline) modulators
can improve BBB integrity at least in experimental studies
Nitric oxide donors
Aggressive versus standard BP lowering (PRESERVE Trial)
Combination cilostazol and ISMN (LACI-2 trial)
Pharmacological treatment and prevention of cerebral small vessel disease a
review of potential interventions International Journal of Stroke
Volume 10 Issue 4 pages 469-478 2 MAR 2015 DOI 101111ijs12466
Summary of clinical manifestations
What do we already know and what
future study results awaited
TARDIS-dual antiplatelets to be avoided as excess harm
CROMIS
PRESERVE
BRIDGE
RESTART
SoSTART
The End
Pantoni L Cerebral small vessel disease from pathogenesis and clinical
characteristics to therapeutic challenges Lancet Neurol (2010) 9689ndash
701101016S1474-4422(10)70104-6
Hugh Markus-genetics
Joanna Wardlaw-MRI imaging
Philip Bath-therapeutics
CROMIS-UCL Pof Werring
RESTART and SoSTART-Edinburgh
Possible therapeutic interventions
Blood brain barrier modulation
both cGMP (dipyridamole) and cAMP (cilostazol pentoxifylline) modulators
can improve BBB integrity at least in experimental studies
Nitric oxide donors
Aggressive versus standard BP lowering (PRESERVE Trial)
Combination cilostazol and ISMN (LACI-2 trial)
Pharmacological treatment and prevention of cerebral small vessel disease a
review of potential interventions International Journal of Stroke
Volume 10 Issue 4 pages 469-478 2 MAR 2015 DOI 101111ijs12466
Summary of clinical manifestations
What do we already know and what
future study results awaited
TARDIS-dual antiplatelets to be avoided as excess harm
CROMIS
PRESERVE
BRIDGE
RESTART
SoSTART
The End
Pantoni L Cerebral small vessel disease from pathogenesis and clinical
characteristics to therapeutic challenges Lancet Neurol (2010) 9689ndash
701101016S1474-4422(10)70104-6
Hugh Markus-genetics
Joanna Wardlaw-MRI imaging
Philip Bath-therapeutics
CROMIS-UCL Pof Werring
RESTART and SoSTART-Edinburgh
Summary of clinical manifestations
What do we already know and what
future study results awaited
TARDIS-dual antiplatelets to be avoided as excess harm
CROMIS
PRESERVE
BRIDGE
RESTART
SoSTART
The End
Pantoni L Cerebral small vessel disease from pathogenesis and clinical
characteristics to therapeutic challenges Lancet Neurol (2010) 9689ndash
701101016S1474-4422(10)70104-6
Hugh Markus-genetics
Joanna Wardlaw-MRI imaging
Philip Bath-therapeutics
CROMIS-UCL Pof Werring
RESTART and SoSTART-Edinburgh
What do we already know and what
future study results awaited
TARDIS-dual antiplatelets to be avoided as excess harm
CROMIS
PRESERVE
BRIDGE
RESTART
SoSTART
The End
Pantoni L Cerebral small vessel disease from pathogenesis and clinical
characteristics to therapeutic challenges Lancet Neurol (2010) 9689ndash
701101016S1474-4422(10)70104-6
Hugh Markus-genetics
Joanna Wardlaw-MRI imaging
Philip Bath-therapeutics
CROMIS-UCL Pof Werring
RESTART and SoSTART-Edinburgh
The End
Pantoni L Cerebral small vessel disease from pathogenesis and clinical
characteristics to therapeutic challenges Lancet Neurol (2010) 9689ndash
701101016S1474-4422(10)70104-6
Hugh Markus-genetics
Joanna Wardlaw-MRI imaging
Philip Bath-therapeutics
CROMIS-UCL Pof Werring
RESTART and SoSTART-Edinburgh
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