pathological processes that affect the small vessels of the brain, including small arteries and arterioles

1. Cerebral Small Vessel
Disease
Ahmed Mohamed Ibrahim
Neurology & Psychiatry
Department

2. Anatomy of small arteries
Cerebral arterial small vessels have two
origins:
• superficially, they stem from the
subarachnoid circulation as the
terminal vessels of medium-sized
arteries, which originate from larger
arteries; and,
• deeper at the base of the brain,
they stem directly from the large
vessels as arterial perforators.
• These two systems converge towards
each other and, after having passed
the cortical layers and the deep grey
structures, respectively, they tend to
merge in the deepest areas of the
subcortical white matter where there
is a watershed area.

3. PHYSIOLOGY OF SMALL ARTEROILES
Small Arteries & arterioles are responsible for:
• Cerebral Auto-regulation
• Keep BBB intact

4. Cerebral Auto-regulation (CA)
Definition
• CA is the homeostatic process of regulation of CBF in response to changes in
cerebral perfusion pressure (CPP).
• done most effectively by modulating the radius of cerebral small arteries and
arterioles .
In the absence of CA:
•  Mean arterial pressure (MAP) ➔  CPP ➔ CBF even if the metabolic
demand of the brain remains constant.
• Therefore, the CA mechanism, which can be seen as a negative feedback loop
mechanism, counteracts the MAP increase by narrowing the vessels’ radius (thus
increasing their resistance to flow) and bringing CBF to the original level.
• Conversely,  Mean arterial pressure (MAP) ➔  CPP ➔  CBF
• CA: regulatory mechanism causes vessel dilation to rebalance the CBF.
(Fantini - Neurophotonics 3(3), 031411 (Jul–Sep 2016))

5. Neurophotonics 3(3), 031411 (Jul–Sep 2016)

6. Definition
• Small vessel disease encompasses all the pathological
processes that affect the small vessels of the brain,
including small arteries and arterioles(↓500um in
diameter) but also capillaries and small veins.
• Small vessel diseases are mainly systemic disorders
that affect various organs and areas of the body.
• In some cases, the brain can be a main target of these
diseases, and the lesions and effects of these diseases
might even be confined to the brain; in other cases,
cerebral areas might not be affected at all.

7. Aetiopathogenic classification of
cerebral small vessel diseases
Type 1: arteriolosclerosis (or age-related and vascular risk-factor-related small vessel
diseases)Fibrinoid necrosis Lipohyalinosis Microatheroma Microaneurysms (saccular, lipohyalinotic,
asymmetric fusiform, bleeding globe)Segmental arterial disorganisation
Type 2: sporadic and hereditary cerebral amyloid angiopathy
Type 3: inherited or genetic small vessel diseases distinct from cerebral amyloid angiopathy
For example, CADASIL, CARASIL, hereditary multi-infarct dementia of the Swedish
type, MELAS, Fabry's disease, hereditary cerebroretinal vasculopathy, hereditary
endotheliopathy with retinopathy, nephropathy and stroke, small vessel diseases caused
by COL4A1 mutations
Type 4: inflammatory and immunologically mediated small vessel diseases
For example, Wegener's granulomatosis, Churg-Strauss syndrome, microscopic polyangiitis,
Henoch-Schönlein purpura, cryoglobulinaemic vasculitis, cutaneous leukocytoclastic angiitis, primary
angiitis of the CNS, Sneddon's syndrome, nervous system vasculitis secondary to infections, nervous
system vasculitis associated with connective tissue disorders such as systemic lupus erythematosus,
Sjögren's syndrome, rheumatoid vasculitis, scleroderma, and dermatomyositis
Type 5: venous collagenosis
Type 6: other small vessel diseases: For example, post-radiation angiopathy and non-amyloid
microvessel degeneration in Alzheimer’s disease

8. Arteriolosclerosis
• Arteriolosclerosis is also known as age-related
and vascular risk-factor-related small vessel
disease.
• Lipohylinosis in small vessel
• Microatheroma

9. Lipohylinosis in small vessel
is characterized by loss of smooth muscle cells
from the tunica media, deposits of fibro-
hyaline material, Narrowing of the lumen,
and thickening of the vessel wall poststenotic
Dilatation(micro-aneurysm) ,thrombosis .

10. Lipohylinosis & fibrinoid necrosis
Fisher found degenerative changes in the walls of the small perforating vessels, consisting
of a segmental process of fatty changes (‘lipohyalinosis’) and fibrinoid necrosis.
.
A)Medial hyperplasia due to reactive smooth
muscle Cell proliferation in early hypertension. This
stage represents the compensated phase of arteriolar
reaction to sustained high blood pressure.
B) Collagenization due to smooth muscle cell death.
&Collagen deposition in the tunica media
Collagenization can result in either ectasia if the
collagen deposition is insufficient to prevent
progressive dilatation or stenosis
C) Occlusion of the lumen. if inward deposition
of collagen occurs, occluding the lumen. The dilated,
collagenized arteriole in B can be considered an early
Charcot-Bouchard aneurysm. (Garnette et al, 2006).

11. • Microatheroma refere to small atheromatous
plaque narrowing or occluding small artery
proximally at its orifice present mainly in
patient with single large isolated lacunar
infarction

12. Microaneurysms
(Charcot-Bouchard aneurysms )
• It is 300–900 μm in diameter they found
multiple, minute outpouchings of small arteries
• They are mostly found in the thalamus and
corpus striatum, the pons, cerebellum and
cerebral white matter .
• Its distribution paralleled that of small
perforating vessel
• These microaneurysms are etiologically related
to hypertension

13. Microaneurysms
X-ray of striate arteries in coronal section of basal ganglia
from elderly hypertensive subject; barium sulphate had been
injected into the arterial tree before formalin fixation of the
brain. Irregularity of main trunks, attenuation of small
arteries and a number of microaneurysms (arrows).

14. (a) Sites of all microaneurysms
discovered in the cerebral
hemispheres of 53 patients (46/100
with hypertension and 7/100 normo-
tensives). Successive front-to-back
sections, from left to right and top to
bottom
(b) Sites of microaneurysms in the hindbrains
of the 53 Patients, represented in a single
section.

15. Arteriolosclerosis: Pathogenesis
Risk factors
Hypertension
Diabetes mellitus
Dyslipidemia
Genetic factors
Stress
Aging

16. • Endothelial damage ➔ leakage of toxic
substance into the subendothelial layer ➔
damage for the vessel wall & swelling &
subsequent ischaemia.
• Extravasations of more toxic materials into the
perivascular space ➔ inflammatory reaction
of perivascular tissue ➔ Direct damage to
neurons and glial cells ➔  CBF + Ischemia
Arteriolosclerosis: Pathogenesis

18. Ischaemic lesion
• Ischaemic lesion
chronic hypoperfusion of the white matter, eventually resulting in
degeneration of myelinated fibres as a consequence of
repeated selective oligodendrocyte
• death.This kind of white matter damage is thought to be
a form of incomplete
• infarct or selective necrosis similar to what has been
described for neurons.
• Other mechanisms
• Blood–brain barrier damage,
• Local subclinical inflammation [
• Oligodendrocytes apoptosis could be involved in the
ischaemic forms of small
• vessel disease and contribute to the final pathological
picture.

19. Alternative hypothesis for white matter changes:
Venous collagenosis
Veins and venules closely located to the lateral ventricles
have an increased thickness of the walls that results in
narrowed lumen and, sometimes, occlusion. The
material in the thickened walls is mainly collagen
Jugular venous reflux
Sustained or long term repetitive retrograde transmitted
cerebral venous hypertension and venous outflow
insufficiency plays a major role in the pathogenesis of
leucoariosis

20. Cerebral Amyloid Angiopathy
• It is characterized by the progressive accumulation of
congophilic, βA4 immunoreactive, amyloid protein in
the walls of small-to-medium-sized arteries and
arterioles predominantly located in the leptomeningeal
space, the cortex, and, to a lesser extent, also in the
capillaries and veins.
• In the most severe form of cerebral amyloid
angiopathy, the vessels become dilated and disrupted,
with focal wall fragmentation and blood extravasation,
with or without microaneurysmal dilatation, and
sometimes show luminal occlusion.

21. Cerebral Amyloid Angiopathy
• It is a pathological hallmark of Alzheimer's disease, in which
it is almost invariably seen also occurs in rare genetically
transmitted diseases and in other disorders such as Down's
syndrome. very frequent in the general elderly population,
as noted on autopsy, and its frequency increases with age,
becoming as frequent as 50% of individuals in the ninth
decade.
• It is particularly associated with large lobar haemorrhages,
which are frequently recurrent. There is also an association
of cerebral amyloid angiopathy with microbleeds on MRI
This type of small vessel disease has also been associated
with the presence of cerebral ischaemic changes such as
white matter lesions and microinfarcts.

22. Cerebral small vessel disease New
classification based on imaging
1. Recent small subcortical infarct
2. Lacune of presumed vascular origin
3. White matter hyperintensity of presumed
vascular origin
4. Perivascular space
5. Cerebral microbleed
6. Brain atrophy
(Lancet Neurol 2013; 12: 822–38)

23. 1.Recent small subcortical infarct
Neuroimaging evidence of
recent infarction in the
territory of one perforating
arteriole, with imaging features
or clinical symptoms consistent
with a lesion occurring in the
previous few weeks

24. 2.Lacune of presumed vascular origin
fluid-filled cavity (signal similar to CSF)
- A round or ovoid
- Subcortical
- of between 3 mm and about 15 mm in diameter
- consistent with a previous acute small subcortical infarct or
haemorrhage in the territory of one perforating arteriole.

25. 3.White matter hyperintensity of
presumed vascular origin
“Signal abnormality of variable size in the white matter showing the
following characteristics:
- Hyper-intense on FLAIR and T2/PD -weighted images without
cavitation (signal different from CSF).
- Lesions in the subcortical gray matter or brain stem are not
included into this category unless explicitly stated. “

27. Leukoaraiosis
• Means rarefaction of the white matter
• It was introduced more than 20 years ago to describe
these lesions in an attempt to prevent confusion with a
specific pathological process that had vague borders (ie,
with no criteria or consensus about the definition of the
disease; so-called Binswanger’s disease) and to avoid
attributing an explicit clinical significance to these white
matter lesions.
• Leukoaraiosis describes a reduced area of x-ray attenuation
on CT, and this term was later adopted to denote
hyperintensity on T2-weighted and FLAIR MRI, and
sometimes also hypointensity on T1-weighted MRI.

28. Leukoaraiosis
Sites:
• Typically supratentorial
• May infratentorial location (ie, the pons) and
this has been called pontine ischaemic
rarefaction or pontine leukoaraiosis

29. Binswanger's disease
• Definition: Binswanger’s disease (BD) is a
progressive form of cerebral small vessel disease
affecting the white matter and other subcortical
structures.
• Risk Factors: Hypertension is almost always
present and its absence should lead to
questioning the diagnosis Other vascular risk
factors, including diabetes, pre-diabetes,
smoking, hyperlipidemia, sleep apnea and atrial
fibrillation

30. Binswanger's disease
Imaging
• WMHs: periventricular and deep by their location.
• small subcortical strokes
• WM atrophy
*Brain atrophy is also a common finding with mild hippocampal atrophy that
is less pronounced than in AD patients
Imaging features of Binswanger’s
disease.
(A) Large white matter hyperintensities
with white matter atrophy in FLAIR.
(B) Subcortical microhemorrhages
(black dots) on gradient echo.
(C) Dilated perivascular spaces on T2.

31. 4.Perivascular Space (PVS) (AKA Virchow–
Robin spaces, type 3 lacune, or état crible)
- “Fluid filled space that follow the typical course
of a vessel as it goes through grey or white
matter.
- The spaces have signal intensity similar to CSF on
all sequences.
- Because they follow the course of penetrating
vessels, they appear linear when imaged parallel
to the course of the vessel, and round or ovoid,
with a diameter generally smaller than 3 mm,
when imaged perpendicular to the course of the
vessel.”

32. Perivascular Space (PVS)

33. 5.Cerebarl Microbleeds
Small (generally 2-5
mm, but sometimes
up to 10 mm) areas
of signal void with
associated
“blooming” seen on
T2 -weighted MRI or
other sequences that
are sensitive to
susceptibility effects.

34. 5.Cerebarl Microbleeds

35. 6.Brain Atrophy
a lower brain volume that is not related to a specific
macroscopic focal injury such as trauma or infarction.

36. Brain Atrophy
Secondary brain atrophy in a 55-year-old patient with documented small vessel disease
• Baseline (middle).
• The follow-up scan (T1-weighted MRI; right) shows clear sulcal widening (arrow B, C, and D),
particularly in occipital regions, and ventricular enlargement (arrow A) without new infarctions
during the observational period. Fluid-attenuated inversion recovery image (left) shows substantial
white matter hyperintensity.

37. Microinfarts
• A recent addition to the spectrum of silent brain infarcts is cerebral
microinfarcts, very small (<1 mm) often cortical infarcts, detected at
autopsy at microscopic examination or at high-field 7T MRI.
• Cerebral microinfarcts may be up to 15 times more frequent than
“conventional” SCIs.
• However, microinfarcts appear to be associated with dementia
even after controlling for other neuropathologies, suggesting that
microinfarct burden may be an important link between small-vessel
disease and cognitive impairment.
• A recent study estimated that even the finding of only a few
microinfarcts on routine pathologic sampling indicate a likely overall
burden of hundreds of these small lesions

38. Microinfarts

39. MRI findings for lesions related to small vessel disease

40. Imaging evolution of symptomatic lacunar
infarcts: not always a “lacune”
Follow-up studies of patients with acute lacunar infarcts
visualized in the acute phase by MRI, have showed that
not all such infarcts cavitate with time and appear as
“lacunes” on later imaging studies.
Journal of Stroke 2015;17(2):94-100

41. Variable fates of lesions related to small vessel disease and the convergence of acute
lesions with different causes but similar late appearances on MRI
-Blue arrows indicate common fates of recent small subcortical infarcts
-Green arrows indicate less common fates
-Red lines indicate least common late fates. ICH=intracranial haemorrhage.

42. Clinical Picture

43. Lacunar
sydnromes
Gait abnormality
Cognitive decline
Inconteince of urine
Vascular depression

44. Lacunar syndromes
• Pure motor stroke.
• Pure sensory stroke.
• Ataxic hemiparesis.
• Dysarthria clumsy hand
syndrome

46. Pantoni, Lancet Neurol 2010; 9: 689–701

47. Investigations
• Acute Stage: Work up of stroke
• Biomarkers

48. Biomarkers of small vessel disease
• Eye examination
• Radiological
• Laboratory

49. Fundus Examination
• Eye is the mirror of the brain
• SVD + Retinopathy
- Retinal Nerve Fiber Layer Defect
- Retinal artery occlusion
- Increased retinal vein caliber

50. Invest Ophthalmol Vis Sci.2017;58:BIO82–BIO87.
Curr Neurol Neurosci Rep. 2015 Jul; 15(7): 40.

51. Invest Ophthalmol Vis Sci.2017;58:BIO82–BIO87.
Cerebral small vessel disease in young
patient with RVO.
(A) Branch RVO with flame-shaped retinal
hemorrhage and cotton wool spot in a
56-year-old man. Arteriovenous
nicking is shown in the proximal
portion of the retinal hemorrhage
(black arrowhead).
(B) White matter hyperintensities (Fazekas
grade 2) on brain MRI (FLAIR image;
white asterisks).
(C) Multiple cerebral microbleeds on T2-
weighted brain MRI (white
arrowhead).
(D) Silent lacunar infarct in a T1-weighted
MRI (white arrow) corresponding to
cerebral small vessel disease.

52. Conclusions.: The results indicate that RNFLD
may be related to the presence of cerebral SVD,
particularly WMLs. Furthermore, being older
and male and having hypertension increase the
risk of RNFLD.

53. • Retinopathy findings, particularly in non-
diabetics and nonhypertensive individuals,
retinal artery occlusion and increased retinal
vein caliber are associated with increased
cerebral vascular events both concurrently
and in the future. These associations persist
after accounting for confounding variables
known to be disease-causing in both
circulations.
Curr Neurol Neurosci Rep. 2015 Jul; 15(7): 40.

54. Radiological
• Load of T2 white matter hyperintensities
• Load of lacunar infarcts.
• Number of microbleeds by T2* or better
SWI
• CSF leak better detected by FLAIR with
Gd.
• Variation of diffusion over the whole brain.
• Cortical thickness.
• Cerebral atrophy.

55. Lab biomarkers
• C-reactive protein
• D-dimer.
• ICAM-1
• Interleukine 6
• Plasma beta amyloid 40
(Fornage, 2009, and Gronis et al.,2009)

56. Neuropsychological assessment

57. Prognosis of small vessel disease
Short term prognosis
Overall, strokes caused by small vessel
disease are less severe than other types of
stroke in terms of the clinical picture during
the acute phase and short-term prognosis
Long-term outcome
Long term outcome of these patients cannot
be thought of as benign in terms of mortality
and functional impairment.

58. Treatment of small vessel disease
- No specific treatment for strokes caused by small
vessel disease in the acute phase has yet been
proposed
- There are no data to support the suggestion that
any of the three approaches with recognised
evidence-based efficacy in the acute setting
(aspirin, thrombolysis, admission to a stroke unit)
are not efficacious in strokes caused by small
vessel disease.
- The presence of small vessel disease is instead a
marker of a poor outcome in some specific
therapeutic settings, including acute phase
thrombolysis.

59. Treatment of small vessel disease
CONTROL OF THE RISK FACTORS
Antiplalets
Cholesterol lowering agents
ACE inhibitor
ARBS
PRECAUTION IN OTHER THERAPEUTIC SITUATION
THROMBOLYSIS
CAROTID ENDARTERECTOMY
ANTICOAGULATION

60. Thrombolysis
. Neuroimaging evidence in small vessel disease indicates a risk
of haemorrhagic transformation of brain infarcts. Ithe rate of
symptomatic cerebral haemorrhages was about 10% in the
presence of moderate-to-severe leukoaraiosis.
• The 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. but should not be taken as a
contraindication
.

61. Carotid endarterectomy
In the 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
peri-operative period (30 days), with a three-times increased risk
in patients with widespread leukoaraiosis in comparison to those
without leukoaraiosis.
These results suggest that the presence of leukoaraiosis
predicts a reduced benefit from the treatment, but should not be
taken as a contraindication to surgical treatment.

62. Anticoagulation
In the 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
Neurology. 1999 Oct 12;53(6):1319-27.

63. • Results: The presence and severity of leukoaraiosis on CT scan
correlated strongly with the occurrence of ICH. Leukoaraiosis was
seen in 24 of 26 cases (92%) compared with 27 of 56 controls
(48%), yielding an odds ratio of 12.9 (95% CI 2.8 to 59.8).
• Conclusions: Leukoaraiosis is an independent risk factor for
warfarin-related ICH in survivors of ischemic stroke, including those
in the commonly employed range of anticoagulation.
NEUROLOGY 2002;59:193–197

64. Antiplatelets
Some data on antiplatelet drugs in secondary stroke prevention after
stroke caused by small vessel disease can be derived from a few trials:
the Accidents, Ischemiques Cerebraux Lies a l'Atherosclerose (AICLA)
trial of aspirin plus dipyridamole versus placebo, the Canadian
American Ticlopidine Study (CATS) trial of ticlopidine versus placebo,
and the Chinese Acute Stroke Trial (CAST) study of aspirin versus
placebo for early prevention after 30 days;
Results from all these studies suggested efficacy of the study drug in
the subgroup of patients with stroke caused by small vessel disease
but there was no evidence that one drug, or combination, was better
than another. Moreover, there are no data about a possible increased
risk of haemorrhage.

65. Cilostazol
Cilostazol is an antiplatelet agent that increases the cyclic
adenosine monophosphate levels in platelets via inhibition of
phosphodiesterase
In the Cilostazol Stroke Prevention Study,1a placebo-
controlled, double blind, multicentre study, 1095 patients
were enrolled and about 75% had a lacunar stroke.
Treatment with cilostazol (100 mg per day) was
associated with a relative risk reduction of recurrence of
lacunar stroke of 43·4% (3·0–67·0), which was on the
border of statistical significance (p=0·04).

67. Cholesterol lowering agent
Results from the Stroke Prevention by Aggressive
Reduction of Cholesterol Levels (SPARCL)
studyhave shown that patients with small vessel
disease and increased low-density lipoprotein
cholesterol have a similar risk of stroke recurrence
as do patients with large vessel strokes, and that
treatment with atorvastatin 80 mg daily is equally
effective in reducing this risk, implying that patients
with small vessel disease also benefit from statin
therapy.

68. Trials in dementia and small vessel disease
Memantine,
an NMDA antagonist used in Alzheimer's disease, slightly improved
cognition in a group of more than 500 patients with vascular dementia. The
authors reported that the largest clinical effect was seen in patients without
cerebrovascular macrolesions, who made up about four-fifths of the group.
Acetylcholinesterase inhibitor
galantamine was superior to placebo in the general population with
vascular dementia in terms of cognition and function but was also superior to
placebo in the vascular dementia subgroups; two of these subgroups could
possibly be defined as small vessel disease groups