Cerebral small vessel disease sonata:

Exploring the key notes of diagnosis and management

Asst.Prof. Duangnapa Roongpiboonsopit, MD, MSc

Director of Stroke Service
Division of Neurology, Department of Medicine
Faculty of Medicine, Naresuan University December, 1st 2023
Topic outline

• What is cerebral small vessel disease?

• How to diagnosis?
• How to management?
What is Cerebral small vessel disease?
• The pathological processes that affect the small vessels of the brain,
including small arteries and arterioles but also capillaries and small veins.

Lancet Neurol 2010; 9: 689–701

Circ Cardiovasc Imaging. 2020;13:e010460.
Annals of Biomedical Engineering, Vol. 41, No. 11, November 2013
Epidemiology and risk factors
• 22% of ischemic stroke,
• “Covert cerebral small vessel disease,” are more common than acute ischemic
stroke(prevalence of 10% to 20% in adults)

• Risk factors
• Non-modifiable
• Age : Almost 100% of adults aged 90 and older have evidence of CSVD, with 36% of
adults aged 80 to 90 demonstrating evidence of cerebral microbleeds

• Black
• Modifiable
• Hypertension, OSA, DM, DLP, Smoking, CKD
CONTINUUM 2023;29(2, CEREBROVASCULAR DISEASE):501–518.
Clinical features of cerebral small vessel disease
A global brain disease with multi-domain involvement

Chinese Medical Journal 2021;134(2)

Diverse presentation
CSVD encounters with general and specialist service

Chinese Medical Journal 2021;134(2)

Defining the trajectory of small vessel disease

Chinese Medical Journal 2021;134(2)

Topic outline

• What is cerebral small vessel disease?

• How to diagnosis?
• How to management?
MRI findings for lesions related to small vessel disease

Lancet Neurol 2013; 12: 822–38

MRI feathers of lesions related to small vessel disease

Lancet Neurology 2023; 22: 602–18

Etiology classification of cerebral SVD

Lancet Neurol 2010; 9: 689–701

Cerebral Microbleeds in patient with atrial myxoma

Chutinet A, Roongpiboonsopit D, Suwanwela NC, Front Neurol. 2014. 1;5:252

Cerebral Microbleeds in patient with cranial irradiation

Roongpiboonsopit D, Hugo J. K, Charidimou A,et al.Neurology.2017;88:1-8

Roongpiboonsopit D, Hugo J. K, Charidimou A,et al.Neurology.2017;88:1-8
Total SVD Score
Estimate full impact of SVD on the brain

Neurology® 2014;83:1228–1234
 Total SVD score predict stroke recurrence after Stroke or TIA

Recurrent stroke

Recurrent ischemic stroke

ICH

Neurology 2017;88:2260–2267
®
Global and dynamic association of lacunar stroke, WMH, CMBs, and microinfarction

JAMA Neurol. 2018;75(10):1273-1281

Progression of CSVD

Lancet Neurol 2019; 18: 684–96

A 67 Y Female present with progressive cognitive decline for 1 year
2562 2563 2565 2566

Cognitive decline Gait disturbance Urinary incontinence Dysarthria

CSVD progression
Clinical spectrum
Asymptomatic Symptomatic

Ischemic stroke Hemorrhagic stroke

Lacunar infarction Deep ICH Lobar ICH
Historical evolution of the knowledge in lacunar stroke

Int. J. Mol. Sci. 2022, 23, 1497

n= 1042, 114 (11%) had 1 or more lacunas

C. Miller Fisher.Neurology Aug 1965, 15 (8) 774

1982 NEUROLOGY (Ny) 32
Stroke 1987;18:545-551
Stroke 1993;24:35-41
Possible mechanism of lacunar infarction

Intrinsic small vessel disease

Peforating arteriolar Atheroma

Parent artery atheroma

Embolism
<6% of emboli injected into carotid arteries entered the lenticulostriate arteries, while the majority entered the cortical arteries

Stroke and Vascular Neurology 2016

Macdonald RL, Kowalczuk A, Johns L. Emboli enter penetrating arteries of monkey brain in relation to their size. Stroke 1995;26:1247–50;
Single subcortical infarction
Small artery disease VS parental artery disease

Current vascular High resolution MRAI

imaging technique

Focal Junctional Atherosclerotic

Parental artery disease Lipohyalinotic distal small vessel disease
paren artery disease atherothrombosis proximal small artery disease

Caplan’s definition : Branch atheromatous disease

Atherosclerotic cause

International Journal of Stroke 2012 8:3, 197-203

 Single subcortical infarction
Parental artery disease

Focal Junctional
paren artery disease atherothrombosis

International Journal of Stroke 2012 8:3, 197-203

Single subcortical infarction
Parental artery disease

Parental artery disease

International Journal of Stroke 2012 8:3, 197-203

Etiology and Clinical phenotype of lacunar stroke

Not all clinically and imaging-defined

Lacunar stroke result from CSVD

JAMA Neurol. 2018;75(10):1273-1281

A 40 Y Female present with abnormal speech

S I L rcts

A
f a
ca l In

D o rti

A
u b c
S

C w i t h
athy
i o p
r ter
a n tA
m in
lD o
s oma
to
l Au
ebra
Cer
 Pathological change and imaging in CADASIL

• From a cellular perspective, CADASIL is

characterized by disruption of the vessel wall
architecture.
• Impaired perivascular clearance may result from
dysfunctional autophagy-lysosomal degradation
of vascular smooth muscle cells. Stroke. 2023;54:e452–e464
Clinical spectrum
Asymptomatic Symptomatic

Ischemic stroke Hemorrhagic stroke

Lacunar infarction Deep ICH Lobar ICH

Hypertensive related ICH Cerebral amyloid antipathy

Diagnosis of CAA
MRI marker

• Definite CAA
• Probable CAA with supporting pathology
• Probable CAA
• Possible CAA

cSS Lobar ICH WMH in a multiple

spot pattern
Lancet Neurol 2022; 21: 714–25 Neurology® 2016;86:505–511 Neurology® 2016;87:1863–1870
Diagnosis of CAA
CT marker

LancetNeurol2018;17:232–40
Topic outline

• What is cerebral small vessel disease?

• How to diagnosis?
• How to management?
 Cerebral small vessel disease management
Clinical spectrum
Asymptomatic Symptomatic

Ischemic stroke Hemorrhagic stroke

Lacunar infarction Deep ICH Lobar ICH

Silent
VS Symptomatic

How should we do?

Silent Brain infarction
Risk for future stroke
Yes No

Silent brain infarct

Risk for future stroke 1.5-3.3 x

Stroke. 2017;48:e44-e71
Silent microbleeds
Risk for future stroke

The presence of microbleeds, and especially multiple microbleeds, was

associated with an increased risk of stroke.

Circulation. 2015;132:509-516
WMHs of presume vascular origin
Risk for future stroke
Significant association of WMHs with risk of future stroke
(HR, 3.1 for high burden of WMH versus low burden; 95% CI, 2.3–4.1; P<0.001)

Stroke. 2017;48:e44-e71
Silent
Prevention
brain infarction

Investigation
Prevention
Silent brain infarct
Stroke. 2017;48:e44-e71
Silent microbleeds
Prevention

Assessment common vascular risk factors

• Hypertension

Cerebral microblees

Stroke. 2017;48:e44-e71
Silent microbleeds
Prevention

Cerebral microblees
Stroke. 2017;48:e44-e71
WMHs of presume vascular origin
Prevention

Assessment common vascular risk factors

• Hypertension
• Diabetes mellitus
• Dyslipidemia
• Smoking
• Physical inactivity
• Active screening for atrial fibrillation

White matter hyper intensity

Stroke. 2017;48:e44-e71
Cerebral small vessel disease management
COVERT

Focus on WMH & lacunas

Silent

Blood pressure lowering

Antiplatelet drug
do
harm
Lipid lowering

Lifestyle modifications
command
Glucose lowering

Anti-dementia treatment

European Stroke Journal 2021, Vol. 6(2)

 Cerebral small vessel disease management
COVERT

Blood pressure lowering

European Stroke Journal 2021, Vol. 6(2)

Cerebral small vessel disease management
COVERT

Antiplatelet drugs

European Stroke Journal 2021, Vol. 6(2)

 Cerebral small vessel disease management
COVERT

Lipid lowering

European Stroke Journal 2021, Vol. 6(2)

Cerebral small vessel disease management
COVERT

Life style modification

European Stroke Journal 2021, Vol. 6(2)

Cerebral small vessel disease management
COVERT

Glucose lowering

European Stroke Journal 2021, Vol. 6(2)

 Cerebral small vessel disease management
COVERT

Anti dementia drugs

European Stroke Journal 2021, Vol. 6(2)

Cerebral small vessel disease management
Silent or covert

Blood pressure Current guideline

Antiplatelet Not recommend

Silent
Lipid lowering Could be considered

Lifestyle Regular exercise, quit smoking,

healthy diet, avoid over weight,

Glucose lowering Current guideline

Antidementia drugs Not recommend

European Stroke Journal 2021, Vol. 6(2)

 Cerebral small vessel disease management
Clinical spectrum

Asymptomatic Asymptomatic

Ischemic stroke Hemorrhagic stroke

Lacunar infarction Deep ICH Lobar ICH

Silent
VS Symptomatic

Lacunar infarction
 Any Stroke

Ischemic stroke
Any single antiplatelet vs Placebo

Patients on antiplatelet monotherapy had significantly

lower rates of any stroke as compared with placebo

Composite endpoint (any stroke, MI, Death)

Stroke. 2015;46:1014-1023
 Any Stroke

Cilostazol, Ticlopidine, Dipyridamole, Terutobran, Sarpogrelate

vs
Placebo

No significant advantage of other single agents above

aspirin alone.
Composite endpoint (any stroke, MI, Death)

Stroke. 2015;46:1014-1023
 Any Stroke

Dual antiplatelet vs Aspirin alone

Ischemic stroke

DAPT may possibly have a modest advantage over

aspirin, but this is driven mainly by the aspirin/
dipyridamole data from ESPS-2.

Composite endpoint (any stroke, MI, Death)

Stroke. 2015;46:1014-1023
SPS3 ASA(325)+ Clopidogrel vs. ASA (325)Alone
in Lacunar Stroke
(SPS 3 trial)

LACUNAR STROKE

Randomized at
Risk of recurrent stroke1 Safety outcome1 t
ren
2 wk – 6 mo after stroke
ur
of Aspirin + Placebo Aspirin + Clopidogrel HR rec
1.0
Aspirin plus clopidogrel
r is k Outcome
(n=1,503) (n=1,517) (95% CI)
p Value

rate he
0.9
t
Aspirin plus placebo
no. rate no.

uce death1.97
(%/yr) (%/yr)
Probability of primary event

0.8

e d
nt r
All major

and
0.7 56 1.1 105 2.1 <0.001
a
hemorrhages (1.41-2.71)
0.6

nif ic in g
0.5
s ig e e d 1.52 Intracranial
15* 0.28 22 0.42 0.21

not k of bl
hemorrhages (0.79-2.93)
0.4

tdid
ris Intracerebral 8 0.15 15 0.28 1.92 0.14
n
0.3
d
(0.82-4.54)
e e
eatm ncreas
0.2 1.23
Unknown effect of t r Subdural or epidural 6 0.11 7 0.13
(0.41-3.64)
0.72

SA ntly i
0.1
DAPT on short term A
re l+ ica
0.0 Other 4 0.07 2 0.04
0.53
(0.10-2.89)
0.46

dog g nif 0 1 2 3 4 5 6 7 8

lopi and si
Years since randomization 2.15 <0.001
Extracranial bleeding 42 0.79 87 1.7
c
No. at risk
(1.49-3.11)

t e rm stroke
Aspirin plus
placebo 1517 1272 1027 788 574 355 189 83 3
2.14 <0.001

ng
Gastrointestinal 28 0.52 58 1.1
(1.36-3.36)

Lo
Aspirin plus
Clopidogrel 1503 1288 1030 802 589 371 205 90 5

Study design
Double-blind, multicenter trial involving 3,020 patients with recent symptomatic lacunar infarcts identified by MRI

1. SPS 3 Investigators, et al. N Engl J Med 2012;367:817-25. microbleed

 Ubar alacna n
Subgroup analysis of CSPS.com
P: High risk non-cardioembolic
stroke or TIA day 8-180 subgroup
lacunar stroke (n=925 from 1884)
I : DAPT with Cilostazol
C: SAPT
O: Efficacy : 1st Rec. ischemic
stroke
Safety : Severe life-
threatening bleeding

Lacunar stroke
Cilostazol+ASA or clopidogrel ASA or clopidogrel

Stroke. 2023;54:00–00.
 FU time 1.4 yr
(SPS 3 FU 3.5 yr)

Stroke. 2023;54:00–00.
 Lacunar stroke (exclude large vessel atherosclerosis)

Stroke. 2023;54:00–00.
CADASIL
Management guideline

Stroke. 2023;54:e452–e464
 Cerebral small vessel disease management
Clinical spectrum

Asymptomatic Asymptomatic

Ischemic stroke Hemorrhagic stroke

Lacunar infarction Deep ICH Lobar ICH

Deep ICH
Silent
Lobar ICH VS Symptomatic
Stroke.2022;53:e282–e361.
Stroke.2022;53:e282–e361.
Stroke.2022;53:e282–e361.
CAA with early recurrent ICH
A 75 Y Male present with severe headache and right hemiparesis

Cortical sub CAA

Cortical SAH

1 month later

Diffused cSS Lobar CMBs

MRI
8

Stroke.2022;53:e282–e361.
Summary
CTMRL
Clinical spectrum
Asymptomatic Symptomatic

Ischemic stroke Hemorrhagic stroke

Lacunar infarction Deep ICH Lobar ICH

Diagnosis

CT : Edinburg criteria/MRI
CT/ MRI:Strive criteria Boston2.0 criteria

Management
CSV
Secondary stroke
Covert Cerebral small vessel disease guideline
prevention guideline (AHA) ICH guideline (AHA)
(ESO)
BRAIN BLEED !