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

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

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

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

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

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

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

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

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

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

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

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