Keunikan anatomi small vessel of the brain dan neurovascular unit, kontroversi peran stganasi vena dalam patofisiologi, klasifikasi small vessel disease, variasi kriteria diagnostik, pitfall dalam neuroimaging, pilihan antiplatelet untuk prevensi sekundar, dampaknya bagi outcome pasien, hubungannya dengan gangguan fungsi kognitif. Hmm, apa lagi nih yang baru?

1. Ersifa Fatimah | 2016 | Surabaya
Small Vessel Disease
Evolving Concept

2. Kim & Kim, 20142

3. Venn diagram showing relationship between small vessel disease
and other forms of stroke
Bath & Wardlaw | Pharmacological treatment and prevention of cerebral small vessel disease: a review of potential
interventions | International Journal of Stroke Vol 10, June 2015, 469–478
3

4. 4
Wardlaw & Dichgans, 2013

5. Schematic representation of penetrating vessel patterns in the cortex. Short (S)
penetrating arterioles (‘‘cortical’’) reaching three different depths in the cortex (i.e.
cortical layer III, V and the gray–white matter junction, S1–3, respectively), while long
penetrators (‘‘medullary’’) continue into the subcortical white matter.
5
Charidimou et al. | The concept of sporadic cerebral small vessel disease: A roadmap on key definitions
and current concepts | International Journal of Stroke 2016, Vol. 11(1)6–18

6. llustration of the
neurovascular unit,
showing arterioles in the
brain encased by
astrocytic processes.
From Iadecola. Nat Rev Neurosci
2004; 5:347-360. Review
6

7. Martini, et al. | A molecular/genetic approach to cerebral
small-vessel disease: Beyond aging and hypertension |
Brain Circulation - Vol 1, Issue 1, January 2015 7

8. 9Gregoire, et al., 2012

9. Pantoni, L |Cerebral small
vessel disease: from
Pathogenesis and clinical
characteristics to therapeutic
challenges | Lancet Neurol
2010; 9: 689–701
Pathogenesis of brain
damage as a result of
small vessel disease
*Based on the hypothesis by
Greenberg and colleagues
11

10. Predominant neuropathological, clinical, and neuroimaging characteristics of the two
major sporadic cerebral small vessel disease subtypes:
13Charidimou et al. , 2016

11. 14
Suggested schematic illustration of
the hypothetical relationship
between vessel diameter,
distribution, and predilection to
different types of pathological
process affecting cerebral small
vessels.
Charidimou et al. | The concept of sporadic cerebral
small vessel disease: A roadmap on key definitions
and current concepts | International Journal of
Stroke 2016, Vol. 11(1)6–18

12. Pathological features of small vessel disease: (A) Lipoyalinosis (basal ganglia ×100). (B) Microaneurysm in the right
thalamus in a 70-year-old hypertensive patient who died 42 days after developing a massive intracerebral haemorrhage
in the left thalamus. Fibrinoid necrosis of the aneurysmal wall is almost ready to rupture. Phosphotungstic acid
haematoxylin stain. Original magnifi cation ×25. (C) Microatheroma (basal ganglia ×20). (D) Fibrinoid necrosis (pons ×20).
| Pantoni, 2010
15

13. Aetiopathogenic
classification of cerebral
small vessel diseases
Pantoni, L |Cerebral small vessel
disease: from Pathogenesis and clinical
characteristics to therapeutic
challenges | Lancet Neurol 2010; 9:
689–701
16

14. Ischemic stroke subclassification #2
OCSP / Bamford
Sindr. Gejala Klinis
TACI 1.Hemiparese +/- Gangguan sensoris kontralateral
2.Hemianopia kontralateral
3. Gangguan fungsi luhur
PACI 1+ 2 / 1+3 / 2+3 / 3 saja /
Defisit motorik/sensorik murni yang kurang extensif dibanding lakunar (hanya monoparese /
monosensorik)
LACI −Tidak ada gangguan fungsi luhur, defisit visual, gangguan fungsi batang otak
−Defisit maximal pada cabang arteri kecil
−Sindrom lakunar: pure motor, pure sensory, sensorimotor, ataxic-hemiparesis, clumsy hand-
dysartria
POCI −Parese Alternans
−Gangguan Motorik/sensorik bilateral
−Gangguan gaze (horizontal / vertikal)
−Disfungsi serebelar tanpa gangguan longtract ipsilateral
−Isolated hemianopsia / cortical blindness
23

15. TOAST Classification | Ischemic stroke subclassification #2
Clinical Radiological Other
Large-artery
Atherosclerosis
Signs of lesion in cortex (aphasia,
apraxia, neglect), subcortex,
cerebellum, or brainstem
−CT/MRI shows lesion >1.5 cm in cortex,
subcortex, cerebellum, or brainstem
compatible with the symptoms.
−CT scan negative when performed shortly
after onset
Color duplex images of
precerebral arteries shows
stenosis ≥50% or occlusion in
symptomatic major intracranial/
extracranial artery
Cardio-embolic Signs of lesion in cortex (aphasia,
apraxia, neglect), subcortex,
cerebellum, or brainstem
−CT/MRI shows lesion >1.5 cm in cortex,
subcortex, cerebellum, or brainstem
compatible with the symptoms.
−CT scan negative when performed shortly
after onset
ECG/TEE confirm high risk /
medium high risk of cardio-
embolic source
Small-vessel
disease
Clinical signs of a lacunar syndrome
(pure motor, pure sensory, sensori-
motor, atactic hemiparesis, or
dysarthria-clumsy hand syndrome)
−CT/MRI shows lacunar infarction (lesion
<1.5 cm) compatible with the symptoms.
−CT scan negative when performed shortly
after onset
No large vessel disease or cardio-
embolic disease identified in
color duplex images of
precerebral arteries or in
ECG/TEE
Other determined Other abnormality on tests
Undetermined 1. Two or more causes identified
2. Negative evaluation
3. Incomplete evaluation
High risk of cardio-embolic source: mechanical heart valve, mitral stenosis + AF, AF, left atrial thrombus, recent myocardial infarction (<4 weeks), left ventricular thrombus,
dilated cardiomyopathy, akinetic left ventricular segment, atrial myxoma, infectious endocarditis.
Medium high risk of cardio-embolic source: mitral stenosis without AF, atrial septum aneurysm, patent foramen ovale, atrial flutter, nonbacterial thrombotic endocarditis,
congestive heart failure, hypokinetic left ventricular segment, myocardial infarction (>4 weeks, <6 months).
Plaque formations >4 mm in aorta ascendens have been added to the list of cardio-embolic sources.
Adams et al., 1993 | Fure at al., 2005 24

16. Lindsay’s Neurology and Neurosurgery Ilustrated 5th ed 25

17. 26
Norrving, 2015

18. 27
Norrving, 2015

19. Lacunar infarct vs Perivascular space
Clue: FLAIR
Mechanisms suggested in the formation of such spaces include altered permeability of
the vessel wall due to inflammation or blood-brain barrier breakdown, amyloid
accumulation along the vessel wall, and cerebral atrophy. However, their potential
mechanistic involvement in SVD is still speculative.
Moran, et al. | Cerebral small vessel disease: a review of clinical,
radiological, and histopathological phenotypes | International Journal
of Stroke Vol7, January 2012,36–46
28

20. Therapeutic aspects
• Thrombolysis
• Carotid endarterectomy
and major vascular
surgery
• Anticoagulation
• Antiplatelet
• Risk factor control
29
Problematic
Ischemia Hemorrhage
Pantoni, 2010

21. • Canadian Alteplase for Stroke Effectiveness
Study (CASES): the multivariable analysis
showed that the increased risk of bleeding
determined by the presence of leukoaraiosis
or multiple lacunes was independent of age
and other factors reported to increase this
risk
• North American Symptomatic Carotid
Endarterectomy Trial (NASCET): the
presence of leukoaraiosis on baseline CT
scans conferred an increased risk of stroke
and death during the perioperative period
(30 days), with a three-times increased risk
in patients with widespread leukoaraiosis
• Stroke Prevention in Reversible Ischemia
Trial (SPIRIT): leukoaraiosis was, together
with an age older than 65 years, the only
independent predictor of major bleeding
during anticoagulation started after cerebral
ischaemia (OR 2·7, 95% CI 1·4–5·3).
30
Pantoni, 2010
Which interventions should be tested for SVD?
1. BP + lipid lowering are standard secondary
prevention intervention  target? drug class?
2. Potent antiplatelet agents (aspirin, clopidogrel)
do not appear to have a role
3. Agents that increase cAMP or cGMP appear
promising with theoretical protective effects on
endothelium and the blood-brain barrier, and
attenuating effects on inflammation, platelets,
smooth muscle cell and white cells.
4. It may be necessary to use either drugs that
have multiple mechanisms of action or
combinations of drugs, or a mix of both.
5. Potential combinations of drugs are either:
• Those that have unrelated but potentially
synergistic effects.
• Combining agents that have related
effects, e.g. by raising cAMP and cGMP
or NO donor and cAMP modulator
6. Some treatment strategies might have
differential effects on the various types of SVD
Bath & Wardlaw, 2015

22. Targets and potential pharmacological interventions for
preventing and/or treating small vessel disease.
31
Bath & Wardlaw | Pharmacological treatment and prevention of cerebral small vessel disease: a review of potential
interventions | International Journal of Stroke Vol 10, June 2015, 469–478

23. Prognostic impact
• in acute treatment of ischemic stroke
• on the functional recovery after stroke
• for incident or recurrent stroke
• on neurocognitive outcomes after ischemic
stroke
• in hemorrhagic stroke patients
32
Kim & Lee | Prognostic Impact of Cerebral Small Vessel Disease on Stroke
Outcome | Journal of Stroke 2015;17(2):101-110

24. 33
Kim & lee | Prognostic Impact of
Cerebral Small Vessel Disease on
Stroke Outcome | Journal of Stroke
2015;17(2):101-110

25. 34
Kim & lee | Prognostic Impact of Cerebral Small Vessel Disease on Stroke Outcome | Journal of Stroke 2015;17(2):101-110

26. 35
Kim & lee | Prognostic Impact of Cerebral Small Vessel Disease on Stroke Outcome | Journal of Stroke 2015;17(2):101-110

27. 36
Rosenberg, et al., 2015

28. 37Rosenberg, et al., 2015

29. BAD: small vessel or large vessel?
40
Louis R Caplan | Lacunar Infarction and Small Vessel Disease:
Pathology and Pathophysiology | Journal of Stroke 2015;17(1):2-6

30. There is another pathological process of the deep small cerebral vessels
that affects the veins, which is known as venous collagenosis. This process,
which has received scarce attention, is associated with one of the
parenchyma changes (namely, white matter lesions)… Venous collagenosis
is a pathological appearance of veins and venules closely located to the
lateral ventricles. These vessels have an increased thickness of the walls
that results in narrowed lumen and, sometimes, occlusion. The material in
the thickened walls is mainly collagen.| Pantoni, 2010
The term SVD refers to the syndrome of clinical, cognitive, neuroimaging,
and neuropathological findings thought to arise from damage to (a) small
arteries, (b) arterioles, (c) capillaries, and (d) small veins and venules in
the brain. | Moody et al. 1995
41
SVD & Small Vein Disease

31. Periventricular venous collagenosis: association with leukoaraiosis.
D M Moody, W R Brown, V R Challa, and R L Anderson
Radiology 1995 194:2, 469-476
PURPOSE: To investigate the association between an age-related degenerative disease of
subependymal veins and leukoaraiosis.
MATERIALS AND METHODS: Brains obtained at autopsy from 22 patients (average age, 73.2 years;
range, 25-95 years) were examined with magnetic resonance (MR) imaging and neuropathologic
methods with alkaline phosphatase microvascular staining. The degrees of leukoaraiosis shown
on MR images and of deep venous occlusion were scored independently and results compared
with logistic regression analysis.
RESULTS: Noninflammatory collagenous thickening of venous walls resulting in severe
periventricular venous stenosis was found in 13 (65%) of 20 patients over 60 years old. Advanced
leukoaraiosis was found in 10 (77%) of these 13 patients. Greater venous disease was associated
with more severe leukoaraiosis.
CONCLUSION: Periventricular venous collagenosis, a commonly observed and previously ignored
degenerative disease of elderly humans, is strongly associated with leukoaraiosis. Stenosis or
occlusion of deep cerebral veins may promote development of leukoaraiosis.
42

32. 43
Discussion